Vitiligo: Problems and Solutions

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hted Ma

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VITILIGO Problems and Solutions

edited by

Torello Lotti University of Florence Florence, Italy

Jana Hercogova Motol University Hospital, Charles University Prague, Czech Republic

n

MARCEL

MARCEL DEKKER, INC.

DEKKER

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Series Introduction

Over the past decade, there has been a vast explosion in new information relating to the art and science of dermatology as well as fundamental cutaneous biology. Furthermore, this information is no longer of interest only to the small but growing specialty of dermatology. Scientists from a wide variety of disciplines have come to recognize both the importance of skin in fundamental biological processes and the broad implications of understanding the pathogenesis of skin disease. As a result, there is now a multidisciplinary and worldwide interest in the progress of dermatology. With these factors in mind, we have undertaken to develop this series of books specifically oriented to dermatology. The scope of the series is purposely broad, with books ranging from pure basic science to practical, applied clinical dermatology. Thus, while there is something for everyone, all volumes in the series will ultimately prove to be valuable additions to the dermatologist's library. The latest addition to the series, edited by Drs. Lotti and Hercogova, is both timely and pertinent. The authors are well known authorities in the field of vitiligo and hypmelanotic syndromes. We trust that this volume will be of broad interest to scientists and clinicians alike. Alan R. Shalita SUNY Health Science Center Brooklyn, New York

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Preface

Very few things can be more outrageously and incredibly discriminated against than the color of the skin. When the authors asked themselves what was the inspiration to begin their interest in vitiligo, they had to agree that, at the most irrational level, their scientific interest in vitiligo is probably related to their hate for discrimination. Still now what is probably more challenging in vitiligo is not the chronicity of this progressive depigmenting disorder, but the irrational feeling that these "white spots" may symbolize a punishment sent by God, i.e., a sign of sin. The word "vitiligo" itself could come from the latin word "vitium", a blemish or fault. Irrationally this feeling is apparently affecting the patients' community, the general population, and, at some level even our scientific community. How many physicians will irrationally tell their patients that there is no treatment for vitiligo? The flist part of this book provides a relevant source of updated information from basic science and clinically oriented to eclectically help the practicing dermatologist to make an appropriate therapeutic choice or, if needed, selected multiple therapeutic approaches. On some controversial issues, we provide at least two points of view from different experts in the field always looking for expert guidance for the selection, initiation and follow-up of the different treatments. A special emphasis is given to the self-esteem, body image and self-perception of the vitiligo subjects and to the essential elements for successful counseling. The last chapter in the section is devoted to the most interesting Internet sources, to give the readers a continuously up-to-date source for additional information. The second part of the book is devoted to the other clinically relevant hypomelanotic disorders-sometimes misdiagnosed as vitiligo-and to their possible treatments. Thanks to the efforts of the distinguished international authorship in this book, we tried to clearly identify the different problems facing

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the researchers and patients dealing with vitiligo and to discuss the many solutions currently available. We hope that all the readers will agree with us that in the end it is not true that there is nothing to do for vitiligo. In fact, just the opposite is true. Torello Lotti, MD Jana Hercogowi, MD

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Contents

Series Inlroduction Preface Contributors

iii v xi

1.

Vitiligo: Disease or Symptom? From the Confusion of the Past to Current Doubts Torello Lotti, Giuseppe Hautmann, and lana HercogoviJ

2.

Historical and Psycho-Anthropological Aspects of Vitiligo AIda Morrone

15

3.

Vitiligo: Epidemiology Luigi Naleli

27

4,

Biology of Hypopigmentation Giovanni Menchini. Torello Lalli, El'ridiki Tsoureli-Nikita, lana Hercogova, and lean Paul Ortonne

33

5.

Disorders in Healthy Relatives of Vitiligo Patients Abelel Monem EI Mofty, Medhat A, EI Mofty, and Samia M. Esmat

51

6.

Basic Research: An Update Karin U. Schallreuter

65

7.

Vitiligo: The Autoimmune Hypothesis lean-Claude Bystryn

79

8.

Vitiligo: A Disorder of the Microvessels? Elena Del Bianco, Giuseppe Muscarella, and Torello Lotti

93

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viii

9.

Pathogenesis of Vitiligo: Evidence for a Possible Ongoing Disorder of the Cutaneous Microenvironment Giuseppe Halltmann, Silvia Moretti, Torello Lotti, and Jana HercogovQ

99

10.

Free Radical Damage in the Pathogenesis of Vitiligo JvJauro Picardo and Maria Lucia Dell'Anna

123

II.

Possible Role of Nitric Oxide in the Pathogenesis of Vitiligo Mario Vaccaro and Fabri::io Guarneri

137

12.

Histopathological and Ultrastructural Features of Vitiligo Daniela Massi

145

13.

Clinical Variants of Vitiligo Seung-Kyung Hann and Sungbin [/11

159

14.

Vitiligo in Children Flora B. de Waard-van der Spek and Arnold P. Oranje

173

15.

Vitiligo: Focusing on Clinical Associations with Endocrine, Hematological, Neurological, and Infectious Diseases Alex Llambrich and Jose MO Mascaro

16.

Clinical Associations: Focusing on Autoimmune and Rare Associations G. Primavera and E. Berardesca

179

189

17.

Ocular and Audiological Disorders in Vitiligo Antonella Tosti, Bianca Maria Piraccini, Mati/de [orizzo, and Giovanni Tosti

201

18.

Differential Diagnosis for Vitiligo Wennie Liao and James 1. Nord/und

207

19.

Vitiligo: Emotional Aspects and Personality Giuseppe Hautmann. Torello Lotti, and Jana HercogovQ

225

20.

Therapeutic Guidelines for Vitiligo M. D. Njoo and W. Westerhof

235

21.

Efficacy and Adverse Effects of Psora len Photochemotherapy in Vitiligo Ljubomir Novakovic and John Hawk

253

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Treatment of Vitiligo with UV and Photosensitizing Substances M.L. Flori, M. Pellegrino, A. Molinu, E. Stanghellini, and L. Andreassi

261

23.

Corticosteroids in Vitiligo Alexander 1. Siratigos and Andreas D. Katsambas

271

24.

Vitamins and Vitiligo Evridiki Tsoureli-Nikita, Claudio Comacchi, Giovanni Menchini, and Torello LOlli

281

25.

Alternative Treatments for Vitiligo l/aria Ghersetich, Benedetta Brazzini, Torello Lotti, and Giovanni Menchini

285

26.

Vitiligo: Problems and Surgical Solutions Rafael Falabella

293

27.

Tissue-Engineered Skin in the Treatment of Vitiligo Lesions Andrea Andreassi, Elisa Pianigiani, Paolo Taddeucci, and Michele Fimiani

28.

UV-B Narrowband Microphototherapy: A New Treatment for Vitiligo Giovanni Menchini, Torello LOlli, Evridiki Tsoureli-Nikita, and lana Hercogovit

313

323

29.

Vitiligo: Problems and Nonsurgical Solutions Giovanni Menchini, Torello Lotti, Evridiki Tsoureli-Nikita, and lana Hercogovit

335

30.

Use of UVB in Vitiligo Mario Lecha

341

31.

Cover-Ups: The View of the Cosmetologist Alida DePase

347

32.

Cover-Ups: The View of the Dermatologist Rossana Capezzera, Cristina Zane, and Piergiacomo Calzavara-Pinton

351

33.

Depigmentation and Vitiligo Christina Antoniou and Electra Nicolaidou

359

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34.

Vitiligo and the Internet Giovanni Menchini, Torello Lotti, Evridiki Tsoureli-Nikita, and lana Hercogow]

365

35.

Halo Nevus DemelJ'is loannides

369

36.

Alezzandrini's Syndrome Fabrizio Guarneri and Mario Vaccaro

377

37.

Acquired HypomeJanoses R. Konkolova

381

38.

Idiopathic Guttate Hypomelanosis Michelangelo La Placa and Sabina Vaccari

389

39.

Leukonychia Aurora Tedeschi, Maria Rita Nasca, and Giuseppe Micah

393

40.

Vogt-Koyanagi-Harada Syndrome Fabrizio Guarneri, Pasquale Aragona, and Mario Vaccaro

403

41.

Nevus Depigmentosus Beatrice Bianchi, Torello Lotti, and lana Hercogow]

413

42.

Hypomelanosis and Tuberous Sclerosis Complex A. Patrizi and 1. Neri

419

43.

Inherited Hypomelanotic Disorders Nicoletra Cassano and Gino A. Vena

433

44.

Piebaldism Giovanni Maria Palleschi

449

45.

Albinism Evridiki Tsoureli-Nikita, Giovanni Menchini, Torello Lotti, and H. Grossman

461

46.

Chediak-Higashi Syndrome Benedetta Bra;:~ini and l/aria Ghersel ich

473

47.

Melanoma and Vitiligo Dan Forsea

479

48.

Vaccines and Vitiligo Silvia Morelli and Paolo Fabbri

485

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Contributors

Arezzo's Hospital and University of Siena, Siena, Italy

Andrea Andreassi L. Andreassi

University of Siena, Siena, Italy

Christina Antoniou University of Athens School of Medicine, "A. Sygros" Hospital, Athens, Greece

University of Messina, Messina, Italy

Pasquale Aragona

E. Berardesca

San Gallicano Dermatological Institute, Rome, Italy

Beatrice Bianchi

University of Florence, Florence, Italy University of Florence, Florence, Italy

Benedetta Brazzini

Piergiacomo Calzavara-Pinton

Spedali Civili, Brescia, Italy

Rossana Capezzera Nicoletta Cassano

Istituto Dermopatico dell'Immacolata, Rome, Italy

Jean-Claude Bystryn New York, U.S.A. Claudio Comacchi

New York University School of Medicine, New York,

University of Siena, Siena, Italy

Flora B. de Waard-van der Spek Elena Del Bianco

Spedali Civili, Brescia, Italy

Erasmus Me, Rotterdam, The Netherlands

University of Florence, Florence, Italy

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Contributors

xii

Maria Lucia Dell'Anna

San Gallicano Dermatological Institute, Rome,

Italy Bergamo, Italy

Alida DePase

Abdel Monem El Mofty Medhat A. El Mofty

Cairo University, Cairo, Egypt

Cairo University, Cairo, Egypt

Cairo University, Cairo, Egypt

Samia M. Esmat

University of Florence, Florence, Italy

Paolo Fabbri

Rafael Falabella

Universidad del Valle, Cali, Colombia

Michele Fimiani

Arezzo's Hospital and University of Siena, Siena, Italy

M.l. Flori

University of Siena, Siena, Italy

Dan Forsea

University of Bucharest, Bucharest, Romania University of Florence, Florence, Italy

Haria Ghersetich

Regional Dermatology Training Center, Moshi, Tanzania

H. Grossman

University of Messina, Messina, Italy

Fabrizio Guarneri Seung-Kyung Hann Giuseppe Hautmann John Hawk

Korea Institute of Vitiligo Research, Seoul, Korea University of Florence, Florence, Italy

St. John's Institute of Dermatology, London, England

Jana Hercogova

Charles University, University Hospital Motol, Prague,

Czech Republic Sungbin 1m

Korea Institute of Vitiligo Research, Seoul, Korea

Demetris loannides

Aristotle University Medical School, Thessaloniki,

Greece University of Bologna, Bologna, Italy

Matilde lorizzo

University of Athens Medical School, Andreas Sygros Hospital for Skin and Venereal Diseases, Athens, Greece

Andreas D. Katsambas

Charles University, University Hospital Motol, Prague,

R. Konkolova

Czech Republic Michelangelo La Placa Mario Lecha

University of Bologna, Bologna, Italy

University of Barcelona, Barcelona, Spain

Alex Llambrich

Hospital Clinic, Barcelona, Spain

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Contributors

xiii

Wennie Liao

University of Cincinnati, Cincinnati, Ohio, U.S.A.

Torello Lotti

University of Florence, Florence, Italy

Jose M a Mascaro Daniela Massi

Hospital Clinic, Barcelona, Spain

University of Florence, Florence, Italy

Giovanni Menchini Giuseppe Micali A. MoLinu

University of Florence, Florence, Italy

CJinica Delmatologica, Universita di Catania, Catania, Italy

University of Siena, Siena, Italy

Silvia Moretti

University of Florence, Florence, Italy

Aldo Morrone

Istituto Dermosifilopatico San Gallicano, Rome, Italy University of Florence, Florence, Italy

Giuseppe Muscarella, Luigi Naldi Italy

U.O. Dermatologia, Ospedali Riuniti di Bergamo, Bergamo,

Maria Rita Nasca Italy 1. Neri

Clinica Dermatologica, Universita di Catania, Catania,

University of Bologna, Bologna, Italy

Electra Nicolaidou University of Athens School of Medicine, "A. Sygros" Hospital, Athens, Greece M. D. Njoo Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands James J. Nordlund

University of Cincinnati, Cincinnati, Ohio, U.S.A.

Ljubomir Novakovic Arnold P. Oranje

St. John's Institute of Dermatology, London, England

Erasmus MC, Rotterdam, The Netherlands

Jean Paul Ortonne

Hopital L'Archet 2, Nice, France

Giovanni Maria Palleschi A. Patrizi

University of Florence, Florence, Italy

University of Bologna, Bologna, Italy

M. Pellegrino

University of Siena, Siena, Italy

Elisa Pianigiani

Arezzo's Hospital and University of Siena, Siena, Italy

Mauro Picardo

San Gallicano Dermatological Institute, Rome, Italy

Bianca Maria Piraccini

University of Bologna, Bologna, Italy

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G. Primavera

Contributors

San Gallicano Dermatological Institute, Rome, Italy

Karin U. Schallreuter University of Bradford, Bradford, United Kingdom and Institute for Pigmentary Disorders e. V. in Association with the ErnstMoritz-Arndt University Greifswald Biotechnikum, Greifswald, Germany

E. Stanghellini

University of Siena, Siena, Italy

Alexander J. Stratigos University of Athens Medical School, Andreas Sygros Hospital for Skin and Venereal Diseases, Athens, Greece Paolo Taddeucci

Arezzo's Hospital and University of Siena, Siena, Italy

Aurora Tedeschi

Clinica Dermatologica, Universita di Catania, Catania,

Italy Antonella Tosti Giovanni Tosti

University of Bologna, Bologna, Italy S. Luca Hospital, Trecenta, Italy

Evridiki Tsoureli-Nikita

University of Siena, Siena, Italy

Sabina Vaccari

University of Bologna, Bologna, Italy

Mario Vaccaro

University of Messina, Messina, Italy

Gino A. Vena

University of Bari, Rome, Italy

W. Westerhof Academic Medical Centre, University of Amsterdam, and Netherlands Institute for Pigment Disorders, Amsterdam, The Netherlands Cristina Zane

Spedali Civili, Brescia, Italy

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1 Vitiligo: Disease or Symptom? From the Confusion of the Past to Current Doubts Torello Lotti and Giuseppe Hautmann University of Florence, Florence, Italy

Jana Hercogova Charles University, Prague, Czech Republic

THE ANCIENT CONFUSION

The word "vitiligo" itselfis said to have been first used by Celsus in the Latin medical classic De re medicina in the first century A.D. With regard to the roots of the term, there seems to be some difference of opinion between lexicographers and dermatologists. Some state that its appearance resembling the white glistening of the flesh of calves (vituli) may have given rise to the generic term vitiligo. Others suggest that it may be derived from vitelius, the Latin word for "calf," because of the white patches in a calf's fur. Some believe that the name represents a blemishing fault that in Latin is called vitium. The origin of the "I" in the word vitiligo is uncertain. It may simply have been introduced for reasons of euphony (1-3). Finally, the Lexicon of the Latin Language published in 1841 in Boston by Facciolati and Forcellini is unable to clarify the terminology. Instead of settling the confusion it even adds to it: "Vitiligo (vitium) a kind of leprosy or cutaneous eruption consisting of spots, sometimes black (?), sometimes white, called morphea, alphus, mel as, leuce; also in general a cutaneous eruption according to Celsus and Pliny (second century A.D.)" (2,4). Thus, it is probable that in ancient times the references to white spots on the skin represented not only vitiligo vulgaris but also other disorders, such as leprosy, that leave white spots on the skin (5). Only in the

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last century has the term" vitiligo vulgaris" been used specifically to refer to the acquired, progressive disorder characterized by destruction of melanocytes in the skin and other organs. It seems likely that vitiligo was recognized several millennia before Christian times. Some of the earliest references date from 1500 B.C. (I). Vitiligo has long been confused with leprosy, which may account for the social stigma attached to white spots on the skin (6). The Egyptian Ebers Papyrus (ca. 1500 B.C.) notes several types of leukoderma, one associated with swelling of the skin, the other macular. The first type might be a description of leprosy, the second a description of vitiligo vulgaris. In the early Vedic scripture Alharvaveda (ca. 1500 B.C.) from India, a Kilar or white disease that might represent vitiligo is described. Around 800 B.C., sVitra, meaning "whiteness," is mentioned in the Charaka samhita, a medical treatise. In the ancient Japanese book Amarakosa (1200 B.C.), a collection of Shinto prayers, a disorder called Shira-bilo, meaning "white man," is described. Whether this reference is to albinism, vitiligo, or both is not known. Hippocrates described white spots on the skin but did not seem to distinguish vitiligo and leprosy or other disorders of depigmentation (7). He described many features of vitiligo that have been emphasized in recent years. He noted that the disorder was more easily treated when first diagnosed rather than many years after its onset. In the Bible a variety of disorders characterized by hypo- or depigmentation is described. The Talmud records the association of sudden onset of white hair with vitiligo vulgaris (7). Mercurialis attempted to explain the pathogenesis of the depigmentation in his book, De morbus cUlaneis, suggesting that if phlegm or "mucous blood" rather than blood nourished the skin, the skin turned white. He distinguished the disease from morphea, which he thought was hyperpigmentation. He distinguished several different forms of depigmentation and suggested some therapeutic approaches (8). Near the end of the nineteenth century, when skin diseases were still presented in alphabetical order in many textbooks of dermatology, vitiligo was defined as a pigmentary dystrophy. Gottheil in the late nineteenth century called vitiligo vulgaris a form of atrophy of the pigment cells (9). Louis Brocq termed the lack of pigmentation (achromy) in vitiligous lesions combined with increases in pigmentation (hyperchromy) in the lesions's peripheries "dyschromy" (10). Kaposi was one of the first to describe the histopathological features of vitiligo. He stated that the only anatomical change in vitiligous skin is the lack of pigment granUles in deep rete cells. An increase in pigmentation can be found in the surrounding lesions. Sparsely pigment-laden cells in the corium are unable to add much to the clinical aspect of the skin's pigmentation (II). Obscure etiological mechanisms such as emotional stressors other than traumatic factors triggering the eruption of vitiligo have been extensively discussed by dermatologists. For them, a connection with the nervous system seemed to be evident (10). At the turn of the Copyrighted Material

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twentieth century, different approaches were developed to the treatment of vitiligo. Systemic application of bromides or iodides (or also valerianates) of mercury, antimony, and arsenic did not show much effect. Besnier recommended subcutaneous injection of pilocarpine and saline or bromoiodic baths. Different mixtures containing croton oil, iodine, sublimate, and naphthol ha ve been used topically without convincing therapeutic results (10,12). PRESENT (PARTIAL) KNOWLEDGE: THE DARK SIDES OF THE ACHROMIC DISORDER

Nowadays, vitiligo may be considered and defined as the prototype of the hypomelanotic disorders (3). As is well known, it occurs idiopathically and is acquired in most cases. Clinically, it presents with circumscribed leukoderma that may arise at any age, but it usually appears before the age of 30 years. Approximately 1--4% of the world population is believed to be afflicted. Variable penetrant autosomal dominant inheritance has been suggested, because familial incidence is common. Few or many white macules appear on the exposed areas, such as the dorsal aspects of the hands and the face and neck. Facial lesions are commonly located around the eyes and mouth. Body folds (axilla and groin) may also be initial sites. There are two major commonly recognized forms of vitiligo: generalized and segmental. The generalized form is characterized by depigmented macules involving both sides of the body in a remarkably symmetrical pattern; for each spot on one side of the body, a spot similar in size and location is found on the other side. This type of vitiligo might better be labeled bilateral, symmetrical vitiligo. Segmental vitiligo is characterized by unilateral, symmetrical depigmentation. It could be termed unilateral, asymmetrical vitiligo. This sharply demarcated distinction may raise the question whether symmetrical and asymmetrical vitiligo present the same etiopathological factors or if they represent two different and distinct nosological entities with similar clinical pictures. Confusion may result from the symmetrical segmental forms. One question that must be addressed concerns halo nevi. Halo nevi have been associated with vitiligo and said to represent the same abnormality in a limited form (13,14). Moreover, it has been observed that halo nevi can be observed in almost a third of young patients (7). The question is: Are halo nevi a form of vitiligo? The answer is as yet unknown. VITILIGO BEYOND THE SKIN

Pigmentation of the ears and eyes may also show degenerative changes in some patients with vitiligo. The eyes have two embryologically distinct layers of pigment cells: Immediately behind the neuroretina is the retinal pigment epithelium, which is heavilCBfj}mfjhWRt iYl:lfeYif1?nd layer is the uveal tract,

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consisting of the choroid, the ciliary body, and the iris. Most patients with vitiligo have few symptoms related to the eyes; they might note a slight decrease in night vision or mild photophobia or slight headaches. Discrete areas of depigmentation, with associated pigment hyperplasia involving the choroid and retinal pigment epithelium as well as active uveitis, have been observed in as many as 40% of patients with vitiligo according to Hann and Nordlund (14). Moreover, vitiligo patients exhibit some audiological abnormalities, such as sensorineural hypoacusis, which may be related to involvement of the inner ear melanocytes (14). A few patients have very severe inflammatory eye problems associated with vitiligo. This has been called the Vogt-Koyanagi-Harada or the uveomeningo-encephalic syndrome. This syndrome is characterized by the association of vitiligo, an inflammatory uveitis, and, in some patients, meningeal inflammation and dysacusis. Eye involvement has been described both with bilateral, symmetrical vitiligo and with unilateral, asymmetrical vitiligo (Alezzandrini syndrome). The Vogt-Koyanagi-Harada syndrome has as one manifestation dysacusis; this association suggests that melanocytotoxic processes causing vitiligo can be active in the pigment cells of the stria vascularis of the inner ear. These pigment cells have been demonstrated to be essential for the normal function of the cochlea and provide a pathophysiological basis for loss of hearing in their absence (7). Thus, another very important question is whether vitiligo represents only a cutaneous pigmentary disorder or a systemic disorder of the pigmentary system. Because several patients with vitiligo who have audiological and ophthalmological changes generally do not present symptoms or have vague complaints, involvement of melanocytes in the extracutaneous parts of the body is often overlooked. Thus, the Vogt-Koyanagi-Harada and Alezzandrini syndromes might be considered the most severe manifestations of vitiligo of the skin and the pigmentation of the eyes. Many researchers tend to consider the Vogt-KoyanagiHarada and Alezzandrini syndromes to be different diseases from vitiligo, according to Hann and Nordlund (14). THE SPECIAL DEPIGMENTATION PATTERN OF VITILIGO

Microscopically, vitiligo features the nearly total absence ofmelanocytes and melanin within the epidermis and an increased cellularity in dermal layers (Figs. I and 2). Characteristic histochemical and ultrastructural changes can be observed. The physical disfigurement caused by vitiligous lesions often leads to social embarrassment (6), and it is a major sociopsychological problem in areas where dark skin predominates. The causes of vitiligo are still unknown. Similarly, the precipitating factors are not well delineated. Some factors, such as melanocytotoxic

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FIGURE 1 Histological picture of vitiligo: a mild diffuse and follicular hyperkeratosis. The papillary dermis shows a minimal fibrotic change. In the basal layer of the epidermis absence of melanocytes is suggested by a lack of cells with perinuclear halo (E-E, x100).

FIGURE 2 Immunohistochemical staining of 8-100 reactivity in vitiligo: presence of dendritic cells in superficial layers of the epidermis (Langerhans cells) and absence of reactivity in the basal layer of epidermis (melanocytes) (x 10).

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chemicals and the Koebner phenomenon (also termed the isomorphic response), are wel1-documented precipitating factors, but their mechanism of action is not completely understood. Depigmentation can be induced by the exposure of some individuals to chemicals that typical1y are derivatives of hydroquinone. It seems that not al1 individuals are equal1y susceptible to the depigmenting effects of wel1-known melanocytotoxic chemicals. Whether this manifestation is vitiligo or depigmentation caused by mechanisms different from those responsible for vitiligo vulgaris is not known. The first chemical to be identified as a melanocytotoxin was monobenzone (15). When workers wore gloves containing this chemical, it destroyed the melanocytes in the skin, leaving the hands of the workers depigmented. This agent has been used for the treatment of individuals with. vitiligo too extensive to repigment (16). There are many other reports of workers in industrial settings exposed to chemicals with structures similar to monobenzone who have developed depigmentation (17-19). There are other reports of individuals developing depigmentation following exposure to commonly encountered items. These include cosmetics (20), possibly paraphenylenediamine hair dyes (21), monobenzone in bleaching creams (22), cinnamic aldehyde in toothpaste (23), and derivatives of hydroquinone in germicides (24). The question is whether such chemical or occupational depigmentation is in fact vitiligo with a known precipitating cause or some other depigmenting disorder. In our opinion, they are different and separate disorders because chemical and occupational depigmentation tend to be limited to the sites of exposure to the melanocytotoxic agent. In addition, the clinical course of depigmentation differs: Vitiligo general1y tends to be progressive throughout the life of affected subjects, whereas chemical depigmentation generally stops spreading after the offending agent is removed. Thus, until there are definitive data to show that the two disorders have a common pathogenetic pathway, we prefer to separate vitiligo from chemical and occupational leukoderma. It is well known that even minor injuries to the skin of patients with vitiligo can leave depigmented areas when healed. This is called the isomorphic response. Small cat scratches, abrasions from fal1ing, surgical wounds, and similar injuries have all been observed to cause depigmentation. Many individuals who develop a sunburn following excessive sun exposure attribute the depigmentation to the burn. These individuals invariably have very fair skin. It is possible that the isomorphic phenomenon activated by the sunburn is responsible for the depigmentation in susceptible individuals. Another explanation is that the individual burned because the skin was depigmented already and did not have the benefit of the protective effects of the pigment system. Gauthier has stressed the importance of the isomor-

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phic response, suggesting that this phenomenon might explain the onset and distribution of vitiligo (25). Repeated mild trauma associated with rubbing, wearing of clothes, and gentle pressure on the skin was thought to ind uce the depigmentation observed in vitiligo. Nevertheless, this hypothesis must be substantiated. Another question may be represented by gray or white hair: Do they represent a form of vitiligo? Gray hair can be considered the aging of melanocytes of hair follicles, a process associated with interruption of melanogenesis (14). In contrast, white hair usually suggests the complete absence of melanocytes from the papilla of the hair follicle. White hair can be classified into two major types: the first type has a genetic or familial etiology and represents a rather common ca use of partial loss of pigment of the scalp hair in younger adults in the third and fourth decades of life. This type of white hair seems to be different from vitiligo. The second type of complete white hair is uncommon but may be associated with vitiligo. White hair is usually accompanied by interfollicular depigmentation, particularly when it is associated with vitiligo (14). It seems likely that loss ofmelanocytes in the follicles of those wi th vi tiligo represen ts the same destructive process active wi thin the hair bulb follicle.

PATHOGENESIS OF VITILIGO: DISEASE OR SPECTRUM?

The pathogenesis of vitiligo vulgaris is not known, but there are many hypotheses extant, each supported by intriguing data that are outlined in other chapters of this volume. We present them briefly here. Autoimmune Hypothesis

Supporting this hypothesis are the clinical associations of vitiligo with polyglandular failure. This might be the strongest clinical indication available. Patients with lymphoma may develop vitiligo. Most such patients have immune deficiencies that are the cause of freq uent infections that could cause vitiligo (3,7). The same problem is encountered in acquired immunodeficiency syndrome (AIDS) patients who develop vitiligo. It has been hypothesized that such patients might be affected by vitiligo because their immune systems, either humoral or cytotoxic, are impaired (7). The antibodies to melanocytes have been implicated. Nevertheless, although autoantibodies are commonly found in high titers in patients with vitiligo, they are not melanocyte specific. Only about 60% of patients with vitiligo have such antibodies; this might be explained by the presence of low titers to the enzyme. Would such low titers be capable of killing melanocytes?

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It has been suggested that subjects without antibodies might have inactive

disease. Thus, to make any conclusions about the presence of antibodies and disease activity, careful clinical studies are needed. Such antibodies could be the markers of the disease rather than the cause of it. This consideration might explain why melanomas from humans but also many animals share the same antigenic determinants identified by these antibodies (some of which are cytoplasmic and not membrane molecules) (7,26,27). Tyrosinase is usually identified by antibodies. Tyrosinase is thought to be expressed exclusively within the cytoplasm of the melanocyte and not on the cell surface; therefore, the contents of the pigment cells are released into the circulation, where they initiate an immune response. Whether the antigen is an intracellular antigen also requires further investigation. It is still unknown whether the response initiates, accelerates, or merely marks the disease. Thus, these data need confirmation. Antibodies can kill melanocytes in vitro. This suggests that the immune system might be involved in some way in killing melanocytes, at least in some patients with vitiligo. Individuals with endocrine disorders but without vitiligo also had such antibodies; this raises the obvious question of the roie of these antibodies in killing melanocytes. Antibodies can kill melanocytes in vitro and in nude mice bearing human xenografts; this observation has been cited as definitive, but, unfortunately, that is not a valid conclusion. The cytotoxic effects of the antibodies in vitro are complex. The concentration of the antibodies and the antigens involved all remain to be elucidated. Common antigens, such as class I MHC complex, might be involved and make the effect nonspecific. These problems are apparently resolved using nude mice, as the loss ofmelanocytes detectable by DOPA oxidase might represent loss of the enzyme only and not destruction of the melanocytic cell (7). Thus, the role of the antibodies remains to be determined. The plethora of data relating to an autoimmune mechanism for some individuals with vitiligo is very supportive of this hypothesis, but cannot be considered proof of this concept. Genetic/Intrinsic Hypothesis

Vitiligo clusters in families (28,29). This could be the result of environmental melanocytotoxins that affect certain families because of where they live. Moreover, this theory could easily be subsumed in other theories, such as the autocytotoxic or autoimmune theories. The cells have some inherent defect (30,31). This seems inescapable. It is not clear the nature of the insult that makes the melanocyte susceptible to Copyrighted Material

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injury. It is possible that phenols are one environmentally responsible agent. It is also possible that one of the numerous cytokines or chemical mediators of inflammation stimulates the cell and in some way become responsible for cellular death (32). The genetic/intrinsic theory seems to be a vague one that can incorporate almost any abnormalities discovered.

Autocytotoxic Hypothesis Vitiligo seems to affect hyperpigmented skin more often than normal-colored skin (33). This observation does not seem verifiable. The skin around body orifices such as the eyes, mouth, nose, and genitalia is considered hyperpigmented and thus susceptible to vitiligo (33). The skin around orifices like the eyes and mouth is darker in some individuals, but that may be related to vascular abnormalities and not melanin concentrations, especially around the eyes. The genitalia are darker, but vitiligo seems to affect these tissues late in many patients. Thus, these clinical observations appear very tenuous (7). Chemicals with structures similar to melanin intermediates have been added to cultures of melanocytes or melanoma cells, and the cells underwent cytolysis (34,35). That melanin precursors have the potential to be cytotoxic seems real. Compounds such as phenols and quinones in fact are highly reactive. It seems that some of these compounds have a cytotoxicity specific for melanocytes. These in vitro data are intriguing but remain to be confirmed. It is now known that melanin formation begins in the transport vesicles. These observations call for further understanding of how melanin formation occurs, the opportunities for leakage into vital areas of the cell, and the effects of stimulating melanogenesis on such leakage.

Neural Hypothesis The melanocyte and the nervous system are both derived from the neural crest. Both cell types use the amino acid tyrosine for their major end products (melanin and catechols, respectively). Catechols are very similar in structure to some of the intermediates of the melanin pathway. The mostly embyological data seem too weak to draw conclusions. It also has been observed that patients that have sympathectomy can develop a hypopigmented iris, an observation suggesting that the melanocyte is innervated (34). This might be explained as due not to a cytotoxic reaction but rather to a loss of stimulation of uveal melanocytes. Ultrastructural studies demonstrate frequent direct contact between cutaneous nerve endings and melanocytes in vitiligous skin or structural alterations (swelling ofaxons, duplication of the basement membrane, etc.) (37,38); the significance of t~p.fPRJffi~81~t¥jm~h1M1dingsis still unknown.

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Aberrations in f?,-endorphins and met-enkephalin secretion have been reported in vitiligo patients (39). Plasma met-en kephalin levels are generally higher in vitiligo patients (especially in ones with active vitiligo) than in controls. Because it is known that the release of met-en kephalin is affected in humans during stress, it has been suggested that this abnormality may be correlated with the emotional stress suggested to precipitate vitiligo in some patients. Moreover, immunohistochemical observations suggest an increased immunoreactivity to neuropeptide Y and vasoactive intestinal peptide (VIP) at the marginal areas or within vitiligo macules (40). These results are very difficult to interpret, and very little is known about the effects of neuropep tides on human melanocytes. The depigmented skin exhibits abnormalities of the autonomic nervous system (i.e., increased adrenergic tone and decreased parasympathetic tone) (41). This should not be surprising as one of three major epidermal cells is absent, at least functionally. Segmental vitiligo has been one of the strongest clinical manifestations suggesting a neural origin. It also has been suggested that segmental vitiligo responds to therapy with agents that alter neural function (36). The distribution of segmental vitiligo is often said to be dermatomal. In actuality, it is not dermatomal (7) (i.e., it does not follow a specific pattern of cutaneous sensory nerves). It has been stated that without implicating the nervous system it is difficult to explain segmental vitiligo. That might be true, but it is not sufficient for generating an hypothesis. The role of the nervous system in the pathogenesis of vitiligo, if any, is still undefined. Furthermore, no functional association has yet been made between melanocytes and neural cells. Other Hypotheses It has been suggested that melanin synthesis stimulated and altered by melatonin generates radical oxygens, causing melanocyte death (42). The role of melatonin in melanocyte physiology is completely unknown at this time. It has an important role in some animals, including other mammals. It seems to have less effect directly on melanocytes than on the production of melanocytestimulating hormone, at least in other animals. It has not been shown to stimulate free radical formation. It has been suggested that a previously unrecognized biochemical pathway for the production ofthioredoxin is involved in the death ofmelanocytes (43,44). The synthesis of tyrosine in the epidermis and the production of tetrahydrobiopterin have also been implicated (45,46). The latter pathway is interconnected with the thioredoxin pathway. It has been suggested that the depigmentation is a result of a blockade of tyrosine synthesis within keratin-

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ocytes related to an excess accumulation of7-tetrahydrobiopterin within the epidermis and catechols in the serum and tissues (45,46). The accumulation of tetrahydrobiopterin is due to a deficiency in the activity of the enzyme 40'hydroxytetrahydrobiopterin dehydratase that normally recycles the biopterins. The accumulation of 7-tetrahydrobiopterin blocks the production of tyrosine from phenylalanine. It is concluded that the melanocytes are deprived of the essential substrate for synthesis of melanin and that, because of this, the skin turns white. This pathway is intriguing, but the thioredoxin reductase pathway is present in most tissues, and its existence in the skin or melanocytes is still debated. Thus, its role in vitiligo is unknown but would be a good candidate mechanism to support a genetic hypothesis. The role of tetrahydrobiopterin remains to be determined. That melanocytes are present in depigmented skin but incapable of synthesizing melanin due to lack of tyrosine does not correlate well with other data. The histology of the depigmen ted skin suggests an absence of melanocytes. Moreover, this hypothesis does not explain the clinical problem of treating non-hair-bearing skin with PUVA. Such skin usually does not respond well for lack of a reservoir. This hypothesis suggests instead that all skin should respond to therapy in a similar fashion (7). Finally, a variety of animals developing vitiligo manifested progressive depigmentation with loss of active melanocytes such as observed in chickens, mice, cats, dogs, pigs, and horses. Nevertheless, because vitiligo is probably a complex syndrome with multiple etiologies, each animal model may only represent a facet of this complex condition. In fact, each of the several animal models proposed (the Sinclair pig, C57 BL 76 mivi'mivit mouse, Smyth chicken, etc.) helps in the study of different facets of melanocyte destruction; however, until a specific marker of vitiligo is demonstrated, none of them can be considered a specific model for this complex condition CONCLUSIONS: IS VITILIGO A DISEASE OR A SYNDROMIC SPECTRUM? As stated above, the etiology and pathogenesis of vitiligo are not yet known. There are many hypotheses extant, each supported by intriguing data that are currently insufficient to prove the accuracy of the theory. It seems likely that vitiligo vulgaris represents at least one, but more likely several processes that cause melanocyte destruction and inactivation. That this is true is suggested by the various clinical presentations. Besides the typical vitiligo vulgaris, there is segmental vitiligo. It seems unlikely that the same mechanism is responsible for both disorders. Patients with associated polyglandular failure might represent another mechanism. Individual patients present with atypical features. Occasionally a

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patient might have many features of vitiligo vulgaris, such as depigmented patches on the extremities, face, and trunk, but the classic distribution on the fingers, feet, and face is not present. Some individuals show marked loss of pigment from the hair; others show none. These differences might have no importance or significance, or they might be hints that different mechanisms are involved. The various theories outlined above are intended to summarize current popular hypotheses. These theories are not all-inclusive and also are not mutually exclusive (7). It is possible that several mechanisms are operative to produce melanocyte destruction in a given individual, as happens in the Smyth chicken. Thus, we believe that although the clinical picture is quite similar, the etiology and pathogenetic mechanisms vary individual by individual; thus, we propose considering vitiligo as a type of leukoderma involving progressive, acquired depigmentation with unpredictable course. It usually involves integument and probably affects the pigmentary system of other organs. There are other forms of leukoderma, but in our opinion these should be considered distinct entities until more information is available about their pathogenetic mechanisms, and these disorders should be classified as specific forms of depigmentation, such as chemical, occupational depigmentation, or depigmentation associated with melanoma. Finally, we agree with those authors who, on the basis of recent investigation, support the hypothesis that melanocytes are never completely absent in the depigmented epidermis and thus capable of recovering their functionality.

REFERENCES 1.

2. 3. 4. 5. 6. 7.

8.

Nair BKH. Vitiligo. A retrospective. Jnt J Dermatol1978; 17:755-757. Kopera D. Historical aspects and definition of vitiligo. Clin Dermatol 1997; 15841-843. Ortonne JP, Mosher DB, Fitzpatrick DB, eds. Vitiligo and Other Hypomelanoses of Hair and Skin. New York: Plenum, 1983:129-310. Sutton RL. One definition of vitiligo (lett). Arch Dermatol 1965; 91 :288. Singh G, Ansari Z, Dwivedi RN. Vitiligo in ancient Indian medicine (lett). Arch Dermatol 1974; 109:913. Hautmann G, Panconesi E. Vitiligo: a psychologically influenced and influencing disease. Clin Dermatol 1997; 15:879-890. Ortonne JP, Nordlund JJ Vitiligo. In: Nordlund JJ, Boissy RE, Hearing VJ, KlIlg Ra, Ortonne JP, eds. The PIgmentary System. New York: Oxford Press, 1998513-551 Mercurialis H. De Morbis Cutaneis et Omnibus Corporis Humani Excrementis Tractatus. Kansas City, MO: Lowell Press, 1752.

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Gottheil WS. Atrophy of the pigment. In: Gottheil WS, ed. Illustrated Skin Diseases: An Atlas and Textbook. New York: E.B. Treat, 1897:292-304. 10. Brocg L. Traitement des Maladies de la Peau. Paris: Doin, 1892:853-855. II. Kaposi M. Pathologie und Therapie der Hautkrankheiten. 5th ed. Berlin: Urban und Schwarzenberg, 1899:703-707. 12. Neumann 1. Lehrbuch der Hautkrankheiten. Vienna: Braumueller, 1880:438. 13. Lerner AB, Nordlund JJ. Vitiligo. What is it? Is it important? JAMA 1978; 239:1183-1187. 14. Hann SK, Nordlund JJ. Definition of vitiligo. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science, 2000:3-6. 15. Oliver EA, Schwartz L, Warren LH. Occupational leukoderma. Arch Dermatol 1940; 16041-44. 16. Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzyl ether of hydroguinone: a retrospective study of treatment of 18 vitiligo patients and a review of the literature. Br J Dermatol 1977; 97:669-679. 17. Bleehen SS. The treatment of hypermelanosis with 4-isopropylcathecol. Br J Dermatol 1976; 94:687-694. 18. O'Malley MA, Mathias T, Priddy M, Molina 0, Grote AA, Halperin WE. Occupational vitiligo due to unsuspected presence of phenolic antioxidant by products in commercial bulk rubber. J Occcup Med 1988; 30:512-516. 19. Tosti A, Gaddoni G, Piraccinl BM, De Maria P. Occupational leukoderma due to phenolic compounds in the ceramic industry? Contact Dermatitis 1991; 25:67-68. 20. Catona A, Lanzer D. Monobenzone, superfade, vitiligo and confetti-like depigmentation. Med J Aust 1987: 146:320-321. 21. Taylor JS, Maibach HI, Fisher AA, Bergfeld WF. Contact leukoderma associated with the use of hair colors. Cutis 1993; 52:273-280. 22. Dogliotti M, Caro 1, Hartdegan RG, Whiting DA. Leucomelanoderma in blacks. A recent epidemic. S Afr J Med 1974; 48: 1555-1558. 23. Mathias CG, Maibach HI, Conant MA. Perioral leukoderma simulating vitiligo from use of a toothpaste containing cinnamic aldehyde. Arch Dermatol 1980; 116:1172-1173 24. Bentley-Phillips R. Occupationalleukodemla following misuse of a disinfectant. S Afr Med J 1974; 48810. 25. Gauthier Y. The importance of Koebner's phenomenon in the induction of vitiligo vulgaris lesions. Eur J Dermatol 1995; 5:704-708. 26. Austin LM, Boissy RE. Mammalian tyrosinase related protein-l is recognized by autoantibodies from vitiligous Smyth chickens. Am J Pat hoi 1995; J 46: 1529-1541. 27. Song YH, Connor E, Li Y, Zorovich B, Balducci P, Maclaren N. The role of tyrosinase in autoimmune vitiligo. Lancet 1994; 344: 1049-1 052. 28. MaJumder PP, Das DK, Li Cc. A genetical model for vitiligo. Am J Hum Genet 1988;43:119-125 29. Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol 1993; 129:994-998. 30. Puri N, Mojamdar M, Ramaiah A. In vitro growth characteristic ofmelanocytes obtained from adult normal and vitiligo subjects. J Invest Dermatol1987; 88434438

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31.

Puri N, Mojamdar M, Ramaiah A. Growth defects of melanocytes in culture from vitiligo subjects are spontaneously corrected in vivo in repigmenting subjects and can be partially corrected by the addiction of fibroblast-derived growth factors in vitro. Arch Dermatol Res 1989; 281:178-184. Moretti S, Pinzi C, Spallanzani A, et al. Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. Int J Cancer 1999; 84: 160-168. Lerner Ab, Nordlund JJ. Vitiligo: loss of pigment in skin, hair and eyes. Jpn J Dermatol1978; 5:1-8. Wick MM. Levodopajdopamine analogs as inhibitors of DNA synthesis in human melanoma cells. J Invest Dermatol ] 989; 92(suppl 5):329s-331 s. Prezioso JA, Fitzgerald GB, Wick MM. Effects of tyrosinase activity on the cytotoxicity of 3,4-dihydroxybenzylamine and buthionine sulfoximine in human melanoma cells. Pigment Cell Res 1990; 3:49-54. Koga M. Vitiligo: a new classification and therapy. Br 1 Dermatol 1977; 97:255261. Morohashi M, Hashimoto K, Guodman F. Ultrastructural studies of vitiligo, Vogt-Koyanagi syndrome and incontinentia pigmenti-achromicans. Arch Dermato] 1977; 113:755-766. Breathnach AS, Bors S, Wyllie LMA. Electronmicroscopy of peripheral nerve terminals and marginal melanocytes in vitiligo. 1 Invest Dermatol 1966; 47: 125140 Mozzanica N, Villa ML, Foppa S, Vignati G, Cattaneo A, Diotti R, Finzi AF. Plasma ex-melanocyte stimulating hormone, l3-endorphin, met-enkephalin, and natural killer activity in vitiligo. J Am Acad Dermatol 1992; 26:693-700. AI'Abadie MSK, Gawkrodger Dl, Senior Hl, Warren MA, Bleehen SS. Neuroultrastructural and neuropeptide studies in vitiligo. Clin Exp Dermatol 1992; 15:284. Al'Abadie MSK, Senior HJ, Bleehen SS, Gawkrodger DJ. Neuropeptide and neural marker studies in vitiligo. Br J Dermatol 1994; 131, 160-165. Slominski A, Paus R, Bomirsi A. Hypothesis: possible role for the melatonin receptor in vitiligo: discussion paper. J R Soc Med 1989; 82:529-541. Schallreuter KU, Wood 1M. Free radical reduction in the human epidermis. Free Radic Bioi Med 1989; 6:519-532. Schallreuter KU, Hordinsky MK, Wood 1M. Thioreduxin reductase: role in free radical reduction in different hypopigmentation disorders. Arch Dermatol 1987; 123:615-619. Schallreuter KU, Wood lN, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, Swanson NN, Hitzemann K, Ziegler L. Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 1994; 263: 1444-1446. Schallreuter KU, Wood lN, Ziegler 1, Lemke KR, Pittelkow MR, Lindsey Nl, Gutlich M. Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochem Biophys Acta 1994; 1226: 181-192.

32.

33. 34. 35.

36. 37.

38.

39

40.

41. 42. 43. 44.

45.

46.

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2 Historical and Psycho-Anthropological Aspects of Vitiligo Aida Morrone Istituto Dermosifilopatico San Gallicano, Rome, Italy

INTRODUCTION It is extremely difficult to investigate the historical origins of vitiligo due to the fragmentary nature of the available data, the lack of conclusive historical information, and the many philological interpretations of terminology that for centuries contributed to making acceptable historical research difficult. Dealing with the psycho-anthropological aspects is even more difficult, and these are even now the subject of discussion and debate. Several authors have described interesting historical aspects (1~6), but their statements are questionable due to difficulties and errors in interpretation. Research on the historical aspects and definitions of vitiligo remind us that the earliest reports on patchy skin disease appeared circa 1500 B.C. Vitiligo has long been confused with leprosy, which is an important explanation for the social and psychoanthropological stigma attached to white spots on the skin.

ANCIENT REFERENCES

The earliest mention of patchy skin disease that can be interpreted as vitiligo dates back to approximately 1500 B.C. The Ebers Papyrus, dealing with medicine in the age of the Pharoahs, describes two types of skin disease involving changes in the color of the skin. One type, involving tumors and mutations, is likely leprosy, since it is affirmed that "thou shalt not do anything to it" (I).

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The other seems to simply involve a lack of pigmentation; it is likely to be vitiligo, because "only a change in color is found." It is said that in this case a cured was effected (2). References from the same era are found in the ancient sacred books of India, the Alharva Veda from 1400 B.C. (3), in which a disease called Shwelakustha is mentioned, which may be vitiligo. [Shwetakustha is derived from shvet (white) and kushtha (skin disease in general) and according to the Sanskrit dictionary means "making the body repugnant or deteriorating the blood."] Village dwellers used the term charak, meaning something that is hidden or which is spread, both indicating a negative social condition (4,5) In the Alharva Veda, particular reference is made to a disease called kilas. The term "kilas" comes from the Sanskrit word kil, which means "white," in the sense of "casting away." In a 1905 translation of the Alharva Veda, kilas was identified as vitiligo. In the same books, a plant with black seeds is mentioned as being used by [ndians in an attempt to restore normal color to discolored skin: "0 plant, thou produced even color! Render this (spot) its uniform color." Ancient Indian medical literature indicates that the plant generally used was the Bavachee, or Psoralea corylifolia (6). Later it was discovered to contain psoralene, a photodynamically active furocoumarin. In the sacred Buddhist book Vina)' Pitah (624-544 B.C.), the word "kilas" is mentioned in reference to those affected by leukoderma. A collection of Shinto prayers from the Far East, Makatominoharai (1200 B.C.), mentions shira bitu, meaning "white man," which in some cases could be interpretated as vitiligo. Another Indian medical compilation, the Charak Samhita (800 B.C.), mentions a disease called sJlilra, a Sanskrit term meaning "spreading whiteness." L 'Ashwngahida)'a (600 H.C.) attempts to explain the prognostic factors involved in these eruptions (2). In the Greek literature there is great emphasis on "white spots"; for example, the historian Herodotus (484-425 B.C.) reported that foreigners affected by these lesions have probably "sinned against the sun" and should leave the country immediately (7). He wrote in 449 B.C.: If a Persian has leprosy or white sickness he is not allowed to enter into a city or to have dealings with other Persians, he must, they say, have sinned against the sun. Foreigners attacked by this disorder are forced to leave the country, even white pigeons are often driven away as guilty of the same offense. Even Aristotle dealt with whiteness of the skin, which at that time was a disturbing sign, particularly among dark-skinned people (7): Why do boys and women suffer less from white leprosy than men, and old women more than young ones? [s it because leprosy is an escape of

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breath, and bodies of boys are not well ventilated but are thick and those of women are less well ventilated than those of men? For the breath is absorbed in the menses; the smoothness shows the thickness of the flesh. But the flesh of older men and of old women is well aired; for they alone like old buildings have gaps in the construction of their parts. Aristotle also observed that gray hair was a feature of leprosy and reasoned that those who do not get gray hair cannot have leprosy. Although skin disorders with anesthesia and paresthesia were described in seventh-century China, as were various skin disorders in India as far back as 7000 years, and alopecia with sensory changes and skin disturbances in the Berlin Papyrus and the Ebers Papyrus, no evidence of leprosy has been found among ancient Egyptian mummies or in the pre-Columbian Americas (although ceramics of pre-Columbian Middle Andean civilizations display evidence of many other diseases). Leprosy must not have been particularly common, and many leukodermas must have been something other than leprosy. Beyond ancient descriptio!ls, the first clear account of leprosy, according to Kaposi (8), was given by Danielssen and Boeck (9) in 1842. Since it is not possible to find definite evidence for leprosy in texts until the nineteenth century, much historical "leprosy" may, in fact, be vitiligo. The Indian Manu Smirti (200 B.C.) describes sweta kushtha, meaning "white disease"-skin lesions that probably indicated vitiligo (3). It also reports on the lack of respect given people affected by svilra, the loss of skin color. People who had stolen clothing in an earlier life would be reincarnated as people affected by svilra. It appears that skin disorders were reported much earlier in Chinese literature, but descriptions remain rather vague until 600 A.D., when Dohi wrote about Pin-yiial1-hon-lul1, probably today's leprosy (7). In the book Al11arkosha (600 A.D.) the term svitra was used as a synonym for padasphola (flowers on the legs), tlllakpuspi (flowers on the skin), and sidhl71ali (spreading whiteness). In ancient Arabic texts, white skin was expressed using the term baras and others like bahak or bohak (3). The word baras is mentioned in the Koran regarding Jesus (Chap.3, vA8 and Chap.S, v.1 09). The Koran states that' In accord with the will of God, Jesus was able to cure those affected by 'baras'" (10). Patchy skin lesions, likely of leprous nature, were the most important skin diseases mentioned in texts from the early European medical schools up to the end of the fifteenth century. At that time a new important differential diagnosis arose in leukoderma syphiliticum, because the number of lepers decreased and the "new" lues venera, later known as syphilis, began to spread over Europe.

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BIBLICAL REFERENCES

The Bible refers to many different skin conditions using the Hebrew word Zara' at. Some of these were interpreted as signifying sin, representing a punishment sent by God. The biblical term indicates "white spots," but does not necessarily denote vitiligo (7). The roots of the controversy over various interpretations of Zara' at can be found around 25GB.C., when Ptolomy II ordered the translation of the Bible into Greek in order to make it accessible to a grea ter number of people. Referring to persons declared unclean by reason of Zara' at, the scholars of the Septuagint used the term "leprosy," which does not correspond to modern dermatological terminology. At the time, theologians also proposed the term "psoriasis" as a synonym for conditions involving whitening of the skin. The term seems useful as an alternative to the biblical concept of leprosy, as it does not imply the idea of a moral sin and indicates simply any "skin condition." For many years researchers have been interested in the true nature of the biblical "white spots," and many have established that not all references are to leprosy. Rather, they represent a variety of skin conditions and sometimes also mean vitiligo (7). "MODERN" DEFINITIONS

The term vitiligo was used for the first time by A. Cornelius Celsus in his classic text De medicina, which today, after careful examination of its contents and biographical notes, is thought to date from around 25 B.C. (11). Regarding the roots of the term, there seems to be some difference of opinion among experts (12-14). ANCIENT TREATMENTS

In Egypt the use of Ammi majus Linn. for the treatment of vitiligo dates back to the time of Ibn El Bitar in the thirteenth century (15). This plant was mentioned in his book Mofradat Al Adwiya under the name of aatrillal, a Berberian word meaning bird foot. In Egypt it is known as Regl El Ghorab, Gazar El Shy tan, and El Khella El Shytani. It was called Al11mi by Gallen, and in the time of Charles the Great it became Ameum (16). Ibn El Bitar stated that the plant resembled apium, but its flowers were white rather than yellow; its fruit resembled those of celery and khellah (Al11ni visnaga Linn.) but are longer, narrower, and have a pungent and slightly bitter flavor. Ibn El Bitar mentioned that the fruit of this plant was used in the treatment of baras (vitiligo or leukoderma). He also mentioned that the first people to recognize the usefulness of the drug were a Berber tribe in northwest Africa called the Ben Shoeib. This tribe sold the drug to vitiligo sufferers but kept its nature

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secret. El Sherif, quoted by Abou Shady (16), maintained that the drug, mixed with dried "snake skin" and Ruta leaves, powdered and administered in doses of 5 derhum for 5 successive days, would cure bohak, especially if the patient remains in the sun until he sweats. Aatril/a/, a yellowish-brown powder, was sold by a few native Egyptian herbalists as a remedy for vitiligo. It was given in daily doses of 4-12 g, followed by exposure of the affected patches to the sun until blisters formed. Microscopic examination of the commercial powder Aatril/al revealed that it is identical to the powdered seeds of Ammi majus Linn. Fahmy and Abou Shady in 1947 isolated three crystalline compounds from the powder, which were named Al11moidina (8-metoxipsoralene), Aml11idina (8-isoamilinoxipsoralene), and Maiudina or Bergapten (5-metoxipsoralene) (17).

VITILIGO IN THE NINETEENTH CENTURY Toward the end of the nineteenth century, when skin diseases were still presented in alphabetical order in many dermatology textbooks, vitiligo was defined as a pigmentary dystrophy. Louis Brocq (1856-1928) called the lack of pigmentation (achromy) in vitiliginous lesions combined with an increase in pigmentation (hyperchromy) at the periphery of the lesions "dyschromy" ( 18). Moritz Kaposi (1837-1902) was among the first to describe the histopathological features of vitiligo. He stated that the only anatomical change in vitiliginous skin is the lack of pigment granules in deep rete cells. An increase in pigmentation may be found in the surrounding lesions (19). Obscure etiological mechanisms, such as emotional stress or other traumatic factors, may trigger the eruption of vitiligo, and a connection with the nervous system seemed obvious (18,20). At the end of the nineteenth century various approaches were developed in the treatment of vitiligo. Systematic application of bromides or iodides (also valerianates) of mercury, antimony, and arsenic showed no evidence of effectiveness. Ernest Besnier (1831-1909) recommended subcutaneous injections of pilocarpine and saline or bromoiodic baths. Various topical mixtures of croton oil, iodine, sublimate, and naphthol have been used without useful therapeutic results (18,20). Casual use of the terms vitiligo and leukoderma introduced confusion into the scientific literature of the last century and is still felt to this day. Beigel in his 1864 memoir reserved the term vitiligo for those cases in which alteration of the structure and loss of skin pigmentation are observed (21). This obviously is not the way vitiligo is diagnosed today. Pearson et aI., at the beginning of the twentieth century, used the term leukoderma to designate a disease that seemed to be vitiligo (22).

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VITILIGO AND SELF-IMAGE

Vitiligo today often causes social embarrassment (more serious in countries where dark skin is predominant), and the peeled physical appearance of the hypopigmented lesions is often an element in serious psychological disturbances, even among light-skinned people (Fig. 1). Although vitiligo is not a serious illness on a biological level, it becomes one at the psychosomatic level: The anthropological and cultural difficulties implied are such that they create inevitable psychological and sometime psychiatric repercussions (Fig. 2). The skin and the central nervous system, as we know, have a common origin at the ectodermic level, and this common origin justifies the interest in the skin of psychologists, psychiatrists, and neurologists. Even anthropolo-

FIGURE 1 Vitiligo major in an Eritrean patient. MUltiple depigmented macules confluent in large achromic lesions spread to cover almost the entire body.

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FIGURE 2 Vitiligo major in an Ethiopian child. Such depigmentation in dark-skinned individuals can lead to serious identity and cultural problems and to difficulties in their social inclusion.

gists have shown great interest when faced with some skin conditions where cultural and environmental aspects present a peculiar role. The connection between the skin and self-image begins very early in our ontogenesis. In fact, as Anna Freud tells us, at the beginning of life, being hugged, caressed, and blandished make the various parts of the child's body sensitive. It helps the child construct a healthy body image and makes his or her narcissistic libido grow, and it simultaneously promotes the love object by consolidating the bond between mother and child (23). The skin is important in relation to the development of the body-self and the mental-self because of its fundamental tactile function. Among its many other functions, there is a so-called "dermo-optical" function, defined by the psychoanalyst Didier

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Anzieu (24). This function presumes that the skin has some visual function other than being visible. It is to this, the visibility of the skin, that cosmetology is related. Another function of the skin is thought to be that it inscribes "sensorial traces," a sort of pictogram (25). Dermato-cosmetologists are familiar with the painting of faces and bodies in various anthropological-cultural settings, from prehistoric times to now, as if the skin were a mirror that reflects reality (26). The skin constitutes an interface between us and the exterior world and can be considered a sort of envelope that limits and contains our body and conditions our exchanges between interior and exterior. Furthermore, if represents the visible self and the esthetic self. Due to its visibility, the skin may be the site where conflicts regarding exhibitionism are expressed. PSYCHO-ANTHROPOLOGICAL IMPLICATIONS OF VITILIGO

The importance of psychic factors in the etiopathogenesis of vitiligo is by now largely recognized, and the dermatologist, as Panconesi states, should always use a psychosomatic method that takes into account important relations between acute and chronic emotional situations and the appearance or worsening of the skin lesions of vitiligo (27). The skin, because of its bio-physiological complexity, is analogous on an organic level to the structural complexity of the "r" on the psychic plane. Furthermore, it is the multiplicity of its functions that aJ]ows it to express itself as the element of separation and delineation of the "1" and communicate with the exterior world (28). The skin represents at the same time, as the organ that contains the body, an element of separation from and means of communication with the outside world (29). The consequences of vitiligo in the social and working life of the patient are grave, especially in people working in professional fields in which the hands and face represent a tool for interaction with the public. The disease may also lead to manifestations of depression and anxiety that cause difficulties in interpersonal relations (30). Although vitiligo occurs everywhere and can affect all populations, it represents a particularly serious problem for those people whose skin is naturally dark (skin phototypes V and VI) due to the contrast produced by the white patches. Even for patients with lighter skin who tan easily (phototype IV), the disease may be perceived as disfiguring and constitute a true medical tragedy and a simple esthetic problem. For thi reason, although vitiligo is pain-free and not associated with kin flaking, as is psoriasis, it can be a devastating pathology. The contrast between the normal skin color and the white patches can intrude into daily life, marriage, family, friendships, and even the workplace, and the fact that these patients suffer from inferiority

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complexes, become aggressive, feel shame, and sometimes become isolated and resentful is not surprising (3]). The presence of hypopigmented lesions, particularly in dark-skinned people, may produce psychic tensions and existential difficulties because of the possibility of being mistaken for a person with leprosy. It is interesting to read the personal correspondence of Dr. Marian Levai, an American physician who works in India, reported by Mosher et al. (32): In South India where the old Dravidian language of Tamil is spoken, the condition is known as ven kushtam, "white leprosy." It is often confused with leprosy, which is very prevalent in this area. In brown skin, leprosy starts as hypopigmented mactlles that may, in later stages, become thickened, insensitive to touch and eventually depigmented. Vitiligo, of course, shows only depigmentation but one individual may show both hypopigmented and depigmented macules in different parts of his body at the same time. The confusion of vitiligo with leprosy in the public mind means that it is difficult for young men or women to obtain jobs, especially when involvement of the face or other exposed areas makes the disease so conspicuous.... In India, women can easily retreat into the seclusion of the home; one of my patients did not even want to be seen in the hospital and requested treatment at home. Men, however, are expected to maintain contact with a hostile and suspicious society. In my experience, psychologic tension, nervousness and depression because of vitiligo seem to be more apparent in the educated city dweller. The fact that vitiligo is a long-lasting disease increases the risk of it becoming a major fact in the daily life of patients and families. Lesions on the genitals cause great anguish to those afflicted. In fact, many young patients with vitiligo on the genitals think they must be repugnant to their partners. The involvement of the hair bulbs (hair is chalk white) also carries a heavy weight of embarrassment and preoccupation (31).

CONCLUSION Ginsburg highlights the fact that, when considerating the psychological impact of a skin disease such as vitiligo, is is necessary to remember that the patient's life situation, including the social support network, consisting of family, friends coworkers, and neighbors (but also people known through their professional capacity, such as physicians or teachers) provides emotional warmth and support, as well as practical help, as with child care or financial assistance (33,34). If the patient has a devoted family and friends, he

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or she will probably be able to weather the storm of emotions and practical problems generated by this chronic skin condition much better than if this network is weak or nonexistent. The attitude of intimates, the people closest to the patient, is among the most important factors that determine the impact of any skin disease, including vitiligo (31).

REFERENCES 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

Ebbell B. The Ebers Papyrus. Copenhagen: Levin and Munksgaard, 1937 Nair BKH. Vitiligo-a retrospect. Int J Dermatol 1978; 17:755-757. Koranne RV, Sachdeva KG. Vitiligo. Int J DermatoI 1966; 93:744-753. Whitney WD. Atharva-Veda Samhita (Translation and Notes). Harvard Oriental Series 1905. Vol. 7. Cambridge, MA: Lanman, Harvard University Press, 1905. Singh G, et al. Vitiligo in ancient Indian medicine. Arch Dermatol 1974; 109:913. Fitzpatrick TB, Pathak MA. Historical aspects of methoxsalen and other furocoumarins. J. Invest. Dermatol. 1959; 32:229. Goldman L, Moraites RS, Kitzmiller KW. White spots in biblical times. Arch Dermatol 1966; 93:744-753. Kaposi M. On albinismus and leucoderma. In: Hebra F, Kaposi M, eds. On Diseases of the Skin. Vol. III. London: New Sydenham Society, 1874: 170-177. Goldman, et al. White spots in biblical times. Arch Dermatol 1966; 93:744-753. EI Mofty AM. Vitiligo and Psoralens. New York: Pergamon, 1968. Fitzpatrick TB. Hypomelanosis. South Med J 1964; 57:995-1005. Ortonne JP, Mosher DB, Fitzpatrick DB, eds. Vitiligo and other hypomelanoses of hair and skin. New York: Plenum, 1983:129-310. Nordlund JJ. Vitiligon. In: Thiel'S BH, Dobson RL, eds. Pathogenesis of Skin Disease. New York: Churchill Livingstone, 1986:99. Sutton RL. On definition of vitiligo (lett). Arch Dermatol 1965; 91:288. Ibn El-Bitar. Mofradat Al Adwiya. I. Egyptian Government Press, 1877:4. (In Arabic.) Abou Shady HAA. Ammi majus Linn Thesis for Master of Pharmacy. Fac Med Cairo University, 1948. Fahmy IR. AboLi Shady HAA. Pharmacognostical study and isolation of crystalline constituent, ammoidin. J Pharm Pharmac 1948; 20:281. Brocq L, ed. Traitement des maladies de la peau. Paris: Doin, 1892:853-855. Kaposi M, ed. Pathologie und Therapie del' Hautkrankheiten. 5th ed. Berlin: Urban Lind Schwarzenberg, 1899:624,703-707. Neumann I, ed. Lehrbuch del' Hautkrankheiten. Vienna: Braumi.iller, 1880:438. Beigel H. Beitrag zur Geschichte Lind Pathologie des Albinismus partialis und del' Vitiligo. Nova Acta Akad, K K Leopold Karolin, 1864. Pearson K, et al. A Monograph on Albinism in Man: Drapers' Company Research Memoirs. London: DLilau, 1911.

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31. 32.

33. 34.

25

Panconesi E, Cossidente, Giorgini S, et al. A psychosomatic approch to dermatologic cosmetology. lnt J Dermatol 1983; 22:449-454. Anzieu D. Le Moi-Peau. Paris: Borda, 1985:1-180. Castoriadis-Aulaguier P. La violence de I'interpretation. Paris: P.U.F., 1975:1157. Ovidio.l cosmetici delle donne. A cura di Rosati G. Venice: Marsilio, 1985: 1-78. Panconesi E. Stress and skin diseases: psychosomatic dermatology. Clin Dermato11984; 2:1-272. Obermayer ME. Psychocutaneous Medicine. Springfield, IL: Charles C Thomas, 1955 Pancheri P. Trattato di Medicina Psicosomatica. Vol. I. Firenze: USES Edizioni Scientifiche, 1984:151-179. LePooIIC, Das PK, Van Den Wijngaard R, Bos JD, WesterhofW. Review of the etiopathomechanisll1 of vitiligo: a convergence theory. Exp Dermatol 1993; 2(4)145-153. Hautmann G, Panconesi E. Vitiligo: a psychologically influenced and Influencing Disease. Clin Dermatol 1997; 15:879-890 Mosher D, Fitzpatrick T, Ortonne J, Hori Y. Hypomelanoses and hypermelanoses. In: Freedberg I, et aI., eds. Fitzpatrick's Dermatology in General Medicine. New York: McGraw-Hill, 1999:949. Ginsburg TH. The psychological impact of skin disease: an overview. Dermatol C1in 1966; 14:473-484. Greenblatt M, Becerna RM, Sorafetinides EA. Social networks and mental health: an overview. Am J Psychiatry 1982; 139:977-983.

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3 Vitiligo: Epidemiology Luigi Naldi U.O. Dermatologia, Ospedali Riuniti di Bergamo, Bergamo, Italy

The main objective of epidemiology is to find a means to prevent disease onset (primary prevention) and to restore health once a disease has developed (secondary prevention). Others are to evaluate and optimize health care. There are limited data on vitiligo to help address these objectives. DESCRIPTIVE EPIDEMIOLOGY

The usual measures used to describe the distribution of a disease in a given population are incidence and prevalence. Incidence refers to those cases newly developed in a population over a given time period. Prevalence refers to those cases that are present in a given population, irrespective of their onset, at a point in time (point prevalence) or over a longer period of time (period prevalence). Prevalence depends on incidence and on the average duration of the disease in the population. If a disease persists without a cure for a long time, it may give rise to significant prevalence rates even if its incidence rates are remarkably low. It should be noted that incidence estimates require an onset for the disease to be precisely defined. For many chronic disorders characterized by subtle prodromal signs and symptoms like vitiligo, such an onset may be difficult to establish. Data on the prevalence of vitiligo in the general population are limited. Point prevalence estimates have been obtained by the First Health and Nutrition Examination Survey (HANES I study) organized by the National Institutes of Health during the period 1971-1974 in the United States and Copyrighted Material

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recruiting a representative sample of7514 people aged 1-74 years (1). Vitiligo prevalence was estimated at 4.9 cases per 1000 people (3.8 cases per 1000 males, 6.2 cases per 1000 females). In the study, the prevalence of vitiligo increased from 0.6 case per 1000 at age 1-5 years to 13.6 cases per 1000 after age 65. A point prevalence estimate of 3.8 cases per 1000 was obtained in a study conducted on the Bornholm Island in Denmark (2). These estimates are lower than the I % commonly reported. To the best of this author's knowledge, no estimates of incidence rates are available. Based on the prevalence rates mentioned above and considering that the disease tends to persist over time, it seems reasonable to foresee incidence rates in the order of a few new cases per 100,000 people per year. The median age at onset as estimated in a sample of patient members of the U.K. Vitiligo Society, was about 13 years (3). In a study of 160 families with at least one member suffering from vitiligo, the mean age at onset was estimated at about 19 years among males and 24 years among females (4). Vitiligo is an important cause of disability, especially in young people. In spite of not being one of the ten most frequently reported skin disorders in the HANES I study, vitiligo ranked fifth in the study among the diseases that were more frequently reported as a reason for concern in the age group 25-34 years. ANALYTICAL EPIDEMIOLOGY The main purpose of analytical studies, including case-control and cohort studies, is to identify factors that may influence the onset of a disease. Their results are expressed in terms of relative risks or odds ratios. The relative risk is the ratio of disease incidence among those exposed to a purported causal factor (risk factor) to the incidence among the unexposed. When derived from case-control studies, odds ratios provide an estimate of the relative risk. Causation of vitiligo is a complex phenomenon, involving both genetic and environmental factors. There are largely divergent estimates of the proportion of individuals with vitiligo reporting a family history of the disease. Reasons for such variations may include heterogeneous criteria to define cases and different modalities to collect a family history of the disease. It should be noted, for example, that it is quite plausible that a history of vitiligo in one family member may influence the request of consultation for another family member (ascertainment bias). Unfortunately, there are no data concerning vitiligo patients sampled from the general population. In most studies, about 20% of people with vitiligo report a first-degree relative as suffering from vitiligo. In a family study, children of the proband had a 1.7-fold increased risk of developing vitiligo as compared with other family members (4). In the same study, the risk of vitiligo as compared with the general population was, respectively, 7-fold higher among the parents of the proband, 12-fold higher

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among brothers and sisters, and 36-fold higher among the proband's children. The family aggregation of vitiligo does not indicate simple mendel ian transmission. It has been proposed that several recessive alleles at different autosomal loci should interact in an epistatic way to develop vitiligo. A number of studies on the association of vitiligo with major histocompatibility antigens (HLA) have been conducted, but they are inconclusive, suggesting, at most, the existence of heterogeneous associations in different ethnic groups: a positive association with HLA-DR4 and a negative one with DR3 in blacks, a positive association with BW-35 among Yemenite Jews, a positive association with DR6 in the Dutch population, and a positive association with the rare DRW 12 antigen in the German population. We are not aware of any formal analytical study assessing the potential role of environmental factors in the development of vitiligo. Interestingly, vitiligo has been associated with a number of pathological conditions which, in many instances, are immune-related diseases (Table I). It should be noted that, even if no confirmatory epidemiological data are available, the disease onset is frequently associated with stressful life events. Finally, it is common clinical experience to observe the development of new vitiligo lesions in the skin site of a physical trauma (Koebner phenomenon).

CLINICAL EPIDEMIOLOGY: NATURAL HISTORY AND PROGNOSIS There are limited data concerning the natural history and prognosis of vitiligo. A prognostic study should be based on a representative sample of affected individuals followed for a sufficiently long period of time, loss to follow-up should be reduced to a minimum, outcome measures should be clearly defined at the beginning of the study, and adequate analytical methods should employed (survival analysis, Cox models).

TABLE 1

Pathological Conditions Associated with Vitiligo

Alopecia areata Pernicious anemia IgA selective defect Thyroid diseases (frequently associated with autoantibodies) Addison's disease Congenital melanocytic nevi MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke episodes syndrome)

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Segmental vitiligo, which in many series accounts for 10-20% of the affected individuals, have an earlier onset and a more rapid evolution as compared with generalized vitiligo (5). Moreover, segmental vitiligo is rarely associated with immune-related disorders, the Koebner phenomenon, or stressful life events. Once it appears, vitiligo follows a chronic course. In segmental vitiligo, disease activity seems usually to cease with the extension of the disease to the involved dermatome within one year, while new lesions can appear lifelong in generalized vitiligo. In a cohort study involving 61 patients, the Koebner phenomenon, experimentally induced, had a prognostic value correlated with disease activity (6). According to a survey conducted on a large sample of patients members of the U.K. Vitiligo Society, only about 14% of patients experienced a spontaneous improvement of their disease at some point during their life. Patients with a more limited extension of the disease more frequently reported spontaneous improvement compared to patients with more extensive disease (3). Vitiligo has a remarkable impact on the patient's quality of life, wellbeing, and social life (7). It has been documented that an intervention providing psychological support according to a cognitive-behavioral paradigm may have an impact on the disease burden and severity (8). Few data are available concerning factors that may influence therapeutic choices and preferences of patients and physicians. In the already mentioned survey involving members of the U.K. Vitiligo Society, about 40% of male patients and 70% of females reported a regular use of camouflage, while only about 20% of all patients had undertaken a medical or surgical procedures at the same stage of their disease. A survey of 332 Dutch dermatologists documented that only 16% of all dermatologists regularly offered their vitiligo patients an active treatment (9). There was no consensus on the active treatment of choice. Such a situation may be common to other countries. In Holland it has been documented that the development and dissemination of clinical guidelines based on the results of three systematic reviews resulted in better agreement between dermatologists on treatment strategies. These systematic reviews indicated that topical high-potency steroids and narrow-band ultraviolet B light irradiation were the treatment modalities supported by the best available evidence for, respectively, localized vitiligo and generalized vitiligo (10). SUMMARY

Vitiligo is a relatively common skin disease affecting 3-5 individuals per 1000 people. The causative model probably involves genetic-environmental interaction, but the environmental factors are largely unknown. Epidemiological research may contribute to a better understanding of the etiological and

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prognostic factors and aid in the evaluation of the long-term outcome of the disease, improving its management.

REFERENCES I.

2. 3. 4. 5. 6.

7. 8.

9.

10.

Johnson M-LT, Roberts J. Skin conditions and related need for medical care among person 1-74 years. U.S. Department of Health, Education and Welfare Publication No. (PHS) 79-1660, Hyattsville, MD, 1978. Howitz J, Brodthagen H, Schwartz M, et al. Prevalence of vitiligo. Arch Dermatol 1977; 113:47-52. Agarwal G. Vitiligo: an under-estimated problem. Fam Pract 1998; 15:S19S23 Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol 1993; 129:994-998. Koga M, Tango T. Clinical features and course of type A and type B vitiligo. Br J Dermatol 1988; 118:223-228. Njoo MD, Das PK, Bos JD, Westerhof W. Association of the Koebner phenomenon with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol 1999; 135:407-413. Kent G, Al'Abadie M. Psychologic effects of vitiligo: a critical incident analysis. J Am Acad Dermatol 1996; 35:895-898. Papadopoulos L, Bor R, Legg C. Coping with disfiguring effects of vitiligo: a preliminary investigation into the effects of cognitive-behavioural therapy. Br J Med Psychol 1999; 72:383-896. Njoo MD, Bossuyt PM, Westerhof W. Management of vitiligo. Results of a questionnaire among dermatologists in the Netherlands. lnt J Dermatol 1999; 38:866-872 Njoo MD, Westerhof W, Bos JD, Bossuyt PM. The development of guidelines for the treatment of vitiligo. Arch Dermatol 1999; 135:1514-1521.

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4 Biology of Hypopigmentation Giovanni Menchini and Torello Lotti University of Florence, Florence, Italy

Evridiki Tsoureli-Nikita University of Siena, Siena, Italy

Jana Hercogova Charles University, Prague, Czech Republic

Jean Paul Ortonne Hopital L'Archet 2, Nice, France

The substance responsible for skin color is melanin, a pigment produced by melanocytes and transferred to surrounding keratinocytes. Absence or loss of pigmentation of the skin is due to three main etiological factors: an absence/ loss of melanocytes, a deficit of melanin formation, or no melanocytic etiology (Table I). The most frequent diseases characterized by white patches are shown in Table 2, along with the related etio-pathogenesis of hypopigmentation. CONGENITAL ALTERATION OF PIGMENTATION

The diseases characterized by congenital alteration of pigmentation are normally due to a genetic defect that alters the melanin synthesis/distribution or that regulates the multistep process of commitment of neural crest cells to a differentiated cell type (primarily the melanocyte) or melanosome biology (transport, transfer, biogenesis, melanization) (Tables 3-6) (44). Of the congenital alterations in pigmentation, only nevus anemicus is not characterized Copyrighted Material

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Co)

.l:-

TABLE

1

Etiological Factors of Hypopigmentary Disorders

Etiological factors ()

Chemical

0

<::l

~

'§:

Melanocytopenic (melanocytes decreased or absent) Catechols Monobenzylether of hydroquinone Para-substituted phenols Sulfhydryls

CD

0..

s: Q)

CD

~

Endocrine

Genetic

Inflammatory

Ataxia telangiectasia Piebaldism Vitiligo (Alezzandrini's syndrome, idiopathic, Vogt-Koyanagi-Harada syndrome) Waardenburg's syndrome Woolf's syndrome Xeroderma pigmentosum Ziprkowski-Margolis syndrome Actinic reticuloid Mycosis fungoides

Melanopenic (melanin decreased or absent) Arsenicals Chloroquin Glucocorticoids Hydroxychloroquino Hydroquinone Mercaptoethylamines Retinoids Addison's disease Hypopituitarism Hypothyroidism Albinism (Types I-III oculocutaneous albinism)

Nonmelanocytic (no melanin defect)

Nevus anemicus

s: (1)

::J (')

:T ::J

Leprosy Pityriasis alba

Woronoff's ring

(1)

~

Onchocerciasis Pityriasis lichenoides chronica Pinta Yaws

Metabolic

Para-neoplastic Nutritional

Leukoderma acquisitum centrifugum Vitamin B 12 deficiency

~

Physical

Burns (ionizing, thermal, UV) Trauma

~

Miscellaneous

Alopecia areata Scleroderma

()

.g ~

'§: CD

0..

CD

CJ

o'

Postinflammatory (OLE, eczema, psoriasis) Post-Kala-Azar Sarcoidosis Syphilis Tinea versicolor Alpert's syndrome Chromosomal 5p defect Osteopathic striae Prolidase deficiency Melanoma (Halo) Chronic protein loss Kwashiorkor Malabsorption Nephrosis Ulcerative colitis Postdermabrasion Postlaser Canities Horner's syndrome Idiopathic guttate Hypomelanosis Vagabond's leukoderma

o

(Q

'<

-

o

::r

'< "0

o

"0

cO' 3(1)

-o-' :;, I II

:;,

Anemia Edema

Co)

U1

36 TABLE

Menchini et al.

2

Dermatological Diseases Characterized by White Patches

Disease

Etio-pathogenesis

Congenital Tuberous sclerosis

Oculocutaneous albinism } types 1, 2, and 3 Ocular albinism Chediak-Higashi syndrome Hermansky-Pudlak syndrome Waardenburg's syndromes types 1,2 & 3 Apert syndrome Pfeiffer syndrome Jackson-Weiss syndrome Crouzon syndrome Hirschsprung syndrome Piebaldism Hypomelanosis of Ito

Nevus-anemicus

Non-congenital Tinea versicolor

Idiopathic guttate hypomelanosis

The inheritance is autosomal dominant; the hypopigmented ash-leaf macule shows normal melanocyte numbers with decreased pigmentation. Electron microscopy shows smaller melanosomes with defective melanization. Mutations in genes that regulate the multistep process of melanin synthesis and distribution by the melanocyte are the basis for these diseases. Failure of melanocytes in the skin, eyes, and/or ears to become completely or partially established in their target sites during embryogenesis.

Genetic unidentified mosaicism; the number of melanocytes is decreased, and the amount of melanin in hypopigmented areas is decreased. Results from a congenital anomaly in which vascular hypersensitivity is localized to catecholamines. The melanocytes are preserved and regularly distributed. Skin lesions are either hypopigmented or hyperpigmented. In patients with hypopigmentation, tyrosinase inhibitors competitively inhibit an enzyme necessary for melanocyte pigment formation. In hyperpigmented macules, there is enlargement of melanosomes made by melanocytes in the basal layer of the epidermis. The exact cause is not agreed upon; however, it is hypothesized that ultraviolet light plays an important role. Significantly less dopa oxidase-positive, KIT +, and melanocytes are seen in the lesions . ht <;QiTlPtared,to normal skin.

C opyng ea lVIalena

Biology of Hypopigmentation TABLE

2

37

Continued

Disease

Etio-pathogenesis

Pityriasis alba

The cause is unknown. On electron microscopy, reduced numbers of active melanocytes and a decrease in number and size of melanosomes are seen in affected skin. Unknown. Autoimmune processes and/or hydrogen peroxide accumulation are the most probable causes.

Vitiligo

by a genetic defect related to melanocyte. The congenital hypopigmentary diseases that result in one or more defects in the production of melanin due to dysfunction of melanocytes in the skin, eyes, and/or ears are the following: oculocutaneous albinism (OCA) types 1,2, and 3; ocular albinism (OA) (I); Chediak-Higashi syndrome (CHS); and Hermansky-Pudlak syndrome (HPS). These diseases all present with a generalized complete or partial loss of pigmentation of the skin and hair (Fig. lc). Mutations in genes that regulate the multistep process of melanin synthesis and distribution by the melanocyte are the basis for these diseases: OCA type I results from mutations in the tyrosinase gene, which maps to human chromosome Ilq 14-2 and is inherited as an autosomal recessive trait. OCA type 2 (2) results from mutation in the P gene, which maps to human chromosome 15qll-13 and is inherited as an autosomal recessive trait. The function of the P protein in melanin synthesis has yet to be determined, but it is probably related to the altered melanosome biology.

TABLE

3

Disorders of Melanosome Transport and Transfer

Human disease

Mouse model

Griscelli syndrome GS1

Rab27A

GS2

Myosin Va

Gene mutated

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Protein function Movement of melanosomes CTL granule secretion Movement of melanosomes

38

Menchini et al.

TABLE

4

Disorders of Melanosome Biogenesis Mouse model

Gene mutated

Protein function

Hermansky-Pudlak syndrome (HPS) HPS1

Pale ear

Human type 1: HPS1

HPS2

Pearl

AP3B1

HPS3

Cocoa

HPS4

Light ear

Chediak-Higashi syndrome

Beige

Human type 3: HPS3 Human type 4: HPS4 CHS1

Trafficking of melanocyte-specific proteins Lysosomes trafficking of membrane proteins ?

Human disease

Similarity with HPS1 Membrane protein

OCA type 3 results from mutation in the tyrosinase-related protein-l (TRP-I) gene, which maps to human chromosome 9p23 and is inherited as an autosomal recessive trait. These mutations provoke both alterations in melanosome maturations and reduction in melanocyte proliferation. OA, CHS, and HPS genes are known (Xp22.3-22.2, Iq42-43, and 1Oq23.l-23.3, respectively) but although they encode proteins of still unknown functions, they seem to be related to melanosome and Golgi melanocyte functions. Waardenburg's syndromes 1-3 and the Apert, Pfeiffer, Jackson-Weiss, and Crouzon syndromes (A, P, J-W, and C), Hirschsprung syndrome, and piebaldism (Fig. Id) are all characterized by the complete or partial absence of melanocytes in the skin and hair. Mutations in genes that regulate the multistep process of commitment of neural crest cells to a differentiated cell type (primarily the melanocyte) are the basis for these diseases. These mutations result in a failure of melanocytes to reach their normal destination in developing skin, hair, eyes, and ears during embryogenesis (3-7). Hypomelanosis ofHo (HI) is a syndrome with hypopigmented whorls of skin along the Blaschko lines described for the first time by Ito in 1952. HI appears to be the negative image of incontinentia pigmenti (IP). Chromosomal mosaicism and sporadic mutations are considered to be the causes, but the identification of a specific altered gene has not yet been confirmed. How-

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Oculocutaneous albinism type 1 (OCA1) Oculocutaneous albinism type 2 (OCA2) Oculocutaneous albinism type 3 (OCA3) Oculocutaneous albinism type 4 (OCM)

Mouse gene locus and mutant name

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Proposed functions

General structure

Tyr (albino)

Tyrosine (11 pi)

Limiting enzyme in melanin biosythesis

Type 1 transmembrane protein

P (pind-eyed dilute)

P (15q11.2-12)

Melanosome acidification

Tyrp (brown)

TRP1fTyrp1 (9p23)

Uw (underwhite)

MATP (15p)

Melanin biosynthesis/tyrosinase stabilization Membrane-associated transporter protein

Protein containing 12 transmembrane receptor Type 1 transmembrane protein

III

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TABLE

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Disorders of Melanocyte Development

Human disease ()

Mouse model

Protein Kit tyrosine kinase

Melanocyte migration/development

PAX3 (2q35)

Pax3 transcription factor

Microphthalmia

MITF (3p12-14)

MITF transcription factor

Transcription factor/melanocyte survival Transcription factor/melanocyte survival

Sploch

PAX3 (3p12-14)

WS3

Dominant megacolon

SOX10 (22q13)

Pax3 transcription factor SRY-box containing gene 10

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EDN3 (20q13.2-13.9) EDNRB (13q22)

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Biology of Hypopigmentation

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FIGURE 1 (a) In normochromic healthy skin, some melanocytes synthesize and transfer melanin to keratinocytes, giving the normal color to the skin. (b) During vitiligo, loss of melanocytes results in areas of hypopigmented skin. (c) Albinism is characterized by a genetic defect that causes a partial or total deficit of melanin synthesis, while melanocytes are normally represented. (d) Piebaldism is characterized by a genetically produced amelanosis due to failure of melanocyte migration to the skin during embryogenesis.

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ever, some authors believe that IP and HI are distinct diseases with separate gene loci: Xp28 for IP and 9q33-ter, 15qll, Xpll, and Xp21.2 for HI (8). Nevus anemicus, described first by Vomer in 1906, is a congenital localized vascular anomaly that presents clinically as a hypopigmented macule or patch. This disorder is believed to be related to a localized hypersensitivity to catecholamines. Nevus anemicus is best termed as a "pharmacological nevus" resulting from increased vascular sensitivity to catecholamines (9). NONCONGENITAL ALTERATION OF PIGMENTATION

Tinea versicolor is a chronic superficial cutaneous fungal infection caused by M alassezia fUijur. Azelaic acid produced by the fungi through oxidation of unsaturated fatty acids of skin surface lipids competitively inhibits tyrosinase and, consequently, melanocyte.pigment formation (10). Idiopathic guttate hypomelanosis (IOH) is an acquired, benign leukoderma of unknown etiology. It is most commonly a complaint of middle-aged, light-skinned women, but is increasingly seen in both sexes and older darkskinned people with a history of chronic sun exposure. The exact cause is not agreed upon. It has been hypothesized that ultraviolet light plays an important role in the development of leukoderma (II). Pityriasis alba is a common hypopigmented dermatitis that occurs primarily in school-aged children. There can be numerous (up to 20 or more) hypopigmented macules, which are well defined and range in size from 1 to 4 cm. A minority of patients have erythema and pruritus that may occur prior to the appearance of the lesions. A subgroup of patients has associated atopy. In these subjects stigmata of that disorder may be found. Histological findings are nonspecific; however, findings may include a basal layer with irregular pigmentation, follicular plugging, edema between epithelial cells (i.e., spongiosis), or atrophy of the sebaceous glands. On electron microscopy, reduced numbers of active melanocytes and a decrease in the number and size of melanosomes are seen in affected skin (12). VITILIGO

Depigmentation resulting from vitiligo is due to loss of melanocytes (or melanosomes) for unknown reasons because of scarce and controversial findings in microscopic specimens (Fig. 1b). On the basis of serological, genetic, immunohistochemical, and metabolic findings, several pathogenetic mechanisms have been proposed (Table 7). In particular, two main areas of research are presently very promising and not reciprocally exclusive: the first examines melanocyte metabolic processes in tetrahydrobiopterin (BH 4 )impaired homeostasis to explain the presence of abnormal levels of 6-bioCopyrighted Material

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Vitiligo: Hypothesized Pathogenetic Mechanisms

TABLE 7

Pathogenetic hypothesis Autoimmune Hydrogen peroxide accumulation Viral Stress Infections Melatonin receptor dysfunction Impaired melanocyte proliferation Impaired melanocyte migration Neurological factors

pterin (via H 2 0 2 oxidation of BH 4 ), which is cytotoxic for melanocytes, and the second analyzes the autoimmune response promoted by cytotoxic CD8 + T lymphocytes versus melanocytes.

METABOLIC PATHOGENESIS OF VITILIGO During the last decade several metabolic abnormalities were demonstrated in the epidermis of subjects affected by vitiligo (14-17) (Table 8). On these findings are based the most important theories of nonimmune pathogenesis of vi tiligo. In particular, some authors have stressed the importance of increased sensitivity of melanocytes to peroxidative agents as a pathogenetic factor in

TABLE

8

Epidermal Metabolic Abnormalities in Vitiligo

Epidermal metabolic abnormalities 6BH 4 levels 7BH 4 levels PAH activity DH dehydratase activity H20 2 levels Catalase levels Phenylethanolamine-N-methyltransferase activity R>2-Adrenoceptors c-kit receptor Calcium uptake Norepinephrine levels

Copyrighted Material

Levels

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15 21 16 15 15 16 22 17 18

T

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1 i 1 1 T

25 29

Menchini et al.

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vitiligo (13). Although the causes of weakness in scavenging free radicals produced during melanin biosynthesis are still not clear, two theories are most convincing: epidermal accumulation of H 20 2 and abnormal expression of tyrosinase related protein-l (TRP-I). H2 0 2 Accumulation

To evaluate this interesting hypothesis recently stressed by Schallreuter et al. (14-17), it is necessary to focus on some peculiar aspects of melanogenesis and on the synthesis/recycling of 6(R)-L-erythro-S,6, 7,8-tetrahydrobiopterin (6BH 4 ). Both keratinocytes and melanocytes are capable of de novo synthesis, regulation, and recycling of 6BH 4 . During melanin synthesis, 6BH 4 is the cofactor for the hydroxylation of L-phenylalanine into L-tyrosine by phenylalanine hydroxylase (PAH). In this reaction 6BH 4 is reduced into 4a-OH-BH 4 (DH). The newly formed DH is dehydrated in to quinonoid dihydrobiopterin (q-BH2) by DH dehydratase. The 6BH 4 recycling is completed with the following NADH-dependent reduction. The rate-limiting step in the synthesis of 6BH 4 is represented by the levels of guanosine triphospate cyclohydrolase I (GTP-CHI) which uses GTP as a starting substrate. In vitiligo patches there is increased de novo synthesis and recycling of 6BH 4 with low DH dehydratase activities. The 6BH 4 accumulation with a low DH dehydratase activity causes abiogenic formation of 7-isomer (7BH 4), which severely inhibits the activity of both PAH and tyrosinase-fundamental enzymes that playa pivotal role in melanin biosynthesis (Fig. 2). The barely detectable activity of PAH is not sufficient to transform enough Lphenylalanine, which increases in vitiligo patches (20-22). Melanocyte accumulation of L-phenylalanine and 7BH 4 causes, thanks to decreased DH and PAH activities, the production of H 2 0 2 during a short circuit in the 6BH 4 recycling process. The high H 2 0 2 levels accumulated (IS) are cytotoxic, especially for melanocytes, because they can: (a) deactivate catalase (16), a catalyst for the conversion of hydrogen peroxide into water and oxygen (it has one of the highest turnover numbers for all known enzymes-40,000,000 molecules/s); (b) oxidize 6BH 4 and 7BH 4 into 6-biopterin, which is cytotoxic for melanocytes and induces activation of dendritic cells followed by selective T-cell proliferation (24). Nowadays, the first step, which leads to the impairment of DH activity or the accumulation of H 2 0 2 still remains obscure. Another important enzyme involved in the pathogenesis of vitiligo is thioredoxin (TR), which is an electron acceptor in 6BH 4 recycling and a reducing agent for hydrogen peroxide, superoxide anion, nitric oxide, and glutathione at pH 7.0 (26,27). Copyrighted Material

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First pathogenetic stressor (metabolic, immune, viral ?)

IL-2, IL-8. IL-6, TNF, IFN-y

FIGURE 2 Possible abnormal cellular and humoral immune mechanisms of vitiligo. Antigens produced by melanocytes (MC) can be recognized by antigen-specific immune effector cells including cytotoxic T cells, T helper cells, and B cells. After processing of antigens by antigen-presenting cells (APC), antigenic peptides are presented to the T-cell receptors of cytotoxic T lymphocytes in the context of major histocompatibility complex (MHC) class I molecules. Cognate help (via cytokine production) by antigen-specific T helper cells, in the context of antigenic peptides presented on MHC class II molecules, is required for a long-lasting cytotoxic T-cell response against melanocytes that can lead to their destruction. In humoral immunity, antigens are captured by the antigen-specific membrane immunoglobulins of B cells (LyB) . The production and secretion of antigen-specific antibodies by B cells are also dependent on cognate help (via cytokine production) by antigenspecific T helper cells (CD4+). Anti-melanocyte antibodies can destroy pigment cells by either antibody-dependent complement-mediated damage or antibodydependent cell-mediated cytotoxicity.

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The thioredoxin production in both keratinocyte and melanocytes is induced by UV-B irradiation. Even if this theory is proved by adequate laboratory tests and the H 2 0 2 removal is accompanied by some vitiligo patch repigmentation (25), several vitiligo clinical characteristics do not find any adequate explanation fitting within this theory. Abnormal Expression of TRP-1

The normal synthesis and distribution of melanin is a highly regulated process restricted to melanocytes and retinal pigment epithelium. A variety of pigment regulatory genes have been identified in the melanin biosynthesis pathway or localized to the melanosome. The rate-limiting enzyme in melanogenesis is tyrosinase, and the deposition of melanin in the melanosomal matrix may require TRP-l, TRP-2, and Pmel 17. These proteins and other melanocytic proteins are presently being used as targets for the immunotherapy of melanoma. In the setting of this immunotherapy of melanoma, vitiligo is a well-known and not unusual side effect. Mutation in the TRP-l protein is associated with oculocutaneous albinism type 3 in humans (26) and with brown pelage in the mouse (27). These mutations both provoke alterations in melanosome maturation and reduction in melanocyte proliferation, opening a new field of research in vitiligo pathogenesis. AUTOIMMUNE PATHOGENESIS

An autoimmune pathomechanism in vitiligo is supported by certain evidence: (a) vitiligo is associated with several autoimmune diseases (thyroiditis, diabetes, atrophic gastritis, etc.); (b) effective therapies in inducing repigmentation also have immunosuppressive effects (i.e., corticosteroids, ultraviolet radiation, cytotoxic drugs); (c) immunotherapies for melanoma often cause vitiligo patches; and (d) many vitiligo patients have abnormal serum levels of autoantibodies and autoreactive T cells against melanocyte antigens. Certain major histocompatibility complex (MHC) antigens, polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene, and mutations in the autoimmune regulator (AIRE) gene have all been associated with the development of autoimmune disorders like vitiligo (Table 9) (18,19,41). A recent study shows that on chromosome I there is a locus associated with susceptibility to autoimmunity and particularly to vitiligo (41). This hypothesis supposes that, in presumably genetically predisposed subjects, autoimmunity arises as a secondary phenomenon following melanocyte destruction resulting from other factors. Aberrant T-cell reactivity (genetically predisposed/

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Biology of Hypopigmentation TABLE 9

Immunological Abnormalities in Vitiligo Subjects

Immune system MHC Class III Peripheral T cells T-cells in vitiligo patches Cytokines

Macrophages

Vitiligo abnormalities C2 deficiency (28), C4 increased frequency of heterozygous (29) Circulating T cytotoxic lymphocytes specific for MelanA and tyrosinase (31,32) T cytotoxic lymphocytes specific for MeianA/MART1 (32) Granulocyte-macrophage colony-stimulating factor (GM-CSF), growth factor for melanocytes (21), is reduced in patients with active vitiligo (33,42) Increased numbers in perilesional skin (40)

induced) most likely arises and causes vitiligo after being stimulated by antigens from the released melanocytes due to their destruction by nonimmunological mechanisms (viral/bacterial infections melanocyte metabolic stress, physical/chemical skin injury, etc.) (Fig. 2). One of the most important antigens implicated in this function is MelanA, as recently stressed by Lang et al. (27).

Both cellular and humoral immunity are probably involved in the pathogenesis of vitiligo, even if the former is considered the most important and the first chronological aberration by the majority of experts in the world.

REFERENCES 1 2. 3.

4. 5.

6.

Amiel J, Watkin PM, Tassabehji M. Mutation of the MITF gene in albinismdeafness syndrome (Tietz syndrome). Clin Dysmorphol 1998; 7( I): 17-20. Boissy RE, Nordlund JJ. Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res 1997; 10(1-2):12-24. Giebel LB, Spritz RA. Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. Proc Natl Acad Sci USA 1991; 88( 19):8696-8699. Park WJ, Theda C, Maestri NE. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet 1995; 57(2):321-328. Park WJ, Meyers GA, Li X. Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet 1995; 4(7):1229-1233. Pulfenberger EG, Kauffman ER, Bolk S. Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet 1994; 3(8):1217-1225.

Copyrighted Material

48

Menchini et al.

7.

Read AP, Newton YE. Waardenburg syndrome. J Med Genet 1997; 34(8):656665. Ruggieri M, Pavone L Hypomelanosis of Ito: clinical syndrome or just phenotype? J Child Neurol 2000; 15(10):635-644. Ahkami RN, Schwartz RA. Nevus anemicus. Dermatology 1999; 198(4):327329 Sunenshine PJ, Schwartz RA, Janniger CK. Tinea versicolor. Int J Dermatol 1998; 37(9):648-655. Falabella R. Idiopathic guttate hypomelanosis. Dermatol Clin 1988; 6(2):241247. Galan EB, Janniger CK. Pityriasis alba. Cutis 1998; 61(1):11-13. Maresca Y, Roccella M, Roccella F, Camera E, Del G, Porto S, Passi P, Grammatico M. Increased sensitivity to perioxidative agents as a possible pathogenetic factor of melanocyte damage in vitiligo. J Invest Dermatol 1997; 109(3): 310-313. Schallreuter KU, Moore J, Wood JM. In vitro and in vivo evidence for hydrogen peroxide accumulation in the epidermis of patients with vitiligo and its successful removal by a UYB-activated pseudocatalase. J Invest Dennatol Symp Proc 1999; 4:91-96. Schallreuter KU, Moore J, Wood JM, Beazley WD, Peters EMJ, Maries LK, Behrens-Williams SC, Dummer R, Blau N, Thony B. Epidermal H 2 0 2 accumulation alters tetrahydrobiopterin recycling in vitiligo: identification of a general mechanism in regulation of all 6BH 4 -dependent processes? J Invest Dermatol 2001; 116(1):167-174. Schallreuter KU, Wodd JM, Berger J. Low catalase levels in the epidermis of patients with vitiligo. J Invest Dermatol 1991; 97(6):1081-1085. Schallreuter KU, Wodd JM, Pittelkow MR, Swanson NN, Steinkraus Y. Increased in vitro expression of beta2-adrenoceptors in differentiating lesional keratinocytes of vitiligo patients. Arch Dermatol Res 1993; 285:216-220. Norris A, Todd C, Graham A, Quinn AG, Thody AJ. The expression of the ckit receptor by epidermal melanocytes may be reduced in vitiligo. Br J Dermatol 1996; 134:299-306. Lang KS, Caroli CC, Muhm A, Wermet T, Moris A, Schittek B, KnaussScherwitz E, Stevanovic S, Rammensee HG, Garbe C. HLA-A2 restricted, melanocyte-specific CD8 + T lymphocytes detected in vitiligo patients are related to disease activity and are predominantly directed against MelanAjMARTI. J Invest Dermatol 2001; 116(6):891-897. Schallreuter KU, Wodd JM, Pittelkow MR. Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 1994; 263: 1444-1446. Schallreuter KU, Wodd JM, LemkeKR, Pittelkow MR, LindseyNJ, Gutlich M, Ziegler I. Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochem Biophys Acta 1994; 1226:181-192. Schallreuter KU, Zschiesche M, Wodd JM. In vivo evidence for compromised phenylalanine metabolism in vitiligo. Biochem Biophys Res Commun 1998; 243:395-399.

8. 9. 10. II. 12. 13.

14.

15.

16. 17.

18.

19.

20. 21.

22.

Copyrighted Material

Biology of Hypopigmentation

23. 24. 25.

26.

27.

28. 29. 30. 31. 32.

33.

34.

35.

36. 37. 38. 39. 40.

49

Aronoff S. Catalase: kinetics of photo-oxidation. Science 1965; 150:72-73. Rutau1t K, Alderman C, Chain BM, Katz DR. Reactive oxigen species activate human peripheral blood dendritic cells. Free Rad Bioi Med 1999; 26:232-238. Schallreuter KU, Wodd JM, Lemke KR, Levenig C. Treatment of vitiligo with a topical application of pseudocatalase and calcium in combination with short term UVB exposure: a case study on 33 patients. Dermatol 1995; 223-229. Boissy RE, Zhao H, Oetting WS, Austin LM, Wildenberg SC, Boissy YL, Zhao Y, Sturm RA, Hearing VJ, King RA, Nordlund JJ. Mutation in and lack of expression of tyrosinase-related protein-I (TRP-I) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as "OCA3." Am J Hum Genet 1996; 58(6):1 ]45-1156. Sarangarajan R, Zhao Y, Babcock G, Cornelius J, Lamoreux ML, Boissy RE. Mutant alleles at the brown locus encoding tyrosinase-related protein-l (TRPI) affect proliferation of mouse melanocytes in culture. Pigment Cell Res 2000; 13(5):337-344. Kahl LE, Atkinson JP. Autoimmune aspects of complement deficiency. Clin Aspects Autoimmunity 1988; 5:8-20. Venneker GT. Molecular heterogeneity of the fourth component of complement (C4) and its genes in vitiligo. J Invest Dermatol 1992; 99:853-858. Grimes PE. T cell profiles in vitiligo. J Am Acad Dermatol 1986; 14:] 96-201. Halder RM. Aberrations in T lymphocytes and natural killer cells in vitiligo: a flow cytometric study. J Am Acad Dermatol 1986; 14:733-737. Lang KS, Caroli CC, Muhm A, Wernet D, Moris A, Scittek B, KnaussScherwitz E, Stevanovic S, Rammensee HG, Garbe C. HLA-A2 restricted, melanocyes-specific CD8 + T lymphocytes detected in vitiligo patients are related to disease activity and are predominantly directed against MelanA/MARTI. J Invest Dermatol 2001; 116(6):891-897. Imokawa G. Granulocyte-macrophage colony stimulating factor is an intrinsic keratinocyte-derived growth factor for human melanocyte in UV A-induced melanosis. J Invest Dermatol 1992; 313:625-631. Yu HS. Alterations in IL-6, IL-8, GM-CSF, TNF-alpha and IFN-gamma release by peripheral mononuclear cells in patients with active vitiligo. J Invest Dermatol ]997; ]08:527-529 Amer ASJ. Selenocysteine incorporation and reactivity: studies of mammalian thioredoxin reductase. In: Proceedings of Cellular Implications of Redox Signalling February 18-21, Abano Terme, Padua, 200 I: 11. Koranne RV, Derm D, Sachdeva KG. Vitiligo. Int J Dermatol1988; 27:676-68]. Rook AJ, Wilkinson DS, Ebling FJ. Textbook of Dermatology. 5th ed. Oxford: Blackwell Scientific Publications, 1992: 1608-1611. Galadari E, Mehregan AH, Hashimoto K. Ultrastructural study of vitiligo. Int J Dermatol 1993; 32:269-271. Fitzpatrick TB, Eisen AZ, Wolff K. Dermatology in General Medicine. 4th ed. New York: McGraw-Hill, 1993:437--443. Van del' Wjngaard R. Local immune response in skin of generalized vitiligo patients. Lab Invest 2000; 80:1299-1309

Copyrighted Material

50

Menchini et al.

41.

Alkhateeb A, Stetler GL, Old W, Talbert J, Uhlhorn C, Taylor M, Fox A, Miller C, Dills DG, Ridgway Ee, Bennett DC, Fain PR, Spritz RA. Mapping of an autoimmunity susceptibility locus (AISJ) to chromosome Ip31.3-p32.2. Hum Mol Genet 2002; 11(6):661-667. Moretti S, Spallanzani A, Amato L, Hautmann G, Gallerani I, Fabiani M, Fabbri P. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002; 15(2):87-92. Bahadoran P, Ortonne JP, King RA, Oetting WS. Albinism. Dermatology in General Medicine. McGraw-Hill, 2003. In press. Ortonne JP, Bahadoran P, Fitzpatrick TB, Mosher DB, Hori Y. Hypomelanoses and hypermelanoses. Dermatology in General Medicine. McGraw-Hili, 2003. In press.

42.

43. 44.

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5 Disorders in Healthy Relatives of Vitiligo Patients

Abdel Monem EI Motty, Medhat A. EI Motty, and Samia M. Esmat Cairo University, Cairo, Egypt

FAMILY HISTORY OF VITILIGO A family history has been reported in 6.25-38% of vitiligo cases in different studies (I-II). About 20% of vitiligo patients have at least one first-degree relative with vitiligo (12). Children are at greatest risk, followed by sisters and brothers (siblings), parents and grandparents (I). A positive family history of vitiligo was reported in about II % in India (13) and Korea (14) compared to around 34% in the French West Indies (6) and Omani patients (15). No significant difference could be detected in the positivity of family history of vitiligo between children and adult cases (14,16).

ASSOCIATION OF VITILIGO WITH OTHER DISORDERS The first report of vitiligo in association with other disorders was that of Thomas Addison, who reported in 1855 the association of vitiligo with adrenal insufficiency (17). In his report of 13 cases of adrenal insufficiency, one case had vitiligo and another had halo nevus. This was followed by many studies that revealed the common association of vitiligo with Addison's disease (18). Vitiligo is now believed to be one of the most frequent autoimmune abnormalities accompanying Addison's disease (19), but it is a very rare sign of secondary adrenal insufficiency (20). Other autoimmune endo-

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crine diseases showed increased incidence with vitiligo. The increased incidence of adult-onset diabetes mellitus has been reported in vitiligo patients. In a study of 512 patients with this type of diabetes, 25 cases (4.9%) had vitiligo (21). A clinical association of vitiligo with juvenile diabetes could not be proven (22). However, reported cases of juvenile diabetes mellitus associated with vitiligo were suggested to have a genetic predisposition (23). Vitiligo is one of the important associations reported with pernicious anemia (24). Pernicious anemia had an incidence of 3.7% in vitiligo patients, which is 30 times higher than in the general population (25). An increased association of vitiligo with polyglandular dysfunction has been reported (26), where vitiligo might precede the glandular disorder by many years (27). Association with myasthenia gravis was also reported (28). Vitiligo is one of the common dermopathies associated with autoimmune thyroid disease (29-31). Among other organ-specific autoimmune diseases, a statistically significant association was observed by Schallreuter et a!. in thyroid disorders, while no others could be confirmed (32). The prevalence of malignant melanoma was found to be seven times more common in vitiligo patients than in the normal population (33). Many other associated autoimmune cutaneous disorders have been reported. These include alopecia areata (13,34), psoriasis (35), atopic dermatitis (13), dermatitis herpetiformis (DH) (36), and collagen diseases such as rheumatoid arthritis (37), lupus erythematosus (LE) (38,39), and scleroderma (40). Reports are also present on associations with other diseases involving the immune system, such as lymphomas (42), Sezary syndrome (43), and acquired immunodeficiency syndrome (AIDS) (44). A high prevalence of vitiligo in patients with lepromatous leprosy was also reported (44). Premature graying of hair is a common finding in vitiligo patients, while halo nevus occurs in 50% of cases (45). In a recent study on 1,436 patients, 2% had associated halo nevi, 1.4% had atopic dermatitis, 0.7% had bronchial asthma, 0.6% had diabetes, 0.5% had thyroid diseases, and 0.4% had alopecia areata (13). In a survey of two large patient groups by the Vitiligo Society in the United Kingdom and the National Vitiligo Foundation in the United States, which included 2,040 vitiligo patients, results revealed that the prevalence of nonvitiligo autoimmune disorders was greater among the U.S. group (43%) versus the U.K. group (21 %). Thyroid diseases comprised half of these associations. No correlation could be detected between the incidence of these disorders and the family history of vitiligo (46). It was found that autoimmune disorders occurred more frequently in patients with nonsegmental vitiligo than in those with segmental vitiligo (10,47), but Hann and Lee maintained that this does not prove that autoimmunity does not playa role in segmental vitiligo (48).

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Associated disorders were found to be less common in children with vitiligo compared to adults (14). This might reflect the normal increase of autoimmune disease that occurs with aging (7). Association of ocular, auditory, and meningeal involvement with vitiligo has been studied, as leptomeninges, inner ear, uveal tract, and retinal pigment all contain melanocytes (4). Asymptomatic iritis and uveitis were detected in 7% of cases, while discrete areas of pigment loss on fundus examination were detected in 30-40% of cases (49). An association of deafness with vitiligo has also been reported, although auditory abnormalities are not common characteristics of vitiligo (50).

GENETIC SUSCEPTIBILITY TO AUTOIMMUNE DISORDERS The association of HLA antigens with vitiligo is a controversial issue. Significant differences in HLA typing were obtained between segmental and nonsegmental vitiligo (51) and between familial and nonfamilial cases (52). The significance of HLA phenotype in the pathogenesis of vitiligo remains to be elucidated. The apparent difference in HLA phenotype suggests a different genetic background for familial and nonfamilial vitiligo. Studies on the major histocompatibility antigens revealed that HLA DR4 and HLA DQW3 have been implicated in susceptibility to a variety of autoimmune disease (53). HLA DR4 was found to influence the susceptibility for vitiligo, especially in cases with family history of vitiligo, in black (54) and Caucasian Americans (55). In a Dutch population, DRB4*0101/0101 and DQB I *0303/0303 alleles were found to predispose individuals to vitiligo, with a significant family-based association with DQBI0303 (56). In 50 Omani patients, HLA DR7 was significantly increased in those patients with acrofacial compared to focal disease (57). Recently, genes other than MHC antigens were found to be likely involved in susceptibility to autoimmunity based on experimental and functional data. The gene encoding toxic T lymphocyte-associated antigen 4 (CTLA 4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity in vitiligo as well as other autoimmune diseases (58). The autoimmune susceptibility locus (1 PAIS I) is associated with vitiligo, while a chromosome 6 locus (AITD I) is associated with susceptibility to autoimmune thyroid diseases. It was found that the AITD I locus might mediate the incidence of Hashimoto thyroiditis in AIS I-susceptible family members of vitiligo patients (59). Another genetic linkage was detected between vitiligo and systemic lupus erythematosus (SLE). Families of SLE patients with members affected by vitiligo were found to share a significant linkage at a susceptibility gene locus SLEV 1 at 17p 13, thus having an important genetic Copyrighted Material

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effect. This might explain the incidence of either disorder in the family members of the other (60). These findings suggest that vitiligo patients and their family members inherit a predisposition to alteration in immunoregulation that may lead to the occurrence of vitiligo as well as other associated autoimmune disorders. The frequent association of vitiligo and other autoimmune diseases in the same family members could be attributable to unstable mutations in a set of genes that control endocrine and gastric epithelium in autoimmune endocrine disorders as well as melanocytes in vitiligo, leading to organ-specific autoimmunity (61), or due to genetic linkage with other autoimmune diseases (60). The genetic predisposition to vitiligo apparently allows for a diversity of anatomical patterns, and it was suggested that a similar mechanism is responsible for the occurrence of different organ-specific autoimmune disorders in members of the same family (62). This might provide clues to the higher prevalence of autoimmune diseases in healthy relatives of vitiligo patients. FAMILY HISTORY OF OTHER DISORDERS IN HEALTHY RELATIVES The association of autoimmune disorders is not limited to vitiligo patients but affects their relatives as well (63). The incidence of such conditions in relatives was found to be higher than their incidence in vitiligo patients themselves (7). A family history of autoimmune endocrine disorders in childhood vitiligo was found to be more common than in adult vitiligo patients (16). While the incidence of a family history of autoimmune disorders was as high as 75% in some studies (7), it was not significantly higher than the normal population in others (64). Multiple studies were done with variable results (Table I). While the incidence of diabetes mellitus in the general population was about 2-4% (65), it ranged up to 22% among relatives of vitiligo patients (7) Thyroid disorders occurred in 20% in vitiligo relatives (7) compared to a range of 5-19% among the normal population (66). Among the first- and second-degree relatives of 62 vitiligo patients, 15 had a family history of diabetes mellitus, 9 had pernicious anemia, and 5 had thyroid disorders (67). In another study at least one first-degree relative was affected by hypothyroidism in 26.1 % of cases and alopecia areata in 4.4% of cases (I). Patients with vitiligo and polyglandular insufficiency syndromes also had a positive family history of similar conditions or endocrinal disorder without vitiligo. In seven cases of vitiligo associated with two or more glandular insufficiencies, a family history of diabetes mellitus was found in one hypothyroidism in one, and pernicious anemia in two (68). Among 92 of European American pedigrees of SLE, 16 had one or more family members affected by vitiligo (61).

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Disorders in Healthy Relatives of Vitiligo Patients TABLE

1

55

Incidence of Various Disorders in Healthy Relatives of Vitiligo Patients Comparison with general population

Ref.

15/20 (75%) 25/70 (36) 166/271 (62%) 105/271 (38%) 23/82 (28%) 57/82 (70%)

Significant Insignificant Not performed

7 64 16

Significant Significant

16

1st & 2nd 1st & 2nd

22% 15/62 (25.1 %)

Significant Not compared

8 67

1st&2nd 1st&2nd 1st

20% 5/62 (8.3%) 6/23 (26.1%)

Significant Not compared Not compared

8 67 1

1st & 2nd

9/62 (2.6%)

Not compared

67

39/271 (14.4%) 47/271 (17.3%) 18/82 (21.9%) 35/82 (42.7%) 1/23 (4.4%)

Significant Significant Not compared

16

Degree of relation

Disorder

Incidence N(%)

Autoimmune and endocrine disorders:

20 patients 70 black patients 271 adult patients 82 child patients

1st&2nd 1st & 2nd *Immediate **Extended *Immediate **Extended

family family family family

Diabetes mellitus:

20 patients 62 patients Thyroid disorders: 20 patients 62 patients 160 white patients Pernicious anemia: 62 patients Others: Early graying of hair 271 adult patients 82 child patients Alopecia areata 160 white patients Early hearing loss Ocular problems

*Immediate **Extended *Immediate **Extended

16

Not compared

1st 1/23 (4.4%)

Not compared

1st **Extended family 1st **Extended family

1/14 (7.1%) 2/23 (8.8%) 1/14(7.1%)

Not compared

1st & 2nd 1st & 2nd

9/40 (22.5%) 13/40 (32.5%)

Significant Significant

Autoantibodies

Antithyroglobulin Antimicrosomal antibodies

family family family family

* Parents and siblings. ** Other blood related family members.

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The incidence of premature graying of hair is a common finding in healthy relatives of vitiligo patients. White streaking starts in the early twenties in vitiligo patients and other members of their families, compared to the thirties in the general population (46). In a study of 82 patients who were children no associated autoimmune disorders were found apart from 2 cases that had alopecia areata. On the other hand, the incidence of autoimmune endocrine disorders and premature graying of hair in immediate and extended families was significantly higher than in controls. When compared to families of adult pa tients, a significant increase in the incidence of autoimmune disorders was observed in extended families of childhood cases, while no significant difference was obtained in the incidence of premature graying of hair in extended or immediate families (16). In an ongoing study of 274 Egyptian vitiligo patients (69), we found a positive family history of vitiligo in 48 (17.5%) cases. The incidence of other autoimmune disorders in healthy relatives was positive in 77 (28.1 %) cases. The incidence of diabetes mellitus and thyroid disorders was higher than the available records in the general population, but the statistical significance was not estimated (Table 2). Vitiligo has been observed among patients with melanoma (32). The presence of vitiligo is thought to be a manifestation of host suppression of malignant melanocytes (70). Lerner et al. (71) were the first to highlight the

2 Prevalence of Autoimmune Endocrine Disorders and Other Associations in Healthy Relatives of 274 Egyptian Vitiligo Patients

TABLE

Disorder Diabetes mellitus Thyroid disorders Early graying of hair Systemic lupus erythematosus Psoriasis Alopecia areata Ocular problems

Degree of relation

Incidence, N (%)

1st 2nd 1st 2nd 1st 2nd 1st 2nd 1st 1st 2nd 1st 2nd

23 (8%) 18 (6.56%) 7 (2.55%) 4 (1.5%) 5 (1.8%) 6 (2.2%) 1 (0.35%) 2 (0.7%) 2 (0.7%) 2(0.7%) 7 (2.55%) 7 (2.55%) 5 (1.8%)

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increased incidence of vitiligo, halo nevi, early graying of hair, or halo primary melanoma in families of melanoma patients. They reported 12 families of melanoma patients who had close family members with these sedimentary disorders. They suggested that the instability of the abnormal pigment cells in both melanoma and vitiligo might be related. Such instability might lead to loss, leading to depigmentation, or transformation leading to melanoma. Patients who develop vitiligo first may have a lower incidence of melanoma than the general population due to the suppressive effect on melanocytes. In their kinships the frequency of transformation may be low, but it is probably higher than the normal population. Therefore, melanocytes of those with a genetic background of vitiligo might be predisposed to malignant transformation (7 I).

LABORATORY FINDINGS In addition to the increased frequency of history of autoimmune disorders, the apparently healthy relatives of vitiligo patients also showed significant altered laboratory findings. Antimelanocyte antibodies were detected in 82% of vitiligo patients (72) and correlated with the extent of depigmentation (73); however, whether their role is primary or secondary is not clear (72). The antibody response to melanocytes was found to be heterogeneous, and this was confirmed by the presence of antibodies to at least three distinct antigens in one third of vitiligo patients but in none of the normal individuals. Antibodies to these antigens were present in 46, 25, and 31 % of vitiligo patients, but in only 19,0, and 0%, respectively of the normal individuals. There was no difference in antibody response between patients with generalized and segmental vitiligo, suggesting a similar pathogenesis (74). Studies are now directed toward determining the melanocyte specific antigens toward which the autoantibodies are directed (75). Melanin concentrating hormone receptor 1 (MCHR1) is a novel autoantigen in which highly specific immune reactivity against this antigen could be observed in vitiligo patients (76). Vitiligo patients were also found to have increased levels of organ-specific autoantibodies compared to the normal population (77). A significant increase in antithyroid globulin was obtained in white (78,79) as well as in black (64) vitiligo patients. Increased incidence of anti-smooth muscle antibodies was also reported (80). The presence of organspecific autoantibodies did not correlate with the clinical features of vitiligo (64), but correlated positively with the incidence of autoimmune disorders in families of patients (64,78), but this relation was not obtained in all studies (7). When the first-degree relatives of 20 vitiligo patients were tested for the presence of organ-specific autoantibodies, there was a significant increase in the frequency of antithyroid globulin and antimicrosomal antibodies in firstCopyrighted Material

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degree relatives compared to normal controls (7). There was no significant increase in antiparietal or antiadrenal autoantibodies. The incidence of antimelanocyte antibodies in relatives has not been tested. When subsets ofT-cell populations were studied in vitiligo patients and their first-degree, apparently healthy relatives, high levels of CD4 + lymphocytes and high CD4jCD8 ratio were obtained compared to normal controls. This immunological abnormality, together with the presence of autoantibodies in the patients and their healthy relatives, seems to be an important finding in vitiligo (81). Whether the presence of these immunological abnormalities in relatives of vitiligo patients indicates an increased risk for developing vitiligo or other autoimmune diseases is not known. However, apparently healthy persons with antithyroid antibodies were found to have a hidden subclinical defect which was identified as exaggerated thyrotropinreleasing hormone response (82). Two apparently healthy relatives with T-cell subset abnormality developed vitiligo 2 years later (81). This could suggest that such abnormalities in humoral (7) or cell-mediated immunity (81) in those relatives indicate latent or subclinical disease that may manifest later on follow-up examination. Healthy relatives of vitiligo patients seem to have a higher risk of developing other autoimmune disorders. This is probably related to genetic factors common to vitiligo and other autoimmune diseases. However, most stuclies done so far have depended mainly on family history, and more sophisticated epidemiological studies are needed to quatitate these risks and compare them to the general population in different parts of the world. Genetic studies are being conducted to identify the susceptibility genes responsible for the association of vitiligo and other autoimmune disorders in vitiligo patients as well as their relatives.

REFERENCES I.

2. 3.

4. 5.

6.

Majumder P, Nordland JJ, Nath SK. Pattern offamilial aggregation of vitiligo. Arch Dermatol 1993; 129:994-998. Behl PN, Bhaha RK. 400 cases of vitiligo: a clinicopathological analysis. Indian J Dermatol 1971; 17:51-54. Majumder P. Genetics and prevalence of vitiligo vulgaris. In: Hann S-K, Nordlund J, eds. Vitiligo, A Monograph on the Basic and Clinical Science. Oxford: Blackwell Science, 2000: 18-20. MD, Njoo, W, WesterhoL Vitiligo, a review. In: Njoo MD, ed. Treatment of Vitiligo. Netherland: Thelia Thesis. 2000: 17-75 Nordlund JJ, Ortone JP. Vitiligo vulgaris. In: Nordlund JJ, Boissy RE, Hearing V, King RA, eds. The Pigmentary System: Physiology and Pathophysiology. Oxford: Oxford University Press, 1998:513-551. Boisseau-Garsand AM, Carsau P, Cale-Quist D, Helenon R, Queneher Claire

c.

Copyrighted Material

Disorders in Healthy Relatives of Vitiligo Patients

7. 8. 9. 10. ] 1. 12. 13. 14. 15. 16. 17.

18. 19. 20.

11. 22.

59

RC. Epidemiology of vitiligo in the French West Indies (lIes of Martiniques). Int J Dermatol2000; 39(1):18-20. Mandry RC. Ortiz LJ, Lugosomoloinos A, Sanchez JL. Organ specific autoantibodies in vitiligo patients and their relatives. Jnt J Dermatol ] 996; (35): 18-21. Kim SM, Chung HS, Hann SK. The genetics of vitiligo in Korean patients. Int J Dermatol 1998; 37( 12):908-9]0. Lacour JP, Ortone JP. Genetics of vitiligo. Ann Dermatol Venereol 1995; 122(4): 167-171. EI Mofty A, EI Mofty M. Vitiligo a symptom complex. Int J Dermalol 1980; 19(5):237-244. Kemp EH, Waterman EA, Weetman AP. Autoimmune aspects of vitiligo. Autoimmunity 2001; 34(1 ):65-77. Nath SK, Majumder PP, Nordlund JJ. Genetic epidemiology of vitiligo: multilocus recessivity-cross-validated. Am J Hum Genet 1994; 55(5):981-990. Handa S. Kaur 1. Vitiligo: ciinicalfindings in 1436 patients. J Dermatol 1999; 26(10)653-657. Cho S, Kang HC, Hahm JH. Characteristics of vitiligo in Korean children. Pediatr Dermatol2000; 17(3):189-193. Venkataram MN, White AG, Leeny WA, AI Suwaid AR, Daar AS. HLA antigens in Omani patients with vitiligo. Clin Exp DermatolI995; 20(1):35-37. Halder RM, Grimes PE, Cowan CA, Enterline JA, Chakrabarti SG., Kenney JA. Childhood vitiligo. J Am Acad Dermatol 1987; 5(1 ):948-954. Nordlund J, Hann S-K. The association of vitiligo with disorders of other organ systems. In: Nordlund J, Seung-Kyung H, eds. Vitiligo, A Monograph on the Basic and Clinical Science. Oxford: Blackwell Science, 2000:89-96. Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison's disease. J Autoimmun 1995; 8(1): 121-130. Kasperlik-Zaluska AA, Czarnocka B, Migda Iska B. Addison's disease. Clin Endocrinol1995; 43:130-131. Kasperlik-Zaluska AA, Czarnocka B, Czech W, Walecki J, Makowska AM, Brzenzinski J, Aniszewski J. Secondary adrenal insufficiency associated with autoimmune disorders: a report of twenty-five cases. Clin Endocrinol (Oxf) 1998; 49(6):779-783. Macaron C, Winter RJ, Traisman HS, Kahan BD, Lasser AE, Green OC. Vitiligo and juvenile diabetes mellitus. Arch Dermatol 1977; 113: 1515-1517. Dawber RPR. Clinical associations of vitiligo. Postgrad Med J 1970; 46:276-

277 23.

24. 25. 26.

Prince MA, Vialettes B, Zevaco-Mattei C, Vague P. Clinical characteristics and etiological markers in IDDM associated with organ specific autoimmune disease. Acta Diabetol Lat 1983; 20(3)221-229. Dawber RPR. Integumentary associations of pernicious anemia. Br J Dermatol 1970; 82:221-223. Grunnet 1. Vitiligo and pernicious anemia. Arch Dermatol 1969; 101:82-85. Viollier E, Staub n. Combined endocrine autoimmune syndrome-incidence, forms manifestations and clinical significance. Schweiz Med Wochenschr 1994; 124(44): 1971-1975.

Copyrighted Material

60

EI Mafty et al.

27.

McGregor BC, Katz HI, Doe RP. Vitiligo and multiple glandular insufficiencies. JAMA 1972; 219(6):724-725. Girija AS. Diseases associated with myasthenia gravis. J Assoc Phys India 1999; 47(3)354. Nordlund JJ, Majumder P. Recent investigations on vitiligo vulgaris. Dermatol Clin 1997; 15:69-78. Hegedus L, Heidenheim M, Gervil M, Hjalgrim H, Hoier-Madsen M. High frequency of thyroid dysfunction in patients with vitiligo. Acta Dermatol Venereol (Stockh) 1994; 74120-123. Niepomniszese H, Amad RH. Skin disorders and thyroid disease. J Endocrinol Invest 200 I; 24(8):628-638. Schallreuter KU, Lemke R, Brandt 0, Schwartz R, Westhofen M, Montz R, Berger J. Vitiligo and other diseases: coexistence or true association? Hamburg study on 321 patients. Dermatology 1994; 188(4):269-275. Schallreuter KU, Levening C, Berger J. Vitiligo and cutaneous melanoma. A case study. Dermatologica 1991; J83:239-245. Edward SJ, Rotter n. Increased risk for type I (insulin dependant) diabetes mellitus in relatives of patients with alopecia areata (AA). Am J Med Genet J994; 51 :239-243. Powell FC, Dicken CH. Psoriasis and vitiligo. Acta Derm Venereol 1983; 63(3): 246-249 Amato L, Gallerani I, Fuligini A, Mei S, Fabbri P. Dermatitis herpetiformis and vitiligo: report of a case and review of the literature. J Dermatol2000; 27(7):462466 Feuerman FJ, Lahat N, Kinatry A. Vitiligo, rheumatoid arthritis and pernicious anemia. J Dermatol 1993; 20:418-423. Robson KJ, Piette WW. Cutaneous manifestations of systemic diseases. Med Clin North Am 1998; 82(6)1359-1379. Khare AK, Singh G, Pandey SS. Vitiligo and disseminated discoid lupus erythematosus. Indian J Dermatol 1988; 33(3):37-39. Finkelstein E, Amichai B, Metzker A. Coexistence of vitiligo and morphea: a case report and review of the literature. J Dermatol 1995; 22(5):351-353. Walker J, Ober RR, khan A, Yuen 0, Rao NA. Intraocular lymphoma developing in a patient with Vogt-Koyanagi-Hrada syndrome. Int Opthalmol1993; 17:331-336 Alcalay J, David M, Shohat B, Sanback M. Generalized vitiligo following Sezary syndrome. Br J Dermatol 1987; 116:851-855. Cho M, Cohen PR, Duvic A. Vitiligo and alopecia areata in patients with HIV infection. South Med J 1995; 88:489-491. Boisseau-Garasaud AM, Vezon G, Helenon R, Garasaud P, Saint-Cyr L Quist O. High prevalence of vitiligo in lepromatous leprosy. lnt J Oermatol 2000; 39( 1):837-839. Lerner AB. On the etiology of vi tiligo and grey hair. AM J Med 1971; 51: 141147. PR Fain, DC Bennett, OJ Curtis I, CA Uhlhorn, GL Settler, KJ Hedman, AJ

28. 29. 30.

31. 32

33. 34.

35. 36.

37. 38. 39. 40. 41.

42. 43. 44.

45. 46.

Copyrighted Material

Disorders in Healthy Relatives of Vitiligo Patients

47. 48. 49. 50. 51.

52.

53.

54. 55. 56.

57. 58.

59.

60.

61. 62. 63.

61

Thody, RA Spritz, Vitiligo: identification of common autosomal dominant families in large-scale population surveys. http://www.faseb.org/gnetics/ashgOO/ fI147.htm.12/29/2001. Mkoga, Tango T. Clinical fealures and course of type A and type B vitiligo. Br J Dermatol 1988; 118223-228. Hann SK, Lee HJ. Segmental vitiligo: clinical finding in 208 patients. J Am Acad Dermatol 1996; 35(5 :671-674. Park S, Albert DM, Bolognia J L. Ocular manifestations of pigmentary disorders. Dermatol Clin 1992; 10(3):609-622. Tosti A, Bradazzi F, Veronesi S, Begonzoni C. Deafness and vitiligo in an ltalian family. Dermatologica 1986; 172(3 :178-179. Ostuka F, Nakagawa H, Mizoguchi M, Kukita A, Ito H, JUJi T. Histocompatibility antigens in vitiligo vulgaris (author's transl). Nippon Hifuka Gakkai Zasshi 1979; 89:485-488 Ando r, Chi HI. Nakagawa H, Ostuka F. Difference in clinical features and HLA antigens between familial and non familial vitiligo of nonsegmental type. Br J Dermatol 1993; 129:408-410. Matsumita S, Fujisao S, Nishimura Y. Molecular mechanisms underlying HLA-DR-associaled susceptibility to autoimmunity. Int J Cardiol 1996; 54: S81-S90. Demston GM, Halder RM. Vitiligo is associated with HLA-DR4 in black patients. Arch Dermatol 1990; 126:56-60. Foley LM, Lowe NJ, Misheloff E, Tiwari JL. Association of HLA-DR4 with vitiligo. JAm Acad Dermatol1983; 8(1):39-40. Zamami M, Spaaepen M, Sghar S, Hang C, Westerhof W, NieuweboerKrobotova L, Cassiman JJ. Linkage and association ofHLA class II genes with vitiligo in a Dutch population. Br J Dermatol 2001; 145(1):90-94. Venkataram MN, White AG, Leeny WA, Asumuid AR, Daar AS. HLA antigens in Omani patients with vitiligo. Clin Exp Dermatol 1995; 20(1):35-37. Kristiansen OP, Larsen ZM, Pociot F. CTLAA in autoimmune diseases-a general susceptibility gene to autoimmunity? Genes Immun 2000; 1(3): 170184. Alkhateeb A, Old StetlerW, Talbert J, Uhlhorn C, Taylor M, Fox A, Miller C, Dills DG, Ridway EC, Bennett DC, Fain PR, Spritz RA. A Mapping of an autoimmunity susceptibility locus (ArS I) to chromosome Ip31.3-p32.2. Hum Mol Genet 2002; 15; 11(6):661-667. Nath SK, Kelly JA, Namjou B, Lam T, Bruner GR, Scofield RH, Aston CE, Haeley JB. Evidence for a susceptibility gene, SLEVl, on chromosome 17p 13 in families with vitiligo-related systemic lupus erythematosus. Am J Hum Genet 2001; 69(6):1401-1406. Ferguson-Smith MA. Unstable mutations in vitiligo and multiple endocrine adrenal peptic ulcer syndrome. Lancet 1980; 2(8189):285-287. Goudie BM, Wilkieson C, Goudie RB. A family study of vitiligo patterns. Scott Med J 1983; 28(4)338-342 ortel B, Alge C, Pandy A. Phototherapeutic options for vitiligo. In: Krutmann J,

Copyrighted Material

EI Matty et al.

62

64.

65. 66.

67. 68. 69. 70. 71.

72. 73.

74. 75.

76.

77. 78. 79. 80.

Honigsmann H, Elmets CA, Bergstresser PR, eds. Dermatological Phototherapy and Photodiagnostic Methods. Berlin: Springer, 200 1: 135-161. Grimes PE, Halder RM, Jones C, Chakrabanti SG, Enterline J, Hinus HR, Kenny lA. Autoantibodies and their clinical significance in a black vitiligo population. Arch Dermatol 1983; 119:300-303. Olefsky TM. Diabetes mellitus. In: Kelly WN, Devita VT, eds. Textbook of Internal Medicine. 2d ed. Philadelphia: JB Lippincott, 1992. Utiger RD. Disorders of the thyroid gland. In: Wyngaarden JB, Smith LH, Bennet JC, eds. Cecil Textbook of Medicine. 19th ed. Philedelphia: WB Saunders,19921993-1998. Bor S, Feiwel M, Chanaria 1. Vitiligo and its relationship to organ specific autoimmune diseases. Br 1 Dermatol 1969; 81 :83-88. Mcgregor VC, Katz HI, Doe RP. Vitiligo and multiple glandular insufficiencies. lAMA 1972; 219(5):724-725. MA El Morty, SM Esmat, AN Noha, T Lehita, M Fawzi, NEL Eishi, AH Abozeid, Vitiligo patients in Egypt. Unpublished. Barnes L, Nordlund 11 Depigmentation: its significance in patients with melanoma. Clin Dermatol 1989; 2:66-72. Lerner AB, Kirkwood 1M. Vitiligo and melanoma: can genetically abnormal melanocytes result in both vitiligo and melanoma within a single family? 1 Am Acad Dermatol 1984; 11(4 pt 1):696-701. Naughton GK, Eisinger M, Bystryn Ie. Antibodies to normal human melanocytes in vitiligo. 1 Exp Med 1983; 158(1 ):246-251. Naughton GR, Reggiardo D, Bystrn Ie. Correlation between vitiligo autoantibodies and extent of depigmentation in vitiligo. 1 Am Acad Dermatol 1986; 15:978-981. Naughton GR, Eisinger M, Bystrn Ie. Detection of antibodies to melanocytes in vitiligo by Western immunoblotting. Yonsei Med 1 1996; 37(6):365-370. Kemp EH, Waterman EA, Gawkrodger DJ, Watson FP, Weetman AP. Molecular mapping of epitopes on melanocyte-specific protein Pmel17 which are recognized by autoantibodies in patients with vitiligo. Clin Exp Immunol2001; 124(3):509-515. Kemp EH, Waterman EA, Hawes BE, O'Neill K, Gottumukkala RV, Gawkrodger Dl, Weetman AP, Watson PF. The melanin-concentrating hormone receptor I, a novel target of autoantibody responses in vitiligo. J Clin Invest 2002; 109(7):923-930. Betterle C, Del Prete GF, Peserico A, Bersani G, Caracciolo F, Trisotto A, Poggi F. Autoantibodies in vitiligo. Arch Dermatol 1976; I 12(9): 1328. Cunlife WI. Hall R, Newell Pl. Vitiligo, thyroid disease and autoimmunity. Br 1 Dermatol 1986; 80: 135-139. Harsoulis P, Kanakouki-Tsakalidis F, Vyzantiadis A, Minas A, Cassimos e. Autoimmunity and vitiligo. Arch Dermatol 1978; 114(10):1554. Hann SK, 1m S, Kim HI, Lee YJ, Park YK. Increased incidence of antismooth muscle antibody in Korean vitiligo patients. J Dermatol 1993; 20(11): 679-683.

Copyrighted Material

Disorders in Healthy Relatives of Vitiligo Patients 81.

82.

63

D'Amelio R, Frati C, Fatorissi A, Aiuti F. Peripheral T-cell subset imbalance in patients with vitiligo and in their apparently healthy first-degree relatives. Ann Allergy 1990; 65(2):143-145. Betterle C, Callegari G, Presotto F, Zanette E, Pedini B, Rampazzo T, Girelli ME, Busnardo B. Thyroid autoantibodies: a good marker for the study of symptomless autoimmune thyroiditis. Acta Endocrinol (Copen h) J987; 114(3): 32J-327.

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6 Basic Research: An Update Karin U. Schallreuter University of Bradford, Bradford, United Kingdom and Institute for Pigmentary Disorders e. V. in Association with the Ernst-Moritz-Arndt University Greifswald Biotechnikum, Greifswald, Germany

INTRODUCTION The incidence of vitiligo worldwide has not been accurately determined, but studie in Europe indicate that 0.5% of the population may be affected. while in India reports of 4% have been suggested (I). Even if the lower value is correct, vitiligo must be regarded as one skin disease confronting physicians worldwide (I). This disabling depigmentation disorder was recognized thousands of years ago, but despite many scientific investigation and numerous clinical reports, the etiology of vitiligo is still unsolved. Several hypotheses have been proposed for the depigmentation process, but none of them can explain the plethora of clinical and basic scientific data (1,2). The clinical signature of the disease is the loss of constitutive pigment from the skin, and most publications account for this by either showing a decreased number of functioning melanocytes or the complete absence of these cells in the depigmented epidermis (1-4). However, a recent study by Tobin et al. clearly proved that melanocytes are still present, even in longstanding vitiligo (4). There has been much debate over how melanocytes lose their functionality and viability in vitiligo, and certainly the most popular hypothesis is selective autoimmunity to melanocytes. Nowadays there is clear evidence that vitiligo is a disease affecting the entire epidermis, although most of the studies have concentrated on the melanocyte (5,6). In addition to the loss of functioning

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melanocytes, the keratinocytes and Langerhans cells are disturbed in this disease (4,7). This chapter is an attempt to highlight some results from basic research and to try to connect these data to the clinical picture of vitiligo. IN VITRO AND IN VIVO EVIDENCE FOR EPIDERMAL H2 0 2 ACCUMULATION IN VITILIGO Over the past two decades it has been demonstrated by several investigators that the entire epidermis of patients with vitiligo shows signs of oxidative stress yielding various degrees of vacuolation in all cellular components (4-10). Only recently has the proof of oxidative stress in vitiligo been accomplished in vivo by measuring hydrogen peroxide (H 2 0 2) directly in the depigmented epidermis by noninvasive Fourier transform (FT)-Raman spectroscopy, where H 2 0 2 yields a distinctive peak due to the 0-0 stretch at 875 cm- I (5,6). This oxidative stress can continue even in melanocytes and keratinocytes cultured under in vitro conditions unless these cultures are protected by anti-oxidant enzymes such as catalase (5, II). This epidermal H 2 0 2 can be removed by a topical cream application containing a catalyst that oxidizes H 2 0 2 to O 2 and H 2 0, thus mimicking the reaction of the antioxidant enzyme catalase. The active catalyst is a narrow band DYB-activated bis MnlJ[ (EDTAh (HC0 3-)2 complex and has been named pseudocatalase (12). Pseudocatalase can successfully remove H 2 0 2 as demonstrated by in vivo FTRaman spectroscopy. The removal of epidermal H 2 0 2 yields cessation of the disease in 90% of all patients and initiates repigmentation in approximately 60% of the patients treated (5,6). These results highlight the importance of oxidative stress in the pathomechanism of vitiligo. CONSEQUENCES OF H2 0 2 ACCUMULATION IN VITILIGO Low Epidermal Catalase and Glutathione Peroxidase Foster H2 0 2 in the Millimolar Range The biochemical basis for the accumulation of H 2 0 2 in patients with vitiligo has been the target of much research. Initially it was shown that patients with vitiligo have low levels of catalase in their entire epidermis (13). However, although catalase levels are decreased, the expression of catalase mRNA remains unaltered in these patients (5). These early data were recently confirmed, showing that melanocytes established from the nonlesional skin of vitiligo patients contained lower than normal catalase activities (14). These in vitro results are in agreement with increased levels of H 2 0 2 in vivo in the epidermis of this patient group, because this reactive oxygen species can

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inactivate catalase by degradation of the porphyrin active site of this enzyme after concentrations exceed Vl1lax levels (15). Recent studies have shown that peripheral blood lymphocytes from vitiligo patients also have low catalase levels and that these cells are susceptible to H 2 0 2 stress. (16). Under normal conditions with low catalase levels, the antioxidant enzyme glutathione peroxidase functions as a backup enzyme for the efficient removal of H 2 0 2 . In this context, it has been shown that these enzyme activities are also compromised following an age-dependent profile (17). Two of the key enzymes for the removal ofH 2 0 2 are impaired in vitiligo. Melanocytes are in particular sensitive to H 2 0 2 stress because even cells under normal physiological conditions have lower catalase and glutathione peroxidase activities than keratinocytes (18). Earlier studies showed that thioredoxin reductase is also decreased in vitiligo (for review, see Ref. 19). This enzyme contains a selenocysteine active site and directly reduces H 2 0 2 to H 2 0 with a Km of2.5 x I 0-3M. Moreover, biochemical studies have recognized six possible sources of H 2 0 2 in active progressive vitiligo (Table I).

Pterins and H2 0 2 in Vitiligo Vitiligo can be diagnosed by demonstrating a distinct fluorescence in the depigmented epidermis when it is exposed to Wood's light (UVA 351 nm), whereas leukodermas of other origin do not fluoresce (20). A comparison of vitiligo and one example of a laser-induced leukoderma is shown in Figure 1. In 1994 it was discovered that the fluorescent compounds in vitiliginous epidermis were oxidized pterins (20,21). The accumulation of oxidized pterins arose from the recognition that patients with vitiligo have a defective de novo synthesis/recycling/regulation of the essential cofactor (6R)-L-erythro-5,6, 7,8-tetrahydrobiopterin (6BH 4 ). The decreased/absent recycling of 6BH 4 causes the production of its abiogenic isomer 7BH 4 , and micromolar con-

TABLE

1

Sources of Epidermal H2 0 2 Accumulation in Vitiligo

1. Defective de novo synthesis/recycling and regulation of the essential cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (20,21) 2. Increased epidermal monoamine oxidase A activities (22) 3. Increased NADPH-oxidase activities from the activation of neutrophils and macrophages that can sometimes be observed in the perilesional infiltrate in vitiligo (1,23) 4. Photo-oxidation of epidermal 6-biopterin and sepiapterin (24) 5. Increased inducible nitric oxide synthase (19) 6. Decreased thioredoxin reductase expression and activity (19)

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FIGURE 1 A comparison of vitiligo (A) and a laser-induced leukoderma (B) upon Woods light examination. The clinical picture presents leukoderma. Upon Woods light examination there is no fluorescence in laser-induced depigmentation. Meanwhile, vitiligo presents the characteristic fluorescence of oxidized pterins (20,21).

centrations of7BH 4 inhibi t phenylalanine hydroxylase (PAH), preventing the turnover of L-phenylalanine to L-tyrosine, consequently causing a buildup of L-phenylalanine in the epidermis (25,26). This buildup has indeed been demonstrated in vivo using FT-Raman spectroscopy (26). The disrupted recycling of 6BH 4 leads to the synthesis of H 20 2 by PAH as the cofactor is rapidly converted to quinonoid dihydropterin (qBH 2 ) by a short circuit (Table 1). A detailed overview of our understanding of the defective pterin metabolism in vitiligo is presented in Figure 2. Only recently has it been discovered that H 2 0 2 deactivates the rate-limiting recycling enzyme 4acarbinolamine dehydratase (DH) because H 2 0 2 alters directly the structure of this enzyme (27). Consequently, the buildup ofH 2 0 2 is autocatalytic. It was demonstrated that H 2 0 2 rapidly oxidizes 6BH 4 to 6-biopterin and this

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L-Phenylalanine R

e g /I

a

!G G

GFRP . - . .

I .

Sepiapterio Reductase

n g

6-Pyruvoyl-PH.-Synthase

...

GTP-Cyclohydrolase I

,.

GTP

• Synonyms: Plcrin-4a-carbinolamine dehydratase (PCD) and Dimerisation Cofactor of Hepatocyte Nuclear Factor 1 (DeoH) FIGURE 2 Defective 6BH 4 synthesis leading to 7BH 4 and H2 0 2 production in vitiligo. Both epidermal melanocytes and keratinocytes have the full capacity for de novo synthesis/recycling and regulation of 6BH 4 (20,21). The rate-limiting step for the de novo synthesis of 6BH 4 is GTP-cyclohydrolase I (GTP-CH-I). This enzyme is controlled by L-phenylalanine (positive feedback) via the GTP-CH-I feedback regulatory protein (GFRP), as well as several cytokines [tumor necrosis factor-a, mast cell growth factor (MGF), interleukin-2, and )I-interferon]. 6BH 4 downregulates GTP-CH-I via GFRP. Furthermore, 6BH 4 is the essential cofactor (a) for phenylalanine hydroxylase to metabolize L-phenylalanine to L-tyrosine in melanocytes and keratinocytes and (b) for tyrosine hydroxylase to convert L-tyrosine to L-dopa in catecholamine biosynthesis in keratinocytes. 6BH 4 is also a regulator of tyrosinase activity in melanocytes, inhibiting the enzyme by an allosteric mechanism. The recycling of 6BH 4 is catalyzed by the rate-limiting 4a-hydroxy-BH 4 dehydratase (DH) via quinonoid dihydropterin (qBH 2 )· In vitiligo, 6BH 4 is overproduced, and DH activities are decreased or absent due to deactivation by H2 0 2 , consequently 4ahydroxy-BH 4 is nonenzymatically converted to 7BH 4 , which in turn inhibits phenylalanine hydroxylase, resulting in accumulation of H2 0 2 and compromised Ltyrosine supply.

oxidation product is cytotoxic to melanocytes under in vitro conditions with an Le so == 10- 7 M (28). Only recently was the presence of epidermal pterin 6carboxylic acid as the final photo-oxidation product of 6-biopterin and other pterins demonstrated, and this photo-oxidation coincides with the generation of H 2 0 2 (24). The results suggested that defective pterin synthesis coupled to oxidative stress can directly influence the melanocyte population and integrity

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in vitiligo primarily due to the cytotoxicity of 6-biopterin and other oxidized pterins. Catecholamine Metabolism in Vitiligo The presence of increased levels of 6BH 4 and low levels of L-tyrosine in vitiligo provides ideal conditions for increased activity of the 6BH 4 tyrosine hydroxylase (TH), the key enzyme for catecholamine biosynthesis (29). Both keratinocytes and melanocytes express TH isoform I, the most active of the four different isoforms of this enzyme (29,30). In this context it has been reported that patients with active vitiligo have elevated levels of noradrenaline in their skin and plasma, as well as high levels of catecholamine metabolites in their urine (21,31). Increased noradrenaline synthesis in the epidermis of these patients causes the induction of the catecholamine-degrading enzymes monoamine oxidase A (MAO-A) and catecholamine-O-methyl-transferase (COMT) (32,33). MAO-A produces H 2 0 2 as a reaction product from the oxidation of noradrenaline, and therefore the increased expression of epidermal MAO-A contributes significantly to the severe H 2 0 2 stress in vitiligo. NADPH Oxidase and the "Oxygen Burst" Several investigators have reported the presence of a cellular infiltrate in the perilesional skin of patients with vitiligo (I). This infiltrate produces an "oxygen burst" leading to the generation of superoxide anion radical (02") from O 2 via NADPH-oxidase (23,34,35). In a normal inflammatory reaction, 02" concentrations increase up to 20-fold. After disproportionation this concentration would produce a IO-fold increase in H 2 0 2 (23). The perilesional border in vitiligo presents in some cases a cellular infiltrate. However, the numbers of infiltrating neutrophils and macrophages are usually very low or even absent in long-lasting disease. Therefore, it is very difficult to assess the true H 2 0 2 contribution deriving from this perilesional infiltrate. Cells in the perilesional epidermis in vitiligo show no difference in vacuolation (i.e., lipid peroxidation) compared to cells in both lesional and nonlesional skin (4-6). However, recently it has been shown that H 2 0 2 can activate peripheral blood dendritic cells by upregulating surface markers involved in T-cell interactions (36). This H 2 0 r driven process promotes interaction with MHC class II molecules (DQ and DR) as well as costimulatory molecules CD 40 and CD 86 (36). After exposing dendritic cells in culture to H 2 0 2 , these cells promote Tcell proliferation compared to untreated controls lacking H 2 0 2 exposure (36). The effect of H 2 0 2 can be blocked in vitro upon the addition of the antioxidant N-acetylcysteine (36). In the same context, it has been shown that simulated solar irradiation upregulates B7.1 and B7.2 costimulatory molecules in epidermal Langerhans cell (37) In vivo H 20 2 generation by UVB (311

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nm) and by solar exposure at the Dead Sea has been shown using FT-Raman spectroscopy (38). Based on these data it is tempting to conclude that H 20 2 could modulate the response of epidermal Langerhans cells in vitiligo (4,5,36). Hence these data could directly link H 20 2 stress to cell damage and the onset of an adaptive cellular immune response (36).

A Possible Role for Tyrosinase-Related Protein-1 in Vitiligo TRP-l is a melanosomal membrane-associated protein which has 43% sequence homology to tyrosinase, and it controls both the activity and stability of this key enzyme in melanogenesis (39,40). Halaban and Moellmann demonstrated catalase/peroxidase activities ofTRP-l, and these authors suggested that this protein protects tyrosinase from oxidative degradation (39). In this context, it has been established that H 2 0 2 is a potent competitive inhibitor of human tyrosinase and that superoxide anion radical (0 2) is a preferred substrate for this enzyme compared to molecular oxygen (41). Thus, melanogenesis could primarily be considered as an antioxidant defense mechanism protecting the melanocyte against oxidative stress (42). Furthermore, it was suggested that TRP-l protects both tyrosinase and melanosomal integrity. Jimbow et al. reported that melanocytes established from the perilesional skin of patients with vitiligo expressed a TRP-I containing II additional amino acids at the C-terminaJ end of its sequence (43). This sequence was identical to murine TRP-l (43). The initial transcript for human and murine TRP-I shows 93% sequence homology (44). Therefore, posttranslational processing via an unidentified protease occurs in the human system, producing a protein lacking II residues from the C-terminal. These authors speculated that this protease appears to be either lost, inhibited, or inactivated in vitiligo (43). In vitiliginous melanocytes, the murine form ofTRP-1 is expressed, and this protein loses its function for protecting melanosome integrity due to defective interactions with both tyrosinase as well as the melanosome chaperone calnexin (43,45). In this context, it is interesting to note that animal models lacking active TRP-I develop an adaptive autoimmune response to melanocytes, providing another example of a potential role for H 2 0 2 in fostering a cellular immune response (36,46).

Epidermal Calcium Homeostasis and Oxidative Stress in Vitiligo The influence of oxidative stress on calcium uptake/efflux has been established for a long time (34). Earlier studies on the transport of isotopically labeled 45 ca lcium with keratinocytes and melanocytes established from the depigmen ted epidermis of pa tients wi th vi tiligo revealed a significan t decrease in the rates for calcium uptake in these cells (47,48). Several investigators have

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shown that the extracellular concentration of calcium, which controls the kinetics for its uptake and efflux, strongly influences melanogenesis in melanosomes (49). Recently it has been confirmed that L-phenylalanine transport and its intracellular turnover to L-tyrosine is a calcium-dependent process in normal human melanocytes under in vitro conditions (50). L-phenylalanine is actively transported in these cells via the well-established L-phenylalanine/ sodium/calcium ATPase antiporter mechanism (50). Because the majority of eumelanin is synthesized in melanocytes from the autocrine conversion of Lphenylalanine to L-tyrosine via PAH, then the perturbation of calcium homeostasis in these cells from patients with vitiligo very likely plays a crucial role in the loss of pigment in vitiliginous melanocytes (48,50).

COMPROMISED L-PHENYLALANINE TURNOVER IN VITILIGO

Previously it was recognized that epidermal cell extracts from patients with vitiligo have low phenylalanine hydroxylase activities (20). The application of in vivo FT-Raman spectroscopy allowed the determination of phenylalanine by following the peak at 1004 cm'), and the results indeed confirmed an accumulation of epidermal phenylalanine in this patient group (26). Utilizing a kinetic analysis of the individual systemic phenylalanine turnover after oral loading with phenylalanine, it was demonstrated that 40% of all patients tested (n > 800) have a significantly slower phenylalanine metabolism compared to healthy controls. However, 60% of the patients have no problems producing L-tyrosine from L-phenylalanine via phenylalanine hydroxylase (26). As described earlier, L-phenylalanine is actively transported into the cell by a calcium-dependent ATPase antiporter mechanism (50). The question arises whether a perturbed calcium homeostasis in vitiliginous cells explains this phenomenon.

VIRAL INFECTIONS IN VITILIGO

Over recent years Grimes et al. have proposed a viral etiology for vitiligo (51,52). Using Polymerase chain reaction (PCR) techn.iq ues, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) have been detected in the epidermis of patients with this disorder in California (51,52). Based on these findings, the authors suggested a viral induced pathomechanism. However, the direct association of CMV with vitiligo in California is difficult to assess, since 85% of the population are positive for CMV, whereas the incidence of vitiligo is only approximately 0.5-1 %. Recent studies from our own group re-evaluated this possibility of viral-induced disease on 72 patients with vitiligo compared to healthy controls (n = 70). There was no direct evidence for CMV, herpesvirus

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IIIL or varicella virus using peR techniques in skin biopsies or in the serum from these patients (53). However, even these findings cannot exclude a viral involved "hit-and-run" mechanism, despite a lack of direct evidence for virus detection in loco or in serum. In fact, it has been shown in animal models that virus infection can trigger an autoimmune response due to molecular mimicry of viral peptide sequences activating subsets ofT cells. This hypothesis could support viral-induced T cells as a target against melanocytes. In these models the virus causing autoimm uni ty escapes detection after the onset of the disease (54,55). In this context, it is noteworthy that viruses can attract an infiltrate of leukocytes and macrophages leading to the oxygen burst concomitant with the production of reactive oxygen species (ROS), such as superoxide anion radical (0 2) and H 2 0 2 , as discussed earlier in this chapter.

VITILIGO AND SKIN CANCER

It is generally accepted that the cutaneous pigment protects against the development of skin cancers. The sun protection factor (SPF) for melanin ranges between 2 and 5 (56). Since patients with vitiligo lack this protective mechanism, it would be anticipated that affected individuals would run a higher risk for developing skin cancers. Surprisingly, patients even with longstanding vitiligo of >25 years duration have no evidence for increased photodamage such as actinic keratosis and solar elastosis as well as increased numbers of basal cell and squamous cell carcinoma (57-59). The reason for this puzzling lack of increased skin cancers in vitiligo is still unknown. Recently, an increased epidermal functioning p53 has been detected (59). Surprisingly, this increased p53 is not associated with increased apoptosis in these patients (4,60). Earlier it was recognized that thioredoxin reductase activities and protein levels are decreased in vitiligo (19): This decreased enzyme expression could well be caused by the increased wild-type p53 levels in this disease considering that thioredoxin reductase is an established transcriptional target for p53 (61). In this context it should be noted that p53 can be induced by flM levels of hydrogen peroxide (62). In vitiligo this scenario could be certainly valid. The question remains whether p53 is induced as a protective mechanism in prevention of skin cancer in vitiligo. This could be an interesting new concept to explain the observed paucity of solar-induced damage and skin cancer overall. Further work is necessary to gain more insight into these interesting observations

THE HUNT FOR THE VITILIGO GENE

Since more than 40% of patients with vitiligo have more than one affected family member with this d6"8~~dhtetf~teH~?isposition is strongly sug-

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gested. Only recently have major attempts been made to find the "vitiligo gene." There is no evidence as yet for any mutation on the PAH gene in vitiligo (KUS, unpublished results). The defective recycling of 6BH 4 via DH suggested the possibility of a polymorphism in the DH gene (20,21). However, recent studies have shown that DH is directly deactivated by HzO z (27). Examination of the sequence of the DH gene in 10 patients with vitiligo revealed only wild-type DH (27). It still remains to be established whether polymorphisms occur on the pathway for de novo synthesis and regulation of 6BH 4 synthesis. Another report suggested that this disease is caused by a mutation in GTP-cyclohydrolase I, the rate-limiting enzyme for 6BH 4 synthesis (63). This result could not be substantiated, as none of the GTPcyclohydrolase I mutations in patients from the world data bank expressed vitiligo (64,65). An attempt to investigate a possible mutation in the regulatory protein GFRP has revealed only a wild-type sequence for the 6BH 4 binding domain (KUS, unpublished results). Only very recently has a genetic association of the catalase gene with susceptibility to vitiligo been reported (66). In this study, a TIC single nucleotide polymorphism (Asp 389) on exon 9 of catalase was discovered. The restriction in the nuclease Bst Nl was used to cleave the T allele and show that this polymorphism is statistically significant in vitiligo. It is proposed that this polymorphism interferes with catalase tetrameric subunit assembly, thus making catalase more succeptible to HzO z stress with a concomitant decreased activity (66). This discovery would certainly be in agreement with all biochemical in vitro and in vivo evidence for H~02 accumulation in vitiligo.

REFERENCES I.

2.

3.

4.

5.

Ortonne JP, Bose SK. Vitiligo: Where do we stand? Pigment Cell Res 1993; 8:61-72. LePoole IC, Das PK, van den Wijngaard RM, Bos JD, Westerhof W. Review of the etiopathomechanism of vitiligo: a convergence theory. Exp Dermatol 1993; 2:146-153. LePoole IC, van dan Wijngaard RM, Westerhof W. Dutrieux RP. Das PK. Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 1993; 100:816-822. Tobin OJ, Swanson NN, Pittelkow MR, Peters EMJ, Schallreuter KD. Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 2000; 19 1:407-416. Schallreuter KU. Moore J. Wood JM, Beazley WD, Gaze DC, Tobin DJ, Marshall HS, Panske A, Panzig E, Hibberts NA. In vivo and in vitro evidence for hydrogen peroxide (H 2 0 2 ) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J Invest Dermatol Symp Proc 1999; 4:91-96.

Copyrighted Material

Basic Research: An Update 6. 7. 8.

9. 10.

11. 12.

13. 14.

15. 16.

17.

18.

19. 20.

21.

22.

75

Schallreuter KU. Successful treatment of oxidative stress in vitiligo. Skin Pharmacol Appl Skin Physiol 1999; 12:132-138. Nordlund 11, Ortonne JP. Vitiligo and depigmentation. Curr Prob Dermatol 1992; 4:3-30. Moellmann G, Klein-Angerer S, Scollay DA, Nordlund 11, Lerner AB. Extracellular granular material and degeneration of keratinocytes in the normally pigmented epidermis of patients with vitiligo. J Invest Dermatol 1982; 79:321330. Bhawan J, Bhutani LK. Keratinocyte damage in vitiligo. J Cutaneous Path 1983; 10:207-212. Boissy R, Liu YY, Medrano EE, Nordlund 11. Structural aberration of the rough endoplasmic reticulum and melanosome compartmentalisation in long term cultures of melanocytes from vitiligo patients. J Invest Dermatol 1991; 97:395-404. Medrano EE, Nordlund 11. Successful culture of adult human melanocytes obtained from normal and vitiligo donors. J Invest Dermatol 1990; 95:441-445. Schallreuter KU, Wood JM, Lemke KR, Levenig C. Treatment of vitiligo with a topical application of pseudocatalase and calcium in combination with shortterm UYB exposure: a case study on 33 patients. Dermatol 1995; 190:223229. Schallreuter KU, Wood JM, Berger J. Low catalase levels' in the epidermis of patients with vitiligo. J Invest Dermatol 1991; 97:1081-1085. Maresca Y, Roccella M, Roccella F, Camera E, Del Porto G, Passi S, Grammatico P, Picardo M. Increased sensitivity to peroxidative agents as a possible pathogenic factor of melanocyte damage in vitiligo. J Invest Dermatol 1997; 109:310-313. Aronoff S. Catalase: kinetics of photo-oxidation. Science 1965; 150:72-73. Dell Anna ML, Maresca V, Brigarti S, Camera E, Falchi M. Mitochondrial impairment in peripheral blood mononuclear cells during the active phase of vitiligo. J. Invest Dermatol 2001; 117(4):908-913. Beazley WD, Gaze DC, Panske A, Panzig E, Schallreuter KU. Serum selenium levels and glutathione peroxidase activities in vitiligo. Br J Dermatol 1999; 141301-303. Yohn 11, Norris DA, Yrastorza G, Buno IJ, Leff JA, Hake SS, Repine JE. Disparate antioxidant enzyme activities in cultured human cutaneous fibroblasts, keratinocytes and melanocytes. J Invest Dermatol 1991; 97:405-409. Schallreuter KU, Wood JM. Thioredoxin reductase-its role in epidermal redox status. J Photochem Photobiol 200 I; 64: 179-184. Schallreuter KU, Wood JM, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, Swanson NN, Hitzemann K, Ziegler 1. Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 1994; 263: 1444-1446. Schallreuter KU, Wood JM, Ziegler I, Lemke KR, Pittelkow MR, Lindsey NJ, Gutlich M. Defective tetrahydrobiopterio and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochim Biophys Acta 1994; 1226: 181192. Schallreuter KU, Wood JM, Pittelkow MR, Buttner G, Swanson NN, Korner

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23. 24.

25.

26.

27.

28.

29.

30.

31. 32.

33 34.

35.

36. 37.

Schallreuter C, Ehrke C. Increased monoamine oxidase A activity in the epidermis of patients with vitiligo. Arch Dermatol Res 1996; 288: 14-18. Darr D, Fridovich I. Free radicals in cutaneous biology. J Invest Dermatol 1994; 102:671-675 Rokos H, Beazley W, Schallreuter K. Photo-Oxidation of pterins produces H 2 0 2 and pterin-6-carboxylic acid: further evidence for oxidative stress in vitiligo. Biochem Biophys Res Commun 2002; 292:805-811. Davis MD, Ribeiro P, Tipper J, Kaufman S. 7-Tetrahydrobiopterin, a naturally occurring analogue of tetrahydrobiopterin, is a cofactor for and a potential inhibitor of the aromatic amino acid hydrolases. Proc Natl Acad Sci USA 1992; 89:10108-10113. Schallreuter KU, Zschiesche M, Moore J, Panske A, Hibberts NA, Herrmann FH, Metelmann HR, Sawatzki J. In vivo evidence for compromised phenylalanine metabolism in vitiligo. Biochem Biophys Res Commun 1998; 243:395399 Schallreuter KU, Moore J, Wood JM, Beazley WD, Peters EMJ, Maries LK, Behrens-Williams SC, Dummer R, Blau N, Thony B. Epidermal H 2 0 2 accumulation alters tetrahydrobiopterin (6BH 4) recycling in vitiligo: Identification of a general mechanism in regulation of all 6BH4 dependent processes? J Invest Dermatol2001; 116:167-174. Schallreuter KU, Buttner G, Pittelkow MR, Wood JM, Swanson NN, Korner C. Cytotoxicity of 6-biopterin to human melanocytes. Biochem Biophys Res Communs 1994; 204:43-48. Schallreuter KU, Lemke KR, Pittelkow MR, Wood JM, Korner C, Malik R. Catecholamines and keratinocyte differentiation. J Invest Dermatol 1995; 104: 953-957. Maries LK, Peters EM, Tobin DJ, Hibberts NA, Schallreuter KU. Tyrosine hydroxylase isozyme I is present in human melanosomes: a new function in pigmentation. Exp Dermatol 2003; 12:61-70. Morrone A, Picardo M, De Luca C, Terminali 0, Passi S, Ippolito F. Catecholamines and vitiligo. Pigment Cell Res 1992; 5:58-62. Schallreuter KU, Wood JM, Pittelkow MR, Buttner G, Swanson NN, Korner C, Ehrke C. Increased monoamine oxidase A activity in the epidermis of patients with vitiligo. Arch Dermatol Res 1996; 288:14-18. LePoole C, Wijngaard Van den, Smit NPM, Oosting J, Westerhof W, Pavel S. Catechol-O-methyl transferase in vitiligo. Arch Dermatol Res 1994: 286:81-86. Marks DB, Marks AD, Smith CM. Oxygen metabolism and oxygen toxicity. Basic Medical Biochemistry: A Clinical Approach. Baltimore: Williams and Wilkins, 1996:327-340. Stark JM. Immunological adjuvance of metabolic origin: oxidative stress, postulated impaired function of thiol proteases and immunogenicity. Scand J Immunol 1998; 48:475-479. Rutault K. Alderman C, Chain BM, Katz DR. Reactive oxygen species activate human peripheral blood dendritic cells. Free Radic Bioi Med 1999; 26:232-238. Laibia JK, Jansen CT. Upregulation of human epidermal Langerhans cell B7-1

Copyrighted Material

Basic Research: An Update

38.

39.

40.

41.

42.

43.

44. 45.

46.

47. 48. 49.

50.

51.

52. 53.

77

and B7-2 costimulatory molecules in vivo by solar stimulating irradiation. Eur J Immunol 1997; 27:984-989. Schallreuter KU, Moore J, Behrens-Williams SC, Panske A, Harari M. Rapid initiation of repigmentation in vitiligo with Dead Sea climatotherapy in combination with pseudocatalase (PC-KUS). Int J Dermatol 2002; 41 :482-487. Halaban R, Moellmann GE. Murine and human b-Iocus pigmentation genes encode a glycoprotein (gp75) with catalase activity. Proc Nat! Acad Sci USA 1990; 87:4809-4813. Orlow SJ. Boissy RE, Moran D, Pifka-Hinst S. Subcellular distribution of tyrosinase and tyrosinase related protein 1: implications for melanosomal biogenesis. J Invest Dermatol 1993; 100:55-64. Wood J, Schallreuter K. Studies on the reaction between human tyrosinase, superoxide anion, hydrogen peroxide and thiols. Biochim Biophys Acta 1991; 1074:378-385. Wood JM, Jimbow K, Boissy RE, Slominski A, Plonka PM, Slawinski J, Wortsman J, Tosk J. What's the use of generating melanin? Exp Dermatol 1999; 8133-164 Jimbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase related in vitiligo. Br J Dermatol 2001; 144:55-65. Boissy RE, Sakai C, Zhao H, Kobayashi T, Hearing VJ. Human tyrosinase related 'protein-I (TRP-I). Exp Dermatol 1998; 7: 198-204. Manga P, Sato K, Ye L, Beerman F, Lamoreux ML, Orlow SJ. Mutational analysis of the modulation of tyrosinase by tyrosinase related proteins 1 and 2 in vitor. J Pigment Cell Res 2000; 13:364-374. Austin LM, Boissy RE. Mammalian tyrosinase related protein-l is recognised by autoantibodies from vitiliginous Smyth chickens. Am J Pathol 1995; 146: 1529-1541. Schallreuter KU, Pittelkow MR. Defective calcium uptake in keratinocyte cell cultures from vitiliginous skin. Arch Dermatol Res 1988; 280: 137-139. Schallreuter KU, Pittelkow MR, Swanson NN. Defective calcium transport in vitiliginous melanocytes. Arch Dermatol Res 1996; 288: 11-13. Halaban R, Pomerantz SH, Marshall S, Lambert DT, Lerner AB. Regulation of tyrosinase in human melanocytes grown in culture. J Cell Bioi 1983; 97:480488 Schallreuter KU, Wood JM. The importance of L-phenylalanine transport and its autocrine turnover to L-tyrosine for melanogenesIs in human epidermal melanocytes. Biochem Biophys Res Commun 1999; 262:423-428. Grimes PE, Sevall JS, Vojdani A. Cytomegalovirus DNA identified in skin biopsy specimens of patients with vitiligo. J Am Acad Dermatol 1996; 35:2126. Grimes PE, Elkadi T, Sanders J. Epstein-Barr virus infection in patients with vitiligo abstr. J Invest Dermatol 1999; 112:604. Wiirfel F, Panske A, Schallreuter KU. Are viral infections a possible cause for the manifestation of vitiligo? J Pigment Cell Res 2000; 13,404.

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Herrath MG, Oldstone MB. Virus induced autoimmune disease. Curr Opin Immunol 1996; 8:878-885. Morse SS, Sakaguchi N, Sakaguchi S. Virus and autoimmunity: induction of autoimmune disease in mice by mouse T-lymphotropic virus (MTLV) destroying CD4 and T cells. J Immunol 1999; 162:5309-5316. Prota G. Melanins and Melanogenesis. New York: Academic Press, 1976. Cole CA, Forbes PD, Davies RE. An action spectrum for UV photocarcinogenesis. Photochem Photobiol 1986; 43:275-284. Calanchini-Postizzi E, Frenk E. Long-term actinic damage in sun-exposed vitiligo and normally pigmented skin. Dermatologica 1987; 174:266-271. Schallreuter Ku, Tobin DJ, Panske A. Decreased photodamage and low incidence of non-melanoma skin cancer in 136 sun-exposed caucasian patients with vitiligo. Dermatology 2002; 204: 194-201. Van de Wijngaard Rm, Aten J, Scheemaker IC, Le Poole AJ, Tigges W, Westerhof K. Expression and modulation of apoptosis regulatory molecules in human melanocytes: significance in vitiligo. Br J Dermatol 2000; 43:573-581. Casso D, Beach D. A mutation in a thioredoxin reductase homolog suppresses p53-induced growth inhibition in the fission yeast. Mol Gen Genet 1996; 16: 518-529 Vile GF. Active oxygen species mediate the solar ultraviolet radiation-dependent increase in the tumour suppressor protein p53 in human skin fibroblasts. FEBS Lett 1997; 412:70-74. De la Fuente-Fernandez R. Mutations in GTP-cyclohydrolase 1 gene and vitiligo. Lancet 1997; 350:640. Schallreuter KU, Blau N. GTP-cyclohydrolase and vitiligo. Lancet 1997; 350, 1254. Blau N, Barnes I, Dhondt JL. lnternational database of tetrahydrobiopterin deficiencies. J lnherit Metab Dis 1996; 19:8-14. Casp CB, She JX, McCormack WT. Genetic association of the catalase gene (CAT) in vitiligo susceptibility. Pigment Cell Res 2002; 15:62-66.

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63. 64. 65. 66.

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7 Vitiligo: The Autoimmune Hypothesis Jean-Claude Bystryn New York University School of Medicine, New York, New York, U.S.A.

POSSIBLE CAUSES OF VITILIGO The immediate cause of vitiligo is the selective destruction of melanocytes. These are absent in established lesions of vitiligo and damaged at the margin of active lesions (1). The cause of the disease is not known. There are three major hypotheses: (a) self-destruction of melanocytes by toxic prod ucts they produce; (b) neutral dysfunction, as vitiligo can be segmental, can stop abruptly at the midline, and may spare denervated areas; (c) autoimmunity against melanocytes-currently the most popular hypothesis. This review summarizes the evidence supporting the autoimmune hypothesis. It falls into two categories: (a) indirect evidence-immune abnormalities which by themselves cannot explain the selective destruction of melanocytes; (b) direct evi.dence-immune abnormalities associated with vitiligo that can selectively destroy these cells. The a utoimmune hypothesis was first suggested by indirect evidence, i.e., the association of vitiligo with a variety of autoimmune diseases and/or autoantibodies. It was greatly strengthened by subsequent direct evidence that vitiligo is associated with abnormal antibodies against melanocytes and that these can cause depigmentation when given to animals.

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VITILIGO IS DEPIGMENTED, BUT NOT ALL DEPIGMENTATION IS VITILIGO

In evaluating the causes of vitiligo, it is critical to be aware that melanocytes can be destroyed in depigmentary diseases other than vitiligo and by different immune mechanisms, and that different mechanisms may be involved in causing depigmentation in different conditions or experiments. To relate an immune abnormality to the pathogenesis of vitiligo, it is necessary to demonstrate not only that the abnormality is present but that it is responsible for the particular type of depigmentation that occurs in vitiligo. This becomes particularly important when relating immune abnormalities in melanoma or in animals with pigment loss to the pathogenesis of human vitiligo.

INDIRECT EVIDENCE THAT VITILIGO IS AN AUTOIMMUNE DISEASE Vitiligo is usually (2,3), but not invariably (4), associated with a 2- to la-fold increase in autoantibodies against numerous organs, particularly the thyroid, adrenals, and gastric parietal glands. Patients with vitiligo are also more likely to have autoimmune diseases such as Hashimoto's thyroiditis, Addison's disease, alopecia areata, pernicious anemia, chronic mucocutaneous candidiasis, and diabetes mellitus (1,5). Conversely, vitiligo is 10-15 times more common in patients suffering from certain autoimmune diseases. Other abnormalities in nonspecific parameters of humoral or cellular immunity have also been reported, but none has been consistent (6). Circulating T cells are variously reported as low (7) or normal (8) in number, and helper T cells and the helper/suppressor T-cell ratio as elevated (9) or decreased (8), and Langerhas cells in depigmented skin as increased, decreased, and normal. Other indirect observations that suggest that vitiligo could be an autoimmune disease include: 1.

2.

Vitiligo is a systemic disease. One quarter of patients with vitiligo have destruction of pigment cells in the eye (10), and choroidal depigmentation associated with panuveitis is common in Sinclair swines (II) and Smyth chickens (12), which develop vitiligo. Thus, vitiligo is a systemic process that can affect pigment cells in all parts of the body. Most effective treatments that induce repigmentation such as PUVA, topical steroids, and topical cytotoxic drugs are immunosuppressive, suggesting that their benefit results from suppression of local immune reactions damaging melanocytes.

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The improved clinical outcome of patients with melanoma and vitiligo suggest that immune reactions targeting malignant melanocytes can also destroy normal melanocytes. Bursectomy, which impairs antibody responses, and cyclosporin A, which inhibits T-cell-mediated immune responses, both delay the appearance and reduce the severity of vitiligo in Smyth chickens, suggesting that both humoral and cellular immue reponses may be involved in the pathogenesis.

Taken together, these observations indicate that the immune system is involved in vitiligo, but they cannot explain the selective damage to melanocytes that occurs in the disease.

DIRECT EVIDENCE THAT VITILIGO IS AN AUTOIMMUNE DISEASE Association of Vitiligo with Melanocyte Antibodies

The most convincing evidence that vitiligo is an autoimmune disease is that specific antibodies to melanocyte cell-surface antigens are present in most patients with vitiligo and that these antibodies can cause the disease when passively transferred into animals. These antibodies are referred to as vitiligo (VIT) antibodies. VIT antibodies were initially demonstrated by immunoprecipitation of melanocyte-surface antigens and by indirect immunofluorescence (13,14). Their presence has since been confirmed by multiple other procedures, including complement-dependent cytotoxicity (15), antibody-dependent cellular cytotoxicity (16), immunoblotting, live-cell and conventional ELISA (17,18), and passive transfer experiments (19). VIT antibodies are found in most patients with vitiligo, particularly in those with active disease (14), but are unusual in persons with nonpigmentary skin diseases. The antibodies target cell-swface antigens because: (a) the antigens can be radioiodinated by the lactoperoxidase technique, a procedure that labels only molecules exposed on the external surface of cells; (b) the antibodies give typical granular patterns of surface staining on viable melanocytes by indirect immunofluorescence; and (c) the antibodies can kill melanocytes in cytolytic assays. VIT Antibodies in Animals with Vitiligo

Antibodies to melanocytes also occur in a variety of animals that develop vitiligo, including Tervuren dogs, Siamese cats, Arabian horses, and Sinclair Copyrighted Material

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miniswines (20,21). They are present in 95% of Smyth chickens with vitiligolike depigmentation, but not in normally pigmented birds (22). The antigens targeted in these animals are similar to those defined by VIT antibodies in humans. Thus, humans and animals with vitiligo have similar immunological abnormalities.

Relation of VIT Antibodies to Vitiligo Activity The incidence and level of VIT antibodies correlates to the extent of depigmentation and to the activity of the disease. They have been reported in 50% of persons with minimal vitiligo and in 93% of those with more extensive disease (23). VIT antibodies have been reported in 80% of patients with active vitiligo but in none with inactive disease using a live cell ELISA assay (17) and in 85% of patients with active disease compared to 44% of those with inactive disease by complement-dependent cytolysis (15). The titer of VIT antibodies decreases in patients who respond to PUVA therapy (24), indicating that titer is related to disease activity.

VIT Antibodies Can Kill Melanocytes VIT antibodies can kill melanocytes in vitro by two different mechanisms: complement-dependent cytotolysis and an tibody-dependent cellular cytolysis (16). In a large study, Cui et al. found complement-dependent cytolytic melanocyte antibodies in 32% of 56 vitiligo patients but in only 6% of 47 control individuals (15). The antibodies reacted selectively to melanocytes, and their level was related to disease activity. Melanocytes are unusually susceptible to immune damage in comparison to other epidermal cells (16). The LD so of melanocytes to peroxidemediated injury (a major effector mechanism of injury mediated by immune cells) is 10 times greater than that ofkeratinocytes and 100 times greater than that of fibroblasts. Thus, even weak immune responses against melanocytes may injure these cells in vivo and may injure them without harming other cells that express the same antigens, resulting in selective destruction of melanocytes.

Induction of Vitiligo by VIT Antibodies The strongest direct evidence that vitiligo is an autoimmune disease is that the disease can be caused in animals by passive transfer of VIT antibodies. Purified IgG of vitiligo patients kills melanocytes in normal human skin in vivo when passively administered to nude mice grafted with human skin (19).

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IS CELLULAR IMMUNITY INVOLVED IN THE PATHOGENESIS OF VITILIGO? Until recently, cellular immunity was not believed to be involved in vitiligo as inflammatory cells are sparse in vitiligo lesions, although not completely absent (25-27). When present, the infiltrate is more prominent at the periphery of active lesions (26,28). The infiltrate consists predominantly of CD8 + T cells, but also contains CD3 +, CD4 +, T cells, and macrophages (28). The T cells express the skin homing receptor, cutaneous lymphocyte-associated antigen (CLA), and are activated as evidenced by increased expression of class II MHC (29), perforin, and granzyme-B (26,30). The infiltrating T cells are mainly clustered in the vicinity of disappearing melanocytes (30). Perilesionalmelanocytes express increased amounts of class II MHC and reAM-I, rendering them more susceptible to attack by T cells (31). These observations have been interpreted to mean that cellular immunity is not involved in vitiligo (because the infiltrate is sparse) or is involved (because the infiltrate is more prominent where' the lesions are most active). It has not been determined whether these abnormalities precede and hence are a possible cause of the disease or are a result of it. With the advent of very sensitive assays for antigen-specific T cells, it became possible to look for T cells reactive against melanocyte antigens in patients with vitiligo. Because these assays are new, only limited information is available. Ogg et al. reported that cytotoxic T lymphocytes (CTL) directed against the pigment cell-associated antigen Melan A/MART-I were present in 7 of9 HLA A*02-positive patients with vitiligo compared to I of 6 normal patients (32). The majority of the positve cells expressed the skin homing receptor CLA. As described below, T cells specifically targeting several pigment cell-associated antigens are present in animals with experimentally induced depigmentation of hair follicles, but the relation of this type of pigment loss to vitiligo is not clear. Overall, these observations suggest that cellular mechanisms may playa role in vitiligo, but the evidence is less direct and weaker than that for antibody responses.

WHICH ANTIGENS ARE TARGETED BY AUTOIMMUNE REACTIONS IN VITILIGO? The antigens targeted by anti-pigment cell immune responses in vitiligo are critical in the pathogenesis of the disease, as these antigens may be both the cause and/or the target of the process that kills melanocytes. The identification of these antigen(s) has been complicated by several erroneous assumptions: that any antigen targeted by antibodies or T cells in vitiligo is a cause of Copyrighted Material

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the disease even when the responses may be present in only a minority of patients, that the immune abnormalities present in melanoma are involved in vitiligo, and that any pigment cell antigen that is immunogenic in humans is involved in vitiligo. Whatever the antigens are, they must be expressed on the surface of melanocytes to account for their ability to kill these cells by complement- or antibody-dependent cellular cytotoxicity. Another clue to their nature is the reciprocal relationship between epidermal and hair follicle melanocytes. The first type of melanocytes is attacked in vitiligo, while the second is spared (hair follicles are the source of melanocytes in vitiligo lesions that repigment) (33), whereas the reverse occurs in alopecia areata, where pigmented hair follicles are preferentially attacked (34). This indicates that the antigenic properties of epidermal and hair follicle melanocytes differ, as confirmed experimentally (34), and that epidermal melanocytes express more of the antigen(s) recognized by vitiligo sera. Thus, at least some vitiligo antigens appear to be differentiation antigens expressed by only epidermal melanocytes. Multiple melanocyte antigens appear to be involved in vitiligo. VIT antibodies react to melanocyte antigens of 40-45, 75, and 90 kDa, denominated VIT40, VIT75, and VIT90. Antibodies to VIT90 are present in 35-45% of patients with vitiligo, but in only < 4% of individuals with unrelated skin diseases (35,36). Antibodies to VIT40 and to VIT75 are present in 74-76% and 57~72%, respectively, of vitiligo patients compared to in 4-14% and 48% of control individuals (35,36). All three antigens are cell-surface antigens as they are labeled by the lactoperoxisase technique, which preferentially labels surface proteins, and are poorly labeled by 3sS-methionine, which labels predominantly internal proteins (37). VIT90 is a pigment cell-associated antigen expressed most strongly by melanocytes and to a lesser extent by melanoma cells, and is undetectable on control cells. VIT40 and VIT75 are common tissue antigens expressed by most pigment and control cells, but they are expressed more strongly on melanoma than on melanocytes. VIT40 is either complexed, or shares an antigenic epitope, with class I HLA. VIT75 and VIT90 differ from most currently known pigment cell antigens as they do not co-migrate and/or are not immunoprecipitated by monoclonal antibodies to these antigens (37). In particular, VIT75 is unrelated to tyrosinase and to TRP-I, even though it is of similar size, because it does not react with monoclonal antibodies TA99 and TMH-L VIT90 is unrelated to gpl00, p97, or S100 as it does not react with monoclonal antibodies to these molecules (37). The fact that some vitiligo antigens may be normal tissue antigens also expressed by non-pigmented cells does not exclude their playing a role in the pathogenesis of vitiligo because melanocytes are unusually susceptible to damage by immune mechanisms (16). Thus, weak immune reactions to these antigens could damage melanocytes while sparing more resistant unrelated cells that express the same antigens. Copyrighted Material

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Another melanocyte surface antigen associated with vitiligo is the melanin-concentrating hormone receptor 1, antibodies to which have been reported in 16% of 55 patients with vitiligo but in none of 74 control individuals (38). Other antigens that have been associated with vitiligo include tyrosinase, gp75jTRP-l, TRP-2, gplOOjPmel17, and Melan-AjMART-1. However, the data indicative of their involvement in human vitiligo is weaker. Tyrosinase has been described as a vitiligo antigen because antibodies to it were initially described in a majority of vitiligo patients (39), CD8 + T cells against this antigen may present in patients with vitiligo (57), and because passive transfer of cytotoxic lymphocytes targeting a tyrosinase peptide can depigment hair follicles in mice (40). However, the association of tyrosinase antibodies with vitiligo has not been confirmed in more recent and larger studies (41,42). The relationship of depigmentation of hair follicles in mice to human vitiligo is unclear, as hair follicle melanocytes are normally spared in vitiligo, the association of vitiligo with T cells to tyrosinase has not been confirmed in other studies (48,49), and immunization to vaccines containing tyrosinase peptides rarely causes depigmentation even though it can induce T-cell responses against this antigen (55,56). Gp75, also known as tyrosinase-related protein-1 (TRP-I), has been described as a vitiligo antigen because antibodies to it were reported in one study (43), active (44) or passive (46) immunization to TRP-I depigments hair follicles in mice, and gp75 is similar in size and tissue distribution to VIT75 (45). However, the association of anti-TRP-I with vitiligo was not confirmed in subsequent studies (38), the loss of pigment in mice is restricted to regrowing hair follicles (46), which is not the melanocyte population targeted in vitiligo, and VIT75 and gp75 are immunologically distinct in immunodepletion experiments (35,36). Furthermore, gp75 is a cytoplasmic antigen, whereas VIT75 is on the cell-surface. Thus, while immune attack against gp75 can cause pigment loss, it is unlikely to be an antigen involved in the pathogenesis of vitiligo. Other antigens described as targets of immune responses in vitiligo include Melan-AjMART-l, TRP-2, andjor gp 100jpme1l7. The most consistent association has been with melan-AjMART-I, with T-cell responses against this antigen being reported in three studies (48,57,49), but the studies were small. A report that immunization to MART-l causes vitiligo is based on a single patient (50), and the pigment loss occurred only at sites of inflammation and blister formation, suggesting that it resulted from postinflammatory depigmentation rather than vitiligo. Reports that antibodies to TRP-2 (54,58) and gp100jpme1l7 (47) are often associated with vitiligo were not confirmed in a subsequent study (38), and T-cell responses to gp 100 are rare in patients with vitiligo (48,49,57). Lastly, immunization to these antigens does not cause pigment loss in mice (44) or humans (55 56), even though it can stimulate im~ftgfifRRfWtaterial

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A clue to the relative importance of the different VIT antibodies in the pathogenesis of the disease comes from the observation that while vitiligo is common in patients with VIT40, VIT75, and VIT 90 antibodies, it is relatively uncommon in patients with melanoma who have the same antibodies. This could be explained by VIT90 playing the predominant role in pathogenesis as this antigen is expressed more strongly on melanocytes than on melanoma cells. ROLE OF IMMUNE MECHANISMS IN THE PATHOGENESIS OF VITILIGO The presence of antibodies to melanocytes in patients with vitiligo, their absence in persons without this disease, and the selective expression of vitiligo antigens on melanocytes provide the essential framework required for vitiligo to be an autoimmune disease. This immune abnormality appears to actually mediate the disease because it appears before rather than after the onset of depigmentation, there are relations between the presence and level of antipigment cell immune responses and the extent and activity of the vitiligo, and because the disease can be passively transferred with antibodies. Key issues in terms of the pathogenic role of the irrul1une abnormalities associated with vitiligo include: I.

2. 3.

Can anti-pigment cell immune responses actually injure melanocytes in vivo or are they simply interesting epiphenomena? Are these immune abnormalities a cause or an effect of the disease? Ifimmune mechanisms do cause pigment cell destruction in vitiligo, how do they do so?

Anti-Pigment Cell Immune Responses Can Injure Melanacytes In Vivo Passive and active immunization studies in mice indicate that antibodies or T cells directed against pigment cell antigens can each individually cause depigmentation. Depigmentation can be caused by purified IgG antibodies or by T cells alone (51). Passive administration of human VIT antibodies to nude mice grafted with normal human skin causes loss of pigmentation in the skin (19). Depigmentation has been induced in mice by immune responses directed to any of several different antigens, including tyrosinase (52), TRP-l (44,53), and TRP-2 (54), and in humans by immune cells targeted against MART-l (SO). While it is unclear whether depigmentation in mice is vitiligo because the melanocytes that are damaged reside in hair follicles rather than in the epidermis, these experiments clearly demonstrate that melanocytes can be

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destroyed in vivo by either antibody or T cells alone and that the damage can be caused by immune responses directed against anyone of several different pigment cell-associated antigens. Which particular immune mechanism and antigen(s) cause vitiligo remains uncertain. As described below, the strongest evidence indicates that vitiligo is the result of an antibody response directed against several different melanocyte antigens.

Immune Abnormalities Associated with Vitiligo: Cause or Result? The strongest evidence that the immune abnormalities are a cause rather than a result of pigment loss comes from studies in Sinclair swine and Smyth chickens with spontaneous depigmentation, where circulating pigment cell antibodies usually appear before the onset of pigment loss (21,22). That, together with the fact that neonatal bursectomy in chickens minimizes depigmentation, suggests that VIT antibodies are not a result of pigment cell destruction. If autoimmune responses against melanocytes are the cause of vitiligo, the stimulus for their appearance remains unknown. One intriguing possibility is tha t it results from exposure to cross-reacting antigens expressed by microorganisms. This is suggested by the high incidence of anti-pigment cell antibodies in patients with chronic mucocutaneous candidiasis (13,14).

Mechanisms of Immune Damage to Melanocytes in Vitiligo Because depigmentation can be caused in vivo by either humoral or cellular immune mechanisms alone, vitiligo could result from either or both of these mechanisms. The available evidence is stronger for antibody responses being the primary mechanism for the following reasons: I.

2. 3. 4. 5. 6.

Multiple large studies confirm the association of vitiligo with antipigment cell antibodies. These antibodies are also present in animals with vitiligo. There is an association between the presence and level of VIT antibodies and the extent and activity of vitiligo. VIT antibodies precede, rather than follow, the appearance of vitiligo in animals. VIT antibodies can kill human melanocytes in vitro and in vivo. Passive transfer of VIT antibodies induces the disease in animals.

In contrast, the evidence supporting a role for cellular mechanisms consists of: (a) the presence of a sparse cellular infiltrate most pronounced at the border of active lesions; (b) the ability of T cells targeted against

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melanocyte antigens to cause depigmentation in vivo; and (c) one small study demonstrating an association between anti-pigment cell T cells and vitiligo. The actual mechanism(s) by which VIT antibodies kill melanocytes are probably multiple, and include both complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, as pigment cells can be killed in vitro and in vivo by both mechanisms. Immune responses against any of a number of pigment cell antigens can result in the killing ofmelanocytes in vivo. The specific antigen(s) targeted by the autoimmune responses in vitiligo are probably multiple and remain to be fully defined. They include cell-surface antigens of 40, 75, and 90 kDa. As some of these antigens are preferentially expressed by pigment cells, whereas others are common tissue antigens, two distinct mechanisms may mediate the selective destruction of melanocytes in vitiligo. One is an immune response directed to antigens preferentially expressed by melanocytes, such as the 90kDa antigen. The other is immune responses against common tissue antigens that are also expressed by cells other than melanocytes (such as the 40 and 75 kDa antigens). These could nonetheless damage melanocytes selectively, as these cells are much more sensitive to immune injury than unrelated cells expressing the same antigens. SUMMARY

There is considerable evidence that vitiligo is an autoimmune disease mediated by immune reactions directed against melanocytes. The particular immune mechanism(s) involved in the disease remains to be fully defined, but the current evidence p-oints to humoral (VIT antibodies) responses playing the predominant role. ACKNOWLEDGMENTS

Supported in part by USPHS Research Grants NIH Grant 5 ROI CA8927002 and by grants from the Rose M. Badgeley Residuary Trust. REFERENCES I.

2. 3.

Lerner AS, Nordlund JJ. Vitiligo: what is it? Is it important? JAMA 1978; 239:1183-1187. Bor S, Feiwel M, Chanarain I. Vitiligo and its aetiological relationship to organspecific autoimmune disease. Br J Dermatol 1969; 81:83-88. Howitz J, Schwartz M. Vitiligo, achlorhydria and pernicious anemia. Lancet 1971; 1:1331-1335.

Copyrighted Material

Vitiligo: The Autoimmune Hypothesis 4. 5. 6.

7. 8. 9.

J O. II.

12. 13. 14. 15. 16.

17.

18.

19.

20.

21.

89

Woolfson H, Finn OA, Mackie RM, el al. Serum anti-tumor antibodies and autoantibodies in vitiligo. Br J Dermatol 1973; 88: 127-137. Ortonne JP, Mosher DB, Fitzpatrick TB, ed . Vitiligo and other hypomelanoses of hair and skin. New York: Plenum, 1983:J29-130. Bystryn J-C, Cui J. Vitiligo. In: Bona CA, Siminovitch KA, ZaneLli M, Theofilopoulos AN, eds. The Molecular Pathology of Autoimmune Diseases. Switzerland: Hardwood Academic, 1993:556-561. Brown AC, Olkowski Z, MacLaren J, et al. Alopecia areata and vitiligo associated with Down's syndrome. Arch Dermatol 1977; J 13: 1269. Grimes PE, Ghoneum M, Stockton T. T cell profile in vitiligo. J Am Acad Dermatol 1986; 14, 196-20 I. Soubiranm P, Benzaken S, Bellet C, et al. Vitiligo: peripheral T-cell subset imbalance as defined by monoclonal antibodies. Br J Dermatol 1985; 113(suppl 28):J24-127. Wagoner A, Lerner A, et al. New observations on vi tiligo and ocular disease. Am J Ophthalmol 1983; 96:16-26. Burns RP, Feeney-Burns L, Hook RR, et al. ARVO Abstracts. Vol. 12. St. Louis: CV Mosby, 1980. Smyth JR, Boissy RE, Fite KV, et al. Retinal dystrophy associated with a postnatal amelanosis in the chicken. Invest Ophthalmol Vis Sci 1981; 20:799. Naughton GK, Eisinger M, Bystryn J-c. Antibodies to normal human melanocytes in vitiligo. J Exp Med 1983; 158:246-251. Bystryn J-C, Naughton GK. The significance of vitiligo antibodies. J Dermatol 1985; 12:1-9 Cui J, Arita Y, Bystryn J-c. Cytolytic antibodies to melanocytes in vitiligo. J Invest Dermatol 1993; 100:812-815. Norris DA, Capin L, Muglia JJ, et al. Enhanced susceptibility of melanocytes to different immunologic effector mechanisms in vitro: potential mechanisms for postinflammatory hypopigmentation and vitiligo. Pigment Cell Res Suppl 1988; 1:113-123 Harning R, Cui J, Bystryn J-c. Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Derm 1991; 97:1078-1080 Fishman P, Azizi E, Shoenfeld Y, Sredni B, Yecheskel G, Ferrone S, Zigelman R, Chaitchik S, Floro S, Djaldetti M. Vitiligo autoantibodies are effective against melanoma. Cancer J993; 72(8):2365-2369. Gilhar A, Zelickson B, Ulman Y, Etzioni A. In vivo destruction ofmelanocytes by the IgG fraction of serum from patients with vitiligo. J Invest DermatoJ 1995; 105:683-686. Naughton GK, Mahaffey M, Bystryn J-c. Antibodies to surface antigens of pigmented cells in animals with vitiligo. Proc Soc Exp Bioi Med 1986; 181 :423426 Cui J, Chen D, Misfeldt M, Swinfard R, Bystryn J-c. Antimelanoma antibodies in swine with spontaneously regressing melanoma. Pigment Cell Res 1995; 8:60-63.

Copyrighted Material

90

Bystryn

22.

Austin LM, Boissy RE, lacobson BS, Smyth lR lr. The detection of melanocyte autoantibodies in the Smyth chicken model for vitiligo. Clin Immunol Immunother 1992; 64(2): 112-120. Naughton GK, Reggiardo MD, Bystryn l-C. Correlation between vitiligo antibodies and extent of depigmentation in vitiligo. 1 Am Acad Dermatol 1986; 15:978-981. Hann S-K, Chen DL, Bystryn 1-C. Systemic steroids suppress anti-melanocyte antibodies in vitiligo. 1 Cutan Med Surg, 1997; 1:193-195. Van Den Wijngaard R, Wankowicz-Kalinska A, Pals S, Weening 1, Das P. Autoimmune melanocyte destruction in vitiligo. Lab Invest 2001; 81(8):10611067. AlBadri AMT, Todd PM, Gariochi 11, Gudgeon lE, Stewart DG, Goudie RB. An immunohistological study of cutaneous lymphocytes in vitiligo. 1 Pathol 1993; 170:149-155. Nordlund 11, Lerner AB. Vitiligo: it is important. Arch Dermatol 1982; 11"8:5-8. LePoole IC, van den Wijngaard RM1Gl, WesterhofW, Das PK. Presence ofT cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am 1 Pathol 1996; 148(4):1219-1228. Abdel-Naser MB, Ludwig W-D, Gollnick H, Orfanos CEo Nonsegmental vitiligo: decrease of the CD45RA + T-cell subset and evidence for peripheral T-cell activation. Int 1 Oermatol 1992; 31(5):321-326. Van den Wijngaard R, Wankowicz-Kalinska A, LePoole C, Tigges B, Westerhof W, Das P. Local immune response in skin of generalized vitiligo patients; destruction ofmelanocytes is associated with the prominent presence ofCLA + T cells at the perilesional site. Lab Invest 2000; 80(8):1299-1309 Al Badri AMT, Foulis AK, Todd PM, Garioch 11, Gudgeon JE, Stewart OG, Gracie lA, Goudie RB. Abnormal expression ofMHC class II and ICAM-I by melanocytes in vitiligo. 1 Pathol 1993; 169:203-206. Ogg GS, Dunbar PR, Romero P, Chen lL, Cerundolo V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo.l Exp Med 1998; 188(6)1203-1208 Cui 1, Shen L, Wang G. Role of hair follicles in the repigmentation of vitiligo. 1 Invest Dermatol 1991; 97:410-416. Tobin 01, Bystryn l-C. Different populations of melanocytes are present in hair follicles and epidermis Pigment Cell Res 1996; 9:304-310. Cui 1, Harning R, Henn M, Bystryn lC. Identification of pigment cell antigens defined by vitiligo antibodies. 1 Invest Dermatol 1992; 98: 162-165. Cui 1, Bystryn l-C. Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol 1995; 131:314318 Cui 1, Arita Y, Bystryn l-C. Characterization of vitiligo antigens. Pigment Cell Res 1995; 8:53-59. Kemp EH, Waterman EA, Hawes BE, O'Neill K, Gottumukkala VSRK, Gawkrodger Dl, Weetman AP, Watson PF. The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. 1 C1in Invest 2002; 109(7):923-930

23.

24. 25.

26

27. 28.

29.

30.

31.

32.

33. 34. 35. 36.

37. 38.

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39. 40.

41. 42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

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Song YH, Connor E, Li Y, Zorovich B, Maclaren N. The role of tyro inase in autoimmune vitiligo. Lancet 1994; 344:1049-1052. Colella TA, Bullock NJ, Russell LB, Mullins DW, Overwijk WW, Luckey CJ, Pierce RA, Restifo NP, Engelhard VH. Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy. J Exp Med 2000; 191;7:1221-1231. Xie Z, Chen D, Jiao D, Bystryn J-c. Vitiligo antibodies are not directed to tyrosinase. Arch Dermatol 1999; 135:417-422. Kemp EH, Gawkrodger OJ, MacNeil S, Watson PF, Weetman A. Detection of tyrosinase autoantibodies in patients with vitiligo using 35 S-Iabeled recombinant human tyrosinase in a radioimmunoassay. J Invest Demlatol J997; 109: 69-73. Kemp EH, Waterman EA, Gawkrodger OJ, Watson PF, Weetman AP. Autoantibodies to tyrosinase-related protein-l detected in the sera of vitiligo patients using a quantitative radiobinding assay. Br J Dermatol 1998; 139:798-805. Overwijk WW, Lee OS, Surman DR, Irvine KR, Toulokian E, Chan CC, Carroll MW, Moss B, Rosenberg SA, Restifo NO. Vaccination with a recombinant vaccina virus encoding a "self' antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4 + T lymphocytes. Proc Natl Acad Sci 1999; 96:2982-2987. Houghton AN, Vijayasaradhi S, Bouchard B, Naftzger C, Hara I, Chapman PB. Recognition of autoantigens by patients with melanoma. In: Bystryn J-C, Ferrone S, Livingston P, eds. Specific Immunotherapy of Cancer with Vaccines (Annals of the NY Academy of Sciences, Vol 690). New York: New York Academy of Sciences, 1993:59-68. Hara I, Takechi Y, Houghton AN. Implicating a role for immune recognition of self in tumor rejection: passive immunization against the brown locus protein. J Exp Med 1995; 1821609-1614 Kemp EH, Gawkrodger OJ, Watson PF, Weetman AP. Autoantibodies to human melanocyte-specific protein pme1l7 in the sera of vitiligo patients: a sensitive and quantitative radioimmunoassay (RIA). Clin Exp Immunol 1998; 114:333-338 Ogg GS, Dunbar PR, Romero P, Chen JL, Cerundol0 V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med 1998; 188(6): 1203-1208. Lang KS, CaroJi CC, Muhm A, Wernet 0, Moris A, Schittek B, KnaussScherwotz E, Stevanovic S, Rammensee HG, Garbe C. HLA-A2 restricted, melanocyte-specific CD8 + T lymphocytes detected in vitiligo patients are related to disease activity and are predominantly directed against MelanAj MARTI. J Invest Dermatol2001; 116:891-897. Yee C, Thompson JA, Roche P, Byrd DR, Lee PP, Piepkorn M, Kenyon K, Davis MM, Riddell SR, Greenberg PD. Melanocytes destruction after antigenspecific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo. J Exp Med 2000; 192: 1637-1643 Bowne WB, Srinivasan R, Wolchok JD, Hawkins WG, Blachere NE, Dyall R, Lewis JJ, Houghton AN. Coupling and uncoupling of tumor immunity and autoimmunity. J Exp Med 1999; 190:1717-1722.

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Colella TA, Bullock TNJ, Rusell LB, Mullins DW, Overwijk WW, Luckey CJ, Pierce RA, Restifo NP, Engelhard VH. Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy. J Exp Med 2000; 191:1221-1231. Trcka J, Moroi Y, Clynes RA, Goldberg SM, Bergtold A, Perales MA, Ma M, Ferrone CR, Carroll MC, Ravetch JV, Houghton AN. Redundant and alternative roles for activating Fc receptors and compliment in an antibody-dependent model of autoimmune vitiligo. Immunity 2002; 16:861-868. Okamoto T, et a!. Anti-tyrosinase related protein-2 immune response in vitiligo and melanoma patients receiving active-specific immunotherapy. J Invest Dermatol 1998; III: 1034--1039. Schaed SG, Klimek VM, Panageas KS, Musselli CM, Butterworth L, Hwu WJ, Livingston PO, Williams L, Lewis JJ, Houghton AN, Chapman PB. T-Cell responses against tyrosinase 368-376(370D) peptide in HLA * A0201 + melanoma patients: randomized trial comparing incomplete Freund's adjuvant, granulocyte macrophage colony-stimulating factor, and QS-21 as immunological adjuvants. Clin Cancer Res 2002; 8:967-972. Reynolds SR, Zeleniuch-Jacquotte A, Shapiro RL, Roses DF, Harris MN, Johnston D, Bystryn J-c. Vaccine-induced CD8 + T-cell responses to MAGE-3 correlate with clinical outcome in patients with melanoma. Clin Cancer Res 2003; 9:657-662. Palermo B, Campanelli R, Garbelli S, Mantovani S, Lentelme E, Brazzelli V, Ardigo M, Borroni G, Martinetti M, Badulli C; Necker A, Giachino C. Specific cytotoxic T lymphocyte responses against Melan-A/MARTI, tyrosinase and gp I00 in vitiligo by the use of major histocompatibility complex/peptide tetramers: the role of cellular immunity in the etiopathogenesis of vitiligo. J Invest Dermatol 200 I; I 17:326-332. Kemp EH, Gawkrodger DJ, Watson PF, Weetman AP. Immunoprecipitation of melanogenic enzyme autoantigens with vitiligo sera: evidence of cross-reactive autoantibodies to tyrosinase and tyrosinase-related protein-2 (TRP-s). Clin Exp Immunol 1997; 109:495-500.

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8 Vitiligo: A Disorder of the Microvessels?

Elena Del Bianco, Giuseppe Muscarella, and Torello Lotti University of Florence, Florence, Italy

Pathogenetic hypotheses of vitiligo include a synergistic one, which indicates that several simultaneous processes (autoimmune, neurobiological, oxidative, infective) could induce, in genetically predisposed subjects, the disappearance of melanocytes at the cutaneous level. The complex of these events eventually produces the appearance of cutaneous nonpigmented patches. IMMUNONEUROENDOCRINE SYSTEM INVOLVEMENT IN VITILIGO

Immunoneuroendocrine system involvement in this pattern of events is suggested by clinical, ultrastructural, and biochemical data. Clinically a segmental distribution of depigmented areas is described in some patients in which vitiligo involves different derma tomes. Occasionally vitiligo has been described as truly dermatomal, e.g., limited to the distribution of trigeminal nerve (I). Moreover, neuronal involvement is supported by other clinical observations: Vitiligo developed in the area supplied by nerves damaged in a brachial plexus injury (2), and it was described in association with viral encephalitis (3) and with Horner's syndrome due to multiple sclerosis (4). In animals it was demonstrated that denervation alters skin pigmentation (5) and that nerve stimulation lightens pigmentation by aggregating melanosomes (6). At the microscopic level studies have shown the presence of nerve fibers in contact with melanocytes, degenerative and regenerative processes in Copyrighted Material

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terminal cutaneous nerve fibers, and altered immunoreactivity for neuropeptides and general neuronal markers in the skin of vitiligo patients (7,8). These neuronal alterations suggest involvement of the autonomic nervous system in events leading to the destruction of melanocytes. AI'Abadie et al. (9) proposed that neuropeptides released in vitiligo patients by endogenous (stress) or exogenous stimuli (traumatic events as in Koebner phenomenon) may initiate a cascade of reactions, involving both the immune system and the vascular system, resulting the destruction of melanocytes. Interestingly, Mozzanica et al. (10) showed an increase in ~-endorphin and met-enkephalin in the plasma of vitiligo patients. Moreover, it is known that neuropeptides can have a stimulatory or inibitory effect on immune cells and are potent vasoactive agents, so that they could be the mediators of the sweating alteration reported in vitiliginous skin (11). Cutaneous microcirculation could represent an important "bridge" between nervous system and melanocytes, which are often a target of neurotransmitters released by cholinergic endings. The sympathetic nervous system has a profound effect on the blood flow through the skin (12), mostly affecting the arterioles and arteriovenous anastomoses, i.e., thermoregulatory vessels. Therefore, one could hypothesize that assessment of cutaneous blood flow can be used as a parameter to reflect the sympathetic nerve function of a certain skin area and that analysis of microcirculation in vitiligo patients could help clarify the pathogenetic mechanism of depigmentation. LASER-DOPPLER FLOWMETRY Laser-Doppler flowmetry (LDF), like other methods for the analysis of microcirculation, can represent a useful tool in vitiligo research. This noninvasive technique provides a semiquantitative assessment of microvascular blood perfusion. LDF measurements from the skin reflect blood flow in capillaries, arterioles, and venules, including in the upper papillary plexus. Detection is not influenced by blood flow to underlying skeletal muscle. Traditional laser-Doppler f10wmeters consist of a helium-neon laser of wavelength 632.8 nm that, via an optical fiber applied on the skin, is assumed to penetrate 1-2 mm below the skin surface. This wavelength corresponds to an optical window in the skin spectrum, which means that at this wavelength the skin is completely translucent. In the tissue a part of the incident light is backscattered with the same wavelength by anatomical static structures and another part is backscattered with a shift in wavelength by moving red blood cells. Only the second part is collected and assessed; the mean spectrum of shifted wavelengths is computed. The blood flow is determined by the product of the number of red blood cells moving in the measured volume (within the surface capillaries of the skin) and the mean velocity of these blood cells. The

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result is a signal with the dimension of a flux (a moving volume) but given in arbitrary units (volts). The curve shows cardiac pulsations on which are superimposed lower frequency vasomotion waves. A software program is available to fully analyze the signal: select the frequency of rhythmical variations, measure the slope of a change, maximum, minimum, and medium values between two points, and make almost any measurements (13).

LDF IN VITILIGO At the cutaneous level is present a complex microcirculatory network that is different in different body regions and that is regulated by numerous physical, chemical, and biological factors. Therefore, before testing by LDF, the patient should rest lying down on a bed for 15 minutes in a room where the temperature is kept at between 22 and 23°C. Moreover, in vitiligo analyses by LDF, several authors reported that it had been necessary to examine both depigmented patches and healthy surrounding areas in order to compare the microcirculatory blood flow (14). Recently, a marked increase in cutaneous blood flow was demonstrated by LDF in segmental-type vitiligo as compared to contralateral normal skin, while a weak difference was found among nonsegmental-type vitiligo, lesion side clinically normal skin, and contralateral normal skin (14). These data correia te with those obtained in our previous study involving vitiligo patients, without differentiating among the two types of vitiligo (segmental and nonsegmental). In fact, our results show blood flow weakly increased in vitiligo patches in comparison with surrounding clinically normal skin (Fig. 1). However using LDF we found in all patients examined an interesting increase in blood flow in repigmenting lesions that resulted in almost two times greater blood flow measured in normal skin at least 2 cm away from the lesions (Fig. 2) (15). It is possible that a regulation of cutaneous vessels, probably through sympathetic nerve fibers, represents an important step in the recovery of depigmented areas; on the other hand, it could be a concurrent phenomenon not yet described. The existence of a correlation between melanogenesis, pigmentation, and functional changes in cutaneous microcirculation is suggested by studies that show an abnormal local pigmentation after venous stasis or after therapeutic venous sclerosis (16). Wu and co-workers showed a disturbance of sympathetic nerve functions in the vitiliginous skin and that this dysfunction plays a role in the pathogenesis of segmental-type vitiligo (14). Based on these preliminary observations, LDF and other methods for analysis of cutaneous microcirculation could be used to study microvascular alteration in vitiligo. Submitting vitiligo patients to periodic LDF analysis Copyrighted Material

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could be useful to assess the evolution of the pathology after therapeutic treatments in order to evaluate efficacy. Further research in this field could document the mechanism by which microcirculation plays a role in the pathogenesis of vitiligo.

REFERENCES 1. 2.

3. 4.

5. 6.

7. 8.

9. 10.

11. 12. 13. 14.

15.

16.

Lerner AB. Vitiligo. J Invest DermatoJ 1959; 32:285-310. Costea V. Leukoderma patches in the course of traumatic paralysis of the brachial plexus in a subject with insular cavities. Dennatol Venereol 1961; 2: 161166 Nellhaus G. Acquired unilateral vitiligo and poliosis of the head and subacute encephalitis with partial recovery. Neurology 1970; 20:965-974. Jonesco-Siseti MM, Vasilesco N, Palade G. Sclerose en plaques avec syndrome de Claude Bernard-Horner et vitiligo. Bull Mem Soc Hop Paris 1973; 53:941944 Fabian G. The spread of black pigment of the denervated skin of the guinea pig. Acta BioI Acad Sci Hung 1951; 4:471-480. Mosher DB, Fitzpatrick TB, Ortonne JP, Hory Y. Abnormalities of pigmentation. In: Fitzpatrick TB, Eisen AZ, Wolff KIM, Freedberg KF, eds. Dermatology in General Medicine. 3d ed. New York: McGraw-Hill, 1987:794876 Chanco-Turner ML, Lerner AB. Physiological changes in vitiligo. Arch Dermatol 1965; 91:390-396. Liu PY, Bondesson L, Lontz W, Johansson O. The occurrence of cutaneous nerve endings and neuropeptides in vitiligo vulgaris: a case-control study. Arch Dermatol Res 1996; 288:670-675. Al'Abadie MSK, Senior HJ, Bleehen SS, Gawkrodger DJ. Neuropeptide and neuronal marker studies in vitiligo. Br J Dermatol 1994; 131: 160-165. Mozzanica N, Villa ML, Foppa S, et al. Plasma alpha-melanocyte-stimulating hormone, beta-endorphin, met-en kephalin, and natural killer cell activity in vitiligo. JAm Acad Dermatol 1992; 26:693-700. Lerner AB. Vitiligo. Prog Dermatol 1972; 6: 1-6. Fox RH, Edholm OG. Nervous control of cutaneous circulation. Br Med Bull 1963; 19:110-114. Halloway GA, Watkins DW. Laser doppler measurement of cutaneous blood flow. J Invest Dermatol 1977; 69:306-309. Wu C, Yu H, Chang H, Yu C, Wu B. Cutaneous blood flow and adrenoceptor response increase in segmental-type vitiligo lesions. J Dennatol Sci 2000; 23:5362. Del Bianco E, Muscarella G, Lotti T. La vitligine: un disturbo microcitcolatorio? Lotti Ted. UTET. Milano: La vitiligine. Nuovi concetti e nuove terapie, 2000: 31-33 Milan. Merlen JF, Coget J, Sarteel AM. Pigmentation in venous stasis. Phlebologie 1983; 36304-314

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9 Pathogenesis of Vitiligo: Evidence for a Possible Ongoing Disorder of the Cutaneous Microenvironment Giuseppe Hautmann, Silvia Moretti, and Torello Lotti University of Florence, Florence, Italy

Jana Hercogova Charles University, Prague, Czech Republic

INTRODUCTION The characteristic histological picture of vitiligo is the total absence of melanin and melanin-forming cell, or melanocytes, with an otherwise normal dermis and epidermis (1--4). The etiology of this event is unknown, and several hypotheses have been proposed to explain the loss of melanocytes. Thus, the pathogenesis of vitiligo is still not known. There are many hypotheses extant, each supported by intriguing data that currently are insufficient to prove the accuracy of the theories. Among the hypotheses so far suggested, the most important seem to be (a) the autoimmune theory, (b) the intrinsic/genetic theory, (c) the autocytotoxic theory, and (d) the neural theory. An eclectic theory has also been suggested.

AUTOIMMUNE THEORY Clinical and experimental data seem to demonstrate the role of an autoimmune reaction in the pathogenesis of vitiligo. In particular, recent data

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underline the relevant role of autoantibodies and of autoreactive T lymphocytes against melanocyte-derived antigens. Briefly, the clinical and epidemiological findings that support this hypothesis are as follows (Table I):

I.

2. 3.

4.

There are many reports of vitiligo in association with organ-specific autoimmune diseases, such as Hashimoto's thyroiditis, hyperthyroidism, Addison's disease, pernicious anemia, juvenile diabetes mellitus, and alopecia areata. In particular, vitiligo represents a common clinical feature (10-15% of the cases) of the so-called autoimmune polyglandular syndromes, which consist of the association of several autoimmunological disorders of thyroid, adrenal glands, blood (pernicious anemia), pancreas (insulin-dependent diabetes mellitus), and chronic mucocutaneous candidiasis (5). Vitiligo often represents a clinical mark of autoimmune diseases that are clinically or subclinically evident (6,7). In a follow-up study lasting 10 years, it has been shown that among the clinically healthy relatives of subjects with vitiligo, disease onset occured in 11.3% of the relatives with antithyroid and/or gastric mucosae autoantibodies and in 0.9 of the relatives without these autoantibodies (6,7); Topical application or systemic administration of corticosteroids can stop disease progression and induce cutaneous repigmentation (8,9).

The experimental findings supporting the autoimmune hypotheses are as follows. Vitiligo patients very often (20-30%) present with organ-specific autoantibodies (mainly directed to thyroid or gastric autoantigens). Similar abnormalities are found in first-degree normal relatives (10-12). Eighty percent of vitiligo patients present with autoantibodies to melanocytic antigens; in normal control subjects these antibodies are present in

TABLE

1

Factors Supporting the Autoimmune Hypothesis

Association with organ specific autoimmune disease Clinical mark of autoimmune diseases clinically or subclinically evident Onset in 11.3% of clinically healthy relatives with antithyroid and/or gastric mucosae autoantibodies Improvement with topical application or systemic administration of steroids Organ-specific circulating autoantibodies in 20-30% of cases Autoantibodies to melanocytic antigens in 80% of cases Role of autoreactive T lymphocytes

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10% of cases. These autoantibodies are usually immunoglobulins of the G class (lgGl, 2, 3) and rarely are IgA. Several laboratory techniques are able to detect them; the incidence and level of antibodies correlates with the extent of depigmentation and the activity of the disease. Vitiligo antibodies have the functional capacity to kill pigment cells by two different mechanisms: complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. The principal target of antimelanocyte antibodies in vitiligo seems to be reprensented by tyrosinase, the key enzyme of melanogenesis. The molecular weight of tyrosinase is 69-75 kDa. Serum antibodies against tyrosinase, a 6975 kDa protein, were detected in 77% of vitiligo patients, 12% of patients with autoimmune endocrine disease without vitiligo or a history of vitiligo, and 0% of normal controls. Antibodies to tyrosinase are prevalently detected during the phases of activity of the disease and in subjects with a great extent of depigmentation. In the serum of vitiligo patients there are other antibodies directed most commonly to the 40-45, 75, and 90 kDa antigens, designated Vit45, VIT75, and VIT90, respectively; these antigens are preferentially (VIT90) expressed on the melanocyte surface. Antibodies to VIT45 and to VIT75 are present in 74-76% and in 57-72% of vitiligo patients, respectively, compared to in 4-14% and in 4-8% of control individuals. Research on transplantation of human lesional skin on athymic mice has clarified the possible pathogenetic role of these autoantibodies. In this experimental setting, the lesional skin repigments, whereas in normal human transplanted skin there is a massive loss of melanocytes after infusion of IgG of vitiligo patients (10-26). Beyond the possible pathogenetic role of these specific autoantibodies, some researchers underline the relevant role of autoreactive T lymphocytes; microscopic analysis shows these cells strictly apposed to aberrant melanocytes and vacuolized keratinocytes, at the lesional border of the active macules; the cellular infiltrate is located mainly under the dermoepidermal junction and is poorly represented at the lesional border of active vitiligo vulgaris, whereas it is abundant in inflammatory vitiligo. Immunohistochemical investigation demonstrated that the cellular infiltrate consists mostly of CD8+ T cells and CD36+ macrophages.The T lymphocytes are CD25+ and DR+ (presenting the signs of activated cells) and are near to basal keratinocytes and melanocytes that express on their surface high levels ofICA M-I and HLA-II molecules. The amount of cell infiltrate in the inflammatory vitiligo correlates with the progressive degeneration and subsequent loss of melanocytes. The characterization of the autoantigens recognized by the T lymphocytes has to be exactly defined, although some data seem to suggest that these are melanocytic differentiation antigens (MDA), such as tyrosinase and Melan-A/MART-I. In fact, if precursors of autoreactive tyrosinasespecific circulating T cells of normal subjects are activated in vitro by a Copyrighted Material

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synthetic tyrosinase-analogue nona peptide, these cells are cytolytic for target cells expressing the antigen on their surface (both constitutively and by passive adhesion). Moreover, in vitiligo subjects there have been demonstrated circulating lymphocytes expressing on their surface a specific hormone receptor able to recognize and lyse HLA-A201 + Melan-A/MART-I + melanocytes (27-34). Finally, experimental studies by Boissy utilizing animal models able to develop vitiligo-like lesions confirm the pathogenetic role of autoreactive T lymphocytes in vitiligo. Thus, it seems demonstrated that the cellular infiltrate is subsequent to the presence of aberrant melanocytes, and that there is not the total loss of melanocytes if neonatal bursectomy, that blocks the onset of the inflammatory infiltrate, is done. These experimental data seem to suggest that the T cell-mediated citotoxicity do not happen in the early phases of the melanocytic damage but is very relevant in the subsequent phases, with the complete depletion of residual melanocytes (33,34). INTRINSIC/GENETIC HYPOTHESIS

This hypothesis emphasizes the central role of a genetically determined susceptibility of melanocytes to environmental factors. At the basis of this hypothesis are several genetic studies demonstrating a genetic predisposition to the phenotypic expression of the disease. In particular, Nath and coworkers and Ramaiah and co-workers (35,36), observing the highest incidence of vitiligo (90.38%) among the Soma Vanishan people in Bangalore, indicated that at least three diallelic unlinked genes are involved in the expression of the disease, so that vitiligo could be considered a polygenic disorder (37). The genetic factors would be able to determine the expression of the disease because they can provoke an increased susceptibility of the melanocyte to several environmental stimuli. This susceptibility has been demonstrated on the basis of both in vitro studies on cultured melanocytes of vitiligo subjects and studies on animal models (38-41). In brief, the research data show that the cultured melanocytes of vitiligo patients present a decreased capacity of growth and proliferation; moreover, they present a decreased and/ or aberrant expression of specific proteins, such as the receptor for SCF (cKit) or the tyrosinase-related protein (TRP-I). Research on animal models confirmed these results and demonstrated the particular sensibility of melanocytes to cell vitality conditioning factors (apoptotic factors) secreted by follicular keratinocytes (42). Moreover, studies on professional vitiligo (vitiligo induced by contact with phenol deriva tives, idroquinone, or catechols) seem to confirm that many depigmentating agents are able to explain their

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activity not aspecifically but as specific cytotoxic agents to genetically susceptible melanocytes (43,44).

AUTOCYTOTOXIC HYPOTHESIS This hypothesis was introd uced by Lerner in 1971 and suggests tbat there is a self-destruction of melanocytes by toxic prod ucts made by tbese cells because of a defect of the natural protective mechanisms that take away the toxic precursors of melanin (45) (Table 2). Experimental evidence supporting this interpretation is as follows:

I. Electron microscopic studies have demonstrated tbat in tbe achro-

2.

3.

mic lesional skin of rapid expanding vitiligo, there is an extracellular storage of granular material in the epidermis. Melanocytes and keratinocytes present vacuolization that is a morpbological expression of early cellular oxidative damage (46). It bas been shown that several depigmentating agents (hidroquinone, catechol, etc.) may bave selective cytotoxic effects on melanocytes; tbe ultrastructural features of this damage overlap the bistological picture of vitiligo (47,48). In vitro and in vivo experimental studies have demonstrated an increased susceptibility of melanocytes to substances produced during melanin synthesis, such as tyrosine-like molecules, melanin precursors, or intermediate metabolites (in particular, phenolic derivatives and dopa-chinones) (49).

Recently, biochemical studies have documentated that tbe intracellular storage of reactive oxygen intermediates (superoxide anion radical, hydrogen peroxide, bydroxyl radicals) could provoke the autocytotoxicity of the melanocyte, whereas the intermediate products of tbe melanin synthesis are not implicated. This occurs because of multiple defects of the activity of several enzymes, such as catalase, thioredoxin-reductase, and tetrahydrobiopterin (50-53). Low catalase levels (catalase is able to transform super-

TABLE

2

Factors Supporting the Autocytotoxic Hypothesis

Electron microscopy: epidermal storage of granular material; vacuolization of melanocytes and keratinocytes Hydroquinone-induced depigmentation is ultrastructurally overlapping to vitiligo Increased suceptibility of melanocytes to substances produced during melanogenesis

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oxide anion radicals in water) have been demonstrated in lesional and perilesional skin (50,51,54), suggesting the hypothesis of toxic damage by hydroxyl radicals to the melanocytic surface (51 ,54). Recently it has been also demonstrated that there is a remarkable increase in the amount ofH 2 0 2 in the lesional skin of vitiligo subjects, and this oxygen intermediate can be removed by UVB-activated pseudocatalase (55). Thioredoxin-reductase is a potent scavenger of free radicals and is present on the melanocytic surface. Keratinocytes of the lesional skin of vitiligous subjects present an increased concentration of Ca 2+ ions in comparison to keratinocytes of both healthy normal control and normal skin of vitiligous patients (52). This increased extracellular concentration of Ca 2+ ions is mediated by the inhibition of the thioredoxin-reductase and induces increased storage of superoxide anions in melanocytes and subsequent cellular death (52,56). On the contrary, each factor that induces an increase in intramelanocyte calcium levels able to increase the thioredoxin-reductase activity with subsequent reduction of superoxide anions. It has been suggested that the beneficial therapeutic effects of UVA treatment are linked to the abovementioned mechanism (57-59). Finally, Schallreuter et al. have suggested that the depigmentation in vitiligo is a result of a blockade of tyrosine synthesis within keratinocytes related to an excess accumulation of7-tetrahydrobiopterin within the epidermis and catechols in serum and tissues (60,61). The accumulation of 7-tetrahydrobiopterin is due to a deficiency of the activity of the enzyme 4a-hydroxytetrahydrobiopterin dehydratase which normally recycles the biopterins. Thus, there is an increased accumulation of 7-tetrahydrobiopterin in the melanocytes and increased synthesis of catecholamines in the keratinocytes, with increased levels in serum and urine (62,63). 7-Tetrahydrobiopterin, acting selectively on the phenylalanine hydroxylase, blocks the synthesis of tyrosine and subsequent reduction of the functional activity of the melanocyte (64). The reduced functional activity of 4a-hydroxytetrahydrobiopterin dehydratase would provoke an increased production of H 2 0 2 that is cytotoxic to the melanocyte (61,62). Strictly related to these data, Maresca's recent research shows that in melanocytes of vitiligous patients there is an imbalance between substances that control oxidative stress (54): in fact, there are increased vitamin E and superoxide dismutase levels and reduced catalase and ubiquinone activities. This imbalance might be the reason for the increased susceptibility ofmelanocytes of vitiligous patients to peroxidant agents and physical and chemical stressors. Recent experimental data demonstrate the very early activation of the melatonin receptor with subsequent intracellular storage of intermediate toxic products of melanogenesis and of reactive oxygen intermediates; these

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results seem to confirm the autocytotoxic theory and supply a further link between the above-examined hypotheses (65,66). NEURAL HYPOTHESIS

This hypothesis (Table 3) is supported by clinical, histological, ultrastructural, and biochemical evidence. This theory emphasizes the possible role of the cutaneous nerve endings and the released neuromediators on the functional activity and vitality of melanocytes. The most important clinical evidences that support this hypothesis are: 1.

2.

3.

Diseases of central nervous system such as neurofibromatosis or sclerosis tuberosa present cutaneous features that may include hypopigmented or hyperpigmented lesions (67,68). Infectious diseases involving the skin and the nervous system (syphilis, leprosy, pinta) present cutaneous lesions that consist of hypopigmentation; in particular, in tuberculoid leprosy, hypopigmentation and anesthesia coexist in the cutaneous areas innervated by the peripheral nerves involved in the disease (69). Vitiligo may occur in the cutaneous areas innervated by a traumatized peripheral nerve or following transverse myelitis. In this last condition, vitiligo begins in the upper part of the body, whereas in the skin areas underlying the spinal damage, the skin was normally pigmented (70,71).

In generalized vitiligo, there have been reported increases in body temperature, bleeding, and sweating (72). In segmental vitiligo, lesional skin presents with increased bleeding and an aberrant response to intradermal injection of epinephrine and to the sweat-inducing factors (73-75). Microscopic and ultrastructural evidence consist of the demonstration of the coexistence of degenerative and regenerative alterations of the sensitive

TABLE

3

Factors Supporting the Neural Hypothesis

Diseases of the central nervous system present cutaneous features including depigmentation Infectious diseases involving the skin and the central nervous system present cutaneous lesions consisting of hypopigmentation Onset of vitiligo in cutaneous areas innervated by a traumatized peripheral nerve Increase of body temperature, bleeding time, and sweating in vitiligo patches Immunoistochemical demonstration of abnormalities of neuropeptidergic innervation in vitiligo patches

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nerve endings in the lesional skin and at the border of the lesion and the demonstration of the presence of a rearrangement and an ultrastructural reorganization of Schwann cells (76). Immunohistochemical studies have shown the role played by neuropeptides, such as neuropeptide Y (NPY), that is particularly expressed perivascularly in the papillary dermis at the peripheral sites of the lesion. Nerve growth factor and calcitonin gene-related peptide receptors (NGFr-IR and CGRPr-IR) have been demonstrated to be overexpressed in the epidermis and papillary dermis at the margin of the lesion (76,77). These neuropeptides can modulate dendricity, adherence, motility of melanocytes, and melanin synthesis and melanosome transfer. Moreover, neuropeptides can play an immunomodulant role and be a potential link with the autoimmune alterations of vitiligo (78,79) High blood and urinary levels of some neurotransmitters (catecholamines, dopamine, norepinephrine, epinephrine) have been shown in patients with vitiligo. These neurotransmitters are cytotoxic both directly by inhibition of enzymatic activities or reactive oxygen intermediate production and indirectly by activation of the a-adrenergic receptors of cutaneous arterioles with subsequent vasoconstriction and hypoxia that supports the reactive oxygen intermediate production. Adrenergic neurotransmitter catabolism is generally due to two enzymes, catechoJ-O-methyltransferase (COMT) and monoamine oxidase (MAO); their expression is usually aberrant in vitiligo. There is increased activity ofCOMT: thus, it follows that ortho-quinone production is increased with cytotoxic activities during melanin synthesis. The increased activity of MAO is linked to the increased production of H 2 0 2 , which is cytotxic to the melanocyte (80). ECLECTIC HYPOTHESIS

The above-mentioned hypothesized pathogenetic mechanisms consider vitiligo as a pathological event that affects, primarily or secondarily, only the melanocyte, without considering the interactions that modulate the relationships among melanocytes and the other epidermal and dermal cells, which are able to influence both the functional activity and the survival of melanocytes. Melanocytes are neural ectoderm-derived cells that migrate during embryonic development to the epidermis, where they are attached to the basement membrane and to surrounding keratinocytes by various types of paired adhesion molecules. There are no melanocyte-keratinocyte adhesion structures that can be detected by electron microscopy, and it is assumed that keratinocytes and melanocytes interact through adhesion pairs that are much Jess organized than those that hold epidermal keratinocytes in place. It is a sum~d that meJanocytes and keratinocytes interact through the homophilic adhesion

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molecule E-cadherin (81), which is expressed on melanocytes and keratinocytes (81,82). Melanocytes probably also interact with keratinocytes through a2()I and a3()1 integrins, possibly binding to laminin Y (LmY) (83). Melanocytes also are stabilized in the basement membrane zone by the a2()1 and a3()J integrins, binding to Iaminins and collagen and to fibronectin through the av()I integrin. The precise nature of these melanocyte-keratinocyte interactions in vivo is unknown. The major biological function of melanocytes is the synthesis of melanin, which is packaged in melanosomes, and the transfer of these organelles

TABLE 4

Factors That Modulate Melanocyte Growth and/or Morphology

in Culture Factor

Main activity

Growth factors, cytokines BFGF MGF/SCF MGF/SF Insulin/IGF-1 EGF NGF GH TGF-a TGF-f.'> LTC 4

Growth stimulation Growth stimulation Growth and motility stimulation Growth stimulation Growth and motility stimulation Growth stimulation Growth stimulation Growth and motility stimulation Growth inhibition Growth and motility stimulation, differentiation inhibition ET-1 Growth, motility, melanogenesis stimulation IL-1 Growth, melanogenesis inhibition; pigmentation IL-6 Growth, melanogenesis inhibition; pigmentation TNF-a Growth, melanogenesis stimulation Melanogenesis stimulation; dendricity PGE 2 , PGD 2 CA2+ - and Cation-binding proteins Growth stimulation Ca 2 + Ceruloplasmin Growth stimulation Transferrin Growth stimulation CAMP-Increasing substances a-MSH Growth, motility stimulation; pigmentation Protein-kinase C activators Growth stimulation TPA Physical agents Growth promotion; melanogenesis stimulation; Ultraviolet rays morphological alterations Source: Modified from Ref. 118.

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5 Semiquantitative Expression of Epidermal Cytokines in Achromic Lesional Skin

TABLE

Cytokine

Positivity location

% of stained c cells

11-30 11-30 11-30 31-50 <10 31-50

GM-CSF SCF bFGF IL-6 TGF-13 TNF-a

a

Basal/suprabasal Basal/suprabasal Basal/suprabasal Basal/suprabasal Basal/suprabasal Basal/suprabasal

a Percentage of stained keratinocytes compared to the entire population of epidermal keratinocytes.

to keratinocytes. Within keratinocytes, melanosomes localize over the nucleus and protect the epidermis from the damaging effects of ultraviolet radiation. This function depends on the intimate interaction of melanocytes and keratinocytes. Thus, a number of studies have led to the delineation of several groups of chemically defined mitogens: we summarize the factors that modulate the growth of melanocyte in culture in Table 4. Recent experimental data underline the intricate interactions that exist between melanocytes and cells present in the skin, such as keratinocytes, Langerhans cells, endothelial cells, fibroblasts, and mast cells. Moreover, lymphocytes and macrophages infiltrating the skin in vitiligo are able to influence melanocytic activity as well as the pituitary hormone ex-melanocyte stimulating hormone (ex-MSH) and the neuropeptides released by sensory nerve endings of the skin. Each of the above-mentioned cells can influence melanocyte activity and survival, both positively and negatively, by soluble mediator production. In particular, keratinocytes, spontaneously or by UV-induced TABLE

6

Semiquantitative Expression of Epidermal Cytokines in Perilesional

Skin Cytokine

% of stained c cells

Positivity location

GM-CSF SCF bFGF IL-6 TGF-13 TNF-a

51-100a 31-50 31-50 11-30 <10 11-30

Basal/suprabasal, continuous disposition Basal/suprabasal, zonal disposition Basal/suprabasal zonal/continuous disposition Basal/suprabasal, zonal/continuous disposition Basal/suprabasal Basal/suprabasal, zonal/continuous disposition

Percentage of stained keratinocytes compared to the entire population of epidermal keratinocytes.

a

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TABLE 7

Expression of Epidermal Receptors

Cytokine

Perilesional skin

Lesional skin

GM-CSF R Rare Rare suprabasal dendrytic suprabasal dendrytic cells «10%8) cells «10%) IL-6 R Rare Rare suprabasal dendrytic suprabasal dendrytic cells «10%) cells «10%) C-KIT+ Several basal dendrytic cells + 1 case with some basal, (mean value of cells with dendrytic cells + (mean value of cells with dendrytic morphology over 200 dendrytic morphology over basal keratinocytes = 22.5) 200 basal keratinocytes = 0.5) Percentage of stained keratinocytes compared to the entire population of epidermal keratinocytes.

a

(a)

(b) FIGURE 1 Immunohistochemical staining of IL-6 reactivity in lesional (a) and perilesional (b) skin (x10): intense presence of IL-6 in the basal and suprabasal layers of the epidermis of lesional skin.

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activation, can synthesize and secrete several cytokines that have both a stimulatory effect (NGF, ILGF, GR, EGF, TGF-a) and an inhibitory action (TGF -[3, II-I, IL-6, IFN-a) on melanocyte activities. Endothelial cells (by production of endothelins) and fibroblasts (by bFGF, FGF-6, SCF, RGF secretion) have a stimulatory effect on the melanocyte. Mast cells are able to produce several inflammatory mediators such as histamine leukotrienes, and prostaglandines that stimulate the melanocyte; moreover, mast cells secrete a growth factor, stem cell factor (SCF), that interacts with melanocytes by the specific receptor c/Kit (84-115). As said above, experimental evidence supports the relevant role that keratinocytes, mast cells, and fibloblasts play in the modulation of growth and/or differentiation of melanocytes. Keratinocytes produce growth factors and cytokines with stimulating (TGF-a, bFGF, NGF) and inhibitory (IL-I, IL-6, TNF-a) effects on melanocytic activity. Fibroblasts produce insulin-like growth factor (IGF-l), which stimulates melanocytes (95,96), whereas mast cells secrete SCF (also known as mast cell growth factor or steel factor), which

(a)

(b) FIGURE 2 Immunohistochemical staining of GM-CSF reactivity in lesional (a) and perilesional (b) skin (x 10): the expression of this cytokine is reduced in lesional skin, whereas it is highly expressed in perilesional skin.

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Pathogenesis of Vitiligo

is able to stimulate melanocyte proliferation. Thus, in healthy skin there is a molecular microenvironment that favors the survival of the melanocyte. The creation of this favorable microenvironment could regulate the possible "cooperative relationship" between these cells-melanocyte, keratinocyte, mast cell, fibroblast. These data enhance and complete the concept of the epidermal melanic unit of Masson and Fitzpatrick (116), as it puts the melanocyte in the center of a series of stimulating and/or inhibitory stimuli produced by keratinocytes, mast cells, fibroblasts, lymphocytes, macrophages or nerve endings. Thus, an alteration of this microenvironment constituted by cytokines and growth factor can explain the disappearance of the melanocyte as a result of its early apoptotic death. Therefore, the achromic lesion of vitiligo may be the result of an alteration in stimulant/inhibing effect signaling (represented by growth factors and cytokines) with a subsequent excess of inhibition. According to this eclectic hypothesis, vitiligo is the expression of a change in the normal

(a)

(b) FIGURE 3 Immunohistochemical staining of bFGF reactivity in lesional (a) and perilesional (b) skin (X10): in lesional skin the expression of this. growth factor is reduced, while it is normally expressed In penleslonal skin, with a continuous disposition in the basal and suprabasal layers of epidermis.

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cellular communications among melanocytes, keratinocytes, mast cells, and fibroblasts with a biochemical imbalance (related to growth factors, cytokines, inflammatory mediators, adhesion molecules) that does not permit melanocytic survival in the epidermal environment. The creation of an adverse microenvironment for the melanocyte should induce the early death of this cell by apoptosis and the formation of achromic lesions that become definitive because near melanocytes and reservoir cells are unable to colonize these areas. Recently researchers have investigated the hypothesis that the expression of epidermal, keratinocyte-derived cytokines may be modified in vitiligo (117). Results show the following: I.

In perilesional skin the number of epidermal melanocytes stained for NKI-beteb ranged from 15 to 32 (per 200 basal cells) and in nonlesional skin from 17 to 33. The Dum bel' of melanocytes stained for HMB45 ranged from 7 to 24 (per 200 basal cells) in perilesional

(a)

(b) FIGURE 4 Immunohistochemical staining of SCF reactivity in lesional (a) and perilesional (b) skin (x 10): in lesional skin the expression of this growth factor is reduced, while it is normally expressed in perilesional skin, with a zonal disposition in the basal and suprabasal layers of epidermis.

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3.

113

skin, whereas in nonlesional skin it varied from 10 to 28. No significant difference in melanocyte number was found between perilesional and nonlesional skin. No melanocytes were found in vitiligo lesional skin. Mast cells have been studied by the identification of tryptase activity. Tryptase-positive cells were localized in the perivascular and periadnexial dermis, with a percentage of 15-20% of the dermal cell population. There was no difference between lesional, perilesional, and nonlesional skin As reported in Tables (5-7), all samples showed some staining for the tested cytokines but because the results in specimens tested for TGF-r?> reactivity always fell below 10% of the epidermis, they were classified as nonreactive. The lesional skin reactivity for GM-CSF, SCF, and bFGF fell into the 11-30% category, and the reaction for IL-6 and TNF-O' into the 31-50% category. On the contrary, in

(a)

(b) FIGURE 5 Immunohistochemical staining of C-Kit reactivity in lesional (a) and perilesional (b) skin (x 10): absence of c-Kit expression in lesional skin and presence of this receptor in perilesional skin on several basal dendritic cells.

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perilesional skin and nonlesional skin, the percentages of stained epidermis for GM-CSF and bFGF were higher (51~100% and 3150%, respectively) and for IL-6 and TNF-Cl' lower (11-30% for both) (117). The findings for SCF were the same for perilesional and nonlesional skin (3l~50%). The expression of the epidermal receptors indicated no significant difference in GM-CSF and IL-6 receptors in lesional and perilesional skin, whereas the expression of c-KIT was significantly higher in perilesional skin than in lesional one. Figures 1-5 show the immunohistochemical reactivity of IL-6, GM-CSF, bFGF, SCF, and c-Kit in lesional and perilesional skin. CONCLUSIONS

The etiology and pathogenesis of vitiligo are not clearly understood. Various causative factors have been implicated in the depigmentation processes of vitiligo, including cytological, environmental, immunological, and neurological destruction of melanocytes. Many pathogenetic hypotheses, each supported by intriguing data, have been proposed. The various theories outlined above are intended to summarize current popular hypotheses. These theories are not all-inclusive, and they are not mutually exclusive. It is possible that several mechanisms are operative in producing melanocyte destruction in a given individual. The recent data here discussed (117) seem to provide evidence of an important change in the expression of epidermal cytokines in vitiligous skin. This modifica tion, which supports the eclectic theory, does not seem to contradict the other hypotheses. REFERENCES I.

2.

3.

4.

5.

Ortonne JP, Bose SK. Vitiligo: where do we stand? Pigment Cell Res 1993; 6:61-72. Ortonne JP, Mosher DB, Fitzpatrick TB, eds. Histopatology of Vitiligo and Other Hypomelanoses of Hair and Skin. New York: Plenum Medical, 1993: 129-310 Birbeck M, Breathnach A, Everall J. An electron microscope study of basal melanocytes and high level clear cells (Langerhans cells) in vitiligo. J Invest Dermatol1961; 37:51-64. Le Poole IC, van den Wijngaard RM, Westerhof W, et al. Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 1993; 100:816-822. Schallreuter KU, Lemke R, Brandt 0, et al. Vitiligo and other diseases: coexistence or true association? Dermatology 1994; 188:269-275.

Copy;ighted Material

Pathogenesis of Vitiligo 6.

7.

8. 9. 10.

I J.

12.

13. 14. 15. J 6.

17.

18.

19.

20. 21. 22.

115

D'Amelio R, Frati C, Fattorossi A. Peripheral T-cell ubset imbalance in patients with vitiligo and in their apparently healthy first-degree relatives. Ann Allergy 1990; 65143-145. Masala C, Frati C, Amendolea MA. Gastric parietal cell antibodies and chronic gastritis in subjects with vitiligo and in their apparently healthy first-degree relatives. lmmunol Clin Sper 1982; I: 1-8. Kumari J. Vitiligo treated with topical clobetasol propionate. Arch DermatoJ 1984; 120:631-633 Kandil E. Treatmant of vitiligo with 0.1 % bethamethazone 17-valerate-a double blind trial. Br J Dermatol 1974; 91 :457-460. Norris DA, Kissinger RM, Naughton GM. Evidence for immunologic mechanisms in human vitiligo: patients' sera induce damage to human melanocytes in vitro by complement mediated damage and antibody-dependent cellular toxicity. J Invest Dermatol 1988; 90:783-789. Harning R, Cui J, Bystryn Jc. Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Dermatol 1991; 97: 1078-1 080. Betterle C, Caretto A, De Zio A, et al. Incidence and significance of organspecific autoimmune disorders (clinical, latent or only autoantibodies) in patients with vitiligo. Dermatologica 1985; 171:419-423. Naughton GK, Eisinger M, Bystryn Jc. Antibodies to normal melanocytes in vitiligo. J Exp Med 1983; 158:246-251 Bystryn JC, Naughton GK. The significance of vitiligo antibodies. J Dermatol 1985; 12:1-9 Xia P, Geoghegan WD, Jordan RE. Vitiligo antibodies: studies of subclass distribution and complement activation. J Dermatol 1991; 96:627. Aronson PJ, Hashimoto K. Association of IgA antimelanoma antibodies in the sera of vitiligo patients with active disease. J Jnvest Dermatol 1987; 88: 475. Aronson Pl, Hashimoto K. Timed immunoperoxidase gray scale cytologic analysis correlates elevated IgA antimelanoma antibodies in vitiligo patients sera with depigmentation. J Invest Dermatol 1989; 92:397. Naughton G K, Reggiardo MD, Bystryn Jc. Correlation between vitiligo antibodies and extent of depigmentation in vitiligo. J Am Acad Dermatol 1986; J5:978-98 J. Norris DA, Capin L, Muglia 11. Enhanced susceptibility of melanocytes to different immunologic effector mechanisms in vitro: potential mechanisms for postinflammatory hypopigmentation and vitiligo. Pigment Cell Res 1988; 1: 113-119 Cui J, Arita Y, Bystryn Jc. Characterization of vitiligo antigens. Pigment Cell Res 1995; 8:53-60 Song YH, Connor E, Li Y. The role of tyrosine in autoimmune vitiligo. Lancet 1994; 344: 1049-1052. Cui l, Harning R, Henn M. Identification of pigment cell antigen defined by vitiligo antibodies. J Invest Dermatol 1992; 98: 162-165.

Copyrighted Material

116

Hautmann et al.

23.

Bystryn IC, Cui I, Hariya Y. Melanoma and vitiligo are associated with antibody responses to similar pigment cell antigen. 1 Invest Dermatol 1992; 4:629 Cui 1, Bystryn Ie. Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol 1995; 131:314318 Gilhar A, Pillar T, David M. Melanocytes and Langerhans cells in aged versus young skin before and after transplantation into nude mice. 1 Invest Dermatol 1991; 96:2JO-214. Gilhar A, Zelickson B, Ulman Y. In vivo destruction of melanocytes by the IgG fraction of serum from patients of vitiligo. 1 Invest Dermatol 1995; 105:683-686. Hann SK, Park YK, Lee KG, et a!. Epidermal changes in active vitiligo. ] Dermatol 1992; 19:217-222. Le-Poole IC, van den Wijngaard RM, Westerhof W. Presence of T cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am I Patho! 1996; 148:1219-1228 Al Bradi AM, Foulis AK, Todd PM. Abnormal expression of MHC class II and ICAM-I by melanocytes in vitiligo. I Pathol 1993; 169:203-206 Ahn SK, Choi EH, Lee SH Immunohistochemical studies from vitiligo. Yonsei Med 1 1994; 35:404-410. Visseren MA, Van Elsas E, Van der Voort M. CTL specific for the tyrosinase can be induced from healthy blood to lyse melanoma cells. 1 Immunol 1995; 134:3991-3998. Ogg GS, Rod DP, Romero P. High frequency of skin-homing melanocytespecific cytotoxic T lymphocytes in autoimmune vitiligo. 1 Exp Med 1998; 188:1203-1208. Boissy RE, Fite KV, Smith 1R 11'. Progressive cytolytic changes during the development of delayed feather amelanosis and associated choroidal defects in DAM chicken line-a vitiligo model. Am I Pathol. 1983; Ill: 197-212. Boissy RE, Lamont S1, Smith IR II'. Persistence of abnormal melanocytes in immunosuppressed chickens of the immune DAM line. Cell Tissue Res 1984; 235663-668. Nath SK, Majumder PP, Nordlund 11. Genetic epidemiology of vitiligo: multi locus recessivity crossvalidated. Am 1 Hum Genet 1994; 55:981-990. Ramaiah A, Mojamdar M, Amarnath VM. Vitiligo in the SSK community of Bangalore. Indian I Dermatol 1988; 54:251-254. Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol 1993; 129:994-998. Puri N, Mojamdar M, Ramaiah A. In vitro growth characteristics of melanocytes obtained from adult normal and vitiligo subjects. I Invest Dermatol 1987; 88:434-438. Boissy RE, Beato KE, Nordlund II. Dilated rough endoplasmic reticulum and premature cell death in melanocytes cultured from the vitiligo mouse. Am I Pathol 1991; l38:1511-1525.

24.

25.

26.

27. 28.

29. 30. 31.

32.

33.

34.

35. 36. 37. 38.

39.

Copyrighted Material

Pathogenesis of Vitiligo

40. 41.

42.

43. 44.

45. 46. 47. 48.

49. 50. 51. 52. 53.

54.

55.

56.

57.

117

Bowers RR, Harmon J, Prescott S. Fowl model for vitiligo: genetic regulation on the fate of the melanocytes. Pigment Cell Res 1992; 2:242-248. Cerundolo R, De Caprariis D, Esposito L. Vitiligo in two water buffaloes. Histological, histochemical and ultrastructural investigations. Pigment Cell Res 1993; 6:23-28. Norris A, Todd C, Graham A, et al. The expression of the c-kit receptor by epidermal melanocytes may be reduced in vitiligo. Br J Dermatol 1996; 134: 299-306. Gellin GA, M'aibach HI, Misiaszek MH. Detection of environmental depigmenting substances. Contact Dermatitis 1979; 5:201-213. O'Malley MA, Mathias T, Priddy M. Occupational vitiligo due to unsuspected presence of phenolic antioxidant by products in commercial bulk rubber. J Occup Med 1988; 30:512-516. Lerner AB. On the etiology of vitiligo and gray hair. Am J Med 1971; 51:141147. Kovacs SO. Vitiligo. J Am Acad Dermatol 1998; 38:647-666. Riley PA. Mechanism of pigment cell toxicity produced by hydroxyanisole. J Pathol 1970; 101:163-169. Frenk E. Experimentelle Depigmentierung der Meerschweinchenhaut durch selektiv toxische Wirkung von Hydrochinon-monoathylather auf die Melanocyten. Arch Klin Exp Dermatol 1969; 235: 16--24. Pawele JK, Korner A, Bergstrom A. New regulator of melanin biosynthesis and the autodestruction of melanoma cells. Nature 1980; 285:617-619. Schallreuter K, Levenig C. Keratinocyte involvement in the pathophysiology of vitiligo. J Invest Dermatol1991; 96:1024. Schallreuter K, Wood J, Berger J. Low catalase levels in the epidelmis of patients with vitiligo. J Invest Dermatol 1991; 97:1081. Schallreuter K, Pittelkow M. Defective calcium uptake in keratinocyte cell cultures from vitili.ginous skin. Arch Dermatol Res 1988; 280: 137-139. Schallreuter K, Wood KU, Wood J. Control of melanogenesis in the human epidermis by the redox-status of tetrahydrobiopterins. Pteridines 1995; 6: 104107. Maresca V, Rocella M. Increased sensivity to peroxidative agents as a possible pathogenetic factor of melanocyte damage in vitiligo J Invest Dermatol 1977; 109:310-313. Schallreuter K, Moore J, Wood JM. In vivo and in vitro evidence for hydrogen peroxide (H 20 z) accumulation in the epidermis of patients with vitiligo and its successful removal by a DYB activated pseudocatalase. J Invest Dermatol 1999; 4:91-96. Schallreuter K, Pittelkow M, Wood J. EF-Hands calcium binding regulates the thioredoxin reductasejthioredoxin electron transfer in human keratinocytes. Biochem Biophys Res Commun 1989; 162:1311-1316. Yada Y, Higuchi K, lmokawa G. Effects of endothelins on signal transduction and proliferation in human melanocytes. J Bioi Chem 1991; 266: 1835218357.

Copyrighted Material

118

Hautmann et al.

58.

Imokawa G, Yada Y, Miyagishi M. Endothelins secreted from human keratinocytes are intrinsic mitogens for human melanocytes. J Bioi Chem 1992; 267:24675-24680. Yohn J, Morelli J, Walchak S. Cultured human keratinocytes synthesize and secrete endothelin-l. J Invest Dermatol 1993; 100:23-26. Schallreuter KU, Wood JM, Pittelkow MR. Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 1994; 263: 14441446. Schallreuter KU, Wood JM, Lemke KR. Defective tetrahydrobiopterin and cathecolamine biosynthesis in the depigmentation disorder vitiligo. Biochim Biophys Acta 1994; 1226:181-192. Dunerva SG. Changes in the content of adrenaline and noradrenaline in the blood of patients with vitiligo. Vestn Dermatol Venereol 1973; 10:33-36. Morrone A, Picardo M. De Luca C Cathecolamines and vitiligo. Pigment Cell Res 1992; 5:62-69 Davis MD, Ribeiro P. Tipper J. '7-Tetrahydrobiopterin, a naturally occurring analogue of tetrahydrobiopterin is a cofactor for, and a potential inhibitor of the aromatic amino acid hydroxylases. Proc Natl Acad Sci 1992; 89:1010810113. Logan A. Weatherhead B. Post-tyrosinase inhibition of eumelanogenesis by melatonin in hair follicles in vitro. J Invest Dermatol 1980; 74:47-50. Slominski A, Paus R, Bomirski A. Hypotesis: possible role for the melatonin receptor in vitiligo: discussion paper. J Roy Soc Med 1989; 82:539-541. Koplon BS, Shapiro L. Poliosis overlying a neurofibroma. Arch Dermatol 1968; 98:631-633 Zvulunov A, Esterly NB. Neurocutaneous syndromes associated with pigmentary skin lesion. J Am Acad Dermatol 1995; 32:915-935. Mosher D, Fitzpatrick T, Hori H. Disorders of pigmentation. In: Fitzpatrick T, Eisen A, Wolff K, eds. Dermatology in General Medicine. 4th ed. New York: McGraw-HilL 1998:903-955. Arnozan L. Vitiligo avec troubles nerveus sensitifs et sympathetiques: I'origine sympathique du vitiligo. Bull Soc Franc Dermatol Syphil 1992: 29:338-342. Costea V. Leukoderma patches in the course of traumatic paralysis of the brachial plexus in a subject with insular cavities. Dermatovenereologica 1961; 2:161-1166 Lerner AB. Snell RS, Chanco-Turner ML. Vitiligo and sympathectomy. The effect of sympathectomy and alpha-melanocyte stimulating hormone. Arch Dermatol 1965; 91:390-396. Chanco-Turner ML, Lerner AB. Physiologic changes in vitiligo. Arch Dermatol 1966; 96:269-278. Dutta AK. Dermat D. Non-nervous vascular reactions in vitiligo patches (an experimental study). Indian J Dermatol 1972: 17:29-36. Dutta AK, Mandai SB. A study non-nervous vasoconstrictor responses. Int J DermatoI1972: 11:177-180. AI' Abadie MS, Senior HJ, Bleehen SS. Neuropeptide and neuronal marker studies in vitiligo. Br J Dermatol 1994; 131:160-165.

59. 60

61.

62. 63. 64.

65. 66. 67. 68. 69.

70. 71.

72.

73 74. 75. 76.

Copyrighted Material

Pathogenesis of Vitiligo 77. 78. 79.

80.

81.

82.

83.

84. 85. 86.

87.

88.

89. 90. 91.

92.

93.

119

Cheng L, Khan M, Mudge A W. Calcitonin gene-related peptide promotes Schwann cell proliferation. J Cell Bioi 1995; 129:789-796. Covelli V, Jirillo E. Neuropeptide with immunoregulatory function: current status of investigations. Functional Neurol 1988; 3:253-261. Rameshwar P, Gascon P, Ganea D. Immunoregulatory effects of neuropeptides: stimulation of interleukin-2 production by substance P. J Neuroimmunol 1992; 37:65-74. Schallreuter KU, Wood JM, Pittelkow MR. Increased monoamine oxidase A activity in the epidermis of patients with vitiligo. Arch Dermatol Res 1996; 288:14-18. Tang A, Eller MS, Hara M, et al. E-cadherin is the major mediator of human melanocyte adhesion to keratinocyte in vitro. J Cell Sci 1994; 107:983992 Horiguchi Y, Furukawa F, Fujita M, et al. Ultrastructural localization of Ecadherin cell adhesion molecule on the cytoplasmic membrane of keratinocyte in vivo and in vitro. J Histochem Cytochem 1994; 42:1333-1340. Symington BE, Takada Y, Carter WG. Interactions of integrins alpha3beta} and alpha2beta\: potential role in keratinocyte intercellular adhesion. J Cell BioI 1993; 120523-535. Rosdah1 IK, Szabo G. Mitotic activity of epidermal melanocytes in UVirradiated mouse skin. J Invest Dermatol 1978; 70: 143-148. Friedman PS, Gilchrest BA. Ultraviolet radiation directly induces pigment production by cultured human melanocytes. J Cell Physiol 1987; 133:88-94. Libow LF, Scheide S. DeLeo VA. Ultraviolet radiation acts as an independent mitogen for normal human melanocytes in culture. Pigment Cell Res 1988; 1:397-401. Stierner U, Rosdahl IK, Augustsson A, et al. UVB irradiation induces melanocytes increase in both exposed and shielded human skin. J Invest Dermatol 1989; 92:561-564. Morelli J. Yohn J, Lyons B, et al. Leukotrienes C4 and D4 as potent mitogens for cultured human neonatal melanocytes. J Invest Dermatol 1989; 93:719722. Halaban R, Ghosh S, Baird A. bFGF is the putative natural growth factor for human meJanocytes. In Vitro 1987; 23:47-52. Halaban R, Ghosh S, Kwon B. bFGF, a natural mitogen for normal melanocytes in culture, i expressed in melanomas. J Invest Dermato1 1987; 88:493. Pittelkow MR, Shipley GD. Serum free growth and growth factor requirements for normal huma~ melanocytes in vitro. J Invest Dermatol 1987; 88: 513 Funasaka Y, Boulton T, Cobb M, et al. C-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas. Mol Bioi Cell 1992; 2:197-209. Rubin JS, Chan AM, Bottaro DP, et al. A broad spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc Natl Acad Sci USA 1991; 88:415-419

Copyrighted Material

120

Hautmann et al.

94.

Balaban R, Rubin 1S, Funasaka Y, et a!. Met and hepatocyte growth factor/ scatter factor signal transduction in normal melanocytes and melanoma cells. Oncogene 1992; 7:2195-2206. Imokawa G, Yada Y, Morisaki N, et a!. Biological characterization of human fibroblast-derived mitogenic factors for human melanocytes. Biochem 1 1998; 330:1235-1239. Pincelli C, Yaar M. Nerve growth factor: its significance in cutaneous biology. 1 Invest Dermatol Symp Proc 1997; 1:31-36. Rodeck U, Berlyn M, Menssen HD, et a!. Metastatic but not primary melanoma cell lines grow in vitro independently of exogenous growth factors. Int 1 Cancer 1987; 40:687-690 Edmonson SR, Russo VC, McFarlane AC, et a!. Interactions between growth hormone, insulin-like growth factor I, and basic fibroblast growth factor in melanocyte growth. 1 Clin Endocrinol Metab 1999; 84:1638-1644. Herlyn M, Rodeck U, Mancianti HD, et al. Expression of melanomaassociated antigens in rapidly dividing human meJanocytes in culture. Cancer Res 1987; 47:3057-3061. Pittelkow MR, Shipley GD. Serum-free culture of normal human melanocyte: growth kinetics and growth factor requirements. 1 Cell Physiol 1989; 140:565576. Morelli 1G, Norris DA Lnfluence of inflammatory mediators and cytokines on human melanocyte function. 1 Invest Dermatol 1993; 100:19Is-195s. Medrano EE, Farooqui 1Z, Boissy RE, et al. Chronic growth stimulation of human adult melanocytes by inflammatory mediators in vitro; implications for nevus formation and initial steps in melanocyte oncognesis. Proc Natl Acad Sci USA 1993; 90: 1790-1794 Morelli 1G, Hake SS, Murphy RC, et al. Leukotriene B4-induced human melanocyte pigmentation and leukotriene C4-induced human melanocyte growth are inhibited by different isoquinoline sulfonamides. 1 Invest Dermatol 1992; 98:55-58 Fossati G, Taramelli D, Balsari A, et a!. Primary but not metastatic melanoma expressing DR antigens stimulate autologous lymphocytes. Int 1 Cancer 1984; 33:591-597 Tomita Y, Iwamoto M, Masuda T, et al. Stimulatory effect of prostaglandin E 2 on the configuration of normal human melanocytes in vitro. 1 D. Investermatol 1987; 89:299-301. Tada A, Suzuki I, 1m S, et al. Endothelin-I is a paracrine growth factor that modulates melanogenesis of human melanocytes and partecipates in their responses to ultraviolet radiation. Cell Growth Differ 1998; 9:575-584. Scott G, Cassidy L, Abdel Malek Z. ('(-MSH and endothelin I have opposing effects on melanocyte adhesion, migration and pp25FAK phosphorylation. Exp Cell Res 1997; 237:19-28. McEwan MT, Parsons PG. Regulation of tyrosinase expression and activity in human melanoma cells via histamine receptors. J Invest Dermatol 1991; 97:868-873.

95.

96. 97.

98.

99.

100.

101. 102.

103.

104.

105.

106.

107.

108.

Copyrighted Material

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109.

J 10.

Ill.

112.

113. 114.

115.

116. 117.

118.

121

Herlyn M, Mancianti ML, Jambrosic J, et al. Regulatory factors that determine growth and phenotype of normal human melanocytes. Exp Cell Res 1988; 179:322-331 Hill S, Bleehen SS, MacNeil S. An investigation of the intracellular messenger systems involved in melanogenesis in B16 melanoma. J Invest Dermatol 1987; 89:323 Chakraborty AK, Funasaka Y, Slominski A, et al. Production and release of proopiomelanocortin (POMe) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B. Biochim Biophys Acta 1996; 1313:130-138 Nakazawa K, Nakazawa H, Sahuc F, et al. Effects of calphostin C, specific PKC inhibitor on TPA-induced normal human melanocyte growth, morphology and adhesion. Pigment Cell Res 1996; 1:28-34. Gilchrest BA, Park HY, Eller MS, et al. Mechanism of ultraviolet light induced pigmentation. Photochem Photobiol 1996; 63:1-10. Abdel-Naser MB, Hann SK, Bystryn Jc. Oral psoralen with UVA releases circulating growth factor(s) that stimulates cell proliferation. Arch Dermatol 1997; 133:1530-1533. Romero Graillet C, Aberdam E, Clement M, et al. Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis. J Clin Invest 1997; 99:635-642. Fitzpatrick TB, Breathnach AS. Die epidermale Melanin-Einheit-System. Dermatol Wochenschr 1963; 147:481-489. Moretti S, Spallanzani A, Amato L, Hautmann G, et al. Vitiligo and epidermal microenvironment: possible involvement of keratinocyte-derived cytokines. Arch Demlatol 2002; 138:273-274. Valyi-Nagy IT, Herlin M. Regulation of growth and phenotype of normal human melanocyte in culture. In: Nathanson L, ed. Melanoma 5, Series on Cancer Treatment and Research. Boston: Kluwer Academic Publishers, 1991:85-101

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10 Free Radical Damage in the Pathogenesis of Vitiligo Mauro Picardo and Maria Lucia Dell' Anna San Gallicano Dermatological Institute, Rome, Italy

INTRODUCTION Several different hypotheses have been proposed to explain the mechanism underlying melanocyte impairment in vitiligo (1-4). Among these, some groups have suggested free radical-mediated damage (5-10). In vitro, ex vivo, and in vivo data have been presented for a shift in the antioxidant/prooxidant ratio responsible for oxidative stress. However, at this time the mechanism of melanocyte disappearance is not fully defined: the possible apoptotic pathway has not been completely demonstrated, and a normal pattern of Bcl2, Bax, p2 I, and p53 expression by melanocytes, even after ultraviolet (UV)-B treatment, has been reported (11). The skin appears to be the target of oxidative stress for two reasons: (a) the location between the external environment and the body makes it an easy target for chemical and physical pro-oxidants and (b) some specific types of cutaneous metabolism generate free radicals (Table I). However, skin is rich in natural defenses against oxidative stress, including small radical trapping, as in the case of vitamins and glutathione (GSH), and enzymes such as superoxide dismutase (SOD), catalase (Cat), glutathione peroxidase (GPx), thioredoxin/thioredoxin reductase, and thioredoxin peroxidase (12,13) (Table 2).

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124 TABLE 1

Species O2

H2 0 2

Picardo and Dell'Anna

ROS Produced During Cellular Activity Sources NADH deydrogenase Ubiquinone cyt c intersection Xanthine oxidase Aldheyde oxidase NADPH oxidase SOD Nitric oxide synthase Xanthine oxidase 6BH 4 recycling NADPH oxidase Pteridines oxidation MAO-A CoO oxidation TNF-a signal

EXPERIMENTAL EVIDENCE OF CUTANEOUS OXIDATIVE STRESS IN VITILIGO

Vitiligo Melanocytes in Culture In vitro melanocytes from perilesional and uninvolved areas of the vitiligo epidermis show a delay in growth, a failure to restart after trypsinization, and may require catalase (14,15). In the long term, culture morphological modifications, such as dilatation of rough endoplasmic reticulum, circular RER profiles, and membrane-bound compartmentalized melanosomes, have been described. These characteristics do not depend on the phase of the disease or passage number and are not necessarily all present at the same time. These aberrations can then alter the interaction with other epidermal ceJls even in normal areas, and in mouse models the dilated RER is associated with an impairment of protein trafficking, including tyrosinase and RER storage (16). However, in reconstructed epidermis, possibly due to the short term of the culture, morphological or functional alterations in melanocytes or keratinocytes were not found (17). Besides the morphological features, a functional impairment has been reported in vitiligo melanocytes. We found an alteration in the antioxidant pattern with increased SOD and lowered Cat activities, associated with an augmented susceptibility to pro-oxidant agents (7). A localized burst of hydrogen peroxide might affect the heme active site of the enzyme, lowering its activity (18), but it is also possible that as a consequence of the low catalase

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TABLE

2

Antioxidant System Components

Antioxidant

..."T1

Property

Activity

Location

(1) (1)

:0

SOD

Cat Lipoic acid system ()

GSH

~

Vitamin E

o

~ (0'

::':3"

CD

GPx

~

GSH reductase

0..

8

MnSOD, tetrameric 80 kDa CuZnSOD, dimeric 32 kDa; constitutive Heme group containing; constitutive Lipoic acid + lipoamide dehydrogenase -y-L-glutamyl-L-cysteinyl-glycine; constitutive Lipid-soluble; lowered by UV; inducible Se-dependent; GPx1 to GPx4 b

2H+ + 20 2'-

2H 20 2

->

->

Mitochondria Cytosol

Co (i' ~

*

Peroxisomes

III

2H 20 + O 2

~

GSH-S-transferase TrxR

Ascorbate CoO

a b C

NADPH-dependent homodimer with Sec in C-terminus motif Gly-Cys-Sec-Gly-COOH Water soluble; inducible Involved in electron flow; lowered by UV before vitamin E; constitutive

0

3

III

to

GSH, Vitamin E, ascorbate and CoO regeneration Free radicals direct scavenger; substrate for GPx. Lipoperoxides reduction

Membrane Mitochondria Mitochondria and cytosol Membrane

2H 20 2 ~ 2H 20 + 02 c ; lipoperoxide reduction GSH regeneration Lipoperoxides and pyrimidine dimer reduction 2H+ + 20 2'- -> H20 2+0 2 ascorbate reduction

Mitochondria and cytosol Mitochondria and cytosol Mitochondria and cytosol Mitochondria and cytosol

Vitamin E reduction Lipoperoxide reduction and vitamin E regeneration

Cytosol Inner mitochondrial membrane

CD ~

III

H20 2 + O 2

MnSOD can be induced by oxidative stress or thioredoxin. GPx isoforms have different locations but all use GSH as substrate. Reduction of hydrogen peroxide to water lowers the hydroxyl radical formation via Fenton reaction.

(1)

:5

<

a: to 0

....

I\)

c.n

Picardo and Dell' Anna

126

activity, following oxidative stress, the cell reaches a toxic level of H 2 0 2 and other peroxides (7). Moreover, both tyrosinase and TRP 1, crucial enzymes of the melanogenetic pathway, which can upregulate the expression of LAMP-I , a scavenger of the toxic intermediates of the melanin pigment, have been shown to be compromised in vitiligo melanocytes; in particular, a marked decrease of TRP-l expression, probably due to posttrascriptional and posttranslational alterations, with a change of its interaction with calnexin, has been described (8) H2 0 2 in Epidermis

Even if the exact order in which antioxidant alteration and peroxidative damage, reported to occur in vitiligo, takes place has not been completely clarified, the generation of reactive oxygen species (ROS) appears to be the cause of a decreased level of antioxidants in the skin. An increased epidermal H 2 0 2 level has been described both in vivo and ex vivo in the active phase of vitiligo. It is associated with reduced catalase and glutathione peroxidase activities. Moreover, histological evidence of oxidative stress-mediated damage with vacuolar degeneration, indicative of lipid peroxidation, and granular deposits in keratinocytes and melanocytes have been reported even in normalappearing skin (6,19). The absence of apoptosis has been linked to the ability of pS3, switched on by H 2 0 2 , to overcome the deleterious effect of hydrogen peroxide itself (18). Vitiligo and Thioredoxin Reductase

In vitiligo, a low level of cutaneous thioredoxin reductase (TrxR) activity was found (18). This enzyme is crucial in the elimination of superoxide anion, is involved in the oxidation/reduction of the (6R)-I-erythro-S,6,7 ,8-tetrahydrobiopterin (6BH 4 ) cofactor, and is the only reductase able to reduce 6-biopterin to quinonoid dihydropterin (qBH 2). After the TrxR inhibition, and in association with oxidative stress, GSSG formation and glutathionylation of protein thiols take place (12,13) (Fig. 1). Biopterin Metabolism

Defective recycling of tetrahydrobiopterin in the phenylalanine hydroxylase (PAH) reaction could participate in intracellular H 20 2 generation (20). In active vitiligo, increased synthesis of 6BH 4 , an essential cofactor for tyrosine hydroxylase (TH) activity, has been reported as probably being due to an alteration of 4a-hydroxy-6BH 4 dehydratase (DH) (21). In the epidermis, both melanocytes and keratinocytes can de novo synthesize and recycle 6BH 4 , Copyrighted Material

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meblin synthesis

TRl"ed

TROll;;

NADPH

'-' t _

NADf.

CaldiUm FIGURE 1 A possible link between melanocyte metabolism and redox status alteration, as proposed by Schalireuter et al. (18).

which, at a high concentration, can be toxic for the melanocytes. Moreover, hydrogen peroxide, as well as UVB, oxidizes 6BH 4 to 6-biopterin, which in vitro is toxic for melanocytes (22,23). Thus, melanocyte degeneration may be the consequence of the 6BH 4 action since the H 2 0 2 removal by addition of catalase restores melanocyte pigmentation (24). The rate-limiting enzyme for the de novo synthesis of 6BH 4 , GTP-cyclohydrolase I (GTP-CH I), is controlled by IFN-)', IL-2, and TNF-ex (5,25), and therefore a higher production of these cytokines by different mechanisms may playa part in the cellular damage. The low DH activity is probably due to a deactivation and not to a gene mutation, as the normal level can be restored after H 2 0 2 removal, and because the H 2 0 2 can induce an oxidation of Cys 81 and Trp 65 near the catalytic site with a consequent alteration of the activity. During 6BH 4 recycling, the isomer 7BH 4 is non-enzymatically produced and is able to inhibit 4a-carbinolamine dehydratase activity leading to a H 2 0 2 accumulation. The 7BH 4 -dependent PAH inhibition causes the release ofH 2 0 2 , which is able in turn to degrade the tetrahydropyrrole ring of catalase even in nonlesional areas (5,25). In addition, a mutation in GTP-CH I has been reported in syndromic vitiligo (vitiligo associated with dopa-responsive dystonia) 'where the GTP-CH I activity in PBMNC is less than 20% with respect to the normal value (5,26,27). Copyrighted Material

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Calcium and the Adrenergic System

Ten years ago, Schallreuter et al. suggested an involvement of keratinocytes in the pathophysiology of vitiligo, describing a defective calcium transport that can cause an increased level of O 2_. An alteration in calcium metabolism has been reported in vitiligo keratinocytes and melanocytes. Calcium is able to inhibit thioredoxin reductase. A rise of intracellular calcium causes a major shift in cellular redox status due to the production of oxidized thioredoxin. Moreover, calcium release turns on NADPH oxidase, thus promoting the oxygen burst by the cellular infiltrate in perilesional areas (18,28,29). The altered intracellular level of calcium is associated with an increased expression of [3radrenoceptors (28). However, there are conflicting reports about adrenoceptor involvement in vitiligo. An increase in cutaneous (X- and [3-adrenoceptor function in segmental vitiligo, with or without a change in plasma catecholamine (probably depending on the phase of the disease), has been described. In any case, local or systemic noradrenergic metabolism dysfunction can be involved in melanocyte death due to a direct cytotoxic effect or the induction of an oxidative stress (30,31). Catecholamine Synthesis in Vitiligo

In vitiligo there is defective catecholamine biosynthesis (5) with an overproduction of norepinephrine associated with increased catecholamine-Omethyl transferase (COMT) activity and COMT metabolite level. The induction of MAO-A is a consequence of the high norepinephrine level. MAO-A is able to oxidize both norepinephrine and epinephrine, yielding ammonia, 3,4-dihydroximandelic aldehyde, and hydrogen peroxide (21). These data are in agreement with previous reports indicating an altered catecholamine synthesis and high plasma and urinary levels of catecholamine metabolites, such as homo vanillic acid (HVA) and vanillylmandelic acid (VMA) in patients with active vitiligo (30). Other authors have further established this in the initial phase of the disease (32), suggesting that the hyperactivity of the monoaminergic system might be involved in the early phase and not in the progression of the disease. Stress-dependent catecholamine discharge may be associated with an epidermal and dermal ischemia-hypoxia, leading to an overproduction of toxic radicals (quinones, semi-quinone radicals, oxyradicals) with a conseq uent epidermal oxidative stress. a-MSH

A great deal of evidence has been accumulated about (X-MSH function in the pigmentation process. (X-MSH controls the level of tyrosinase activity through a receptor-independent pathway beyond a receptor-dependent

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mechanism (33). a-MSH-induced tyrosinase activation could protect melanocytes from the damaging effect of the superoxide anion as it is used by the enzyme. The antioxidant activity of a-MSH is also carried out through its ability to complex 6BH 4 . Moreover, it is able to antagonize the action of proinflammatory cytokines, protecting melanocytes by cell-mediated cytotoxicity. In vitiligo the low epidermal level is possibly due to a reduced ability of the vitiligo melanocytes to cleave proopiomelanocortin to a-MSH (34,35). The effect of a-MSH is counteracted by MCH (melanin-concentrating hormone), which reduces the rise in cAMP and melanogenesis via the specific receptor MCHRI. Interestingly, in vitiligo, autoantibodies against MCHRI have been reported, although the exact clinic relevance has not yet been clarified (36) Modification of Epidermal Behavior

In the lesional area of vitiligo us skin, the growth factors released by keratinocytes (GM-CSF, bFGF, SCF), appear to be reduced, whereas the level of cytokines (JL-Ia, lL-6, TNF-a, TGF-(?» that inhibit melanogenesis is increased. Keratinocytes producing TNF-a induce ICAM-I expression on melanocytes, facilitating the lymphocytic oxygen burst. Superoxide anion can destroy the tetrapyrrole ring of Cat, inhibit tyrosinase, and, once converted in OH', bleach melanin (19).ln addition, TNF-a might inhibit melanocyte function through tyrosinase and TRP-l impairment (37,38). EXPERIMENTAL EVIDENCE OF SYSTEMIC OXIDATIVE STRESS IN VITILIGO

Recently, a systemic alteration of the antioxidant pattern similar to that described in melanocytes (7) has been reported during the active phase of vitiligo. Moreover, increased ROS generation (Fig. 2) and a higher percentage of apoptosis were found in peripheral blood mononuclear cell (PBMNC) from active vitiligo patients with respect to stable patients or normal subjects, inhibited by cyclosporin A, a drug acting on the mitochondrial permeability transition pores (39). These results suggested the hypothesis that an impairment of the mitochondrial electron transport chain (ETC), a source of both ATP and ROS, plays a central role in the destruction of melanocytes during vitiligo. The threshold of sensitivity of the ETC to peroxidative damage is dependent on cell type and intracellular content of the antioxidant, which could explain the specific melanocyte degeneration (40). Moreover, the ETC is susceptible to several exogenous and endogeneous factors, such as calcium, TNF-a, ROS, and catecolamines, all reported to be altered during the active phase of vitiligo (Fig. 3). Copyrighted Material

Picardo and Dell'Anna

130

*p
··~.OS

170

E 160

ft.

~ 1~

~

a:~ is ~~

140 130 12.0 110

100

+-~L-_-'--r---L

oonlrol

_ _L - - - - r - - L . . _ - - L - - - r - . . . L - _ - ' - - . ,

dable

mc:tJv~CaA

FIGURE 2 In PBMC from active vitiligo patients, an increased intracellular ROS generation was found with respect to those from stable patients or normal subjects, Pretreatment with CsA significantly reduces the intracellular ROS level.

FIGURE 3 Mitochondria appear to originate from both ATP and ROS, The increased susceptibility of melanocytes to pro-oxidant stimuli could be dependent on an intrinsic mitochondrial defect.

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GENETIC DATA Recent genetic studies have shown a possible basis for the reduced Cat activity in vitiligo epidermis. A catalase gene polymorphism (TIC heterozygosis), leading to an alteration of the correct assembly of the subunits, was reported (41 ). In contrast to the results of the Schallreuter group, a lower COMT activity in acrofacial vitiligo was found, possibly due to allelic polymorphism. In the COMT-LL genotype the G-A substitution leads to lower enzymatic activity and higher a-quinone levels with respect to COMT-HL and COMTHH genotype (42).

ANIMAL MODELS The avian model of vitiligo is found in Barred Rock Plymouth (BPR) and White Leghorn (WL) chickens. The low level of GSH and SOD (50-60%) in feather melanocytes from BPR and WL with respect to wild-type jungle fowl (IF) leads to their premature death. The possibility of mimicking the WL phenotype by treating the JF melanocytes with buthionine sulfoxime (BSO) indicates GSH involvement (2,9,43). THERAPEUTIC ASPECTS Some treatment approaches for vitiligo further support the free radical theory. The topical application of pseudocatalase, a low molecular weight inorganic compound with catalase activity, plus calcium chloride and UVB phototherapy has been reported as stimulating repigmentation in most patients treated (44-46), even if the preliminary results have not been confirmed by other groups. Administration of an antioxidant cocktail containing vitamin E acetate, selenium methionine, f?>-carotene, and ubiquinone is frequently associated with UBV narrow band phototherapy and seems to increase the positive results with respect to UYB alone and reduce the UYB doses (47,48). The association of oral supplementation with vitamin E and PUYA (psoralen plus UV-A) phototherapy was found to reduce the lipoperoxidative process induce by UYA without affecting the clinical improvement of the vitiligo lesions (49). Finally, considering the potential dangerous effects of sun exposure in connection with cutaneous oxidative stress, lifestyle modifications could prevent disease reactivation. In particular, the use of a broad spectrum sunscreen (SPF 15 or greater) should be suggested with the aim to decrease the shortand long-term side effects of UV and contrast between the normally pigCopyrighted Material

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men ted skin and the lighter areas. On the other hand, local application of a cream containing low molecular weight antioxidant molecules, including tocopherol, ascorbic acid derivatives, carnosine, etc., could reduce the side effects of UV exposure without inhibiting the possible repigmentation induced by the natural sun irradiation. CONCLUDING REMARKS The pathogenetic mechanisms underlying vitiligo have yet to be completely understood, and different hypotheses, probably not mutually exclusive, have been advanced (3,4). However, several metabolic impairments and an increased release of pro-inflammatory cytokines, which can lead to prooxidant effects, have been reported in vitiligo. The increased susceptibility of melanocyte, could be dependent on an intrinsic defect such as the impairment of mitochondrial function. The persistent alteration of the pro-oxidant/ antioxidant ratio could be the first pathogenetic event in melanocyte degeneration, occurring even after external stimuli. The subsequent release of melanocyte antigens could lead to an autoimmune response, which can maintain and propagate the disease (Fig. 4)

(

/.:::~ :eJatonin

{

receptor I;eactivity

\

toxic intermediates '\ catecholamins "'" discharge ",

~oclies

FIGURE

4

A revised convergence theory including mitochondrial impairment.

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REFERENCES I.

2.

3. 4. 5.

6.

7.

8.

9.

10.

II.

12

13 14. 15.

16

Nordlund JJ, Boissy RE, Heming VJ, King RA, Ortonne JP, eds. Vitiligo vulgaris. In: The Pigmentary System. New York: Oxford University Press, 1998:513-551. Castanet 1, Ortonne lP. Pathophysiology of vitiligo. Clin Dermatol 1997; 15:845-851. Le Poole IC, Boissy RE. Vitiligo. Semin Cutan Med Surg. 1997; 16(1):3-14. Taieb A. Intrinsic and extrinsic pathomechanisms in vitiligo. Pigment Cell Res 2000; 13:41-47. Schallreuter KU, Wood JM, Pittelkow MR. Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 1994; 263:1444-1446. Schallreuter KU, Moore J, Wood 1M, Beazley WD, Gaze DC, Tobin DJ, Marshall HS, Panske A, Panzing E, Hibberts NA. In vivo and in vitro evidence for hydrogen peroxide (H 2 0 2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. 1 Invest Dermatol Symp Proc 1999; 4:91-96. Maresca V, Roccella M, Roccella F, Camera E, Del Porto G, Passi S, Grammatico P, Picardo M. Increased sensitivity to peroxidative agents as a possible pathogenic factor of melanocyte damage in vitiligo. J Invest Dermatol 1997; 109:310-313. limbow K, Chen H, Park JS, Thomas PD. Increased sensitivity ofmelanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br J Dermatol 2001; 144:55-65. Bowers RR, Lujan J, Biboso A, Kridel S, Varkey C. Premature avian melanocyte death due to low antioxidant levels of protection: fowl model for vitiligo. Pigment Cell Res 1994; 7(6):409-418 Passi S, Grandinetti M, Maggio F, Stancato A, De Luca C. Epidermal oxidative stress in vitiligo. Pigment Cell Res 1998; 11 (2):81-85. van den Wijngaard RM1GJ, Scheepmaker JAA, Le Poole IC, Tiggers Al, Westerhof W, Das PK. Expression and modulation of apoptosis regulatory molecules in human melanocytes: significance in vitiligo. Br J Dermatol 2000; 143:573-581. Hennsley K, Robinson KA, Gabbita SP, Salsman S, Floyd RA. Reactive oxygen species, cell signalling, and cell injury. Free Rad Bioi Med 2000; 28(10): 1456-1462. Nordberg J, Arner ESJ. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Rad BioI Med 200 I; 31 (II): 1287-1312. Medrano EE, Nordlund JJ. Successful culture of adult human melanocytes obtained from normal and vitiligo donors. J Invest Dermatol 1990; 95:441-445. Puri N, Mojamdar M, Ramaiah A. In vitro growth characteristics of melanocytes obtained from adult normal and vitiligo subjects. 1 Invest Dermatol 1987; 88:434-438. Boissy RE, Liu YY, Medrano EE, Nordlund JJ. Structural aberration of the rough endoplasmic reticulum and melanosome compartmentalization in longterm cultures of melanocytes from vitiligo patients. 1 Invest Dermatol 1991; 97:395-404.

Copyrighted Material

Picardo and Dell'Anna

134

17.

18. 19. 20.

21.

22.

23.

24.

25. 26. 27.

28. 29. 30.

31.

32.

33.

Cario-Andre' M, Bessou S, Gontier E, Maresca V, Picardo M, Taieb A. The reconstructed epidermis with melanocytes: a new tool to study pigmentation and photoprotection. Cell Mol Bioi (Noisy-Ie-grand) 1999; 45(7):931-942. Schallreuter KU, Wood JM. Thioredoxin reductase-its role in epidermal redox status. J Photochem Photobiol B 2001; 64:179-184. Schallreuter KU, Wood JM, Berger J. Low catalase levels in the epidemlis of patients with vitiligo. J Invest Dermatol 1991; 97:1081-1085. Schallreuter KU. Zschiesche M, Moore J, Panske A, Hibberts NA, Herrmann FH, Metelmann HR, Sawatzki J. In vivo evidence for compromised phenylalanine metabolism in vitiligo. Biochem Biophys Res Commun 1998; 243:395399 Schallreuter KU, Wood JM, Pittelkow MR, Buttner G. Swanson N, Korner C, Ehrke C. Increased monoamine oxidase A activity in the epidermis of patients with vitiligo. Arch Dermatol Res 1996; 288:14-18. Schallreuter KU, Moore J, Wood JM, Beazley WD, Peters EMJ, Maries LK, Behrens-Williams SC, Dummer R, Blau N, Th6ny B. Epidermal H 2 0 2 accumulation alters tetrahydrobiopterin (6BH 4 ) recycling in vitiligo: identification of a general mechanism in regulation of all 6BH 4 -dependent processes? J Invest Dermatol2001; 116:167-174. Patel KB, Stratford MRL, Wardman P, Everett SA. Oxidation of tetrahydrobiopterin by biological radicals and scavenging of the trihydrobiopterin radical by ascorbate. Free Rad Bioi Med 2002; 32(3):203-211. Tobin OJ, Swanson NN, Pittelkow MR, Peters EM, Schallreuter KU. Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 2000; 191:407-416. Schallreuter KU, Schultz-Douglas V, Bunz A, Beazley W, Korner C. Pteridines in the control of pigmentation. J Invest Dermatol 1997; 109:31-35. de la Fuente-Fernandez R. Mutations in GTP-cyclohydrolase I gene and vitiligo. Lancet 1997; 350:640. Bandyopadhyay 0, Lawrence E, Majumder PP, Ferrell RE. Vitiligo is not caused by mutations in GTP-cyclohydrolase I gene. Clin Exp Demlatol 2000; 25: 152153. Schallreuter KU, Wood JM, Pittelkow MR, Swanson NN. Defective calcium transport in vitiliginous melanocytes. Arch Dermatol Res 1996; 288: 11-13. Schallreuter KU. A review of recent advances on the regulation of pigmentation in the human epidermis. Cell Mol Bioi (Noisy-Ie-grand) 1999; 45(7):943-949. Picardo M, Passi S, Morrone A, Grandinetti M, Di Carlo A, Ippolito F. Antioxidant status in the blood of patients with active vitiligo. Pigment Cell Res 1994; 7:110-115. Wu CS, Yu HS, Chang HR, Yu CL, Yu CL, Wu BN. Cutaneous blood flow and adrenoceptor response increase in segmental-type vitiligo lesions. J Dermatol Sci 2000; 23:53-62. Cucchi ML, Frattini P, Santagostino G, Orecchia G. Higher plasma catecholamine and metabolite levels in the early phase of nonsegmental vitiligo. Pigment Cell Res 2000; 13:28-32. Peters EMJ, Tobin OJ, Seidah NG, Schallreuter KU. Pro-opiomelanocortin-

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34. 35. 36.

37.

38.

39.

40.

41. 42.

43.

44.

45. 46. 47. 48. 49.

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related pep tides, prohormone convertases I and 2 and the regulatory peptide 7B2 are present in melanosomes of human melanocytes. 1 Invest Dermatol 2000; 114:430-437. Thody AJ. a-MSH and the regulation of melanocyte function. Ann NY Acad Sci 1999; 885:217-229. Graham A, WesterhofW, Thody Al. The expression of a-MSH by melanocytes is reduced in vitiligo. Ann NY Acad Sci 1999: 885:470-473. Kemp EH, Waterman EA, Hawes BE, O'Neill K, Gottumukkala RVSRK, Gawkrodger Dl, Weetman AP, Watson PF. The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. 1 Clin Invest 2002; 109:923-930. Moretti S, Spallanzani A, Amato L, Hautmann G, Gallerani 1, Fabbri P. Vitiligo and epidermal microenvironment: possible involvement of keratinocyte-derived cytokines. Arch Dermatol 2002; 138(2). Moretti S, Spallanzani A, Amato L, Hautmann G. Gallerani I, Fabiani M, Fabbri P. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002; 15(2):87-92. Dell'Anna ML, Maresca V, Briganti S, Camera E, Falchi M, Picardo M. Mitochondrial impairment in peripheral blood mononuclear cells during the active phase of vitiligo. 1 Invest Dermatol 2001; 117:908-913. Cassarino DS, Bennett lP. An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Rev 1999; 29:1-25. Casp CB, She lX, Mccormack WT. Genetic association of the catalase gene (CAT) with vitiligo susceptibility. Pigment Cell Res 2002; 15:62-66. Tursen U, Kaya TL Erdal ME, Derici E, Gunduz 0, Ikizoglu G. Association between catechol-O-methyltransferase polymorphism and vitiligo. Arch Dermatol Res 2002; 294:143-146. Bowers RR, Nguyen B, Buckner S, Gonzales Y, Ruiz F Role of antioxidants in the survival of normal and vitiliginous avian melanocytes. Cell Mol Bioi (NoisyIe-grand) 1999; 45(7): 1065-1074. Schallreuter KU, Wood 1M, Berger 1. Treatment of vitiligo with a topical application of pseudocatalase and calcium in combination with short-tem1 UVB exposure: a case study on 33 patients. Dermatol 1995; 190:223-229. Schallreuter KU, Wood 1M. Antioxidants in the treatment of vitiligo. 1 Eur Acad Dermatol Venereol 1997; 9(suppl 1):94-95. Mandel AS, Haberman HF. Pawlowski D, Goldstein E. Non PUVA nonsurgical therapies for vitiligo. Clin Dermatol 1997; 15:907-919. Shapiro SS, Saliou C. Role of vitamins in skin care. Nutrition 2001; 17:839844. Leone G. Combined phototherapy in vitiligo. Proceedings of 10th Annual European Society of Pigment Cell Research Meeting, Rome, 2001:380. Akyol M, Celik VK, Ozcelik S, Polat M, Marufihah M, Atalay A. The effects of vitamin E on the skin lipid peroxidation and the clinical improvement in vitiligo patients treated with PUVA. Eur 1 Dermatol 2002; 12(1 ):24-26.

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11 Possible Role of Nitric Oxide in the Pathogenesis of Vitiligo Mario Vaccaro and Fabrizio Guarneri University of Messina, Messina, Italy

Vitiligo is a common progressive depigmentation of the skin, due to destruction of melanocytes. Although its cause is still to be exactly defined, the hypothesis of an autoimmune etiology of vitiligo is supported by increasing evidence (I) (Table 1). Recent studies have suggested that vitiligo could be the result of programmed melanocyte death or destruction due either to increased sensitivity to oxidative stress, coming from toxic intermediates of melanin (a melanocyte-specific protein) or from other sources (melanocytes of patients suffering from vitiligo are highly sensitive to oxidative stress, UVB exposure in comparison with normal melanocytes) (2), or to an ongoing local immune response, likely mediated by skin-homing T cells (T cells were frequently found in apposition to activated melanocytes) (3). Increasing evidence suggested the greater complexity of the scenario: several cells are involved (antigen-presenting cells, lymphocytes, keratinocytes, endothelial cells), communicating through a network of many different mediators that affect melanocyte migration, proliferation, and differentiation. In fact, the epidermal microenvironment can be considered a crucial milieu for the normal life and function of melanocytes (4-6). The immunological network, and all of its circuits, seems to be also modulated by neuropeptides released by sensitive nerves (7,8) in response to several factors of various nature. Neuropeptides can, in fact, influence the Copyrighted Material 137

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Defining Criteria for an Autoimmune Pathogenesis in Vitiligo

Criterion

Comment

Autoantibody transfer of disease

Reproduction of disease in experimental animal models Genetically determined animal models Identification within lesion autoantibody or autoreactive T cell Statistical association with particular MHC haplotype Lymphocyte infiltrate in target organ Association with other autoimmune diseases in the same individual or family Favorable response to immunosuppression

IgG from vitiligo patients elicits melanocyte destruction when injected into nude mice grafted with human skin IgG from vitiligo patients induces depigmentation when injected into nude mice grafted with human skin Well studied Smyth line chickens Autoreactive, melanocyte-specific T cells and autoantibodies were found in blood of vitiligo patients, but still not demonstrated in skin lesions Significant association of HLA-DR4 in several populations Observation of activated T lymphocytes at the periphery of lesions Frequent association of vitiligo and autoimmune thyroiditis or Addison's disease Good response to topical steroids, topical cytotoxic drugs, and PUVA

Source: Ref. 1.

reactions of cutaneous blood vessels and the activity of immune cells, keratinocytes, and melanocytes. Summarizing three hypotheses are currently proposed to explain melanocyte death/dysfunction in vitiligo: autoimmune, autocytotoxic, and neural. They are not mutually exclusive, and the real pathogenic mechanism probably resul ts from their concurrence (I). Mutual interaction between melanocytes, keratinocytes, lymphocytes, Langerhans cells, and innervation, mediated by inflammatory mediators, cytokines, and nitric oxide, could have a central role in the regulation of main cell functions, as well as in melanocyte dysfunction and/or destruction observed in vitiligo (Fig. I). Nitric oxide, a highly reactive free radical with a short half-life, is involved in several biological processes like vascular homeostasis, neurotransmission, immunomodulation, and inflammation (9,10). Nitric oxide, in fact, plays an important role in inflammatory processes: it is a powerful vasodilatatory agent, increases vascular permeability and cytokine production,

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Possible role of nitric oxide in the pathogenesis of vitiligo.

increases cell production of hydrogen peroxide, and can interact with superoxide anion to produce peroxynitrite, an important mediator of free radicalinduced cell damage. The idea of a vital principle in a gaseous state, suggested by Galeno in De usu partiwn corporis, has been considered only in the last 10 years, with a remarkable impact on clinical and basic research: the role of nitric oxide in many biological systems is well known and widely documented, but the comprehension of the fine regulatory mechanisms of cell growth and death, inflammation, and immune response is a recent and still not complete acquisition. Nitric oxide has several roles in skin physiology (important endogen regulator of microcirculation, melanogenesis, keratinocyte response to UV radiation, cell growth and differentiation), and increasing evidence has been found for its critical role in many inflammatory, hyperproliferative, and autoimmune diseases, other than in carcinogenesis and in tumor diffusion (11-15). The exact knowledge and the characterization of the role of this mediator in cutaneous diseases will not only provide another contribution to the comprehension of skin biology, but also will create the basis for the development of new therapeutic approaches able to modify, stop, or retard the course of several pathologies. Nitric oxide, a highly reactive messenger (it has no electric charge and can then pass through membranes; it also has an unpaired electron and can thus bind oxygen free rad\9t>\eyfJ§n~mli_fMfn), is produced during the

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conversion of L-arginine into L-citrulline (a NADPH-dependent reaction), catalyzed by enzymes belonging to the family of nitric oxide synthase (NOS). Two major isoforms of NOS are known: "constitutive" (c-NOS), further divided into neuronal (n-NOS) and endothelial (e-NOS) types, and "inducible" (i-NOS), involved in the regulation of cell homeostasis and in the modulation of immune and cytotoxic response, respectively (9,10,16). Nitric oxide has important functions, both regulatory and cytotoxic: the former are realized through modifications of transcription factors, cell motility, mitochondrial functions, and apoptosis, while the latter are realized through energetic damage, glycolysis block, destruction of the Krebs cycle and oxidative phosphorylation, inhibition of ATP production and DNA synthesis, and DNA deamination (16). In cutaneous physiopathology the prevalence of its cytotoxic activity over the regulatory one is due, probably, to the concentration of nitric oxide produced, the cell types involved, the stage of the disease, and many other factors. Low levels of nitric oxide generated by c-NOS are thought to be important in signal transduction mechanisms, while high levels produced by i-NOS could play an important role in cytostasis and cytotoxicity and hence in the limitation of Thl-induced tissue damage that occurs in various inflammatory conditions (16,17). Despite the well-known importance of nitric oxide in several physiological and pathophysiological conditions, its role in human melanogenesis is still under investigation. It has been found that in normal skin UVA and UVB induce production of nitric oxide, particularly by keratinocytes and melanocytes, through the activation of c-NOS, leading to an increase in tyrosinase activity and melanin synthesis (paracrine and autocrine mediation of UVinduced melanogenesis) (18). Many inflammatory mediators and cytokines have been demonstrated able to directly affect melanogenesis (4-6), but their site of action and their possible effects on pigment production are not perfectly known. The induction of i-NOS also requires multiple cytokines and endotoxins, including TNFa, IFN)', IL-I, IL-2, IL-6, IL-8, GM-CSF, and LPS (16). Recent studies have demonstrated that normal human melanocytes in culture can express i-NOS when stimulated by LPS/cytokines, suggesting a possible participation of i-NOS in hypopigmentary disorders (19). Cytokines can also induce overproduction of tetrahydrobiopterin, a potent inhibitor of melanin biosynthesis (20) and essential cofactor in enzymatic activity of i-NOS (21,22). Large amounts of nitric oxide could lead to self-destruction of melanocytes (11) and reduce de novo attachment ofmelanocytes to the extracellular matrix (23), causing skin depigmentation (19). This mechanism could be important in vitiligo, where an initial imbalance of epidermal cytokines at sites of lesions could cause tetrahydrobiopterin overexpression and i-NOS activation, with consequent nitric oxide overproduction leading to loss and self-destruction of melanocytes (Fig. 2). Copyrighted Material

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FIGURE 2 Confocal image obtained in "depth coding mode" (Iesional skin). Overexpression of i-NOS in basal and suprabasal layers.

However. it is still to be verified whether this complex scenario is due to an immune disturbance, an intrinsic susceptibility of melanocytes, an altered regulatory epidermal milieu. or all these factors. In any case, in vitiligo the inadequate response to nitric oxide represents an event sufficient to induce depigmentation. If vitiligo is really a nitric oxide-mediated disease, the use of NOS inhibitors (24), nitric oxide scavengers (25), or tetrahydrobiopterin inhibitors (22) should be considered in its treatment. However, because of nitric oxide's involvement in many different physiological functions, secondary effects of this approach should be carefully evaluated, especially with regard to its possible toxicity. Further studies are then needed to develop more selective inhibitors in order to achieve better efficacy and fewer collateral effects of this potential treatment.

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REFERENCES I. 2.

3.

4.

5. 6.

7. 8.

9. 10. II. 12. 13. 14. 15.

16. 17. 18.

Kemp EH, Waterman EA, Weetman AP. Autoimmune aspects of vitiligo. Autoimmunity 2001; 34:65~77. limbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br 1 Dermatol 2001; 144:55-65 van den Wijngaard R, Wankowicz-Kalinska A, Le Poole C, Tigges B, Westerhof W, Das P. Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA + T cells at the perilesional site. Lab Invest 2000; 80: 1299-1309. Gordon PR, Mansur CP, Gilchrest BA. Regulation of human melanocyte growth, dendricity, and melanization by keratinocyte derived factors. 1 Invest Dermatol 1989; 92:565-572 Morelli lG, Norris DA. Influence of inflammatory mediators and cytokines on human melanocyte function. J Invest Dermatol 1993; 100:19IS-195S. Moretti S, Spallanzani A, Amato L, Hautmann G, Gallerani I, Fabiani M, Fabbri P. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002; I 5:87~92. AI'Abadie MS, Senior HJ, Bleehen SS, Gawkrodger Dl. Neuropeptide and neuronal marker studies in vitiligo. Br J Dermatol 1994; 131:160--165. AI' Abadie MS, Warren MA, Bleehen SS, Gawkrodger Dl. Morphologic observations on the dermal nerves in vitiligo: an ultrastructural study. Int 1 Dermatol 1995; 34:837-840 Knowles RG, Moncada S. Nitric oxide synthase in mammals. Biochem 1 1994; 298:249-258. Lowenstein Cl, Dinerman lL, Snyder SH. Nitric oxide: a physiologic messenger. Ann Intern Med 1994; 120:227-237. Qureshi AA, Lerner LH, Lerner EA. From bedside to the bench and back. Nitric oxide and cutis. Arch Dermatol 1996; 132:889-893. Weller R. Nitric oxide~a newly discovered chemical transmitter in human skin. Br 1 Dermatol 1997; 137:665-672. Bruch-Gerharz D, Ruzicka T, Kolb-Bachofen V. Nitric oxide in human skin: current status and future prospects. 1 Invest Dermatol 1998; 110:1-7. Weller R. Nitric oxide, skin growth and differentiation: more questions than answers? Clin Exp Dermatol 1999; 24:388-391. Ormerod AD, Copeland P, Hay I, et al. The inflammatory and cytotoxic effects of a nitric oxide releasing cream on normal skin. J Invest Dermatol 1999; 113:392-397. Kolb H, Kolb-Bachofen V. Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator? Immunol Today 1998; 19:556-561. Ahmed B, Van Den Oord JJ. Expression of the inducible isoform of nitric oxide synthase in pigment cell lesions of the skin. Br J Dermatol 2000; 142:432-440. Romero-Graillet C, Aberdam E, Clement M, Ortonne JP, Ballotti R. Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis. 1 Clin Invest 1997; 99:635-642.

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19.

20.

21.

22.

23.

24. 25.

143

Rocha 1M, Guillo LA. Lipopolysaccharide and cytokines induce nitric oxide synthase and produce nitric oxide in cultured normal human melanocytes. Arch Dermatol Res 2001; 293:245-248. Schallreuter KU, Wood JM, Ziegler I, Lemke KR, Pittelkow MR, Lindsey NJ, Gutlich M. Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochem Biophys Acta 1994: 1226:181192. Sakai N, Kaufman S, Milstein S. Tetrahydrobiopterin is required for cytokineinduced nitric oxide production in a murine macrophage cell line (RAW 264). Mol Pharmacol 1993; 43:6-10. Bune AJ, Brand MP, Heales SJ, Shergill JK, Cammack R, Cook HT. Inhibition of tetrahydrobiopterin synthesis reduces in vivo nitric oxide production in experimental endotoxic shock. Biochem Biophys Res Commun 1996; nO(l): 1319. Ivanova K, Le Poole IC, Gerzer R, WesterhofW, Das PK. Effect of nitric oxide on the adhesion of human melanocytes to extracelluar matrix components. J Pathol 1997; 183:469-476 Hobbs AJ, Higgs A, Moncada S. Inhibition of nitric oxide synthase as a potential therapeutic target. Annu Rev Pharmacol Toxicol 1999; 39:191-220. Fricker SP, Slade E, Powell NA, Vaughan OJ, Henderson GR, Murrer BA, Megson IL, Bisland SK, Flitney FW. Ruthenium complexes as nitric oxide scavengers: a potential therapeutic approach to nitric oxide-mediated diseases. Br J Pharmacol 1997; 122:1441-1449.

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12 Histopathological and Ultrastructural Features of Vitiligo Daniela Massi University of Florence, Florence, Italy

INTRODUCTION

Vitiligo is an acquired, idiopathic, and, in the majority of cases, progressive disorder of the skin characterized by depigmented patches of variable size, which enlarge and coalesce to form extensive areas of leukoderma (1-3). On clinical examination, stable patches of vitiligo appear as completely depigmen ted areas sharply demarcated from the surrounding skin. In expanding lesions, there may occasionally be a rim of erythema at the border and a thin zone of transitory partial depigmentation. Repigmentation may lead to several shades of color within a particular lesion. In the pathogenesis of vitiligo, biochemical (4), neurological (5), and immunological (6) factors appear to be involved to a varying extent according to the clinical subset of the disease. Recently, a "convergence theory" combining all pathogenetic hypotheses, has been suggested. Patients with vitiligo note the loss of color from their skin when the disorder first begins or spreads. There are basically two mechanisms by which the melanin might disappear from the skin and the skin turn white: (1) melanocytes may be absent from depigmented areas, or (2) melanogenesis may have been silenced in melanocytes still present within the lesion. In this regard, there is a long-standing controversy over whether melanocytes in vitiligo lesions are actually lost or are still present but functionally dormant or inactivated. Needless to say, both pathogenesis and response to treatment are Copyrighted Material 145

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dependent on this crucial issue. In this view, the histopathological and ultrastructural investigations undertaken to demonstrate the morphological changes in the skin in patients affected by vitiligo are of outmost importance in order to gain insights into the pathophysiology of the disease. LESIONAL SKIN

The clinical presentation of the disease may be quite variable and complex. Likewise, under the microscope, the histopathological features observed in skin specimens taken from affected patients are not uniform, depending on the site (lesional vs. perilesional vs. normally pigmented, nonlesional skin), type, and duration oflesion under examination. However, most of the earlier studies almost unanimously concluded that long-standing depigmented patches show a complete loss of melanin and absence of melanocytes from the epidermis (Figs. 1-5). To enhance the visualization of melanin synthesis and deposition in the epidermis, the Masson-Fontana silver reduction staining technique (7) was perfomed on split skin obtained from depigmented patches (8) demonstrating the absence of melanin. In addition, histochemical procedures specific for the identification ofmelanocytes have been developed to detect quiescient or inactive melanocytes in tissues. For these histochemical procedures, tissues or cells were fixed or incubated in a buffer solution containing either tyrosine or I-dihydroxyphenylalanine (DOPA), the substrates for melanin reaction products at sites where functional tyrosinase exists, i.e., within the melanosomes located in the cytoplasm of melanocytes. Hu et aI., performing DOPA histochemistry, demonstrated that most vitiligo lesions were DOPA-negative (8). Occasionally, islands of DOPA-positive cells were observed in the vitiliginous skin. These DOPA-positive cells were smaller and less dendritic than normal melanocytes. The authors suggested that these cells likely represented inactive melanocytes. Subsequent studies employing DOPA histochemistry on split vitiligo skin also demonstrated the loss or presence of a few abnormal melanocytes in depigmented areas (9). . In line with these observations, Le Poole et a1. in 1993 published a comprehensive immunohistochemical study using a panel of I polyclonal and 17 monoclonal antibodies directed against melanocytes and concluded that melanocytes are indeed absent within vitiliginous lesions, although in epidermal split-skin preparations residual staining attributed to degenerated melanocytes was occasionally observed (10). In addition, Dippel et a1. demonstrated that the c-kit receptor, a molecule expressed early in melanocyte differentiation, was undetectable in vitiligo skin (II). This finding is consistent with the hypothesis that nonfunctional melanocytes are absent from vitiligo lesions. However, there are some sporadic reports indicating that vitiligo lesions are not fully devoid of melanocytes (12, I3). Also in our experience melanoCopyrighted Material

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FIGURE 1 Normal skin (hematoxylin and eosin). Epidermal melanocytes appear as clear cells in and immediately beneath the basal cell layer. Nuclei of melanocytes are smaller and more deeply basophilic than those of contiguous keratinocytes. Melanin is present at all levels of the epidermis, but the basal cell layer is the most heavily pigmented.

FIGURE 2 Perilesional skin (Giemsa). Melanocytes are absent from the basal cell layer while melanin is still p~~dtM~J<eratinocytes.

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FIGURE 3 Perilesional skin (S-100). S-100 immunohistochemical expression shows absence of melanocytes, whereas suprabasal Langerhans cells are evident.

FIGURE 4 Normal skin (semi-thin section, toluidine blue). Scattered vacuolated melanocytes are present within the epidermis. The clear space is an artifact of fixation.

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FIGURE 5 Lesional skin (semi-thin section, toluidine blue). Melanocytes are absent from the basal cell layer.

cytes may be detected at ultrastructural level and are indeed present in lesional skin from vitiligo patients (unpublished observations) (Figs. 6-8). In particular, Husain et al. showed that enzymatic hydroxylation of tyrosine to DOPA in epidermal homogenates of vitiligo was due to the presence of tyrosinase (12). Such residual amounts of the melanocyte-specific enzyme tyrosinase detected in lesional vitiligo provided evidence for the presence ofmelanocytes within lesional skin. A more recent study reported that although in 1- to 3year-old vitiligo lesions neither active or inactive melanocytes are found, nonnegligible amounts of melanin were detected in a few keratinocytes in the basal epidermal layer (14). In particular, late-stage maturation (III/IV) melanosomes were detected and clumped as melanin granules within basal keratinocytes (14). The authors concluded that melanosomes can persist in keratinocytes for some time after the onset of vitiligo (14). In agreement with these observations, Tobin et al. showed that melanocytes could be isolated and established in vitro from all samples of lesional and normal skin, independent of disease duration and independently from treatment (13). In addition, small amounts of mature melanin granules were observed in the amelanotic skin of vitiligo patients, suggesting that some partially functioning melanocytes must be retained in this disorder. The retention of rare intact melanocytes in lesional skin of vitiligo was therefore taken to support the view that a subpopulation of "resistant" epidermal melanocytes could be present. Copyrighted Material

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FIGURE 6 Normal skin (electron micrograph). Uptake of numerous compound melanosomes released from melanocytes into adjacent keratinocytes.

While these rare melanocytes were usually amelanotic, some contained poorly melanized granules. Interestingly, the authors also found extracellular melanin granules lying free in the interstitial space within both amelanotic and normal epidermis. Since these granules were not always associated with melanocyte cytoplasm or melanocyte dendrites, they could possibly be released by degenerative or partially functioning melanocytes. A premature delivery of pre-melanosomes from melanocytes to keratinocytes or ingestion

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FIGURE 7 Perilesional skin (electron micrograph). Although reduced in number, scattered melanosomes are still observed within rare melanocytes.

of immature melanosomes by keratinocytes after fragmentation/degeneration of melanocytes was postulated (13). It is commonly thought that repigmentation is associated with repopulation of amelanotic areas by the melanocytic reservoir of the hair follicles (15,16). In particular, a combination of hair follicle split-DOPA stains and hair follicle split-scanning electron microscopy demonstrated inactive, DOPA-negative melanocytes in the outer root sheaths of normal hair follicles. These inactive melanocytes are also seen in the outer root sheaths of hair Copyrighted Material

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8 Lesional skin (elecron micrograph). Rare melanocytes are still present, although no melanosomes are seen. Keratinocytes contain numerous bundles of tonofilaments. FIGURE

follicle from vitiliginous patches. Treatment of vitiligo stimulates these inactive melanocytes in the middle and lower parts of the outer root sheaths to divide, proliferate, and migrate upward to the dermal-epidermal junction of overlying skin. Melanocytes then spread to form the pigmented islands clinically visible in repigmented lesions (15,16). However, if rare melanocytes are indeed present also in lesional skin, as recent studies have suggested, it is likely that this is not the only mechanism by which repigmentation occurs. Copyrighted Material

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In one study, Merkel cells were reported to be absent from stable Jesional skin, supporting a neural involvement in vitiligo (17). Conversely, in long-standing patches of vitiligo, Langerhans cells were reported to be normal in number although distributed more basally than usual (18). However, a recent study evaluating Langerhans cell distribution in vitiliginous epidermis by immunohistochemistry demonstrated that there were no topographical differences in the presence of Langerhans cells in lesions, at the border, or in pigmented skin of patients with inflammatory vitiligo (19). Degenerative changes affecting nerves have also been reported. In particular, numerous nerve endings were seen in close contact with the basal lamina (20). On ultrastructural examination, approximately three quarters of all dermal nerves in vitiligo biopsies show an increased thickness of the basal membrane of Schwann cells (21). Furthermore, about half of the abnormal dermal nerves in vitiligo skin showed minor axonal degeneration and nerve regeneration, the latter possibly being a reactive change to earlier axonal damage (21). Overall, these observations suggest that neural factors may play a role in the pathogenesis of the disease. PERILESIONAL SKIN

Data from the literature suggest that the peripheral area of expanding lesions that are clinically hypopigmented rather than fully depigmented usually shows a few melanocytes and some melanin granules within the basal layer of the epidermis, although reduced in number as compared with normal skin (22). At the advancing border of vitiligo patches, melanocytes are often prominent, increased in size, and show long dendritic processes containing melanin granules. In contrast, some reports have described the melanocytes at the border to be histopathologically (9) and ultrastructurally (23) normal. Still to be determined is whether different melanocytes' conditions at the border of the vitiligo patches correlate to the state of the lesions (progressing vs. dormant disease). Boissy and Nordlund have occasionally noticed that melanocytes in the perilesional normally pigmented skin immediately nearby an amelanotic vitiligo lesion exhibit cellular shrinkage and increased nuclear heterochromatin, indicating that these cells might be in the initial stages of apoptosis (24). The authors suggested that, theoretically, keratinocytes could effectively phagocytize fragmented apoptotic melanocytes and carry the debris with them as they migrate up the stratum corneum where they desquamate off the epidermis. Removal of melanocytes undergoing apoptosis by the keratinocyte would be consistent with the lack of prominent inflammation and immune response at the lesional borders of most patients with vitiligo. Keratinocyte damage has also been demonstrated at the edge of the vitiligo lesions. Indeed, f~y1lightfM~Mfltion of the basal cell layer

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associated with a mild lymphohistiocytic infiltrate has been described (23,25,26). Ultra-thin sections have better shown vacuolated keratinocytes and extracellular granul~r material between the melanocytes and the keratinocytes, as well as between keratinocytes themselves, suggesting that the keratinocyte is also affected by the pathological process causing vitiligo (23,27). Fibrillar masses similar to colloid bodies may also be present in the upper dermis and in the basal lamina (20). The border of depigmented areas often shows a scant perivascular lymphohistiocytic infiltrate within the superficial dermis as well as superficial edema. Inflammatory cells are invariably present if there is an inflammatory border on clinical examination. If serial sections are examined, a lymphocyte will be sometimes found in close apposition to a melanocyte at the advancing edge. Erythematous borders are also usually associated with variable teleangectasies. A heavy Iymphohistiocytic infiltrate in the upper dermis is more rarely observed (27). Immunohistochemical studies confirmed a highly significant increase in the number of lymphocytes in epidermis and superficial dermis around the margin of the zone of melanocyte depletion in lesions of vitiligo and have shown that the infiltrate is almost entirely composed ofT cells, many of which are activated (MHC class II + , IFN 'Y + ) (28). In particular, the most intense epidermal T-cell infiltration was detected within 0.6 mm of the edge of the lesion. These observations are consistent with the hypothesis that lesional T cells-rather than circulating antimelanocytic antibody-may be responsible for the supposedly autoimmune, but characteristically patchy destruction of melanocytes in vitiligo. Nevertheless, many of the infiltrating T cells are probably innocent bystanders, recruited from the circulation by upregulated cell-adhesion molecules near sites of melanocytic damage. In three cases of inflammatory vitiligo patients, an immunohistochemical investigation demonstrated that in perilesional dermis CD68 + macro phages are more numerous than in lesional and nonlesional skin (19). CD3 + T cells were significantly increased in perilesional as compared with nonlesional or lesional skin. More importantly, within the epidermal compartment, T cells were substantially more numerous in perilesional skin than in control skin. Such T cells were mainly concentrated where the melanocyte destruction takes place, within the basal layer of the epidermis (19). NORMALLY PIGMENTED NONLESIONAL SKIN

The pigmented skin at di tant sites from depigmented patches has been considered histologically unremarkable, with melanocytes being normal in number and morphology. However, electron microscopic studies have shown that these areas may show signs of melanocytic degeneration in the form of

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intracellular edema and vacuolar formation (23). In addition, it has also been demonstrated that melanocytes in the pigmented skin ofpatients with vitiligo may exhibit ultrastructural abnormalities including dilation of rough endoplasmic reticulum, circular RER profiles, and/or membrane-bound compartments ofmelanosomes (29). However, these abnormal structures in cultured melanocytes were not always concomitantly expressed and could not be associated with any specific clinical feature of vitiligo (29).

CONCLUSIONS The pathogenetic mechanisms by which the melanocytes are lost in vitiligo patients have not been yet unequivocally identified. Likewise, at present some controversies exist concerning the histopathological and ultrastructural features in skin specimens from affected patients. Although earlier studies repeatedly indicated that lesional skin shows an absence of melanin and melanocytes, along with degenerative changes affecting both melanocytes and basal/supra basal keratinocytes, more recent investigations demonstrated that melanocytes are never completely absent in the depigmented epidermis and that these melanocytes maintain the capability of recovering their functionality. Further studies are therefore needed to clarify this highly debated issue that has obvious therapeutic implications.

REFERENCES 1. 2. 3. 4. 5. 6.

7. 8. 9.

]0.

Koranne RV, Sachdeva KG. Vitiligo Int J Dermatol 1988; 27:676-681. Nordlund JJ, Lerner AB. Vitiligo. It is important. Arch Dennatol 1982; 118:5-8. Sharquie KE. Vitiligo. Clin Exp DermatoJ 1984; 9:117-126. Lerner A. On the etiology of vitiligo and gray hair. Am J Med 1971; 51:141147. Ortonne JP, Mosher DB, Fitzpatrick TB. Vitiligo and other hypomelanosis of hair and skin. New York: Plenum Medical Book Co., 1983:1-55. Harning R, Cui J, Bystryn Je. Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Dermatol 1991; 971078-1080. Masson P. Pigment cells in man. NY Acad Sci Special Publication 1948; 4: 1551. Hu F, Fosnaugh RP, Lesney PF. In vitro studies on vitiligo. J Invest Dermatol 1959; 33:267-280. Bleehen SS. Histology of vitiligo. In: Klaus N, ed. Pigment Cell 5: Part II of Preceedings of the X International Pigment Cell Conference Cambridge, MA. Basel: S. Karger, 1979:54-61. Le Poole IC, van den Wijngaard RM, Westerhof W, Dutrieux RP, Das PK.

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II.

12.

13.

14. 15. 16. 17 ]8.

19.

20.

21. 22. 23.

24. 25. 26. 27.

Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 1993; 100:816-822. Dippel E, Haas N, Grabbe J, Schadendorf D, Hamann K, Czarnetzki BM. Expression of the c-kit receptor in hypomelanosis: a comparative study between piebaldism, naevus pigmentosus and vitiligo. Br J Dermatol 1995; 132182-189. Husain I, Vijayan E, Ramaiah A, Pasricha JS, Madan NC. Demonstration of tyrosinase in the vitiligo skin of human beings by a sensitive f1uorimetric method as well as by '4C(U)-L-tyrosine incorporation into melanin. J Invest Dermatol 1982; 78243-252. Tobin DJ, Swanson NN, Pittelkow MR, Peters EM, Schallreuter KU. Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 2000; 191:407-416. Bartosik J, Wulf HC, Kobayasi T. Melanin and melanosome complexes in long standing stable vitiligo-an ultrastructural study. Eur J Dermatol 1998; 8:95-97. Cui J, Shen LY, Wang Gc. Role of hair follicle in the repigmentation of vitiligo. J Invest Dermatol 1991; 97:410-416 Arrunategui A, Arroyo C, Garcia L, et al. Melanocyte reservoir in vitiligo. Int J Dermatol 1994; 33:484-487. Bose SK. Probable mechanism of loss of Merkel cells in completely depigmented skin of stable vitiligo. J Dermatol 1994; 21:725-728. Birbeck MS, Breathnach AS, Everall JD. An electron microscope study of basal melanocytes and high-level clear cells (Langerhans cells) in vitiligo. J Invest Dermatol 1961; 3751. Ie Poole IC, van den Wijngaard RMJGJ, WesterhofW, Das PK. Presence ofT cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Pathol 1996; 148:1219-1228. Morohashi M, Hashimoto K, Good TF, Newton DE, Rist T. Ultrastructural studies of vitiligo, Vogt-Koyanagi pigmenti achromians. Arch Dermatol 1977; 113:755-766. AI'Abadie MS, Warren MA, Bleehen SS. Morphologic observations in the dermal nerves in vitiligo: an ultrastructural study. Int J Dermatol 1995; 34:837-840. Brown J, Winkelmann RK. Langerhans cell in vitiligo: a qualitative study. J Invest Dermatol 1967; 49:386-390. Moellmann G, Klein-Angerer S, Scollay DA, Nordlund JJ, Lerner AB. Extracellular granular material in the normally pigmented epidermis of patients with vitiligo. J Invest Dermatol 1982; 79:321-330. Boissy RE. Histology of vitiliginous skin. Tn: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000:23-34. Hann SK, Park YK, Lee KG, Choi EH, 1m S. Epidermal changes in active vitiligo. J Dermatol 1992; 19:217-222. Galadari E, Mebregan AH, Hashimoto K. Ultrastructural study of vitiligo. Int J Dermatol 1993; 32:269-271. Bhawan J, Bhutani LK. Keratinocyte damage in vitiligo. J Cutan Pathol 1983; 10:207-212

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29.

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al Badri AMT, Todd PM, Garioch 11, Gudgeon J E, Stewart DG, Goudie RB. An immunohistological study of cutaneous lymphocytes in vitiligo. J Pathol 1993; 170:149-155. Boissy R, Liu YY, Medrano EE, Nordlund JJ. Structural aberration of the rough endoplasmic reticulum and melanosome compartmentalisation in long term cultures of melanocytes from vitiligo patients. J Invest Dermatol 1991; 97:395-404

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13 Clinical Variants of Vitiligo

Seung-Kyung Hann and Sungbin 1m Korea Institute of Vitiligo Research, Seoul, Korea

CLINICAL VARIANTS OF VITILIGO

Vitiligo may occur on any part of the integument, but the face, dorsum of the hands, axillae, umbilicus, nipples, sacrum, and inguinal regions are the most frequently involved sites, exhibiting two general patterns: unilateral or bilateral. In the previous chapters the most common forms of vitiligo have been described. These include: I.

2.

Localized forms: a. Focal: one or more macules localized in one area not showing zosteriform or segmental pattern b. Segmental form: involving a unilateral segment of the body and stopping abruptly at the midline of the affected segment c. Mucosal form: limited to mucous membranes Generalized forms: a. Universalis: with complete or nearly complete depigmentation b. Vulgaris: with scattered macules c. Acrofacial: involving the distal part of the extremities and the face d. Mixed Copyrighted Material

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In this chapter we will describe the most interesting clinical variants of the disease: the segmental, bilateral segmental, and trichrome forms, vitiligo with raised borders, and blue vitiligo.

SEGMENTAL VITILIGO In 1977, an investigator divided vitiligo into segmental and nonsegmental types. He described segmental vitiligo as depigmented patches confined to a definite dermatome, akin to herpes zoster (I). He proposed that the pathogenesis and clinical manifestation of the two types were different from each other, based on his experiment in which sweat secretion was stimulated by local injection of physisotigmine. The segmental type results from dysfunction of the sympathetic nervous system in the affected skin area, while the nonsegmental type results from an immunological mechanism. The clinical features of vitiligo have been reported by many investigators. However, the study of segmental vitiligo has rarely been reported, and the numbers of patients studied limited. The incidence of segmental type is variable; one group of investigators reported 5% (2), another group reported 27.9% (3), and previous Korean studies showed a range between 5.5 and 161 % (4,5). Vitiligo develops at all ages, but it usually occurs in young people between the ages of 10 and 40. However, according to an epidemiological study reported in 1977 (6), abollt half of the patients developed vitiligo after 40 years of age, which was very different from other clinic-based studies. On the other hand, one group reported that onset of nonsegmental vitiligo could occur at any age, whereas segmental vitiligo generally affected the young. In our report (7), segmental vitiligo developed before 30 years of age in 87.0% of

TABLE

1

Site of Segmental Vitiligo

Site

Men (%)

Women (%)

Total (%)

Head and neck Face Neck Scalp Trunk Chest and abdomen Back Extremities Upper extremities Lower extremities Total

57(62.6) 49(53.8) 7(7.7) 1(1 .1) 21(23.1) 17(18.7) 4(4.4) 13(14.3) 7(7.7) 6(6.6) 91

87(65.9) 65(49.2) 20(15.2) 2(1.5) 34(25.8) 31 (23.5) 3(2.3) 11 (8.3) 7(5.3) 4(3.0) 132

144(64.6) 114(51.1) 27(12.1) 3(1.4) 55(24.7) 48(21.5) 7(3.1) 24(10.8) 14(6.3) 10(4.5)6 223

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the patients, and 41.3% were younger than 10 years. This is in accord with the report that segmental vitilligo occurs in young people before age 30 (3). The commonly involved sites of vitiligo are exposed areas, such as the face and dorsum of the hand. In our study of segmental vitiligo, the involved sites were the face, trunk, neck, extremities, and scalp, in descending order (Table I). An older study reported that vitiligo occurs as single lesions in 75% of cases (8), which was the situation with 87% of the patients in our study. Dermatomal distribution revealed that the trigeminal nerve (Fig. I) was most frequently involved, followed by the thoracic (Fig. 2), cervical, lumbar, and sacral nerves (Table 2).

FIGURE 1 Segmental vitiligo distributed in ophthalmic and maxillary branches of trigeminal dermatome. Copyrighted Material

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FIGURE 2

Segmental vitiligo distributed along thoracic dermatome.

We appraised whether hand dominancy has any relation with vitiligo involving the right or left side of the body, but there was no significant relationship between these two factors. The left side was slightly more involved, regardless of the dominant hand. Poliosis, known to be associated with vitiligo in 8.9-45% of cases, occurred in 48.6% in our study. The eyebrows and scalp hair were mostly involved (46.7%); this is because when vitiligo involves the face, neck, and scalp, poliosis of the eyebrows and scalp hair is commonly present (67.4%). Physical trauma, sunburn, psychological

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2

Dermatomal Distribution of Segmental Vitiligo

Dermatome

Men (%)

Women (%)

Total (%)

Trigeminal Cervical Thoracic Lumbar Sacral Total

49(53.9) 12(13.2) 19(20.9) 10(11.0) 1(1.1) 91

65(50.8) 26(20.3) 31 (24.2) 4(3.1) 2(1.6) 128

114(52.1) 38(174) 50(22.8) 14(64) 3(14) 219

stress, inflammation, pregnancy, contraceptives, etc. are known to be the precipitating factors of vitiligo. But unlike other reports, there was nothing particularly worth mentioning except for sunburn, trauma, and pregnancy. Family history was present in 11.5%, compared to the 7.4% reported by one group (5) and 12% by another (9). A pair of investigators claimed that segmental vitiligo is not associated with other autoimmune diseases (2), but another group found that they were associated in about 9.5% of cases (5). One group of investigators asserted that an autoimmune disease occurred more significantly in nonsegmental vitiligo than in segmental vitiligo and that this difference was due to different pathogenetic mechanisms (3). In our report, association with thyroid diseases, diabetes mellitus, pernicious anemia, and halo nevus, which frequently accompany vitiligo, was seen in 3.4% (7), and this was lower than in the other report (10); however, that could not justify the conclusion that autoimmune mechanisms are restricted to nonsegmental vitiligo, because systemic and topical steroid treatment and psoralen and ultraviolet A (PUVA) therapy can inhibit spreading and induce repigmentation of new lesions of segmental vitiligo, especially on the face (11).

BILATERAL SEGMENTAL VITILIGO The depigmented lesions of segmental vitiligo do not always assume a true dermatomal pattern according to the peripheral nervous system. Not all the patterns of segmental vitiligo follow dermatomal distribution, unlike herpes zoster. Blaschko's lines or acupuncture lines can be applied to the pattern of segmental vitiligo. In our recent study (12), 5 cases of bilateral segmental vitiligo were found among 240 cases of segmental vitiligo, in which the vitiligo lesions appeared on the same or different derma tomes on both sides of the body (Fig. 3). The clinical characteristics of bilateral segmental vitiligo are shown in Table 3. PUVA therapy and steroid treatment could induce repigmentation or stop progression of vitiliginous lesions in bilateral segmental vitiligo. Copyrighted Material

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FIGURE 3 Bilateral segmental vitiligo distributed in linear pattern on both right and left thoracic dermatome. The right side lesions are located at the shoulder and arm; the left side lesions are located at the lower chest and upper abdomen, which do not cross the midline.

Because segmental vitiligo has clinical features that differ from nonsegmental vitiligo, it is quite important to classify the type of vitiligo. The depigmented patches of segmental vitiligo usually remain unchanged for the rest of the patient's life. Therefore, stable segmental vitiligo is a good candidate for epidermal grafting and can be cured almost completely without recurrence. Copyrighted Material

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Clinical Characteristics of Bilateral Segmental Vitiligo Distribution

Patient sex/age

Duration

F/4 F/6 F/8 F/27 F/12

2 4 2 3 2

months yr yr yr yr

Left Chest, Chest, Chest, Chest, Chest,

back, back, back, back, arm

arm arm arm arm

Right

Treatment

Response to treatment

Chest, arm Buttock, thigh Chest, back, arm Chest, back, arm Chest, back, arm

Systemic steroid Topical steroid Topical steroid Systemic PUVA Systemic PUVA

No progression No change Repigmentation Repigmentation Repigmentation

On the other hand, if segmental vitiligo occurs bilaterally, following the same or different dermatomes, it may cause confusion in defining the type of vitiligo. As segmental vitiligo can rarely appear bilaterally following dermatomal distribution, such as in herpes zoster, it may mimic some other type of nonsegmental vitiligo. The clinical course of bilateral segmental vitiligo seems to be the same as unilateral segmental vitiligo.

TRICHROME VITILIGO The term trichrome vitiligo was first suggested in 1964 by Fitzpatrick (13). The lesions have an intermediate zone of hypochromia located between the achromic center and the peripheral unaffected skin. This results in three shades of color-brown, tan, and white-in the same patient (14) (Fig. 4). The trichrome lesion naturally evolves to a typical vitiligo macule. The significance of trichrome is unknown, but it is clearly a metastable or transitional pigmentary state, though it may persist for months to years with little change. Fitzpatrick (13) and Pincus (15) interpreted trichrome as suggestive of a gradual centrifugal spread of hypomelanosis or a stepwise depigmentation. However, other reports pointed out that the sharp demarcation between the three areas in their cases, as well as the lack of gradual changes of color and the stability of the lesion, is inconsistent with the interpretation of trichrome vitiligo as an active centrifugal spreading lesion. Therefore, whether trichrome vitiligo is a temporary phenomenon of active spreading vitiligo or a hypomelanosis showing an unusual progression pattern remained to be defined. However, our recent study (16) showed that trichrome vitiligo is an active, centrifugally spreading lesion through clinico-histopathological studies. The study showed that among the 21 vitiligo patients showing trichrome lesions, 95.2% were classified as having vitiligo vulgaris and 85.7% had spreading lesions clinically. Histopathological findings also showed the characteristics of active spreading vitiligo. Therefore, trichrome vitiligo was regarded as a phenomenon ~pyHl1J:lmMYfe;OO-areas of active vitiligo.

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FIGURE 4 Trichrome vitiligo showing light brown band between vitiliginous and dark brown perilesional skin.

Of the trichrome lesions, 85.5% were localized to the trunk region, including the abdomen, back, and buttock, leading to the assumption that trichrome vitiligo predominates in unexposed skin (Table 4). According to previous reports, sun-exposed areas are the predilection sites of vitiligo and lesions in these areas commonly show rapid progression. In contrast, the fact that trichrome vitiligo lesions predominated in unexposed skin could be one of the reasons the characteristic trichrome features appeared, possibly because of slow progression of the disease. Melanocyte density and skin thickness could also be factors contributing to the development of trichrome features. Blacks have a relatively higher frequency of trichrome vitiligo compared with whites and similarly most of the patients in

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Location of Trichrome Vitiligo

Location

No. of patients (%)

Back Abdomen Buttock Chest Arm Leg Total

12(57) 4(19) 2(9.5) 1(4.8) 1(4.8) 1(4.8) 21(100)

our study had skin type IV or darker. Therefore dark skin also seems to be a contributing factor to the pathogenesis of trichrome vitiligo. The histological findings of trichrome vitiligo showed the most dense distribution of melanin granules in the perilesional normal skin, followed by normal skin, light brown skin, and vitiliginous skin, in descending order. As such, the characteristic trichrome color may be an expression of changes in melanin granules rather than melanocyte numbers. Hyperpigmentation seen around the periphery of white patches is typically found in vitiligo. This was also observed in the trichrome lesions in which perilesional normal skin showed a slightly darker color compared with normal skin and histologically a higher density of melanin granules. Other histological findings such as vacuolar degeneration of the basal cell layer, monon uc1ear cell infiltration of the epidermis and dermis, and melanophage deposition in the dermis were more prominent in light brown skin and perilesional normal skin than in vitiliginous and normal skin. Among these changes, vacuolar degeneration of the basal cell layer and inflammatory cell infiltration were especially accen tuated around the melanocytes in the basal cell layer (Table 5; Fig. 5). However, overall destruction of keratinocytes

TABLE 5

Histological Findings of Trichrome Vitiligo Inflammatory cell infiltration

Vitiliginous skin Light brown skin Perilesional normal skin Normal skin a

Epidermis

Dermis

Vacuolar degeneration of basal cells

1 (4.8)a 13(61.9) 16(762) 2(9.5)

6(28.6) 12(57.1 ) 16(76.2) 3(14.3)

5(23.8) 13(61.9) 19(90.5) 7(33.3)

Number (percentage in parent~f/f»figp,~eifffflfcJ&r7al

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FIGURE 5 Hematoxylin-eosin staining of trichrome vitiligo. Vacuolar degeneration of the basal cell layer and mild inflammatory cell infiltration in epidermis and dermis are more prominent in light brown skin (LBS) and perilesional normal skin (PLNS) than vitiliginous skin (VS) and normal skin (NS) of trichrome vitiligo. (Original magnification x 200.)

coexisted, and we presume that the target of destruction is not limited to melanocytes but also involves keratinocytes as well. Perilesional normal skin shows more severe vacuolar change of the basal layer and inflammatory cell infiltration than light brown skin and histologically is already in the process of vitiligo evolution, despite its normallooking appearance. Therefore, without appropriate treatment, a change clinically into light brown skin can be predicted. Light brown skin clinically and histologically shows features of active vitiligo, although the degree of histological change is subtle compared with perilesional normal skin. The histological features of light brown skin and perilesional normal skin are congruent with findings of active vitiligo lesions of more than 1 year's duration showing vacuolar degeneration of basal cell layer, mononuclear cell infiltration of the epidermis and dermis, and melanophage deposition (17,18). In view of such similarities, trichrome vitiligo could be a variant form of active vitiligo. The number of melanocytes in trichrome vitiligo was greatest in perilesional normal skin followed by light brown skin and vitiliginous skin, with

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vitiliginous skin showing at least a few melanocytes, albeit less than that of normal skin (Table 6). These results are contradictory with other studies of vitiligo (17,19,20), which report absence of melanocytes in the depigmented patches confirmed by immunohistochemical staining or electron microscopy. The clinical and histological findings of trichrome vitiligo suggest a slower progression of lesions than typical vitiligo, and this could be why melanocytes remain in the white patches. Langerhans cells may playa major immunological role in vitiligo. Interaction between keratinocytes, melanocytes, and Langerhans cells is thought to initiate depigmentation, but the exact mechanism is unknown. In patients with nonsegmental-type vitiligo, a marked depletion of Langerhans cells was noted in active lesions and a repopulation of Langerhans cells was noted in stable lesions (21). In inflammatory vitiligo, an increase in Langerhans cells was observed in adjacent normal skin compared with vitilignous skin and normal skin (22). Our study showed that light brown skin and perilesional normal skin exhibit an increase in Langerhans cell number compared with vitiliginous skin and normal skin (Table 7). From our findings, an increased number of Langerhans cells may be involved in actively spreading vitiligo. Vitiligo lesions of the trunk are known to respond favorably to systemic PUV A therapy in comparison to systemic steroid therapy, and the existence of inactive melanocytes in the epidermis or follicles is a decisive factor influencing treatment results (23,24).

TABLE

6

Numbers of S-100+ Melanocytes in Patients with Trichrome Vitiligo

1 2 3 4 5 6 7 8 9 10 Mean

LBS

VS

Patient no.

5 5 2 4 5 8 8 4 2

± SOb

4.8

± 2.2

14 15 14 8 15 13 8 13 7 11.9 ± 3.3

PLNS

NS

23 a 19 18 13 14 16 15 17 16 11

23

16.8

± 3.0

20 15 16 17 16 12 16 14 16.3 ± 3.5

LBS, light brown skin; NS, normal skin; PLNS, perilesional normal skin; VS, vitiliginous skin. Number of melanocytes per 6 high-power fields (x400). b PLNS and LBS: p < 0.05; LBS and VS: p < 0.05

a

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Number of CD1a+ Langerhans Cells in Patients with Trichrome

Vitiligo Patient no. 1 2 3 4 5 6 7 8 9 Mean ± SDb

VS

LBS

PLNS

NS

62 a 52 67 28 50 65

36 47 37

14

52 34

73 58 54 44 50 47 60 44 36

295 ± 9.8

55.7 ± 11.1

54.3 ± 10.4

39 36 21 33 34

45 24 31 33 28 36.7 ± 8.6

LBS, light brown skin; NS, normal skin; PLNS, perilesional normal skin; VS, vitiliginous skin. Number of Langerhans cells per 6 high-power fields (x400). b LBS and PLNS compared with VS and NS: p < 0.05.

a

Trichrome vitiligo responded especially well to systemic PUVA treatment. This is because a few melanocytes were still remaining in the white lesions, thereby contributing to the repigmentation process. Therefore, early systemic PUVA therapy should be considered in patients with trichrome features to shorten treatment duration and achieve satisfactory end results. VITILIGO WITH RAISED BORDERS

Generally, vitiligo macules have distinct margins. However, raised borders have, on a few occasions, been observed at the margins of the depigmented borders. This is a rare macroscopic presentation of vitiligo, and only few cases have been reported (25,26). Vitiligo with raised borders has been reported in males and females at any age. The red, raised borders may be present from the onset of vitiligo or may appear several months or years later. A mild pruritus may be present. Histological features of the raised borders show eczematous changes in the epidermis with absence or decrease of melanin pigmentation and fairly dense lymphocytic and histocytic infiltrate in the upper dermis. Complete regression of the red, raised borders has been reported in several patients either spontaneously or after topical steroid therapy. The significance of this localized inflammatory reaction is unknown. According to several histological studies, the presence of a mild lymphocytic

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infiltrate at the border of active vitiligo may be observed even in the absence of clinical inflammation. Thus, the occurrence of red, raised borders could represent simply an amplification of the usual inflammatory process occurring in vitiligo (26). Inflammatory vitiligo macules with an edematous border and slight scali ness are very unusual. As the inflammatory component disappears, the skin becomes depigmented. It has been suggested that this inflammatory pattern occurs in atopics (27).

BLUE VITILIGO The blue coloration of vitiligo macules has been observed in a patient already affected by postinftammatory hyperpigmentation in whom vitiligo developed. Histological examination of the blue vitiligo lesions showed an absence of epidermal melanocytes and numerous melanophages in the dermis. The blue coloration subsequently disappeared with follicular repigmentation typical of resolving vitiligo (28).

REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. 10 II. 12. 13.

Koga M. Vitiligo: a new classification and therapy. Br J Demlatol 1977; 97:255261. EI Mofty AM, EI Mofty M. Vitiligo: a symptom complex. Int J Dermatol 1980; 19:238-247. Koga M, Tango T. Clinical features and course of type A and type B vitiligo. Sr J Dermatol 1988; 118:223-228. Song MS, Hann SK, Ahn PS, Ims, Park YK. Clinical study of vitiligo: comparative study of type A and type B vitiligo. Ann Dermatol 1994; 6:22-30. Park KC, Youn JI, Lee YS. Clinical study of 326 cases of vitiligo. Korean J Dermatol 1988; 26:200-205. Howitz J, Brodthagen H, Schwartz M. Prevalence of vitiligo: epidemiologic survey on the Isle of Borholm, Denmark. Arch Dermatol 1977; 113:47-52. Hann SK, Lee HJ. Segmental vitiligo: clinical findings in 208 patients. J Am Acad Dermatol 1996; 35:671-674. Lerner AB. On the etiology of vitiligo and gray hair. Am J Med 1971; 51: 147-156. Hann SK, Park YK, Whang KC, Kim HJ Clinical study of 174 patients with generalized vitiligo. Korean J Dermatol 1986; 24:798-805. Park SY, Youn JI, Lim SD. A clinical study of217 cases ofvitiljgo. Korean J Dermato] 1981; 19:145-152. Kim SN, Lee HS, Hann SK. The efficacy of low dose of oral corticosteroids in vitiligo patients. Int J Dermatol 1999; 38:546-550. Lee HS, Hann SK. Bilateral segmental vitiligo. Ann Dermatol1998; 10:129-131. Fitzpatrick TB. Hypomelanosis. South Med J 1964; 57:995-1005.

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14. 15. 16. 17. 18. 19.

20

21. 22.

23. 24. 25. _6. 27. 28.

Fargnoli MC, Bolognia JL. Pentachrome vitiligo. J Am Acad Dermatol 1995; 33853-856. Pincus H. Vitiligo: what is it? J Invest Dermatol 1959; 32:281-284. Hann SK, Kim YS, Yoo JH, Chun YS. Clinical and histopathologic characteristics of trichrome vitiligo. ] Am Acad Dermat01 2000; 42:589-596. Hann SK, Park YK, Lee KG, Choi EH, 1m S. Epidermal changes in active vitiligo. ] Dermatol 1992; 9:217-222. Gokhale BB, Mehta LN. Histopathology of vitiliginous skin. Int J Dermatol 1983; 22:477-480. Le Poole IC, Das PK, van den Wijngaard RM]G], Bose JD, Westerhof W. Review of the etiopathomechanism of vitiligo: a convergence theory. Exp Dermato11993; 2:145-153. Le Poole Ie. van den Wijngaard RMJGF, WesterhofW, Dutrieux RP, Das PK. Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. ] Invest Dermatol 1993; 100:816-822. Kao CH, Y u HS. Depletion and repopulation of Langerhans cells in nonsegmental type vitiligo. J Dermatol 1990; 17:280-296. Le Poole IC, van den Wijngaard RM]G], WesterhofW, Das PK. Presence ofT cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am ] Pa thol 1996; 148: 1219-1228. Ortonne JP, Schmitt D, Thivolet]. PUVA-induced repigmentation of vitiligo: scanning electron microscopy of hair follicles. J Invest Dermatol 1980; 74:40-42. Cui 1, Shen L, Wang G. Role of hair follicles in the repigmentation of vitiligo. 1 Invest Dermatol 1991; 97:410-416. Michaelsson G. Vitiligo with raised borders. Report of two cases. Acta Dermatol Venereol (Stockh) 1968; 48:158-161. Eng AM. Marginal inflammatory vitiligo. Cutis 1970; 6:1005-1008. Ortonne ]P. Special features of vitiligo. In: Hann SK, Nordlund ]1, eds. Vitiligo. Blackwell Science Ltd., 2000:70-75. Ivker R, Goldaber M, Buchness MR. Blue vitiligo. J Am Acad Dermatol 1994; 30829-831.

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14 Vitiligo In Children Flora B. de Waard-van der Spek and Arnold P. Oranje Erasmus Me, Rotterdam, The Netherlands

Vitiligo is an acquired idiopathic hypomelanotic disorder characterized by circumscribed depigmented macules resulting from the loss of cutaneous melanocytes. Cutaneous depigmentation is most obvious. However, mucous membranes and eyes may also reveal loss of pigmentation in vitiligo. The general prevalence of vitiligo throughout the world is about I per 200 individuals, and both sexes are affected equally. However, there are locations in the world, such as isolated villages in India, where the prevalence is much higher, as high as 8% (I). There are numerous hypotheses about the etiology of vitiligo, but no data to definitely prove one theory above the other. There are numerous causes for the loss of melanocytes. An autoimmune etiology has been suggested (2). Several observers noted that a number of their patients with vitiligo had other disorders considered to be of autoimmune origin. Such disorders included thyroid and adrenal disease, alopecia areata, and insulin-dependent diabetes mellitus. Furthermore, circulating antibodies an T lymphocytes which react against melanocyte an tigens are present in the sera of a significant proportion of vitiligo patient compared with healthy individuals (2). Recently the melanin-concentrating hormone receptor I (MCHRI) was identified as a novel autoantigen related to vitiligo (3). Vitiligo seems to have a predilection for sibs, although its transmission does not follow Mendelian genetics (l). Other pathogenetic factors mentioned Copyrighted Material

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are neurological factors, toxic metabolites, and lack of melanocyte growth factor (4). Two known mechanisms for the destruction of cells are necrosis and apoptosis. Recently apoptosis, rather than necrosis, has been hypothesized as the mechanism for removal of melanocytes in vitiligo (5). Apoptosis can be induced by a variety of factors, including immune cytokines, some environmental chemicals, or other molecular mechanisms.

CLINICAL FEATURES OF VITILIGO IN CHILDREN Vitiligo typically begins during childhood or adolescence. Approximately 25% of individuals develop the first signs of cutaneous depigmentation before 10 years of age and 50% before 23 years. Less than 10% of those afflicted develop vitiligo after the age of 42 years (6). Depigmented patches can occur anywhere on the body. Vitiligo is often first noticed as pale maCltles on sun-exposed sites of the face or the dorsal aspects of the hands. The distribution is usually symmetrical and may show a periorificial pattern. Another pattern is unilateral or segmental vitiligo, sometimes in a dermatomal distribution (7). Early or advancing lesions may be partially depigmented and have a freckled appearance or multishaded hue. This is called trichrome vitiligo. As the disease progresses most lesions become completely devoid of pigment. Although vitiligo causes destruction of interfollicular melanocytes, it often spares the follicular pigmented cells. Hairs within patches of vitiligo often remain pigmented, but in older lesions the hairs also become amelanotic. Some patients with vitiligo also have halo nevi. Trauma to the skin can also result in further depigmentation (Koebner phenomenon) (8).

DIFFERENTIAL DIAGNOSIS The diagnosis of vitiligo is made clinically based on the symmetrical distribution of depigmentation developing in most cases in the first two decades of life. The diagnosis can be difficult in the early course. In the differential diagnosis skin diseases like pityriasis alba, pityriasis versicolor, hypopigmented macules like ash leaf spots, albinism, piebaldism, postinflammatory hypopigmentation, leukcoderma, or leprosy in patients immigrating from an endemic area must be kept in mind.

TREATMENT Treatment ofvitiJigo in children requires an approach that manages not only pathophysiological aspects of the disease, but also the psychological and social implications of having a visible skin disorder as vitiligo. Psychological

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support is often necessary as the condition can have a profound effect on the self-image of the affected individual (9). A causative treatment is not yet available for vitiligo. Current modalities are directed to stop progression and to achieve repigmentation in order to repair the morphology and functional deficiencies of the depigmented skin areas. Treatment of vitiligo can be divided into nonsurgical repigmentation therapies, autologous transplantation methods, and depigmentation therapies (10). Different sources of ultraviolet (UY) light can be used to stimulate repigmentation either alone ("unsensitized" phototherapy) or in combination with chemicals which are activated by light, as with photochemotherapy. As "unsensitized" phototherapy, broad-band UYB seems only to be moderately effective in treating vitiligo. It is being replaced by narrow-band UYB: the more erythemogenic wavelengths are removed, and wavelengths between 305 and 311 nm are used. This therapy has certain advantages over PUVA (psoralen + UYA) in that no pills are required for treatment and the effects on photocarcinogenesis and photoaging could possibly be reduced (II). A study on the effect of narrow-band UVB therapy in seven patients with vitiligo showed rapid repigmentation in many of them, including those with skin photo types IV and V. This study extended previous observations that narrowband UYB is a useful and well-tolerated treatment option for patients with vitiligo (12). With PUVA therapy, oral or topical, results vary and complete repigmentation is achieved only in a few patients, while cosmetically acceptable improvement is achieved in a majority of the patients. The total number of treatments required is between 50 and 300. PUVA has not been approved for children (11). Phenylalanine is not phototoxic, but the combination of UV light and phenylalanine seems to result in some pigmentation. Reported success rates vary from 14 to 83%. Topical calcipotriol may enhance the effect ofPUVA in the treatment of vitiligo (13,14). Melanocytes are known to express 1,25-dihydroxyvitamin D 3 receptors, and, although their exact role in melanogenesis is not clear, some investigators have suggested that 1,25-dihydroxyvitamin D 3 is involved in the regulation of melanin synthesis (14). Vitamin D 3 is also known to have immunomodulatory effects, which may be an important mechanism of action if vitiligo is considered to be an autoimmune T-cell~mediated disease. Very recently, promising casuistic results have been obtained with application of Taurotimus ointment. The idea of stopping the process causing destruction of melanocytes via the immune hypothesis seems to be very attractive. Growth factors and leukotriens have found to be important in melanocyte proliferation and miCopyrighted Material

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gration. A possible potential practical use of any of these polypeptides and proteins remains to be determined. Some immunomodulating agents have been successfully used in vitiligo. Topical corticosteroids can be useful for small localized lesions. In an open retrospective assessment comparing the results of treatment of vitiligo with topical steroids in adults and children, using moderately potent to very potent steroids, children appeared to have a better outcome than adults. Younger or darker skinned patients and those with vitiligo affecting the head and neck had better results with topical steroid use than older or paler skinned patients and those with vitiligo affecting other parts of the body (15). Systemic corticosteroids can be very helpful in arresting rapidly spreading disease and can induce repigmentation, but their role in the treatment of vitiligo remains controversial because of the potential for serious side effects (II). Surgical methods intended to repigment leukoderma are a therapeutic option if patients have stable disease. Two types of surgical techniques are available: tissue grafts and cellular grafts, with in-between autologous cultured epithelial grafts. Tissue grafts are full-thickness punch grafts, splitthickness grafts, and suction blister grafts (16). In cellular grafts noncultured keratinocytes and melanocytes or cultured melanocytes can be used. The method with cultured melanocytes is time consuming and requires special laboratory equipment. The first commercially available product in this new field for the treatment of vitiligo is MelanoSeed (Bio Tissue Technologies AG, Freiburg, Germany). This consists of autologous melanocytes, which are cultured in Good Manufacturing Practice (GMP) laboratories certified according EU guidelines. A skin biopsy of healthy well-pigmented skin is taken (full thickness skin). Within 28 days the cell quantity necessary for the transplantation is cultured. The transplantation area is prepared in an optimal way by means of a dennabrasion. After healing the treated vitiligo area can be given narrow-band UVB phototherapy to ensure optimal repigmentation (17). Micropigmentation is another name for tattooing and may be helpful for very stable recalcitrant small lesions. The color often does not match perfectly with the normal skin. In widespread disease with only a few areas of normal pigmented skin, treating the normal skin with depigmentating agents is an option. This is a permanent irreversible process, which can be performed with a depigmentation cream or treatment with the Q-switched ruby laser (II). In a meta-analysis and review of available literature on the nonsurgical repigmentation therapies, class 3 corticosteroids and UV-B were the most effective and safe therapies for localized and for generalized vitiligo, respectively. Considering autologous transplantation methods, no comparative controlled trials were included, so the treatment recommendations for transplantation should be viewed with caution. Split-thickness skin or epi-

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dermal blistering grafting can be recommended as the most effective and safest techniques. Only a small number of patients treated with culturing techniques has been studied. Limited data on depigmentation therapies are available: using a depigmentation cream (monobenzone) or using a laser (Q-switched ruby laser). Bleaching with cream take months or years to result in evident signs of depigmentation; laser therapy could give faster results (10). Most of the above-mentioned therapies require many months. There is always the option of using camouflaging cosmetics. The use of sunscreens is also recommended. Sunburn reactions of the depigmented skin will be prevented, and the tanning response of normally pigmented skin will be limited.

PROGNOSIS Depigmented patches remain for life. Partial repigmentation is common in isolated spots of individuals of all ages who have had the disease for variable periods of time. The amount of spontaneous repigmentation is rarely cosmetically sufficient (6).

CONCLUSIONS Vitiligo is an acquired idiopathic hypomelanotic disorder. There are numerous hypotheses about the etiology of vitiligo, but no data to definitely prove one theory above the other. There is no standard treatment. Treatment of vitiligo can be divided into nonsurgical repigmentation therapies, autologous transplantation methods, and depigmentation therapies. Future studies of treatment should also focus on the permanency of the induced repigmentations and the long-term risk-benefit ratios of the modalities.

REFERENCES l.

2. 3.

4. 5.

Nordlund 11. The epidemiology and genetics of vitiligo. Clin Dermatol 1997; 15:875-878. Kemp EH, Waterman EA, Weetman AP. Autoimmune aspects of vitiligo. Autoimmunity 2001; 43(1):65-77. Kemp EH, Waterman EA, Hawes BE, et a!. The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. 1 Clin Invest 2002; 109(7):923-930. Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am 1 Clin Dermatol 2001; 2(3):167-181 Huang CL, Nordlund 11, Boissy R. Vitiligo: a manifestation of apoptosis? Am 1 Clin Dermatol 2002; 3(5):301-308

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178 6. 7. 8. 9.

10. II. 12.

13.

14.

15.

16. 17.

de Waard-van der Spek and Oranje Lamerson C, Nordlund 11. Vitiligo. In: Harper JI, Oranje AP, Prose NS, eds. Textbook of Pediatric Dermatology. London: Blackwell Science, 2000:880-891. Shaffrali FCG, Gawkrodger DJ. Management of vitiligo. Clin Exp Dermatol 2000; 25:575-579 Handa S, Kaur 1. Vitiligo: clinical findings in 1436 patients. J Dermatol 1999; 26(10):653-657. Papadopoulos L, Bor R, Legg C. Coping with the disfiguring effects of vitiligo: a preliminary investigation into the effects of cognitive-behavioural therapy. Br J Med Psychol 1999; 72385-396. Njoo MD, Westerhof W, Bos JD, et al. The development of guidelines for the treatment of vitiligo. Arch Dermatol1999; 135:1514-1521. Taneja A. Treatment of vitiligo. J Dermatol Treatm 2002; 13: 19-25. Scherschun L, Kim 11, Lim HW. Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo. J Am Acad Dermatol 2001; 44(6):9991003. Ermis 0, Alpsoy E, Cetin L, et at Is the efficacy of psora len plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? A placebocontrolled double-blind study. Br J Dermatol 2001; 145:472-475. Ameen M, Exarchou Y, Chu AC. Topical calcipotriol as mono therapy and in combination with psoralen plus ultraviolet A in the treatment of vitiligo. Br J Dermatol 200 I; 145:476-479. Cockayne S, Messenger AG, Gawkrodger DJ, et at Vitiligo treated with topical steroids: children with head and neck involvement respond well. J Am Acad Dermatol 2002; 46(6):964-965. Geel N van, Ongenae K, Naeyaert J-M. Surgical techniques for vitiligo: a review. Dermatology 200 I; 202: 162-166. Westerhof W, Lantz W, Yanscheidt W, et at Vitiligo: news in surgical treatment. JEADY 2001; 15:510-511.

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15 Vitiligo: Focusing on Clinical Associations with Endocrine, Hematological, Neurological, and Infectious Diseases Alex L1ambrich and Jose Ma Mascaro Hospital Clinic, Barcelona, Spain

INTRODUCTION Vitiligo is a common, acquired, depigmentary disorder of the skin that affects 1-2% of the general population, without racial, sex, or regional differences (1-3). The majority of vitiligo patients are healthy and have no associated pathology, but it is well known that vitiligo occurs in relation to other diseases, mainly linked with the immune system. Since the I960s, numerous reports have tried to prove the association between vitiligo and autoimmune disorders. The clinical observation that 10-15% of patients with autoimmune diseases develop vitiligo in comparison with 1-2 % of the general population (4) and the high prevalence of autoantibodies to melanocytes in the serum of patients with vitiligo (5,6) support the autoimmune hypothesis. Segmental vitiligo, characterized by localized lesions in a dermatomal distribution, seems to be linked less frequently to autoimmune disorders than nonsegmental vitiligo (7,8). A pathogenic mechanism involving a dysfunction of sympathetic nerves in the affected area in segmental type may be the cause for these differences (Fig. 1). Copyrighted Material 179

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VITILIGO AND ENDOCRINE DISORDERS Thyroid Disease

Thyroid dysfunction is the endocrine disease most frequently associated with vitiligo. In 1929,25 patients with vitiligo and Grave's disease were reported by Parhon and Derevici (9). Since then, some authors have thought that patients with vitiligo have a propensity to develop thyroid dysfunction, and several reports of thyroid disease, including hyperthyroidism (Graves' disease, thyrotoxicosis, toxic goiter) (l0-15) and hypothyroidism (Hashimoto's thyroiditis) (16,17) in association with vitiligo have been published. Depending on the series, the prevalence of thyroid dysfunction in vitiligo patients is quite variable, ranging from 30% (18) to 0.5 % (19). This difference makes it difficult to come to any definite conclusion about this association. These studies show that the prevalence of thyroid dysfunction is higher in females than in males, especially from the fifth decade. Routine screening for thyroid disease Copyrighted Material

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(T3, T4, and TSH tests) in vitiligo patients may be useful (18,20), although some authors suggest that screening tests are only justifiable when a vitiligo patient shows suspected clinical manifestations of thyroid disease (21). Autoantibodies to thyroid gland (anti thyroglobulin and anti microsomal antibodies) are found more commonly in the serum of vitiligo patients than in the general population (5,18). These can be found on average in 10-17% of patients with vitiligo (6). Some patients with vitiligo may exhibit autoantibodies to thyroid gland in the serum but no dysfunction (5,20,22). On the other hand, it has been estimated that 0.62% (23) to 12.5% (24) of patients with thyroid disease can develop vitiligo. One should bear in mind that vitiligo and associated thyroid dysfunction do not follow any exact chronology, i.e., vitiligo can occur before, during, or after the onset of thyroid disease. Also, the clinical courses of both disorders are independent, and the treatment of either does not affect the other's evolution (25).

Polyglandular Syndrome Polyglandular syndrome is a multiendocrine dysfunction associated with organ-specific autoantibodies. At present two forms of this disease are considered: type I (Addison's disease and hypoparathyroidism) and type II (diabetes mellitus type I, Addison's disease, and autoimmune thyroid disease). Organ-specific autoantibodies to glandular tissue and activation of lymphocytes T are the main causes of destruction of the endocrine system. This syndrome is commonly linked with other nonendocrine autoimmune diseases, such as vitiligo, alopecia areata, pernicious anemia, and mucocutaneous candidiasis. An association between polyglandular syndrome and vitiligo, mainly the generalized type, has been posited (26-29), and in several cases autoantibodies to melanocytes have been detected in the serum of these patients (26). This association supports the hypothesis that vitiligo, at least in these patients, is an autoimmune disorder (30).

Others In 1855 Addison described 13 patients with adrenal insufficiency caused by tuberculosis, two of whom also had vitiligo (31). Numerous cases of vitiligo associated with autoimmune adrenal insufficiency have since been reported, although less frequently than thyroid dysfunction (32,33). Diabetes mellitus, a disease caused by the destruction of Langerhans islets of the pancreas mediated sometimes by autoantibodies, may also be associated with vitiligo (34-37). Dawber (34,35) found that vitiligo was present in 4.8% of diabetic patients and moreover observed that 1-7% of vitiligo patients were also diabetic€o~gf.7~§i~m#inlyappears in cases of late-

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onset vitiligo (34). At present it is not possible to confirm if an authentic association between both diseases exists or if this association is casual. There are some reports of gonadal atresia associated with vitiligo in the context of autoimmunity (38,39). VITILIGO AND HEMATOLOGICAL DISEASES

Pernicious and hemolytic anemia, two types of autoimmune anemia, may occur associated with vitiligo. Pernicious anemia is a disease resulting from the destruction of parietal gastric celJs mediated by autoantibodies that cause defective synthesis of intrinsic factor and, therefore, a defective absorption of vitamin B 12. Of patients with pernicious anemia, 1.6~1 0.6% exhibit vitiligo (23,40). Bleifeld found defective vitamin B 12 absorption (Schilling test) in one-third of patients with vitiligo (41). It is estimated that 13% of patients with vitiligo have antiparietal cell antibodies in their serum (6). An association between vitiligo and autoimmune hemolytic anemia is less common (42,43). Other hematological diseases, such as lymphoma (44) and leukemia (45), have been occasionally associated with vitiligo. VITILIGO AND NEUROLOGICAL DISEASES

Yogt-Koyanagi-Harada syndrome (YKHS) (46-48) is a uncommon disease, probably autoimmune, which causes multiple manifestations including cutaneous (vitiligo, poliosis, alopecia areata), ocular (uveitis, optic neuritis) auditory (labyrinthitis), and neurological (meningoencephalitis) alterations. Some authors suggest that VKHS is a systemic disease with a wide clinical spectrum. Vitiligo with asymptomatic ocular affectation would constitute one of the extremes of these spectrum; we found a complete presentation of VKHS (20). Myasthenia gravis is an autoimmune neurological disease that has been associated with vitiligo in a few cases. Kubota et al. studied the frequency of vitiligo among 202 patients with myasthenia gravis (49). Only one of their patients (0.5%) showed vitiligo. VITILIGO AND CUTANEOUS DISEASES

One of the diseases most frequently linked to vitiligo is alopecia areata. In 1968 Cunliffe et al. found that 16% of patients with vitiligo had patches of alopecia areata (18). This average is quite variable depending on the study. In a recent study that analysed 1436 Indian patients with vitiligo, only 0.4% exhibited alopecia areata (19).

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A FIGURE 2

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B Onset of vitiligo in a patient diagnosed with melanoma.

Halo nevus has been commonly described in patients with vitiligo (25). These cases have been explained by the activation of lymphocytes that destroy melanocytes of the normal skin and melanocytes of the nevus. Association between malignant melanoma and vitiligo is rare, but very interesting (Fig. 2). Onset of vitiligo in patients affected with malignant melanoma has been widely discussed (50-54). Some authors have suggested that the response of the immune system to malignant melanocytes may also destroy some normal meJanocytes of the skin (6). This hypothesis is supported by studies that have proved the presence of antibodies to melanocytes in the serum of patients with melanoma similar to antibodies of vitiligo patients (55) Some dermatoses commonly present in patients with vitiligo, such as atopic dermatitis (19), psoriasis (56,57), and lichen planus, are considered casual associations. Other dermatoses rarely associated with vitiligo, such as dermatitis herpetiformis (58), morphea (59), and 20-nail dystrophy (60), could be linked with a common pathogenic mechanism.

VITILIGO AND INFECTIOUS DISEASES Hepatitis C virus (HCY) has been associated with many cutaneous disorders (61). Frequently in these skin alterations immunological mechanisms are involved, suggesting that HCY is involved in immunological abnormalities.

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Recently, Yamamoto reported five patients with vitiligo who were infected by HCV; he recommended HCV serological screening in patients with vitiligo (62). Vitiligo has also been associated with human immunodeficiency virus (HIV) infection. Partial repigmentation of vitiligo lesions after administration of antiretroviral treatment suggests that HIV may also have a role as a precipitating factor in vitiligo (63).

OTHER DISEASES Padula et al. in 2001 studied 234 patients with seronegative spondyloarthritis (SpA). This study showed that 3.4% of patients with SpA also presented vitiligo lesions, whereas only 1.06% of control patients exhibited vitiligo lesions. The difference between the two groups was statistically significant (p < 0.005). These results suggest that vitiligo and SpA do not coexist by chance, but that vitiligo should be included in the list of diseases associated with SpA (64). Sporadic cases of vitiligo have been published associated with other internal diseases such as sarcoidosis (65,66), systemic lupus erythematosus (67), discoid lupus erythematosus, and rheumatoid arthritis (68-70).

REFERENCES I.

2. 3.

4. 5. 6. 7. 8. 9.

10. II.

Lerner AB. On the etiology of vitiligo and gray hair. Am J Med 1971; 51:141147. Schwartz RA, Janniger CK. Vitiligo. Cutis 1997; 60:239-244. Howtiz J, Brodthagen H, Schwartz M, Thomsen K. Prevalence of vitiligo. Epidemiological survey in the Isle of Bornholm, Denmark. Arch Dermatol 1977; 113:47-52 Norlund 11, Lerner AB. Vitiligo: itis important. Arch Dermatol 1982; 118:5-8. Brostoff J, Bor S, Feiwel M. Autoantibodies in patients with vitiligo. Lancet 1969; 2:177-178 Bystryn Jc. Serum antibodies in vitiligo patients. Cbn Dermatol1989; 7: 136-145. Koga M, Tango T. Clinical features and course of type A and type B vitiligo. Br J Dermatol 1988; 118:223-228. Hann SK, Lee HJ. Segmental vitiligo: clinical findings in 208 patients. J Am Acad Dermatol 1996; 35:671-674. Parhon CI, Derevici M. Sur I'association du syndrome de Basedow avec Ie vitiligo. Contribution a I'etude de la pathogenie des dyschromies cutanees. Re Fr Endocrinol 1929; 7: 12. Godeau P, Herreman G, Saltiel H, Butler J, Alpern J. Hiperthyroidie-purpura thrombopenique-vitiligo. Ann Med Interne (Paris) 1973; 124:327-331. Lamartine de Assis J, Scaff M, Nagahashi SK, et a!. Vitiligo, hyperthyroidism,

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12.

13.

14. 15.

16. 17.

18. 19. 20. 21. 22. 23. 24.

25.

26.

27. 28. 29.

185

periodic paralysis and myasthenia gravis. Report of a case. Med Cut lLA 1983; 11: 195-200 Midelfart K, Moseng D, Kavli G, Stenvold SE, Volden G. A case of chronic urticaria and vitiligo, associated with thyroiditis, treated with PUVA. Dermatologica 1983; 167:39-41. Ramanathan M, Abidin MN, Muthukumarappan M. The prevalence of skin manifestations in thyrotoxicosis-a restropective study. Med 1 Malaysia 1989; 44:324-328. Mullin GE, Eastern JS. Cutaneous signs of thyroid disease. Am Fam Phys 1986; 34:93-98. Hegedus L, Heidenheim M, Gervil M, Hjalgrim H, Hoier-Madsen M. High frequency of thyroid dysfunction in patients with vitiligo. Acta Derm Venereol (Stockh) 1994; 74:120-123 Shong YK, Kim JA. Vitiligo in autoimmune thyroid disease. Thyroidology 1991; 3:89-91. Saban J, Rodriguez-Garcia JL, Gil J, Pais JR, Medina S. Porphyria cutanea tarda associated with autoimmune hipothyroidism, vitiligo and alopecia universalis. Neth J Med 1991; 39:350-352. Cunliffe WJ, Hall R, Newell D1, Stevenson CJ. Vitiligo, thyroid disease and autoimmumity. Br J Dermatol 1968; 80:135-139. Handa S, Kaur 1. Vitiligo: clinical findings in 1436 patients. J Dermatol 1999; 26:653-657 Barnes L. Vitiligo and the Vogt-Koyanagi-Harada syndrome. DermatoJ Clin 1988; 6:229-239. Dupont C. Vitiligo and endocrine disorders. Clin Exp Dermatol 1996; 21: 173. Bor S, Feiwel M, Chanarin 1. Vitiligo and its aetiologicaJ relationship to organ specific autoimmune disease. Br J Dermatol 1969; 81:83-88. Allison JR, Curtis AC. Vitiligo and pernicious anemia. Arch Dermatol 1955; 72:407. Miklaszewska M, Zukowski W, Dankiewicz J, Nowak A. Clinical and immunological aspects of the relation of acquired leukoderma (vitiligo) to thyroid diseases. Arch Immunol Ther Exp (Warsz) 1972; 20:855-892. Mosher DB, Fitzpatrick TB, Ortonne JP, Hori Y. Hypomelanoses and hypermelanoses. In: Freedberg 1M, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, Fitzpatrick TB, eds. Dermatology in General Medicine. New York: McGraw-Hill, 1999:945-1017. Peserico A, Rigon F, Semenza to G, et al. Vitiligo and polyglandular autoimmune disease with autoantibodies to melanin-producing cells. A new syndrome? Arch Dermatol1981; 117:751-752. Bloch MH, Sowers JR. Vitiligo and polyglandular autoimmune endocrinopathy. Cutis 1985; 36417-419,421. Torrelo A, Espana A, Balsa J, Ledo A. Vitiligo and polyglandular autoimmune syndrome with selective IgA deficiency. Int J Dermatol 1992; 31:343-344. Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 pa tients. N Engl J Med 1990; 322: 1829-1836.

Copyrighted Material

186 30.

31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

43. 44.

45. 46.

47. 48. 49. 50.

L1ambrich and Mascaro Nordlund JJ, Hann SK. The association of vitiligo with disorders of other organ systems. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd, 2000:89-96. Addison T. On the Constitutional and Local Effects of Disease of the Suprarenal Capsules. London: Samuel Highley, 1855. Mulligan TM, Sowers JR. Hyperpigmentation, vitiligo and Addisons disease. Cutis 1985; 36:317-3 I 8, 322 Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison's disease. J Autoimm 1995; 8:121-130. Dawber RP. Clinical association of vitiligo. Postgrad Med J 1970; 46:276-277. Dawber RP, Bleehen SS, Vallance-Owen J. Vitiligo and diabetes mellitus. Br J Dermatol 1971; 84:600. Jacyk W, Mazurek W, Baran E. Bielactwo nabyte, choroby tarczycy i cukrzyca. Przegl Dermatol 1976; 63:59-64. Gould 1M, Gray RS, Urbaniak SJ, Elton RA, Duncan LJ. Vitiligo in diabetes mellitus. Br ] Dermatol 1985; 113: 153-155. Collen RJ, Lippe BM, Kaplan SA. Primary ovarian failure, juvenile rheumatoid arthritis and vitiligo. Am J Dis Child 1979; 133:598-600. Gulden KD. Pernicious anemia, vitiligo and infertility. J Am Board Fam Pract 1990; 3:217-220. Grunnet I, Howitz J, Reymann F, Schwartz M. Vitiligo and pernicious anemia. Arch Dermatol 1970; 101:82-85. Bleifeld W, Gehrmann G. Vitamin B 12 , mangel und vitiligo. Blut 1969; 19:223225. Sidi Y, David M, Shohat B, Feuerman EJ, Pinkhas J. Vitiligo, autoimmune hemolytic anemia and T lymphocyte dysfunction: a mere coincidence or a new entity? Dermatologica 1978; 157: 136-137. Walters TR, Lerner AB, Nordlund JJ. Vitiligo, chronic thrombocytopenia, and autoimmune hemolyitc anemia. Arch Dermatol 1978; 114: 1366-1367. Walker J, Ober RR, Khan A, Yuen D, Rao NA. Intraocular lymphoma developing in a patient with Vogt-Koyanagi-Harada syndrome. Int Ophtalmol 1993; 17:331-336. Alcalay J, David M, Shohat B, Sandbank M. Generalized vitiligo following Sezary syndrome. Br J Dermatol 1987; 116:851-855. Vogt A. Frlihzeitiges Ergrauen der Zilien und Bemerkungen liber den sogenannten plotzlichen Einritt dieser Veranderung. Klin Monatsbl Augenheilkd 1906; 44:228. Harada E. Clinical study of non-suppurative choroiditis: a report of acute dilfuse choroiditis. Acta Soc Ophthalmol Jpn 1926; 30:356. Koyanagi K. Dysakusis, Alopecia und Poliosis bei schwerer Uveitis nicht traumatischen Ursprunges. Klin Monatsbl Augenheilkd 1929: 82:194. Kubota A, Komiyama A, Tanigawa A, Hasegawa O. Frequency and clinical correlates of vitiligo in myasthenia gravis. J Neurol 1997; 244:388-389. Klaus SN, Lerner AB, Bystryn Jc. Malignant melanoma and vitiligo. J Invest Dermatol 1971; 73:491-494.

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51. 52.

53. 54. 55. 56. 57 58.

59. 60. 61. 62. 63. 64. 65.

66.

67. 68.

69. 70.

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Nordlund JJ, Kirkwood JM, Forget BM. Vitiligo in patients with metastatic melanoma: a good prognostic sign? J Am Acad Dermatol 1983; 9:689-696. Lerner AB, Kirkwood JM. Vitiligo and melanoma: can genetically abnormal melanocytes result in both vitiligo and melanoma? J Am Acad Dermatol 1984; 11:696-701. Bystryn JC, Rigel D, Friedman RJ, et al. Prognostic significance of hypopigmentation in malignant melanoma. Arch Dermatol 1987; 123: 1053-1055. LindelOf B, Hedblad MA, Sigurgeirsson B. On the association between vitiligo and malignant melanoma. Acta Derm Venereol (Stockh) 1998; 78:483-484. Cui J, Bystryn JC. Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol 1995; 131 :314-318. Powell FC, Dicken CH. Psoriasis and vitiligo. Acta Derm Venereol (Stock h) 1983; 63:247-249. Moragas JM, Winkelmann RK. Psoriasis and vitiligo. Arch Dermatol 1970; 101:235-237. Amato L, Gallerani r, Fuligni A, Mei S, Fabbri P. Dermatitis herpetiformis and vitiligo: report of a case and review of the literature. J Dermatol 2000; 27:462466 Finkelstein E, Amichai B, Metzker A. Coexistence of vitiligo and morphea: a case report and review of the literature. J Dermatol 1995; 22:351-353. Khandpur S, Reddy BS. An association of twenty-nail dystrophy with vitiligo. J Dermatol 2001; 28:38--42. Pawlotsky JM, Dhumeaux D, Bagot M. Hepatitis C virus in dermatology. Arch Dennatol 1995; 131:1185-1193. Yamamoto T, Nishioka K. Vitiligo vulgaris associated with hepatitis C virus. J Dermatol 2000; 27:416-417. Garcia-Patos V, Rodriguez L, Capdevila JA, Castells A. Vitiligo asociado a sindrome de la inmunodeficiencia adquirida. Med Clin (Barc) 1994; 103:44. Padula A, Ciancio G, Civita L. Psoriasis and vitiljgo. Association between vitiligo and spondyloarthritis. J Rheumatol 2001; 28:313-314. Barnadas MA, Rodriguez-Arias JM, AlomaI' A. Subcutaneous sarcoidosis associated with vitiligo, pernicious anaemia and autoimmune thyroiditis. Clin Exp Dermatol 2000; 25:55-56. Terunuma A, Watabe A, Kato T, Tagami H. Coexistence of vitiligo and sarcoidosis in a patient with circulating autoantibodies. Int J Dermatol 2000; 39: 551-553 Forestier JY, Ortonne JP, Thivolet J, Souteyrand P. Lupus erythemateux et vitiligo. Ann Dermatol Venereol 1981; 108:33-38. Abraham Z, Rozenbaum M, Gluck Z, Feuerman EJ, Lahat N, Kinarty A. Vitiligo, rheumatoid arthritis and pernicious anemia. J Dermatol 1993; 20:418423. Durance RA, Hamiltoo EB. Myasthenia gravis, rheumatoid arthritis, vitiligo and autoimmune haemolytic anaemia. Proc R Soc Med 1971; 64:61-62. Goudie RB, Spence JC, MacKie R. Vitiligo patterns simulating autoimmune and rheumatic diseases. Lancet 1979; 2:393-395.

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16 Clinical Associations: Focusing on Autoimmune and Rare Associations G. Primavera and E. Berardesca San Gallicano Dermatological Institute, Rome, Italy

Large population surveys have shown a prevalence of vitiligo ranging from 0.5 to 2% (1,3,4). Vitiligo is usually considered a cosmetic problem not influencing the general health conditions of the patients (1-4). Nevertheless, it is sometimes associated with other disorders: cutaneous (common or unusual) abnormalities (Table I), ocular and otic abnormalities, and some autoimmune diseases (Tables 2, 3). CUTANEOUS ABNORMALITIES Halo nevi (Sutton's nevi) have been reported in 1-20.6% of vitiligo patients (5-10). These nevi may be multiple or solitary, and vary greatly in number and size (7). Barona et aL found that halo nevi could be considered as a risk factor for the development of vitiligo (5). Leukotrichia in vitiligo occurs commonly, with a prevalence of 9-42% (6,10-13). Depigmented hairs occur with or without an underlying vitiligo macule. Dutta et aL consider poliosis a marker for poor prognosis in repigmentation (II), but this observation has not been confirmed. The prevalence of canities (premature graying of hair) in vitiligo patients is said to be 1.5-21.4% (6,7,14). Halder et aL (14) found that premature graying hair occurs more frequently in adults with vitiligo compared to children with vitiligo (21.4% vs. 3.8%), and this would be expected because graying normally occurs as one gets older. However, they also found

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TABLE 1

Prevalence of Cutaneous Abnormalities in Vitiligo Patients

% Prevalence Cutaneous abnormalities

No. of studies

Min.

Max.

6 3 6

9.00 1.50 1.00

45.00 21.40 20.60

Leukotrichia Canities Halo nevi

a statistically significant increase in prevalence of canities in the family of vitiligo children, so it is probable that the premature graying in these children with vitiligo was related to the increased incidence of early graying in their immediate families (14). ORGAN DISORDERS Human melanocytes, whose embryonic origin is from the neural crest, are located in the skin, hair follicles, mucous membranes, leptomeninges, uveal tract, and retinal pigment epithelium (RPE) of the eye and the inner ear (in the cochlea, wall of the modiolus, spiral lamina, Reissner's membrane, stria vascularis in the vestibular system, saccule, utricle, ampullae). Thus, pigmentary disorders of the skin may be associated with similar pigmentary abnormalities in the eye and in the ear. The pathogenesis of these associated defects, which could indicate that vitiligo is a systemic disease of melanocytes, is unknown. Patients with vitiligo who demonstrate audiological and oph-

TABLE

2

Prevalence of Vitiligo in Autoimmune Disorders

% Prevalence Autoimmune disorders Thyroid Diabetes IDDN NIDDN Anemia perniciosa Addison PGA type 1 PGA type 2 Alopecia areata

No. of studies

Min.

1

6.83

3

2.70 1.7 0.4 9 9.6

3 2 2 1

2 4 1

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Max.

10.00 9.6 3.3 10.6

8

13

4.5 3.5

30

Autoimmune and Rare Associations TABLE

3

191

Prevalence of Autoimmune Disorders in Vitiligo

% Prevalence Autoimmune disorders Thyroid Diabetes Anemia perniciosa Addison Autoimmune gastritis Alopecia areata

No. of studies

Min.

Max.

12 7 5 2 2 6

0.50 0.60 0.4 0.4 9.6 0.4

43.00 7.10 30 2.1 15 16

thalmological changes are usually free of symptoms, and these changes may be more interesting to the biologist than to the clinician. The association of vitiligo with inflammation of the uveal tract and hypopigmentation and/or degeneration of the retinal pigment epithelium not secondary to ocular inflammation is well established. In 1979 Albert et al. described 44 (36.6%) patients with RPE depigmentation and 9 (7.5%) with uveitis in 120 patients with vitiligo (15). In 1983 Wagoner et al. found 60 (27%) of 223 patients with vitiligo to have some evidence of RPE hypopigmentation or atrophy, or both; II (4.8%) of these 223 patients also had uveitis (16). Direct evidence of significant melanocyte alterations of the inner ear in vitiligo patients has not been reported. If melanocytes of the inner ear do in fact prevent hearing loss, their possible involvement in vitiligo may be evidenced by audiometric analysis. The results of three studies indicate that patients with vitiligo had a significant prevalence of auditory abnormalities in comparison with healthy subjects, even though none of the hypoacusis patients were deaf and the auditory changes detected were all of minimal disturbance to the patients (17-19). In particular, Tosti et al. found 8 patients (16%) with neurosensorial hypoacusis in 50 patients affected by vitiligo (17). On the contrary, both Orecchia et al. (20) and Ozuer et al. (21), in contrast with previous reports, suggest that there is no proof of involvement of ear melanocytes in vitiligo. Auditory investigations may provide more accurate knowledge in vitiligo patients.

AUTOIMMUNE DISEASE Vitiligo is frequently associated with other autoimmune disorders such as autoimmune thyroid disease, diabetes mellitus, alopecia areata, pernicioLls anemia, Addison's disease, autoimmune gastritis, and autoimmune polyenCopyrighted Material

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docrine syndromes. Examples are shown in Tables 2 and 3. This frequent association supports the hypothesis that an autoimmune response is involved in the pathogenesis of vitiligo. Patients with generalized vitiligo seem to have more frequent association with autoimmune disease than do patients with segmental vitiligo (5). Thyroid diseases, particularly hyperthyroidism, hypothyroidism, Graves' disease, and Hashimoto's disease, but not thyroid carcinoma [only 3 cases reported in which vitiligo was associated to carcinoma of the thyroid (22)], have a prevalence of 0.5-43% in vitiligo patients, a figure that is significantly higher than the I % reported for autoimmune thyroid disease in the general population (6,7,9,10,22-28) (Table 3). In the same way, the prevalence of vitiligo in the general population is 0.5-2% (1,3,4), whereas in subjects with autoimmune thyroid disease it rises to 6.8% (29). Indeed, Shong and Kim found vitiligo in 20 out of 293 patients with autoinunune thyroid disease (6.83%) and in only 2 of 227 patients with nonautoimmune thyroid disease (0.88 %) (29). There was no significant difference in frequency of vitiligo between nonautoimmune thyroid disease patients and the general population. These findings are consistent with the possibility that vitiligo is very closely associated with autoimmune thyroid disease but not with nonautoimmune thyroid disease. In addition, circulating thyroid autoantibodies (Ab anti-thyroid microsomes, Ab anti-thyroid cytoplasm, Ab anti-thyroglobulin), along with other organ-specific antibodies (such as gastric parietal cell antibodies), are commonly detected in the sera of vitiligo patients (9,30,31) (Table 4). Vitiligo may begin before, at the same time, or after thyroid disease (29,32). The course of thyroid disease and vitiligo do not have any predictable relationship; treatment of the thyroid disease has no bearing on the vitiligo and vice versa. Both insulin-dependent diabetes mellitus (IDD) and non-insulindependent diabetes mellitus (NIDD) occur in 0.6-7.1 % of vitiligo patients (6,7,9,10,24-26), which corresponds with the frequency in the normal population. Conversely, vitiligo occurs in 2.7-10% of diabetic patients (33-35) compared to 0.5-2% reported in the general population. Few studies confirm the association between insulin-dependent diabetes and vitiligo (33,36,37) (prevalence, 1.7-9.6%), while the prevalence of vitiligo in NIDD (0.4---3.3%) was no higher than that reported in the nondiabetic population (33,38). Dawber describes the majority ofvitiliginoLls diabetics to be "maturity onset" (39), but this apparent relationship with age of onset of vitiligo appears to be artifactual, with vitiliginoLls diabetics being older at onset simply because they had time to develop both diseases. The prevalence of pernicious anemia in vitiligo patients is 0.4-30% compared with 0.13% of the normal population (40-42). Among those with pernicious anemia, vitiligo has been documented in 1.6-10.6% (40,41,43).

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Autoimmune and Rare Associations TABLE

4

Prevalence of Organ-Specific Autoantibodies in Vitiligo Patients

Autoantibody Thyroglobulin TgHA Thyroglobulin TgHA Thyroglobulin TgHA Thyroglobulin TgHA Microsomal TMA Microsomal TMA Microsomal TMA Microsomal TMA Gastric parietal cell GPCA Gastric parietal cell GPCA Gastric parietal cell GPCA Gastric parietal cell GPCA Gastric parietal cell GPCA Adrenal gland Adrenal gland Adrenal gland

No. of patients

20 321 80 52

373 321 20 35

20 321 373 80 65

321 20 80

% with Ab

40 6,9

Ref.

31 6

9

45

25 18,5 12,8 50 25,7

25

30 5,6 9,6 21 15 0,9 0,5 4

24 6

31 23 31 6 24

45 46 6

31 45

Grunnet et al. (40) observed these patients to have the most widespread vitiligo, and Dawber (41) found that pernicious anemia is more common among those with late-onset vitiligo, but neither of these observations has oeen confirmed. Addison's disease is normally associated with a peculiar generalized melanosis, but Thomas Addison described two patients affected also by vitiligo. The prevalence of Addison's disease in vitiligo patients is reported to be 0.6-2% (6,24), while in subjects with Addison's disease the prevalence of vitiligo seems to be higher than that reported for the general population (44). In a study of91 Addison patients, 9 were found to have vitiligo (9.8%) (44). The adrenal gland antibodies are not commonly detected in the sera of vitiligo patients (31,45) (Table 4). Two studies suggest an association between vitiligo and autoimmune atrophic gastritis. Zauli et al. performed in 65 patients with vitiligo gastric biopsies and titers of antihuman parietal cell antibodies (GPCA). Histological evidence of autoimmune atrophic gastritis was obtained in 10 cases (15%), all of whom were positive for the antibodies (46). Betterle et al. also found in 373 vitiligo patients 36 cases positive for GPCA, and in 34 (94%) of these cases a gastric biopsy revealed signs of atrophic gastritis (24). Many other studies confirm the higher incidence of GPCA in the sera of vitiligo patients (6,31,45) (Table 4) Copyrighted Material

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Human vitiligo patients are known to have greater chance of having alopecia areata than people without vitiligo, although the prevalence is still disputed. There is great variability; in fact alopecia areata has been reported in 04-16% of vitiligo patients (6,7,10,24-26). Conversely vitiligo occurs in 1.8% of adult and 3.5% of children patients with alopecia areata (47,48). Vitiligo is always present in multiple endocrinopathy syndromes, in particular in the autoimmune polyglandular syndrome (PGA) type I and type II. PGA is characterized by the coexistence of several autoimmune diseases, affecting predominantly the endocrine glands. PGA type I is variably associated with mucocutaneous candidiasis, autoimmune tissue destruction, and ectodermal dystrophy. Vitiligo occurs in 8-13% of cases (49,50). PGA type II is a disorder of the thyroid, adrenal, and pancreas (IDDM). Vitiligo is present in 4.5-30% of patients affected by this syndrome (50-52). Although the association of myasthenia gravis (MG) and vitiligo has been well described in the literature (53), only 5 case reports have been published (54-58). In all these, the authors suggest a possible underlying autoimmune basis for both diseases. However, because vitiligo is a common skin disorder, the question of whether simultaneous vitiligo and MG represent a coexistence or true association has yet to be answered. Kubota et al. (54). revealed a rather low frequency (0.5%) of vitiligo in 202 patients with MG, suggesting that the association between MG and vitiligo may be infrequent. Cruz et al. (55) reported that only 1 of over 60 MG patients « 1.7%) who also had thyroiditis developed vitiligo. Because both MG and vitiligo are frequently associated with thyroid disease, a possible genetic factor closely linked with thyroid disease may explain the coexistence of the two disorders. Hyperpigmentation and depigmentation in morphea or scleroderma have been mentioned in the medical literature since 1898 (59), but an association with vitiligo has been reported infrequently. Only 14 case reports have been published (5,60). Lerner and Sansung (61) reported that 6 of 191 patients with scleroderma or morphea had vitiligo as well. Two retrospective studies (5,62) confirm the low prevalence of morphea and scleroderma in vitiligo patients (0.2-0.9%). RARE ASSOCIATIONS

Few cases in the literature describe the association between vitiligo and 20nail dystrophy (63-65), dermatitis herpetiformis (66,67), and spondyloarthritis (68) (Table 5). Vitiligo has also been observed in Vogt-Koyanagi-Harada syndrome, and recently in human immunodeficiency virus (HIV)~ and acquired immunodeficiency syndrome (AIDS)~infected patients. Vitiligo is present in about 10-20% of patients affect by Vogt-Koyanagi-Harada syndrome (69,70). This disease is an autoimmune systemic dis-

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Autoimmune and Rare Associations TABLE 5

Vitiligo and Rare Associations

Disease Dermatitis herpetiform is Nail dystrophy Morphea/scleroderma Spondyloarthritis Myasthenia gravis

No. of patients described in literature 12 11

14 8 5

Ref.

66, 67 63-65 5, 60

68 54-58

order where an autoimmune mechanism, influenced by genetic factors, appears to be directed against melanocytes. In this syndrome inflammatory disorders occur in multiple organs containing melanocytes, including uvea (resulting in acute bilateral pan uveitis), skin (resulting in vitiligo and alopecia areata), central nervous system (resulting in meningitis), and inner ear (resulting in hearing loss and tinnitus). It is postulated that the VogtKoyanagi-Harada syndrome may be part of the systemic disease vitiligo (71). In 1987 Duvic et al. reported the development of vitiligo in 4 patients with HIV-related conditions and in I patient with hepatitis who later developed AIDS (72). Two other reports demonstrated the onset of vitiligo in patients with HIV infection (73,74). Although few vitiligo cases among several hundred HIV -positive persons is not higher than expected, these reports suggest that vitiligo may be an example of an autoimmune disease triggered by viral infection in a genetically predisposed host. In 2002 Yamauchi et al. (75) described the first patient with vitiligo who fulfilled the criteria for idiopatic CD4 + T lymphocytopenia (ICTL). Although the exact origin of ICTL is still unclear, the concurrence of both rTCL and vitiligo in this patient does not preclude the possibility of an underlying occult viral infection, which may trigger the decrease in CD4 + T cells, thus eliciting an autoimmune reaction towards melanocytes that results in their depletion.

REFERENCES 1. 2. 3. 4.

Ortonne JP. Vitiligo In: Saurat JH, Grosshans E, Laugier P, eds. Textbook of Dermatology. 2d ed. Paris: Masson SA., 2000:458-459. Majumder PP, Nordlund n, Nath SK. Pattern offamilial aggregation of vitiligo. Arch Dermatol 1993; 129:994-998. Howitz J, Brodthagen H, Schwartz M. et a1. Prevalence of vitiligo: epidemiologic survey on the Isle of Borholm, Denmark. Arch Dermatol 1977; 113:47-52. Lerner AB. On the etiology of vitiligo and grey hair. Am J Med 1971; 51:14.

Copyrighted Material

Primavera and Berardesca

196 5. 6. 7. 8. 9. 10. II. 12. 13. 14. 15. 16.

17. 18. 19. 20. 21. 22.

23. 24.

25.

Barona MI, Arrumltegui A, Falabella R, Alzate A. An epidemiologic case-control study in a population with vitiligo. J Am Acad Dermatol1995; 33:621-625. Schallreuter KU, Lemke R, Brandt 0, et al. Vitiligo and other diseases: coexistence or true association? Dermatology 1994; 188:269-275. EI Mofty AM, El Mofty M. Vitiligo: a symptom complex. Int J Dermatol1980; 19(5)237-244. Cho S, Kang HC, Hahmj H. Characteristics of vitiligo in Korean children. Pediatr Dermatol 2000; 17(3): 189~193. Ortonne JP, Perrot H, Thivolet 1. Clinical and statistical study of 100 patients with vitiligo II: associated lesions. Sem Hop 1976; 52(1 1):679-686. Sanjeev H, Inderjeet K. Vitiligo: clinical findings in 1436 patients. J Dermatol 1999; 26:653-657. Dutta AK, Mandai SB. A clinical study of 650 cases of vitiligo and their classification. Ind J Dermatol 1969; 14:103-105. Sehgal VN, et al. A clinical evaluation of202 cases of vitiligo. Cutis 1974; 14:439~ 445. Hann SK, Chun WH, Park YK. Non-infective skin associations of diabetes mellitus. Int J Dermatol 1997; 36:353-355. Halder RM, Grimes PE, et al. Childhood vitiligo. J Am Acad Dermatol 1987: 16:948-954. Albert DM, Nordlund JJ, Lerner AB. Ocular abnormalities occurring with vitiligo. Opthalmology 1979; 86(6):1145-1160. Wagoner MD, Albert DM, Lerner AB, Kirkwood J, Forget BM, Nordlund JJ. New observations on vitiligo and ocular disease. Am J Ophthalmol 1983; 96(1) 16---26. Tosti A, Bardazzi F, Tosti G, et al. Audiologic abnormalities in cases of vitiligo. J Am Acad Dermatol 1987; 17:230-233. Nikiforidis GC, Tsambaos DG, Karamitsos DS, et al. Abnormalities of the auditory brainstem response in vitiligo. Scand Audiol 1993; 22(2):97-100. Ardic FN, Aktan S, Kara CO, Sanli B. High-frequency hearing and reflex latency in patients with pigment disorder. Am J Otolaryngol 1998; 19(6):365-369. Orecchia G, Marelli MA, Fresa D, Robiolio L. Audiologic disturbances in vitiligo. J Am Acad Dermatol 1989; 21(6):1317~1318. Ower MZ, Sahiner T, Aktan S, et al. Auditory evoked potentials in vitiligo patients. Scand Audiol 1998; 27(4):225-228. Frati R, Frati C, Sassano PP, et al. Vitiligo, autoimmune thyroiditis: a rare thyroid cancer arising with bone metastases on maxillofacial area. J Exp Clin Cancer Res 1999; 18:85. Hegedus L, Heidenheim M, et al. High frequency of thyroid dysfunction in patients with vitiligo. Acta Derm Venereol 1994; 74: 120-123. Betterle C, Caretto A, De Zio A, et al. Incidence and significance of organspecific autoimmune disorders (clinical, latent or only autoantibodies) in patients with vitiligo. Dermatologica 1985; 171(6):419-423. Cunliffe WJ, Hall B, Newell DJ, Stevenson CJ. Vitiligo, thyroid disease and autoimmunity. Br J Dermatol 1968; 80: 135-139.

Copyrighted Material

Autoimmune and Rare Associations

197

Koga M, Tango T. Clinical features and course of type A and type B vitiligo. Br J Dermatol 1988; 118:223-228. 27. Boisseau-Garsaud AM, Garsaud P, Cales-Quist D, et al. Epidemiology of vitiligo in the French West Indies (Isle of Martinique). Int J Dermatol 2000; 39( I): 18-20. 28. Wood L, et al. High frequency of subclinical thyroid disease in older patients with vitiligo, in Thyroid Reserch VII. In: Stockigt JR, Nagatadu S, eds. Proceedings of the 8th International Thyroid Congress, Sydney, Australia, 3--4 Febrary 1980. Canberra: A ustralian Academy of Science, 1980:546. 29. Shong YK, Kim JA. Vitiligo in autoimmune thyroid disease. Thyroidology 1991; 3(2):89-91. 30. Kemp HE, Waterman EA, Weetman AP. Autoimmune aspects of vitiligo. Autoimmunity 2001; 34:65-77. 31. Mandry RC, Ortiz LJ, Lugo-Somolinos A, Sanchez JL. Organ-specific autoantibodies in vitiligo patients and their relatives. Int J Dermat 1996; 35(1):18-21. 32. Miklaszewska M. Clinical and immunologic aspects of the relation of acquired leukoderma (vitiligo) to thyroid diseases. Arch Immunol Ther Exp (Warsz) 1972; 20:885. 33. Gould 1M, Gray RS, Urbaniak SJ, Elton RA, Duncan LPJ Vitiligo in diabetes mellitus. Br J Dermatol1985; 113:153-155. 34. Romano, et al. Skin lesions in diabetes mellitus: prevalence and clinical correlation. Diabetes Res Clin Pract 1998; 39(2):101-106. 35. Wahid Z, Kanjee A. Cutaneous manifestations of diabetes mellitus. J Pak Med Assoc 1998; 48(10):304--305. 36. Montagnani A, Tosti A, Patrizi A, Salardi A, Cacciari E. Diabetes mellitus and skin diseases in childhood. Dermatologica 1985; 170:65-68. 37. Macaron C, Winter RJ, et al. Vitiligo and juvenile diabetes mellitus. Arch DermatoI1977; 113:1515-1517. 38. Vijayasingam, et al. Clinical characteristics of progressive vitiligo. Ann Acad Med Singapore 1988; 17(4):526--535. 39. Dawber RPR. Vitiligo in maturity-onset diabetes mellitus. Br J Dermatol 1968; 80:275. 40. Grunnet I, Howitz J, Reymann F, et al. Vitiligo and pernicious anemia. Arch Dermatol 1970; 101:82. 41. Dawber RP, et al. Integumentary associations of pernicious anemia. Br J Dermatol1970; 82:221-223. 42. Bloch MH, Sowers JR. Vitiligo and polyglandular autoimmune endocrinopathy. Cutis 1985; 36(4):317-318. 43. Allison JR, Curtis AC Vitiligo and pernicious anemia. Arch Dermatol 1955; 72: 407 44. Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison's disease. 1995; 8(1):121-130. 45. Brostoff J, Bor S, Feiwel M. Autoantibodies in patients with vitiligo. Lancet 1969; 2177-178. 26.

Copyrighted Material

Primavera and Berardesca

198 46. 47. 48. 49.

50.

51.

52.

53. 54. 55. 56. 57. 58 59.

60. 61. 62. 63. 64. 65.

Zauli D, Tosti A, et al. Prevalence of autoimmune atrophic gastritis in vitiligo. Digestion 1986; 34(3): 169-172. Sharma VK, Dawn G, Kumar B. Profile of alopecia areata in northern India. Int J Dermatol 1996; 35:22-27. Sharma VK, Kumar B, Dawn G. A clinical study of childhood alopecia areata in Chandigarah, India. Pediatr Dermatol 1996; 13(5):372-377. Ahonen P, et al. Clinical variations of autoimmune polyendocrinopatycandidiasis-ectodermal dystropy (APECED) in a series of 68 patients. N Engl J Med 1990; 322: 1829-1836 Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different Polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981; 60:355-362. Forster G, Krummenauer F, Kuhn T, Beyer J, Kahaly G. Polyglandular autoimmune syndrome type II: epidemiology and form of manifestation. Dtsch Med Wochenschr 1999; 124(49):1476-1481. Weyermann D, Spinas G, Roth S, Guglielmetti M, et al. Combined endocrine autoimmune syndrome incidence, forms of manifestation and clinical significance. Schweiz Med Wochenschr 1994; 124(44):1971-1975. Lisak RP, Barchi RL. Myasthenia Gravis. Saunders: Philadelphia, 1982. Kubota A, Komiyama A, Tanigawa A, Hasegawa O. Frequency and clinical correlates of vitiligo in myasthenia gravis. 1997; 244:388-389. Cruz MW, Maranhao Filho PA, Andre C, et al. Myasthenia gravis and vitiligo. Muscle Nerve 1994; 17:559-560. Sehgal VN, Rege VL, Desai sc. Vitiligo and myasthenia gravis. In J Dermatol Vener Leprol 1976; 42: 1-2. Topoktas S, Dener S, Kenis M, Dalkara T. Myasthenia gravis and vitiligo. Muscle Nerve 1993; 16:566-567. Tan RS. Ulcerative colitis, myasthenia gravis, atypical lichen planus, alopecia areata, vitiligo. Proc R Soc Med 1974; 67: 195-196. Beutner EH, Hale WL, Nisengard RJ, et al. Defined immunofluorescence in clinical immunopathy. In: Beutner EH, Chorzelski TP, Bean SF, et aI., eds. Immunopathology of the Skin: Labeled Antibody Studies. Stroudsburg, PA: Dowden, Hutchinson & Ross Inc, 1973: 197-247. Finkelstein E, Amichai S, Metzker A. Coexistence of vitiligo and morphea: a case report and review of the literature. J Dermatol1995; 22:351-353. Lerner AB, Sansung J. Vittligo and linear scleroderma. Arch Dermatol 1973; 108286-287. David M, Metzker A, Feuerman EJ. Vitiligo and associated diseases. Harefuah 1977; 93: 141 143. Khandpur S, Reddy BS. An association of twenty-nail dystrophy with vitiligo. J Dermatol2001; 28(1): 8-42. Barth JH, Telfer NR, Dawberr PRo Nail abnormalities and autoimmunity. J Am Acad Dermatol 1988; 18: I062-1 065. Peloro TM, Pride HB. Twenty-nail dystrophy and vitiligo: a rare association. J Am Acad Dermatol 1999; 40:488-490.

Copyrighted Material

Autoimmune and Rare Associations

66. 67.

68. 69. 70.

71. 72.

73. 74. 75.

199

Reunala T, Collin P. Disease associated with dermatitis herpetiformis. Br J Dermatol 1997; 136:315-318. Amato L, Gallerani I, Fuligni A, Mei S, Fabbri P. Dermatitis herpetiformis and vitiligo: report of a case and review of the literature. J Dermatol 2000; 27:462466. Padula A, Ciancio G, La Civita L, et al. Association between vitiligo and spondyloarthritis 2001; 28:313-314. Beniz J, Forster DJ, Leon JS, et al. Variations in clinical features of the VogtKoyanagi-Harada syndrome. Retina 1991; 11 (3):275-280. Boutimzine N, Laghmaki A, Ouazzani J, Ibrahimi W, Mohcine Z. VogtKoyanagi-Harada syndrome. Epidemiological, clinical and disease progression aspects. Twenty cases. J Fr Ophtalmol 1998; 21(10):746-754. Barnes L. Vitiligo and Vogt-Koyanagi-Harada sind rome. Dermatol Clin 1988; 6(2):229-239. Duvic M, Rapini R, .Hoots WK, Mansell PW. Human immunodeficiency virusassociated vitiligo: expression of autoimmunity with immunodeficiency? J Am Acad Dermatol 1987; 17:652-656. Tojo N, Yoshimura N, Yoshizawa M, et al. Vitiligo and chronic photosensitivity in human immunodeficiency virus infection. Jpn J Med 1991; 30(3):255-259. Cho M, Cohen PR, Duvic M. Vitiligo and alopecia areata in patients with human immunodeficiency virus infection. South Med J 1995; 88(4):489-491. Yamauchi PS, Nguyen NQ, Grimes PE. Idiopathic CD4+ T cell lymphocytopenia associated with vitiligo. Dermatology 2002; 46(5):779-782.

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17 Ocular and Audiological Disorders in Vitiligo Antonella Tosti, Bianca Maria Piraccini, and Matilde lorizzo University of Bologna, Bologna, Italy Giovanni Tosti S. Luca Hospital, Trecenta, Italy

OCULAR MELANOCYTES The melanocytes of the eye consists of: (a) uveal, iris stroma, and conjunctival melanocytes; and (b) specialized pigment cells of the retinal and ciliary body pigment epithelia. The embryonic origins of ocular tissues take place from neural ectoderm (optic cup), neural crest (connective tissue), surface ectoderm (epithelium), and mesoderm (muscle and vascular endothelium). Ocular melanocytes derive from the optic cup neural ectoderm, except for uveal and iris stroma melanocytes that, like skin and hair melanocytes, originate from the neural crest. Whereas skin and hair melanocytes produce melanized melanosomes for exportation to the adjacent cells, uveal melanocytes and pigment epithelia are continent and do not release their melanosomes. Melanogenesis is only a transient activity of ocular pigment cells. Pigment cells play multiple roles in the eye. They create the black room environment necessary for the visual function, adsorbing diffracted light energy and preventing image degradation by light scattering and reflection within the eye, contributing to the achievement of clear retinal images, free of glares and halos. Moreover, ocular melanocytes probably contribute to the Copyrighted Material 201

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degradation of toxic derivates from photochemical reactions that take place continuously in the eye. Retinal pigment epithelium (RPE) cells have multiple specialized functions, including: I. 2. 3. 4. 5.

Preservation of photoreceptor integrity Phagocytosis of rod and cone outer segments Heterophagy of waste molecules from photoreceptor outer segmen ts Vitamin A esterification, isomerization, storage, and transport Metabolite transport to and from outer retina and choroidal circulation

The ciliary body pigment epithelium produces the aqueous humor. Uveal and iris stroma melanocytes appear during the 20th gestational week and continue their melanogenesis for several years after birth, explaining the changes in the iris color from light blue to dark and the darkening of the iris stroma and choroid during childhood (I). Melanogenesis in the RPE starts at the 4th week of gestation and is completely stopped shortly after birth. Retinal pigment epithelial cells are reactive to many stimuli, but do not seem to be able to resume melanogenesis. Acquired changes in fundus pigmentation are caused by clearing or migration of RPE cells or by the accumulation of pigment into macrophagic cells following focal destruction of RPE.

VITILIGO AND THE EYE Ocular abnormalities observed in vitiligo rarely have a clinical impact or cause visual disturbances. On the other hand, they have high theoretic and pathogenetic interest. Vitiligo patients may present various pigment changes in the fundus, in particular atrophic spots in the RPE or cborioretinal scars, probably related to previous inflammatory events (2). Uveitis occurs more frequently in vitiligo patients compared with the general population (3). Moreover, RPE function may be impaired in vitiligo, in fact the electro-oculographic Arden index, which represents an overall evaluation of the standing electrical potential of the photoreceptor-RPE complex, is significantly depressed in vitiligo patients (4). These findings suggest a more widespread involvement of RPE cells in vitiligo (5). The evidence of a significant link between fundus abnormalities and vitiligo is currently under discussion (6). On the other hand, there is a spectrum of well-known ocular diseases that presents with associated depigmented skin patches and systemic symptoms with leptomeningeal or inner ear pigment cell involvement (Table I). All of these diseases present a common condition of a probable autoimmune

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TABLE

1

Syndrome Vogt-Koyanagi-Harada

Sympathetic ophthalmia () 0

'b

~

~


0..

Birdshot retinopathy

s: Q)


~

0 0 c:

Hypounpigmented Alterations Associated with Ocular Diseases

Melanoma-associated vitiligo and retinopathy

Vogt-Koyanagi-Harada syndrome after cutaneous injury

Ocular involvement

Cutaneous involvement

Bilateral iridocyclitis, posterior uveitis, serous retinal detachment, optic disk swelling, atrophic RPE patches Bilateral granulomatous pan uveitis after penetrating injury of the eyeball due to either accidental trauma or surgery Bilateral multiple depigmented or cream-colored lesions at the level of the RPE Bilateral iridocyclitis, posterior uveitis, serous retinal detachment, optic disk swelling, atrophic RPE patches Bilateral iridocyclitis, posterior uveitis, serous retinal detachment, optic disk swelling, atrophic RPE patches

Vitiligo, alopecia, poliosis

Qj"

Systemic manifestations

...

III

::J

Q.

Vitiligo, alopecia, poliosis (rare)

CSF pleocytosis; meningismus with headache; tinnitus, hearing loss and vertigo; cranial nerve involvement Meningismus, tinnitus, hearing loss and vertigo (rare)

l:>

c:

Q.

o'

0

lC

o' ~

0 (ii' 0

... ...CD

Q.

CIl

Audiological anomalies

::J

<

a:

to' Vitiligo

CSF pleocytosis; meningismus with headache; tinnitus, hearing loss and vertigo; cranial nerve involvement

Vitiligo, alopecia, poliosis

CSF pleocytosis; meningismus with headache; tinnrtus, heaMng loss and vertigo; cranial nerve involvement

0

I\J

0 W

Tosti et al.

204

reaction against melanocytes. This fact may explain the widespread involvement of pigment cells in these diseases. A similar diffuse movement of the melanocytic population may be posited in vitiligo (7).

EAR MELANOCYTES The inner ear epithelium contains many melanocytes, particularly in the vascular streak of the cochlea. The embryonic source of ear melanocytes is not yet well established; studies on mice mutant for different alleles oflocus W, the regulator of development and migration of melanocytes deriving from neural crest, reported that melanocytes migrate toward the inner ear during growth and do not originate from the epithelium, in contrast with melanocytes of retinal pigmented epithelium. It is probable that ear melanocytes, such as cutaneous and uveal melanocytes, derive from neural crest. Ear melanocytes produce melanin, and studies on animals suggest that the number of melanosomes can be higher after an acoustic trauma (8). Although the role of ear melanocytes is still unknown, data on both animals and humans are suggestive of the importance of pigmented melanocytes for the development and preservation of uditive function. Hypoacusis is, for example, typical of Waardenburg's syndrome and piebaldism, where the development of melanocytes is altered. Cochlear melanocytes also seem to be important for the transmission of electrical impulses at the audiological receptor level, as has been demonstrated in studies that have identified an altered inner cochlear potential in albino mice (9). Some authors think that melanin has a protective role against audiological traumas due to toxins or noise. The loss of hearing associated with aging could be related to a reduction of pigmentation of the inner ear ( 10).

THE EAR AND VITILIGO Most patients with vitiligo do not have audiological diseases, and from a practical point of view audiological examination is not necessary. In the literature there are two reported families with both vitiligo and neurosensorial deafness probably transmitted as an autosomal recessive defect, and some cases, at times familial, of vitiligo associated with neurosensorial deafness and pigmentary retinopathy (I I). Audiological studies on patients with vitiligo give contrasting results: our experience, like that of Ardic et al., indicates that patients with vitiligo, above all males, suffer from light neurosensorial hypoacusis more often than controls (12,13). Other authors, however, did not confirm these data (14,15).

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11 is important to point out that studies carried out so far have not evaluated whether vitiligo represents a risk factor for the development of hypoacusis from toxins or noise. These studies have, in fact, excluded from the beginning patients exposed to well-known causes of hypacusia. In the future it would be important to evaluate if patients with vitiligo exposed to noise or taking ototoxic drugs have an higher incidence of hypoacusis or a more serious form ofhypoaclisis than subjects without vitiligo exposed to the same injuries. If melanin is protective only against traumas from other causes, these are the patients who should be studied.

REFERENCES J. 2. 3. 4. 5.

6. 7. 8. 9. 10.

II. 12. 13. J4. 15.

Wolff E. Anatomy of the Eye and Orbit. 7th ed. Philadelphia: WB Saunders, 1976:434. Barnes L. Vitiligo and the Vogt-Koyanagi-Harada syndrome. Dermatol Clin 1988; 6:229-239. Albert DM, Nordlund JJ, Lerner AB. Ocular abnormalities occurring with vitiligo. Opthalmology 1979; 86: J 145-1160. Tosti A, Maccolini E, De Pad ova MP, et al. Anomalie funzionali dell'epitelio pigmentato retinico nella vitiligine. Cron Dermatol 1987; 3:375-378. Colombati S, Tosti G, Zotti CA, et al. The retinal pigment epithelium in vitiligo. Retinal Pigment Epithelium, Proceedings. Amsterdam: Kugler and Ghedini, 1989:303-305. Cowan CL, Hadler RM, Grimes PE, et al. Ocular disturbances in vitiligo. J Am Acad Dermatol 1986; 15: 17-24. Rathinam SR, Namperumalsamy P, Nozik RA, et al. Vogt-Koyanagi-Harada syndrome after cutaneous injury. Opthalmology 1999; 106:635-638. Gratton MA, Wright CG. lperpigmentation of chinchilla stria vascularis following acoustic trauma. Pigment Cell Res 1992; 5:30-37. Conlee JW, Bennert MI. Turn-specific differences in the endocochlear potential between albino and pigmented guinea pigs. Hear Res 1993; 65:141-150. Boissy RE. Extracutaneous melanocytes. In: Nordlund JJ, Boissy RE, Hearing VJ, et al. eds. The Pigmentary System. Physiology and Pathopysiology. New York: Oxford University Press, 1998:59-73. Tosti A, Bardazzi F, De Padova MP, et al. Deafness and vitiligo in an Italian family. Dermatologica 1986; 172: 178- J79. Tosti A, Bardazzi F, Tosti G, et al. Audiologic abnormalities in cases of vitiligo. JAm Acad Dermatol 1987; 7:230-233. Ardic FN, Aktan S, Kara CO, et al. High-frequency hearing and reflex latency in patients with pigment disorders. Am J Otolaryngol 1998; 19:365-369. Orecchia G, MareHi MA, Fresa D, et al. Audiologicdisturbances in vitiligo. JAm Acad Dermatol1989; 21:1317-1318. Escalante-Ugalde C, Publano A, Montes de Oca E, et al. No evidence of hearing loss in patients with vitiligo. Arch Dermatol 1991: 127:1240.

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18 Differential Diagnosis for Vitiligo Wennie Liao and James J. Nordlund University of Cincinnati, Cincinnati, Ohio, U.S.A.

Vitiligo is one of many disorders that can present as leukoderma or cutaneous hypopigmentation (1-6). It is characterized by asymptomatic, well-demarcated, smooth, chalk-white macules (5-7). The epidermis is normal except for rare cases of inflammatory vitiligo (8,9). The depigmented lesions are accentuated under Wood's lamp examination, even in individuals with very light, type I skin color. The Wood's lamp emits a blue light, which illuminates only the epidermis, in contrast to white light, which illuminates both the epidermis and the dermis. Under blue illumination, epidermis with small amounts of melanin appears dark, and that without melanin appears white. It should be noted that the accentuation of depigmentation is not unique to vitiligo but is observed in any disorder in which there are alterations in the quantity of epidermal melanin. The absence of melanin in vitiligo is due to an absence of melanocytes (lO). Histological studies confirm an absence of melanocytes (II). Vitiligo may be classified as either segmental, localized, or generalized. In the segmental form, depigmentation is limited to one area of the skinoften one side of the face or unilaterally on an extremity. Although the areas of depigmentation are patterned, they do not seem to conform to dermatomes or to Blaschko's lines. Localized vitiligo is characterized by a few small-tolarger patches of depigmentation with no identifiable preceding rash or cause. The areas tend to be stable for many years. In the generalized form, depigmentation typically is symmetrical and involves the dorsa of the hands,

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face, wrists, elbows, knees, and periorificial areas (around the eyes, nostrils, mouth, umbilicus, and genitalia). It is almost always progressive. The differential diagnosis for vitiligo is extensive (12) given the wide range of disorders that can present with leukoderma (Table l). However, a thorough history and a careful examination of the morphology and distribution of hypopigmented lesions often enable one to easily differentiate

TABLE 1

Differential Diagnosis of Vitiligo

Genetic

Chediak-Higashi syndrome Hermansky-Pudlak syndrome Hypomelanosis of Ito Oculocutaneous albinism Piebaldism Tuberous sclerosis Vogt-Koyanagi-Harada syndrome Waardenburg's syndrome Infectious Leishmaniasis (post kala-azar) Leprosy Onchocerciasis Pinta Secondary syphilis Tinea versicolor Yaws Neoplastic Melanoma with associated depigmentation Mycosis fungoides Iatrogenic Arsenic Azelaic acid Dermabrasion Monobenzyl ether of hydroquinone Liquid nitrogen Tretinoin Topical/intralesional corticosteroids Nutritional Kwashiorkor Selenium deficiency Physical/Chemical Burn Irradiation Phenols/catechols

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Inflammatory Atopic dermatitis Discoid lupus erythematosus Pityriasis lichenoides chronica Psoriasis Miscellaneous Halo nevus Idiopathic guttate hypomelanosis Lichen sclerosus et atrophicus Morphea Nevus anemicus Nevus depigmentosus Pityriasis alba Sarcoidosis

vitiligo from other disorders. Some of the more common disorders mimicking vitiligo and their distinguishing features will be discussed in this chapter. These disorders include tinea versicolor, postinflammatory hypopigmentation, pityriasis alba, chemical leukoderma, idiopathic guttate hypomelanosis, halo nevus, nevus depigmentosus, nevus anemicus, cutaneous scleroderma, mycosis fungoides, lichen sclerosus et atrophicus, sarcoidosis, leprosy, pinta, and piebaldism.

TINEA VERSICOLOR Tinea versicolor is a common superficial infection caused by the yeast Malessezia furfilr. Often involving the upper trunk (Fig. 1), as well as the neck and upper arms, this disorder presents with multiple, scaling, annular, hypopigmented macules. The spots in a few individuals are moderately pruritic but more often they are asymptomatic and unsightly. The macules may also be brown or pink, hence the name "versicolor." Scrapings of the powdery scale from these lesions after the addition of potassium hydroxide reveal numerous hyphae and spores ("spaghetti and meatballs") under the microscope. Wood's lamp examination reveals a golden fluorescence of the lesions. The presence of scale, the typical distribution on the upper trunk, and the findings on microscopy should distinguish this yeast infection easily from vitiligo.

POSTINFLAMMATORY HYPOPIGMENTATION Postinflammatory hypopigmentation and depigmentation occur most often with the various forms of dermatitis, with psoriasis, or with discoid or sub-

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FIGURE 1 Extensive tinea versicolor on the back of a young man. There are large confluent patches of hypopigmented skin. The small, annular lesions at the periphery of the patches are suggestive of tinea versicolor. A KOH confirms the diagnosis.

acute cutaneous lupus erythematosus. But any inflammatory disorder has the potential to produce hypo- or depigmentation. Lesions usually are ill-defined, off-white irregular macules or patches located at the sites of previous inflammatory lesions. A history of ill-defined pruritic patches and of an atopic diathesis would suggest atopic dermatitis as an etiology. Well-defined, erythematous, scaly plaques, especially on the elbows or knees, would suggest psoriasis. Lesions of discoid lupus, typically located on the ears, scalp, and sun-exposed areas, often are well demarcated and have accompanying features such as epidermal atrophy and scale to distinguish them from the smooth lesions of vitiligo. In all cases of postinflammatory hypopigmentation, a history or the presence of inflammatory lesions would differentiate this form of leukoderma from vitiligo. In addition, the epidermis in most forms of postinflammatory hypo- or depigmentation is atrophic, scaly, or altered in some way. Vitiligo by definition has a normal epidermis except for the absent melanin. Were there any doubt clinically about the nature of the lesion, a biopsy would definitively distinguish vitiligo from postinflammatory pigment changes.

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FIGURE 2

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Pityriasis alba in one of twin boys. The face is hypopigmented.

PITYRIASIS ALBA

Pityriasis alba is an asymptomatic disorder affecting mostly children (Fig. 2) and young adults with atopic diatheses. The ill-defined, hypopigmented, finely scaling patches of this disorder are lIsually located on the lateral aspects of the cheeks and upper arms and on the thighs. The ill-defined borders of the lesions, their scaliness, and their typical distribution contrast with the welldemarcated, smooth maCltles and patches of vitiligo, which are lIsually located around the eyes and mouth on the face and on the distal parts of the hands and feet. CHEMICAL LEUKODERMA

Chemical leukoderma is an entity that closely mimics vitiligo morphologically and histologically. Chemical leukoderma is caused by exposure to a variety of chemicals, mostly derivatives of phenols and catechols such as monobenzone, para-tert-butyl phenol, or catechol or similar aliphatic and aromatic compounds (13-29). Exposure usually occurs in the workplace such as hospitals, factories, or chemical industries and results in well-demarcated, depigmented macules (Fig. 3), usually isolated on the hands and forearms, where exposure is most common. Occasionally, inflammation or allergic contact dermatitis of

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the affected skin may precede the development of chemical leukoderma. Histologically, the lesions cannot be distinguished from those of vitiligo. Idiopathic vitiligo and chemical leukoderma both show reduced numbers of melanocytes. A thorough occupational/exposure history and a high index of suspicion for chemical leukoderma (especially in patien ts who work in industrial settings), in addition to patch testing, would help to establish this diagnosis and distinguish it from vitiligo. For some individuals, idiopathic vitiligo may truly be due to chemical leukoderma secondary to an unidentified contactant such as foods, some of which are known to contain phenolic derivatives. IDIOPATHIC GUTTATE HYPOMELANOSIS

Idiopathic guttate hypomelanosis (IGH) is a very common, asymptomatic disorder affecting the sun-exposed areas of the arms and legs of middle-aged and older people. Characterized by multiple, well-demarcated, small (usually 2-5 mm) white macules, this disorder may progress with an increasing number of lesions. Despite their numbers, their size typically remains small,S mm, although some as large as 2 cm have been observed. The epidermis has an atrophic and shiny surface. This alteration in the surface makes distinction of vitiligo from IGH easy. In addition, the distribution and typically larger size oflesions in vitiligo differentiate vitiligo from IGH.1f necessary, histology can distinguish between the two disorders. Lesions of IGH usually reveal epidermal atrophy and a patchy decrease of melanin/melanocytes. HALO NEVI

A halo nevus, also known as Sutton's nevus, is a melanocytic nevus surrounded by a well-demarcated, depigmented ovoid halo of otherwise normal skin (Fig. 4). With time, the central melanocytic nevus disappears and a welldemarcated, white, smooth macule or patch remains. Almost always the depigmented macule itself disappears with time. Most common in children and adolescents, a halo nevus usually occurs on the trunk and extremities. Often patients have more than one, and some individuals may have over 50. The histology of a halo nevus is dependent on the stage of its evolution. Characteristic findings include nevus cells admixed with a dense lymphocytic

FIGURE 3 (A) Chemical leukoderma on the right hand of a woman working with phenolic germicides. Only the hand had depigmentation, most prominent between the fingers where the chemical is occluded. (B) A depigmented spot on the forehead of an Indian woman who wore a bindi that contained monobenzone in the glue.

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FIGURE 4

Multiple halo nevi with depigmentation surrounding nevi.

infiltrate at the dermal-epidermal junction and in the dermis and a loss of melanocytes within the halo. A history of a melanocytic nevus within a depigmented macule is usually sufficient to distinguish a halo nevus from a lesion of vitiligo. If this history is uncertain, the presence of other halo nevi (in earlier stages with a central nevus) and/or a biopsy will differentiate between the two entities. Some observers suggest that halo nevi are localized versions of vitiligo (30-36). Vitiligo may occur more frequently in patients with halo nevi compared to the general population (33). On the other hand, halo nevi are common in young people, as is vitiligo. NEVUS DEPIGMENTOSUS Nevus depigmentosus is a peculiar disorder that is usually a congenital lesion characterized by a stable, well-demarcated, hypopigmented macule or patch

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FIGURE 5 A nevus depigmentosus in a dermatomal distribution around T10. The patch was hypopigmented and appeared in adult life.

with an irregular border (37-39). Occasionally it may be depigmented, as may the hairs within such a lesion. It may mimic the distribution of segmental vitiligo or may occasionally be distributed along Blaschko's lines or even over a dermatome (Fig. 5). Thus, the lesion may be ovoid or rectangular but may also be linear or whorled. Most often found on the trunk or neck, this lesion grows only as the patient grows and usually is solitary. Because it is congenital, stable, and usually solitary, nevus depigmentosus is easily distinguished from vitiligo. Nevus depigmentosus can also be acquired, often around the time of puberty. When acquired, it is hypopigmented and patterned such that it usually does not resemble either segmental vitiligo or localized vitiligo. However, a localized nevus depigmentosus that is depigmented might be difficult to distinguish from segmental vitiligo.

NEVUS ANEMICUS Nevus anemicus is a congenital or acquired lesion most often found on the chest or back of female patients (40-44). The lesion is often a well-defined, hypopigmented irregular macule surrounded by similar, adjacent smaller mantles. This lesion does not enhance with Wood's lamp examination as it is due to an abnormality of the dermal blood vessels rather than of epidermal

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melanocytes or melanin. In addition, with pressure applied by a glass slide (diascopy), the border of the lesion becomes obscured. This diascopic finding and the Wood's lamp examination differentiate nevus anemicus from vitiligo. CUTANEOUS SCLERODERMA

Scleroderma is an acquired disorder that begins with tightening of the skin of the face and fingers. Follicular depigmentation and repigmentation give the skin a "salt-and-pepper" appearance. On palpation, the skin is firm and "bound down" because of decreased skin elasticity. Histology reveals an increased amount of compacted collagen with thickening of the dermis. The

FIGURE 6 A man with widespread mycosis fungoides, a lymphoma of the skin. Note the numerous depigmented patches of skin. At times, mycosis fungoides can present as hypopigmented macules on the skin.

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texture of the lesion often is enough to distinguish scleroderma and its localized forms from vitiligo. MYCOSIS FUNGOIDES Mycosis fungoides, a type of cutaneous T-cell lymphoma, can present as welldemarcated, hypopigmented macules (Fig. 6), more often in patients with darker skin. While these macules may exhibit some erythema, epidermal atrophy, and/or fine scale, many times these lesions may be clinically indistinguishable from those of developing vitiligo. A biopsy is usually required to distinguish the two disorders. The histology of hypopigmented mycosis fungoides is diagnostic and typically shows atypical lymphocytes and epidermotropism. Both of these features are absent in vitiligo. LICHEN SCLEROSUS ET ATROPHICUS (LS&A) LS&A is a disorder affecting females predominantly. Most often involving the genitalia (Fig. 7), lesions consist of ill-defined, white, atrophic, smooth patches. On extragenital sites, the lesions may begin as well-demarcated papules with follicular plugging, which coalesce into plaques that eventually become atrophic with a shiny surface and white color. Genital lesions are often symptomatic. Pruritus and dysesthesia are the most common complaints. Vitiligo may share a similar distribution as LS&A but the shiny surface and other changes and symptoms of the latter help distinguish it from the former. At times, a biopsy is necessary to distinguish LS&A from vitiligo, especially when the lesions are situated on the genital areas of young girls. SARCOIDOSIS Sarcoidosis is a multisystem disorder characterized by non-caseating granulomata in internal organs as well as in the skin. While skin lesions classically present as red-brown firm papules and plaques, ill-defined, hypopigmented macules (Fig. 8) and plaques have been described in patients with this disorder. The ill-defined borders of lesions, histology, and inyolvement of other organs all distinguish sarcoidosis from vitiligo. LEPROSY (HANSEN'S DISEASE) Leprosy is a chronic infection with a predilection for the skin and nerves caused by Mycobacterium leprae, an acid-fast bacillus endemic in Asia, Africa, and Latin America. Cutaneous manifestations of leprosy are varied, depending on the type ofleprosy. Well-defined, hypopigmented macules and

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A

B FIGURE 7 (A) Lichen sclerosus et atrophicus of the vulva. This disorder often is very pruritic. However, it may not be possible to distinguish this disorder from vitiligo by clinical observation alone and a biopsy might be necessary. (8) Lichen sclerosus et atrophicus on the penis, also labeled balanitis xerotica obliterans. The skin is atrophic. A biopsy is diagnostic.

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FIGURE 8

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Sarcoidosis presenting as numerous hypopigmented macules on the

trunk.

patches which are anesthetic are most often found in tuberculoid and borderline leprosy. The lesions are few in number, usually randomly scattered and hypopigmented. The loss of color is never complete in lesions of leprosy. Palpable or enlarged nerves sometimes may be detected near these lesions. The hypopigmentation, the anesthetic nature and spotty distribution of the lesions, the palpable nerves, and a geographical history distinguish leprosy from vitiligo. PINTA

Pinta is an infection endemic to rural Central and South America caused by the spirochete Treponema cm-aleuIn. The infection causes the serological test for syphilis to be reactive. The tertiary or late stage of pinta is characterized by symmetrical, hypo- or depigmented patches typically over bony prominences (elbows, knuckles, wrists, knees, and ankles). Histologically, the epidermis of these lesions often shows marked atrophy and loss of hair follicles. These lesions may be admixed with brown or slate-gray patches. Tertiary pinta usually occurs months to years after the scaly papules and plaques of secondary pinta (termed pintides)_ An antecedent eruption of these papules and plaques and a geographical history, in addition to positive treponemal tests, differentiate pinta from vitiligo. Copyrighted Material

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B FIGURE 9 (A) Piebaldism manifested as depigmented patches on the neck extending to the chest. The child was born with these depigmented patches and a white forelock. Note the dark macules within the white area. (B) Piebald skin on the knees. Note the pigmented macules within the white patch. The depigmentation was present at birth.

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PIEBALDISM Piebaldism is a type of localized depigmentation. It is first manifested at birth in most individuals as a white forelock on the scalp and as areas of depigmentation on the ventral surface (Fig. 9A) of the trunk and at times on the arms or legs (Fig. 9B). If a child is very fair in color at birth, the depigmentation might not be noted until the child is older, around 4-6 months of age. Usually there is a strong family history of similar lesions, since the disorder is tran mitted as an autosomal dominant trait. The lesions are clinically and histologically identical to those of vitiligo. However, there are no definitive cases of vitiligo present at birth. The earliest documented cases of vitiligo ha ve been observed at around 6 months of age. The white forelock, the pattern of depigmentation on the ventral surface, and the family history make the distinction between vitiligo and piebaldism easy. OTHER DISORDERS Many other disorders are associated with or characterized by localized, partial, or generalized loss of pigmentation such as albinism. These usually are not difficult to distinguish from vitiligo because many are congenital, genetic, or have associated findings. Details about other disorders listed in Table 1 can be found in textbooks of dermatology or in Nordlund et al.'s comprehensive review of pigmentation and its disorders (45). REFERENCES 1.

2.

3. 4.

5. 6. 7.

8.

Nordlund JJ, Majumder PP. Recent investigations on vitiligo vulgaris. Dermatol Clin 1997; 15(1):69-78. Das SK, Majumder PP, Chakraborty R, Majumdar TK, Haldar B. Studies on vitiligo.!. Epidemiological profile in Calcutta, India. Genet Epidemiol 1985: 2(1):71-78. Das SK, Majumder PP, Majumdar TK, Haldar B. Studies on vitiligo. II. Familial aggrega tion and genetics. Genet Epidemiol 1985; 2(3):255-262. Howitz J, Brodthagen H, Schwartz M, Thomsen K. Prevalence of vitiligo. Epidemiological survey on the Isle of Born holm, Denmark. Arch Dermatol 1977; 113(1):47-52. Hann S-K, Nordlund JJ, eds. Vitiligo: A Monograph on the Basic and Clinical Science. Oxford, London: Blackwell Science Ltd, 2000. Hann SK, Chun WH, Park YK. Clinical characteristics of progressive vitiligo. Int J Dermatol 1997; 36(5):353-355. Hann S-K. Definition of vitiligo. In: Hann S-K, Nordlund J, eds. Vitiligo: Monograph on the Basic and Clinical Science. Oxford: Blackwell Science Ltd, 2000:3-6 Arata J, Abe-Matsuura Y. Generalized vitiligo preceded by a generalized figurate erythematosq uamous en~jfJWi!Jfif!ff{fl'A!lfjte~PJr,21 (6):438-441.

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10.

II.

12.

13. 14. 15. 16. 17. 18.

19. 20.

21.

22. 23. 24.

25.

26.

Le Poole IC, van den Wijngaard RM, WesterhofW, Das PK. Presence ofT cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Patho11996; 148(4):1219-1228. Nordlund J. The loss of melanocytes from the epidermis: the mechanism for depigmentation in vitiligo vulgaris. In: Hann S-K, Nordlund J, eds. Vitiligo: Monograph on the Basic and Clinical Science. Oxford: Blackwell Science Ltd, 2000:7-12. Boissy R. Histology of vitiliginous skin. In: Hann S-K, Nordlund J, eds. Vitiligo: Monograph on the Basic and Clinical Science. Oxford: Blackwell Science Ltd, 2000:23-34. Sheth P. The differential diagnosis of vitiligo vulgaris. In: Hann S-K, Nordlund J, eds. Vitiligo: Monograph on the Basic and Clinical Science. Oxford: Blackwell Science Ltd, 2000:101-122. Bajaj AK, Gupta SC, Chatterjee AK. Contact depigmentation from free paratertiary-butyl phenol in bindi adhesive. Contact Dermatitis 1990; 22(2):99-102. Calnan CD. Occupational leukoderma from alkyl phenols. Proc Roy Soc Med 1973; 66(3)258-260. Gellin GA, Maibach HI, Misiaszek MH, Ring M. Detection of environmental depigmenting substances. Contact Dermatitis 1979; 5(4):201-213. Goldmann PJ, Thiess AM. [Occupational vitiligo caused by para-tertiary-butylphenol, a trias of vitiligo, hepatosis and struma]. Hautarzt 1976; 27(4): 155-159. James 0, Mayes RW, Stevenson CJ. Occupational vitiligo induced by p-tertbutylphenol, a systemic disease? Lancet 1977; 2(8050):1217-1279. Ito Y, Jimbow K, Ito S. Depigmentation of black guinea pig skin by topical application of cysteaminylphenol, cysteinylphenol, and related compounds. J Invest Dermatol J987; 88(1):77-82. Kahn G. Depigmentation caused by phenolic detergent germicides. Arch Dermatol1970; 102:177-187. Le Poole IC, Yang F, Brown TL, Cornelius J, Babcock GF, Das PK, et al. Altered gene expression in melanocytes exposed to 4-tertiary butyl phenol (4TBP): upregulation of the A2b adenosine receptor l. J Invest Dermatol 1999; 113(5)725-731 Malten KE, Seutter E, Hara I, Nakajima T. Occupational vitiligo due to paratertiary butylphenol and homologues. Trans St Johns Hosp Dermatol Soc 1971; 57(1):115-134. Mancuso G, Reggiani M, Berdondini RM. Occupational dermatitis in shoemakers. Contact Dermatitis 1996; 34(1): 17-22. Morrone A, Picardo M, de Luca C, Terminali 0, Passi S. Catecholamines and vitiligo. Pigment Cell Res 1992; 5(2):65-69. O'Malley MA, Mathias CG, Priddy M, Molina D, Grote AA, Halperin WE. Occupational vitiligo due to unsuspected presence of phenolic antioxidant byproducts in commercial bulk rubber. J Occup Med 1988; 30(6):512-516. O'Sullivan 11, Stevenson CJ. Screening for occupational vitiligo in workers exposed to hydroquinone monomethyl ether and to paratertiary-amyl-phenol. Bri J Indust Med 1981; 38(4):381-383. Rodermund OE, Wieland H. [Vitiligo-like depigmentation by paratertiary

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butylphenol. First observations in the German Federal Republic]. Zeitschr Hautkrankh 1974; 49(11):459-465. Rodermund OE. Letter: occupational vitiligo caused by paratertiary butylphenol. Arch Den11atol 1976; 112(4):554-555. Romaguera C, Grimalt F. Occupational leukoderma and contact dermatitis from paratertiary-butylphenol. Contact Dermatitis 1981; 7(3): 159-160. Cummings M, Nordlund JJ. Chemical leukoderma: fact or fancy. Am J Contact Derm 1995; 6:122-127. Becker MD, Marcks KM, Trevaskis AE, Heffernan AG, Puchner G. Halo nevus of Sutton. Plast Reconstruct Surg 1966; 37(5):413-415. Cooke KB, Bennett C, Staughton RC. Melanoma specific protein: occurrence in the urine of patients with halo naevus and vitiligo. Br J Dermatol 1978; 98(6):663-668. Hudson LD. The humoral immune system in melanoma, vitiligo, and halo nevus: a review of recent literature. J Assoc Military Dermatol 1979; 5: I 5-18. Lerner AB, Kirkwood JM. Vitiligo and melanoma: can genetically abnormal melanocytes result in both vitiligo and melanoma within a single family? J Am Acad Dermatol 1984; 11(4 pt 1):696-701. Nordlund n, Albert D, Forget B, Lerner AB. Halo nevi and the Vogt-KoyanagiHarada syndrome. Manifestations of vitiligo. Arch Dermatol 1980; 116(6):690692. Pass C, Robinson HM Jr. Sutton's nevus (halo nevus). Birth Defects: Original Article Series 1971; 7(8):238 Swanson JL, Wayte DM, Helwig EB. Ultrastructure of halo nevi. J Invest Dermatol 1968; 50(6):434-450. Lee HS, Chun YS, Hann SK. Nevus depigmentosus: clinical features and histopathologic characteristics in 67 patients. J Am Acad Dermatol 1999; 40( 1):21-26. Pinto FJ, Bolognia J L. Disorders of hypopigmentation in children. Pediatr Clin North Am 1991; 38(4):991-1017. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54 cases of hypopigmentation and hyperpigmentation along the lines of Blaschko [see comments]. Arch Dennatol 1996; 132(10):1167-1170. Jimbow M, Jimbow K. Pigmentary disorders in oriental skin. Clin Dermatol J989; 7(2) 11-27. Daniel RH, Hubler WR, Wolf JE, Holder WR. Nevus anemicus. Donordominant defect. Arch Dermatol 1977; 113(1 ):53-56. Fleisher TL, Zeligman 1. Nevus anemicus. Arch Dermatol1969; 100(6):750-755. Greaves MW, Birkett D, Johnson C. Nevus anemicus: a unique catecholaminedependent nevus. Arch Dermatol 1970; 102(2):172-176. Mountcastle EA, Diestelmeier MR, Lupton GP. Nevus anemicus. J Am Acad Dermatol 1986; 14(4):628-632. Nordlund JJ, Boissy RE, Hearing VJ, King RA, Ortonne J-P. eds. The Pigmentary System: Physiology and Pathophysiology. New York: Oxford University Press, 1998.

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19 Vitiligo: Emotional Aspects and Personality

Giuseppe Hautmann and Torello Lotti University of Florence, Florence, Italy

Jana Hercogova Charles University, Prague, Czech Republic

Vitiligo is often considered as emotionally triggered. Sometimes there are associated eye abnormalities, autoantibodies, and a high incidence of associated disorders, such as Hashimoto's thyroiditis, diabetes mellitus, pernicious anemia, Addison's disease, myasthenia gravis, lupus erythematosus, Crohn's disease, scleroderma, alopecia areata, atopic dermatitis, and biliary cirrhosis. Many of these disorders have been reported to be associated with psychological problems (1,2). There are observations supporting an autosomal incomplete inheritance with variable expression and incomplete penetrance (I). To date, the etiology and the pathogenesis of vitiligo are still unknown, although there have been reports of several precipitating factors, such as severe sunburn, repeated trauma, and emotional stress (vitiligo has been reported to be more frequent during wars, after bombing attacks) (1-4). Obermayer (5), one of the first to investigate psychosomatic dermatology (he used the improper but apt term "psychocutaneous"), in fact classified vitiligo among the dermatoses "sometimes influenced by emotional factors," while Whitlock (6) thought it generally unwise to base one's opinion "on patient' reports of alleged emotional causes" when concluding a psychogenesis of vitiligo. Griesemer and Nadelson (7) calculated that 33% of their Copyrighted Material 225

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cases of vitiligo could be considered emotionally triggered, with a biological incubation period of 2-3 weeks between the stress event and the clinical manifestation of the vitiligo patches. Lerner (8) reported the statistical data obtained from 200 subjects with vitiligo by a questionnaire. When asked the question: "Do you think your vitiligo is associated with (or caused by) any particular event such as emotional upset, accident, sunburn, etc.?," 70% of patients answered that several events (e.g., relevant emotions, nervousness, internal diseases, accidents, surgery, pregnancy, or birth) aggravated or provoked vitiligo; 35% of this 70% was attributed to emotions, traumatic events, and nervousness. Moreover, to the question: "What factors make your vitiligo spread?," 15% of patients responded: nervousness. Finally, when asked the question: "What illnesses besides vitiligo do you have at the present time?," 35% of the interviewed patients associated vitiligo with nervousness and to psychosomatic diseases (8). Ortonne et al. (9) obtained overlapping results; in 46 of 100 patients it was possible to delineate a possible factor that had provoked the disease. In 24 cases it was due to psychological distress, such as familial, scholastic, affective troubles, emigrations, or the birth of a sibling, whereas in 22 cases it was due to physical traumas, such as accidents, surgery, illnesses, pregnancies, sunburns, etc. (9). Nevertheless, although several cases have been reported of the onset of vitiligo after emotional stress, there are few psychodynamically oriented studies detailing the premorbid personality traits that might account for the disease. Corraze and Dupre (10), examining 16 subjects (10 men and 6 females) with vitiligo, reported that the reaction to this disease consists ofa distressing and tormented affect that has long-ranging repercussions. In these cases it was possible to analyze the early periods of the infancy of the patients, finding that these subjects presented marked traits of neuroticism, consisting of psychomotor agitation, pavor nocturnus, and enuresis. A common trait of these subjects was the affective immaturity, with a real infantilism. There were behaviors that suggested a regression to the oral phase, such as bulimia nervosa, tabagism, and alcoholism. Their sleep was often interrupted by anxiety and nightmares. There were often panic attacks. Men suffering from vitiligo presen ted significant trai ts of avoidan t and dependent personali ty; moreover, they idealized their mothers as strong, dictatorial figures and tried to rediscover this figure in their wives. Men often presented marital conflicts and many were divorced or separated; some had sexual dysfunctions. Women presented psychomotor agitation, sexual dysfunction, somatizations, and anger and aggressivity toward the male sex. In several cases the relationship between the onset of the skin disease and life stress events was well established: frequently there was the loss of a loved object (anxious separation from the family, marital separation, death of one parent, etc.). In two cases the vitiligo

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onset was related to the notice of conjugal betrayal. In three women, vitiligo was related to undesired pregnancies. Even the localization of the dermatosis has been reported as related to these evident affective relationships (that may re-actualize unconscious conflicts): two men who had been betrayed developed vitiligo on the genital areas; two women who did not accept their pregnancy developed vitiligo on their abdomens; and a woman who cleaned the sheets where her son's girlfriend had aborted developed disease on the hands in a few hours (10). As is well known, vitiligo can occur at any age, but it appears preferentially in younger adult females. Its peak incidence is between 10 and 30 years of age: the patient notes the appearance of one or more sharply circumscribed white spots (especially noticeable when the skin is tanned), often with clearly hyperpigmented margins. Thus, because of the contrast, the lesions are particularly evident and the subject is disturbed by the unaesthetic effect (especially in the case of young women). At onset, the lesions are only a few small, well-circumscribed foci, but they may increase in number and become confluent or take on bizarre shapes, the diffusion and course of these patches being capricious, irregular, and unpredictable with generally little possibility for spontaneous or therapeutic repigmentation. It progresses primarily without other symptoms; in fact, only rarely is there itching, which may be very intense when the partially unprotected patient exposes himself to the sun. Vitiligo is usually classified on the basis of its extension: there are localized types (focal and segmental), generalized types (acrofacial and vulgaris), and a universal type. The treatment of vitiligo is still not satisfactory; there are several approaches (systemic with PUVA, l3-caroteneor topical with sunscreens, corticosteroids, camouflage), with variable results. Thus, this skin disease creates important aesthetic problems, sometimes with noteworthy somatopsychic repercussions, in particular when the white macules are diffuse or located on normally exposed skin areas (hands and face), especially in young women. The low rate of therapeutic success, even with relatively recent methods (PUVA, Kellin, and UVA treatment), and the necessity to touch up or hide the unpleasant white spots aggravate the state of "psychic suffering." Only the microphototherapy Bioskin ®, a new therapeutic regimen using puntiform irradiation with a light with peak at 311 nm, which permits repigmentation without concomitant increased darkening of the apparently normal skin, seems to reduce "psychic suffering" in a group of subjects. We cite here a case reported by Bassi of a pretty 22-year-old young woman, married with a child, who was admitted to the hospital because she was afraid that her skin lesions would enlarge. She presented vitiligo localized on her right hand and three little spots on her breast and abdomen. A psychologically oriented interview revealed (she had not noted before) that Copyrighted Material

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her lesions were locaJized in the same areas where her father presented war wounds, making evident a process of identification (1 J). WhiJe vitiligo occurs worldwide and affects all races, it is particularly a problem in persons whose normal skin color is brown or black (skin phototypes V and VI) because of the strong contrast of brown and black skin with the chalk-white color of the vitiligo macules. White persons who can acquire a deep tan (skin phototype IV) also have a more serious problem of disfigurement. For these people, vitiligo can be a major medical tragedy and not simply a cosmetic disorder. Therefore, although vitiligo is painless and not associated with shedding scales of skin as in psoriasis, it can be a devastating malady. The contrast between the normally colored skin and the white spots gives these affected people a harlequin or leopard-like appearance that can limit their potential for leading normal lives in terms of marriage, famiJy, friendship, and even work. It is no wonder that patients with vitiligo have been found to suffer from feelings of inferiority, to become aggressive, to feel a sense of shame, and sometimes to become secluded and resentful (I). In the study by Porter et al. (12) conducted on III subjects with vitiligo, vitiligo-induced anxiety and psychological distress is intensely represented; about two thirds of the interviewed patients admitted to being very embarrassed due to the skin disease, and many of them attempted to hide the spots. Many of these patients employed cosmetics, clothes, gJoves, and socks in the summer to hide the lesions. In this study, patients indicated that family members did not give enough support (12). According to Porter et al. (12), patients adopt three different behaviors to cope with vitiligo: (a) some adopt so-called "mastery active" psychological mechanims: they read and study about the skin disease, and in this way they learn to accept it with minor embarrassment; (b) the "acceptors," about 40% of all the patients, show good self-esteem and do not seem to be embarrassed or try to hide the skin lesions; (c) the third group is aJmost always depressed due to the vitiligo: they do not accept it and are usually embarrassed, making "heroic" attempts to hide the white spots. They have very few social contacts and often Jose their jobs. This usually happens in young people, especially males who are not willing to use cosmetics to camouflage the achromic skin. Morever, this group feels less desirable sexually. An example of this reaction is the following letter from one patient with vitiligo, as reported by Fitzpatrick (13). These words show how the subject's adult life was dominated by the scourge of vitiligo and how this seriously restricted her activities, especially in the summer: Many people seem to believe that it shouldn't bother me because it isn't painful. Sure it isn't painful, but it certainJy is doing a job on me mentally. Well, I have had vitiligo almost half my life and to be

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honest I feel as though life stopped somewhere around age 23 or so for me. This is when it started getting bad. Since then I have been in a sort of limbo waiting for a cure to take place. I am not enjoying life the way it was meant to be. I am simply existing, waiting for my cure so I can catch up with and join the rest of the beautiful people. I may sound bitter about this and maybe I am. I don't recall doing anything bad enough to deserve this, and why has it been decided for me to have instead of you anyway? Why did I get it now instead of when I got real old and wouldn't care? People just expect me to accept it and continue on. I get these disgusted looks, as if "Here she comes, the walking talking horror show." I feel I should join the circus as one of their freak acts. They have the snake man, an albino lady, a fat lady, now what they need is the bleach lady. I feel like "Casper the friendly ghost." All I want is to be friends, but the sight of me makes people feel ill at ease, very uncomfortable with me. When the doctor asked me what vitiligo means to me, my first answer was that I feel like a mistake. If it isn't a mistake then all you one-colored persons are the mistake. I don't see all you one-colored persons trying to get bleached out till you're two colors. So this shows that it is just that: I am a mistake! I believe if there were no hope for me I would crack up, but if I were lucky I would end it all first. They say where there is life there is hope. The doctors say they will treat me only as long as I am repigmenting. At least fully dressed, with long pants and long-sleeved shirts, I look almost like one of you humans. To be rid of vitiligo would be like being reborn for me, to be normal and happy. In examining what the patient brings to the equation, it is clear that age and sex are likely to be important factors influencing the impact of this aesthetically disabling skin disease. In fact, a cutaneous disorder like vitiligo that usually starts during adolescence or early adulthood, when people typically consolidate their sense of self and sexual identity, may have a profound impact on self-image, self-esteem, and interpersonal relationship. Furthermore, the status of patients' self-esteem and body image as they were before this disfiguring dermatological illness can be seen clinically as an important determinant of how they are likely to cope with the skin disease. Basically, an individual's self-image relates to early developmental experiences, to how the young child was perceived, accepted, and taken care of within the family. A person who, as result of "good enough" parenting, believes that he or she is a good person who is competent, cared for by other people, in reasonable control of his or her life, has a healthy self-love, approves of his of her own values, and looks reasonably attractive would be

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expected to cope with a skin disease better than a person who saw himself or herself as worthless, ugly, and rejected before its onset (1,14). The fact that vitiligo is a chronic disease increases the risk that it will become a major fact in the daily lives of patients and their families. Skin lesions on the face and hands (very frequent in vitiligo) can be seen by any casual observer and may make it impossible for the patient to work, especially if the occupation requires direct interaction with the public (e.g., salesperson or child care worker). Lesions on the genitals are fraught with meaning and anguish for those afflicted. In fact, many yOllng patients with vitiligo localized on the genitals (or with particularly evident genital lesions) think they will be repugnant to a sexual partner and consider themselves obliged to make love only in the dark. The involvement of the hair bulbs (the hair is chalk white) also carries a heavy weight of embarrassment and concern. Another aspect of vitiligo that may have psychological repercussions is the treatment: PUVA treament is at present one of the most effective therapies; however, three to four treatments per week for many months are required before repigmentation from perifollicular openings is achieved. Thus, the duration of this treatment may induce the patient to embark on a "career of patienthood," connoting once more the intrusion of the disease into many aspects of daily life (15). According to Ginsburg (14) one must take into account the patient's life situation, including the social support network, attitudes of intimates, work situation, and the actual experiences of rejection. The social support network (16), consisting of family, friends, co-workers, and neighbors (but also physicians, teachers), provides emotional warmth and support as well as practical help, such as with child care or financial assistance. If a vitiligo patient has devoted friends and family, he/she probably will weather the storm of emotions and practical problems generated by this chronic skin affection much better than if this network is weak or nonexistent. The attitudes of intimates, the people closest to the patient, are among the most important determinants of the impact of skin disease, including vitiligo. Children with vitiligo (17) will deal with the disease well or be devastated by it depending on the attitude of their parents and siblings, other relatives, friends, teachers, babysitters, and so on. When parents' unconscious resentment of the demands of such children was gradually acknowledged through counseling (18), they were able to reverse the dysfunctional parent-child relationship. If parents are direct, affectionate, and understanding, without allowing themselves to be manipulated, and if they are not secretive or ashamed, the child has a good chance of growing up relatively unscathed psychologically. If the patient can work productively and experience positive relationships with co-workers and supervisors, self-esteem will be enhanced and the impact of the disease mitigated.

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People with visible disfiguring skin disease, which vitiligo can be, are extremely sensitive to the way others perceive them and often will withdraw because they anticipate being rejected. Indeed, strangers and even intimate friends can make extremely hurtful and humiliating comments. When this does happen the impact is profound: patients can experience subjective emotional distress; some seek professional help and experience interference with various aspects of employment; others use tension-lessening, oblivionproducing substances such as alcohol (1,14). The concept of disability as a result of skin disease leads to a heightened appreciation of the intrusiveness of these diseases into daily life, affecting occupational and recreational activities as well as the emotional concomitants. Ryan (19.20) proposed the concept of organ failure with regard to skin, parallel to heart failure, kidney failure, and respiratory failure. Along with protection against environmental injury, thermoregulation, and sensory perception, display is an essential function of the skin. Failure of display may result in reduced social and sexual communication and, often, social rejection, isolation, and severe disability in the afflicted person's life. In certain cultures vitiligo is a major social problem. The ex-Prime Minister of India, Nehru, ranked vitiligo as one of his country's three major medical problems, alongside malaria and leprosy. In India, a woman may have many problems and experience great difficulties in getting married if she has vitiligo, and if a woman develops vitiligo after marriage it is grounds for divorce by the husband. In India vitiligo (or leukoderma) is regarded as "white leprosy" (13). Moreover, if people do not know what macules are, fantasies about the cause and contagion may be a problem. In fact, cultural attitudes are crucial for the repertoire of feelings, thoughts, and responses that define health and disease as experienced by the person with a skin disease, as well as by the onlooker who does not have a skin disorder. Although patients may project their own self-disgust onto others, many people avoid the afflicted person or intrude with questions and unsolicited advice, sometimes making cruel and tactless comments. Such is the complexity of the psychology that patients say that if they did not have skin disease, they too would avoid people who do. The unconscious assumptions and fantasies underlying these behaviors probably relate to anxiety about maintaining control of one's psychological and physical borders, to narcissistic longings for perfection, and to guilt. In fact, when a person develops any severe or chronic ailment, they often ask: Why me? Such a thought seems to imply that the disease is experienced as a punishment, presumably caused by unconscious feelings of guilt. And it is surprising how people (our patients included) attribute skin lesions to sexual causation and contagion. The spot, the "dirty" macule that erupts onto the skin, is linked symbolically to "dirty" thoughts and wishes (generally related to sexual activities), with the skin lesions implying impurity and danger. Copyrighted Material

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The white patch of vitiligo, made even whiter by the hyperchromic border, is seen and experienced by some patients as a "strange, brilliant, reflecting white." According to one of our patients, it appears to be like an object of "extraterrestrial" origin, confirming the sensation of that certain subjects experience when they first note that "negative-like" mark on the skin, a sensation that is repeated each time the mark is seen. The threat ofa possible diffusion/extension that some subjects foresee as fatal (despite our reassurance and that of their relatives) is heightened because it is in complete opposition with the current diffuse idea that "tanned is beautiful" (for men and women) and/or the ideology predominant in mass media, art, and romantic cinema that, especially for females, seduction and attraction are favored (for these patients, these factors are conditioned sine qua non) by skin without blemishes (with all the psychological meanings implicit in a spot or blemish, even when it is white, expressing absence and negativity, but also guilt, sin or defect, lack, and, above all, diversity). The anthopologist Douglas (21), studying a New Guinea tribe, says: "Reaction to dirt is continuous with other reactions to ambiguity and anomaly which lead to anxiety and from there to suppression and avoidance. . . . A polluting man is always in the wrong. He has developed some wrong condition or simply crossed some line which should not have been crossed, and this displacement unleashes danger for someone." This concept refers back to the assumption by many onlookers that a skin disease is inherently contagious and probably of sexual origin. As Susan Sontag wrote (22): "nothing is more punitive than to give a disease a meaning-that meaning being invariably a moralistic one." This kind of thought may represent an insult to a patient's narcissism and self-integrity; thus, it is possible that shame ensues. Sometimes, deep-seated feelings of defectiveness can be intensified. Feelings about the skin lesions may be displaced onto the self as a whole, as though patients formulate the syllogism: skin lesions are ugly, and I have skin lesions; therefore I am ugly. Skin disease, even when visible only to the patients themselves (e.g., vitiligo on the genitals), implies imperfection. If a person is without blemish, whether the blemish is physical, moral, or psychological, he or she is safe from shame and humiliation. A 23-year-old female university student declared that she would never "force" her boyfriend whom she loved (he was in love with her, open, and intelligent) to bear the sight of her as she was and thus to diminish (she was sure) his amorous capacities out of disgust provoked by her "leprosy-like" skin. Above all, she added, even if the young man's sexual prowess held up and he was psychologically able to bear and overcome the situation for now, with time and the "inevitable" lessening of passion the problem would reemerge in full drama. Long-term treatment, first in consultation with us-dermatologists and psychiatrists-and then strict psychotherapy,

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together with the affectionate and comprehensive behavior of the boyfriend and, finally, the fortunate arrest of the extension of the patches with no new lesions in a year, permitted, in this very difficult case, slow acceptance by the patient of her condition and a stable couple relationship (I). In fact, the aim ofliaison consultation is close collaboration between the non psychiatric medical staff and the psychia trist. The purpose is to teach the non psychiatric physician to include psychosocial variables in patient care programs and enable him/her to deal with patients in making an integrative diagnosis. Thus, liaison psychiatric consultation with psychiatrists and/or psychologists is to be distinguished from psychiatric consultation, tout court, which the patient often does not want, indeed fears, and which could be dangerous if forced (immediate insensitive referral to a psychiatrist can even lead to suicide in especially delicate subjects). The patient has chosen the dermatologist for assistance, superficial and deep, regarding his or her surface and depths, and the dermatologist must give care using any and all treatments possible, supplying counseling, sometimes in collaboration (but in direct contact: two to one) with a psychologist or psychiatrist, even in the case of patients with vitiligo.

REFERENCES I. 2. 3. 4. 5. 6. 7.

8. 9. J O.

II. 12.

Hautmann G, Panconesi E. Vitiligo a psychologically influenced and influencing disease. Clin Dermatol 1997; 15:879-890 Ortonne JP, Bose SK. Vitiligo: where do we stand? Pigment Cell Res 1993; 6:6172 Panconesi E. Stress and Skin Diseases. Lippincott: Philadelphia, J 984. E Panconesi, Lo Stress, Ie Emozioni, la Pelle. Milano: Masson ed, 1989. Obermayer ME. Psychocutaneous Medicine. Springfield, IL: Charles C Thomas, 1955 Whitlock FA. Psychophysiological Aspects of Skin Disease. Philadelphia: WB Saunders, 1976. Griesemer RD, Nadelson T. Emotional aspects of cutaneous disease. In: Fitzpatrick 1M, Eisen AZ, Wolff K, et aI., eds. Dermatology in General Medicine. New York: McGraw-Hili, 1979:1353-1363. Lerner AB. Vitiligo. J Invest Dermatol1959; 32:285-310. Ortonne JP, Perrot H, Thivolet J. Etude c1inique e statistique d'une population de 100 vitiligos. Sem Hop 1976; II :679-686. Conaze J, Dupre A. Apercus psychosomatiques sur Ie vitiligo. Bull Soc Franc Derm Syph 1974; 81 :532-534. Bassi R. La Ragazza che Odiava gli Specchi. Torino: Bollati Boringbieri, 1996: 165 Porter JP, Beuf A, Nordlund 11, Lerner AB. Personal responses of patients to vitiligo. Arch Dermatol1978; 114:1384-1385.

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16. 17. 18. 19. 20. 21. 22.

Fitzpatrick TB. The scourge of vitiligo. Fitzpatrick's J Clin Dermatol 1993; Nov-Dec, 68-69. Ginsburg IH. The psychological impact of skin disease: an overview. DermatoJ Clin 1996; 14:473-484 Jobling R. Learning to live with it: an account of a career of chronic dermatological illness and patienthood. In: Davis A, Horobin G, eds. Medical Encounters. The Experience of Illness and Treatment. New York: St. Martin's Press, 197783. Greenblatt M, Becerna RM, Sorafetinides EA. Social networks and mental health: an overview. Am J Psychiatry 1982; 139:977-983 Hill-Beuf A, Porter JDR. Children coping with impaired appearance. Social and psychologic influences. Gen Hosp Psychiatry 1984; 6:294--300 Koblenzer CS. Chronic intractable atopic eczema. Arch Dermatol 1988; 124: 1673-1675. Ryan TJ. The confident nude or whither dermatology. Dermatol Pract 1987; 5:812. Ryan TJ. Disability in dermatology. Br J Hosp Med 1994; 46:33-38. Douglas M. Purity and Danger, an Analysis of the Concept of Pollution and Taboo. London, AK, 1984. Sontag S. Illness as Metaphor. New York: Vintage Books, 1978:3.

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20 Therapeutic Guidelines for Vitiligo M. D. Njoo Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands W. Westerhof Academic Medical Centre, University of Amsterdam, and Netherlands Institute for Pigment Disorders, Amsterdam, The Netherlands

It is regrettable that many physicians consider vitiligo a trivial cosmetic skin disorder and tell the patients they should just live with their pigmentary disorder and that any treatment for it is a waste of time and effort. Due to this fatalistic attitude the patients are discouraged from seeking therapy. Therefore a positive approach to the patient by explaining to them the nature of the disease process, the likely prognosis, and the treatment options with expected results is recommended. Although there is still no therapeutic panacea for vitiligo, many options may lead to satisfactory results in most patients. A review of the literature is presented to discuss the efficacy and safety of some classical and some interesting new therapies. Finally, evidence-based guidelines for the treatment of vitiligo are presented.

NONSURGICAL REPIGMENTATION THERAPIES Narrowband UV-B Narrowband fluorescent tubes (Philips TL-O I/ I 00 W) with an emission spectrum of 310-315 run and a maximum wa velength of 311 nm are used for this

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therapy (1-3). The starting dose is 250 mJjcm 2 (for all skin types), which is increased 10-20% until minimal erythema occurs in the depigmented areas. Because some parts of the body (sllch as the face) may reach minimal erythema faster than others, different dosimetry per body region may be needed. Treatment frequency is twice weekly and never on two consecutive days. The advantages of narrowband UV-B over oral psoralen plus UV-A (PUVA) therapy include shorter treatment times, no oral drugs required (no systemic effects), no drug costs, fewer burning incidents, no hyperkeratosis seen after long-term irradiation, less contrast formation between depigmen ted and normal pigmented skin, no need for posttreatment eye photoprotection, and safe use in children and pregnant and lactating women (4). Short-term side effects of narrowband UV -8 may include pruritus and xerosis cutis (1,2). This can be treated with emollients. Long-term side effects of narrowband UV-B are unknown. The mechanisms of UV-B-induced repigmentation in vitiligo are still being investigated. Narrowband UV-B is becoming more popular than oral PUVA because of the frequently observed short- and long-term side effects of oral PUVA. Narrowband UV-B is considered the first-line therapy for adults and children (>6 years old) with generalized vitiligo. Psoralen Plus UV-A

Psoralen photochemotherapy consists of the combined use of the photosensitizing chemical compound psora len and UV radiation to induce a beneficial effect not produced by either alone. Psoralens can be applied either topically or orally, followed by exposure to either artificial UV or natural UV (PUVASOL) (5). Most often used in modern vitiligo treatment are methoxsalen or 8-methoxypsoralen, bergapten or 5-methoxypsoralen, trioxsalen or 4,5',8-trimethylpsoralen, and unsubstituted psoralen (PS) (Fig. 1). The UV dose is gradually increased until minimal asymptomatic erythema of the depigmented skin occurs. Treatments are given twice weekly. UV-blocking sunglasses should be worn for 8 hours after the psoralen is taken orally and during the next day when exposed to natural sunlight. Absolute contraindications for PUVA therapy include skin type I, skin malignancies, and pregnant or lactating females (for oral PUVA). Relative contraindications are patients younger than 12 years (for oral PUVA) (6,7). Short-term cutaneous side effects of PUV A therapy are increased contrast formation between normal pigmented skin and lesional skin, photo toxic reactions (from erythema to blisters and burns), pruritus, xerosis cutis, and Koebner phenomenon (7). Short-term systemic side effects are only observed with oral PUV A and may include nausea, vomiting, mild epigastric discomfort, headaches, dizziness, (transient) elevation of liver function tests, insom-

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FIGURE 1 Results of one-year narrowband UV-B therapy in a child with generalized vitiligo.

nia, nervousness, fatigue, and drowsiness (7). Long-term effects of PUVA therapy have also been described (7). Most commonly reported are lichenification, desquamation, telangiectasia, lentigines or freckles, leukoderma punctata, aging, wrinkling, and skin malignancies. Cataract is related only to the use of oral PUVA. The major advantages of topical PUVA over oral PUVA therefore include lower required UV -A doses and lack of systemic and ocular toxicity (5). Because of the possible side effects, pretreatment diagnostic tests such as liver and renal function tests and ophthalmological examination should be repeated annually (5). Several studies ha ve indicated that PUVA therapy is probably beneficial via a variety of complex mechanisms. Light microscopic and ultrastructural studies have shown that PUVA stimulates hypertrophy (increase in size), proliferation, and enzymatic activity of the melanocytes residing in the outer root sheath of hair follicles as well as melanocytes located at the margins of vitiliginous lesions (8-11). Repigmentation is therefore regarded as the result of the migration of these stimulated melanocytes into the depigmented skin areas (12). Another study suggested that PUVA therapy may elicit the release of a certain melanocyte-stimulating growth factor that is capable of stimulating melanocyte proliferation in vitiligo (13). It is also suggested that PUVAinduced repigmentations are at least in part immunologically mediated. Investigators found that the so-called vitiligo-associated melanocyte antigens

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(14) and antimelanocyte antibodies (15) were decreased after a course of PUVA therapy. Broadband UV-B

The results of this phototherapeutic modality in the treatment of vitiligo were first reported in 1990 by Koster and Wiskemann (16). Surprisingly, no phototoxic reactions were observed. However, caution is needed during the UV-B dose increments because it is known that shorter wavelengths are responsible for erythema formation in the skin. According to the German study, broadband fluorescent tubes (Philips TL- 12, Westinghouse FS, Waldmann UV-6 or UV-21) with an emission spectrum of290-320 nm can be used. Thestart dose is 20 mJ/cm 2 (for all skin types), which should be increased by 20% until lesional minimal erythema occurs. Patients are treated twice to thrice weekly. Short-term side effects may include erythema, pruritus, and xerosis cutis. The shorter wavelengths of broadband UV-B may more rapidly and frequently lead to erythema reactions when compared to narrowband UV-B. Long-term side effects of broadband UV-B are unknown. The mechanisms of action of broadband UV-B in vitiligo are unknown. Long-Term Cancer Risk of Photo(chemo)therapy in Vitiligo

There is a reluctance among dermatologists to prescribe prolonged photo(chemo)therapy as it may increase the risk for carcinogenesis in the long term, as observed in patients with psoriasis (17). In patients with psoriasis, longterm PUVA therapy was found to be associated with an increased risk for skin cancer, especially squamous cell carcinoma (SeC) (18). Based on epidemiological data, a statistically increased incidence of nonmelanoma skin cancer has been observed in patients who had received a cumulative UV-A dose exceeding 1000 J/cm 2 More recently, Stern et al. also found the risk of melanoma to be increased among those receiving at least 250 PUVA treatments (19). These findings cause concern, but remarka bly, a similar increased risk for these skin cancers has not been documented among patients with vitiligo (20,21). Patients with vitiligo receiving photo(chemo)therapy do not have a higher risk of developing skin cancer than do patients with psoriasis-the risk may even be lower. Unlike patients with psoriasis, those with vitiligo do not expose themselves to extra sun rays (most patients use sun-protective agents), do not use tar preparations, cytostatic drugs (methotrexate), or immunosuppressive drugs (cyclosporine), and receive lower cumulative PUVA or UV-B doses. To date, only two vitiligo patients have been described with squamous

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cell carcinoma after oral PUV A therapy (22,23). A striking aspect of these cases was that the time between the start of oral PUVA therapy and the development of the skin cancer was only 3 years, which is a relatively short time for tumor induction in general. This suggests that these two cases may have suffered from a defective DNA repair mechanism and/or an abnormal immune surveillance. In daily clinical practice, some precautions can be undertaken to minimize the risk of cancer in duction by photo(chemo) therapy. First, the "skinsaving principle" can be applied: parts of the body where no lesions are present (especially the face) should be shielded during treatments. Also, parts that have repigmented satisfactorily should, if possible, be shielded during subsequent treatments (for example, by wearing trousers). Genitals should also be shielded, because genital tumors have also been observed after PUVA therapy (18) and beca use these areas, as a rule, do not respond to photo(chemo)therapy (20). Other safety measures include the prevention of unnecessary exposure to natural sunlight on both treatment and non treatment days and the use of UV-blocking agents on sun-exposed areas. Until more epidemiological data become available, we suggest that recommendations for vitiligo patients regarding safe maximum cumulative PUVA doses and safe maximum number of UV-B treatments follow those advised for psoriasis patients: 1000 J/cm '(2,24) and 300 treatments (25), respectively.

Other Forms of Photo(chemo)therapy According to the results of our meta-analysis, other forms of photochemotherapy, such as khellin plus UV-A or phenylalanine plus UV-A, are not effective and/or are associated with side effects. These modalities are not recommended for vitiligo and are therefore not mentioned in this review.

Corticosteroids Corticosteroids can be administered in different ways: topically (26-28), intralesionally (29), and orally (30-34). Low-, mid-, and high-potency preparations have been used. The mechanism of action of corticosteroids in vitiligo is unclear. It is often assumed that corticosteroids suppress inflammatory processes that are frequently observed in active progressing lesions (35). The use of oral corticosteroids was associated with decreased serum levels of antimelanocyte antibodies among patients with active vitiligo (36,37). It is not known whether the corticosteroids used in the clinical studies in vitiligo have a direct stimulating effect on melanocyte division and migration. Furthermore, it is striking that the best results are achieved on sun-exposed areas (such as Copyrighted Material

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face and neck). Both perifollicular as well as perimarginal repigmentation patterns can be seen with corticosteroids. Because most studies were not controlled, (unintentional) UV exposure may also have contributed to the repigmentations associated with the use of these corticosteroids. Regular follOw-up visits are needed to monitor the well-known corticosteroid-induced local and systemic side effects.

AUTOLOGOUS TRANSPLANTATION METHODS

In general, autologous transplantation methods are only indicated after medical treatment has failed. These methods can be used in combination with medical and/or irradiation therapies. Transplantation may also be considered as a first option to treat patients with stable and/or focal (segmental) vitiligo. Autologous transplantation of melanocytes should not be regarded as a causal therapy. Even after a successful grafting, depigmentation of the grafts may still occur when reactivation of the disease takes place. All procedures can be performed under local anesthesia. The general selection criteria for autologous transplantation methods are (38,39): 1. 2. 3. 4. 5. 6.

Resistance to medical therapy Stable vitiligo Absence of the Koebner phenomenon Positive minigrafting test No tendency for scar or keloid formation Patient older than 12 years

Minigrafting (Fig. 2)

Two mm full thickness punch grafts are harvested [rom normally pigmented donor sites (such as the hip, buttocks, and outer thigh) and are subsequently transplanted to depigmented acceptor sites in which similar punched-out skin had been removed. The grafts are placed 5-8 mm apart and are covered with a transparent adhesive tape. Subsequently, grafted areas are irradiated with UV -A (10 J/cm 2) twice a week to promote the outgrowth o[ pigment cells from the minigrafts. A [acial tanner or a sunbed can be used as the UV-A light source that can be performed at home. Pigment can be observed concentrically migrating, within a maximum diameter 0[8 mm, [rom the grafts into the depigmented skin within 8 weeks following transplantation (40). Complications at the donor site may include light scarring, postinflanimatory hyper- or hypopigmentation, and infection. At the recipient site, cob-

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FIGURE 2 The minigrafting technique to repigment localized and stable vitiligo patches, (a) before and (b) after the treatment.

blestone-effect or variegated appearance of the grafts, sinking pits, and infection have been observed as adverse effects (40).

Thin Split-Thickness Skin Grafting The recipient area is dermabraded with a diamond burr until uniform pinpoint capillary bleeding occurs. A very thin split-thickness epidermal graft (0.1-0.15 mm thick) is then removed from a normally pigmented donor area (usually the hips or buttocks) with an electrically driven dermatome. As an alternative, the same dermatome can also be used to remove the lesional recipient skin instead of dermabrasion. The maximum size of the grafts is about 150 cm 2 The graft is gently placed onto the dermabraded achromic areas. Donor areas are covered with dry sterile gauzes and an adhesive foil. Wound dressings of the recipient area consist of sterile suture strips, sterile gauze impregnated with an antibiotic, dry sterile gauze, and adhesive bandage. After removal of the wound dressings after 2 weeks, the grafted area and the donor site can be irradiated with UV-A twice weekly to promote repigrnentation (41). At the donor site, light scarring, postinflammatory hyper- or hypopigmentation, and infection may occur as adverse effects. Milia, hematoma, Copyrighted Material

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thick graft margins, wrinkles in graft, and infection are possible complications at the recipient site (41). Grafting of Epidermal Blisters

For this method, a suction blister apparatus that is capable of exerting 200 mmHg negative pressure to separate the epidermis from the dermis at the normally pigmented donor skin is essential (42). Two days before transplantation, blistering of the depigmented lesion is induced using liquid nitrogen or topical psoralens plus UV-A therapy. After blister formation, the depigmented epithelium is removed and the roofs of the pigmented donor blister are grafted to the denuded lesional areas. Scarring does not occur at the donor site. Infection is sometimes seen at the recipient site. Grafting of Cultured Autologous Melanocytes

During this procedure, autologous melanocytes are expanded by in vitro culturing techniques and transplanted into a previously denuded achromic skin area. This is an expensive technique that requires special laboratory expertise. However, it may represent an adequate method to repigment larger vitiliginous skin areas in the future. There are several methods to obtain cultured autologous melanocytes. Grafting of Pure Melanocytes. Autologous melanocytes are grown for a period of 4 weeks in a special medium containing 12-0-tetradecanoyl-phorbol 13-acetate (TPA), cholera toxin (CT), and isobutylmethylxanthine (IBMX). Then suction blistering is performed in the recipient achromic sites. The cultured melanocytes are then injected into the blister cavities. Using this method, Lerner et a1. in 1987 observed a satisfying degree of repigmenta tion in two patients with piebaldism (43). Because TPA is a potent tumor promoter, the safety of this medium remains questionable. Therefore, culturing of melanocytes in physiological reagents is highly recommended (43,44), but this is very expensive. Grafting of M elanocvtes Mixed with Keratinocytes (45-48). Autologous melanocytes and keratinocytes are mixed cultured on a collagen-coated membrane for 2 weeks. The membrane is then transplanted into dermabraded or liquid nitrogen denuded Vitiliginous skin. After 1-2 weeks the collagen membrane detaches from the graft spontaneously. Repigmentation in the graft gradually occurs 2-6 months after the day of transplantation. A major advantage is that TPA or cholera toxin is not required. In mixed cultures, the essential melanocyte growth factors are provided by the keratinocytes. In

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some cases the treated skin area appears lighter than the normal pigmentation because the number of the grafted melanocytes is too low. The recipient area may also show light hypertrophic scarring or atrophy. At the donor si te, slight scarring, postinflammatory hyper- or hypopigmentation, and infection are possible adverse effects. The recipient site is sometimes complicated by improper color matching and infection. Grafting of Noncultured Melanocyte Suspension More simplified methods of grafting of fresh epidermal cell suspensions bearing melanocytes have also been successfully used to repigment vitiligo maCltles. After trypsinization ofa shave biopsy taken from the occipital area, Gauthier and Surleve-Bazeille injected a suspension containing keratinocytes and melanocytes into liquid nitrogen blisters induced within the vitiligo macules (49). Olsson and Juhlin modified the technique in 1998 (50). They took a shave biopsy from the buttocks, separated the cells, and concentrated the melanocytes in vitro. The final suspension, containing the basal layer and about half of the stratum spinosum, was subsequently applied to dermabraded vitiliginous areas with a size 8-10 times larger than the donor area. Slight scarring, postinflammatory hyper- or hypopigmentation, and infection may complicate the donor site. Improper color matching and infection can sometimes be seen at the recipient site.

DEPIGMENTATION THERAPY For patients with extensive areas of depigmentation (>80%) and/or disfiguring lesions on the face who do not respond to repigmentation therapies, depigmentation of the residual melanin should be considered. These patients should be informed that bleaching or removal of the remaining pigmentation is a permanent and irreversible process. During and upon completion of the therapy, patients are permanently at risk for acquiring sunburn from acute solar irradiation. Patients must therefore be advised to minimize sun exposure and to apply broad-spectrum sunscreens. Bleaching Agents Monobenzylether of hydroquinone (MBEH) is nowadays mostly applied to remove residual melanin in patients with vitiligo universalis. MBEH is a potent melanocytotoxic agent. The modes of actions are diverse and are well summarized elsewhere (51). Loss of pigment can also occur at distant sites of application. The mechanism behind this phenomenon is unclear (52). Copyrighted Material

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The treatment should start with a single daily application to a test spot. Ifno adverse reactions occur, greater skin areas can be gradually treated with a frequency of once to twice daily. It normally requires 1-3 months to initiate response (52). Depending on the percentage of the residual pigmentation, 6 months to 2 years may be required to complete the therapy. Patients must avoid direct contact of the treated area with untreated skin or with normal pigmented skin of other individuals (partners) for at least 2~3 hours after application of the cream. In the Netherlands, 4-methoxyphenol (monomethyl ether of hydroquinone or 4-hydroxyanisole) in a 20% cream can be used as an alternative to MBEH (53). Short-term side effects are (contact) dermatitis, pruritus (54), and corneal and conjunctival melanosis (55). Long term, leukomelanoderma en confetti and exogenous ochronosis may occur as adverse effects (56). These long-term effects have not yet been reported in patients with vitiligo universalis.

Laser Therapy

Another form of depigmentation therapy for vitiligo has also been developed, making use of a Q-switched ruby (QSR) laser apparatus. The QSR laser beam with a wavelength of 694 nm is capable to selectively destroy melanin and melanin-containing structures in the skin. As a result, the risk for scar formation is minimal (57). Depigmentation by laser therapy is reported to achieve faster depigmentation, compared with depigmentation using a bleaching agent (53,57). On the other hand, some health insurance companies do not reimburse the treatment costs, so that some patients cannot afford this therapy. Since laser treatment is thought to cause depigmentation by koebnerization, patients with a negative Koebner phenomenon will not respond to this therapy.

NOVEL THERAPEUTIC APPROACHES Fluticasone Propionate plus UV-A Therapy

A recent study showed that combination therapy using a potent corticosteroid (ftuticasone propionate) applied once daily and UV-A irradiation (10 2 J/cm ) performed twice weekly is an effective and safe method to repigment localized vitiligo lesions (58). The combination therapy led to a higher percentage of repigmentation than either ftuticasone propionate or UV-A alone. Perifollicular and marginal repigmentation could be observed as soon as 6 weeks after the start of therapy in both adult and pediatric patients. After 9 months of therapy, clinical and histological examinations revealed no signs of

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atrophy or telangiectasia in the treated skin. A major benefit of this modality is that it can be performed easily at home using UV-A tanning equipment (e.g., a facial tanner) as the light source.

Focused Microphototherapy The clinical effects of focused microphototherapy have been studied since 1990 by a group of investigators in Milan, Italy (59). For this form of phototherapy, UV-B light with a spectrum of280-315 n111 is used. The skin is prepared by application of water and glycerin to facilitate the penetration of the UV-B rays in the skin. Subsequently, a dark pad with 2 111m holes is applied to the skin. The light is shined through the holes and causes a mild to moderate burn on the skin. Treatments are given daily for a week and thereafter several times weekly or twice a month. In addition, the therapy requires a highly advanced computer program and a videocamera to control and to monitor the UV-B-delivering equipment. The results of the study showed that the more frequent the treatments, the more rapid the pigment returns. About 25% of the patients experience excellent results, having most oftheir pigment back, whereas 50% have only moderate repigmentation. As with other forms of photo(chemo)therapy, acral sites of the body reveal a poor response. It is regarded as a major advantage that, by using the focused microphototherapy, only depigmented skin can be treated so that unaffected skin areas are not unnecessarily exposed to UV-B irradiation. In this manner, contrast formation between the depigmented and the normal pigmented skin can be avoided. However, this therapy requires expensive equipment and trained personnel and will therefore not be available for many patients around the world.

Pseudocatalase plus UV-B Therapy Based on the results of oxidative stress and calcium dysregulation in vitiligo, a substitute for depleted catalase together with calcium, a new topical treatment modality has been developed. A low molecular weight manganese complex (MW 328) has been synthesized that functions effectively to remove hydrogen peroxide from patients. Intracellular matrix concentrations of calcium are adjusted with 10- 2 M calcium chloride. Therapy involves a twice-daily application of pseudocatalase cream and a suberythemal dose of UV-B light twice a week. The treatment yielded more than 90% repigmentation of hands and faces in a pilot study with 33 patients (60). However, this study was uncontrolled, and it is unknown whether the observed repigmentation should be attributed to pseudocatalase alone, to the combination of the substance with UV-B therapy, or to UV-B therapy alone. Copyrighted Material

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Systemic Antioxidant Therapy

Based on the antioxidant theory, a clinical trial is being performed in Italy using the oral administration of compounds such as ubiquinone, vitamin E, selenium, and methionine (61). It is unknown whether this trial has included a placebo group. The rationale to use these substances for vitiligo is controversial; antioxidants are also used as alternative forms of therapy for a variety of disorders, although their mechanism of action is unknown and probably nonspecific. Melagenine and Infrared and/or UV Radiation

Melagenine is a hydroalcoholic extract of the human placenta that is synthesized in Cuba (62). Topical melagenine in combination with infrared radiation or exposure to natural sunlight have been reported to be effective for the treatment of vitiligo. However, this could not be confirmed by other investigators (63). Not much is known about the biochemistry, biological activity, or pharmacology of this drug. Melagenine may contain a lipoprotein that stimulates melanogenesis and melanocyte proliferation. To date there seems to be poor quality control in the production of this drug (64). Grafting of Follicular Melanocytes

Repigmentation of leukotrichia in vitiligo has been achieved using epidermal blister grafting in combination with oral PUVA by Halm et al. (65) and using a single hair grafting technique by Na et al. (66). These observations suggest that epidermal melanocytes could migrate or transfer to the hair follicle. Direct evidence for such a mechanism has not yet been provided. Because outer root sheath (ORS) melanocytes constitute a natural reservoir for the repigmentation process in vitiligo, they may be useful for grafting purposes. Further studies are needed to investigate the therapeutic possiblities of such techniques in vitiligo.

EVIDENCE-BASED GUIDELINES FOR THE TREATMENT OF VITILIGO

We have performed a meta-analysis of the literature in order to position, in relation to each other, currently available forms of nonsurgical and surgical repigmentation therapies and depigmentation therapies in terms of their effectiveness and safety profiles (67,68). A treatment was regarded as being successful when more than 75% repigmentation was observed. Based on the

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results of these studies, treatment with a potent local corticosteroid is advised for patients with localized vitiligo [mean success rate, 56% and 95%, respectively; confidence interval (CI), 50-62%]. When patients exhibit generalized vitiligo, UV-B therapy is recommended (mean success rates, 63% and 95%, respectively; CI, 50-76%). However, there were no statistical differences in the success rates of oral PUVA, narrowband UV-B, and broadband UV-B. With regard to autologous transplantation methods, splitthickness skin grafting and epidermal blister grafting can be recommended as the most effective and safest techniques (mean success rates, 87%, 95%; CI, 82-91 %; and mean success rates, 87%, 95%; CI, 83-90%, respectively). Minigrafting had the highest rates of adverse effects, but was shown to be the easiest, fastest, and least expensive method. No definite conclusions can be drawn with regard to the effectiveness of culturing techniques, because only a small number of patients have been studied. The choice of method also depends on certain disease characteristics and the availability of specialized personnel and equipment. During formal consensus meetings, the results of these studies were discussed, and evidence-based guidelines for the treatment for vitiligo have been developed. The guidelines consist of a treatment scheme. Recommendations regarding first and alternative choices are given according to the age of the patient, clinical type, severity of disease, and disease activity. In all cases, advice regarding the use of camouflage and sunblocking agents should always be given. If necessary, psychological counseling may be recommended. These guidelines were disseminated and implemented at the Netherlands Institute for Pigment Disorders and the Department of Dermatology of the Academic Medical Center in Amsterdam, the Netherlands (69). The literature studies have also identified some shortcomings in current vitiligo research. So far, only a few randomized controlled trials (RCTs) have been performed for patients with localized as well as generalized forms of vitiligo. Some recommendations in our guidelines are based on data from noncontrolled studies. RCTs are regarded as the "best available scientific evidence." The inclusion of the results of such trials into practice guidelines can increase the strength and validity of treatment recommendations. Physicians would also feel more confident with guidelines that contain the best available evidence. More RCTs should therefore be performed in future.

REFERENCES I. 2.

WesterhofW, Nieuweboer-Krobotova L. Treatment of vitiligo with narrowband UV-B versus topical psoralen plu UV-A. Arch Dermatol 1997; 133:1525-1528. Njoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children

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3. 4.

5. 6. 7. 8.

9. 10. II.

12. 13.

14.

15.

16. 17.

18.

19.

with narrowband (TL-OI) UV-B radiation therapy. J Am Acad Dermatol 2000; 42:245-253. Scherschun L, Kim JJ, Lim HW. Narrowband ultraviolet B is a useful and well tolerated treatment for vitiligo. J Am Acad Dermatol 2001; 44:999-1003. British Photodermatology Group. An appraisal of narrowband (TL-OI) UV-B phototherapy. British Photodermatology Group Workshop Report (April 1996). Br J Dermatol1997; 137:327-330. Grimes PE. Psoralen photochemotherapy for vitiligo. Clin Dermatol 1997; 15: 921-926 Drake LA, Ceilley RI, Dorner W, et a1. Guidelines of care for phototherapy and photochemotherapy. J Am Acad Dermatol 1994; 31:643-653. Gupta AK, Anderson TF. Psoralen photochemotherapy. J Am Acad Dermatol 1987; 17:703-734 Ortonne JP, MacDonald DM, Micoud A, Thivolet J PUVA-induced repigmentation of vitiligo: a histochemical (split-DOPA) and ultrastructural study. Sr J Dermatol 1979; 101:1-12. Ortonne JP, Shmitt D, Thivolet J. PUVA-induced repigmentation of vitiligo: scanning elctron microscopy of hair follicles. J Invest Dermatol 1980; 74:40-42. Cui J, Wang Gc. Role of hair follicles in the repigmentation of vitiligo. J Invest Dermatol 1991; 97:410-416. Horikawa T, Norris DA, Johnson TW, et a1. DOPA-negative melanocytes in the outer root sheath of human hair follicles express premelanosomal antigens but not a melanosomal antigen or the melanosome associated glycoproteins tyrosinase TRP-I and TRP-2. J Invest Dermatol1996; 106:28-35. Norris DA, Horikawa T, Morelli JG. Melanocyte destruction and repopulation in vitiligo. Pigment Cell Res 1994; 7: 193-203. Abdel Naser MB, Hann SK, Bystryn JC. Oral psoralen with UV-A therapy releases circulating growth factors that stimulate cell proliferation. Arch Dermatol 1997; 133:1530-1533 Kao C, Yu H. Comparison of the effect of 8-methoxypsoralen (8-MOP) plus UVA (PUV A) on human melanocytes in vitiligo vulgaris and in vitro. J Invest Dermatol 1992; 98:734--740. Hann SK, Shin HK, Song MS, Park YK. The effect of systemic PUVA on the proliferation of melanocytes and the titer of anti-pigment cell autoantibodies in patients with vitiligo. Korean J Dermatol 1997; 35:57-70. Koster W, Wiskemann A. Phototherapy with UV-B in vitiligo. Zeitschr Hautkrank 1990; 65:1022-1024. Njoo MD, Bossuyt PMM, Westerhof W. Management of vitiligo. Results of a questionnaire among dermatologists in The Netherlands. Int J Dermatol 1999; 38:866-872. Stern RS. Lange R, Members of the photochemotherapy follow-up study. Nonmelanoma skin cancer occuring in patients treated with PUVA five to ten years after first treatment. J Invest Derma tol 1988; 91: 120-124. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUV A). N Engl J Med 1997; 336:1041-1045.

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21. 22. 23. 24. 25. 26.

27. 28. 29. 30. 31. 32.

33. 34. 35.

36.

37. 38.

39.

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Nordlund 11, Ortonne JP. Vitiligo vulgaris. In: Nordlund JJ, Boissy RE, Hearing VJ, King RA, Ortonne JP, eds. The Pigmentary System. Physiology and Pathophysiology. New York: Oxford University Press, 1998:513-514. Lindelof B, Hedblad MA, Sigurgeirsson B. On the association between vitiligo and malignant melanoma. Acta Derm Venereol (Stockh) 1998; 78:483-484. Buckley DA, Rogers S. Multiple keratoses and squamous carcinoma after PUVA treatment of vitiligo. Clin Exp Dermatol 1996; 21:43-45. Takeda H, Mitsuhashi Y, Kondo S. Multiple squamous cell carcinomas in situ in vitiligo after long-term PUVA therapy. J Am Acad Dermatol 1998; 38:268-270. British Photodermatology Group. British Photodermatology Group guidelines for PUVA. Br J Dermatol 1994; 130:246-255. Studniberg HM, Weller P. PUVA, UV-B, psoriasis and nonmelanoma skin cancers. J Am Acad Dermatol1993; 29:1013-1022. Koopmans-van Dorp B, Goedhart-van Dijjk B, Neering H, van Dijk E. Treatment of vitiligo by local application of betamethasone 17-valerate in a dimethyl sulfoxide cream base. Dennatologica 1973; 146:310-314. Bleehen SS. The treatment of vitiligo with topical corticosteroids. Light and electronmicroscopic studies. Br J Dermatol 1976; 94(suppl 12):43-50. Kumari J. Vitiligo treated with topical c1obetasol propionate. Arch Dermatol 1984; 120:631-635. Kandil E. Treatment of localized vitiligo with intradermal injections of triamcinolonacetonide. Dermatologica 1970; 140: 195-206. Moon TK, 1m SB, Hann SK, Cho SH, Park YK. The effect of small doses of oral cortico steroids in vitiligo patients. Korean J Dermatol 1995; 33:880-885. Kim SM, Lee HS, Hann SK. The efficacy of low-dose corticosteroids in the treatment of vitiligo. Int J Dermatol 1999; 38:546-550. Pasricha JS, Khaitan BK. Oral mini-pulse therapy with betamethasone in vitiligo patients having extensive or fast-spreading disease. Int J Dennatol 1993; 32:753757. Kanwar AJ, Dhar S, Dawn G. Oral minipulse therapy in vitiligo. Dennatologica 1995; 190:251-252. Radakovic-Fijan S. Furnsinn-Friedl AM, Honigsmann H. Oral dexamethasone treatment for vitiligo. J Am Acad Dermatol2001; 44:814-817. Xunquan L, Changgeng S, Peiying J, Huaiqu W, Gan-yun Y, Yawalkar S. Treatment of localized vitiligo with Ulobetasol cream. Int J Dermatol 1990; 29:295-297 Hann SK, Kim HI, 1m S, Park YK, Cui J, Bystryn Jc. The change of melanocyte cytotoxicity after systemic steroid treatment in vitiligo patients. J Dermatol Sci 1993; 6:201-205 Hann SK, Chen D, Bystryn Jc. Systemic steroids suppress antimelanocyte antibodies in vitiligo. J Cut Med Surg 1997; 14:193-195. Falabella R, Arrunategui A, Barona MI, Alzate A. The minigrafting test for vitiligo: detection of stable lesions for melanocyte transplantation. J Am Acad Dermatol 1995; 32:228-232. WesterhofW, Boersma B. The minigrafting test for vitiligo: detection of stable lesions for melanocyte transplantation. JAm Acad Dermatol 1995; 33: 1061-1062.

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250 40.

4 I.

42. 43. 44. 45.

Njoo and Westerhof Boersma BR, Westerhof W, Bos JD. Repigmentation in vitiligo vulgaris by autologous minigrafting: results in nineteen patients. JAm Acad Dermatol 1995; 33:990-995. Njoo MD, Nieuweboer-Krobotova L, Westerhof W. Repigmentation of leukodermic defects in piebaldism by dermabrasion and thin split-thickness skin grafting in combination with minigrafting. Br J Dermatol 1998; 139:829-833. Falabella R. Epidermal grafting. An original technique and its application in achromic and granulating areas. Arch Dermatol 1971; 104:592-600. Lerner AB, Halaban R, Klaus SN, Moellmann G. Transplantation of human melanocytes. J Invest Dermatol 1987; 89:219-224. Olsson MJ, Juhlin L. Transplantation of melanocytes in vitiligo. Br J Dermatol 1995; 132:587-591. Falabella R, Escobar C, Borrero I. Transplantation of in vitro cultured epidermis bearing melanocytes for repigmenting vitiligo. J Am Acad Dermatol 1989; 21: 257~264.

46.

47.

48.

Plott RT, Brysk MM, Newton RC, Raimer SS, Rajaraman S. A surgical treatment for vitiligo: autologous cultured-epithelial grafts. J Dermatol Surg Oncol 1989; 15:1161-1166. Andreassi L. Pianigiani E, Andreassi A, Taddeucci P, Biagioli M. A new model of epidermal culture for the surgical treatment of vitiligo. Int J Dermatol 1998; 37:595-598 Guerra L, Capurro S, Melchi F, Primavera G, Bondanza S, Cancedda R, Luci A, de Luca M, Pellegrini G. Treatment of stable vitiligo by timedsurgery and transplantation of cultured epidermal autografts. Arch Dermatol 2000; 136: 1380~1389.

49.

50. 51. 52.

53.

54.

55.

56.

Gauthier Y, Surleve-Bazeille JE. Autologous grafting with noncultured melanocytes: a simplified method for treatment of depigmented lesions. J Am Acad Dermatol 1992; 26:191-194. Olsson MJ, Juhlin L. Leucoderma treated by transplantation of a basal layer enriched suspension. Br J Dermatol 1998; 138:644-648. Nordlund JJ. Vitiligo. In: Thiers BH, Dobson RL, eds. Pathogenesis of Skin Disease. New York: Churchill Livingstone, 1986:99-127. Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzylether of hydroquinone. A retrospective study of treatment of 18 vitiligo patients and a review of the literature. Br J DermatoI1977; 97:669-679. Njoo MD, Vodegel RM, Westerhof W. Depigmentation therapy in vitiligo universalis with 4-methoxyphenol and the Q-switched ruby laser. J Am Acad Dermatol 2000; 42760-769. Nordlund JJ, Forget B, Kirkwood J, Lerner AB. Dermatitis produced by applications of 1l10nobenzone in patients with active vitiligo. Arch Dermatol 1985; 12l:J 141-1144. Hedges TR, Kenyon KR, Hanninen LA, Mosher DB. Corneal and conjunctival eRects of monobenzone in patients with vitiligo. Arch Ophthalmol 1983; 101 :6468. Snider RI, Thiers BH. Exogenous ochronosis. J Am Acad Dermatol 1993; 28: 662-664

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Therapeutic Guidelines for Vitiligo 57. 58.

59.

60.

61.

62. 63.

64. 65. 66. 67.

68.

69.

251

Thissen M, WesterhofW. Laser treatment for further depigmentation in vitiligo. lnt J Dermatol 1997; 36:386-388. Westerhof W, Nieuweboer-Krobotova L, Mulder PGH, Glazenburg EJ Leftright comparison study of the combination f1uticasone propionate and UV-A vs either f1uticasone propionate or UV-A alone for the long-term treatment of vitiligo. Arch Dermalol 1999; 135:1061-1066. Lotti T, Rebora A. Vitiligo therapy: The Ratok terapia. Clinical assessment of focussed microphotostimulation treatment by means of the Ratokderm equipment and method during five years (1990-1995). Vitiligo Special 1998. Schallreuter KU, Wood JM, Lemke LR, et al. Treatment of vitiligo with a topical apllication of pseudocatalase and calcium in combination with short term UY-B exposure. Dermatology 1995; 190:223-229. Maresca Y, Roccella M, Rocella F, et al. Increased sensitivity to peroxidative agents as possible pathogenetic factor of melanocyte damage in vitiligo. J Invest Dennatol 1997; 109:310-313. Cao CM. Melagenine: a Cuban product. A new and effective drug for the treatment of vitiligo. Series of National Reports, Republic of Cuba, Havana, 1986. Souto MG, Manhaes, Milhomens CH, Succi ICB. Estudo comparativo entre melagenina e placebo no tratamento do vitiligo. Bras Dermatol Rio de Janeiro 1997; 72:237-239 Nordlund JJ, Halder R. Melagenina. An analysis of published and other available data. Dermatologica 1990; 181:1-4. Hann SK, 1m S, Park YK, Hur W. Repigmentation of leukotrichia by epidermal grafting and systemic psoralell plus UYA. Arch Dermatol 1992; 128:998-999. Na GY, Seo SK, Choi SK. Single hair grafting for the treatment of vitiligo. J Am Acad Dermatol 1998; 38:580-584. Njoo MD, Spuls Ph I, Bos JD, Westerhof W, Bossuyt PMM. Nonsurgical repigmentation therapies in vitiligo. Meta-analysis of the literature. Arch Dermatol 1998; 134: 1532-1540. Njoo MD, Westerhof W, Bos JD, Bossuyt PMM. A systematic review of autologous transplantation methods in vitiligo. Arch Dermatol 1998; 134:15431549. Njoo MD, WesterhofW, Bos JD, Bossuyt PMM. The development of guidelines for the treatment of vitiligo. Arch Dermatol 1999; 135:1514--1521.

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21 Efficacy and Adverse Effects of Psoralen Photochemotherapy in Vitiligo Ljubomir Novakovic and John Hawk St. John's Institute of Dermatology, London, England

INTRODUCTION

Psoralen photochemotherapy with a combination of the furocoumarin psoralen (P), ingested or topically applied, and cutaneous ultraviolet A (UVA) irradiation, is often used and considered the most effective therapy for vitiligo. Such treatment with natural sunlight and topical psoralens dates back to ancient times, the Hindus in India having used the seeds of Psoralea corylifolia Linnaeus and the Egyptians Ammi majus Linnaeus as sources for the active chemical. EI Mofty was the first to perform careful clinical studies, however, and reported the successful repigmentation of vitiligo with oral 8methoxypsoralen (8-MOP) and sunlight in 1948 (1). Such ingestion, rather than the topical use of psoralens and subsequent exposure to sunlight, appeared at that stage to be the most successful treatment of vitiligo yet available. However, one disadvantage was long treatment times because of inadequate intensities of UVA radiation sources. The development of a highintensity UVA lamp in 1974, therefore-initially used for the treatment of psoriasis (2) and subsequently also vitiligo (3)-marked the beginning of convenient therapy, while accurate UVA dosimetry, crucial for safe and efficient PUVA therapy, was also introduced at that time. This chapter will concentrate on key issues facing dermatologists in phototherapy clinics, namely which vitiligo patients are likely to do well with Copyrighted Material 253

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PUVA, what adverse effects they may face, and what treatment schedule is best. PRETREATMENT ASSESSMENT AND CONSULTATION

All vitiligo patients should be assessed for their suitability for PUVA prior to commencement of treatment. Contraindications are the same as for other PUVA-responsive disorders (4), and although the suggested lower age limits are only guidelines, topical PUVA should be considered first for children if at all possible. A further important issue is the assessment of patient skin cancer risk, which should include documentation of the patient's skin type and any prior severe sunburning episodes as well as previous exposure to sunlight and artificial ultraviolet radiation, including any past phototherapy. Any previous history of photosensitivity should also be noted and evaluated as well as any current potentially photosensitizing medication; usually the photosensitivity from psoralen far outweighs any possible drug photosensitivity. Before PUVA treatment is initiated, it is also extremely important to give a detailed explanation of the potential treatment advantages and also drawbacks to patients. They should thus understand that for both oral and topical PUVA, up to 15-20 treatments are normally required for any visible pigmentary response, and up to 100 or more for complete repigmentation, ifit occurs, especially for widespread disease. Therefore, it is necessary that the patients comply with their long-term treatment schedule carefully and understand that many months are normally required to achieve a satisfactory result. Patients should also be aware that the initial therapeutic response is usually in the form of widespread perifollicular repigmentation and that the contrast between normal and vitiligo skin will initially become more obvious as PUVA stimulates the darkening of the unaffected skin. Once satisfactory repigmentation has been achieved, however, maintenance PUVA should not be undertaken. Patients should also be provided where possible with a written information leafiet on PUVA treatment containing a detailed explanation of the possible acute and long-term side effects of treatment. In addition, an explanation should be provided of the chances of repigmentation for the patient in question. Finally, at the end of consultation, patients should sign a consent form as a useful formal means of pointing out the PUVA risks.

TREATMENT PROTOCOLS Patients with widespread vitiligo are best managed with oral PUVA therapy, the psoralens of choice being 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen (5-MOP). Trimethylpsoralen (TMP) is also available but much less Copyrighted Material

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phototoxic because of poor gastrointestinal absorption and is therefore less frequently used. The ora] preparations are available in different formulations, and this should be taken into consideration as the different forms may achieve different peak blood levels. Thus, patients take 8-MOP in a dose of25 mg/m 2 body surface 2 hours prior to UVA exposure or 5-MOP in a dose of 50 mg/m 2 body surface 3 hours before; irradiations are given twice weekly, the initial UVA dose for all skin types being 0.5 J/cm 2 The dose is then increased by 0.5 J/cm 2 at each visit with the aim of not inducing any erythema (or at the most, barely perceptible erythema) of the vitiligo patches. The maximum single exposure dose should not exceed 5 Jjcm 2 , but should be less if erythema shows any sign of development. Topical PUYA therapy may be considered for patients with limited vitiligo, generally affecting less than 10% of skin surface. Topical PUVA is also preferable to oral PUVA in children, in patients with significant hepatic dysfunction or a tendency to gastrointestinal disturbance, in patients with cataracts, and where compliance with the eye protection may be poor or psoralen-drug interactions anticipated, for example, with warfarin (5). Although topical PUVA is associated with an increased risk of a blistering phototoxic reaction, its lack of systemic side effects makes it a very reasonable choice for this selected group of patients. For topical PUVA, 8-MOP is generally preferred to 5-MOP and TMP as it is less phototoxic; the treatment is given twice weekly as for oral PUVA. For whole body bath PUVA, 30 mL of 1.2% 8-MOP in an aqueous solution are diluted in ]00 L water to a concentration of 3.6 mg/L. A IS-minute psoralen bath is then followed by immediate exposure to UVA, an initial UVA dose is 0.05 Jjcm 2 being increased by 0.05 J/cm 2 at each visit, adjusted if necessary to diminish the chances of significant or even just perceptible erythema of the vitiligo patches; the exposure dose should not exceed 0.6 J/cm 2 . For paint PUYA, undiluted 0.15% 8-MOP may be used, the initial UVA dose again being 0.05 J/cm 2 for the face but 0.1 J/cm 2 for the body, and is increased by 0.05 J jcm 2 for the face and O. I J/cm 2 for the body at each visit, again so as 2 to avoid erythema of the patches and with a maximum dose of 0.6 Jjcm . Progress is best monitored by clinical photographs at about 3- to 4month intervals in all patients on PUYA therapy to enable an easy assessment of response. If definite, albeit often mild, repigmentation has not occurred within the initial 3--4 months, PUYA is unlikely to be effective thereafter and should be discontinued.

COMBINATION THERAPY Combination therapy has been claimed to improve the results of PUYA therapy alone, several studies having suggested that topical calcipotriol the Copyrighted Material

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active metabolite of vitamin 0, in conjunction with PUVA may be more effective than PUVA alone, the combination perhaps achieving earlier repigmentation with a lower cumulative UV A dose (6-8). Topical corticosteroids, frequently used alone as the first-choice therapy for vitiligo, have also been advocated for use in combination with PUV A, while epidermal grafting has been claimed a very useful adjunct to PUVA therapy for areas that do not respond to PUY A.

EFFICACY OF PUVA IN THE TREATMENT OF VITILIGO The efficacy of PUYA in the treatment of vitiligo depends mostly on the anatomical site affected by vitiligo and, to a lesser extent, the patient skin type and the recency of onset of the disease. Hair follicles in particular are a major reservoir of melanocytes, from which they can migrate into the surrounding pale skin during repigmentation; other mechanisms are migration from adjacent dark skin and reactivation of still present melanocytes within any recently developed vitiliginous areas. Therefore, large vitiligo patches not of recent onset affecting parts of the body that lack hair follicles, such as acral sites, peri orificial areas of the face, genitalia, nipples, and scars, usually respond minimally to PUVA. In contrast, patients with vitiligo of the face, trunk (Fig. I), arms, and legs (Fig. 2)

FIGURE 1 Virtually total repigmentation after many months of PUVA therapy; however, the color of the repigmented areas is inappropriate.

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FIGURE 2 Good but cosmetically still unsatisfactory repigmentation; very obvious white areas persist, and the color of repigmented areas is again inappropriate.

frequently achieve good or complete repigmentation; however, leukotrichia (the loss of hair color in any vitiligo patch), implying the loss of follicular melanocytes as well, suggests a poor response. Segmental vitiligo also often responds poorly to PUVA, being frequently associated with the loss of hair pigmentation. A recent 10-year retrospective study (9) has confirmed the results of previous studies (10,11) that PUVA is at best moderately effective in widespread vitiligo because of slow repigmentation over many months in widespread longstanding disease, failure of acral sites to repigment, abnormal repigmentation color, and high relapse rates, leading to poor cosmetic outcomes. The only statistically significant prognostic indicator of relapse was patient age at the start of treatment, with younger patients tending to retain their pigmentation longer than older patients. Only about 10% of patients repigmented fully, although 60% more had good but not full repigmentation; however, about 50% began to relapse within 1-2 years of ceasing PUVA. Vitiligo of recent onset, however, is probably more likely to respond to PUVA than longstanding disease, although this appears not to be well documented. Patients with darker skins are more likely to achieve successful repigmentation, although this may often be unsightly (Fig. 3). However, this does appear to revert toward normal over many months in many patients. Copyrighted Material

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FIGURE 3 Widespread repigmentation after many months of PUVA; once again the outcome is cosmetically unsatisfactory, with white areas still persisting and repigmentation of the wrong color.

PUVA SIDE EFFECTS

The acute side effects of PUVA are related to psoralen phototoxicity, the clinical features being erythema, edema, vesiculation, and necrosis similar to those seen in sunburn but with a more delayed time course, with peak at about 72-96 hours; this is more likely with topical PUVA. Oral PUVA with 8-MOP is sometimes associated with nausea and vomiting and in such cases should be replaced with 5-MOP, which is nearly free of such side effects as well as being less phototoxic to the skin. Following oral ingestion, 8-MOP can be detected in the ocular lens in humans for at least 12 hours (12). Thus, although there is in fact no definite evidence from PUVA follow-up studies of an increased incidence of cataracts, UVA-protective glasses must be worn for at least 12 hours after psoralen tablet ingestion to prevent theoretically possible long-term ocular damage by patients on oral PUYA. The long-term side effects of PUYA include premature photoaging of the skin and an increased risk of the development of skin cancer. Thus, studies have reported an increased number of actinic keratoses and squamous cell carcinomas (SeC) in PUVA-treated vitiligo patients (13-15). This incidence in PUV A-treated psoriasis correlates with cumulative UYA dose; because it is

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much lower in vitiligo patients, however, squamous cell carcinoma (SCC) incidence also appears to be significantly less. A recent long-term PUVA follow-up study of psoriasis patients has also suggested a slightly increased risk of melanoma (16), with a greater risk in patients exposed to high doses with increasing lengths of time since treatment began. Thus, although similar studies have not yet been published for vitiligo patients on long-term PUVA therapy, it is expected, as with SCC, that they may be at a lower risk and virtually negligible risk for melanoma as they receive much lower cumulative UVA dose than for psoriasis. CONCLUSION PUV A has become established in one form or another over thousands of years as a moderately to occasionally very effective treatment for vitiligo, usually with no major adverse effects in the short term. However, it is by no means a cure. All suitable patients should be given a detailed explanation beforehand of the proposed treatment schedule and the potential advantages and drawbacks of the therapy. After many months of around twice-weekly therapy, more or less satisfactory but usually not complete repigmentation, not infrequently abnormally formed, is achieved in carefully selected patients. However, increasing evidence for the comparable efficacy and probably greater safety of narrowband UVB phototherapy in the treatment of vitiligo suggests that the use of PUVA may steadily decrease over the coming years. ACKNOWLEDGMENT We thank Sister Trish Garibaldinos for her help with PUVA treatment protocols. REFERENCES I. 2,

3. 4. 5.

EI Morty AM. A preliminary clinical report on the treatment of leukoderma with Ammi majus Linn. J Egypt Med Ass 1948; 31 :651-660. Parrish JA, Fitzpatrick TB, Tanenbaum L, et al. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med 1974; 291: 1207-1211. Parrish lA, Fitzpatrick TB, Shea C, et al. Photochemotherapy of vitiligo. Arch Dermatol1976; 112:1531-1534 British Photodermatology Group. British Photodermatology Group guidelines for PUVA. Br J Dermatol 1994; 130:246-255. Halpern SM, Anstey AV, Dawe RS, et al. Guidelines for topical PUVA: a report of a workshop of the British Photodermatology Group. Br J Dermatol 2000; 142:22-31.

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7.

8.

9.

10. Ii.

12. 13.

i4. 15.

i6.

Ermis 0, Alpsoy E, Cetin L, et al. Is the efficacy of psoralen plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? A placebocontrolled double-blind study. Br J Dermatol 145; 200 I :472~75. Ameen M, Exarchou V, Chu AC. Topical calcipotriol as monotherapy and in combination with psora len plus ultraviolet A in the treatment of vitiligo. Br J Dermatol 2001; 145:476~79. Al Rubaie S. An open randomised study of treatment of 39 patients of generalised vitiligo with narrow-band UVB versus topical calcipotriol + PUVA therapy for a maximum period of 12 months. Ann Dermatol Venereol 2002; 129: IS107. Kwok YKC, Anstey AV, Hawk JLM. Psora len photochemotherapy (PUVA) is only moderately effective in widespread vitiligo: a 10-year retrospective study. Clin Exp Dermatol2002; 27:104-110. Elliott JA. Methoxsalen in the treatment of vitiligo: an appraisal of the permanency of the repigmentation. Arch Dermatol 1959; 79:237-243. Wildfang IL, Jacobsen FK, Thestrup-Pedersen K. PUVA treatment of vitiligo: a retrospective study of 59 patients. Acta Derm Venereol (Stockh) 1992; 72:305306 Lerman S, Megaw J, Willis I. Potential ocular complications from PUVA therapy and their prevention. J Invest Dermatol 1980; 74:197-199. Halder R, Battle EF, Smith EM. Cutaneous malignancies in patients treated with psoralen photochemotherapy (PUVA) for vitiligo. Arch Dermatol 1995; 131: 734-735. Buckley DA, Rogers S. Multiple keratoses and squamous carcinoma after PUVA treatment of vitiligo. Clin Exp Dermatol 1996; 21 :43~5. Takeda H, Mitsuhashi Y, Kondo S. Multiple squamous cell carcinomas in situ in vitiligo lesions after long-term PUVA therapy. J Am Acad Dermatol 1998; 38: 268-270. Stern RS, the PUVA Follow-Up Study. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermato12001; 44:755-761.

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22 Treatment of Vitiligo with UV and Photosensitizing Substances M.L. Flori, M. Pellegrino, A. Molinu, E. Stanghellini, and L. Andreassi University of Siena, Siena, Italy

INTRODUCTION Vitiligo is difficult to treat. The objective of therapy is currently to stabilize the disease and promote repigmentation of achromic areas so that skin color becomes even. This objective can be achieved by various methods based on a recent series of biological discoveries. Immunohistochemical methods and electron microscopy have demonstrated that there is a reserve population of amelanotic, functionally inactive DOPA-negative melanocytes, having ample cytoplasm and condensed nuclear chromatin, in the peripheral part ofpilosebaceous follicles. In vitiligo, these follicular melanocytes are the anatomical substrate through which repigmentation may be obtained. Recent studies have confirmed that in areas ofrepigmentation of vitiligo obtained by proliferation of reserve melanocytes, these cells progressively migrate into the superficial part of the infundibula and hence into the surrounding epidermis. As a result of this process, the melanocytes become morphologically and functionally mature. Their migration is promoted byexposure to ultraviolet (UV) radiation. UV RADIATION Ultraviolet radiation is nonionizing electromagnetic radiation in the 100--400 nm band, corresponding to photon energies of 3.1-12.4 eV. The Commission Copyrighted Material 261

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Internationale de I'Eclairage (CIE) has divided this spectral region into three bands: UV-A (400-315 nm), UV-B (315-280 nm), and UV-C (280-100 nm). In the medical literature, however, one frequently finds band limits different from these. Indeed, the UV-B region is regarded as being from 280 to 320 nm and the UV-A band is subdivided into UV-A2 (320-340 nm) and UV-Al (340-400 nm). The well-known benefits of sunlight for treating vitiligo and many other skin diseases led to the development of increasingly sophisticated artificial sources, which now rival or supersede results obtainable by heliotherapy. In the early twentieth century, carbon arc lamps, introduced by Finsen in 1890, were widely used. They were superseded by the more practical mediumpressure mercury arc lamps, which emit more UV radiation, first used by Andersen to treat psoriasis in 1923. For many years dermatologists endeavored to use sources that reproduced sunlight artificially, such as arc and xenon lamps. The introduction of mercury vapor lamps with the subsequent addition of heavy metal halogens to make spectral emission more homogeneous was an enormous advance. The most modern and versatile sources are currently low-pressure mercury vapor fluorescent lamps. The emission spectrum is continuous with variable percentages ofUV-A and UV-B and almost no UV-c. By combining lamps in different ways and using filters to eliminate UV-C and/or UV-B below 295 nm, instruments with improved clinical versatility for various types of therapy have been developed. These therapies range from selective phototherapy with UV-B and widespectrum phototherapy with UV-AB, to UV-A phototherapy which mayor may not be used in conjunction with photosensitizing agents. A further therapeutic aid was recently obtained with a new fluorescent lamp (Philips TL-Ol) emitting with high intensity in a very limited band (310-315 nm) having a narrow principle emission band peaking at 311 ± 2 nm and two small lines at 304 and 334 nm as well as modest emission in the visible band. This new lamp has proved to have better activity than traditional UV-B sources, and lower long-term cancer risk has been demonstrated in mice. Narrowband UV-B phototherapy is more effective and less irritating than traditional phototherapy. NARROWBAND UV-B PHOTOTHERAPY

Although successful therapy of vitiligo with narrowband UV-B has been reported, no standard protocol yet exists. Treatment variables (doses, usually below the erythema threshold, total number of exposures, and any associated topical or systemic treatments) are usually adapted on an individual basis, including personal phototype. In our experience, narrowband UV-B exposure can be given three times a week with doses increasing by 50 mJ/cm 2 per session

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up to a maximum single do e of 1800-2000 mJ/cm 2 . In most cases, color is restored after 50-100 sessions. Patients beginning therapy from the first manifestations of vitiligo enjoy the best resul ts. The response is particularly good in young subjects with lesions situated on the face and neck. Longstanding. extensive, and acral forms of vitiligo respond less well or not at all. Interestingly, most patients do not experience progression of lesions in the course of therapy. Recovery from vitiligo is an extremely gradual process, even with narrowband UV-B therapy. Repigmentation usually takes place in three phases: (a) a long latent phase with large variations from subject to subject; (b) a rapid improvement phase, presumably associated with migration and multiplication of melanocytes causing a 30-50% reduction in patch area; (c) a slower response phase or resistance (in older parts of patches where melanocytes have been absent for the longest and where conditions are presumably less favorable for their colonization).

MICROPHOTOTHERAPY AND EXCIMER LASER The idea of targeted microphototherapy was recently suggested. Narrowband UV-B is used with a fiber optics system to direct radiation to specific areas of skin. The instrument includes a computer for programming and controlling intensity (0.02-0.2 JIcm 2 Is) and application time. One protocol consists of one session per day for 5 consecutive days followed by a 'lO-day pause and then one session per week for about 20 weeks. Treatment is usually well tolerated and without side effects. Another recent innovation, still in the experimental phase, is excimer laser therapy with monochromatic rays at 308 nm for treating limited stable patches of vitiligo.

PHOTOCHEMOTHERAPY Photochemotherapy consisting of UV phototherapy after topical or systemic administration of photosensitizing substances is still one of the most effective treatments of vitiligo. The best known is PUVA therapy in which psoralens are the substance administered before exposure to UV-A radiation. Table 1 shows other photosensitizing agents used for this purpose. Psoralens are tricyclic furocumarines of the furochrome family, widespread in the plant kingdom and currently produced by chemical synthesis. Their major feature is strong photosensitizing activity on various biological substrates mediated by UV-A. This capacity to induce skin pigmentation was used historically in popular medicine to heal white skin patches. A herbaceous leguminous plant, Psoralea corylifolia, containing psoralens was used in India. In Egypt, an umbrellifera known as Ammi majus, which grows wild in

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Agents Used in Photochemotherapy

TMP in tablets 8-MOP in gelatin capsules 5-MOP in tablets or capsules Khellin in tablets Phenylalanine in tablets TMP in solution for local application 8-MOP in solution for local application Khellin in solution for local application Angelicine cream Miscellaneous (L-dopa, tyrosine, melagenin, pseudocatalase, extract of Polypodium leucotomus, etc. )

the Nile valley and contains 8-methoxypsoralen (8-MOP, xanthotoxin or amoidine), was used. The plants are described as being reduced to a poultice and applied to the achromic patches before exposure to sunlight. Modern use of 8-MOP in the treatment of vitiligo is attributed to El Mofty, a doctor of Egyptian origin. In 1948 he initially used extracts of the plant; later, when the chemists Fahmy and Abu Sady isolated pure furocumarine, he used it orally and topically to treat vitiligo. Widespread use of photochemotherapy began in 1947 when Parrish et al. administered 8-MOP systemically and used instruments providing high-emission UV-A. In the absence of light, psoralens form complexes with DNA bases. After absorption of UV-A rays, monofunctional 3,4- or 4',5' -cyclobutane adducts form with pyrimidine bases ofONA. In the presence of psoralens that. absorb a second photon, bifunctional adducts with double 5,6-pyrimidine bonds form between opposite chains that prevent DNA synthesis and hence cell division. This mechanism is the reason that PUVA therapy is effective in diseases characterized by hyperproliferation of cells. It is not yet clear what mechanism is responsible for stimulating melanocyte proliferation. Melanocyte growth factors have been reported in circulation after PUVA treatment. PUVA therapy also has an immunosuppressive effect on T lymphocytes and Langerhans cells and a selective toxic effect on mononuclear phagocytes as well as inhibiting mast cell degranulation. Photochemotherapy with psoralens has been found to release many cytokines, which means that it affects the environment in which melanocytes and keratinocytes interact. After irradiation with UV, keratinocytes produce a series of cytokines (SCF, GM-CSF, b-FGF, TGF-O') that stimulate melanocytes and others (TGF-r\ IL-l, IL-6, IFN-O') that inhibit them. It seems likely that together, these effects act synergically to promote conditions favorable for recolonization of achromic areas by melanocytes.

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The choice of the type of PUVA treatment, namely topical or oral administration of psoralens, depends on factors such as age of patient (oral administration is contraindicated in children under 12 years of age), extent of lesions (topical application is advisable when less than 20% of the skin surface is affected by vitiligo), and site of lesions (distal achromic areas and segmental forms respond relatively poorly to topical treatment). Topical PUVA therapy is indicated for patients suffering gastrointestinal side effects such as nausea and vomiting after oral administration of photosensitizing substances, as well as for patients with cataracts, retinopathy, liver and/or kidney disorders, and cardiovascular disease. Before systemic PUVA therapy, pa tients should be screened for contraindications, such as liver disorders, autoimmune diseases, and photodermatitis. Other contraindications are cancer, pregnancy, lactation, and phototype I according to Fitzpatrick.

TMP TMP is preferable to 8-MOP in terms of phototoxicity and is safer if sunlight is used (chemoheliotherapy) and with UV-A sources. In TMP + UV-A treatment with a high-intensity artificial source, TMP is given about an hour before exposure at a dose in the range 0.6-0.9 mg/kg. The interval is necessary so that maximum concentration of TMP can be reached in the skin, though the pharmacokinetics of the drug show wide variations within and between patients. The initial dose of UV-A given is the minimum photo toxic dose (MPD) calculated by phototest. Before TMP is administered, increasing doses of UV -A are directed to a target area of skin not normally exposed to sunlight, for example, a buttock. Forty-eight hours later, the skin response is recorded. The MPD is the minimum dose of UV-A that produces slight pigmentation with clear borders. Individual initial UV-A doses are 2 J/cm 2 in weekly sessions. The dose is then increased by I J/cm 2 each week up to a single maximum dose of 12 J/ cm 2 Treatment with sessions every 2 or 3 weeks usually continues for at least 10-12 months. To be effective, the protocol must be observed rigorously with regard to dose, frequency of sessions, and duration. Because photosensitization persists after the session the patient must wear protective sunglasses for the rest of the day and protect exposed areas of skin against sunlight by means of sunscreen and clothing for at least 8 hours. In a recent retrospective study, Kwok et al. (2) found that about 8% of patients treated achieved complete or almost complete repigmentation, 60% of patients achieved 30-90% repigmentation, 30% achieved more than 30% repigmentation, and only 2% continued to worsen despite treatment. The number of sessions necessary to achieve these results ranged from 50 to 100. Copyrighted Material

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In subjects unresponsive to PUVA therapy, efficacy can be potentiated by combining treatments, for example, topical application of steroids or calcipotriol.

TOPICAL AND SYSTEMIC 8-MOP AND 5-MOP

One of the most widely used sensitizers is 8-MOP administered at a dose of 0.6 mg/kg 2 hours before irradiation with UV-A. In order to avoid qualitative and quantitative variations that could confound the results of treatment, patients should be given the drug at the same time of day and after the same quantity of food. After the phototherapy session, the patient should wear protective sunglasses and cover achromic areas with clothing or sunscreen. For patients developing strong photo toxic reactions or gastrointestinal problems, 5-methoxypsoralen (5-MOP) at a dose of 1.2 mg/kg may be a valid 2 alternative. The dose ofUV-A is 1-2 J/cm 2 with increments of I J/cm every two sessions until moderate erythema develops. Some authors maintain slight erythema in the achromic patches during treatment. Two or three treatments are given per week. It is generally advisable not to exceed a maximum single dose of 12 J/cm 2 PUVA treatment can also be done with topical sensitization. A 0.010.10% propylene glycol solution of 8-MOP is generally applied 30 minutes before exposure of achromic areas to UV-A. The initial dose ofUV-A is 0.120.25 J/cm 2 with two sessions per week and similar increments every week. Once slight erythema is obtained, the dose is kept constant. After each session, the treated areas are cleansed and protected with high SPF sunscreen. This type of treatment avoids administration of systemic agents, which is important for patients with liver disease and for children. However, the technique is not easy to carry out, there being a high risk of hyperpigmentation at the periphery of the treated area and a high incidence of severe photo toxic reactions.

TOPICAL AND ORAL KHELLIN

Another possibility is to use khellin associated with UV-A (KUVA). Khellin is a natural furochromone extracted from the plant Ammi visnaga, used in the past at much higher doses as a coronary dilator in the therapy of angina pectoris. Like psoralens, khellin reacts with DNA bases in the presence ofUV rays, forming cross links between the two chains and preventing their replication. Khellin is less mutagenic than psoralens in vitro and less phototoxic. This means that exposure to sunlight or UV sources can be longer without the need for protection in the hours following treatment. Copyrighted Material

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Therapy consists of an oral dose of 100 mg khellin 2.5 hours before irradiation with high-intensity UV-A lamps. The initial dose ofUY-A is 6-8 J/cm 2 twice a week with increments up to a maximum of 12 J/cm 2 Reported side effects include gastrointestinal symptoms such as nausea, vomiting, lack of appetite, and headache, and changes in liver function (increased -y-GT and transaminase), which reverse 5-12 weeks after suspension of therapy. Patients should therefore be screened for liver function before undergoing KUYA. Khellin has also been used topically as a 3-5% cream or 2% lotion (acetone and propylene glycol~based) and shows an evident pigmentation capacity with exposure to UV-A. The topical approach is useful for localized and small patches of vitiligo, especially in children. An advantage of topical KUY A with respect to topical PUYA is that exposure time is not limited by the possibility of phototoxic reaction.

ANGELICINE

Another approach became possible with the synthesis of so-called angelicines, angular furocumarines extracted from certain umbrelliferae. The natural extracts do not provoke erythema or pigmentation. Introduction of methyl groups increases pigmentation capacity up to that of psoralens but without any of their disadvantages. Angelicine rriethylated in position 6 (6-MA) has low phototoxicity and is therefore suitable for local treatment of vitiligo by virtue of their capacity to stimulated epidermal melanocytes to produce melanin. Good results have also been obtained applying an ethanol glycol solution of 6,4,4' -trimethylangelicine to vitiligo patches 30 minutes before irradiation with UV-A. Three sessions are given per week with an initial dose of 1 J/cm 2 and progressive increments of 0.5 J/cm 2 every three sessions for 3 months. Retrospective studies have shown slight side effects (slight itching and erythema), and follow-up after 6 months confirmed stability of the results obtained.

ORAL PHENYLALANINE

The amino acid phenylalanine has also been used to treat vitiligo. The mechanism of action is unclear. It is postulated that phenylalanine modifies surface markers of Langerhans cells, inhibiting synthesis of autoantibodies usually present in increased numbers in vitiligo. The number of patients treated has not yet been sufficiently large to evaluate the efficacy of this therapy. Oral doses of 50 mg/kg have been given 30--45 minutes before 2 exposure to UY-A three times a week. An initial UY-A dose of I J/cm with progressive increments of I J/cm 2 per session up to a maximum of9-12 J/cm 2 Copyrighted Material

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have been used. Available data indicate mean treatments for 5-6 months before pigmentation becomes evident.

MISCELLANEOUS Various substances are reported in the international literature to be used systemically and/or topically with natural or artificial irradiation in the treatment of vitiligo. Most studies have been without controls and patient numbers too few for statistical analysis of the results. It is therefore too early to propose these agents for clinical use. For the sake of completeness, we mention substances such as L-dopa, tyrosine, melangenin, pseudocatalase, and Polypodium leucotol1luS extract. Psoralens have also been used in conjunction with UV-B (290-320 nm). On the hypothesis that psoralens are also activated by exposure to broadband UV-B, a comparative study was done between PUVA and PUVB in the treatment of vitiligo. The treatments were found to be equally effective, but UV-B was associated with a higher risk of phototoxicity due to its greater capacity to cause erythema. CONCLUSIONS The only photosensitizing agents currently registered for medical use in Italy are 8-MOP and TMP, but it has recently been difficult to obtain them in tablet form The problem of obtaining both new and registered agents has meant that PUVA has been used much less, particularly since phototherapeutic alternatives, such as narrowband UV-B became available. These alternatives are as effecti ve as PUV A for treating vitiligo and other skin diseases, with the advantages of lower risk of phototoxic reactions and the possibility of dispensing with systemic administration of drugs and with sun protection after irradiation. However, the two treatments are complementary rather than really alternative REFERENCES I.

2.

3.

Badawy Abdel-Naser M, Hann S-K, Bystryn J-c. Oral psora len with UV-A therapy releases circulating growth factor(s) that stimulate cell proliferation. Arch Dermatol 1997; 133:1530-1533. Kwok YKc. Anstey AV, Hawk JLM. Psoralen photochemotherapy (PUVA) is only moderately effective in widespread vitiligo: a 10-year retrospective study. Clin Exp Dermatol2002; 27:104-110. Yalc;in B, Sahin S, BLikLilmez G, et al. Experience with calcipotriol as adjunctive

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5.

6.

7. 8. 9.

10. 11.

12.

13. 14.

15. 16.

17. 18. 19.

20.

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treatment for vitiligo in patients who do nOl respond to PUVA alone: a preliminary study. J Am Acad Dermatol2001; 44:634-637. Ameen M, Exarchou V, Chu AC. Topical calcipotriol as monotherapy and in combination with psora len plus ultraviolet A in the treatment of vitiligo. Br J Dermatol 2001; 145:476-479. Ennis 0, Alpsoy E, Cetin L, et al. Is the efficacy of psora len plus ultravjolet A therapy for vitiligo enhanced by concurrent topical calcipotriol. A placebocontrolled double-blind study. Br J Dermatol 2001; 145:472-475. Westerhof W, Nicuwcboer-Krobotova L, Mulder PGH, et al. Left-right comparison study of the combination of fluticasone propionate and UV-A vs either fluticasone propionate or UV-A alone for the long-term treatment of vitiligo. Arch Dermatol 1999; 135:1061-1066. EI Mofty M, Zaher H, Esmat S, et al. PUVA and PUVB in vitiligo-are they equally effective. Photodermatol Photoimmunol Photomed 200 I; 17: 159-163. Abdel-Rahman H, Keshk EM, el Telbani EM. Linearly fused furochromones by intramolecular enaminone reactions. Z Naturforsch 2002; 57b:557-562. Njioo MD, Bos JD, Westerhof W. Treatment of generalized vitiligoin children with narrow-band (TLOI) UVB radiation therapy. J Am Acad Dermatol 2000; 42:245-253 Scherschum L, Kim JJ, Lim HW. Narrow-band ultraviolet B is a useful and welltolerated treatment for vitiligo. JAm Acad Dermatol 2001; 44:999-1003. Moretti S, Spallanzani A, Amato, et al. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002; 15(2):87-92. Lotti TM, Menchini G, Andreassi L. UV-B radiation microphototherapy. An elective treatment for segmental vitiligo. J Eur Acad Dermatol Venereol 1999; 13(2): I02-1 08. Spencer JM, Nossa R, Ajmeri J. Treatment of vitiligo with the 308-nm excimer laser: a pilot study. J Am Acad Dermatol 2002 May; 46(5):727-731. Njoo MD, Westerhof W, Bos JD, Bossuyt PM. The development of guidelines for the treatment of vitiligo. Clinical Epidemiology Unit of the Istituto Dermopatico delrImmacolata-Istituto di Recovero e Cura a Carattere Scientifico (IDI-IRCCS) and the Archives of Dennatology. Arch Dermatol 1999; 135(12): 1514-1521 Taneja A. Treatment of vitiligo J Dermatol Treat 2002; 13(1):19-25. Tran D, Kwok YK, Goh CL. A retrospective review of PUVA therapy at the National Skin Centre of Singapore. Photodermatol Photoimmunol Photomed 2001; ]7(4):164-167. Shaffrali F, Gawkrodger D. Management of vitiligo. Clin Exp Dermatol 2000 Nov; 25(8):575-579. WesterhofW. Vitiligo management update. Skin Ther Lett 2000; 5(6):1-25. Bethea D, Fullmer B, Syed S, Seltzer G, Tiano J, RischkoC, Gillespie L, Brown D, Gasparro FP. Psoralen photobiology and photochemotherapy: 50 years of science a)1d medicine. J Dermatol Sci 1999; 19(2):78-88. Handa S, Pandhi R, Kaur 1. Vitiligo: a retrospective comparative analysis of trea tment modalities in 500 patients. J Dermatol 200 J ; 28(9):461-466.

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23 Corticosteroids in Vitiligo

Alexander J. Stratigos and Andreas D. Katsambas University of Athens Medical School, Andreas Sygros Hospital for Skin and Venereal Diseases, Athens, Greece

INTRODUCTION

Since there is no definite cure for vitiligo, current treatment modalities aim to achieve repigmentation in the lesions and to stabilize the depigmentating process. PUVA therapy, phototherapy (UYB or narrowband UVB), topical and systemic corticosteroids, levamisole, melagenina, 5-fluorouracil, topical pseudocatalase, and surgical techniques (autologous minigrafting, autologous epidermal grafting) have been used in vitiligo patients with variable success (1-4). Even in the case of partial or complete response to any of these treatments, the risk of disease relapse remains indefinitely. In this chapter we review the role of corticosteroids in the treatment of vitiligo and discuss their efficacy and safety profile in the management of this common condition.

TOPICAL CORTICOSTEROIDS

Topical steroid preparations are often the first line of treatment for vitiligo, primarily due to the ease and convenience of their application on the affected areas. They are particularly useful in pa tien ts wi th localized patches of vitiligo and with vitiliginous lesions that have an inflammatory component. They are also the preferred mode of treatment for vitiligo in children. In a questionnaire-based interview of physicians managing vitiligo patients in the Netherlands, topical corticosteroid therapy was chosen by 79% of the respondents Copyrighted Material

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for localized and generalized vitiligo in children less than 12 years old. In adults, topical steroid therapy was prescribed by 64 % and 71 % of the interviewed physicians for localized and generalized vitiligo, respectively (5). Several studies have reported the efficacy of topical steroids in repigmenting vitiliginous skin, but only a few have addressed this issue in a rigorous manner. The reported rates of repigmentation following topical steroid therapy in localized vitiligo vary significantly among investigators, and efforts to compare these results objectively are hampered by interstudy differences with regard to the type, extent, and duration of vitiligo, the steroid preparations used, the clinical end points, and the overall study design (controlled versus noncontrolled). In general, good to excellent repigmentation has been reported to occur in 9-92% of patients after a treatment period of2 to several months (6-9). In a meta-analysis of 10 randomized controlled studies on nonsurgical repigmentation, therapies for localized vitiligo showed that the pooled odds ratio for topical class III steroids versus placebo was 14.32 (95%; CI, 245-83.72), while in 29 patient series the success rate of repigmentation for topical class 3 and 4 corticosteroids was 56% and 55%, respectively (5). Atrophy was the most common adverse effect for local corticosteroid therapy, occurring most commonly in patients receiving intralesional steroids (33%), followed by patients treated with class 4 corticosteroids (14 %) and class 3 corticosteroids (2 %). When considering the therapeutic effect of topical corticosteroids in vitiligo, several parameters should be taken into account, e.g., the location of vitiligo, the duration of the disease, the patient's skin type, and the type of vitiligo. In a study by Kandil (6), facial lesions responded most favorably to topical steroid treatment, showing a diffuse increase of pigmentation until normal skin color was attained. Lesions on the trunk, neck, and extremities also responded well to treatment, exhibiting a follicular pattern of repigmentation. Acral sites, such as the distal parts of the fingers, showed the least response to topical steroids, although the dorsal surface of the hands achieved partial repigmentation. On the face, patches of vitiligo around the eyes and on the eyelids repigmented satisfactorily, although caution should be exercised when using topical steroids on the eyelid area due to the risk of increased intraocular pressure and glaucoma. It is unclear why facial vitiligo repigments more readily compared to other body sites, but the high permeability of facial skin to topical steroids, the increased numbers of residual melanocytes in the unaffected facial skin, and the apparent reversibility of melanocyte damage in facial lesions have been proposed as potential explanations (10). The type of vitiligo has been reported to influence the success rate of topical steroids in vitiligo. In one study using 0.12% betamethasone-17valerate, 0.01 % fluocinolone acetonide, or 0.1 % triamcinolone acetonide in patients with vitiligo, segmental vitiligo did not respond to treatment, in

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contrast to generalized or bilateral localized vitiligo, which showed a partial or complete response in 82.5% of patients (7). Other studies, however, have reported a better response of segmental vitiligo to steroid therapy if the treatment is done at an early stage (ll). In a study by Geraldez and Gutierrez (I 2),25 Filipino patients with vitiligo oflimited extent (less than 20% of body surface involved) were treated intermittently with clobetasol propionate cream, twice daily for 2 weeks and then once daily thereafter. Six months after the completion of the therapeutic trial, 22 of the 25 patients experienced at least 90% repigmentation, while two patients (8%) failed to show any response. Younger lesions appeared to respond faster and better, suggesting that the duration of the disease may playa role in the therapeutic response to corticosteroids. In addition, the age of the patient, the anatomical site of the lesions, and the presence or absence of achromotrichia appeared to be significant prognostic factors of the response to treatment. A retrospective comparative analysis of nonsurgical repigmenting modalities for vitiligo in 500 Indian patients showed that topical steroids (clobetasol propionate and sun exposure) induced moderate to excellent repigmentation in 89% of patients (207/232) with localized vitiligo (less than 10% involvement of total body surface), compared to 93% of the psoralen plus sun exposure group (73 of 78 patients) and 79% in the topical psoralen plus UVA radiation group (15 of 19 patients) (13). Contrary to these findings, Goldstein et al. (9) reported a low rate of repigmentation in vitiligo patients after a 3- to 4-month course of topical steroid therapy. About 70% of patients failed to respond to treatment with hydrocortisone I %, hydrocortisone butyrate 1%, desonide 0.05%, or other low-potency steroids. The remaining 30% were treated with medium- to high-potency fluorinated steroids without showing considerable response. Skin type may also affect the rate of repigmentation in vitiligo. In a comparative study by Kumari (8), facial lesions of vitiligo in dark-skinned individuals (Asian or black) responded better to intermittent use of clobetasol propionate compared to similarly treated lesions in light-skinned patients. Repigmentation of 90-100% was achieved in more than 8 of patients with facial vitiligo and more than 40% of patients with vitiligo on other parts of the body. The higher response rate in dark-skinned people has been attributed to a higher prevalence of reversible melanocyte damage in these patients. In practical terms, the selection of the appropriate topical steroid depends mainly on the site of application. In general, medium strength topical steroids are preferentially used in children and on nonfacial and nonintertriginous sites on a daily basis for several months, provided that the treated sites are observed regularly for early signs of telangiectasia or atrophy. Superpotent topical steroids can be applied in selected treatment areas (elbows, knees, hands), but obviously the risk of cutaneous atrophy is higher with these agents. Treatment with topical steroids should last for at least 3 months. If

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repigmentation is observed during this period, then the treatment can be continued for a total of 6-9 months, provided that the treatment sites are closely supervised for potential adverse effects telangiectasia, atrophy. If the treated area does not show any signs of repigmentation after 3 months of topical steroid use, then the treatment should be discontinued. Caution should be exercised in delicate areas of application, for example, the eyelids, where the prolonged use of topical steroids may complicate developmental glaucoma in children and aggravate adult glaucoma (14). INTRALESIONAL STEROIDS Intralesional steroids have been used in vitiligo in an effort to improve the efficacy of steroid treatment and increase their delivery to deeper epidermal and dermal structures. In an uncontrolled study, Knadil (IS) treated 26 patients with vitiligo by intralesional injections of triamcinolone acetonide (10 mgjmL). He noted a "complete" or "almost complete cure" in 58% of treated patches (30/52) and a "satisfactory hyperpigmentation" in 29% of lesions (15/52). A low risk of adverse effects was observed with only 8% of patches exhibiting atrophy 10 months after the last injection. In contrast to these findings, Visistha and Singh (16) compared the efficacy of intralesional steroids with water injections in vitiligo and did not observe any significant difference in repigmentation between the two groups. In addition, they reported a high incidence of various adverse effects in the steroid group, such as atrophy, telangiectasia, and intradermal hemorrhage. Similar findings were noted by Goldstein et al. (9), who concluded that intralesional triamcinolone is ineffective for vitiligo and left slight dermal atrophy and telangiectasia. Other adverse effects of intralesional therapy include the f0l111ation of striae distensae, a decrease in the mobility of finger joints from atrophy of the skin after steroid injections, and the severe pain associated with the injections in certain anatomical areas (10). For these reasons, the use of this modality is generally avoided in the treatment of vitiliginous skin, with the exception perhaps of vitiligo-associated leukotrichia, where topical application of steroids is quite cumbersome. SYSTEMIC STEROIDS Vitiligo is widely considered an autoimmune disorder leading to the destruction of melanocytes. It has been proposed that systemic corticosteroids may arrest the progression of vitiligo through their immunosuppressive properties and lead to repigmentation of the affected lesions. This hypothesis has been supported by evidence of a decrease of complement-mediated cytotoxicity by autoantibodies to melanocytes and reduced antibody titers to surface anti-

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gens of melanocytes in the serum of vitiligo patients who received oral corticosteroid therapy with clinical improvement (17). Based on these data, systemic corticosteroids have been used to treat extensive and actively spreading vitiligo. An initial approach involved the use of long-acting adrenocorticotropin hormone (ACTH), which was thought to have a direct stimulatory effect on epidermal melanocytes via the MSH receptors located on the surface of melanocytes. One group of investigators administered 25-40 JU of ACTH twice weekly for a period of 5-6 weeks in vitiligo patients who had previously failed therapy with PUVA (18). Repeat treatments were given with 2- to 4week break intervals and to a maximum of four courses. After 6 months, 80% repigmentation occurred in 16 (59%) of those treated, 50% repigmentation in 6 (22%), and ~20% repigmentation in 4 patients (15%). These findings were contradicted by the study of Hermandez-Perez (19), who administered two 5week courses of 40 mg of ACTH gel in vitiligo patients and noted poor results in 70% of patients (14/20) with less than 20% ofrepigmentation. Only 30% of treated patients (6/20) exhibited more than 80% repigmentation but depigmentation occurred rapidly after discontinuation of therapy. Imamura and Tagami (20) used a mixture of prednisolone, betamethasone, paramethasone acetate, and methylprednisolone in 22 patients with generalized and localized vitiligo. They noted a satisfactory response in 35% patients (6/22) with more than 75% repigmentation in at least one patch within 6 months of therapy. They also noted that repigmentation became evident after 4 weeks of treatment and that vitiligo patches on exposed areas had a more marked response. In addition, patients with generalized lesions responded better than those with localized vitiligo. Lesions of more than 10 years duration or those refractory to other treatments, e.g., PUVA therapy, responded less well to oral steroids. The use of systemic steroids has been associated with a long list of side effects, including gastrointestinal distress, facial swelling, body weight increase, striae distensae, acneiform eruptions, menstrual disturbances, osteoporosis, and avascular necrosis of bone. In order to minimize these potential side effects, safer steroid regimens, such as low-dose oral steroids or oral intermittent (pulse) therapy with betamethasone or dexamethasone, have been used in patients with extensive or rapidly spreading vitiligo. Kim et al. (21) used low-dose steroid therapy (0.3 mg prednizolone/kg) in actively spreading vitiligo and noted an arrest of the progression of the disease in 71 of81 patients (87.7%) and some repigmentation in 57 of81 patients (70.4%) after 4 months of tapered treatment. Interestingly, patients with <2 years disease duration had a better response, with repigmentation occurring in 38 of 49 patients (77.6%). In patients with vitiligo of >2 years duration, repigmentation was achieved in 20 of 32 patients (62.5%), while spreading oc-

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curred in 9 of the treated patients (28.1 %). Differences in repigmentation rates were also noted depending on the type of vitiligo, with lesions of segmental vitiligo showing repigmentation in 76.7% of 30 patients, localized vitiligo in 87.5% of 8 patients, and generalized vitiligo in 62.8% of 43 patients. In addition to these observations, the study confirmed once more the favorable outcome of facial lesions to oral steroid therapy, with repigmentation occurring in 69.8% of 63 patients. Of the 81 patients in the study, 35 did not report any side effects, while 46 complained of one or more side effects, the most common being facial edema (21 % of patients), weight gain (17.3 %), and acneiform eruptions (9.9%). Other reported symptoms were gastrointestinal distress, frequent urination, increased appetite, abdominal pain, hypertrichosis, menstrual irregularities, diarrhea, and striae distensae. The authors concluded that low-dose oral corticosteroids were effective in preventing the progression and inducing repigmentation of actively spreading vitiligo. Pasricha and Khaitan (22) treated 40 Indian patients with extensive or fast-spreading vitiligo with an oral minipulse therapy with betamethasone/ dexamethasone 5 mg given as a single oral dose after breakfast on 2 consecutive days every week. After 1-3 months of treatment, the vitiligo was arrested in 32 of 36 patients (89%), while in 2 patients higher steroid doses of 7.5 mg/day were required to achieve complete arrest of their vitiligo. Within 2--4 months, 32 of the patients (80%) showed evidence of lesional repigmentation, the extent of which differed from patient to patient and from lesion to lesion in the same patient. Six patients (15%) showed 76-99% repigmentation, 3 patients (7.5%) had 51-75% repigmentation, and 21 patients (58.3%) achieved < 25% of repigmentation. Weight gain (5-7 kg), bad taste, headache, transitory general weakness, facial puffiness, and acne were the most frequently experienced symptoms by these patients. Kanwar et al. (23) studied a different oral minipulse therapy in patients with rapidly spreading vitiligo (23). The regimen consisted of dexamethasone (5 mg for adults, 2.5 mg for children) given on 2 consecutive days a week. A range of 5-25 doses was tried. Only 14 of the 32 patients (43.8%) who completed the trial had a mild-tomoderate repigmentation without appearance of new lesions. In 18 patients (56.2%) no response was observed. In patients who repigmented, the response occurred after the first 15 weeks of treatment. Of the 9 children that completed the study, only 4 had mild-to-moderate repigmentation. No significant side effects were reported by the treated patients. Both of these studies on the role of pulse steroid therapy on vitiligo were centered on Indian or Asian patients. Since ethnic background has been suggested to playa role in the therapeutic response of vitiligo, a study by Radakovic-Fijan et al. (24) explored the efficacy and safety of dexamethasone pulsed therapy in 29 Austrian patients with progressive or stable disease. The patients were given weekly pulses of to mg of dexamethasone each on

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2 consecutive days followed by 5 days off treatment for a maximum of 24 weeks. Although the disease activity was arrested in 22 of 25 patients (88%) with active vitiligo, only 2 patients (6.9%) showed more than 50% repigmentation. No response was noted in 21 patients (72.4%). As in the study of Pasricha and Khaitan (22), the probability of marked repigmentation was found to correlate wi th increasing duration of the treatment. Side effects were recorded in 20 patients (69%) and included weight gain, insomnia, acne, agitation, menstrual disturbances, and hypertrichosis. The plasma levels of cortisol and corticotropin were markedly decreased 24 hours after the second dexamethasone dose, but returned to baseline during the off-treatment periods. These findings suggested that oral dexamethasone pulse treatment was effective in arresting progression of vitiligo but had a limited capacity to induce cosmetically acceptable repigmentation when given as monotherapy in this patient population. Finally, in a smaller European study of 14 patients with generalized vitiligo, high-dose methylprednisolone pulse therapy (8 mg/ kg body weight) induced an arrest of the disease activity in 85% of the treated patients (25). Repigmentation occurred in 71 % of patients with progressive vitiligo but in none of the six patients with stable disease. With the exception of one patient who developed intermittent arterial hypertension during therapy, all other patients tolerated the treatment well. COMBINATION THERAPIES Topical steroids have been effectively combined with other modalities in the treatment of vitiligo. Daily application of potent topical steroids has been noted to substantially improve the results of PUVA therapy on recalcitrant vitiligo lesions (26). In a recent left-right comparative study, it was shown that the combined treatment with fluticasone and UV A radiation led to a higher repigmentation response compared to treatment with either fluticasone or UVA radiation alone (27). CONCLUSIONS The outcome of steroid treatment in patients with vitiligo appears to depend on several factors, such as the type and extent of vitiligo, the location of the lesions, and the duration of the disease. Topical steroids are considered the first line of treatment for localized vitiligo in children and adults. As with other treatment modalities in vitiligo, facial lesions show the most favorable response to topical steroids, while acral lesions respond the least. The efficacy of intralesional corticosteroids in vitiligo remains questionable and is generally associated with a high incidence of adverse effects such as cutaneous atrophy and telangiectasia. Systemic steroids have been shown to arrest the Copyrighted Material

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progression of vitiligo and induce repigmentation in the affected areas, but their use requires careful patient screening and serial laboratory tests. Lowdose systemic steroids or pulsed regimens with dexamethasone or betamethasone are currently preferred due to their lower risk of side effects.

REFERENCES I.

2.

3. 4.

5. 6 7. 8. 9.

10. J I.

12. 13. 14. 15. 16. 17.

Antoniou Ch, Katsambas A. Guidelines for the treatment of vitiligo. Drugs 1992; 43(4):490--498. Le Poole IC, van den Wijingaard RMJGJ, Westerhof W, et al. Presence or absence ofmelanocytes in vitiligo lesions: an immunohistochemical evaluation. J Invest Dermatol 1993; 100:816-822. Shaffrali FCG, Gawkrodger DJ. Management of vitiligo. Clin Exp Dermatol 2000; 25:575-579 Antoniou Ch, Schulps H, Michas T, Katsambas A, Frajis N, Tsagaraki S, Stratigos J, Vitiligo therapy with oral and topical phenylalanine with UVA exposure. lnt J Dermatol 1989; 28(8):545-547. Njoo MD, WesterhofW, Bos JD, Bossuyt PMM. The development of guidelines for the treatment of vitiligo. Arch Dermatol1999; 135:1514-1521. Kandil E, Vitiligo response to 0.2% betamethasone 17-valerate in flexible colloidum. Dermatologica 1970; 141:277-281. Koga M, Vitiligo: a new classification and therapy. Br J Dermatol 1999; 97:255261. Kumari J, Vitiligo treated with topical clobetasol propionate. Arch Dermatol 1984; 120631-635. Goldstein E, Haberman HF, Menon lA, Pawlowski D. Non-psoralen treatment of vitiligo. Part II. Less commonly used and experimental therapies. Int J Dermatol1992; 3l:314-319, Hann SK. Steroid treatment for vitiligo. In: Hann Seung-Kyung, James J Nordlund, eds. Vitiligo. Oxford: Blackwell Science, 2000: 173-] 81. Moon TK, 1m S, Har1ll SK, Cho SH, Park YK. The effect of small doses of oral corticosteroids in vitiligo patients. Korean J Dermatol 1995; 33:880-885. Geraldez CB, Gutierrez GT A clinical trial of clobetasol propionate in Filipino vitiligo patients. Clin Therap 1987; 9:474--482. Handa S, Pandhi R, Kaur I. Vitiligo: a retrospective comparative analysis of treatment modalities in 500 patients. J Dermatol 2001; 28:461--466, Morgan MR. Possible side effects of topical steroids. Am Fam Phys 1981; 23: 171-174. Knadil E. Treatment of localized vitiligo with intradermal injection of triamcinolone acetonide. Dermatologica 1970; 140: 195-206. Visistha LK, Singh G. Vitiligo and intralesional steroids. Ind J Med Res 1979; 69:308-311. Hann SK, Kim HI, 1m S, et al. The changes of melanocyte toxicity after systemic steroid treatment in vitiligo patients. J Dermatol Sci 1997; 6:201-205.

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Gokhale BB, Gokhale TB. Corticotropin and vitiligo (preliminary observations). Br J Dermatol 1976; 95:329. Hermandez-Perez E. Vitiligo treated with ACTH. lnt J Dermatol 1979; 18:587589. Imamura S, Tagami H. Treatment of vitiligo with oral corticosteroids. Dermatologica 1976; 153:179-185. Kim SM, Lee HS, Hann SK. The efficacy oLlow-dose oral corticosteroids in the treatment of vitiligo patients. lnt J Derrnatol 1999; 38:546-550. Pasricha JS, Khaitan BK. Oral mini-pulse therapy with betamethasone in vitiligo patients baving extensive or fast-spreading disease. lnt J Dermatol 1993; 32:753757 Kanwar AJ, Dhar S, Dawn G. Oral minipulse therapy in vitiligo. Dermatology 1995; 190:251-252. Radakovic-Fijan S, Furnsinn-Friedl, Honigsmann H, Tanew A. Oral dexamethasone pulse treatment for vitiligo. JAm Acad Dermatol2001; 44:814-817. Seiter S, Urugel S, Tilgen W, Reinhold U. Use ofbigh-dose methylprednisolone pulse therapy in patients with progressive and stable vitiligo. lnt J Dermatol 2000; 39:624-627. Honig B, Morison WL, Karp D. Photochemotherapy beyond psoriasis. J Am Acad 1994; 31:775-790. Westerhof W, Nieuweboer-Krobotova L, Mulder PG, Glazenburg EJ. Leftright comparison study of the combination of f1uticasone propionate and UV-A vs eitber f1uticasone propionate and UV-A alone for the long treatment of vitiligo. Arch Dermatol2999; 135:1061-1066.

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24 Vitamins and Vitiligo

Evridiki Tsoureli-Nikita, Claudio Comacchi, Giovanni Menchini, and Torello Lotti University of Siena, Siena, Italy University of Florence, Florence, Italy

The hypothesis that a deficiency of certain nutritional elements contributes in part to the pathogenesis of vitiligo has been proposed. Recent research has sought to demonstrate that replacement therapy with deficient vitamins or trace elements can lead to successful repigmentation (1). Vitamins are organic substances necessary in small quantities for cellular metabolism. These compounds need to be ingested because they cannot be synthesized by the organism, yet playa crucial role in the development and maintenance of vital functions. Vitamins can be classified as water-soluble or lipid-soluble (Table I) (2). Provitamins are the inactive precursors of vitamins that can be activated to become vitamins through external factors [e.g., ultraviolet (UV) radiation] or enzymatic action. Recently vitamins such as vitamin B 12 , folic acid, ascorbic acid, and vitamin D derivatives, alone or in association with phototherapy, have been introduced in the treatment of vitiligo (2--4). In 1992 Montes et al. (3) found abnormally low levels of vitamin B I2 and folic acid in 15 patients affected by vitiligo. For the next 3 years, certain patients recovered oral supplementation of folic acid, vitamin C, and vitamin B 12 . After only 3 weeks of treatment, vitiligo spread ceased, and at the end of the second year, more than 80% of patients treated had experienced significant repigmentation of vitiligo patches (3).

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Hydrosoluble and Liposoluble Vitamins

Hydrosoluble vitamins Thiamine (B 1 ) Riboflavin (B 2 ) Nicotinamide (PP) Pantothenic acid Pyridoxine (B 6 ) Biotin Folic acid Cobalamin (B 12 ) Ascorbic acid (C)

Liposoluble vitamins Retinol (A) Vitamin 0 ex-Tocopherol (E) Vitamin K

Juhlin et al. (4), based on the positive results described above, utilized an association of oral folic acid and vitamin B I2 with eliotherapy (or UVB exposure in winter) to treat patients affected by vitiligo. The results obtained have been encouraging, far better than those obtained with phototherapy or vitamins alone (4). A possible explanation for this therapeutic effect seems to be associated with metabolism of pteridins contained in folic acid. Schallreuter et al. (5) have suggested that the pteridin part of folic acid could interfere with the recycling of reduced pteridins found in vitiligo. Pteridins deficiency could significantly decrease tyrosine concentration, leading to inhibition of pigmentation. It is known that N-N-methylene-tetrahydrofolate regulates plasma levels of homocysteine, giving a methyl group to homocysteine in order to produce methionine. This process is vitamin B l2 dependent; it seems that vitamin B I2 downregulates the metabolism of homocysteine, partly responsible for the depigmentation in vitiligo (I). It has recently been hypothesized that the cofactor 5,6,7,8-tetrahydrobiopterin (6BH 4 ) is involved in the pathogenesis of vitiligo. During vitiligo there is increased de novo synthesis and recycling of 6BH.j with low DH dehydratase activity. The 6BH 4 accumulation with low DH dehydratase activity causes the formation of a 7-isomer (7BH 4 ), which inhibits phenylalanine hydroxylase enzyme (PAH) and tyrosinase, an enzyme that plays a pivotal role in melanin biosynthesis. The weak activity of PAH is not sufficient to transform an adequate quantity ofL-phenylalanine, and the consequent melanocyte accumulation of L-phenylalanine and 7BH 4 causes, thanks to the decreased DH and PAH activities, production of H 2 0 2 during a short circuit in the 6BH 4 recycling process (6,7). The high H 2 0 2 levels accumulated are cytotoxic to melanocytes in that they: (a) deactivate catalase (a catalyst for the conversion of hydrogen per-

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oxide into water and oxygen, with one of the highest turnover rates for all known enzymes-40,000,000 molecules/sec); (b) oxidize 6BH 4 and 7BH 4 into 6-biopterin, which is cytotoxic for melanocytes; and (c) induce activation of dendritic cells followed by selective T-cell proliferation. The dietary intake of a-tocopherol (vitamin E) and ascorbic acid (vitamin C) in patients with vitiligo reinforces the organism against oxidative stress and free radical formation due to the mechanism described above (8). Because vitiliginous areas that respond best to phototherapy are those containing black or brown hair (vs. white), the presence of melanocyte precursors (melanoblasts) in the hair bulbs has been proposed in the context of the vitiligo patches. In fact, vitamin B J2 and folic acid would exert their beneficial effects not only by correcting the BH4 excess, but also by stimulating dermis and hair bulb melanoblasts (9,10). It has recently been demonstrated that patients with vitiligo exhibit reduced levels of intracellular calcium in both keratinocytes and melanocytes (II). The calcium decrease leads to high thioredoxin levels, which could inhibit tyrosinase activity. For this reason it has been hypothesized that synthetic derivatives of vitamin D act on melanocyte receptors for 1,25-dihydroxy vitamin D, modifying and equilibrating the altered calcium homeostasis. In 1998 Parsad et al. demonstrated that the combination of PUVA plus calcipotriol permitted a more rapid repigmentation of vitiliginous patches compared to PUVA treatment alone (12). The effective treatmen t of vitiligo requires prompt evaluation of the site and extent of the lesions, as well as the degree of pigmentation of the surrounding skin. Vitamin therapy has proven to be useful and leads to satisfactory repigmentation when applied consistently and in appropriate dosages. Nevertheless, the long time required for the treatment-months or even years-before seeing results, indicates the need for further study of such supplementation in order to better understand how and when to use vitamins for vitiligo.

REFERENCES I.

2. 3. 4.

5.

Hann SK, Nordlund n, eds. Vitiligo. London: Blackwell Science, 2000:222-240 Lotti T, ed. La Vitiligine: Nuovi Concetti e Nuove Terapie. Milan: Utet, 2000:96140 Montes LF, Diaz ML, Lajous J, Garcia NJ. Folic acid and vitamin B12 in vitiligo: a nutritional approach. Cutis 1992; 50:39-42. Juhlin L, Olsson MJ. Improvement of vitiligo after oral treatment with vitamin B12 and folic acid and the importance of sun exposure. Acta Derm Venereol 1997; 77:460-462 Schallreuter KU, Schulz-Douglas V, Bunz A, Beazley W, Korner C. Pteridines in the control of pigmentation. J Invest Dermatol 1997; 109(1 ):31-35.

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Rokos H, Beazley WD, Schallreuter KU. Oxidative stress in vitiligo: photooxidation of pterins produces H 2 0 2 and pterin-6-carboxylic acid. Biochem Biophys Res Comm un 2002; 292(4):805-811. 7. Schallreuter KU, Moore 1, Wood 1M, Beazley WD, Peters EM, Maries LK, Behrens-Williams SC, Dummer R, Blau N, Thony B. Epidermal H 2 0 2 accumulation alters tetrahydrobiopterin (6BH4) recycling in vitiligo: identification of a general mechanism in regulation of all 6BH4-dependent processes? 1 Invest Dermatol 200 I; 116(1): 167-174. 8. Akyol M, Celik YK, Ozcelik S, Polat M, Marufihah M, AtaJay A. The effects of vitamin E on the skin lipid peroxidation and the clinical improvement in vitiligo patients treated with PUYA. Em 1 Dermatol 2002; 12(1):24-26. 9. Norris AL, Bailey A, Askham 1, Whitehouse A, Clissold PM, Markham AF, Meredith DM. The expression of the c-kit receptor by epidermal melanocytes may be reduced in vitiligo. Br 1 Dermatol 1996; 134(2):299-306. 10. Grichnik 1M, Ali WN, Burch lA, Byers JD, Garcia CA, Clark RE, Shea CR. KIT expression reveals a population of precursor melanocytes in human skin. 1 Invest Dermatol 1996; 106(5):967-971. J1. Schallreuter KU, Pittelkow MR, Swanson NN. Defective calcium transport in vitiliginous melanocytes. Arch Dermatol Res 1996; 288: 11-13. 12. Ameen M, Exarchou Y, Chu AC. Topical calcipotriol as monotherapy and in combination with psoralen plus ultraviolet A in the treatment of vitiligo. Br 1 Dermatol200J; 145(3):476.

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25 Alternative Treatments for Vitiligo

lIaria Ghersetich, Benedetta Brazzini, and Torello Lotti University of Florence, Florence, Italy Giovanni Menchini University of Siena, Siena, Italy

Alternative and experimental treatment options have been added to the armementarium of established treatments used for vitiligo including psoralen photochemotherapy (PUYA), UYB phototherapy, corticosteroids, cosmetic camouflage, depigmentation, permanent tattooing, and surgical treatments. Considering these options, it is not always easy to determine the efficacy of alternative treatment options for vitiligo, as nearly 10% of patients vitiligo can undergo spontaneous repigmentation. In addition, the placebo effect of any treatment must also be considered.

L-PHENYLALANINE Several studies have demonstrated that treatment with oral and/or topical L-phenylalanine and sunlight or UYA induces repigmentation of vitiligo patches, especially if used in combination with other treatments. Phenylalanine is not photo toxic; it actually induces tolerance to sun exposure ofvitiligo patches. Phenylalanine inhibits the activities of cytolytic antibodies, allows sunlight to stimulate the migration of melanocytes from adjacent areas, and encourages the production of melanin in the damaged melanocytes of the follicular bulb (1-3). Copyrighted Material 285

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Existing algorithms suggest that 50 mg/kg of L-phenylalanine be given to patients 30 minutes to I hour before UVA therapy. The initial dosage of 1 J/cm 2 is increased I J/cm 2 every two treatments up to a maximum dose of 7-9 J/cm 2 for skin types I-III and 12-15 J/cm 2 for skin types IV-V. It is recommended to treat patients twice weekly for 12-36 weeks (1). A second method is to give patients 50 mg/kg of phenylalanine daily 45 minutes before 30 minutes of sun exposure and to have patients apply a 10% phenylalanine gel 15 minutes after the oral dose (2). L-Phenylalanine can also be used in combination with narrowband UVB microphototherapy. Patients ingest 1500 mg ofL-phenylalanine 3 hours before UVB exposure. Follicular repigmentation of the hypopigmented macules usually occurs after 3-6 months of therapy. Good repigmentation occured on the periorificial areas, especially the face, but no satisfying results were seen on the trunk or distal portions of the limbs (1-3). No serious side effects have been reported aside from mild nausea. Contraindications include phenylketonuria, abnormal kidney and liver function, malignant skin diseases, pregnancy breast-feeding, history of arsenic exposure, prior radiotherapy (Fig. I) and autoimmune disorders.

KHELLIN AND UVA

Khellin is a furanochromone derivative isolated from seeds of the plant (Ammi visnaga) found in eastern Mediterranean areas. Its chemical structure is very similar to that of psora lens, and it exerts similar photobiological therapeutic effects. Khellin forms prevalently monofunctional photoadducts with cellular DNA and is therefore less photo toxic, mutagenic, and carcinogenic than psoralens, but it is apparently able to induce repigmentation similarly to psoralens (4). It has been reported that khellin is a useful alternative drug, when combined with UVA (KUVA), for the treatment of patients with localized (nonsegmental) or generalized vitiligo. Khellin can be administered either systemically or topically and in combination with sunlight or UV A therapy (5-7). For topical treatment, a 2% solution of khellin in acetone 90% and propylene glycol 10% must be applied to affected areas I hour before UV exposure. When topical khellin is combined with sunlight exposure, the patient is recommended to sunbathe initially for 10 minutes and increase the exposure time 10 minutes each week up to a maximum of90 minutes. The therapy is performed 3 days a week on alternate days for at least 4 months. When UVA exposure is chosen, patients undergo a constant UVA dose that

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FIGURE

1 Ammi visnaga.

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varies, according to the skin phenotype, between 10 J/cm 2 for skin types I-III and IS J/cm 2 for skin types IV-V. For systemic therapy, patients are treated with an oral daily single 100 mg dose of khellin. On the day ofUV exposure 100 mg of khellin must be administered 2.5 hours before irradiation. The UV therapy is the same as for topical khellin. Therapy is maintained as long as the repigmentation process continues and should be stopped when repigmentation ceases. Short-term side effects may occur with both topical and systemic administration of khellin, but longterm side effects other than hyperpigmentation of healthy skin have not been reported. The short-term side effects are mainly represented by mild nausea, orthostatic problems, and elevation of liver transaminase (8). When liver transaminase levels increase, khellin must be discontinued.

MELAGENINA I AND II

Melagenina 1 is a hydroalcoholic extract of the human placenta identified in Cuba in 1976 (9). Melagenina I contains lipids, free fatty acids, amino acids, phospholipids, and mineral salts (copper). The active ingredient is an a-lipoprotein prepared by crushing the cotyledons of human (or other mammalian) placentas and extracting the low molecular weight lipoprotein with 95% ethanol (10, II). This purified active principle is called melagenina II. The a-lipoprotein EP-50 added to dihydroxyphenylalanine (DOPA) seems to accelerate the conversion of DOPA to melanin. However, this reaction is dependent on the pH (alkaline pH) and the presence of mineral salts (copper and other cations) in the solution. Melagenina should be applied to all vitiliginous areas of the body three times a day, usually at 8-hour intervals. The treated areas are exposed once a day for 15 minutes to infrared light or sunlight. To date, no adverse local or systemic effects have been reported. The results, in terms of repigmentation, reported in the literature are very controversial (12,13), and the quality and safety controls used are unclear. For example, it is not clearly specified whether each placental sample is screened for the presence of infectious agents (in particular AIDS and hepatitis viruses). The use of mel agenina remains experimental until random double-blind studies are performed for both efficacy and safety.

MINOXIDIL

Topical application of rninoxidil (14) in combination with PUVA seems to accelerate repigmentation in vitiligo patients. The theory behind this therapy

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was based on the fact that repigmentation in vitiligo patches occurs first in the perifollicular areas and that minoxidil induces darkening of hair in addition to regrowth. However, later experiences failed to demonstrate the effectiveness of this therapy (15).

HOMEOPATHY

The disciplines of homeopathy and homeotossicology consider vitiligo not as a cutaneous disease, but as an external reflection of an inner pigment disorder. Vitiligo is therefore considered a disorder of the entire human system and not just of the skin. On these bases, homeopathic doctors strongly believe in treating vitiligo exclusively with oral therapy. In addition, each individual suffering from vitiligo (or any other disease) is considered a unique case, and therefore homeopathy believes in treating the patient and not the disease. This means that each patient is specifically treated as a whole. Homeopathy promotes a constitutional approach based on the analysis and evaluation of various factors affecting the human constitution to determine the disease diagnosis and the exact treatment. Every case of vitiligo requires evaluation of the patient's "constitution," which includes various aspects of the physical features as well as an in-depth study of the emotional sphere (emotions, psychosocial background, etc.). When the homeopathic remedy selected is administered in the correct dose, it brings back harmony at the constitutional level, stimulating normal pigmentation. Unfortunately, double-blind studies are lacking.

AYURVEDIC MEDICINE

Ayurveda was originally a Hindu medical healing system which had its beginning more than 2500 years ago in the sixth century R.C. (Fig. 2). It was adapted by Buddhists and other religious groups and has recently undergone a rebirth in India and throughout the western world, where it is considered a viable alternative to allopathic Western medicine. Ayurveda is actually a humoral medical model. The humors are defined as air, bile, phlegm, and blood. Ayurveda postulates that most humans are born in humoral balance but soon lose this balance due to unbalanced diet, unbalanced emotional experiences, or traveling away from the physical location on the Earth which is most in harmony with his or her constitution. The primary means of returning to humoral balance is diet. While Ayurveda has general recommendations for diet that anyone can follow for optimal health, more serious illnesses are treated by a qualified Ayurvedic physician. For the treatment of vitiligo, Copyrighted Material

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FIGURE

2

Symbol of ayurvedic medicine.

ayurvedic medicine usually uses vegetarian products made with leaves, fruits, radishes, and barks of various plants administered orally. Accompanying exposure to sunlight or UV radiation is not necessary. Usually 3-6 months of therapy is needed. Double-blind studies are not available. CLIMATOLOGICAL AND BALNEOLOGICAL THERAPIES

Vitiligo is a dermatological disease that can benefit from sun exposure and the use of mineral spring waters and mud from the Dead Sea (16,17). The Dead Sea is located at the lowest point on Earth-400 m below sea level-and it is the saltiest lake, its salinity reaching 290 giL. The natural elements and minerals in the sea, in addition to the mud present on its shores, give the water their curative powers. An other important factor in this cure is from the naturally filtered ultraviolet radiation, which permits prolonged exposure to sunlight with minimal phototoxicity. The therapeutic effects are in part due to the thick atmospheric layer over the Dead Sea, with its vapor and haze, and

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to the large amounts of ozone present. The climatic conditions may also have a positive effect on the neuro-immuno-cutaneous-endocrine system, by inducing the release of neuropeptides such as a-melanocyte-stimulating hormone and proopiomelanocortin (POMe), the precursor of endorphins, that seem to playa central role in OYB-induced cutaneous melanogenesis (18,19).

REFERENCES 1.

2.

3. 4.

5. 6. 7. 8. 9

10. II. 12.

13. 14. 15,

Cormane RH, Siddiqui AH, WesterhofW, Schutgens RBH. Phenylalanine and UV A light for the treatment of vitiligo. Arch Dermatol Res 1985; 277: I26130 Cormane RH, Siddiqui AH, WesterhofW, Schutgens RBH, Hu R, Mohan VI. Treatment of vitiligo with L-phenylalanine and light. Sr J Dermatol 1986; 115: 587 Camacho F, Mazuecos J. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Arch Dermatol 1999; 135:216-217. Morliere P, Honigsmann H, Averbeck D, Dardalhon M, Huppe G, Ortel B, Santus R, Dubertret L. Photo therapeutic, photobiologic and photosensitizing properties of khellin. J Invest Dermatol 1988; 90:720-724. Mandell AS, Haberman HF, Pawlowski D, Goldstein E. Non PUVA nonsurgical therapies for vitiligo. Clin Dermatol 1997; 15:907-9 I9. Orecchia G, Perfetti L. Photochemotherapy with topical khellin and sunlight in vitiligo. Dermatology 1992; 184(2):120-123. Ortel B, Tanew A, Honigsmann H. Treatment of vitiligo with khellin and ultraviolet A. JAm Acad Dermatol 1988; 18(4 pt 1):693-701. Duschet P, Schwartz T, Pusch M, Gschnait F. Marked increase of liver transaminase after khellin and UVA therapy. J Am Acad DermatoJ J989; 21:592-593. Cao CM, Taboas M, Garcia J, Gonzalez E. Estudio experimental y c1inico del efecto pigmentante epidermico del extracto placentario humano. In: Melagenina, ed. Seleccion de Trabajos de Investigacion Publicados y Presentados en Eventos Cientificos, 1976-1989. Havana, Cuba: Palacio de las Convenciones de Cuba, 1989:21-30. Cao CM, Taboas M. Placental alfa-lipoprotein for stimulating the synthesis of melanin. German Patent. 3229-738 (Ch-AG J-K-37-07) February 16, 1984. Nordluna 11, Halder R. Melagenina: an analysis of published and other available data. Dermatologica 1990; 181:1-4. Cao Me. Melagenina: 16 anos de experiencia cubana en el tratamiento del vitiligo. La Melagenina, Nuevo Medicamento Cubano para el Trattamento del Vitiligo. Havana, Cuba: lmpreso, 1989:3-20. Suite M. Quamina DBE: Treatment of vitiligo with topical melagenina-a human placental extract. J Am Acad Dermatol 1991; 24: 1018-1019. Oumeish OY. Climatotherapy at the Dead Sea in Jordan. Clin Dermatol 1996; 14:659-664. Srinivas CR, Shenoi SD, Balachandran e. Acceleration of repigmentation in

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16.

17.

18.

19.

Ghersetich et al. vitiligo by topical minoxidil in patients on photochel11otherapy. Int J Dermatol 1990; 29(2): 154-155. Orecchia G, malagoli PG, Santagostino L. Topical minoxidil does not potentiate the effect of sunlight in vitiligo repigmentation. Ann Ital Dermatol Clin Sper 1994; 4881-83 Kushelevsky AP, Harari M, Kudish AI, Hristakieva E, Ingber A, Shani J. Safety of solar phototherapy at the Dead sea. J Am Acad Derl11atol 1998; 38(3): 447-452. Chakraborty A, Slol11insky A, Ermak G, Hwang J, Pawelek J. Ultraviolet B and melanocyte stimulating hormone (MSH) stimulate mRNA production for alpha MSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes. J Invest Dermatol 1995; 105:655659. Lotti T, Bianchi B, Brazzini B, Hercogova J, Ghersetich 1. Can the brain inhibit inflammation generated in the skin? The lesson of alpha-melanocyte-stimulating hormone. lnt J Dermatol2002; 41(6):311-318.

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26 Vitiligo: Problems and Surgical Solutions Rafael Falabella Universidad del Valle, Cali, Colombia

GENERAL CONSIDERATIONS

Most vitiligo patients become affected between 5 and 30 years of age, but a good number of them develop this condition thereafter (1); sometimes the disease appears after age 50, although it is infrequent after the seventh decade of life. The condition does not produce a physical handicap, it is asymptomatic, but may be psychologically devastating (2). The cause of vitiligo is not completely known, but many factors contributing to depigmentation have been documented. Although medical therapy has improved considerably in recent years, at the present time complete repigmentation cannot always be achieved, particularly in acral regions. Surgical therapy has provided additional success for refractory areas, offering higher repigmentation rates, but proper selection of patients for such treatments is important to reach adequate results. Vitiligo is a condition with two main clinical forms of presentation: unilateral vitiligo (segmental, asymmetrical) and bilateral vitiligo (nonsegmental, symmetrical) (3). Unilateral vitiligo affects young patients mainly before the age of 20, most of them having a rapid course for a few months after which stabilization occurs without further depigmentation. Involvement of regional areas on one side of the cutaneous surface is usually observed, and remarkably high rates of repigmentation with surgical techniques are frequently achieved in this form of vitiligo (4,5). In contrast, bilateral vitiligo is a slow-developing condition, sometimes rapid spread, with a tendency to progress throughout the years, and with fewer possibilities of stabilization. Copyrighted Material 293

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In a small percentage of these individuals, arrest of the condition may occur, but surgical repigmentation may only be obtained in less than 50% of the treated patients (5,6). This chapter will deal not only with the techniques, but also with the problems associated with the mechanisms of repigmentation and specific difficulties observed when surgery is performed.

PATHOGENESIS OF VITILIGO: CLUES FOR SURGICAL SOLUTIONS When surgical intervention is considered, general knowledge as to why depigmentation occurs in vitiligo is important for understanding the possibilities and limitations of such therapies. Intrinsic damage to melanocytes leading to the intracellular accumulation of abnormal proteins (7), immune alterations with humoral and cellular participation (8), autocytotoxic damage to pigment cells because of the generation of catechols, phenols, and other molecules during melanin synthesis (9), pathological changes of fine nerve endings within the epidermis and upper dermis together with neuropeptide disturbances (10), and biochemical altera tions of pteridines wi th subseq uent increase of hydrogen peroxide and free radicals (II) have been implicated in the pathogenesis of vitiligo as etiological theories, in which different molecules may provoke toxic and/or inhibitory effects on pigment cells, but the real cause and sequence of events leading to depigmentation are yet to be determined. A convergence theory, suggesting that all factors described in these theories may contribute to the pathogenesis of vitiligo, has also been proposed (12). In other ailments associated with vitiligo, such as endocrine disorders, which are the most frequently observed, organ-specific antibodies have also been described. Among these alterations, thyroid disorders, diabetes, hypoparathyroidism, adrenal insufficiency, and hypogonadism, either alone or in combination, as in the polyglandular endocrine syndromes types I and II, are the endocrinopathies reported (13). In summary, although the ultimate cause of vitiligo is not completely known, this condition reflects not a mere pigmentation loss but the result of profound immunological alteration and other molecular defects acting for variable periods of time that originate melanocyte destruction; nevertheless, and regardless of the affected area, melanocytes may be present in depigmented skin even after years of onset (14) and may still respond to medical therapy under appropriate stimulation. When the condition becomes stabilized and the acting depigmenting noxa becomes in some way arrested, the possibilities for repigmentation are considerably higher and surgical therapies may be successful.

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THE REPIGMENTATION PROCESS When melanocytes are stimulated during medical therapy, pigment cells originate and proliferate from three different sources: (a) from the pilosebaceous unit, which provides the highest number of cells, migrating from the external root sheath toward the epidermis (15); (b) from spared melanocytes that were not affected during depigmentation, present in large numbers within hypopigmented areas, and being less numerous in depigmented lesions (14); and, finally, (c) from the border of lesions, migrating up to 3-4 mm from the edge. Jn recent years a new population of immature melanocytes expressing the C-kit protein (an important molecule implicated in melanocyte development and migration during embryogenesis), located mostly around the follicular ostium but less abundant in the rete pegs and eccrine sweat ducts, has been described; these cells have been suggested as the true melanocyte reservoir and would provide pigment cells for repigmentation of the new epidermis regenerating after trauma or other types of skin injury or to replace melanocytes tha t disappear by destruction or apoptosis, as may happen in vitiligo (16). VITILIGO: A "COSMETIC" VERSUS "SOCIAL" DISEASE Vitiligo is a symptom-free disease and does not provoke the usual manifestations of cutaneous illness, namely pruritus, pain, burning or stinging sensations, paresthesia, and so on. However, patients are very concerned with this ailment and feel that developing depigmentation will interfere with their interacting with other individuals. Social rejection is not uncommon, and employment opportunities are frequently limited by some sort of stigmatization not observed in other common dermatoses (2,17). However, it is frequently claimed by insurance companies and health programs that this is a "cosmetic" disease, and coverage is denied as a general rule. Dermatologists must be aware of this difficulty and should make every effort to prove, beyond a doubt, that patients did not have the condition when they enrolled in their insurance program and that the disease imposes limitations on many normal life activities, as in other physical ailments, leading to important social implications. For vitiligo surgery, but also for medical therapy, this is a very important issue. SELECTION OF CANDIDATES FOR SURGICAL REPIGMENTATION Repigmentation surgery is done with invasive methods, and for this reason, since vitiligo may initially respond well to a number of medical therapies,

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these should be tried as a first-line therapeutic approach; therefore, although much improvement may be achieved with surgical interventions, they are only useful when lesions become refractory to medical treatments, in which case melanocyte grafting and/or transplantation may offer additional benefit to some selected patients. Stable Disease

In spite of the difficulty in assessing the stability of vitiligo, the more accurately this factor is determined, the higher the possibility of success. It has been proven beyond a doubt that unilateral (segmental) vitiligo is the most stable form of vitiligo and the one that responds best to surgical maneuvering, with numerous publications supporting this fact (18). On the other hand, when bilateral vitiligo exhibits stability, repigmentation may also be attained with surgical therapy, but as a rule only half of these patients will improve (5). The most important factors that help to establish stability are: 1.

2. 3.

4. 5.

No progression of lesions or development of additional depigmentation during at least 2 years: although some patients may become stable before this time, a relatively recent and apparently nonprogressive lesion may be active and unresponsive to surgical treatment, or a slow progressing one may be difficult to evaluate. Spontaneous repigmentation, which is a sign of vitiligo inactivity. A positive minigrafting test showing repigmentation around 4~5 minigrafts of 1.0 or 1.2 mm, implanted 3--4 mm apart within an achromic area to be repigmented, is a clear indication of future recovery, if surgical methods are used, and may also disclose the type of response; besides, it is the most accura te evidence of vitiligo stability and, when the test is positive, it may predict a high rate of success. Absence of new koebnerization, including response at the donor site after removing small punches for the minigrafting test. Diagnosis of unilateral (segmental) vitiligo per se is almost a synonym for stable disease with an excellent repigmentation response when treated.

Methods and Size of Lesions

Depending on the size of the area to be treated, the method may vary and becomes an important factor to be defined. Simple methods such as minigrafting and suction epidermal grafting are useful for small- or medium-sized lesions; in contrast, the only methods that may be feasible for extensive depigmented defects are those involving in vitro culture techniques (19).

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Lesions on Exposed Areas Most patients express a desire for treatment of at least those lesions on exposed areas that are visible to other people. In addition, one of the most important refractory anatomical regions, namely the dorsum of the hands, can sometimes be successfully repigmen ted in patients with stable disease (20); although the dorsum of the fingers does not usually respond to surgical therapies, repigmentation can also be achieved in selected patients with stabilized disease (18,21). Age Because of the invasive nature of surgical procedures, they are not recommended in children; nevertheless, highly motivated preadolescents can be treated if there is a high possibility ofrepigmentation, but sedation or general anesthesia should be considered. It is not surprising to see patients beyond the age of 50 who may be interested in surgical repigmentation. Psychological Aspects This is an important factor that needs to be evaluated. Some patients with high emotional trauma because of depigmentation may seek advice about invasive procedures. Surgical methods are not perfect and may result in minor side effects that may not be accepted by these patients. A psychological evaluation may be needed to ascertain the real need for surgical treatment. Photographic Records Adequate photographic documentation of lesions before the procedure, complemented by postsurgical illustrations, is recommended to help in determining the percentage of improvement, quality of repigmentation, and possible occurrence of side effects. Patient's Expectations Photographs of other patients may be of value in illustrating the expected outcome. Repigmentation is not often comparable with normally pigmented skin, and the final results vary considerably from patient to patient. However, most individuals are pleased with the achieved results, if performed adequately, and the minor imperfections are far less important than the noticeable improvement of vitiliginous skin, mainly in patients with a dark complexion (22); however, in some patients it is surprising to see that surgical repigmentation may look even better than is observed in many patients after medical therapy. Copyrighted Material

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Achromia Versus Hypopigmentation The best lesions to treat are those corresponding to completely depigmented lesions in patients with skin types III-VI. Hypopigmented lesions do not repigment appropriately and sometimes may develop moderate hyperpigmentation. Once again, a mini grafting test may disclose this possible side effect before it happens. Method and Donor Site Appropriate training with a specific method is an important prerequisite to performing surgical therapy. The donor site should be as hidden as possible, and the gluteal region may be a suitable donor area for this purpose in most patients. These facts should be taken into consideration, as patients will not be satisfied if significant side effects occur Donor sites should also be appropriately handled to prevent additional damage to healthy and normally pigmented donor skin during surgical procedures (23). Serial Procedures Most procedures require more than one intervention, especially in relatively large lesions, and several stages may be needed to accomplish full recovery or to treat minor depigmented defects not responding to previous interventions. Combination methods may be of value to accomplish this goal. Contraindications A bleeding defect, if not corrected, is a contraindication for surgery. Patients who developed hyperpigmentation in previous areas of trauma should be carefully evaluated before making a decision on surgical therapy. Cost and Insurance Reimbursement Costs depend on the method used, and although culture techniques are the most expensive, at present they are usually covered by research centers. When performing minigrafting, thin dermo-epidermal graft or suction epidermal graft costs can be estimated by comparing these procedures with other osmetic methods; for example, the time involved in these techniques is helpful to determine more accurately the possible procedure costs. Perhaps most important is to provide all the necessary information to insurance companies, to make clear that this is not merely a "cosmetic" repair, since the patient did not have the achromic defect at birth or when enrolling in their insur-

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ance coverage, and also because depigmented lesions frequently become a handicap by decreasing job opportunities and social interaction.

SURGICAL COMBINATION THERAPY The possibility of combination therapy should be kept in mind from the beginning of surgical repigmentation, and this is an important concept that should always be considered (24). It is not infrequent for small spots within a repigmented area to remain depigmented in spite of an appropriate procedure; if these areas are large enough, the intervention may be repeated to overcome the repigmentation failure; if small, minigrafting is a very useful method for residual depigmented areas. When repigmentation becomes unsuccessful, another method could be tried, although chances of repigmentation may be lower when previous failures occur. In addition, combining surgical methods with PUVA therapy (25,26) may be very useful to obtain deeper and faster repigmentation.

DIFFICULT-TO-TREAT AREAS With surgical procedures, much improvement is achieved, particularly in unilateral vitiligo; however, there are certain areas that are difficult to repigment, such as joints, lips, eyelids, genitalia, cutaneous folds, dorsum of hands and feet, and especially fingers and toes. In some of these anatomical sites, postoperative movement of grafted zones prevents a good take, and in spite of appropriate immobilization, repigmentation is difficult to achieve; some of these areas may need regrafting, and recovery is possible in some patients. Nevertheless, other factors not known at present may prevent a good repigmentation response. Further research to render these areas more susceptible to medical or surgical therapy, either alone or in combination, will be a great contribution for treating acral vitiligo. METHODS Five basic methods have been described for repigmentation surgery, but several modifications of such methods ha ve also been published. These methods can be summarized as follows: (a) non cultured epidermal suspensions; (b) thin dermo-epidermal grafts; (c) suction epidermal grafting; (d) punch minigrafting; and (e) cultured epidermis with melanocytes or cultured melanocyte suspensions (23). How to decide on a specific method is a matter of the surgeon's preference and knowledge of a given technique. In general, all methods are

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useful for repigmentation, and the most important factor leading to acceptable results is expertise when performing the technique. Also, the less invasive the method and the less dermal manipulation is done, the fewer are the possibilities of scarring. Graft size and thickness when manipulating the dermis is critical in obtaining a smooth repigmented surface. These facts should be discussed with the patient.

Noncultured Melanocyte Suspensions

This is a rather simple method by which repigmentation is achieved when grafting a noncultured epidermal suspension bearing both keratinocytes and melanocytes; after grafting, the depigmented defects recover within months because of the pigment cells present in this cellular suspension. Initially a thin shave from the donor site is harvested and immediately digested with 0.25% trypsin for 2 hours at 3rc. Separation of the epidermis from the dermis occurs, and with vigorous pipetting, epidermal cells, including melanocytes, will separate and form a cell suspension. After washing the cells with phosphate buffer saline and reconstituting the cell suspension, it is injected into blisters raised by liquid nitrogen freezing or "seeded" on the recipient site previously prepared by removing the depigmented epidermis with superficial dermabrasion (27). The recipient site is covered for 5-7 days with nonadherent or semi-permeable dressings. After complete healing, repigmentation will begin and continue gradually during the following months. A modification of this method, by adding a melanocyte culture medium to prepare the epidermal suspension, has been described (28); with this enriched cell suspension, it is possible to enhance the repigmentation yield and cover larger depigmented defects (Fig. 1).

Thin Dermo-epidermal Grafts

The aim of thin dermo-epidermal grafts is to replace the achromic lesions of vitiligo with very thin sheets of epidermis and dermis, harvested from the donor site with a suitable dermatome at a depth of 0.1-0.3 mm, which is critical to avoid the scarring that usually occurs when using thicker grafts. The recipient site is prepared by removing the epidermis and papillary dermis with superficial dermabrasion; once this is done, the thin dermo-epidermal sheets are grafted directly on the already abraded area. Grafts are placed next to each other, covered with petrolatum gauze, and secured with surgical wrappings which are kept on for one week. Repigmentation is shortly achieved in the following weeks, since me1anocytes are present within the thin grafts. The method is very useful, although the yield is that of a l-to-l ratio. Difficult

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~ ~: ~

b

'

FIGURE 1 Noncultured melanocyte suspensions: (a) donor site: a thin dermoepidermal sample is harvested by shaving; (b) after digestion with 0.25% trypsin, a melanocyte-keratinocyte suspension is obtained; (c) recipient site: the epidermal suspension is spread onto a superficially dermabraded depigmented surface; (d) repigmentation occurs by coalescence of neighboring treated spots until complete recovery is achieved.

areas, such as the dorsum of hands and fingers, have been grafted with success (29). However, good to excellent results depend on the thin nature of grafts and appropriate immobilization (Fig. 2). It is important to rule out a keloidal diathesis to avoid developing this complication on both donor and recipient sites. Since the superficial dermis is manipulated, the cosmetic result may disclose minor defects such as hyperor hypopigmentation, and in some patients slight scarring may occur. A modification of this technique is the so-called flip-top graft, where small 35 mm thinly shaved dermo-epidermal fragments are inserted under very thin similar flaps raised on the recipient site (30); with this method, multiple grafts separated a few mm from each other provide small pigmentary islands that will coalesce by pigment spread within a few months after grafting.

Epidermal Grafting Epidermal grafting has become very popular and yields excellent results; many publications refer to the absence of secondary effects, particularly

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\-, IA v\. 'vlf\A.l

d FIGURE 2 Thin dermo-epidermal grafts: (a) recipient site: the depigmented epidermis is removed by very superficial dermabrasion; (b) donor site: a thin dermoepidermal graft is harvested with a suitable dermatome; (c) recipient site: the thin graft is placed onto the dermabraded area; (d) recipient site: repigmentation occurs shortly after healing and pigmentation also spreads between adjacent grafts.

scarring, which allows reusing the donor site for treating additional areas. The method is performed in two phases: I.

2.

Donor site: the grafts are harvested with any of the diverse types of custom-made suction devices so far reported (21,25,26,31); different types of syringes have been also used as suction devices with success (32,33). The preferred suction diameter for individual blisters should not be larger than I cm to avoid excessive bulging of the skin within the suction device that may interfere with blistering. Blisters develop in 3-4 hours, but ifheat is provided during suction, epidermal grafts may be harvested in less than I hour (25,34). Recipient site and grafting maneuvers: removal of the achromic epidermis may be achieved in different ways; if liquid nitrogen is used, the procedure is done b¥ freezing small 5-10 mm spots; blistering occurs a few hours later, but grafting is performed 2

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days later when the inflammatory changes originated by freezing su bside; the blistered epidermis is only removed on the day of grafting, just prior to implanting the epidermal sheets. An alternative method is to remove the epidermis from the recipient site by superficial dermabrasion or ultrapulse CO 2 laser (35,36). Immediately after the recipient site is properly denuded, the blister grafts are then cut with iris scissors, transferred to a thin transparent grafting spatula, and grafted onto the recipient site (37), a maneuver that can also be performed with thin acetate films (38). When the procedure is terminated, nonadherent dressings are placed on the grafted surface and wrapped with elastic bandages for 5 days (Fig. 3); after healing, sunlight exposure for 10-15 minutes daily is recommended for stimulating neo-melanogenesis. Repigmentation occurs gradually by melanocyte and pigment spread around the

I

0J

FIGURE 3 Suction epidermal grafting: (a) donor site: 1-3 hours after suction, donor blistered epidermis is ready for grafting; (b) donor site: the blister graft is released with iris scissors and harvested with a thin grafting spatula; (c) recipient site: the graft is placed onto a depigmented area, previously blistered 2 days before with liquid nitrogen freezing; (d) recipient site: repigmentation occurs by melanocyte proliferation and pigment spread arising from the grafted spots.

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grafted epidermis until complete coalescence is achieved. PUVA may enhance markedly the repigmentation process (25,26). Minigrafting Because of its simplicity minigrafting has become one of the most commonly used method for vitiligo surgery. Two phases are necessary in this procedure: I.

2.

Donor site: after local anesthesia, multiple perforations are made with a small punch measuring 1.0-1.2 mm. Minigrafts are then harvested with iris scissors and manipulated with a fine-tipped forceps or hypodermic needles used as handling instruments, placed on a nonadherent dressing moistened with normal saline solution and kept under sterile conditions until transferred to the recipient site. The gluteal region, near to the midline, is an excellent donor site for most patients. Recipient site and grafting maneuvers: the depigmented skin must be prepared before harvesting the minigrafts by perforating the recipient holes with a punch of a similar size, at a distance of 3--4 mm from each other. For facial lesions in young patients a 1.0 mm punch is recommended, leading to good repigmentation and no scarring at all; punches of a larger size may provoke unsightly scarring provoking a "cobblestone" appearance (23). The harvested minigrafts are transferred to the recipient site, and Monsel solution is applied to the grafted surface to seal the periphery of minigrafts and thus prevent postoperative transudation that may interfere with a good take. The grafted surface is finally covered with Micropore tape directly on the minigrafts to assure adequate immobilization without any other special dressing, which is removed 2 weeks later after adequate healing occurs. Other methods that can be tried for covering the treated surface are transparent semi-permeable or nonadherent dressings, according to the surgeon's experience (Fig. 4). After an appropriate take, repigmentation occurs gradually around each minigraft up to 2 mm from the edge and by coalescence of the small pigmentary islands, but moderate daily sunlight exposure is important after healing for several months to stimulate melanogenesis (37,39) (Fig. 5).

Cultured Epidermis with Melanocytes and Melanocyte Suspensions With modern technology, cultured epidermis with melanocytes and pure melanocyte suspensions have been successfully used to repigment vitiliGo. Copyrighted Material b

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4 Minigrafting: (a) donor site: minigrafts are harvested with a small 1.0 or 1.2 mm punch; (b) donor site: minigrafts are removed to be transferred to nonadherent surgical dressing moistened with saline solution; (c) recipient site: minigrafts are placed within perforations of similar size previously done at a distance of 3-5 mm apart from each other; (d) recipient site: repigmentation gradually occurs by coalescence of melanocytes and pigment spread arising from adjoining minigrafts. FIGURE

Epidermal sheets may be obtained with a small donor skin sample, from which an epidermal suspension is made by 0.25% trypsin digestion and seeded in culture flasks with appropriate culture media to stimulate both keratinocytes and melanocytes. A thin epidermal sheet is obtained after 3 weeks, which is removed from the culture vessel, placed onto a nonadherent gauze, and finally transferred to the recipient site previously denuded with liquid nitrogen freezing (40), superficial dermabrasion (35), CO 2 or pulsed Erbium-Y AG lasers (36,41). Melanocyte suspensions may also be cultured in a similar manner with very specific media but without epidermal cells, spread onto the recipient surface, and covered for 5-7 days until a good cellular take occurs (42,43). Repigmentation is attained in both cases during the following weeks and months, but sunlight exposure or PUVA will enhance and facilitate the recovery of the grafted lesions (Fig. 6). When using a hyaluronic artificial matrix for growing keratinocytes and melanocytes (44) or transplantation of epidermal sheets with melanocytes on achromic areas denuded with diather1110surgery (45), remarkabltc5pWR)Ht~tfIMmt#l~1s have also been reported.

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(a)

(b) FIGURE 5 (a) Unilateral vitiligo on the side of the face in this 17-year-old boy developed 10 years before and remained stable. A positive minigrafting test (arrow) discloses the possibility of repigmentation by surgical methods. (b) One and a half years later, after three minigrafting procedures, the lesion was completely repigmented. (From Ref. 51.)

Melanocyte suspensions kept under freezing for several months and recultured again after thawing have been transplanted onto achromic defects, resulting in successful repigmentation, indicating an enormous potential for future repigmentation technologies (46). One advantage of these methods is that a large population of cells may be obtained from a small donor site, and large areas can be treated in a single session.

ARTIFICIAL UV OR SUNLIGHT EXPOSURE FOLLOWING TREATMENT Neomelanogenesis begins shortly after melanocyte grafting or transplantation and continues for several months at a slow rate. However, faster and

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FIGURE 6 Cultured epidermis with melanocytes and melanocyte suspensions: (a) donor site: a small thin skin sample is harvested; (b) the skin is processed in the laboratory through several stages to develop melanocyte suspensions or epidermal sheets with melanocytes; (c) recipient site: the thin, in vitro cultured epidermal sheet is placed on a depigmented defect previously prepared by superficial dermabrasion, or the melanocyte suspension is spread onto a similar lesion; (d) recipient site: repigmentation gradually develops within the following months by coalescence of the epidermal grafts or by proliferation of melanocytes arising from the grafted pigment cell suspension.

deeper repigmentation is observed when UV exposure, either with natural sunlight or PUVA, is done. It is frequently observed that if no UV exposure is additionally administered, repigmentation may be slow, incomplete, or may even fail. UV exposure may be initiated after graft survival is demonstrated and continued until full repigmentation is attained. Initially, grafts and the repigmented surface frequently exhibit a hyperpigmented appearance, but in time this effect will fade and gradually subside, matching the surrounding skin appearance in most patients. SIDE EFFECTS OF VITILIGO SURGERY

Surgical procedures are invasive methods in which manipulation of donor and recipient sites is performed. Careful handling of both sites should be properly done to avoid important side effects.

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Keloids

A keloidal diathesis should be ruled out, and patients bearing keloids should not be treated. This complication can be easily prevented by observing the patient's old scars. If doubts still persist, a small test area, such as the minigrafting test, should be done before performing the definitive procedure. Hyperpigmentation

A similar approach is recommended for patients with a tendency for posttraumatic hyperpigmentation. In such cases, a hypopigmented lesion could be converted into a markedly pigmented defect, which may look unsightly and even worse than the initial depigmented lesion; this complication could be more likely due to an enhanced pigmentation diathesis than a common side effect of melanocyte grafting and UV light exposure. Old trauma to the skin may disclose permanent areas with hyperpigmentation that may be interpreted as a warning against performing repigmentation surgery. "Cobblestoning"

This effect occurs when performing grafting with large punches; punch grafts of 3-4 mm are not recommended because of the poor cosmetic results (47). The preferred sizes are 1.2 mm for trunk and extremities and 1.0 mm for facial areas, particularly in young patients (23). Scarring

Hypertrophic scars, thick grafts, and grafted areas with uneven surfaces are the most important side effects occurring when dealing with dermo-epidermal grafts. Very thin sheets are necessary for obtaining good to excellent results. For this purpose, a suitable dermatome with the ability to shave very thin dermo-epidermal sheets is important; the thickness should be around 0.1-0.3 mm, and therefore a plain knife or surgical blade for surgical shaving does not provide suitable graft thickness. Infection

When procedures are carried out with adequate asepsia, this is an infrequent complication.

CONCLUSIONS AND POSSIBLE SOLUTIONS

Surgical methods are important for treating stable and refractory vitiligo after failure with medical therapies. High repigmentation rates are obtained with all procedures so far described in most anatomical locations, but they are of Copyrighted Material

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little success for acral areas. Unilateral vitiligo is the clinical form with the best response to grafting and transplantation methods, although a good proportion of patients with inactive bilateral disease also respond well. Nevertheless, appropriate patient selection is important to achieve maximal results. What can we expect from future therapy? The ideal situation would be that melanocytes could migrate continuously under the influence of a specific molecular signal, since they are only able to migrate a few mm, mostly from the periphery of the hair follicle reservoir or from the edge of lesions, when adequate therapy is administered. In recent years several molecules acting as signals, such as leukotriene C4, transforming growth factor alpha (48), basic fibroblast growth factor, stem cell factor, and endothelin-l (49), have been shown to stimulate pigment cell migration in culture in a random, nonlinear manner. If similar and more potent and/or specific molecules become identified and available, it is conceivable that when applied to vitiliginous skin, they could stimulate melanocyte migration, originating a continuous movement of these cells from the edge of pigmented skin toward depigmented skin that would be very useful for recovering extensive vitiligo areas. Furthermore, if small grafts of normally pigmented skin are implanted within large depigmented defects, even several cm apart from each other, theoretically, melanocytes arising from these artificially created pigmentary reservoirs could be stimulated with such molecules and a faster and probably complete repigmentation would be achieved. In addition, combination therapy with PUVA, UVB, or lasers. together with these stimulatory molecules, could also help to enhance repigmentation (50). Future research will provide the answers, but perhaps, in this regard, the future is not too far away.

REFERENCES I.

2. 3. 4. 5.

6.

7. 8.

Hann SK. Nordlund n. Clinical features of generalized vitiligo. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000:35-48. Porter 1, Beuf A, Lerner A, Nordlund 11. Response to cosmetic disfigurement: a study of patients with vitiligo. Cutis 1987; 39:493-494. Hann SK, Nordlund 11. Definition of vitiligo. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000:3-6. Falabella R. Treatment of localized vitiligo by autologous minigrafting. Arch Dermatol 1988; .124:1649-1655. Falabella R, Arrunategui A, Barona MI, Alzate A. The minigrafting test for vitiligo: detection of stable lesions of melanocyte transplantation. 1 Am Acad Dermatol 1995; 32:228-232. Hann SK, Chun WH, Park YK. Clinical characteristics of progressive vitiligo. Int 1 Dermatol 1997; 36:353-355. Boissy RE. The intrinsic (genetic) theory for the cause of vitiligo. In: Hann SK, Nordlund 11, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000:123-128. Bystryn 1C. Theories oe6Mt,Jfg~wmlerfaJepigmentation.Immune hypo-

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9.

10. II.

12. 13.

14.

15. 16.

17. 18. 19. 20.

21.

22. 23. 24. 25. 26.

thesis. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000: 129-136. Hann SK, Chun WHo Autocytotoxic hypothesis for the destruction of melanocytes as the cause of vitiligo. In: Hann SK, Nordlund JJ, eds. Vitiligo. OxFord: Blackwell Science Ltd., 2000: 137-141. Orecchia GE. Neural pathogenesis. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000: 142-150. Schallreuter KU, Beazley WD, Wood JM. Biochemical theory of vitiligo: a role of pteridines in pigmentation. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000:151-159. Njoo M D, WesterhoF W. Vitiligo. Pathogenesis and treatment. Am J Clin Dermatol 2001; 2:167-181. Klisnick A, Schmidt J, Dupond JL, Bouchou K, Rousset H, Thieblot P, Humbert P, Vidal E, Aumaitre O. Vitiligo in multiple autoimmune syndrome: a retrospective study of II cases and a review of the literature. Rev Med Interne 1998; 19:348-352. Tobin DJ, Swanson NN, Pittelkow MR, Peters EM, Schallreuter KU. Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 2000; 191407-416 Cui J, Shen LY, Wang Gc. Role of hair follicles in the repigmentation of vitiligo. J Invest Dennatol 1991; 97410-416 Grichnik JM, Ali WN, Burch JA, Byers JD, Garcia CA, Clark RE, Shea CR. KIT expression reveals a population of precursor melanocytes in human skin. J Invest Dermatol 1996; 106:967. Porter J, Beuf A, Lerner A, Nordlund JJ. Psychological reaction to chronic skin disorders: a study of patients with vitiligo. Gen Hosp Psych 1979; 1:73-77. Falabella R. Surgical therapies for vitiligo. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000 193-200. Olsson MJ, Juhlin L. Transplantation ofmelanocytes in vitiligo. Br J Dermatol 1995; 132:587-911. Falabella R, Escobar C, Borrero 1. Treatment of refractory and stable vitiligo by transplantation of in vitro cultured epidermal autografts bearing melanocytes. J Am Acad Dermatol 1992; 26:230-236. Falabella R. Surgical techniques for repigmentation. In: Robinson SK, Arndt KA, LeBoit PE, Wintroub BU, eds. Atlas of Cutaneous Surgery. Philadelphia: W.B. Saunders Co., 1996:175-184. Falabella R. Grafting and transplantation of melanocytes for repigmenting vitiligo and leukoderma. Int J Dermatol 1989; 28:363-369. Falabella R. Surgical therapies For vitiligo. Clin Dermatol 1997; J5:927-939. Falabella R, Barona M, Escobar C, Borrero I, Arrunategui A. Surgical combination therapy for vitiligo and piebaldism. Dermatol Surg 1995; 21 :852-857. Skouge JW, Morison WL. Vitiligo treatment with a combination of PUVA therapy and epidermal autografts. Arch Dermatol J995; 13J:1257-1258. Hann SK, 1m S, Bong HW, Park YK. Treatment of stable vitiligo with autologous epidermal grafting and PUVA. J Am Acad Dermatol 1995; 32:943-948.

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31. 32.

33. 34. 35.

36.

37. 38. 39. 40.

41.

42.

43. 44.

45.

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Gauthier Y. Les techniques de gretfe melanocytaire. Ann Dermatol Venereol 1995; 122627-631. Olss n MJ, Juhlin L. Leucoderma treated by transplantation of a basal cell layer enriched suspension. Br J Dermatol 1998: 138:644-648. Kahn A, Cohen MJ. Vitiligo: treatment by dermabrasion and epithelial sheath grafting. J Am Acad Dermatol 1995; 33:646-648. McGovern TW, Bolognia J, Letfell DJ. Flip-top pigment transplantation: a novel transplantation procedure for the treatment of depigmentation. Arch Dermatol 1999; 135:1305-1307. Falabella R. Repigmentation of leukoderma by autologous epidermal grafting. J Dermatol Surg Oncol 1984; 10:136-144. Kim HU, Yun SK. Suction device for epidermal grafting in vitiligo: employing a syringe and a manometer to provide an adequate negative pressure. Dermatol Surg 2000; 26:702-704. Gupta S, Shroff S, Gupta S. Modified technique of suction bli tering for epidermal grafting in vitiligo. Int J Dermatol 1999; 38:306-309. Peachey RD. Skin temperature and blood flow in relation to the speed of suction blister formation. Br J Dermatol 1971; 84:447-452. van Geel N, Ongenae K. De Mil M, Naeyaert JM. Modified technique of autologous noncultured epidermal cell transplantation for repigmenting vitiligo: a pilot study. Dermatol Surg 2001; 27:873-876. Oh CK, Cha JH, Lim JY, Jo JH. Kim SJ, Jang HS, Kwon KS. Treatment of vitiligo with suction epidermal grafting by the use of an ultrapulse CO 2 laser with a computerized pattern generator. Dermatol Surg 200 I; 27:565-568. Falabella R. Surgical therapies for vitiligo and other leukodermas, part I: minigrafting and suction epidermal grafting. Dermatol Ther 200 I; 14:7-14. Albert S, Shenoi SD. Acetate sheets in the transfer of epidermal grafts in vitiligo. JAm Acad Dermatol 2001; 44:719-720. Falabella R. Treatment of localized vitiligo by autologous minigrafting. Arch Dermatol 1988; 124:1649-1655. Falabella R, Escobar C, Borrero 1. Transplantation of in vitro cultured epidermis bearing melanocytes for repigmenting vitiligo. J Am Acad Dem1atol 1989; 21 :257-264. Kaufmann R, Greiner D, Kippenberger S, Bernd A. Grafting of in vitro cultured melanocytes onto laser-ablated lesions in vitiligo. Acta Derm Venereol 1998; 78:136-138. Lontz W, Olsson MJ, Moellmann G, Lerner AB. Pigment cell transplantation for treatment of vitiligo: a progress report. J Am Acad Dermatol1994; 30:591597. Olsson MJ, Juhlin L. Transplantation of melanocytes in vitiligo. Br J Dermatol 1995; 132:587-591. Andreassi L. Pianigiani E, Andreassi A, Taddeucci P, Biagioli M. A new model of epidermal culture for the surgical treatment of vitiligo. Int J Dermatol 1998; 37:595-598. Guerra L, Capurro S, Melchi F, Primavera G, Bondanza S, Cancedda R,

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46.

47.

48.

49.

50. 51.

Falabella

Luci A, De Luca M, Pellegrini G. Treatment of "stable" vitiligo by timed surgery and transplantation of cultured epidermal autografts. Arch Dermatol 2000; 136: 1380-1389. Olsson MJ, Moellman G, Lerner A, Juhlin L. Vitiligo repigmentation with cultured melanocytes after cryostorage. Acta Derm Venereol (Stockh) 1994; 74:226-228. Malakar S, Dhar S. Treatment of stable and recalcitrant vitiligo by autologous miniature punch grafting: a prospective study of 1,000 patients. Dermatology 1999; 198:133-139 Morelli JG, Kincannon l, Yohn JJ, Zekman T, Weston WL, Norris DA. Leukotriene C4 and TGF-alpha are stimulators of human melanocyte migration in vitro. J Invest Dermatol 1992; 98:290-295. Horikawa T, Norris DA, Yohn JJ, Zekman T, Travers lB, Morelli JG. Melanocyte mitogens induce both melanocyte chemokinesis and chemotaxis. J Invest Dermatol 1995; 104:256-259. Falabella R. What's new in the treatment of vitiligo (editorial). J Eur Acad Dermatol Venereol 200 I; ] 5:287-289. Falabella R. Repigmentation of segmental vitiligo by autologous minigrafting. lAm Acad Dermatol 1983; 9:514-521.

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27 Tissue-Engineered Skin in the Treatment of Vitiligo Lesions

Andrea Andreassi, Elisa Pianigiani, Paolo Taddeucci, and Michele Fimiani Arezzo's Hospital and University of Siena, Siena, Italy

INTRODUCTION Vitiligo is a disfiguring disease that causes selective destruction of melanocytes and leads to the development of achromic lesions. Several surgical techniques have been developed in order to achieve repigmentation of the grafted achromatic areas in stable vitiligo, such as transplant of the tops of suction blisters (1,2), minigrafts (3,4), thin grafts (5), and transplant of suspensions of noncultured melanocytes and keratinocytes (6). Recently, surgical and cultural methods have furthered the possibilities of treating stable cases of vitiligo unresponsive to standard therapies. Membranes of autologous epidermis containing melanocytes grown in vitro (7), or suspensions of cultured melanocytes applied directly to abraded achromatic areas of the skin (8), have been demonstrated to be effective in this field. In 1991 we developed a new model of epidermal cultures consisting of cells grown on a membrane of hyaluronic acid (HA) completely esterified with benzyl alcohol (Laserskin). The membranes were perforated in order to allow cell proliferation in the holes and early colonization of the wound bed. For some time, we used HA composite cultures as grafts in burn patients with good results in terms of reepithelization and functional recovery (9). We observed that melanocytes also proliferated in these cultures and were detectable by

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DOPA reaction and S-100. This led us to graft this composite cultures in patients suffering from vitiligo (10).

OUR EXPERIENCE

The study population consisted of 59 patients (36 women, 23 men) ranging in age between 16 and 66 years (median: 33, 22), apparently free of systemic disease. All had localized, focal, or segmental vitiligo, refractory for at least 6 months to conventional topical and systemic therapies. The history of vitiligo ranged from 2 to 20 years and had been stable for at least 2 years. Results were evaluated by image analysis after 3, 6, 12, and 18 months and expressed as percent repigmentation. Materials

The biomaterial used as a support for the cell culture was a semi-synthetic biopolymer of hyaluronic acid, 100% esterified with benzyl alcohol, in the form of a transparent, flexible, perforated membrane with orderly arrays of laser drilled 40 [.lm micropores and larger 0.5 mm holes for fluid drainage (Laserskin, Fidia Advanced Biopolymers, Abano Terme, Italy). The high degree of esterification makes the membrane insoluble. The membrane was sterilized by gamma radiation. Cultures

Split thickness sheets of normally pigmented skin measuring 2 x 3 cm were obtained from the buttock of each patient under local anesthesia by means of an electric dermotome. Primary keratinocyte cultures were prepared by the classic method of Rheinwald and Green (II). Briefly, the sample was washed in phosphate-buffered saline (PBS) supplemented with antibiotics and cut into strips. The strips were placed in Petri dishes containing 0.5 gjL trypsin and 0.2 gjL ethylene-diaminotetra-acetic acid (EDTA) solution and incubated for 20 minutes at 3rC. The epidermis was separated from the dermis and scraped to obtain a cell suspension. Cells were washed in Dulbecco-modified Eagle's medium (D-MEM) supplemented with antibiotics, 10% fetal calf serum (FCS), L-glutamine, and then resuspended in 15 mL culture epithelial cell medium (CEC) consisting of D-MEMjHam's (3: I) with 10% FCS, 0584 mgjmL L-glutamine, 100 UjmL penicillin, 100 mgjmL streptomycin, 0.4 [.lgjmL hydrocortisone succinate, 5 [.lgjmL insulin, 5 [.lgjmL transferrin, 2 x 10- 9 M triiodothyronine and 10-9 cholera toxin without epidermal growth factor (EGF). All materials were procured from Sigma unless otherwise noticed.

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The cell suspension was seeded at a density of30,000 cellsjcm 2 in 75 cm 2 flasks previously provided with 20,000 cellsjcm 2 of lethally irradiated 3T3 fibroblasts. Composite cultures on Laserskinmembranes were obtained from primary semiconfluent cultures (Fig. I). HA membranes were cut into pieces 4-6 cm 2 in area and fixed to the bottom of 6 cm diameter Petri dishes by means of white petrolatum. The cell suspension was plated at a density of 30,00050,000 cells cm2 on the membranes, prepared the previous day with a feeder layer of lethally irradiated 3T3 fibroblasts. The medium was replaced completely every 2 days until confluence; 10-15 days after plating the membranes were detached and grafted.

Grafting Procedure All subjects were treated as outpatients. The day before the operation the areas to be treated were chosen. Achromatic lesions to be treated, each 10-200 mm 2 in size, were deepithelized by laser ablation. The epithelium was removed with pulsed Er:YAG laser (pulse energy: 5 Jjcm 2 ) using four pulse series. The area was then covered with the keratinocyte sheets, held in place with oily antiseptic gauze, which was changed every 5 days. The carrier was left in place until it detached spontaneously (7-10 days). The dressing was removed 5-7 days later and the area medicated with normal saline solution. The buttock wound was medicated daily with silver sulfodiazine cream until healed. The results were evaluated as an extent of

FIGURE 1

Composite cultures of Laserskin ™

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TABLE 1 Results in Vitiligo Patients Grafted with Autologous Epidermis on HA Biopolymer Support

Patients no., age (yr), sex 1.23, F 2.27, M 3.66, M 4.47, M 5.32, M 6.37, M 7.26, M 8. 60, F 9.21, F 10.39, F 11.31, M 12.34, M 13.38, F 14. 30, F 15.46, M 16.49, M 17. 19, F 18.42, F 19.28, F 20.26, M 21.41,M 22. 22, F 23.16, F 24. 17, M 25.34, F 26. 18, F 27. 19, F 28.36, M 29. 18, F 30. 20, F 31.31, F 32.40, F 33.27, M 34.28, M 35.21, F 36. 26, F 37.42, M 38.52, M 39. 24, F 40. 44, F

Duration of vitiligo (yr)

Grafted area

Size (cm 2 )

Repigmentation (%)

2 4 2 4 10 8 10 4 2 10 9 7 5 3 11 5 3 8 4 3 4 6 3 4 7 3 6 4 6 4 5 8 4 2 5 6 7 20 5 12

Face Left hand Right arm Neck Hands Left hand Left chest Left arm Chest Neck, forearms Arms Chest Left forearm Right forearm Left forearm Right hand Left forearm Forearms Face Forearms Face, neck Back Legs Hands Forearms Hands Left forearm Neck Left leg Face Left forearm Neck Face Thigs Neck Forearms Genitalia Face, neck Hands Forearms

10 60 80 60 80 80 200 40 20 80 100 100 100 100 100 50 100 100 40 100 50 100 100 60 100 50 100 80 100 50 100 100 50 100 80 100 20 80 60 100

100 95 96 100 0 53 90 40 91 49 71 60 42 53 82 72 90 82 60 72 65 85 85 25 70 25 62 90 100 32 65 75 20 85 65 85 0 35 52 72

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Continued

Patients no., age (yr), sex 41.20, 42.61, 43. 34, 44.65, 45. 16, 46. 17, 47.28, 48. 43, 49. 35, 50. 65, 51. 47, 52. 34, 53. 23, 54. 43, 55. 23, 56. 16, 57. 17, 58. 39, 59. 37,

F M F M M M M F F F F F F F F F F F F

317

Duration of vitiligo (yr) 8 15 6 4 2 4 8 6 4 18 12 8 3 11

5 4 3 5 6

Grafted area Face Forearms Forearms Face Hands Neck Face, neck Hands Left forearm Forearms Left forearm Forearms Face Forearms Hands Left forearm Left leg Forearms Left forearm

Size (cm 2 )

Repigmentation (%)

40 100 100 80 60 80 80 60 80 100 100 100 50 100 60 80 80 100 100

25 75 82 90 35 55 75 48 100 60 62 70 35 80 65 65 100 85 90

repigmentation of the achromatic area. The surface of repigmentation was calculated by image analysis using a special algorithm 3, 6, 12, and 18 months after the operation and was expressed as a percent area of repigmentation. The difference between the percent of repigmentation observed at each time period was then evaluated using the Wilcoxon signed rank test. Results The clinical re ults obtained in our patients are summarized in Table I. No relevant side effects were observed in our patients. Compliance was excellent in alJ cases, since all cases were treated as outpatients. The first signs of repigmentation were observed 1 month after grafting. InitialJy, islands of pinkish pigmentation were observed. Later, these spread to form patches that were sometimes hyperchromatic. In some cases, these patches finalJy fused completely and became pigmented like the surrounding skin. In most cases, repigmentation continued to increase for 3-6 months after grafing. The Koebner effect was not observed at the site of the skin biopsy in any patient, and there were no cases of relapse at follow-up after 18 months (Figs. 2, 3).

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(A)

(8) FIGURE 2 (A) Vitiligo on hands of 26-year-old man. (8) Twelve months after graft of same patient.

DISCUSSION

Vitiligo may be treated in many ways (12,13). The planning of a successful low-risk protocol requires the evaluation of many parameters, such as the site, degree of involvement, phototype, psychological impact, compliance, and type of treatment. Many authors have used different surgical techniques to treat certain forms of vitiligo. These methods have achieved different degrees

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(A)

(8) FIGURE 3 (A) Vitiligo on thighs of 28-year-old man. (8) Twelve months after graft of same patient.

of repigmentation and include transplantation of the tops of suction blisters (1,2), minigrafts (3,4), thin grafts (5), and transplantation of suspensions of noncultured melanocytes and keratinocytes (6). Some of these methods may have side effects that compromise the outcome: pebbly pigmentation is common with minigrafts, and graft retraction may occur with thin grafts. More recently, epidermal cultures (7) or cultured autologous melanocytes (8) Copyrighted Material

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have been shown to improve the outcome of surgical treatment of vitiligo. Interestingly, it is likely that transplantation is a sufficient stimulus for inducing melanocytes to reenter the cell cycle, even when inactive (14). Since vitiligo seems to be related to a dysfunctioning of the epidermal melanin unit (15), autologous cultured epidermis may be an optimal therapeutic choice in selected cases. Epidermal cultures obtained from normally pigmented sites may, in fact, provide a source of healthy melanocytes and keratinocytes for the repigmentation of achromatic patches (7,16). Moreover, in our opinion, therapies combining surgery and cell culture have advantages over the direct transplantation of epidermis, because only one biopsy is performed and the culture cells can be stored frozen and used in subsequent grafts. Cultured epidermis is difficult to handle, and manipulation affects cell vitality. The present method has none of these disadvantages, being simple, easy to perform, and using cultures that are vital when grafted. Also, this method, using composite cultures of autologous keratinocytes and melanocytes grown on membranes of HA polymer, is more effective than traditional cultured epidermis without the biomaterial support. The cells are seeded on the perforated membrane and grow actively in the holes, colonizing the wound bed and enabling repigmentation and reepithelialization. The membrane is easy to handle on the graft site and does not require any special medication. The fact that melanocytes can be cultured together with keratinocytes makes this technique useful in vitiligo patients refractory to all other known therapies. It gives good results even for large areas of achromatic skin, which can be grafted in stages with membranes stored in liquid nitrogen. Moreover, it seems preferable to use this type of composite culture, rather than a monoculture ofmelanocytes, because recent results suggest that the metabolic alteration of the keratinocytes within the framework of the epidermo-melanin unit plays a primary role in the pathogenesis of vitiligo (15). Our results show that in compliant vitiligo patients in whom the disease has been stable at least 2 years, the present technique produces complete and lasting repigmentation without side effects. This method is also successful for large areas of achromatic skin, which can be grafted in stages.

REFERENCES 1. 2. 3. 4.

Koga M. Epidermal grafting using the tops of suction blisters in the treatment of vitiligo. Arch Dermatol 1988; 124: 1656-1658. Na GY. Autologous suction blister grafting for the treatment of vitiligo. Ann Dermalol 1996; 8:9-24. Falabella R. Re-pigmentation of segmental vitiligo by autologous minigrafting. J Am Acad Dermatol 1983; 9:514-521. Boersma BR, Westerhof W, Bos JD. Re-pigmentation in vitiligo vulgaris by

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7,

8, 9.

10. II.

12. 13. 14. 15. 16.

321

autologous minigrafting: results in 19 patients. J Am Acad Dennatol 1995; 33: 990-995. Kahn AM, Cohen MJ. Vitiligo: treatment by dermabrasion and epthelial sheet grafting. J Am Acad Dermatol 1995; 33:646-648. Gauthier Y, Surleve-Bazeille JE. Autologous grafting with non cultured melanocytes: a simplified method for treatment of depigmented lesions, J Am Acad Dermatol1992; 26:191-194. Falabella R, Escobar C, Borrero I. Treatment of refractory and stable vitiligo of in vitro cultured epidermal autografts bearing melanocytes, J Am Acad Dermatol 1992; 26:230-236. Olson MJ, Juhlin L. Transplantation of melanocytes in vitiligo. Br J Dermatol 1995; 132:587-591. Andreassi L, Casini L, Trabucchi E, et al. Human keratinocytes cultured on membranes composed of benzyl ester of hyaluronic acid suitable for grafting. Wounds 1991; 3:116-126. Andreassi L, Pianigiani E, Andreassi A, et al. A new model of epidermal culture for the surgical treatment of vitiligo. Int J Dermatol 1998; 37:595-598. Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes in defined clonal and serum-free culture. J Invest Dermatol 1975; 6331-342. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for vitiligo. J Am Acad Dermatol 1996; 35:620-626. Antoniou C, Katsambas A. Guidelines for the treatment of vitiligo. Drugs 1992; 43:490-498. Haddad MM, Xu W, Medrano EE. Aging in epidermal melanocytes: cell cycle genes and melanins. J Invest Dermatol Symp Proc 1998; 3:36-40. Schallreuter KU, Wood JM, Pittelkow MR, et al. Increased MAO-A activity in the epidermis of patients with vitiligo. Arch Dermatol Res 1996; 288: 14-18. Zachariae H, Zachariae C, Deleuran B, et al. Autotransplantation in vitiligo: treatment with epidermal grafts and cultured melanocytes. Acta DermatoVenereol 1993; 73:46-48.

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28 UV-B Narrowband Microphototherapy: A New Treatment for Vitiligo Giovanni Menchini and Torello Lotti University of Florence, Florence, Italy Evridiki Tsoureli-Nikita University of Siena, Siena, Italy Jana Hercogova Charles University, Prague, Czech Republic

INTRODUCTION Although the precise biological mechanisms stimulated by ultraviolet (UY) light have yet to be confirmed, the efficacy of UY-B in vitiligo therapy is probably due to the high production of cis-urocanic acid, responsible for the cutaneous immune suppression that includes morphological and functional alterations of Langerhans cells (1-4). Data show that the mechanisms underlying UY-B-induced melanogenesis depend on a linear nitric oxide-GMPc transduction pathway. In fact, nitric oxide and GMPc, through the activation of protein kinase G, mediate the effects of UY-B radiation on melanocytes (3,4). Other reports attribute the increased melanocyte proliferation and melanogenesis to the activation of the cyclic-AMP pathway by a-melanotropin (5) or through melanocyte-stimulating hormone receptor-binding activity and melanocortin receptor gene expression, which are enhanced by UV-B irradiation (6). Thanks to these achievements in the last 10 years, we have taken part in a gradual transformation of the practice of phototherapy for vitiligo. The first Copyrighted Material 323

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step was the modification of the wavelength used from ultraviolet A (UV-A) to UV-B (7-10). Unfortunately, phototherapy with UV-B light was delayed because of its hypothesized role in carcinogenesis. In fact, at equal doses UVB induces more DNA dimers than UV-A (5,6). Simultaneously, other studies showed that the UV-B wavelength that is most effective in inducing repigmentation is the band at 311 nm (II). This evidence had critical importance in the development of new UV-B bulbs providing less intensity and a more restricted spectrum. The narrowband UV-B generator (Philips TL-OI) produces a high percentage of UV-B close to the peak of 311 nm and allows the dermatologist to use a lower intensity and cumulative dose, obtaining optimal efficacy on vitiligo patches (12,13). Nevertheless, patients suffering from vitiligo receive a high cumulative dose of radiation during their lives, and this leads to other cutaneous disorders like excessive tanning, photoaging, telangiectasis, etc.

FIGURE 1

The Bioskin microphototherapy device.

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Simplified scheme of the Bioskin device: a potent xenon generator (1) emits a beam of visible and UN irradiation (2), which is filtered by a particular interference filter (4) to obtain UV-B narrowband only. The time of emission is controlled by the operator, which acts on a time-controlled leaf shutter (3). The operator can also modify the intensity of the UV-B beam thanks to an iris diaphragm (6). Finally, the UB-V narrowband beam passes through a specific optical fiber (7) to reach the skin of the patient. FIGURE 2

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Wave-length (nanometers) FIGURE 3

Bioskin emission spectrum: the maximum peak is at 311 nm.

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In order to avoid side effects, a new phototherapy device, Bioskin ®, has been developed that allows selective narrowband UV-B (311 nm) treatment limited to the white patches. This new device has been particularly efficient in the treatment of limited affected areas of vitiligo vulgaris and segmental vitiligo (14,15). This new technique has several advantages: it does not increase the color contrast between normal pigmented and affected skin the total irradiation dose is minimal and depends on the percentage of body

TABLE

1

Characteristics of Patients

Characteristic Age (y) 8-10 11-20 21-30 31-40 41-50 ~51

Type of vitiligo Segmental Nonsegmental Sex Male Female Skin type I II III IV

<1

1-5 6-10 11-20 21-30 31-40 41-50 Course of disease Stable Unstable

=

22 94 167 201 132 118 68 666 331 403 1

V VI Disease duration (y)

aN

No. of subjects a

18 131 557 25 2

156 151 219 116 55 29 8

479 255

748.

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2 Mean Irradiation Doses of Various Areas During Each Session

TABLE

Area

Mean dose (mJ/cm 2 )

Eyebrows Face Chest Arms Legs Hands Feet

70

120 220 300

280 500

480

surface affected, and it is possible to irradiate different parts of the body (i.e., hands and feet) with a dose five or six times higher than the dose used for other parts (i.e., eyelids). BIOSKIN EQUIPMENT

Bioskin (Fig. I) is a phototherapy device consisting of a short arc generator emitting a beam of visible and ultraviolet radiation, filtered by a particular

(b) (a) FIGURE 4 (a) This 68-year-old woman has suffered from vitiligo vulgaris for 30 years; (b) after 9 months of Bioskin treatment, more than 90% of the vitiliginous areas were repigmented.

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interference filter in order to obtain the UV-B narrowband (Fig. 2). The time of emission is regulated by the operator, which acts on a time-controlled 2 shutter. Bioskin can provide a spectrum of intensity up to 400 mW/cm with an emission spectrum ranging from 300 to 320 nm and a peak emission of 311 nm (Fig. 3). According to the extent of the vitiligo patches, different conical hoods (1-5 cm diameter) can be applied at the end of the optical fiber to obtain different light spot diameter (Fig. 3).

(b) FIGURE 5 Complete repigmentation (a) before and (b) after therapy in a 57-yearold woman with a neck-localized form of vitiligo.

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BIOSKIN MICROPHOTOTHERAPY In a recent study (16) (Table I) 734 patients were irradia ted once every 2 weeks for 12 consecutive months. The UV-B narrowband irradiation was performed by the Bioskin device. During each microphototherapy session, all vitiligo patches were irradiated (excluding genital areas and mucous membrane). Although Bioskin equipment can provide a large spectrum of intensity (0-400 2 mW/cm ), in this study an intensity of 50 mW/cm 2 was used for all patients during all sessions. The initial dose of irradiation was 20% less than the minimum erythema dose (MED) evaluated on a vitiligous area at least 3 days before the beginning of the treatment. During the following sessions the dose was increased by 20% in every session until the development of erythema was noted. When erythema developed, the dose of the next session was diminished by 20% only in the erythematous area. Approximately 94% of our patient population had skin types II or III. The MED of Iesiona I skin in these patients was between 180 and 810 mJ/cm 2 evaluated with an intensity of irradiation of 50 mW/cm 2 Since the various body areas of the same subject show different erythema levels, the irradiation

(a) (b) FIGURE 6 Complete repigmentation (a) before and (b) after of a man affected by Vitiligo vulgaris after 4 months of Bioskin microphototherapy.

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dose for certain areas (i.e., hands, feet) was considerably increased compared to others (i.e., eyebrows, axillae). Table 2 shows the mean doses used during each session on different body areas. The extent of depigmentation varied from 3% to 38%. THE EFFICACY OF BIOSKIN MICROPHOTOTHERAPY

The duration of the clinical study was 2 years and 8 months (February 1999 through October 2001); the number of the patients recruited was 734. A mean of 40 treatment sessions were scheduled for each patient. After 6 months of treatment, 108 patients discontinued Bioskin microphototherapy treatment after reaching a level of cosmetically acceptable repigmentation, while 14 subjects dropped out for personal reasons. In the majority of the cases, repigmentation started about 2 months after the beginning of the microphototherapy. Usually the face showed faster and better repigmentation (Figs. 4-7) than the distal areas (Fig. 8).

FIGURE 7 A young man affected by the vulgaris form of Vitiligo: (a,b) at the beginning of Bioskin microphototherapy; (c,d) after 9 months of treatment, the repigmentation rate is 92%.

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FIGURE 8 Repigmentation results on the hand of a 65-year-old woman affected by a acrofacial form of vitiligo. After 9 months of treatment the repigmentation results were 85%.

At the end of the study period the results were as follows (Fig. 9): 510 subjects (69.8%) of the 734 had achieved normal pigmentation on more than 75% of the treated areas (112 of these were totally repigmented), 155 (21.12%) individuals achieved 50-75% pigmentation of the treated areas, and only 69 (9,40%) showed less than 50% repigmentation (vitiligo was aggravated in 5 of these subjects). The differences in the repigmentation of segmental and nonsegmental vitiligo were not statistically significant. The repigmentation rate obtained from this study is similar to those reported in other international studies using total body irradiation with UV-B normal band light sources and, overall, demonstrate the numerous advanCopyrighted Material

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RESULTS

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I II Q.

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CII

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Percentage of repigmentation of the treated vitiligo patches FIGURE 9 Results after 12 months of Bioskin microphototherapy in 734 subjects affected by vitiligo.

tages of the microphototherapy. The subjects enrolled in this study, as well as in other studies, presented a maximum skin involvement (vitiligous patches) of30% with respect to the total body surface, which means that the other 70% of the skin surface was not exposed at the UV-B radiation. Since the possibility of developing skin tumors is directly proportional to the cumulative irradiation dose and to the number of cells irradiated (in this case the extension of the cutaneous surface treated), this new phototherapy method has been suggested to reduce carcinogenic risk. This technique also permits the treatment of children younger than 10 years having vitiligo patches on less than 10% of the cutaneous skin surface, in light of the extremely low UV-B cumulative dose applied. In addition, the absence of hyperpigmentation of the perilesional (nonaffected) skin offers all patients the chance to undergo phototherapy that, if ineffective, will not worsen the dyschromic aspect, i.e., will not increase the darkness of the skin surrounding the white patches. An interesting aspect of this new technique is the possibility to vary the irradiation dose according to the specific anatomical location of the areas to be treated and their different responsiveness. The irradiation dose of each single area is, in our algorithm, 20% lower than the MED of that particular area. In this way, the irradiation dose can be adjusted according to the reaction of the irradiated areas. It is possible to increase the dose in less responsive areas, using constant irradiation on the areas that respond. Some Copyrighted Material

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areas are apparently more sensitive than others and tend to develop some erythema even after low-dose irradiation (i.e., eyebrows, axilJae). UV-B Bioskin microphototherapy, despite being a relatively expensive and not yet well-established treatment for vitiligo, is in our experience an efficacious, safe, and well-tolerated treatment for vitiligo when limited to less than 30% of the body surface.

REFERENCES I.

2.

3.

4.

5.

6. 7. 8. 9.

10, II.

12.

Amerio P, Toto P, Feliciani C, Suzuki H, Shivji G, Wang B, Sauder DN. Rethinking the role of tumour necrosis factor-alpha in ultraviolet (UV) B-induced immunosuppression: altered immune response in UV-irradiated TNFRI R2 gene-targeted mutant mice. Br J Dermatol2001; 144(5):952-957. EI-Ghorr AA, Pierik F, Norval M. Comparative potency of different UV sources in reducing the density and antigen-presenting capacity of Langerhans cells in C3H mice. Photochem Photobiol 1994; 60(3):256-261. Goettsch W, Garssen J, de Gruijl FR, van Loveren H. UV-B and the immune system. A review with special emphasis on T cell-mediated immunity. Thymus 1993; 21 (2):93-1 14. Moodycliffe AM, Kimber I, Norval M. The effect of ultraviolet B irradiation and urocanic acid isomers on dendritic cell migration. Immunology 1992; 77(3):394399 Cooke MS, Mistry N, Ladapo A, Herbert KE, Lunec J. Immunochemical quantitation of UV-induced oxidative and dimeric DNA damage to human kera tinocytes. Free Radic Res 2000; 33(4):369-381. de Gruijl FR. Photocarcinogenesis: UV A vs UYB. Methods Enzymol 2000; 319:359-366. Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UY-B radiation vs topical psora len plus UY-A. Arch Dermatol 1997; 113: 1525- J 528. Scherschun L, Kim JJ, Lim HW. Narrow-band ultraviolet B is a useful and welltolerated treatment for vitiligo. JAm Acad Dermatol 2001; 44(6):999-1003. Njoo MD, WesterhofW, Bos JD, Bossuyt PM. The development of guidelines for the treatment of vitiligo. Clinical Epidemiology Unit of the Istituto Dermopatico dell'Immacolata-Istituto di Recovero e Cura a Carattere Scientifico (IDIIRCCS) and the Archives of DermatoJogy. Arch DermatoJ 1999; 135(12):15141521. Koster W, Wiskemann A. Phototherapy with UY-B in vitiligo. Z Hautkr 1990; 65( II) 1022-1024 EI-Ghorr AA, Norval M. The UY waveband dependencies in mice differ for the suppression of contact hypersensitivity, delayed-type hypersensitivity and cisurocanic acid formation. J Invest Dermatol1999; 112(5):757-762. Njoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children with narrow-band (TL-O I) UYB radiation therapy. J Am Acad Dermatol 2000; 42(2 pt 1):245-253.

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334 13. 14.

15.

16.

Njoo MD, Spuls PI, Bos JD, Westerhof W, Bossuyt BB. Nonsurgical repigmentation therapies in vitiligo. Arch Dermatol 1998; 134: 1532-1540. Lotti TM, Menchini G, Andreassi L. UV-B radiation microphototherapy. An elective treatment for segmental vitiligo. J Eur Acad Dermatol Venereol 1999; 113(2): 102-108. Mechini G, Tsoureli-Nikita E, Hercogova J, Lotti T. UV-B Radiation microphototherapy in vitiligo vulgaris: results after one year of treatment in 528 patients. Int J Immunopath Pharmacol 2002; 13(5):365-369. Menchini G, Tsoureli-Nikita E, Hercogova J, Lotti T. Narrow-band UVB microphoto-therapy: a new treatment for vitiligo. J Eur Acad Dermatol Venereol. In press.

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29 Vitiligo: Problems and Nonsurgical Solutions

Giovanni Menchini and Torello Lotti University of Florence, Florence, Italy Evridiki Tsoureli-Nikita University of Siena, Siena, Italy Jana Hercogova Charles University, Prague, Czech Republic

The treatment of vitiligo, a chronic and recalcitrant disease, is difficult, and patients and dermatologists are often frustrated and discouraged by the persistence and irregular remission and relapses of the psychologically influenced and influencing disease. Nevertheless, a positive and emphatic approach to the vitiligo patient is mandatory. In our experience, subjects present with three major questions: I. 2. 3.

Can the progression of the disease be stopped? Can hyperpigmentation of the nonaffected skin be avoided during trea tment? Is 100% repigmentation possible?

When asked these questions, our replies include the following nonsurgical explanations and proposals. Copyrighted Material 335

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CAN THE PROGRESSION OF THE DISEASE BE STOPPED?

Vitiligo is progressive in 73.6% of cases and regressive in 1.3 % (1). We usually explain to our patients that progression (and prognosis) depends on the modality of spreading: segmental or nonsegmental. In 89% of the cases of segmental vitiligo, disease activi ty ceases after 11-25 months of rapid spreading over the affected dermatome, while nonsegmental vitiligo shows less progression only when it starts on the face (52.4% of cases). Furthermore, Koebner phenomenon and mucosal involvement are signs of significant progression (2). In 89% of cases we can arrest patch extension in nonsegmental vitiligo with oralminipulse corticosteroid therapy (5 mg betamethasone on 2 consecutive days per week) (3), and extension of segmental vitiligo can be blocked with PUVA therapy. Nevertheless, we inform our patients that treatment results are unpredictable and clinical trials are still ongoing.

CAN HYPERPIGMENTATION OF NONAFFECTED SKIN BE AVOIDED DURING TREATMENT?

Avoiding hyperpigmentation of nonaffected skin is a primary request of subjects who are concerned with the disfiguring effects of the disease and various treatments. Thus, total body phototherapy and photochemotherapy must be avoided in such cases. There are only two ways to avoid border hyperpigmentation during cure: application of topical corticosteroids or Bioskin ® 311-UV-B-focused microphototherapy.

Topical Corticosteroids

Low-, medium-, high-, and very high-potency topical corticosteroids (CCS) can be used as first-line treatment for patients with vitiligo (5~7). The most effective CCS seem to be class III and IV (betamethasone valerate 0.1-0.2% and clobetasol propionate 0.05%) (8-10). However, when the face, eyelids, or intertriginous areas need to be treated, class I and II steroids (hydrocortisone, fluocinolone acetonide 0.0 I %, or triamcinolone acetonide 0.1 %) should be used in order to decrease the risk of onset or worsening of glaucoma. Topical CCS should be used in cases of localized vitiligo « 20% of the skin surface involved), but not in segmental vitiligo. Good results have been obtained in generalized vitiligo, but the possible side effects limit this as a firstchoice treatment. Early lesions, especially these localized on the face and neck, respond best and most quickly to topical steroids, and this treatment is most effective

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on vitiligo patches of dark-skinned subjects (8,9). Corticosteroid cream should be applied on depigmented skin I or 2 times a day for not more than 4 months (10-14). If there is no evidence ofrepigmentation after 3 months, the treatment should be discontinued. Caution must be exercised when using topical steroids. The possibility of onset of side effects must be considered and therapy discontinued if necessary. Continuous use of topical steroids frequently leads to steroid-induced acne, epidermal atrophy, telangiectasia, local soreness, erythema, striae distensae, ecchymosis, hypertrichosis, pruritus, rosacea, or red-face syndrome (15). Vitiligo may affect children under 12 years of age (16), and physicians must consider that children, especially infants, are at an increased risk for side effects from topical steroid therapy. Thus, it is important not to use mid- or high-potency steroids, but only low-potency corticosteroids such as hydrocortisone, dexamethasone, and flumethasone, in children. Recent studies recommend the use of class III topical CCS (fluticasone propionate and betamethasone valerate) for children under 12 years of age (17). Narrowband Focused Microphototherapy

It is possible to treat only the vitiligo patches, avoiding normal skin, especially in subjects like children and if the surface affected does not exceed 20% of the total body surface. This allows reducing total dosage without compromising the results of the therapy (18). In order to limit side effects, a new phototherapy device, Bioskin, has been introduced that allows selective narrowband UV-B (311 nm) treatment limited to the white patches. The predominant part of the Bioskin device is the UV-B generator that generates a focused beam of UV-B light. This light is transmitted on vitiligo skin by a special optical fiber. The main characteristics of the Bioskin generator are that it produces UV -B rays, in a spectrum of300320 nm, with maximum emission at 311 nm; the energy displayed by the UV-B generator is 0-400 mJ/cm 2 /s and the diameter of the light spot is of 1-5 cm. This method has been particularly efficient in the treatment oflimited affected areas and segmental vitiligo (23-25) and has several advantages; in particular, it does not increase the color contrast between normal pigmented and affected skin, and the total irradiation dose is minimal depending on the percentage of body surface affected. The method consists of weekly sessions of irradiation of all vitiligo patches. The dose is 20% lower than the minimum erythema dose (MED), which is measured before the beginning of the treatment. Since the treatment permits differentiated irradiation, it is possible to irradiate hands and feet with a dose five or six times higher than the dose used for eyelids.

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IS 100% REPIGMENTATION POSSIBLE? It is frustrating for us as dermatologists to inform our patients that presently there is no sure treatment for vitiligo. Nevertheless, in our experience patients respond well to a sympathetic approach, including information about the social, cultural, and psychological aspects of the disease and even facts from relevant studies in the literature. In particular, we emphasize three trends: I.

2.

3.

In 1978, an investigator reported a case of a 73-year-old man who had a 20-year history of "piebaldism" on the face. After I year of treatment with oral prednisone (15-30 mgjday) for polymyalgia rheumatica, his face was completely repigmented (20). Up to 100% repigmentation has been observed after 1-2 years of continued treatment of oral folic acid and ascorbic acid plus parental treatment with vitamin B I2 (21). Spontaneous regression of the disease is seen in 1.3% of cases (2).

Finally, we inform patients that microphototherapy (23-25) and surgery (i.e., melanocyte grafting and transplantation or suction epidermal grafting) have been reported to result in 100% repigmentation on limited and stable patches of vitiligo (22). However, we also point out that: I.

2. 3. 4. 5.

It is not wise to administer 15-30 mgjdie per os prednisone for one year in an attempt to obtain total repigmentation of the face, and after stopping the treatment, vitiligo can re-present. The results of Montes et al. (21) with vitamin B I2 require confirmation. Spontaneous regression is not a common event in vitiligo. Bioskin microphototherapy may be costly and time consuming, In cases of vitiligo surgical treatments should can be used only for small, stable lesions.

At the end of such a discussion, patients are usually much more relaxed, and sometimes they even say "Actually, maybe for now there isn't anything to do for my vi tiligo. "

CONCLUSIONS Subjects with vitiligo present continually to us asking for a cure. In fact, most of them know that there is no sure cure and that the outcome of possible treatments is unpredictable. Nevertheless, in reply to their three main question, today we can propose some interesting, highly effective treatment strategies that are well tolerated and safe in the long term (22-25), including

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local steroid treatment, Bioskin focused microphototherapy, and surgical procedures plus a series of general treatments.

REFERENCES l. 2. 3.

4. 5.

6. 7. 8. 9. 10. II. 12. 13. 14. 15. 16. 17.

18.

Hann SK, Chun WH, Park YK. Clinical characteristics of progressive vitiligo. Int J Dermatol 1997; 36(5):353-355. Hann SK, Park YK, Chun WHo Clinical features of vitiligo. Clin Dermatol1997; 5(6):891-897. Pasricha JS, Khaitan BK. Oral mini-pulse therapy with betamethasone in vitiligo patients having extensive or fast-spreading disease. Int J Dermatol 1993; 32(10): 753-757. Korean J Dermatol 1995; 33:880. Njoo MD, Bossuyt PMM, Westerhof W. Management of vitiligo. Results of a questionaire among dermatologists in the Netherlands. Int J Derrnatol 1999; 38: 866-872. Mandell AS, Haberman HF, Pawlowski D, Goldstein E. Non PUVA nonsurgical therapies for vitiligo. Clin Dermatol 1997; 15:907-919. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for vitiligo. American Academy of Dermatology. J Am Acad Dermatol 1996; 35:620-626. Kumari J. Vitiligo treated with topical clobetasol propionate. Arch Dermatol 1984; 120:631-635. Geraldez CB, Gutierrez GT. A clinical trial of clobetasol propionate in Filipino patients. Clin Ther 1987; 9:474-482. Kandil E. Vitiligo-response to 0._ 010 betamethasone 17-valerate in flexible collodion. Dermatologica 1970; 141:277-28l. Kandil E. Treatment of vitiligo with 0.1 % betamethasone 17-valerate in isopropyl alcohol-a double-blind trial. Br J Dermatol 1974; 91 :457-460. Clayton R. A double blind trial of 0.05% clobetasol propionate in the treatment of vitiligo. Br J DermatoI1977; 96:71-73. Guozhu H, Changgeng S, Ganyun Y, et a!. The terapeutic effect of sicorten oinJllent in patients with vitiligo. Br J Dermatol 1977; 97:255-26l. Koga M. Vitiligo: a new classification and therapy. Br J DermatoI1977; 97:25526l. Jaisankar TJ, Baruah MC, Garg BR. Vitiligo in children. Int J Dermatol 1992; 31:621-623. Holbrook K, Sybert V. Basic science. In: Schahner L, Hansen R, eds. Pediatric Dermatology. New York: Churchill Livingstone, 1995:J7-18. Pasricha JS, Khaitan BK. Oral minipulse therapy with betamethasone in vitiligo patients having estensive or fast-spreading disease. Int J Dermatol 1993; 32:753757 Gibbs NK, Traynor NJ, MacKie RM, Campbell I, Johnson BE, Ferguson J. The phototumorigenic potential of broad-band (270-350 nm) and narrow-band (311-313 nm) phototherapy sources cannot be predicted by their edematogenic potential in hairless mouse skin. J Invest Dermatol 1995; 104(3): 359-363.

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340 19. 20. 21. 22. 23.

24.

25.

Menchini et al. Njoo MD, Spuls PI, Bos JD, Westerhof W, Bossuyt MM. Nonsurgical repigmentation therapies in vitiligo. Arch Dermatol1998; 134:1532-1540. Brostoff H, Brostoff J. Vitiligo and steroids. Lancet 1978; 2:688. Montes LF, Diaz ML, Lajous J, Garcia NJ. Folic acid and vitamin B12 in vitiligo: a nutritional approach. Cutis 1992; 50:39--42. Falabella R. Surgical therapies for vitiligo. Clin Dermatol 1997; 15:927-939. Lotti TM, Menchini G, Andreassi L. UV-B radiation microphototherapy. An elective treatment for segmental vitiligo. J Eur Acad Dermatol Venereol 1999; 113(2):102-108. Menchini G, Tsoureli-Nikita E, Hercogova J, Lotti T. UV-B Radiation microphototherapy in vitiligo vulgaris: results after one year of treatment in 528 patients. lnt J Immunopath Pharmacol 2002; 13(5):365-369. Menchini G, Tsoureli-Nikita E, Hercogova J, Lotti T. Narrow-band UVB microphoto-therapy: a new treatment for vitiligo. J Eur Acad Dermatol Venereol 2003; 17(2):171-177.

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30 Use of UVB in Vitiligo

Mario Lecha University of Barcelona, Barcelona, Spain

INTRODUCTION

In the treatment of vitiligo, phototherapy has been the most successful approach, especially for patients with widespread lesions. There is a long experience in the use of photochemotherapy since the introduction of this modality, usually with 8-MOP (PUVA), both oral and topical (1). The evolution of phototherapy in the last decade with the appearance of new modalities has prompted the use of these new modalities in the treatment of vitiligo with the aim to improve the results obtained with PUVA and avoid side effects, mainly of psoralen administration or application (2). There has been long experience with PUVA UVB phototherapy and especially narrowband UVB (NBUVB). The design of fluorescent tubes emitting UVB around 311 nm (NBUVB) has been a consequence of the results obtained in the study of therapeutic action spectrum for psoriasis (3). The success of this modality in psoriasis led to its indication in other diseases such as vitiligo. Previous experience in the treatment of vitiligo with UVB compared with PUVA was minimal (4). Because the therapeutic action spectrum in vitiligo is not known, all wavelengths may be used.

BACKGROUND, TREATMENT PROTOCOLS, AND RESULTS

The first data on UVB treatment of vitiligo (broadband UVB) appeared in 1990 when Koster and Wiskemann (4) reported their results. The first report of treatment with NBUVB appeared in 1997 (2). In this study, Westerhofand Copyrighted Material 341

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Nieuweboer-Krobotova compared this modality of treatment with topical psoralen plus UV A. The authors concluded that NBUVB was more effective compared to topical PUV A, with faster repigmentation. It is also notable that with NBUVB, the contrast between normally pigmented skin and depigmen ted skin was less striking as reported by these authors. In 1998 a first meta-analysis on nonsurgical treatments for vitiligo repigmentation appeared (5). Several treatment modalities were compared by the authors, including, for generalized vitiligo, UVA associated with methoxsalen, trioxsalen, bergapten, psoralen, phenylalanine, khellin, oral corticosteroids and one study with broadband UVB and another with NBUVB. The conclusion of this report is that the best levels of repigmentation in generalized vitiligo are obtained with UVB broadband or NBUVB and methoxsalen plus UVA, although for UVB treatments data are still insufficient. Subsequently, two other papers about NBUVB treatment for vitiligo appeared in the literature, the first about treatment in children (6) and the second including adults (7), both reporting good results. EI Mofty et al. reported in 2001 (8) results of comparing PUVA with 8-MOP plus broadband UVB with 8-MOP, indicating a similar efficacy for both treatment modalities. The use of UVB in the treatment of vitiligo has been also considered with combinations as topical application of pseudocatalase and calcium chloride or calcipotrioJ (9,10). Phototherapy with phenylalanine has been used since 1985 with either UVA and UVB. The major drawback of this combination treatment is side effects from oral phenylalanine administration. This protocol has been applied much more frequently with UVA than with UVB (II). For segmental vitiligo UVB has also been considered with a specific microphototherapy modality (12). Although experience with UVB treatment for vitiligo is still limited, most treatment series reported refer to NBUVB phototherapy. Treatment protocols (Table I) show slight differences in initial doses, increments per treatment, maximal dose per treatment, and treatment frequency. Treatment

TABLE 1

Treatment Protocols Ref 2

Initial dose Increments of dose after each treatment Highest dose per treatment No. treatments per week

0.075 J/cm 20%

2

Ref 6 2

0.25 J/cm 20%

2

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Ref 7 2

0.200 J/cm 0.050 J/cm 2

0.280 J/cm 2 15%

0.800 J/cm 2 2

3

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results are summarized in Table 2. These results are for patients achieving >75% repigmentation. Side effects in these cases were minimal, and no treatment discontinuation was needed. According to the results of Westerhof et al. (2), NBUYB seems to produce faster repigmentation. In 48% of their patients, 25-75% repigmentation was achieved after the first 3 months of treatment. Taking into account that not all patients will show the same level of repigmentation and considering that we may have at present a choice of phototherapic modalities to apply, it could be of interest to establish what type of patient would respond better to NBUYB or to PUYA. Parameters that have been considered in outcome evaluations are sex, age, phototype, years of onset of lesions, and extension. According to Scherschun et al. (7), in a report on a small series of patients, a better response with NBUYB was achieved in patients with phototypes IY and Y and short-lasting disease. The major advantages of the use of UYB or NBUYB are systemic psoralen side effects (i .e., no need for eye protection between treatments) and low cumulative total doses of radiation. These treatment modalities may be used in children and pregnant or lactating women. On the other hand, UYB treatments produce less erythema, no photo toxic effects, no epidermal thickening after long-term irradiation, and less contrast between normally pigmented skin and vitiligo patches. The ultraviolet radiation cumulative dose is lower and treatments are shorter. There is incomplete understanding of the mechanism of UYB repigmentation, but it appears that there may be no specific differences between UYB and PUYA. An interesting report regarding the possible mechanisms of UBY repigmentation by Imokawa et al. (13) indicated that human keratinocytes show increased expression of tyrosinase, endothelin-I, and IL-I a after UYB irradiation. Synthesis of endothelin-l is stimulated by IL-la, has melanogenic properties, and may be involved in UYB-induced repigmentation.

TABLE

2

Treatment Results with NBUVB Ref. 2

Ref. 6

Ref. 7

Number of patients Results (>75% repigmentation) Side effects Treatment duration

51 32 patients (63%)

51 27 patients (53%)

7 5 patients (71.4%)

No side effects 12 months

Itching erythema 12 months

Mean cumulative total dose

32.34 J/cm 2 (9.58-128.01)

Itching xerosis 12 months (100 treatments) 91.3 ± 46.6 J/cm 2

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Previous studies regarding mechanisms involved in vitiligo were related to oxidative stress in lesions of this disease, with local accumulation of H202 associated with low catalase levels and vacuolation of melanocytes. This phenomenon can be reversed by addition of catalase. These results prompted the topical application of pseudocatalase and its activation by UVB as a treatment approach for vitiligo. It has been used mainly in focal disease by Schallreuter et a!. (14). Other anecdotal treatment protocols have been suggested, but this fact unfortunately only reflects that we are still far from a satisfactory treatment for vitiligo. Even phototherapy, which gives the best possible results, is not satisfactory and is associated, moreover, with possible long-term side effects. This may also be the case for NBUVB, a phototherapy modality with very good short-term results (15). Evidence-based guidelines for the treatment of vitiligo indicate that for generalized vitiligo UVB phototherapy is recommended, but no statistical differences exist between PUVA, NBUVB, or broadband UVB regarding success rates.

REFERENCES I.

2. 3. 4. 5.

6

7. 8.

9.

Ortel B, Gonzalez S. Photo- und Photochemotherapie der Vitiligo. In: Krutmann 1, Honigsmann H, eds. Handbuch der dermatologischen Phototherapie und Photodiagnostik. Berlin: Springer-Verlag, 1997: 111-135. WesterhofW, Nieuweboer-Krobotova L. Treatment ofvitligo with UV-B radiation vs topical psoralen plus UV-A. Arch Dermatol 1997; 133:1525-1528. Parrish lA, laenicke KF. Action spectrum for phototherapy of psoriasis. 1 Invest Dermatol 1981; 76:359-362. Koster W, Wiskemann A. Phototherapie mit UV-B bei Vitiligo. Z Hautkr 1990; 65:1022-1029. Njoo MD, Spuls PI, Bos lD, Westerhof W, Bossuyt PMM. Nonsurgical repigmentation therapies in vitiligo. Meta-analysis of the literature. Arch Dermatol 1998; 134: 1532-1540 Njoo MD, BosJD, WesterhofW. Treatment of generealized vitiligo in children with narrow-band (TL-OI) UVB radiation therapy. 1 Am Acad Dermatol 2000; 42:245-253. Scherschun L, Kim JJ, Lim HW. Narrow-band ultraviolet B is a useful and welltolerated treatment for vitiligo. 1 Am Dennatol 200 I; 44:999-1003. EI Mofty M, Zaher H, Esmat S, Youssef R, Shahin Z, Bassioni D, El Enani G. PUVA and PUVB in vitiligo-are they equally effective? Photodermatol Photoimmunol Photomed 2001; 17: 159- 163. Schallreuter KU, Wood 1M, Lemke KR, Levenig C. Treatment ofvitilicro with a topical application of pseudocatalase aand calcium in combination wi~h short-

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10. II. 12.

13.

14.

15. 16. 17.

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term UVB Exposure: a case study on 33 patients. Dermatology 1995; 190:223229. Parsad D, Saini R, Nagpal R. CaJcipotriol in vitiligo: a preliminary study. Pediatr Dermatol1999; 16:317-320. Cormane RH, Siddiqui AH, Westerhoff W. Treatment of vitiligo with phenylalanine and light. Arch Dermatol Res 1985; 277:126-130. Lotti TM, Menchini G, Andreassi L. UV-B radiation microphototherapy. An elective treatment for segmental vitiligo. 1 Em Acad Dermatol Venereol 1999; 13:102-108. Imokawa G, Miyagishi M, Yada Y. Endothelin-I as a new melanogen: coordinated expression of its gene and the tyrosinase gene in UVB-exposed human epidermis. 1 Invest Dermatol 1995; 105:32-37. Schallreuter KU, Moore 1, Wood 1M, Beazley WD, Gaze DC, Tobin DJ, Marshall HS, Panske A, Oanzig E, Hibberts NA. In vivo and in vitro evidence for hydrogen peroxide accumulation in the epidermis of patients with vitiligo and its succesful removal by a UVB-activated pseudocatalase. 1 Invest Dertmatol Dermatol Symp Proc 1999; 4:91-96. Halder RM, Young CM. New and emerging therapies for vitiligo. Dermatol Clin 2000; 18:79-89. Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am 1 Clin Dermatol 2001; 2:167-181. Zanolli MD, Feldman SR, Clark AR, Fleischer AB II'. Phototherapy Treatment Protocols. New York: Parthenon Publishing, 2000:63-79.

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31 Cover-Ups: The View of the Cosmetologist

Alida DePase Bergamo, Italy

A global approach to vitiligo by the patient should take all physical and psychological aspects of the disease into consideration, and therefore the dermatologist should not only try a therapy, but also suggest products that can make the patient feel as normal as possible. Patients suffering from vitiligo can use camouflage: an aid that can help them overcome the emotional stress deriving from the uncomfortable relationship with their own appearance, which changes to an undefined extent as a result of this disfiguring disease. Three different types of cosmetic products can be used for camouflage or corrective make-up specific for vitiligo: cover creams, instant self-tanning creams and lotions, and stains and dye. Dermatologists are currently focusing great attention and interest on corrective make-up, because it can increase the patient's confidence and improve his or her quality of life. In addition. it is readily accepted by women, who, unlike children and men, are already accustomed to using make-up products. Even men Jearn the technique easily when they feel the need for it. The few dermocosmetic industries in the world that have focused on this specific sector in recent years have developed a range of effective and userfriendly products, with results very close to perfection. Reliability is the one common feature that cover creams, self-tanning creams and lotions, and stains and dyes specific for vitiligo must ha ve. In fact, these products are applied for very long periods of time, for many years or Copyrighted Material 347

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even for the patient's entire lifetime, until a safe and effective treatment can be found to totaIIy resolve the problem of vitiligo. Low toxicological effect is achieved thanks to tested formulas and ingredients for which the toxicological effects are widely known using selected substances. Formulas must be tested so as to guarantee perfect consistency over time. The formulas for these specific products must take their function into account; their specific features are represented by guaranteed stability over time, being insensitive to temperature changes, adhesiveness, and natural coloring, which should remain unchanged during the day. These specific products should be capable of creating films of different thicknesses, be waterproof, sweatproof, and heatproof. Cover techniques are not easy to learn, especiaIIy for beginners; but with patience and commitment using the right cosmetic products specific for vitiligo, results close to perfection can be achieved. COVER CREAMS

Cover creams can be liquid, compact, or in a stick. Their texture is denser than traditional foundation creams; in fact, this is necessary to provide effective cover. Cover creams contain up to 50% mineral oils and wax. Their different texture is due to titanium dioxide, used as a thickening and shielding agent. The coloring is provided by iron oxides. In general, these products are weII tolerated by patients. However, comedo phenomena, dermatitis and allergies can occasionally occur. These reactions are mainly due (in two-thirds of the cases identified) to fragrances and preservatives contained in these products. Dermocosmetic industries producing cover creams for camouflage provide us with a wide range of base colors, and in the majority of cases these are identical to the patient's skin coloring. SELF-TANNING PRODUCTS

People who do not suffer from vitiligo often use self-tanning products, because they not only provide a healthy and bright coloring but also moisturize and protect the skin. Self-tanning products have been marketed for about 30 years, but they were not very successful at first due to the yellowish and uneven coloring they provided; today's new formulas produce exceIIent aesthetic results. Self-tanning products are based on DHA (dihydroxy acetone), a substance that reacts with the proteins of the surface layer of the epidermis, "coloring" the skin a few hours after application and simulating a tanning effect. In the past, bergamot oil was also used to trigger a hyperactivation of

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melanin synthesis and create a tanning effect. However, the use of bergamot oil has been prohibited due to the high level of phototoxicity and the effects it may have on DNA stability. Therefore, bergamot oil is no longer contained, as was previously the case, in the formulas of self-tanning products intended for use by the general public. The use of psora lens has now been limited to the treatment of skin diseases such as vitiligo. With normal washing and natural skin renewal, DHA coloring gradually fades away, and the products currently on the market are safe and do not present any side effects. It is necessary to adopt specific application techniques of self-tanning products in vitiligo. The patient will choose from among colorless lotions with different DRA concentrations, which can be used for pale-medium-dark skin types. These lotions can be used throughout the year; they are waterproof and do not stain clothes and sheets. Sun-shielding products can also be applied after the desired color intensity has been obtained. Before applying the self-tanning products, it is necessary to ensure that the skin is adequately moisturized. It is also advisable to rub the skin with a soft brush to eliminate dead cells and obtain an even skin coloring. It is advisable not to apply the product during the hot hours of the day, because excessive sweat can result in an uneven application. Only a small quantity of the product should be applied at first; if the desired coloring is not achieved, it is possible to intensify the color with additional applications after a few minutes. If too much of the product is used, the result will be too dark or produce stains. Use a cotton swab for small-sized vitiligo lesion, and dip the tip in the selected product. Then spread the product working from the center of the lesion towards the outside, up to 1-2 mm from the lesion edge. The product can be spread over the entire skin area, including the naturally pigmented areas. Subsequently, application can be repeated over the white areas using a cotton swab dipped in the product. Avoid washing for 3 hours after the product has been applied.

OTHER PRODUCTS Vitiligo patients who do not like cover creams or self-tanning products can use liquid or gel dyes, which are very easy to apply using a cotton ball or while wearing gloves. Dyes immediately provide a natural, amber-like coloring, which can be adjusted to the desired shade by applying a single layer to get a lighter hue or additional layers to get a darker shade. A wide range of dyes in different hues are currently available. Their only disadvantage is that they fade away when washed with soap and water, but they are extremely easy to use and provide a natural result; they do not stain clothing and they are not greasy. The coloring agents are products normally used in the food industry

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and therefore are nontoxic. In brief, there are many ways to conceal vitiligo areas-even large ones-and give vitiliginous skin a natural color. The resulting aesthetic effect is a natural appearance, and the patient feels more confident. Coping with everyday life without having to face embarrassing questions or indiscreet looks; enjoying the possibility of wearing a shortsleeved shirt or shorts in the summer without being forced to hide hands in pockets; greeting a person with a handshake without fearing repulsion: this is what camouflage can do for vitiligo. The patient's life is definitely improved.

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32 Cover-Ups: The View of the Dermatologist

Rossana Capezzera, Cristina Zane, and Piergiacomo Calzavara-Pinton Spedali Civili, Brescia, Italy

INTRODUCTION

Results of standard and experimental treatment options for vitiligo are often disappointing, with no or only partial results. In addition, most therapies require treatment periods lasting months or years before repigmentation occurs, if at all (I). In the mean time, irrespecti ve of the extent of the disease, the cosmetic disfigurement of vitiligo may lead to emotional distress and loss of self-image and impair considerably the patient's private and professional life. The relevant psychological and social impact of the disease fosters the need for palliative treatments. Therefore, practically all patients with vitiligo may need adjunctive therapies for a short-or perhaps lifelong-period of time. A broad and heterogeneous group of cosmetics can mask the white spots, temporarily or permanently. Permanent camouflage involves cosmetic tattoo, whereas cosmetic makeup and skin dyes are a ready and practical, albeit temporary, solution that masks totally or partially the hypopigmented areas and restores a normal-looking appearance. These have been used since ancient times. The use of cosmetics does not improve or modify results of dermatological therapies but generally enhances the compliance with treatment programs because patients enjoy the psychological benefits of looking better while receiving specific medical care. Unfortunately, the psychological conCopyrighted Material 351

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sequences of impaired appearance are not sufficiently appreciated by physicians. Few dermatologists are fully aware of the benefits that can be obtained by the skilled use of cosmetics, and, as a consequence, their knowledge regarding colored foundations, lotions, cleansers, bleachers, self-tanning preparations, and tinted covers is often poor.

SKIN CAMOUFLAGE

Camouflage is a makeup technique for masking aesthetic damage. It can be permanent (tattoos) or temporary (cosmetic camouflage). Permanent Camouflage

Permanent camouflage is obtained with a cosmetic tattoo. The most effective pigments have peculiar physical and cosmetic characteristics. Unlike pigments used for ritual or symbolic tattoos, they are inert iron oxides that do not migrate or appear "blotchy" over time. The color is implanted into the dermal layer with specialized techniques and cannot be washed off. Very satisfactory results are obtained when only small areas of the face, particularly in the perioral area, and the dorsal hands are involved. Dark photo types are more easily treated than people with fair skin. Cosmetic results are strongly dependent on the doctor's or technician's skill in matching perfectly the color of the tattoo with the color of the surrounding skin area. Unfortunately, only a few have been adequately trained in color theory and understand the role that the skin's natural undertones play in the achievement of maximum uniformity. The colors of the tattoo fade naturally over time, requiring periodic maintenance, usually every 2-5 years. Temporary Camouflage

The uniform applica tion of thin films of selected opaque cosmetics wi th lightreflecting ingredients are very effective for covering, or at least reducing, the visual impact of white patches. Products for covering vitiligo are specific and quite different from other common cosmetic make-ups. Their main characteristics include (2,3): Varied colors for matching all ethnic skin tones and individual skin nuances. This can be achieved by mixing several cream bases. High opacity for concealing or masking achromic skin with the application of a thin layer of cream. High resistance against wash-off to ensure that they can be worn in the rain or when active in sports.

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Easy application, because cumbersome and time-consuming application will discourage their use. Persistence and adherence to ensure that they will be long wearing and easily repaired if necessary. Cosmetic products for camouflage are complex formulations of several components, as described in the following paragraphs. Pigments are colored substances that are chemically inert in regard to perspiration and sebum secretion. They are contained as insoluble ingredients in wet products (powders, compact cream, eye shadows) or suspended in a vehicle (cover cream emulsion) through physical and chemical links. The cover index (Cl.) identifies both chemical class and formulation. There are two chemical classes: inorganic (mineral) and organic (lacq uer) compounds. The former are more commonly used (Table I). Organic pigments are lacquering compounds obtained through the absorption and co-precipitation of hydroxides or sulfates of calcium, strontium, barium, and soluble dyes. (4,5). Natural or synthetic pearls give brightness to cosmetic products. Natural pearls are rarely used because of the very high cost, whereas synthetic ones are less expensive. They contain crystallized bismuth oxychloride, which has a metallic luster but poor light resistance, or titanium dioxide monomolecular layers and other pigments over mica layers. Ore charges have many functions: adhesion to the skin (calcium, magnesium, and zinc stearates), improvement of compactness (wax, rice starch, and modified starch), stickiness (talc), and transparency and absorption of skin lipids (talc, calcium precipitate carbonate, magnesium carbonate, colloidal kaolin, pyrogenic silica) Talc is most widely used, but it must be free of chlorine and amianthus fibers as well as bacterial contamination. Thyxotropic agents (purified organophilic bentonites, pyrogenic silica in addition to polymethacrylate and modified celluloses) can modify the

TABLE

1

Inorganic (Mineral) Pigments Available for MakeUp Products

Chemical nature Iron oxide Iron hydrate oxide Iron dioxide Titanium dioxide Zinc oxide Chromium oxide Chromium hydrate oxide Prussian blue

C.1.

Color

Composition

77491 77491 77492 77891 77947 77288 77289 77510

Red-ochre Yellow-ochre Brown-black White White Green Green-blue Blue-green

Fe203 FeO(OH)nH 20 FeOFe203 Ti0 2 ZnO Cr203 Cr2034H20 Cr4" 1 [Fe" (CN)6b

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viscosity of cosmetic products in order to prevent precipitation of the pigments. They are widely used for colored emulsions. Waxy vehicles enhance the compactness of the powders. They can be of animal (beeswax, lanolin wax), vegetable (carnauba, pedilanthus pavonis, rice bran, wax), or mineral (microcrystalline wax) origin. Fatty vehicles (e.g., vegetable glycerides, lanolin derivatives, hydrogenate lanolin, hydrogenated coconut oil, oily alcohols, white vaseline, synthetic glycerides) increase oiliness, softness, doughiness, and lubrification of cosmetic products and have high emollient activity. At room temperature, oily vehicles moisten and carry pigments because of their fluidity and ability to penetrate into the pores of the polymers. They can be of mineral (vaseline oil), vegetable (fluid glycerides, e.g., castor oil, oryza sativa, zea mays), animal (distillate alcohol of lanolin), or synthetic or semisynthetic (oleilic alcohol, silicone) origin. Solvent and emulsion vehicles used in cover-tinted creams are usually aqua and glyceryl stearate. Antioxidative alimentary agents, particularly tocopherol acetate, vitamin A, vitamin C, vitamin E, and lecithin, are natural moistening agents that allow the skin to breathe and function naturally. In addition, some studies claim they have reparative, antiaging, and antiphotoaging properties. The time onset of rancidity is used to assess their resistance over time. The most common cosmetic preservatives, parabens, have antifungal and antimicrobial properties. A defilement test (challenge test) assesses the minimal dose that ensures safety over a reasonable period of time. Fragrances are aromatic blends of natural or synthetic essential oils. Irritants as well as products with sensitizing and photosensitizing properties must be carefully ruled out. Sunscreens are added in order to avoid sunburn of white patches and prevent tanning of the surrounding normal skin that would enhance any chromatic difference.

COVER-UPS FOR TEMPORARY CAMOUFLAGE

Several different make-up products are available, including conventional compact and liquid foundations, stick foundations, pressed powders, fixing sprays, cleansers and "self-tanning" preparations. The prescription is based on the patient's individual needs and the location and size of the vitiligo areas. Cosmetics specifically designed for application on the face, body, or limbs are available. For example, tinted cover creams in a loose (liquid foundation) or pressed (compact foundation) form as well as loose and pressed powders are usually applied on the face (4,5).

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Compact Foundation Compact foundations have a high covering and masking ability and give brightness, opacity, and transparence to the skin. They are usually hypoalIergenic and allow the makeup to be long lasting, water- and sweat-resistant, as well as protecting the skin. In addition, they can filter partially or totally ultraviolet rays. Application with a soft sponge is easy, and removal is done with cleansing milk or makeup remover. These foundations are available in various tinted shades, allowing a perfect match to normal skin color.

Liquid Foundation Liquid tinted cover creams are available in various shades. Application is very easy, and soon after, a thin, fixing, absorbent and water-resistant powder can be applied. In addition to masking activity, they moisten, soothe, and soften the skin.

Stick Foundation Pink sticks are used for covering ivory vitiliginous areas. Colored stick foundations must be covered with makeup fluid or compact creams.

Pressed Powder Various pink shades of pressed powder, alone or in combination with colored sticks, are available for mimicking all skin colors. They can be applied with a small paint brush or a synthetic sponge for quick and easy retouch.

Fixing Spray A fixing spray dries and maintains the cover all the day. It is formulated with silicon and polymers, which create an elastic film on the makeup.

Self-Tanning Creams Self-tanning creams may be considered camouflage products as well. They allow the achievement of a coloration that mimics a tan (pseudo-tan) and masks the achromic areas without the exposure to ultraviolet radiation. Various formulations-creams, emulsions and lotions-are available. They contain 3-5% dihydroxyacetone, derived from sugar cane, which oxidizes the keratin of the horny layer, producing colored compounds that vary from yellow to brown. A natural-looking tan appears 4 or 5 hours after application and disappears gradually within a few days. They are usually well tolerated without relevant adverse effects. However, careful washing of hands and nails is needed after application in order to avoid unwanted coloration of Copyrighted Material

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the palms. Application is not recommended during phototherapy because self-tanning products can filter UV rays. Cleanser

Cleansers remove makeup products and residual skin impurities from the skin Several different formulations-emulsions, lotions, soap-free foaming gel, creams-are available.

METHODS OF APPLICATION

Several recommendations help to obtain optimal results: Cover creams must be tested directly on vitiliginous skin in order to closely match the color of the normal surrounding skin. The skin must be washed with a cleanser and a synthetic sponge in order to remove residual skin impurities and sebaceous secretions that reduce the holding power of the cover cream. The stick corrector must be applied before the makeup foundation to neutralize discoloration. Tinted cover creams must be applied with a foam rubber or synthetic sponge in a patting motion. The patting motion uniformly applies the product and avoids obstructing the pores.

FIGURE 1

Correct application of foundation.

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Camouflage of perioral vitiligo.

A small amount of the selected shade is placed on the outer surface of the hand before application to warm the foundation to body temperature. The foundation is applied with a sponge over the skin area by pressing to obtain maximum adherence. The setting powder should be colorless and translucent so that the camouflage product does not change color (Fig. 1). The finishing pressed powder is spread generously, and 2-3 minutes are needed for it to incorporate with the foundation. Brush off the excess powder and settle by pressing a damp tissue or sponge onto the skin surface. The fixing spray must be vaporized from a distance of about 50 em. It will become dry within a few seconds. Camouflage products are best removed with a water-soluble makeup remover. Alcohol- or acetone-based removers excessively dry and irritate sensitive skin. Apply the remover liberally to emulsify the camouflage makeup, wipe off with cotton pads, wash the areas with a mild, glycerine soap, rinse off thoroughly with warm water and pat dry, and, finally, apply the preferred moisturizer or emollient for sensitive skin. An example of camouflage of vitiliginous areas of the face is shown in Figure 2.

SIDE EFFECTS Permanent tattoing of the perioral skin is sometimes followed by recurrences of herpes simplex infection (2). Chronic granulomatous reactions to the implanted pigment are exceedingly rare. Copyrighted Material

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Cosmetic products for temporary camouflage are generally well tolerated if applied correctly. Nevertheless, it is not advisable to use camouflage products on chapped, dry, or inflamed skin. Allergic contact dermatitis to fragrances and preserving agents has been described and, if suspected, must be assessed with patch tests and photo patch tests. CONCLUSIONS

The addition of cosmetics to dermatological treatment programs improves the compliance to the treatment protocol because patients enjoy the psychological benefits of looking better while receiving specific medical care. If the disease is refractory to all standard and investigative therapies, camouflage of the skin disfigurement is even more important. It is hoped that dermatologists will become more skilled in temporary and permanent makeup techniques and increase their awareness of the psychological benefits of appearanceenhancing cosmetic treatments. REFERENCES I.

2. 3. 4. 5.

Radokovic-Fijan S, Fiirnsinn-Friedl AM, H6nigsmann M, Tanew A. Oral dexamethasone pulse treatment for vitiligo. 1 Am Acad Dermatol 2001; 44(5):814817. Graham lA, Kligman AM. The psychological benefits of cosmetics in health care: dermatologic perspectives. 1 Appl Cosmetol 1984; 2:7-18. Westmore MG. Camouflage and makeup preparations. Clin Dermatol 2001; 19 (4):406-412. Engasser PG, Maibach H. Cosmetics and dermatology bleaching creams. JAm Acad Dermatol1981; 5(2):143-147. Rigano L. Cosmetici decorativi: formulazioni e componenti. Cosmesi Dermatol 7: I 1~21.

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33 Depigmentation and Vitiligo Christina Antoniou and Electra Nicolaidou University of Athens School of Medicine, "A. Sygros" Hospital, Athens, Greece

Despite the several therapeutic options that we now have for the management of vitiligo, depigmentation of the normally pigmented skin still remains, for selected vitiligo patients, the only way to a uniform skin color. Depigmentation is a process that destroys the remaining cutaneous melanocytes in vitiligo patients, enabling them to achieve the same very light complexion all over their body. The U.S. Food and Drug Administration (FDA) has approved the use of monobenzylether of hydroquinone (MBEH) for depigmentation in patients with vitiligo involving at least 50% of their body surface area (BSA) (1). Patients with less widespread vitiligo can, however, also benefit from depigmentation therapy, and recently substances such as 4-methoxyphenol (2) and modalities such as Q-switched ruby laser (2) and cryotherapy (3) have also been used for depigmentation with promising results. INDICATIONS FOR DEPIGMENTATION Proper selection of patients is the most important step in depigmentation therapy. The procedure usually leads to permanent destruction of melanocytes and leaves the patient for the rest of his/her life with a skin that has a different tone than before and is extremely photosensitive. Not every patient can cope with that. Furthermore, the possibility of future, more successful therapies for vitiligo must be discussed with the patient. As mentioned above, the main indication for depigmentation therapy is widespread vitiligo that extends to more than 50% of BSA. The more Copyrighted Material 359

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extensive the depigmentation, the stronger the indication for depigmentation therapy. Some patients have only a few residual dark spots scattered over their face and body. These patients are ideal candidates for depigmentation. Another group of patients who can benefit from depigmentation are those with less extensive disease (30-50% of BSA), which is very resistant to treatment. These patients may have failed repeated courses of standard therapeutic interventions and see depigmentation as their last resort. However, the risk/benefit ratio must be weighed more carefully for those patients. Children are generaUy not good candidates for depigmentation, because they cannot give their informed consent to the procedure. However, for children who suffer in such a way from their disfigurement that they cannot attend school in a normal fashion, depigmentation therapy of their exposed skin is an option that must be discussed in great detail with both the parents and teachers before being initiated.

METHODS OF DEPIGMENTATION Chemical Agents

MBEH, a phenolic compound, is by far the most widely used agent for depigmentation and, as mentioned above, the only one approved by FDA for that indication. Recently, 4-methoxyphenol has also been used with good results (2) Monobenzylether of Hydroquinone (Monobenzone). The first observation of the depigmenting properties ofMBEH was made in the 1930s, when workers began to develop depigmented macules mainly-but not exclusively-in areas of their skin that were in contact with some new rubber gloves (4). The gloves were analyzed and found to contain an antioxidant known as agerite alba, or MBEH. Patch testing with MBEH induced depigmentation, and when the agent was removed from the gloves, repigmentation was observed (5). Thus, the etiological association of MBEH and depigmentation was established. The sites of distant depigmentation were at that time attributed to contact with the gloves while perspiring. Following its association with depigmentation, MBEH was initially used for the treatment of hyperpigmentation disorders. Again, distant sites of depigmentation were observed in some patients, but the tendency to blame accidental contact with the cream still prevailed. Eventually it became evident that the depigmentation caused by MBEH is not restricted to the sites of application but can also occur at distant sites of the body. This side effect, along with reports of leukome1anoderma with patients developing areas of hyper-, hypo-, and depigmentation both on sites of application and at distant

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sites (6), led to the limitation of MBEH's indications to depigmentation in vitiligo patients. MBEH is metabolized into reactive free radicals which are capable of destroying melanocytes (7). This is why depigmentation is usually permanent. However, follicular melanocytes very often survive. This explains why, after depigmentation has been completed, some patients develop a few to many perifollicular pigmented macules, either after exposure to the sun or even spontaneously. Why epidermal melanocytes are more sensitive than follicular ones is not very clear. One theory is that MBEH cannot penetrate down to the level of the hair matrix (I), while another one states that there are two populations of melanocytes in the skin, an epidermal and a perifollicular one (8) and the epidermal is more sensitive to both the mechanism of vitiligo and depigmentation therapy. That is why the presence of dark hair in vitiligo patches is a good prognostic sign for repigmentation therapy but a bad one for depigmentation. MBEH is commercially available as a 20% cream. The patient usually first treats a test spot (e.g., forearm) to exclude an allergic reaction. If there is no reaction after one week, the cream is applied to pigmented skin once daily for another week. If the patient tolerates the applications, the medication is then applied twice daily. Some patients may develop contact dermatitis, more often irritant than allergic, at the sites of application, which is usually restricted to pigmented and not to white skin. In such cases, MBEH can be diluted to a 10% or even 5% concentration. Mild topical steroids can also be applied simultaneously. If the dermatitis is more severe, applications of MBEH are withheld until the dermatitis is treated and then resumed usually at a 5% concentration, which is increased gradually. The risk of irritant contact dermatitis is the reason why some authors (9) prefer to start not with a 20% but with a 10% concentration of MBEH applied twice daily and increased by 5% every I or 2 months until reaching the 20% level. Depigmentation therapy of a particular site can last from months to 1-2 years. In one study (10), 8 out of 18 patients who used MBEH for up to 10 months achieved complete depigmentation. Most the patients who did not depigment fully used the cream for less than 4 months, and one had to stop therapy because of severe contact dermatitis. During therapy, the skin lightens gradually. It usually takes 1-3 months of therapy for a response to be seen. If after a course of 3~ months with 20% MBEH some sites, such as the elbows or knees, have failed to lighten, the concentration can be increased to 30% or even 40%. Application of the cream with occlusive plastic wraps can also help. It is possible for a patient to use different concentrations of MBEH at different sites of the body, according to their sensitivity and response. Areas such as the eyelids or periocular skin are usually not treated at all, because application of MBEH to these areas has been reported to cause conjunctival Copyrighted Material

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melanosis and corneal deposits of pigment (II). Patients are also advised to avoid direct contact of their treated skin with the skin of others for 2-3 hours after application of the cream. Most of the side effects of MBEH have already been mentioned. To summarize them, short-term adverse effects include contact dermatitis, pruritus, xerosis, depigmentation at distant sites, graying of the hair (12), and, following application to periocular skin, conjuctival melanosis and corneal deposits of pigment. Long-term side effects include leukomelanoderma and exogenous ochronosis (13). These long-term side effects have, however, been noticed only in patients being treated for hyperpigmentation disorders, not in vitiligo patients undergoing depigmentation. Systemic side effects have not been reported for MBEH. However, it is better not to prescribe it during pregnancy and lactation. 4-Methoxyphenol (Mequinol or p-Hydroxyanisole or Monomethylether of Hydroquinone). In many European countries (including Greece), MBEH is no longer available, mainly because of its side effects. 4-Methoxyphenol (4MP), another phenol derivative with melanocytotoxic properties similar to those of MBEH (14), has been used in one study (2) for depigmentation in vitiligo universalis. Among 16 treated patients, 11 achieved total depigmentation, a rate comparable to that of MBEH (10). However, the first signs of depigmentation appeared after 4-12 months of therapy, whereas with MBEH, depigmentation can start as soon as I month after initiation of therapy (10). Contact dermatitis after application of 4-MP seems to be less common and less severe, compared to MBEH, but reports about irregular leukoderma have also been made (15), and, therefore, as with MBEH, the indications of 4-MP include only depigmentation of vitiligo patients. A 36% relapse rate was reported in the above study after a treatment-free period that lasted between 2 and 36 months. Repigmentation occurred after sun exposure, and its pattern was perifollicular, which implies that perifollicular melanocytes are not as sensitive to 4-MP as epidermal ones and survive its melanocytotoxic actions. Therefore as is also the case with MBEH, sun protection is essential for preservation of depigmentation. Q-Switched Ruby Laser The Q-switched ruby (QSR) laser beam can selectively destroy melanin and melanin-containing structures in the skin (16) and has been used for depigmentation therapy in patients with vitiligo universalis (2,17). In one study (2), 9 of the 13 treated patients showed complete depigmentation. The depigmentation started between 7 and 14 days after the laser treatment, faster than the results achieved with creams. The number of treatments needed for total depigmentation depended on the size of the treated areas and varied between

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2 and lO treatments. The only side effect reported was that of pain, which be managed with the application of an anesthetizing cream (EMLA) 2 hours before the procedure. Of the 9 successfully depigmented patients, 4 showed a return of pigmentation in a perifollicular fashion after a treatment-free period, which varied from 2 to 18 months. The perifollicular pattern of repigmentation indicates that perifollicular melanocytes are not destroyed by the laser therapy, as is also the case with both MBEH and 4-MP. All four patients who showed repigmentation had reported a negative Koebner phenomenon, in contrast to the five patients who remained depigmented and who had reported a positive Koebner phenomenon. This indicates that a positive Koebner phenomenon is a favorable prognostic sign for the long-term results of QSR laser depigmentation. Cryotherapy

Cryotherapy, even though it is known to be melanotoxic (18), had not been reported to be used for depigmentation in vitiligo patients until very recently (3). In this study, five patients were treated with one to three sessions of cryotherapy and all of them achieved complete depigmentation. No side effects were reported. Within 8 months of follow-up, however, two patients developed lentigo-like macules on sun-exposed skin, which were retreated with cryotherapy or chemical peeling. Cryotherapy seems to be a safe, costeffective, and rapid method of depigmentation, but return of pigment is still a problem, as is the case with all the other methods of depigmentation described above.

REFERENCES 1.

2.

3. 4. 5. 6.

7.

Bolognia JL, Lapia K, Somma S. Depigmentation therapy. Dermatol Ther 200 I; 14:29-34. Njoo MD, Vodegel RM, WesterhofW. Depigmentation therapy in vitiligo universalis with topical4-methoxyphenol and the Q-switched ruby laser. J Am Acad Dermatol 2000; 42:760-769 Radmanesh M. Depigmentation of the normally pigmented patches in universal vitiligo patients by cryotherapy. J Eur Acad Dennatol 2000; 14:149-152. McNally WD. A depigmentation of the skin. Indust Med 1939; 8:405-410. Oliver EA, Schwartz L, Warren LH. Occupational leukodel111a. JAMA 1939; 113:927-928. Canizares 0, Jaramillo FU, Kerdel Vegas F. Leukomelanoderma subsequent to the application of monobenzylether of hydroquinone. Arch Dermatol 1958; 77: 220-223. Westerhof W, Njoo MD. Bleaching agents. In: Katsambas AD, Lotti TM, eds.

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8. 9. 10.

II.

12.

13. 14. 15. 16. 17. 18

European Handbook of Dermatological Treatments. Berlin: Springer, 1999:766777. Tobin DJ, Bystryn Jc. Different populations of melanocytes are present in hair follicles and epidermis. Pigment Cell Res 1996; 9:304-310. Antoniou C, Katsambas A. Guidelines for the treatment of vitiligo. Drugs 1992; 43:490-498. Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzylether of hydroquinone. A retrospective study of treatment of 18 vitiligo patients and a review of the literature. Br J Dermatol 1977; 97:669-679. Hedges TR TIl, Kenyon KR, Hanninen LA, Mosher DB. Corneal and conjunctival effects of monobenzone in patients with vitiligo. Arch Ophthalmol 1983; 101:64-68. Katsambas AD, Lotti TM, Ortonne JP. Vitiligo. Tn: Katsambas AD, Lotti TM, eds. European Handbook of Dermatological Treatments. Berlin: Springer, 1999: 617-623. Snider RI, Thiel'S BH. Exogenous ochronosis. J Am Acad Dermatol 1993; 28: 662-664. Riley PA. Mechanism of pigment cell toxicity produced by hydroxyanisole. J Pathol 1970; 101:163-169. Boyle J, Kennedy CTC. Leucoderma induced by monomethylether of hydroquinone. Clin Exp Dermatol1985; 10:154-158. Spicer MS, Goldberg DJ. Lasers in dermatology. J Am Acad Dermatol 1996; 34:1-25 Kim YJ, Chung BS, Choi KC. Depigmentation therapy with Q-switched ruby laser after tanning in vitiligo universalis. Dermatol Surg 200 I; 27:969-970. Kuftik GE. Cryosurgery updated. J Am Acad Dermatol 1994; 31:925-944.

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34 Vitiligo and the Internet Giovanni Menchini and Torello M. Lotti University of Florence, Florence, Italy Evridiki Tsoureli-Nikita University of Siena, Siena, Italy Jana Hercogovci Charles University, Prague, Czech Republic

The internet has become the most important media source of information thanks to its simplicity and speed. Using the internet is easy and inexpensive: it is far more simple to publish data on a web page than via the normal editorial procedure associated with a periodical publication (Table I). Thus, the internet provides not only scientific information (often not peer-reviewed), but also commercial product, advertisements patient recommendations, information about scientific associations or organizations, and much more (Fig. I). In this "info-jungle," it can be very hard to find the information one is looking for. The simplest way is to used a search engine (e.g., Altavista, Google, Yahoo) (1-3), refining the search with terms that specify the kind of information desired along with the subject (vitiligo and treatments and UYB, etc). The internet is now certainly the major working tool used in medicine in all fields, from research activity to on-line teaching. The quantity of medical information included in the web pages of the global network is enormous and permits everyone access to detailed information about all kinds of pathologies, updated with the latest news. Nevertheless, when the interest is in a single Copyrighted Material 365

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TABLE 1 Web Pages and Scientific Publications Dedicated to Vitiligo and Other Common Skin Diseases

Vitiligo Psoriasis Herpes simplex Acne Vasculitis Melanoma

Web pages

Scientific publications

67,000 368,000 121,000 194,000 69,500 402,000

1,351 8,352 13,598 3,202 4,839 23,919

Ratio 50 44 9 61 14 17

to to to to to to

1 1 1 1 1 1

Web pages about some dermatological disorders

160. 000-'/'

,

VI

,-

140. 000- vi

if

V

120. 000-

if:

,/,

100. 000-

-

(i

80. 000-

-

/'

60. 000- ,/,

----

/f=.

"

,........

~

20. 000.~

F;

'"" b_ .;:

;\ Psoriasis

..

-

ii; it

-,

,........

I·;·" !:::i1),

WiJigo

,........

'.

1-"" Herpes sirrplex

o Therapies

~

.0:::

T

Products

rtfl

"'~~

40. 000-

o University

.:;::l

Acne

d'

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pathology, such as vitiligo, it is advisable to utilize authorized websites of worldwide scientific importance, such as those of international professional organizations (e.g., European and/or American Academy of Dermatology, International Society of Dertmatology) (4,5), medical journals (e.g., Archives ofDermatology, Journal of the American Academy ofDermatology, Journal of the European Academy of Dermatology and Venereology) (6-8), or medical web portals (e-medicine, PubMed) (9 10). Consulting websites of well-established dermatological professional societies is of importance mainly when one is interested in therapeutic aspects of a disease. "Treatment" and "therapy," used in conjunction with the relative disease (e.g., vitiligo and treatment), seem to be two of the most commonly used key words in internet searches. The amount of information available is immense, and in addition to established scientific websites, many commercial or even self-made websites contain questionable information. This is true especially in the field of dermocosmetology, where websites promote products that in some cases do not offer proper treatment of the disease, but more of a cosmetic adjuvant use. Treatment of acute forms of vitiligo, as well as chronic or maintenance treatment, should be accurately researched on dermatological manuals on-line (e.g., Merck) (11-13), at sites that include large clinical reviews of dermatological diseases, and/or the websites of established journals or scientific publications. The internet must be used carefully and critically. The enormous quantity of information available must be carefully analyzed and checked before being exploited for a research project or treatment protocol of any type. To facilitate internet surfing and avoid the obstacles mentioned above, we include here some addresses that, in our opinion, could be helpful for the dermatologist and provide reliable, updated information: Associations: National Vitiligo Foundation: http://www.vitiligofoundation.org/ menu.htm American Vitiligo Research Foundation: http://wwwavrf.org/ Products: Sacha Cosmetics: http://www.sachacosmetics.com/camoufiage.htm Vitiligosupport: http://www.vitiligosupport.com/ Therapies: Vitiligo Switchboard: http://web.onramp.ca/cadd/vitiligo.htm Bioskin: Narrowband UVB microphototherapy: www.vitiligo.it

REFERENCES 1.

2.

Altavista: www.altavista.com. Google: www.google.com. Copyrighted Material

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Yahoo: www.yahoo.com. American Academy of Dermatology: www.aad.org. European Academy of Dermatology and Venereology: www.eadv.org. Archives of Dermatology: archderm. ama-assn.org. Journal of American Academy of Dermatology: www.eblue.org. Journal of European Academy of Dermatology and Venereology: www. blackwell-synergy.com. www.eadv.orgjjournal. E-medicine: www.emedicine.com. PubMed: www.ncbi.nlm.nih.govjPubMed. Merck Manual: www.merck.comjpubsjmmanual. American Medical Association: www.jama.ama-assn.orgjissuesjv283nI2jffullj jsc00054.html. eHealth Code of Ethics: www.ihealthcoalition.orgjethicsjehealthcode0524. html.

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35 Halo Nevus Demetris loannides Aristotle University Medical School, Thessaloniki, Greece

INTRODUCTION The halo nevus is a distinctive benign melanocytic nevus that occurs mainly in childhood and adolescence (1). Clinically the nevus has a ring of depigmentation (Fig. I). It was originally described by Hebra and made known by Sutton as leukoderma acquisitum centrifugum in 1916 (2). The term "halo phenomenon" describes the zone or margin of depigmentation occurring in association with a variety of both neoplastic and inflammatory cutaneous lesions. The first description of the halo phenomenon has been attributed to the artist Mathias Grunewald. In his masterpiece, Wandelaltar (1512-1516), he depicts a bull-like monster with multiple halo lesions that are most likely nevi (3). The term halo phenomenon was particularly used by Mescon in his pu blished discussion of an article by Kopf et al. (4).

EPIDEMIOLOGY AND CLINICAL PICTURE The typical history of a halo nevus is that a ring of depigmentation forms around a preexisting pigmented nevus. Most individuals are children and young adults. In a study of 142 cases (5), the average patient age was 16 years. The halo nevi may be located in any anatomical site, but there is a predilection for the back (5). They are usually solitary, but authors have reported that 2550% of individuals present with multiple lesions, occurring either simultaneously or successively (6). The incidence of halo nevi has been estimated at 1% of the population (6). Copyrighted Material 369

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A halo nevus on the thorax of a 20-year-old girl.

Familial occurrence can be rarely observed. Two sisters with halo nevi were known to Ortonne et al. (6), and Chisa (7) reported a brother and a sister with halo nevi. Two more sisters were included in a series of 35 patients reported by Kopf et al. (4), and of 100 patients reported by Wayte and Helwig, 2 had a positive family history of similar lesions (8). There is also one report with the simultaneous occurrence of such nevi in four members of one family (9). The time needed for the depigmentation of the halo to develop is not known. Patients report that the halo phenomenon may take days to weeks to fully evolve. The central nevus may remain unchanged or become less pigmented over time. Sometimes the nevus involutes, leaving a localized area of depigmented skin (8). Frank and Cohen declared that at least 50% of halo nevi disappear spontaneously (10). The areas of depigmentation may persist unchanged for months or years or repigment totally. Some authors (6,10) describe four stages of nevus progression and regression. Stage I is the appearance of a classic halo nevus, which is a brown nevus with a surrounding rim of depigmentation. In stage II the central nevus may lose its pigmentation and appear as a pin-colored papule with a surrounding halo, whereas in stage III the central papule may disappear, leading to a circular area of depigmentation. Finally, in stage IV the depigmented area may repigment leaving no trace of its existence. Whether a particular halo nevus will progress through all four stages of regression is difficult to predict. It is even more difficult to predict the rate at

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which the progression will occur. Moreover, there is a report in which darkening rather than lightening of the central nevus was observed (II). The distinctive feature in the patient described in this report is not only the darkening of the central nevus, but also the pattern of hyperpigmentation. It had a net-like appearance with perifollicular sparing (II). HISTOLOGY AND PATHOPHYSIOLOGY

The microscopic criteria for the halo phenomenon include the obligate presence of a band-like Iymphohystiocytic infiltrate and a diminution or absence of melanin pigment at the dermoepidermal junction at the periphery of the lesion. Especially in early lesions, lymphocytes may be seen around damaged melanocytes in the halo. Later, more scattered nevus cells than nests are observed. Even when melanin is still present in the nevus cells, these cells often show evidence of damage to their nuclei and cytoplasm, and some apoptotic nevus cells are commonly found (5,12). The nevus is usually a benign melanoytic nevus, predominantly compound in nature. It can be also junctional or intradermal nevus. Nevomelanocytic lesions associated with the halo phenomenon include congenital nevi, blue nevi, neuroid nevi, Spitz nevi, and mongolian spots (5,12). Some halo nevi may show some degree of atypia related to the intensity ofinfiammation (I). Atypia, as a feature of halo nevus, is mentioned in several textbooks. Okun and Edelstein stated that it has been suggested that halo nevus may be a spontaneously regressing melanoma (13). In their description of halo nevus, Clark et al. (14) commented that, in some cases, the hyperplasia of melanocytes might be extensive with cytologic atypia. McGovern (15) proposed that junctional nevus cells might assume a disturbing atypical appearance. Lever and Schaumberg-Lever (12) refer to nevus cell nests, which may appear as if they were atypical. In a study of 142 cases of halo nevi, it was demonstrated that there is a great deal of variation in the degree of atypia and that the spectrum of nevi identified was similar to acquired nevi in general (5). Coperman and Elliot (16) demonstrated a cytoplasmic antibody against melanoma cells in patients with involuting halo nevi, but not in patients with ordinary nevi. Cooke et al. reported (17) that melanoma specific protein is detected in the urine of patients with actively developing halo nevi, but not in normal controls. In one report (18), the histological changes observed in a halo nevus resembled those of epidermal erythema multiforme. Meyerson's nevus has been described as a melanocytic nevus with an associated eczematous halo reaction (19). Eczematous halo developing around atypical nevi has been also reported in four patients (20). Copyrighted Material

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In an interesting study (21), Lai et al. sent a questionnaire to 87 pediatric dermatologists asking whether the physician had ever seen a child under 18 years who presented with a halo nevus that turned out to be melanoma. None of the dermatologists from whom they received answers (90%) had ever seen a typical halo nevus with melanoma. They concluded that a halo nevus in childhood very rarely undergoes malignant transformation and therefore very rarely, if ever, is a biopsy required (21). The congenital nevi with a halo phenomenon were excluded from the study, because melanoma arising in such nevus is a well-recognized pathobiologic event (22). The underlying pathophysiology responsible for the halo phenomenon is not well understood. During the formation and regression of halo nevi, infiltrates composed ofT cells, in particular CD8 + cytotoxic suppressor cells, have been observed (23). In addition, circulating activated lymphocytes were seen in patients with halo nevi and their disappearance was documented following surgical excision (24). It has been suggested that the mononuclear inflammatory infiltrate of the halo phenomenon acts via a cytotoxic cellmediated immune response to cause regression of nevi (25). Bergman et al. proposed (26) that the identical distribution of HLA-A,B,C antigens found present on the melanocytes, and the composition of the inflammatory infiltrate in both halo nevi and malignant melanoma, suggest a very similar immune response operative in these conditions. Aside from whether a unique antigen or several antigens are recognized by this family of T cells, the nature of the halo nevi antigens remains unknown; however, it does not belong to the proteins that are known thus far to be specifically expressed by melanoma cells. The halo nevus antigen(s) might be an auto-antigen, part of the differentiation program of the normal nevi to which the immune system is normally tolerant (27). The immunopathogenesis of halo nevus seems to overlap with that of inflammatory vitiligo, in which T-cell infiltrates with elevated numbers of CD8 + cells and CD25-expressing cells (a marker for T-cell activation) have been observed (28). Patients with vitiligo were shown to have circulating skinhoming autoreactive cytotoxic lymphocytes, and similar cells may be present in those with halo nevi (29). However, the association of halo nevus and vitiligo is not sufficiently common for halo nevus to be regarded as a form of vitiligo (J 2). In an epidemiological case-control study in a population of patients with unilateral and bilateral vitiligo, halo nevi were infrequent in the total vitiligo group, and no difference was observed between vitiligo types (30). Besides the more common halo nevus with histologically apparent inflammation, there are also cases of noninflammatory halo nevi, in which no inflammatory infiltrate was shown in histological examination (12,31). In such instances the nevus does not involute. In addition, there is the so-called

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halo nevus without halo (32). In these instances, histological signs of inflammation are shown in the nevus, but clinically a halo around the nevus has not been developed. Such nevi may involute (31,32).

DIFFERENTIAL DIAGNOSIS Halo nevus may be difficult to differentiate from rare halo malignant melanoma. The latter is usually asymmetrical, including the halo, and in most cases some clinically obvious melanoma remains. With melanoma, the perilesional pigment loss usually appears only along a portion of the perimeter rather than along the entire circumference, as is seen with typical halo nevi (33). Histologically, the inflammatory infiltrate in halo nevi is more pronounced than in melanoma and extends diffusely through the lesion, rather than being concentrated at the periphery as in most examples of tumorigenic melanoma (12).

REFERENCES I.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13.

Blessing K. Benign atypical nevi: diagnostic difficulties and continued controversy. Histopathology 1999; 34: 189-198. Sutton RL. An unusual variety of vitiligo (leukoderma acquisitum centrifugum). J Cutan Dis 1916; 34:797-800 Borroni G, Vignati G. Should Sutton nevus really be called Grunewald-Sutton nevus? Am J Dermatopathol 1993; 92: 14-15. Kopf AW, Morrill SD, Silberberg 1. Broad spectrum of leukoderma acquisitul11 centrifugum. Arch Dermatol 1965; 92: 14-35. Mooney M, Barr R, Buxton MG. Halo nevus or halo phenomenon? A study of 142 cases. J Cutan Pathol 1995; 22:342-349. Ortonne JP, Mosher DB, Fitzpatrick TB. Vitiligo and Other Hypol11elanoses of Hair and Skin. New York: Plenum Publishing Corporation, 1983:567-611 Chisa N. MUltiple halo nevi in siblings. Arch Derl11atol 1965; 92:404-405. Wayte DM, Helwig BB. Halo nevi. Cancer 1968; 22:69-90. Herd RM, Hunter JAA. Familial halo nevi. Clin Exp Derl11atol1998; 23:68-69. Frank SB, Cohen HJ. The halo nevus. Arch Dermatol, 1964,367-371 Huynh P, Lazova R, Bologna J. Unusual halo nevi-darkening ather than lightening of the central nevus. Dermatology 2001; 202:324-327. Elder D, Elenitsas R. Benign pigmented lesions and malignant melanoma. In: Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, eds. Lever's Histopathology of the Skin (8th ed.). Philadelphia JB Lippincott, 1997:652-654 Okun MR, Edelstein LM. Gross and Microscopic Pathology of the Skin. Boston: Dermatopathology Foundation Press, 1975:942-944.

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15. 16. 17.

18. 19. 20. 21. 22.

23. 24.

Clark WH Jr, Elder DE, Guerry D. Dysplastic nevi and malignant melanoma. In: Farmer ER, Hood AF, eds. Pathology of the Skin. CT: Appleton and Lange, 1990:747-749. McGovern VJ. Melanoma: Historical Diagnosis and Prognosis. New York: Raven Press, 1983:87-89. Coperman FWM, Elliot PG. Melanoma cytoplasmic humoral antibody test. Br J Dermatol 1976; 94:565-568. Cooke KB, Bennett C, Staughton RCD. Melanoma specific protein: occurrence in the urine of patients with halo nevi and vitiligo. Br J Dermatol 1978; 98:663669. Fabrizi G, Massi G. Halo nevus with histological changes resembling epidermal erythema multiforme. Br J Dermatol 1999; 141:369-370. Nicholls DSH, Mason GH. Halo dermatitis around a melanocytic nevus: Meyerson's nevus. Br J Dermatol 1988; 118:125-127. Elenitsas R, Halpern AC. Eczematous halo reaction in atypical nevi. J Am Acad Dermatol 1996; 34:357-361. Lai CH, Lackbart S, Mallory SB. Typical halo nevi in childhood: Is a biopsy necessary? J Pediatr 200 I; 138:283-284. Bouffard D, Barnhill RL, Mihm MC, Sober AJ. Very late metastasis (27 years) of cutaneous malignant melanoma arising in a halo giant congenital nevus. Dermatology 1994; 189:162-166. Akasu R, From L, Kahn HJ. Characterization of the mononuclear infiltrate involved in regression of halo nevi. J Cutan Pathol 1994; 21:302-311. Baranda L, Torrez-Alvarez B, Moncada B, Portales-Perez D, de la Fuente H, Layseca E, Gonzalez-Amaro R. Presence of activated lymphocytes in the peripheral blood of patients with halo nevi. J Am Acad Dermatol 1999; 41:567-

572 25. 26.

27.

28.

29.

30.

Zeff RA, Freitag A, Grin CM, Grant-Kels GM. The immune response in halo nevi. J Am Acad Dermatol 1997; 37:620-624. Bergman W, Willemze R, De Graaf-Reitsma C, Ruiter DJ. Analysis of major histocompatibility antigens and the mononuclear cell in.filtrate in halo nevi. J Invest Dermatol 1985; 85:25-31. Musette P, Bachelez H, Flaguel B, Delarbre C, Kourilsky P, Dubertret L, Gachelin G. Immune-mediated destruction of melanocytes in halo nevi is associated with the local expansion of a limited number of T cell clones. J Immunol 1999; 162:1789-1794. Le Poole IC, van del' Wijngaard RM, Westerhof W, Das PK. Presence ofT cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance.AmJPathoI1996; 148:1219-1228. Ogg GS, Dunbar PR, Romero P, Chen J, Cerundolo V. High frequency of skinhoming melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med 1998; 1881203-1208 Barona ML Arrunategui A, Falabella R, Alzate A. An epidemiologic casecontrol study in a population with vitiligo. J Am Acad Dermatol 1997; 36:282283.

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Halo Nevus 31. 32. 33.

Brownstein MH. Halo nevi without dermal infiltrate. J Invest Dermatol 1978; 114:1718-1721. HappJe R, Echternacht K, Scotola 1. Halonaevus ohne Halo. Hautartz 1975; 26:44-47 Bystryn J-C, Xie Z. Neoplastic hypomelanosis. In: Nordlund J, Boissy R, Hearing V, King R, Ortonne J-P, eds. The Pigmentary System. New York: Oxford University Press, 1998:647-662.

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36 Alezzandrini's Syndrome

Fabrizio Guarneri and Mario Vaccaro University of Messina, Italy

Alezzandrini's syndrome is a oculo-cutaneous disease characterized by hypomelanosis associated with retinic degenera tion and, sometimes, auditory involvement. The first case of this extremely rare syndrome was described in 1959, by Casala and Alezzandrini (I). They reported the clinical history of a 12-year-old patient with unilateral retinitis pigmentaria, who successively developed ipsilateral vitiligo and poliosis, in association with hypoacusia. In 1961 the same authors, together with Cremona, published another case report (2) on a 22-year-old subject with similar clinical features, but not affected by hypoacusia. In 1964, the observation of a third patient (3) led Alezzandrini to propose the definition of a new syndrome, characterized by the onset, in young subjects, of unilateral tapetoretinic degeneration, followed, in a variable time (3-13 years), by ipsilateral vitiligo and poliosis and inconstant auditory involvement. Because of the rarity of this syndrome, a new case was not reported until 1992, by Hoffman and Dudley (4): a diabetic (type I) patient developed unilateral facial vitiligo and ipsilateral poliosis and, 9 years later, unilateral retinal detachment. The latter sign, not included in the original definition by Alezzandrini, was also observed, in 1994, by Shamsadini et al. (5). Their patient presented a unilateral retinal detachment, followed one year later by ipsilateral poliosis and 3 years later by controlateral retinal detachment. According to Lorincz, retinal detachment has to be considered another criterion for the diagnosis of Alezzandrini's syndrome. Copyrighted Material 377

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The etiopathogenesis is still unknown. No familial inheritance has been evidenced: in the case described by Shamsadini et al. (5), some signs of the disease were present in the family: a grandfather of the patient had become blind at 19 years of age, but the cause of blindness was unknown, and the brother presented with acral asymmetric vitiligo, but without any ophthalmological disorder or poliosis. Because of similarities with other multisystemic syndromes, an autoimmune mechanism has been hypothesized by many authors to explain the clinical manifestations of Alezzandrini's syndrome. Differential diagnosis includes mainly Vogt-Koyanagi-Harada syndrome, a combination of Vogt-Koyanagi syndrome and Harada's disease characterized by meningitic symptoms (in its first phase), generalized vitiligo with destruction of basal melanocytes, poliosis, chronic bilateral uveitis, dysacusia, and alopecia areata (6). Lorincz proposed that Alezzandrini's syndrome and Vogt-Koyanagi-Harada syndrome could be different expressions of a single disease (7). Other syndromes and diseases can resemble some features of Alezzandrini's syndrome and should then be considered in differential diagnosis: vitiligo, albinism, piebaldism, tuberous sclerosis, Waardenburg's syndrome, Chediak-Higashi syndrome, Marfan's syndrome, Rubinstein-Taybi syndrome, hyperthyroidism, hypoparathyroidism, Addison's disease, hypopituitarism, pernicious anemia, halo nevus (leukoderma acquisitum centrifugum-Hyde and Sutton), nevus depigmentosus, leprosy-tuberculoid, pityriasis alba, postinflammatory depigmentation, phenylketonuria (pigment dilution), idiopathic guttate hypomelanosis, syphilitic leukoderma, and scleroderma/morphea (7,8). The extremely limited number of cases, and their temporal and geographical distance, has not allowed studies on predisposing, causative, and prognostic factors, and no specific therapy is therefore available. It must be noted, however, that Alezzandrini's syndrome is largely unknown, and this could lead to an underestimation of its low undoubtedly low incidence. Ophthalmologists and dermatologists should be aware of its existence and consider it among possible diagnoses. This should provide researchers with more data, contributing to the progress of medicine, better knowledge and a therapy for this disease.

REFERENCES l.

2. 3.

Casala AM, Alezzandrini AA. Vitiligo y poliosis unilateral con retinitis pigmentaria y hipoacusia. Arch Argent Derm 1959; 9:449-456. Cremona AC, Alezzandrini AA, Casala AM. Vitiligo, poliosis y degeneracion macular unilateral. Arch onal B Aires 1961; 36:102-106. Alezzandrini AA. Manifestation unilaterale de degenerescence tapeto-retinienne,

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5. 6. 7. 8.

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de vitiligo, de poliose, de cheveux blancs et d'hypoacusie. Ophtalmologica 1964; 147:409-419 Hoffman M D, Dudley C. Suspected Alezzandrini's syndrome in a diabetic patient with unilateral retinal detachment and ipsilateral vitiligo and poliosis. JAAD 1992; 26:496-497 Shamsadini S, Meshkat M, Mozzafarinia K. Bilateral retinal detachment in Alezzandrini's syndrome. Int J Derm 1994; 33:885-886. Barnes L, Nordlund 11. Vogt-Koyanagi-Harada and Alezzandrini's syndromes. In: Clinical Dermatology. Philadelphia: Lippincott-Raven, 1988. Lorincz AL. Disturbances of melanin pigmentation. In: Moschella SL, Hurley JH, eds. Dermatology. Vol. 2. Philadelphia: WB Saunders, 1985:1297. Monti M. La sindrome di Alezzandrini. In: Lotti TM, Bianchi B, Ghersetich I, eds. La Vitiligine-Nuovi Concetti e Nuove Terapie. Milan: UTET Periodici Scientifici, 2000: 120-121.

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37 Acquired Hypomelanoses R. Konkolova Charles University, University Hospital Motol, Prague, Czech Republic

The occurrence of acquired hypomelanoses (hypopigmentation, depigmentation, leukoderma) on human skin is more frequent than of vitiligo, albinism, or other congenital hypomelanoses. In many cases the mechanism of origin has not yet been fully clarified. They can be either reversible or permanent. In a general sense, among the group of acquired hypomelanoses can be included idiopathic guttate hypomelanosis, Vogt-Koyanagi-Harada syndrome, halo nevus, leukonychia, and others. This list can be further supplemented with hypopigmented mycosis fungoides, symmetrical progressive leukopathy, a group of inflammatory and postinfectious hypomelanoses, chemical substances-induced hypomelanoses, hypomelanoses due to physical effects, and hypomelanoses occurring in some internal diseases or disorders. Hypopigmented mycosis fungoides is a rarely occurring form of mycosis fungoides. The incidence is significantly higher in persons with dark skin, but it has also been reported in Caucasians. Depigmented macules are found on the trunk, hips, and limbs. They usually respond readily to the most commonly used psoralen UVA (PUVA) therapy. Repigmentation occurs after the treatment. Patients with this diagnosis require the same follow-up as those diagnosed with mycosis fungoides (1,2). Symmetrical progressive leukopathy is relatively frequent in young adults (e.g., in Japan and Brazil). From a clinical viewpoint, it consists of permanent symmetrical punctate hypopigmentations located above the extensors of the limbs, in the abdominal region, and interscapularly. Its etiology is unknown (3). Copyrighted Material 381

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POSTINFLAMMATORY AND POSTINFECTIOUS HYPOMELANOSES Almost any skin inflammation can heal with hypopigmentation or a hypopigmented scar (depending on depth). The most frequent incidence is in hypomelanotic nests in patients with healed psoriatic manifestations, lupus erythematosus, lichen planus, and atopic dermatitis. A case of residual leukoderma following erythema multiforme has been also described (4), clinically copying the original pathological manifestations (Fig. I). Other hypopigmen ted lesions, macular as well as papular, can occur in sarcoidosis (5).

FIGURE 1

Postinflammat°[Jot;fjll{JJftl98W&terial

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Two clinical diseases are sometimes classified as pseudoleukoderma. Pityriasis simplex alba is frequent in atopic children. The affected parts are usually the face or the limbs, where the hypopigmented nest is clinically found, sometimes with fine scaling on the surface. Its etiopathogenesis is thought to involve blocked transition ofmelanosomes from melanocytes into keratinocytes due to inflammation and edema of the involved area. The manifestation is asymptomatic; it disappears with time. The recommended therapy is lubrication with emolients with addition of antiseptics or mild corticosteroids. A frequent infectious cause of hypopigmentation is pityriasis versicolor. The causative agent of the disease is MalasseziajUijur, a saprophyte of the human skin that induces the disease only in predisposed individuals. Clinical symptoms of the affected skin are whitish oval macules that can fuse into larger patches. They are usually located on the back and in the presternal region. They are probably a result of the inhibition of tyrosinase with lipids originating during oleic acid metabolism (6) or a simple, so-called umbrella effect, which reduces the penetration of sunlight. The usual treatment is local application of imidazol-based topical preparations; general treatment is used only in more severe cases. Other infectious diseases associated with the onset of hypomelanotic patches are syphilis with syphilitic leukoderma, leishmaniasis, onchocercosis, leprosy, pinta (7), and herpes simplex.

CHEMICAL SUBSTANCE-INDUCED HYPOMELANOSES

Through their external effects on the skin or their systemic use, chemical substances can lead to hypopigmentations. Of the substances with such effect, the most common are those used for the therapy of hyperpigmentation. The principle of their effect is usually irreversible melanotoxicity or reversible blocking of melanogenesis. Such therapy may result in undesirable cosmetic hypopigmentation. Among the bleaching agents used are the following: Phenol and its derivatives (e.g., isopropylkatechol), used for their antiseptic effects in germicide agents and for their melanotoxic and caustic effects for the chemical peeling and bleaching of the skin. They are also slightly anesthetic, nephrotoxic, hepatotoxic, and cardiotoxic. Hydroquinone and its derivative hydroquinone monobenzylether block tyrosinase, the key enzyme in melanin synthesis. They can also be components of substances used in industry. Cojic acid, used as a component of bleaching creams. Its derivatives are also used in the food industry and photography for their fungicide, insecticide, and h~~'N/.aterial

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Azelaic acid, which restrains tyrosinase activity and inhibits DNA synthesis in keratinocytes and melanocytes. It has a selective effect on hyperactive melanocytes and does not lead to formation of hypopigmentation. Oxidation substances result in the bleaching of the skin and hair via melanin oxidation. These include hydrogen peroxide, benzoylperoxide, and chlorates. The reduction agents change melanin into leukomelanin (e.g., acetic acid, citric acid). The principle of the bleaching effects of the mercury compounds has not been fully clarified. Mild bleaching agents include corticosteroids and ascorbic acid (reduction agents). Mild bleaching effects also occur in retinoids. Other substances having a bleaching effect include aldehydes present in cucumbers, arbutin and methylarbutin in other kinds of vegetables, sandalwood oil, and unsaturated fatty acids (8). Onset of hypomelanosis has been observed following contact with certain plants (e.g., primula, piperaceae) (9) or other contact allergens (e.g., chloroxylenol, paraphenylendiamin, nickel, dental acrylates) (10) and locally administered medications (e.g., minoxidil) (II). Systematically administered antimalarial agents may induce hypopigmentation of the skin or hair, and following PUVA therapy reversible punctate leukoderma can be observed. Other systemically administered substances that may induce hypomelanoses are sulfonamides, phenytoin, barbiturates, or chronic arsenic intoxication.

HYPOMELANOSES AS SEQUELAE OF PHYSICAL EFFECTS

Any physical trauma of the skin (e.g., surgical interventions), the healing of which is associated with an inflammation, can result in dyschromia and therefore also hypomelanoses. In heat-induced skin damage, hypopigmentation occurs most often in second- and third-degree burns. In general, hypomelanoses occur more frequently in subjects with darker skin, which applies also in this case. Hypopigmentation on skin damaged with chronic UV exposure is relatively common. It occurs on the parts of the body permanently or frequently exposed to sunlight (head, dorsa of the hands, back) and is associated with hypopigmentation and other signs of chronic solar damage. Actinotherapy is also a relatively frequent cause of hypomelanoses at the site of its action. A case of ionizing radiation-induced lentigo was described in individuals from the Chernobyl disaster area (12). The importance of a number of surgical procedures leading to improvement of skin conditions has increased. Such corrective dermatological and surgical methods are, however, almost always associated with complications in the terms of dyschromia. Hyperpigmentation can be avoided by means of a proper selection of patients, thorough consequent photoprotection, or the use

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of above-mentioned bleaching agents. The resulting hypopigmentation is difficult to control. Its onset may be due to previous cryotherapy, chemical peeling, or dermabrasion. Even periocular permanent depigmentation following the application of botulotoxin has been reported (13). The use of lasers represents a certain risk of the incidence of hypomelanoses. In subjects with darker complexion, the use of ruby laser for epilation may result in hypopigmentation in the treated area (Fig. 2), but this is usuaJJy temporary (14).

FIGURE

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Hypomelanosis after testing ruby laser for epilation.

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The most frequent incidence of hypopigmentation is reported after CO 2 laser treatment. This may be cosmetically insignificant, but on the other hand it may result in the permanent appearance of alabaster skin (15-17). Erbium: YAG laser treatment is less often associated with this complication (18). The risk of hypopigmentation in the treatment of vascular lesions with the pulsed dye laser is about 1% (19).

HYPOMELANOSES IN INTERNAL DISEASES AND DISORDERS Among the nutritional factors influencing the onset of hypomelanoses belong chronic protein deficiency (kwashiorkor) with reversible hypomelanosis starting in the face and with hair dyschromia, copper deficiency (hair hypopigmentation) (20), and pernicious anemia, as well as vagabond's leukoderma, occurring in individuals with poor hygiene, insufficient nutrition, and chronic alcohol abuse (21). Endocrinological disorders causing hypomelanoses include Addison's disease, thyroid gland disorders, and hypopituitarism. Disseminated reticular hypomelanosis has been described in primary biliary cirrhosis (22) and lightened hair and skin in hemodialyzed uremic patients (23).

THERAPY OF HYPOMELANOSES A number of hypomelanoses are reversible, and as such do not require any treatment. Therapy of permanent hypomelanoses is, in contrast, very difficult and often unsuccessful. In cosmetically unfavorable sites, any surgical procedure represents a high risk. Relatively good results were reported following tattoo techniques (dermatography, micropigmentation) (24), PUVA therapy, and a combination of dermabrasion or the use of carbon dioxide laser with subsequent transplantation of suspension of autologous keratinocytes and melanocytes or thin skin grafts. In mild pigmentation shifts (positive or negative), local tretinoin application can be tried (25). Local application of dihydroxyacetone yields uneven results. Systemic use of f)-carotene in postinflammatory hypomelanoses has been recommended (26). In differential diagnosis of acquired hypomelanoses, it is necessary to mention at least two diseases of connective tissue. Morphea is a localized form of scleroderma. In the central recession of the inflammatory phase it leaves whitish-yellow, tough, atrophied patches Lichen sclerosus et atrophicus, which is a chronic disease of unknown etiology, can be associated with autoimmune diseases, morphea, lichen planus, diabetes mellitus, and vitiligo. It affects females more frequently, possibly due to hormonal etiopathogenetic factors. Certain areas (e.g., lateral parts of the neck, clavicular region, shoulders,

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central part of the chest, flexural part of the forearm, external genitals, mucosa) manifest porcelain white or blue-white macules with pinkish inflammatory borders, resulting in atrophy of the affected site,

REFERENCES I,

2, 3.

4.

5, 6. 7.

8, 9, 10, II, 12.

13.

14,

15,

16,

Epps RE, Kenney JA Jr. Diseases of black skin, In: Braun-Falco 0, Plewig G, Wolff HH, Burgdorf WHC, eds, Dermatology, 2d ed, Berlin: Springer-Verlag, 2000: 1681-1691. Amichai B, Grunwald MH, Avinoach I, Halevy S, Hypopigmented mycosis fungoides in a white female, 1 Dermatol 1996; 23(6):425-426, Bleehen SS, Ebling Fl, Champion RH, Disorders of skin colour, In: Rook A, Wilkinson DS, Ebling FlG, eds. Textbook of Dermatology. 5th ed. Oxford: Blackwell Scientific Publications, 1992: 1561-1622. Fustes-Morales AJ, Soto-Romero I, Estrada Z, Duran-McKinster C, OrozcoCovarrubias L, Tamayo-Sanches L, Ruiz-Maldonado R. Unusual leukoderma after erythema multiforme: a case report. Pediatr Dermatol 200 I; 18(2): 120-122, Handa S, Handa U. Sarcoidosis presenting as cutaneous hypopigmentation, Int J Dermatol 1995; 34( II ):824, Bose SK, Ortonne JP. Pigmentation: dyschromia. In: Baran R, Maibach HI, eds, Cosmetic Dermatology. UK: Martin Dunitz Ltd, 1994:277-296, Bolognia JL, Shapiro PE. Albinism and other disorders of hypo pigmentation. In: Arndt KA, LeBoit PE, Robinson JK, Wintroub BU, eds. Cutanous Medicine and Surgery. Philadelphia: W.B. Saunders Company, 1996:1219-1230. Konkolova R, Korektivne dermatologick(: metody. Praha: Maxdorf Jessenius, 2001:65-74 Bhushan M, Beck MH. Allergic contact dermatitis from primula presenting as vitiligo. Contact Dermatitis 1999; 41(5):292-293. Kanerva L, EstJander T Contact leukoderma caused by patch testing with dental acrylics, Am J Contact Dermat 1998; 9(3):196-198 Malakar S, Dhar S. Leucoderma associated with the use of topical minoxidil: a report of two cases. Dermatology 2000; 201(2):183-184. Peter RU, Gottlober P, Nadeshina A, Krahn G, Plewig G, Kind P. Radiation lentigo. A distinct cutaneous lesion after accidental radiation exposure, Arch Dermatol 1997; 133(2):209-21 L Roehm PC, Perry JD, Girkin CA, Miller NR, Prevalence of periocular depigmentation after repeated botulinum toxin A injections in African American patients, J Neuroophthalmol 1999; 19(1 ):7-9, Liew SH, Grobbalaar A, Gault D, Sanders R, Green C, Linge C. Hair removal using the ruby laser: clinical efficacy in Fitzpatrick skin types I-V and histological changes in epidermal melanocytes, Br J Dermatol 1999: 140(6):1105-1109, Manuskiatti W, Fitzpatrick RE, Goldman MP, Long-term effectiveness and side effects of carbon dioxide laser resurfacing for photoaged facial skin, JAm Acad Derma tol 1999; 40(3):401-411, Laws RA, Finley EM, McCollough ML, Grabski Wl, Alabaster skin after

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17.

18. 19.

20. 2 I.

22. 23

24. 25.

26.

carbon dioxide laser resurfacing with histologic correlation. Dermatol Surg 1998; 24(6):633-636 Bernstein LJ, Kauvar AN, Grossman MC, Geronemus RG. The short- and longterm side effects of carbon dioxide laser resurfacing. Dermatol Surg 1997; 23(7): 519-525. Zachary CB. Modulating the Er: YAG laser Lasers Surg Med 2000; 26(2):223226. Wlotzke D, Hohenleutner D, Abd-EI-Raheem TA, Baumler W, Landthaler M. Side-effects and complications of flashlamp-pumped pulsed dye laser therapy of port-wine stains. A prospective study. Br J Dermatol 1996; 134(3):475-480. Olivares M. Dauy R. Copper as an essential nutrient. Am J Clin NutI' 1996; 63(5): 79 IS-796S Mosher DB, Fitzpatrick TB, Ortonne JP. Abnormalities of pigmentation. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg 1M, Austen KF, eds. Dermatology in General Medicine. New York: McGraw-Hill, 1979:568-620. Viraben R, Couret B, Gorguet B. Disseminated reticulate hypomelanosis developing during primary biliary cirrhosis. Dermatology 1997; 195(4):382-383. Hmida MB, Turki H, Hachicha J, Reygagne P, Rabier D, Zahaf A, Jarraya A. Hypopigmentation in hemodialysis. Acquired bair and skin fairness in a uremic patient undergoing maintenance bemodialysis: case report and review of tbe literature. Dermatology 1996; 192(2):148-152. Guyuron B, Vaughan C. Medical-grade tattooing to camouflage depigmented scars. Plast Reconstr Surg 1995; 95(3):575-579. Pagnoni A, Kligman AM, Sadiq I, Stoudemayer T. Hypopigmented mantles of photodamaged skin and their treatment with topical tretinoin. Acta Derm Venereo11999; 79(4):305-310. Orfanos CE, Garbe C. Therapie der Hautkrankheiten. Berlin: Springer-Verlag, 1995:770-778.

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38 Idiopathic Guttate Hypomelanosis Michelangelo La Placa and Sabina Vaccari University of Bologna, Bologna, Italy

Idiopathic guttate hypomelanosis (IGH) is a common disorder characterized by multiple rounded hypopigmented macules of the extremities, first described by Costa in 1951 as leucopalhie symetrique progressive des exlremiles (I).

CLINICAL FEATURES

IGH usually appears in elderly individuals after the third decade of life, and lesions tend to increase in number and size with advancing age (2-9). The disorder is characterized by circular or angular maculae, from few to many in number, measuring 2-6 mm in diameter. The spots are white-porcelain in color, well circumscribed, usually without sign of atrophy or hyperkeratosis, and mainly localized on the sun-exposed areas of the legs and the forearms (Figs. I and 2). When IGH is found in younger patients (20 years), lesions appear smaller (1-2 mm) and are fewer in number (less than five). Although asymptomatic, these lesions can provoke an aesthetic concern that is cause for dermatological consultation (5). IGH affects all individuals, with no genderor race-related differences. However, a slight prevalence in women and in subjects with skin types II and III has been reported (5). Copyrighted Material

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FIGURE 1

Hypopigmented maculae of the legs in IGH.

PATHOLOGY Histologically there is an evident hyperkeratosis of the horny layer with typical "basketweave" appearance, atrophy of the epidermis, decreased number ofmelanocytes and melanosomes, with a predominance of immature forms. In sections stained with the Fontana-Masson method, the melanin content in lesional skin is markedly less than in the perilesional epidermis.

FIGURE

2 Magnified view of Figure 1.

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Moreover, there is either a significant reduction in or an absence of dopapositive melanocytes (2,7). Within the hypomelanotic epidermis, the melanin granules are irregularly distributed. Electron microscopy examination shows rounded and less dendritic melanocytes in lesional skin, with fewer melanosomes uncompletely melanized (2,7). Immunochemistry studies, using a panel of melanocyte differentiation antigens to compare normal and IGH skin, demonstrated again an absolute decrease in the number of melanocytes (8).

PATHOGENESIS The cause of this macular depigmentation is unknown, although actinic influence has been suggested by many authors as a possible etiological factor. In fact, the location of the lesions suggests that sun exposure plays an important etiological role (9). However. lesions can be observed less frequently in unexposed areas, suggesting that other pathogenic mechanisms should be considered (5). One study detected gastric parietal cell antibodies in three of nine patients, indicating a possible autoimmune phenomenon (4). Genetic factors could playa causal role because more than 60% of patients have a family history of IGH, sometimes with diffuse skin xerosis (3). These data support the idea that two types of IGH exist: an idiopathic form and an inherited form.

TREATMENT Therapeutic procedures include intralesional triamcinolone with or without minigrafts of normally pigmented skin (5), cryotherapy (7), and PUVA therapy. However, all these treatments remain unsatisfyng, and relapses are common. In our opinion, it is most important to reassure patients of the benign nature of this disorder. Lastly, the application of topical tretinoin gives some cosmetic benefit (9).

REFERENCES I.

2. 3. 4.

Costa OG. Leucopathie symetrique progressive des extremites. Ann Dermatol 1951; 78:452. Ortonne JP, Perrot H. Idiopathic guttate hypomelanosis. Ultrastructural study. Arch Dermatol 1980; 116:664-668. Savall R, Ferrandiz C, Ferrer L Peyri J. Idiopathic guttate hypomelanosis. Br J Dermatol 1980; 103:635-642. Wilson PD, Lavker RM, Kligman AM. On the nature of idiopathic guttate hypo melanosis. Acta Den641pyeig/rl~lftj/2;62:301-306.

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392 5.

6. 7.

8.

9.

Falabella R, Escobar C, Giraldo N, Rovetto P, Gil J, Barona MI, Acosta F, Alzate A. On the pathogenesis of idiopathic guttate hypomelanosis. J Am Acad Dermatol 1987; 16:35-44. Gilhar A, Pillar T, Eidelman S, Etzioni A. Vitiligo and idiopathic guttate hypomelanosis Arch Dermatol 1989; 125:1363-1366. Ploysangam T, Dee-Ananlap S, Suvanprakorn P. Treatment of idiopathic guttate hypomelanosis with liquid nitrogen: light and electron microscopic studies. J Am Acad Dermatol 1990; 23:681-684 Wallace ML, Grichnick JM, Prieto VG, Shea CR. Numbers and differentiation status of melanocytes in idiopathic guttate hypomelanosis. J Cutan Pathol 1998; 25375-379. Pagnoni A, Kligman AM, Sadiq I, Stoudemayer T. Hypopigmented macules of photodamaged skin and their treatment with topical tretinoin. Acta Derm Venereol 1999; 79:305-310.

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39 Leukonychia Aurora Tedeschi, Maria Rita Nasca, and Giuseppe Micali Clinica Dermatologica, Universita di Catania, Catania, Italy

Leukonychia is a chromatic anomaly of the nail which appears white in color (1,2). Clinically, three main types of leukonychia are recognized: true leukonychia and pseudoleukonychia, in which there is an alteration of the nail plate, and apparent leukonychia, in which subungual tissue is involved (2). Pseudoleukonychia and apparent leukonychia may be due to several factors and usually disappear when the underlying local or systemic diseases are corrected (Table I) (2). Some authors also include onycholysis and subungual hyperkeratosis as forms of apparent leukonychia (1). Several clinical variants of leukonychia have been described, making its classification controversial because of poor knowledge about pathogenesis and histological features. Unusual clinical variants recently described include variegata and distal leukonychias (2), as well as sporadic congenital leukonychia with partial phenotype expression (3). The simultaneous occurrence of partial and total leukonychia in different members of the same family or in single patients (1,4-6) has been described. In such cases, partial leukonychia has sometimes been interpreted as a phase of total leukonychia (5-7). True leukonychia involves the nail plate (I) and is considered a keratinization disorder. The structural abnormality is due to the persistence of nuclei or nuclear debris in keratotic cells (parakeratosis) leading to decreased transmission of incident light. With polarized light, the nail structure appears disrupted due to disorganization of keratin fibrils (2). True leukonychia may be complete (total leukonychia), when the nail is totally white; subtotal, when Copyrighted Material 393

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Koilonychia Acrokeratosis verruciformis (Hopf) Leopard syndrome Knuckle pads and deafness Multiple sebaceous cysts and renal calculi Pancreatitis Duodenal ulcer and cholelithiasis Palmoplantar keratoderma and atrophic fibrosis Palmoplantar keratoderma and deafness Palmoplantar keratoderma and hypotrichosis Koilonychia, onychorrhexis, hypothyroidism, cataracts, and dental alterations KID's syndrome Epiphyseal dysplasia, short stature, small head, mental retardation, visual problems, hypoplasia of the corpus callosum Hemochromatosis Trazodone Exposure to extremely cold temperatures Acanthosis nigricans Leprosy exposure to: Nitric acid, Nitrite solution, Concentrated sodium chloride

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Drug reaction: cyclophosphamide, 5-f1uorouracil, doxorubicin, bleomycin, pilocarpine, sulfonamide, emetine hydrochloride, corticosteroids Poisoning: antimony, arsenic, fluorosis, thallium, CO, lead paraquat Nutritional disorders and deficiencies: pellagra, hypocalcemia, severe hypoalbuminemia, hypoproteinemia, zinc deficiency Neurological disorders: peripheral neuropathy, psychosis Darier's disease Hailey-Hailey's disease Hemochromatosis

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a pink area is present, usually close to the edge as an arch; or partial, when the nail plate involvement is not uniform (2). Congenital and acquired forms for each clinical variant have been described (2,8). Total leukonychia (Fig. I) is a rare condition in which the nail may be milky, chalky, bluish, ivory, or porcelain white in color (2). It is usually seen at birth and may follow an autosomal dominant inheritance, although an autosomal recessive transmission and a parental somatic mutation with gonadal mosaicism have also been hypothesized (8,9). Inherited totalleukonychia may be isolated or associated with other malformations listed in Table I (1,2,8,10-12). Idiopathic acquired forms (4,13), as well as forms following ingestion of trazodone, exposure to extremely cold temperatures, or associated with dermatoses such as acanthosis nigricans (I) and leprosy (2), have also been described. Total leukonychia may also be observed in association with various systemic diseases. In these cases inheritance may vary according to the main underlying disease. Subtotal leukonychia, sometimes preceding a total leukonychia (2,4,7), is characterized by a pink arch of about 2---4 mm width distal to the white area (2). The presence of this pink arch can be explained by loss of keratohyalin granules and by decreased parakeratotic cells as the nail plate approaches its distal end (2). Subtotal leukonychia may be congenital, transmitted as an autosomal dominant trait, or acquired following exposure to nitric acid or concentrated sodium chloride solutions (14).

FIGURE 1 Hereditary/congenital total leukonychia of the fingernails in a 44-yearold woman. The toenails were not affected. A similar condition was also present in her son and daughter.

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Partial leukonychia is distinguished into punctate leukonychia (very common), striate leukonychia (relatively common), and longitudinal or distal leukonychia (very rare). Each variant may either be congenital or acquired. Partial punctate leukonychia is characterized by white spots 1-3 mm in diameter appearing on the nail proximal end. The spots grow distally with the nail, disappearing in most cases during progression towards the free edge (2). They are caused by a local or general fault in keratinization and/or air infiltration. Partial punctate leukonychia may be acquired, especially following repeated trauma, or idiopathic (2,15,16). It is common in kids and in women who practice excessive and traumatic manicuring. An association with alopecia areata and acanthosis nigricans has been reported. A congenital form of punctate leukonychia, transmitted as an autosomal dominant trait, has also been described in association with pili torti (l,8, 17). Striate or transverse leukonychia shows transversal and parallel white streaks 1-2 mm wide involving one or several nails. Mees' lines belong to this form (8). Although acquired forms are considered more common, congenital forms may be observed. Causes of acquired striate leukonychia include chemical (contact with 2-ethylcyanoacrylate glue) and physical traumas (mechanical, thermic), psychophysical stress, menstrual cycle, and systemic diseases (Table I) (1,2,8,18). Those forms associated with a systemic disease are easily recognized, since they usually involve all nails Longitudinal or distal leukonychia is characterized by permanent grayish-white longitudinal bands of about I mm width due to localized damage of the nail matrix, sometimes following the development of benign tumors or cysts proximally to the nail plate (2). Longitudinal leukonychia is a typical feature of Darier's disease, a genodermatosis transmitted as an autosomal dominant trait and characterized by the onset of red longitudinal streaks, which in time turn white. Longitudinal leukonychia has also been described in patients with Hailey-Hailey disease (19) and hemochromatosis (2), in both cases transmitted as an autosomal dominant pattern. The term pseudoleukonychia is used when fungal parasitization of the ventral surface of the nail plate clinically appears as superficial white onychomycosis. The nail becomes friable and can easily be removed by a curette. Pseudoleukonychia associated with the use of nail polish has also been reported (2). Apparen't leukonychia is due to vasoconstriction and anemia, causing pallor of the nail bed (1). It uniformly involves all nails and remains unchanged as the nail grows (2). Terry's nails, formerly considered a typical feature of hepatic cirrhosis, have recently been described also in healthy subjects or in patients with cardiac insufficiency and/or type II diabetes. The nails are an opaque white color, with persistence of a pink area of 1-2 mm width, corresponding to the onychodermal band, in the distal edge (2). A variant of

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Terry's nails is represented by Morey and Burke's nails in which the nail whitening is limited exclusively to its central segment (2). Usually observed in cases of hypoalbuminemia (albumin <2.2 gjdL) or in patients undergoing chemotherapy, Morey and Burke's nails are characterized by multiple transverse white bands, separated one from another and from the lunula by pink streaks, which disappear pressing the distal phalanx. These alterations are more evident in the second, third, and fourth fingernail and vanish when serum albumin levels return to normal, reappearing when it falls again (2). Their pathogenesis is probably due to edema of the connective tissue caused by hypoalbuminemia, changing the compact arrangement of collagen fibrils into a looser texture (2). Finally, Lindsay's half-and-half nails, occurring in hyperazotemia, are sometimes considered a sign of chronic renal failure. In most cases the nails appear white and opaque in their proximal half, and reddish, pink, or brown (20-60% of the toal nail) in the distal area. The brownish color of the distal part can be due to increase in either melanosomes or capillar density.

REFERENCES I.

2. 3. 4. 5. 6. 7. 8. 9. 10. II.

Grossmann M, Scher R. Leukonychia. Review and classification. lnt J Dermatol 1990; 29:535-541. Baran R, Barth J, Dawber R. Nails Disorders. Common Presenting Signs, Differential Diagnosis and Treatment. London: Martin Dunitz, 1991:146-149. Brown PJ, Padgett JK, English JC III. Sporadic congenital leukonychia with partial phenotype expression. Cutis 2000; 66: 117-119. Stewart L, Young E, Lim HW. Idiopatic leukonychia totalis and partialis. JAm Acad Dermatol 1985; 12:157-158. Bettoli V, Tosti A. Leukonychia totalis and partialis: a single family presenting a peculiar course of the disease. J Am Acad Dermatol 1986; 15:535. Albright S, Wheeler SP. Leukonychia. Arch Dermatol 1964; 90:392. Butterworth T. Leukonychia partialis: a face of leukonychia totalis. Cutis 1982; 29363-367 Stevens KR, Leis PF, Peters S, Baer S, Orengo 1. Congenital leukonychia. J Am Acad Dermatol 1998; 39:509-5 J 2. Frydman M, Cohen HA. Leukonychia total is in two sibs. Am J Med Genet 1993; 47:540-541. Micali G. Knuckle pads-leukonychia-deafness. Birth Defects Encyclopedia. Cambridge: Blackwell, 1990: 1019-1020. Yamamoto T, Tohyama J, Koeda T, Maegaki Y, Takahashi Y. MUltiple epiphyseal dysplasia with small head, congenital nystagmus, hypoplasia of corpus callosum, and leukonychia totalis: a variant of Lowry-Wood syndrome? Am J Med Genet 1995; 56:6-9

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Basaran E, Yilmaz E, Alpsoy E, Yilmaz GG. Keratoderma, hypotrichosis and leukonychia totalis: a new syndrome? Br J Dermatol 1995; 133:636-638. Claudel CD, Zic JA, Boyd AS Idiopathic leukonychia totalis and partialis in a 12-year-old patient. 1 Am Acad Dennatol 2001; 44(suppl 2)379-380. Zaun H. Leukonychias. Semin Dermatol1991; 10:17-20. Mahler RH, Gerstein W, Watters K. Congenital leukonychia striata. Cutis 1987; 39:453-454 Dotz WI, Lieber CD, Vogt Pl. Leukonychia punctata and pitted nails in alopecia areata. Arch Dermatol 1985; 121:1452-1454. Giustina T, Woo TY, Campbell JP, Ellis CN. Association of pili torti and leukonychia. Cutis 1985; 35:533-534. Ena P, Mazzarello Y, Fenu G, Rubino C. Leukonychia from 2-ethyl-cyanoacrylate glue. Contact Dermatitis 2000; 42: 105-106. Kirtschig G, Effendy I, Happle R. Leukonychia longitudinalis as the primary symptom of Hailey-Hailey disease. Hautarzt 1992; 43:451-452.

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40 Vogt-Koyanagi-Harada Syndrome Fabrizio Guarneri, Pasquale Aragona, and Mario Vaccaro University of Messina, Messina, Italy

A rare multisystem inflammatory disease, Yogt-Koyanagi-Harada syndrome is part of the group of melanocyte disorders. It was first described in 1906 by Yogt, who described a patient with bilateral idiopathic uveitis, poliosis, and alopecia (l). Four years later, a case of generalized vitiligo followed by bilateral uveitis and optic neuritis was reported by Gilbert (2). In 1926, Harada described five cases of bilateral posterior uveitis and retinal detachment, often presenting after meningitis. He also studied the cerebrospinal fluid of these subjects, showing the presence of increased protein levels and pleocytosis (3). Clinical signs and symptoms of the syndrome were better defined 3 years later by Koyanagi in a study on 16 patients with headache, fever, dysacusis, vitiligo, poliosis, alopecia, and anterior or posterior uveitis bilaterally, with occasional exudative retinal detachment (4). The term Yogt-Koyanagi-Harada (YKH) syndrome was suggested by Babel in 1939, in consideration of the several similarities between clinical pictures ofYogt-Koyanagi syndrome and Harada syndrome. Synonyms for Yogt-Koyanagi-Harada syndrome, used particularly in the ophthalmological and neurological literature, include uveoencephalitis, oculocutaneous syndrome, and idiopathic neuraxitis. The prevalence and incidence of YKH syndrome are reported to be very low. According to the literature, classic clinical manifestations are reported in 4-7% of patients with uveitis, a disease affecting approximately 15 out of 100,000 subjects. However, some authors noted that many patients with common vitiligo, a more frequent disease, have subclinical manifestations of sparse poliosis or uveitis and could be considered as cases of subclinical YKH Copyrighted Material 403

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syndrome. Males and females are equally affected; incidence seems to be higher in people with pigmented skin, but no race is spared. The onset is reported mainly between 10 and 52 years of age, with peak frequency in the third and fourth decades; pediatric cases are rare. No familial inheritance was found. Some HLA haplotypes (DR4, Dw53, LD-Wa) seem to be present in a statistically significant number of patients. Etiopathogenesis of VKH syndrome is still unknown. Its frequent association with several well-known autoimmune diseases, like Hashimoto's disease, nontuberculous Addison's disease, thyrotoxicosis, and mucocutaneous candidiasis, led many authors to hypothesize an autoimmune origin for it. In vitro studies showed that lymphocytes from subjects affected by VKH syndrome undergo blast transformation in the presence of bovine uveal pigment cells and are cytotoxic against allogenic melanoma cells. In vivo, presence of activated CD4 + lymphocytes in depigmented skin areas of patients affected by vitiligo (a frequent clinical sign of VKH syndrome) was demonstrated, strengthening these theories. According to some authors, autoimmune reaction against melanocytes could be triggered by a viral infection, still of undefined nature (5). Once activated, the inflammatory process causes destruction of pigmented cells in all areas of the body. The widespread presence of meJanocytes in the human body explains the variety of clinical signs and symptoms typical of VKH syndrome. In addition to the skin and central nervous system, meJanocytes are, in fact, present in eyes and ears. In the eye, melanocytes localized in uvea and iris absorb part of the incident light, improving the visualization of images on the retina, and playa role in the catabolism of toxic substances produced in retinal photochemical reactions, while melanocytes present in the retinal pigmented epithelium are important in maintaining the functions of photoreceptors, and those situated in ciliary bodies are involved in the production of aqueous humor. The functions of melanocytes in the ear, in contrast, are still not clearly defined, but it is well known that an altered development of ear melanocytes (as in Waardenburg syndrome or piebaldism) results in hypoacusis. This suggests a role for these cells in the transmission of electric signals from receptors to central nervous system, demonstrated until now only in rats. Moreover, some authors showed an increased number ofmelanosomes in ear melanocytes after an acoustic trauma, and suggested that melanin could have a protective role against damage caused by noise or toxic agents (6). Considering the role ofmelanocytes in different organs, clinical features ofVKH syndrome are easy to explain. Clinically, this disorder has a triphasic evolution. The first stage, the meningoencephalitic phase, often begins abruptly and is characterized by headache, malaise, fever, nausea, and vomiting, of variable intensity. Confusion, psychosis, hemiparesis, paraplegia, aphasia. Copyrighted Material

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syncope, and general muscle weakness can also be present. During this phase, electroencephalographic abnormalities can be shown, as well as an increase in the concentration of proteins and in the number of white blood cells in the cerebrospinal fluid. The second, or ophthalmic stage, of uveitis usually occurs several weeks later and may last for 10 years or more. It is characterized by ocular and supraorbital pain, photophobia, eye irritation, sudden or gradual decrease of visual acuity (progressing in some severe cases to permanent blindness, due to retinal detachment). Histological features in the affected areas resemble those of a granulomatous uveitis, with close aggregation of lymphocytes around melanocytes. Transient dysacusis, usually bilateral, occurs, according to different authors, in 50-80% of patients during this phase. Headache and slight fever can also be present. The convalescent state, the third stage of the syndrome, begins when the uveitis subsides, and its hallmarks are poliosis, alopecia, and vitiligo, occurring in 90%,73%, and 63% of patients, respectively. Poliosis can involve the scalp as well as eyelashes and eyebrows, with variable extension, and is usually noted after the onset of alopecia. Alopecia in VKH syndrome can involve a subtle diffuse loss of hair or may occur in patches, while alopecia totalis is only sometimes observed. Histological features of involved skin-periappendageal infiltrates of lymphocytes and plasma cells-are indistinguishable from those of alopecia areata, but it is not clear if alopecia associated with VKH syndrome can be classified as alopecia areata. Cutaneous depigmentation observed in course ofVKH syndrome is clinically and histologically identical to vitiligo. It usually consists of patches of hypomelanosis, symmetrical and centrifugally enlarging, most commonly localized to the head and shoulders, nape of the neck, and eyelids (as in segmental vitiligo), with rarely occurring spontaneous repigmentation. Halo nevi were reported in some cases as the first manifestation of VKH syndrome. Histologically, edema, vasodilatation of the dermis, melanophages full of pigment, and the above-mentioned lymphocytic infiltrate are visible in specimens of depigmented skin. Electron microscopy shows absence of melanocytes, replaced by Langerhans cells and indeterminate dendritic cells. Colloid-amyloid bodies are found at the dermoepidermal junction (5,7,8). Diagnostic criteria for VKH syndrome specified by the American Uveitis Society during the 2nd Annual Meeting in Kansas City, Missouri, in 1978 (9) are listed in Table 1. These criteria have some limitations: patients may present with incomplete or delayed appearance of the extraocular manifestations, especially if treated early with steroids or immunosuppressive agents, and the patterns of symptoms may vary between racial groups. In 1999 revised criteria for diagnosis were proposed by the First International Workshop on Vogt-Koyanagi-Harada Disease, held at the University of California at Los Angeles (Table 2) (10). Copyrighted Material

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Diagnostic Criteria for Vogt-Koyanagi-Harada Syndrome

1. Absence of previous ocular trauma or surgery 2. At least three of the following: Bilateral iridocyclitis Posterior uveitis (including exudative retinal detachment or sunset glow fundus) Central nervous system problems: tinnitus, vertigo, dysacusis, meningism (with fever, headache, nausea, vomiting), cranial nerve dysfunction, cerebrospinal fluid pleocytosis Cutaneous findings: alopecia, poliosis, vitiligo Source: American Uveitis Society, 1978.

Some clinical signs of VKH syndrome are very similar to those of vitiligo and AJezzandrini's syndrome, both of which should be considered in differential diagnosis. Some authors, on the basis of many clinical, histopathological, and immunological findings common to these three disorders, proposed that they could be different expressions of a single etiopathogenetic mechanism, but this very interesting hypothesis is yet to be clearly demonstrated. Other diseases that could resemble some clinical features of VKH syndrome are albinism, piebaldism, tuberous sclerosis, Waardenburg's syndrome, Chediak-Higashi syndrome, Marfan's syndrome, Rubinstein-Taybi syndrome, hyperthyroidism, hypoparathyroidism, Addison's disease, hypopituitarism, pernicious anemia, halo nevus (leukoderma acquisitum centrifugum-Hyde and Sutton), nevus depigmentosus, leprosy-tuberculoid, pityriasis alba, postinflammatory depigmentation, phenylketonuria (pigment dilution), idiopathic guttate hypomelanosis, syphilitic leukoderma, scleroderma/morphea, alopecia (caused by various etiological agents), uveitis, bacterial or viral meningitis, tumors of the central nervous system, Lyme disease, and sarcoidosis. The ocular features are characterized by a sudden presentation of bilateral granulomatous iridocyclitis, often asymmetrical, with the onset in one eye followed by the involvement of the fellow eye 2-4 weeks later. Asian patients may present with a perilimbal vitiligo known as the Sigiura's sign (11). The cornea may show granulomatous or nongranulomatous deposits in the endothelium. The iris may demonstrate nodules in the stroma or in the pupil margin with possible posterior synechiae formation between iris and lens capsule. This may lead to the development of a secondary glaucoma. The ciliary body may also be involved in the disease with edema and inflammatory cell infiltration. In this case the intraocular pressure tends to decrease due to reduced aqueous humor production. Vitritis (Fig. 1) and exudative retinal detachment may be present, most frequently in the inferior retina. Disc edema Copyrighted Material

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2

407

Revised Diagnostic Criteria for Vogt-Koyanagi-Harada Disease

1.

No history of penetrating ocular trauma or surgery preceding the initial onset of the uveitis 2. No clinical or laboratory evidence suggestive of other ocular disease entities 3. Bilateral ocular involvement, with findings dependent on stage of disease when the patient is examined (see below) 4. History or presence of neurological andlor auditory findings (see below) 5. Integumentary findings occurring concurrent or after (not preceding) the onset of CNS or ocular disease (see below).

Criteria present

Diagnosis

1, 2, 3, 4, and 5 1, 2, 3, and (4 or 5) 1,2, and 3 Other

Complete Vogt-Koyanagi-Harada disease Incomplete Vogt-Koyanagi-Harada disease Probable Vogt-Koyanagi-Harada disease Not Vogt-Koyanagi-Harada disease

Ocular involvement (earlv):

3E1.

3E2.

Diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction or optic disc hyperemia) which may be manifested by one or both of the following: 3E1 a. Focal areas of subretinal fluid 3E1 b. Bullous serous retinal detachments With equivocal fundus findings, both of the following must be present as well: 3E2a. Fluorescent angiography shows focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of hyperfluorescence pooling within subretinal fluid and optic nerve staining (in order of sequential appearance) 3E2b. Diffuse choroidal thickening without evidence of posterior scleritis by ultrasonography

Ocular involvement (late):

3L1. 3L2.

3L3.

History suggestive of prior presence of early ocular involvement, both 3L2 and 3L3, or multiple signs from 3L3 Ocular depigmentation, one or both of the following: 3L2a. Sunset glow fundus (pale choroidal pigmentation) 3L2b. Sigiura sign (perilimbal vitiligo) Other ocular signs: 3L3a. Nummular chorioretinal depigmented scars 3L3b. Retinal pigment epithelium clumping andlor migration 3L3c. Recurrent or chronic anterior uveitis

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2 Continued

Neurological and/or auditory findings-one or more of the following:

4a. 4b. 4c.

Meningismus (combination of malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back. Headache alone is insufficient) Tinnitus Pleocytosis in the cerebrospinal fluid

Integumentary findings-one or more of the following:

5a. Alopecia 5b. Poliosis 5c. Vitiligo Source: First International Workshop on Vogt-Koyanagi-Harada Disease, 1999.

FIGURE 1

Active vitritis with vitreal exudates.

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is also a common feature (12). Nodular, yellow choroidal infiltrates, identical to the Dalen-Fuchs nodules of sympathetic ophthalmia, may be found in the mid-periphery. Neovascularization of optic disc and the retina may lead to vitreous hemorrhages (J 3) (Fig. 2). Choroidal neovascular membrane may cause hemorrhagic macular detachment with consequent visual loss and poor visual prognosis. The presence of subretinal neovascular membrane is usually associated with anterior chamber inflammation. Scleral melting may occur due to an immune reaction against the melanocytes connected with the scleral nerves. When the clinical features resolve, the eyes are characterized by the presence of a generalized pigment alteration that can be seen either as a pigment rearrangement or as a pigment loss resulting in a blond appearance of the fundus. Cataract and glaucoma occur in 35% of patients (11,12). Glaucoma associated with VKH is difficult to control. Visual acuity may be severely impaired by the retinal alterations consequent to the inflammation. Fluorescein angiography and HLA typing can be useful in confirming the diagnosis of VKH syndrome. It is often necessary to perform additional radiographic, histopathological, and/or laboratory tests to exclude some of the above-mentioned disorders in the differential diagnosis.

FIGURE 2

Granulomatous choroidal inflammation and area of choroidal atrophy.

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Early diagnosis of YKH syndrome is essential for an early start of therapy that has proved effective in preventing the progression of uveitis, thus avoiding blindness. The preferred drug is prednisone at an initial dose of 1 mg/kg/day, which can be increased in more severe cases. Duration of the treatment depends on clinical response, but is usually around 6 months. Widespread cutaneous depigmentation can be treated with psoralens and ultraviolet light (PUYA), as described for vitiligo. However, a careful evaluation of the risk/benefit ratio should be made in each patient: in particular, phototherapy might aggravate an eventually present anterior uveitis. Moreover, it has to be considered that repigmentation of relatively hair-free areas (such as the eyelids) can prove difficult. Clinical manifestations and prognosis ofYKH syndrome are extremely variable. Frequently, not all signs are present (see Table 2). Relapses can be present in the clinical course of the disease. Uveitis is the main problem because of its possible consequences. It is usually self-limiting, but can lead to a variable reduction of visual acuity and, in some cases, to blindness. Hypoacusis is, in the majority of cases, only temporary, and auditory sequelae are infrequent. Cutaneous manifestations, instead, tend to persist, especially when widespread depigmentation is present (5,7). In conclusion, disorders of cutaneous pigmentation are not only aesthetic problems involving skin and mucosae. Sometimes, as in the case of Yogt-Koyanagi-Harada syndrome, they can be the exterior manifestation of a multisystemic pathology of extracutaneous origin, possibly with severe consequences; this reminds us once more, if needed, that a careful and complete clinical examination of the patient is always to be performed, even in apparently "simple" cases.

REFERENCES 1.

2. 3. 4. 5.

6.

Vogt A. Fri.ihzeitiges Ergraven der Zilien und Bemerkungen uber den sogenannten plotzlichen einentt dieser Veranderugn. Klin Monatsbl Augenheilkd 1906; 44:228-242. Gilbert W. Vitiligo und Auge, ein Beitrag zur Kenntnis der herpetischen Augenerkrankungen. Klin Monatsbl Augenheilkd 1910; 48:24-31. Harada E. Clinical study of nonsuppurative choroiditis: a report of acute diffuse choroiditis Acta Soc Ophtalmol Jpn 1926; 30:356-377. Koyanagi Y. Dysakusis, Alopecia und Poliosis bei schwerer Uveitis nicht traumatischen Ursprunges. Klin Monatsbl Augenheilkd 1929; 82:194-21 L Barnes L, Nordlund 1J. Vogt-Koyanagi-Harada and Alezzandrini's syndromes. In: Demis 1, ed. Clinical Dermatology. Vol. 2. Philadelphia: 1 B Lippincott Company, 1991:unit 11-34. Tosti A, Piraccini BM, Tosti G. Vitiligine: disturbi oculari e audiologici. In: Lotti

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TM, Bianchi B, Ghersetich I, eds. La Vitiligine-Nuovi Concetti e Nuove Terapie. Milano: UTET Periodici Scientifici, 2000:63-66. 7. Patrizi A, Trestini D. La sindrome di Vogt-Koyanagi-Harada. Ill: Lotti TM. Bianchi B, Ghersetich J, eds. La Vitiligine-Nuovi Concetti e Nuove Terapie. Milano: UTET Periodici Scientifici, 2000:137-140. 8. Immunopathologic study of Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1988; 105(6):607-611. 9. Beniz J, Forster DJ, Lean JS, Smith RE, Rao NA. Variations in clinical features of the Vogt-Koyanagi-Harada syndrome. Retina 1991; 11:275-280. 10. Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, Arellanes-Garcia L, Pivetti-Pezzi P, Tessler HH, Usui M. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol2001; 131:647-652. II. Sigiura S. Vogt-Koyanagi-Harada disease. Jpn J Ophthalmol 1978; 22:99. 12. Nussenblatt RB, Palestine AG. Uveitis: Fundamentals and Clinical Practice. Vol. 15 Chicago: Year Book Medical Publishers, 1989:274. 13. Harada T, Matsuzaki S, Okada H, Yumiyama A, Majima Y. Occurrence of optic disc hemorrhage in the course of Vogt-Koyanagi-Harada syndrome. Klin Monatsbl Augenheilkd 1991; 199(3):206-208.

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41 Nevus Depigmentosus Beatrice Bianchi and Torello M. Lotti University of Florence, Florence, Italy Jana Hercogova Charles University, University Hospital Motol, Prague, Czech Republic

Nevus depigmentosus (NO), described first by Lesser in 1884 (I), is a wellcircumscribed hypomelanosis that is present at birth and remains stable in its relative size and distribution throughout life (2,3). Some authors have reported its initial presentation at various ages, probably because the infants or young children have untanned skin and the color contrast of NO lesions may not be readily visible. NO occurs sporadically and is of no medical significance. There is no known pattern of inheritance or sex predominance. Examination of NO by light microscopy, as well as electron microscopy, has revealed the presence of either a normal or decreased number ofmelanocytes (5), with stubby dendrites poorly developed and DOPA reduced reactivity. Histological study on lesional skin compared with perilesional normal skin shows in melanocytes a significant reduction in the density of the melanosomes, which are aggregated and heteromorphic (4). Within the affected keratinocytes, small melanosomes tends to reunite in masses surrounded by a limiting membrane and are present in reduced numbers. NO pathophysiology is probably associated with a developmental defect of the fetal melanocytes (4). In particular a defect has been reported in the transfer of melanosomes from melanocytes to keratinocytes (2). NO can clinically present in three different ways: (a) as an isolated patch, circular, rectangular, or irregular in shape and size, with geographic margins, involving a quite small segment of the body (Fig. I), (b) as a cirCopyrighted Material 413

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Trunk and extremities

Trunk, legs, arms

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Marble cake Neurological, mental, ocular, dental, hair, musculoskeletal abnormalities

Treatment

None

None

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NO, nevus depigmentosus; HI, hypomelanosis of Ito; TS, tuberous sclerosis; SV, segmental vitiligo.

SV Acquired from birth to old age, half by age 20 Unilateral in a dermatomal or quasidermatomal distribution Chalk- or milk-white Round, scalloped margins

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cumscribed, unilateral band or streak arranged in a blocklike configuration or along Blaschko lines, or (c) as a segmental variant. The segmental variant is usually confined to one side of the body, more often on the trunk. A systematized pattern, consisting of multiple, irregular hypopigmented whorls or streaks, without preceding vesicular or verrucous stages is also described (2). The back and buttocks are the most commonly affected sites, followed by the chest and the abdomen, the face, the neck, and the arms, in descending order of frequency (4). The lesions are uniformly hypomelanotic but not amelanotic, and they become more apparent with a Wood's lamp examination. CLINICAL DIAGNOSIS

Clinical diagnostic criteria commonly accepted and proposed by Coupe (6) in 1976 are: 1. 2.

FIGURE 2

Leukoderma present at birth or onset early in life No alteration in distribution of leukoderma throughout life

Segmental vitiligo.

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3. 4.

417

No alteration in texture, or change of sensation, in the affected area No byperpigmentation border around the achromic area

The differential diagnoses of ND include (7) (Table I): (a) segmental vitiligo (Fig. 2), which is amelanotic and acquired and is milk-white in color under Wood s lamp iJlumination; (b) hypomelanosis of Ito (incontinentia pigmenti achromians), in which there are hypopigmented bands and whorls occurring along Blaschko's lines, which tend to occur within the first year of life, with a variability in clinical presentation and association with other congenital abnormalities predominantly neurological, leading to frequent characterization as a neurocutaneous syndrome; (c) segmental tuberous sclerosis, which is usually associated with other hypomelanotic lance-ovate-shaped macules with other cutaneous findings and neurological involvement; (d) nevus anemicus (Fig. 3), which is a localized vascular abnormality that presents as an area of pale skin and which lacks a flare response to rubbing or heat.

FIGURE 3

Nevus anemicus.

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418

TREATMENT No effective treatment is available.

REFERENCES 1. 2. 3. 4. 5.

6. 7.

Lesser E. In: von Zeimssen H, ed. Handbuch der Hautkrankheiten. Leipzig: Vogel,1884:183. Bolognia JL, Pawelek JM. Biology of hypopigmentation. J Am Acad Dermatol 1988; 19:217-247. Orlow SJ. Congenital and genetic disorders associated with hypopigmentation. Curr Probl Dermatol1994; 6:157-184 Lee HS, Chun YS, Hann SK. Nevus depigmentosus: clinical features and histopathologic characteristics in 67 patients. J Am Acad Dermatol 1999; 40:21-26. Ogunbiyi AO, Ogunbiyi JO. Nevus depigmentosus and inflammatory linear epidermal nevus. An unusual combination with a note on histology. Tnt J Dermatol 1998; 37:600-602. Coupe RL. U nila teral systematized achromic naevus. Dermatologica 1976; 134: 19-35. Mosher DB, Fitzpatrick TB, Ortonne JP, Hori Y. Hypomelanoses and hypermelanoses In: Freedberg 1M, Eisen AZ, Wolff K, et aI., eds. Fitzpatrick's Dermatology in General Medicine. 5th ed. New York: McGraw-Hili, 1999:9451017.

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42 Hypomelanosis and Tuberous Sclerosis Complex

A. Patrizi and I. Neri University of Bologna, Bologna, Italy

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder where the term "complex" emphasizes the multisystemic involvement of this disease and its genetic heterogeneity. TSC is characterized by seizures, mental retardation, and development of multiple cutaneous and visceral hamartomas mainly located in the brain, eyes, kidneys, and heart. TSC hamartomas are benign and rarely progress to malignant tumors. TSC affects 1 in 6,00010,000 subjects in the general population, and 50-75% of affected patients are sporadic cases caused by a de novo mutational event (1--4). TSC shows a high penetrance and variable expressivity (1--4). Males and females are equally affected, and there is no racial predilection. GENETICS

TSC is the result of the mutation of two different genes: TSCI and TSC2 (5,6). TSCI, cloned in 1997, is a gene located on chromosome 9 at 9q34.3, producing a messenger RNA of 8.6 kb and encoding for a 1164-amino-acid protein named hamartin. TSC2 is a gene located on chromosome 16 at 16p 13.3, producing a messenger RNA of 5.5 kb and encoding for a 1784amino-acid protein named tuberin. The functions of hamartin and tuberin are not well defined, but in vivo they form a complex, and the inactivation of this complex leads to TSC (7). As a consequence, mutations to either gene result in the same phenotypic spectrum. Much evidence would appear to indicate that Copyrighted Material 419

420

Patrizi and Neri

TSC genes are tumor suppressor genes. Screening oflarge numbers of patients reveals that the majority of cases carry TSC2 mutations (80%). In familial cases the ratio of TSC 1 to TSC2 mutations is approximately I: 1, while in sporadic cases the disorder results from a new dominant mutation occurring in the TSC2 gene in two-thirds of patients and TSCI in the other third. There may also be germline mosaicism when thoroughly evaluated parents with no features ofTSC have two or more affected children (8). If parents or siblings of an affected individual wish to ha ve children, a meticulous screening should be made for genetic counseling. The widespread distribution of both TSCI and TSC2 mutations hinders the development of a simple molecular commercial diagnostic test on account of the many different mutations reported in patients with familial or sporadic TSC. DIAGNOSTIC FEATURES

In the past the disease was diagnosed on the basis of the Vogt triad-mental retardation, epilepsy and facial angiofibromas-but recently this triad has been found in less than one-third of patients, and in some children none of the features are evident (9). Gomez first proposed diagnostic criteria for TSC (10,11), and in 1992 the National Tuberous Sclerosis Association proposed a long list of diagnostic criteria for TSC, divided into primary, secondary, and tertiary features (12). Hypomelanotic mantles and "confetti" skin lesions were encompassed in the tertiary criteria. In July 1998, in the TSC Consensus Conference in Annapolis, Maryland, the diagnostic criteria for TSC were revised on the basis of new information from clinical and genetic studies, and a new panel of revised diagnostic criteria was proposed (Table 1), divided into two groups of features: major and minor (8). There are 11 major features, 4 of which are cutaneous: facial angofibromas or forehead plaque, nontraumatic ungual and periungual fibroma, hypomelanotic macules (more than 3), and shagreen patch (connective tissue nevus). The only cutaneous feature of the 9 minor features is that of the so-called confetti skin lesions. All the cutaneous features may be diagnosed clinically, and histological confirmation is not necessary. Dermatological manifestations are crucial in this panel of diagnostic criteria, and the diagnosis of TSC is often made by dermatologists, as 96% of patients with TSC have one or more typical skin lesions which are often the first sign to draw attention to the disorder. CLINICAL FEATURES OF TSC

In very small children the most frequently observed clinical signs are epileptic seizures, mainly as infantile spasms. They affect more than 60% of affected infants (9,13-15). Subependymal nodules are the most frequently observed Copyrighted Material

Hypomelanosis and Tuberous Sclerosis Complex TABLE 1

421

Revised Diagnostic Criteria for Tuberous Sclerosis

Complex Major features 1. Facial angiofibromas or forehead plaques 2. Nontraumatic ungual or periungual fibrome 3. Hypomelanotic macules (three or more) 4. Shagreen patch (connective tissue nevus) 5. Multiple retinal nodular hamartomas 6. Cortical tuber 7. Subependymal nodule 8. Subependymal giant cell astrocytoma 9. Cardiac rhabdomyoma, single or multiple 10. Lymphangiomyomatosis 11. Renal angiomyolipoma Minor features 1. Multiple, randomly distributed pits in dental enamel 2. Hamartomatous rectal polyposis 3. Bone cysts 4. Cerebral white matter radial migration lines 5. Gingival fibromas 6. Nonrenal hamartoma 7. Retinal achromic patch 8. Confetti skin lesions 9. Multiple renal cysts Definite tuberous sclerosis complex Either two major features or one major feature plus two minor features Probable tuberous sclerosis complex One major plus one minor feature Possible tuberous sclerosis complex Either one major feature or two or more minor features Source: Ref. 8.

cerebral lesions, detected by computed tomography or by magnetic resonance imaging. Cardiac rabdomyomas are present in up to more than 50% of infants (J3-IS). The first observed cutaneous changes include hypomelanotic macules, present in more than 80% of patients, and forehead fibrous plaques, whereas facial angiofibromas (Fig. I), shagreen patches (Fig. 2), periungual fibromas, and gingival fibromas usually appear later in life.

CLINICAL FEATURES OF HYPOMELANOTIC MACULES Hypomelanotic macules (HM) ofTSC appear very early in infancy or may be already present at birth ~~ertJll.0a6waJpresentthe earliest cutaneous

422

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Facial angiofibromas.

sign ofTSC (2,16). Moreover, at birth and in children less than 2 years of age, HM are the most frequent lesion ofTSC (16-19). The etiopathogenesis ofHM is still unknown. In 2000 Chudnow et al. reported that in most HM ofTSC the eccrine sweat glands produce less sweat than normal skin when stimulated with pilocarpine. They suggested that focal abnormal postganglionic sympathetic innervation may be responsible for both impaired sudomotor

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function and decreased pigmentation (20). HM of TSC vary remarkably in size, shape, morphology, site, and number (16-19). Size and Shape HM of TSC have been reported as typically lance-ovate macules (Fig. 3) called "ash leaf spots" due to their resemblance to the shape of a mountain ash leaf, but they may present many differences in size and shape, and the most frequently observed lesions are polygonal (16,21) (Fig. 4). They may also be round, oval, or linear, and the largest may be segmental with a dermatomal pattern of distribution. The latter type of HM, similar to a nevus depigmentosus, is generally considered the rarest clinical aspect of HM in TSC and usually appears only in association with other types of HM (9). The most frequently found HM have a diameter of 1-5 cm in children under 5 years, but they may vary from 4 mm to several cm. HM more rarely occur as a group of numerous macules, often symmetrical and 1-3 mm in diameter, named confetti spots (Fig. 5).

Morphology

Hypopigmented macules show a smooth surface with absence of scale and are not as white as suggested by their former name, ash leaf-shaped white spot. The adjective "hypomelanotic" or "hypopigmented" is due to the fact that these lesions are somewhat clearer than the surrounding skin. In Caucasian patients, in particular fair-skinned individuals, they may be not readily visible under normal room light but become evident with the use of a Wood's lamp. The use of a Wood's lamp is mandatory in screening of each individual for hypopigmented lesions, particularly for small lesions such as confetti skin lesions, which are easily missed without such an examination. The borders of HM ofTSC may be well demarcated or not, and, although the majority show a smooth contour, some may have irregular outlines. Morphologically they may be indistinguishable from hypopigmented macules of normal individuals, as the latter are also hypochromic and not achromic (16-19,22). Site

Hypomelanotic macules of TSC are distributed neither symmetrically nor in crops; they are scattered over the entire skin surface, except for the palms and soles. The Wood's lamp examination should therefore be made in a totally undressed state. The macules are situated mainly on the trunk and buttocks but may also be present on the limbs alone (16-19,21). The head and neck are more rarely involved, but on the scalp HM may produce tufts of hypopigmen ted hairs (poliosis), which more rarely occur in the eyebrows and eye-

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A typical lance-ovate macule, named "ash leaf spot," on the right

buttock.

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FIGURE 4

A polygonal hypopigmented macule.

lashes. Only rare and isolated white hairs may be seen, and leukotrichia of body and pubic hair may also be observed. No HM are usually found on the mucous membranes. Confetti skin lesions are usually spread over the lower legs and forearms, where they are often symmetrically distributed and may involve the full circumference of the lim b.

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Confetti skin lesions on the leg.

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Number

HM are usually about 3-6 in number but may sometimes be more than 25 (Fig. 6). In rare cases they may only be 1 or 2 in number. Some HM may totally disappear with age, and for this reason the number of HM is frequently reported as higher in young children than in adults (14). HISTOPATHOLOGY OF HYPOMELANOTIC MACULES HM are lighter than the surrounding skin but are not completely lacking in pigment. At electron microscopic examination the melanocytes appear normal or slightly decreased in number and size, but their melanosomes are few or absent, smaller in diameter, and with reduced melanization (21). DIFFERENTIAL DIAGNOSIS OF HYPOMELANOTIC MACULES HM of TSC are clinically indistinguishable from hypochromic macules of normal people. In 1996, in a large study of 423 white individuals younger than 45 years of age, screened with ambient light and Wood's lamp, 20 subjects (4.7%) showed at least one HM but none had more than 3 (22). In 1998, on the basis of this study, HM numbering 3 or more were included in the major diagnostic features of TSC, while confetti skin lesions remained in the group of minor diagnostic features (8). Differential diagnosis ofHM includes: patches of vitiligo, where there is a complete lack of pigmentation and sometimes hyperpigmented borders; nevus anemicus, which is not a pigmentary abnormality and does not redden when rubbed; nevus depigmentosum, which is usually larger, sometimes segmental, and is congenital. Pytiriasis alba and areas of postinfiammatory hypopigmentation usually appear later and often have fine scale. Congenital achromic patches of piebaldism contain some normally pigmented areas and are always associated with poliosis. In Waardenburg's syndrome, however, there is congenital leukoderma, poliosis, and many other clinical features such as dystopia canthorum, broad nasal root, heterochromia irides, and deafness. Idiopathic guttate hypomelanosis and multiple endocrine neoplasia type I may be considered in differential diagnosis of confetti skin lesions. TREATMENT AND EVOLUTION There is no treatment for the HM of TSC apart from the use of sun blocks to prevent sunburn. Moreover, HM frequently become more pigmented and less obvious with age, and so~tffi!aIM~i113pear.

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REFERENCES I.

2.

3. 4. 5.

6.

7.

8. 9.

10. II. 12. 13.

14.

15.

16. 17. 18. 19.

Kwiatkowski Dl, Short P. Tuberous sclerosis. Arch Dermatol 1994; 130:348354 Harper 11. Genetics and genodermatoses. In: Champion RH, Burton lL, Burns DA, Breathnach SM, eds. Rook/Wilkinson/Ebling Textbook of Dermatology. Oxford: Blackwell Scientific Publications, 1998:384--388. Osborne lP, Fryer AE, Webb D. Epidemiology of tuberous sclerosis. Ann NY Acad Sci 1991; 615:125-127. Webb DW, Clarke A, Fryer A, Osborne lP. The cutaneous features of tuberous sclerosis: a population study. Br 1 Dermatol 1996; 135:1-5. Van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, lanssen B, Verhoef S , et al. Identification of the tuberous sclerosis gene TSCI on chromosome 9q34. Science 1997; 227:805-808 The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75:1305-1315. Nellist M, van Slegtenhorst M, Goedbloed M, van den Ouweland AMW, Halley DJJ, van del' Sluijs P. Characterization of the cytosolic tuberin-hamartin complex. 1 Bioi Chem 1999; 274(50)35647-35652. Roach ES, Gomez MR, Northrup H. Tuberous Sclerosis Complex Consensus Conference: revised clinical diagnostic criteria. 1 Child Neuro11998; 13:624-628. Jozwiak S, Schwartz RA, lanniger CK, Michalowicz R, Chmielik 1. Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course and diagnostic significance. Int J Dermatol 1998; 37:911-917. Gomez MR. Tuberous Sclerosis. New York: Raven Press, 1979. Gomez MR. Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria. Ann NY Acad Sci 1991; 615: 1-7. Roach ES, Smith M, Huttenlocher P, Bhat M, Alcorn D, Hawley L. Diagnostic criteria: tuberous sclerosis complex. 1 Child Neurol 1992; 7:22 I-224. Ellis SS, Bayliss Mallory S. Hypopigmentation disorders. In: Eichenfield LF, Frieden IJ, Esterly NB, eds. Textbook of Neonatal Dermatology. Philadelphia: W.B. Saunders Company, 2001:362-364. Sybert VP. Selected hereditary diseases. In: Eichenfield LF, Frieden IJ, Esterly NB, eds. Textbook of Neonatal Dermatology. Philadelphia: W.B. Saunders Company. 2001 :454-457 Jozwiak S, Schwartz RA, lanninger CK, Cymermann lB. Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol 2000; 15:652-659. Fitzpatrick TB, Szabo G, Hori Y. et al. White leaf-shaped macules. Earliest visible sign of tuberous sclerosis. Arch Dermatol 1968; 98: 1-6. Fois A, Pindinelli CA, Berardi R. Early signs of tuberous sclerosis in infancy and childhood. Helv Paediatr Acta 1973; 28:313-321. Osborne lP. Tuberous sclerosis. In: Harper 1, Oranje A, Prose N, eds. Textbook of Pediatric Dermatology. Oxford: Blackwell Science Ltd., 2000: 1225-1136. Hurwitz S, Braverman 1M. White spots in tuberous sclerosis. 1 Pediatr 1970; 77:587-594

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Hypomelanosis and Tuberous Sclerosis Complex 20.

21.

22. 23.

431

Chudnow RS, Wolfe OJ, Sparagana SP, Delgado MR, Batchelor L, Roach ES. Abnormal sudomotor function in the hypomelanotic macules of tuberous sclerosis complex. J Child Neurol 2000; 15:529-532. Fitzpatrick TB. History and significance of white macules. Earliest sign of tuberous sclerosis. Tuberous Sclerosis and Allied Disorders: Clinical, Cellular and Molecular Studies. Ann NY Acad Sci 1991; 133:26-29. Vanderhooft SL, Francis JS, Pagan RA, et al. Prevalence of hypopigmented maCltles in a healthy population. J Pediatr 1996; 129:355-361. Harris R, Moynahan EJ. Tuberous sclerosis with vitiligo. Br J Dermatol 1966; 78:419-420

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43 Inherited Hypomelanotic Disorders Nicoletta Cassano Istituto Dermopatico dell'lmmacolata, Rome, Italy Gino A. Vena University of Bari, Rome, Italy

Numerous advances have been made in the field of inherited hypomelanosis thanks to genetic and molecular studies. The study of mouse mutant models has provided insight into the biology of melanin formation and the mechanisms underlying abnormalities of melanin synthesis. A great variety of loci that affect the pigment system has been identified in the mouse; some homologous genes have been found in the human genome and correlated with clinical phenotypes and with specific biological functions.

ALBINISM Albinism is a heterogeneous group of inherited disorders in which the synthesis of melanin is absent or reduced, despite the normal distribution of melanocytes. It can be divided into a generalized form, oculocutaneous albinism COCA), which involves the skin, hair, and eyes, and a localized form, which mainly involves the eyes, ocular albinism (OA). Albinism affects people from all races with variable prevalence; OCA is more frequent than OA. Analysis of mutations has shown that the phenotypic spectrum of albinism is broad and complex (1-3); for this reason, it is currently preferred to classify albinism on the basis of the specific gene involved (Table I) rather than clinical appearance. Copyrighted Material 433

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TABLE

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Cassano and Vena Variants of Albinism and Affected Genes in Humans Involved gene (chromosome)

Variant

Tyr (11q21)

Type 1: Tyrosinase-related Type 1A: Tyrosinase-negative Type 1B: Phenotypes: yellow mutant, temperature-:>ensitive minimal pigment, platinum Type 2: Tyrosinase unrelated Tyrosinase positive Brown Type 3: Rufous/red Type 4 Hermansky-Pudlak syndrome Type I Type II Type III Type IV Chediak-Higashi syndrome Ocular albinism type 1

Heredity Autosomal recessive

P gene (15q11.2-q12)

TYRP1 (9p23) MATP (5p) HPS1 (10q23.1-q23.3) HPS2 or AP3B1 (5) HPS3 (3q24) HPS4 (22q11.2-q12.2) CHS1 (1q42.1-42.2) OA1 (chromosome Xp22.3)

X-linked

Oculocutaneous Albinism OCA affects approximately I in 20,000 people worldwide. It was traditionally categorized as two major variants, tyrosinase-positive or tyrosinase-negative, based on the ability of hair bulbs to produce pigment or not when incubated with tyrosine or dopa. Ultrastructural examination of hair and skin reveals stage 1 and stage 2 melanosome in tyrosinase-negative albinos without melanization, whereas other types may show up to stage 3. It is now known that type 1 (tyrosinase-related) OCA is caused by different mutations of the gene encoding tyrosinase, the enzyme that catalyzes at least the first two steps of melanin biosynthesis. Mutations can lead to a complete inactivation of tyrosinase, thus causing a total absence of the pigment (type I A or tyrosinase-negative), or to a reduced activity of the enzyme capable of producing variable amounts of melanin (type 1B). Individuals with OCA I B appeared tyrosinase-negative at birth but subsequently developed some pigment in the hair or skin. In general, the color of eyelashes is darker than that of the scalp hair; some patients can also tan with sun exposure. Among OCA I B phenotypes are included "yellow mutant" OCA, so named

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for the yellow-blond or golden color of the hair described in Amish communities of North America (4), and temperature-sensitive OCA, in which tyrosinase activity is low at 35°C but is absent in body areas with higher temperatures (scalp, axillae) (5). OCAI accounts for approximately 40% of OCA worldwide. OCA2 (tyrosinase-positive) accounts for approximately 50% of OCA worldwide and has a high prevalence in sub-Saharan African blacks (1/3900). In this form, some pigment is produced and may be found in the skin, iris, and hair. OCA2 is associated with mutations of the P gene; the encoded protein is a transmembrane polypeptide with possible transport functions. Mutations at this locus are also responsible for the milder phenotype seen in individuals with brown OCA (6,7). OCA3 is a rare form ofOCA, also known as rufous/red albinism, which seems to affect more commonly southern African blacks (1/8500). Patients present unusual red skin color, ginger to reddish hair color, low susceptibility to sun damage, and minimal visual problems. OCA3 is linked to mutations in TYRPI (encoding tyrosinase-related protein I) (8). In contrast to the murine system, human TYRPI does not express DHICA-oxidase activity (9). Its role in humans is still obscure, although it was suggested that TYRPI can modulate the stability and activity of tyrosinase, melanosome ultrastructure, and melanocyte proliferation/survival (10). Recently, the mouse underwhite gene (uw) and its human orthologue, involved in a new form of human OCA (OCA4), has been identified. The encoded protein, MATP (mem brane-associated transporter protein), may function as a transporter (3). All types of OCA are associated wi th ocular signs of varia ble severity: photophobia, reduced visual acuity, foveal hypoplasia (more common in OCA-IA), congenital nystagmus, albinotic fundi, translucent irides, errors of refraction (more frequent in OCA-IA), lack of stereopsis, and strabism secondary to misrouting of the optic axons (II). A direct correlation has been found between stereopsis and both visual acuity and amounts of pigment in the iris and macula (12). In type 2, visual acuity and nystagmus may improve with age. Cutaneous hypopigmentation leads to diminished photoprotection and increased risk for skin cancers. In sun-exposed regions of the skin, localized pigmentary lesions (nevi, freckles, and lentigines) can develop, especially in tyrosinase-positive OCA. UV-induced cutaneous tumors are common in patients with albinism, with squamous cell carcinoma being the most frequent. Although dysplastic nevus and melanoma are less common, they create great diagnostic difficulties in these patients because of their hypopigmented appearance (13). The medical approach to albinism includes photoprotective measures and regular skin examination for the early detection and treatment of preCopyrighted Material

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malignant and malignant conditions. Low vision devices and glare filters are helpful in correcting ocular problems (14). Prenatal diagnosis of OCAI is available using histological and electron microscopic examination of fetal skin biopsies or even molecular genetic techniques (15). Ocular Albinism OA type I (OAI) is an X-linked recessive disorder characterized by a severe reduction in visual acuity, hypopigmentation of the retina that leads to nystagmus, strabismus, varying degrees of corneal astigmatism, and photophobiajphotodysphoria. Ultrastructural studies show the presence of macromelanosomes in skin melanocytes and retinal pigment epithelium, suggesting that there can be a defect of melanosome biogenesis. The OA I gene product can act as an intracellular G-protein-eoupled receptor (16). Some findings indicate that OA I and X-linked OA with lateonset sensorineural deafness may be allelic variants or may be caused by contiguous gene defects (17). Autosomal recessive OA is now regarded as OCAIB or OCA2 with absent or minimal changes in skin pigmentation.

ALBINOIDISM Albinoidism is a name applied to a condition in which there is some hypopigmentation of the skin and hair-less marked than in OCA-and minimal ocular changes (18). A diffuse, punctate pattern of iris is revealed by transillumination. Eyes are usually normal, although there may be photophobia and severe myopia. This variant is regarded as tyrosinase-positive and inheritable in an autosomal dominant or recessive fashion. The genetic bases and the relationship with true albinism have not yet been defined.

HERMANSKI-PUDLAK SYNDROME Hermansky-Pudlak syndrome (HPS) results from defects in melanosomes, platelet granules, and lysosomes responsible, in turn, for tyrosinase-positive OCA, prolonged bleeding, and lysosomal deposition of ceroid lipofuscin deposition in many tissues. In the mouse, the disorder is multigenic and can cause several phenotypes (19). In humans four genes have been identified, two of which (HPSI and HPS2) have been more widely studied. HPSI gene encodes an ubiquitous protein of unknown function; HPS2 gene encodes the beta-3 subunit of the adaptor protein 3 (AP-3) complex, which is implicated in the vesicular formation (20,21). HPS is a rare syndrome throughout the

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world, with the exception of Puerto Rico, in which the prevalence is high, especially in the northwestern quarter of the island (1/1800) (22). The pigmentary phenotype of HPS patients resembles that of other types of OCA. Ocular findings in HPS include reduced visual acuity, congenital nystagmus, strabismus, and cataract (23). Ceroid Iipofuscinosis can lead to fibrotic restrictive lung disease, commonly between the ages of 20 and 44 years, and granulomatous enteropathic disease, which usually has its onset after 13 years (24,25). Moreover, renal failure and degenerative cardiac disease can occur. Hemorrhagic diathesis has been attributed to storage pool-deficient platelets. In some patients low levels of plasma von Willebrand factor have also been detected, which were, however, unrelated to history of bleeding (26). The major causes of death are pulmunar fibrosis, hemorrhagic episodes, and seq uelae of granulomatous enteropathic disease. The most reliable method of diagnosing HPS is by a deficiency of platelet dense bodies observed by electron microscopy. Measures apt to prevent or minimize bleeding (trauma, surgical intervention, use of aspirin and NSAIDs) are mandatory. CHEDIAK-HIGASHI SYNDROME

Chediak-Higashi syndrome (CHS) is a rare disorder which shares with HPS some clinical findings, represented by variable degrees of OCA and easy bruisability and bleeding due to platelet storage pool deficiency. The two diseases may also have similar pathogenic mechanisms linked to vesicle anomalies at the lysosomal level; in particular, it is thought that CHS may result from a defect in vesicle trafficking (27) The only known CHS-causing gene, CHSI or LYST, codes for a large protein of unknown function that shows similarities with proteins associated with cellular signal response coupling (28). The hallmark of CHS is the presence of huge cytoplasmic granules in circulating granulocytes and many other cell types. These granules are peroxidase-positive and contain lysosomal enzymes, suggesting that they are giant lysosomes or, in the case of melanocytes, giant melanosomes. There are severe immune defects (neutropenia, impaired chemotaxis and bactericidal activity, and abnormal natural killer cell function) that are responsible for the high susceptibility to recurrent infections. Neurological involvement is variable and progressive and often includes peripheral neuropathy. Most patients developed an "accelerated phase," which is a nonmalignant Iymphohistiocytic infiltration of multiple organs resembling lymphoma. Death often occurs in the first decade from infection, bleeding, or development of the accelerated phase unless patients are treated by bone marrow transplantation. About 10-15% of patients exhibit a milder phenotype and Copyrighted Material

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survive longer, but they can undergo severe and often fatal neurological dysfunctions (29,30).

GRISCELLI-PRUNIERAS SYNDROME (PARTIAL ALBINISM WITH IMMUNODEFICIENCY)

This is a rare autosomal recessive disorder distinct from CHS. Two genetic loci have been isolated on chromosome l5q2l, one of which colocalizes with the myosin-Va gene (31). Pigmentary dilution mainly affects the hair, which has a silver-metallic color; hair shafts show large clumped melanosomes, and stage 4 melanosomes are contained in skin melanocytes. Immunological abnormalities include reduced natural killer (NK) and helper T-cell functions, defective cell-mediated immunity, hypogammaglobulinemia, and impaired response to mitogens. Patients are prone to develop neurological disturbances, accelerated phases, and hemophagocytic syndrome related to viral infections, especially Epstein-Barr virus (EBV). The prognosis is poor without bone marrow transplantation (32,33).

ELEJALDE SYNDROME (NEUROECTODERMAL MELANOLYSOSOMAL DISEASE)

This is a rare autosomal recessive disease characterized by silvery hair and neurological involvement (seizures, severe hypotonia, and mental retardation), often fatal. Skin becomes bronze after sun exposure. Large granules of melanin unevenly distributed in the hair shaft are observed. Abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblasts may be present. It should be differentiated from CHS and Griscelli syndrome. Despite the similarities between Elejalde syndrome and Griscelli syndrome, the possibility that they are two different entities, although probably allelic related, has been suggested (34).

CROSS SYNDROME (OCULOCEREBRAL SYNDROME WITH HYPOPIGMENTATION)

This is a rare syndrome determined by an autosomal recessive gene, with ocular and cutaneous hypopigmentation, mental and psychomotor retardation, with spasticity and atheto is. The mixed pattern of hair pigmentation seems very typical (35). The clinical spectrum can include microphthalmos, opaque corneas, iris atrophy, dental defects, and multiple-site malformations (36,37).

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VICI SYNDROME

Several reports (38,39) indicate a new syndrome, probably with autosomal recessive inheritance, characterized by OCA, agenesis of corpus callosum, and primary immunodeficiency leading to repeated infections. Cardiomyopathy has been also described.

PRADER-WILLI AND ANGELMAN SYNDROMES

Loss of the 2-Mb domain of human chromosome 15qll-ql3 on the paternal or maternal allele results in Prader- Willi syndrome (PWS) or Angelman syndrome (AS), respectively (40). Other modalities of inheritance are uniparental disomy or translocation and biparental inheritance. Different genetic mechanisms are responsible for variable phenotypes (41,42). The two syndromes present with mental retardation, abnormal behavior, and hypopigmentation. The hypopigmentation has been associated with OCA2 and is characterized by light skin, reduced retinal pigment, low hair bulb tyrosinase activity, and incomplete melanization of melanosomes (43). Other clinical findings are hyperphagia, obesity, hypogonadism, small hands and feet in PWS, and developmental delay, microcephaly, ataxia, hyperactivity, inappropriate laughter, EEG abnormalities, and seizures in AS (44,45).

PIEBALDISM

This is an autosomal dominant disorder of melanocyte development in which the major clinical features are patchy hypopigmentation of the skin (leukoderma), often localized in the frontal median or paramedian area, and poliosis (white forelock). Piebaldism is quite rare but widely distributed among racial groups. The presence of lesions from birth and the static course help to differentiate piebaldism from vitiligo. With age, hyperpigmented macules within depigmented and normal skin can be observed. Ultrastructurally, the hypomelanosis results from the absence of functional meJanocytes; in the hypermelanotic areas melanocytes contain abnormal as well as normal melanosomes (46). Uncommon associations were described with RubinsteinTaybi syndrome, congenital deafness (Woolf's syndrome), and neurofibromatosis type I (47--49). The molecular basis of piebaldism involves several mutations of the human KIT gene (chromosome 4q 12), encoding c-kit receptor, a tyrosine kinase transmembrane receptor for mast cell growth factor (steel factor, stem cell factor, or c-kit ligand). This factor plays a crucial role in migration, differentiation, and proliferation of melanoblasts (50).

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WAARDENBURG'S SYNDROME Waardenburg's syndrome (WS) is a rare syndrome inherited in a variably penetrant autosomal dominant fashion (51). It has an estimated frequency of 1 in 20,000 in Kenya and I in 40,000 in the Netherlands. The frequency of deafness is lower, estimated at I in 50,000-212,000. WS actually comprises different clinical and genetic variants (Table 2) (51-54) The affected genes ha ve pleiotropic effects on the development of melanocytes and other neural crest-derived lineages and can be hierarchically related to each other (e.g., MITF expression can be regulated by SOXIO and PAX3) (55,56). Hypopigmentation of WS is quite similar to that of piebaldism, with absence of melanocytes and stable course throughout the lifetime although an atypical

TABLE 2

Type of WS WS-I

WS-II

WS-lIl a

WS-IV b

a b

Variants of Waardenburg's Syndrome Phenotype (frequency) Dystopia canthorum (99%) Synophrys (17-69%) Broad nasal root (78%) Depigmentation of hair and/or skin (17-58% with white forelock) Heterochromia/hypochromia of iris (> 20%) Congenital deafness (9-38%) Similar to WS-I, without dystopia canthorum

Similar to WS-I, but with associated musculoskeletal abnormalities of limbs Similar to WS-I, with associated bowel aganglionosis (Hirschsprung disease)

Gene (chromosome)

Gene product: function

PAX-3 (2q35)

PAX-3 transcription factor: neural tube development

MITF (3p14.1-p12.3)

Microphthalmia-associated transcription factor: melanocyte survival and differentiation PAX-3 transcription factor: neural tube development

PAX-3 (2q35)

EDN3 (20q13.2-q13.3) EDNRB (13q22) SOX10 (22q13)

Klein-Waardenburg syndrome. Waardenburg-Shah syndrome or Hirschsprung disease type II.

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Endothelin 3: melanocyte development Endothelin receptor B: melanoblast differentiation SRY-related transcription factor: transcription activation

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Most Relevant Characteristics of Tuberous Sclerosis and Phenyketonuria Tuberous sclerosis (Bourneville's disease)

Heredity

Gene (chromosome) Gene product/function

Type of hypopigmentation

UItrastructu ral findings

Mechanism of hypopigmentation

Main additional clinical findings

Autosomal dominant with variable expression (new mutations are however common) TSC-1 (9q34) TSC-2 (16p13.3) Hamartin (TSC-1 )/regulation of cell proliferation Tuberin (TSC-2)/regulation of cell growth and differentiation Ash-leaf-shaped hypopigmented macules (trunk or limbs) (tertiary features) Possible segmentary or guttate hypomelanosis Hypopigmented iris spot Punched-out chorioretinal depigmentation Abnormal melanocytes with reduced tyrosinase activity; defective melanization of melanosomes Hypofunctioning melanocy1es with reduced transfer of melanosomes to keratinocytes and decrease of the overall melanin content in the affected skin Focal abnormalities of sympathetic innervation (7) Mental retardation, epilepsy, skin lesions (facial angiofibromas, multiple periungual fibromas, shageren patch, and others), ocular and pulmonary signs, cardiac, renal and gastrointestinal tumors Clinical features are divided in three groups according to the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association (1992)

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Phenyketonuria Autosomal recessive

PAH (12q22-q24.1) + other loci (rarely) Phenyalanine hydroxylase/ formation of tyrosine from phenylalanine Decreased pigmentation (pigment dilution) in skin, eyes, hair

Reduction of keratinocytes containing melanin and of melanosomes in melanocy1es Reduced melanin formation due to the inhibition of tyrosine-tyrosinase reaction by phenylalanine (darkening of the hair towards normal color with tyrosine treatment)

Mental retardation, epilepsy, hyperactivity, psychomotor delay, extrapyramidal symptoms, long eyelashes, eczema, dermographism

Syndrome rarely observed thanks to the early recognition and treatment (restriction of phenylalanine intake)

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spontaneous pigmentation was described in some cases affected with WS-I (51). Premature greying of hair can occur. TIETZ SYNDROME

This syndrome is determined by an autosomal dominant gene with complete penetrance. Clinical hallmarks are congenital severe deafness and generalized hypopigmentation of the skin. There can be hypoplasia of the eyebrows; eyes are normal. Interestingly, the gene affected appears to be the same as for WS type II (MITF) (57). YEMENITE DEAF-BLIND HYPOPIGMENTATION SYNDROME (WARBURG'S SYNDROME)

In 1990, Warburg and co-workers described two Yemenite siblings with microcornea, colobomata of the iris and choroidea, nystagmus, severe early deafness, and patchy hypo- and hyperpigmentation. Melanocytes were absent in leukoderma I areas. They proposed the disorder as a new syndrome with autosomal recessive inheritance. Subsequently, a mutation in the SOX 10 gene was associated with a milder phenotype (58). ZIPRKOWSKI-MARGOLIS SYNDROME

In 1962 Ziprkowski et al. (59) reported an Egyptian-Jewish family with deafmutism, heterochromia of iris, diffuse poliosis, and piebald-like leukoderma associated with hypermelanotic patches. An X-linked gene seemed to be implicated. OTHER HEREDITARY CONDITIONS

The most important conditions that can be associated with the presence of peculiar hypomelanotic lesions are tuberous sclerosis (46,60-65) and phenylketonuria (66-69) (Table 3). In other diseases, such as Menkes' disease or disorders of methionine metabolism, the color dilution results from defective keratinization and not from disturbances of melanin synthesis. REFERENCES 1.

2.

Oetting WS, King RA. Molecular basis of albinism: mutations and polymorphisms of pigmentali on genes associated with albinism. Hum Mutat 1999; 13:99liS Oetting WS. Albinism. CUlT Opin Pediatr 1999; 11:565-571.

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4.

5. 6.

7.

8.

9.

JO. ] 1. 12. 13. 14. 15.

16. 17. 18. 19. 20.

443

Newton JM, Cohen-Barak 0, Hagiwara N, Gardner JM, Davisson MT, King RA, Brilliant MH. Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Am J Hum Genet 2001; 69:981-988. Giebel LB, Tripathi RK, Strunk KM, Hanifin JM, Jackson CE, King RA, Spritz RA. Tyrosinase gene mutations associated with type IE ("yellow") oculocutaneous albinism. Am J Hum Genet 1991; 48:1159-1167. Tomita Y. Tyrosinase gene mutations causing oculocutaneous albinisms. J Invest Dermatol 1993; 100(suppl 2): 186S-190S. Lund PM, Puri N, Durham-Pierre D, King RA, Brilliant MH. Oculocutaneous albinism in an isolated Tonga community in Zimbabwe. J Med Genet 1997; 34: 733-735. Kerr R, Stevens G, Manga P, Salm S, John P, Haw T, Ramsay M. Identification ofP gene mutations in individuals with oculocutaneous albinism in sub-Saharan Africa. Hum Mutat 2000; 15:166-J72. Manga P, Kromberg JG, Box NF, Sturm RA, Jenkins T, Ramsay M. Rufous oculocutaneous albinism in southern African blacks is caused by mutations in the TYRPI gene. Am J Hum Genet J997; 6J:J095-1I01. Boissy RE, Sakai C, Zhao H, Kobayashi T, Hearing VJ. Human tyrosinase related protein-I (TRP-I) does not function as a DHJCA oxidase activity in contrast to murine TRP-l. Exp Dermatol 1998; 7:J98-204. Sarangarajan R, Boissy RE. Tyrp I and oculocutaneous albinism type 3. Pigment Cell Res 2001; 14:437--444. Lacour JP, Ortonne JP. Albinisme oculo-cutane. Ann Pediatr (Paris) 1992; 39: 409--418. Lee KA, King RA, Summers CG. Stereopsis in patients with albinism: clinical correlates. J AAPOS 2001; 5:98-104. Perry PK, Silverberg NB. Cutaneous malignancy in albinism. Cutis 200 I; 67: 427--430. Hoeft WW. Albinism-a clinician's low vision perspective. JAm Optom Assoc 1991; 62:69-72. Rosenmann E, Rosenmann A, Ne'eman Z, Lewin A, Bejarano-Achache I, Blumenfeld A. Prenatal diagnosis of oculocutaneous albinism type 1: review and personal experience. Pediatr Dev Pathol 1999; 2:404--414. Shen B, Samaraweera P, Rosenberg B, Orlow SJ. Ocular albinism type I: more than meets the eye. Pigment Cell Res 200 I; ]4:243-248. Winship JM, Babaya M, Ramesar RS. X-linked ocular albinism and sensorineural deafness: linkage to Xp22.3. Genomics 1993; 18:444--445. Wiktop CJ. Inherited disorders of pigmentation. Clin Dermatol 1985; 3:70134. Swank RT, Novak EK, McGarry MP, Rusiniak ME, Feng L. Mouse models of Hermansky Pudlak syndrome: a review. Pigment Cell Res 1998; 11:60-80. Swank RT, Novak EK, McGarry MP, Zhang Y, Li W, Zhang Q, Feng L. Abnormal vesicular trafficking in mouse models of Hermansky-Pudlak syndrome. Pigment Cell Res 2000; 13(suppl 8):59-67.

Copyrighted Material

Cassano and Vena

444 21. 22.

23. 24.

25.

26.

27.

28.

29. 30.

31.

32.

33.

34.

Shotelersuk V, Gahl WA. Hermansky-Pudlak syndrome: models for intracellular vesicle formation. Mol Genet Metab 1998; 65:85-96. Witkop CJ. Almadovar C, Pineiro B, Nunez Babcock M. Hermansky-Pudlak syndrome (HPS). An epidemiologic study. Ophthalmic Paediatr Genet 1990; II: 245-250 Izquierdo NJ, Townsend W, Hussels IE. Ocular findings in the HermanskyPudlak syndrome. Trans Am Ophthalmol Soc 1995; 93:J91-202. Gahl WA, Brantly M, Kaiser-Kupfer MI, Iwata F, Hazelwood S, Shotelersuk V, Duffy LF, Kuehl EM, Troendle J, Bernardini I. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (HermanskyPudlak syndrome). N Engl J Med 1998; 338:1258-1264. Brantly M, Avila NA, Shotelersuk V, Lucero C, Huizing M, Gahl WA. Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1. Chest 2000; 117:129-136. McKeown LP, Hansmann KE, Wilson 0, Gahl W. Gralnick HR, Rosenfeld KE. Rosenfeld SJ, Horne MK, Rick ME. Platelet von Willebrand factor in Hermansky-Pudlak syndrome. Am J Hematol 1998; 59: 115-120. Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syndrome and ChediakHiga hi syndrome: disorders of vesicle formation and trafficking. Thromb Haemost 200 I; 86:233-245. Barbosa MD, Nguyen QA, Tchernev VT, Ashley JA, Detter JC, Blaydes SM, Brandt SJ, Chotai D, Hodgman C, Solari RC, Lovett M, Kingsmore SF. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature 1996; 382:262-265. Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects ofChediak-Higashi syndrome. Mol Genet Metab 1999; 68:283-303. Karim MA, Suzuki K, Fukai K, Oh J, Nagle DL, Moore KJ, Barbosa E, FalikBorenstein T, Filipovich A, Ishida Y, Kivrikko S, Klein C, Kreuz F, Levin A, Miyajima H, Regueiro J, Russo C, Uyama E, Vierimaa 0, Spritz RA. Apparent genotype-phenotype correlation in childhood. adolescent. and adult ChediakHigashi syndrome. Am J Med Genet 2002; 108: 16-22. Past ural E, Ersoy F, Yalman N, Wulffraat N, Grillo E, Ozkinay F, Tezcan I, Gedikoglu G, Philippe N, Fischer A. de Saint Basile G. Two genes are responsible for Griscelli syndrome at the same 15q21 locus. Genomics 2000; 63:299-306. Klein C, Philippe N, Le Deist F, Fraitag S, Prost C, Durandy A, Fischer A. Gri celli C. Partial albinism with immunodeficiency (Griscelli syndrome). J Pediatr 1994; 125:886-895. Mancini AJ, Chan LS, Paller AS. Partial albinism with immunodeficiency: Griscelli syndrome: report of a case and review of the literature. JAm Acad Dermatol 1998; 38:295-300. Duran-McKinster C, Rodriguez-Jurado R, Ridaura C, de la Luz Orozco-Covarrubias M, Tamayo L, Ruiz-Maldonando R. Elejalde syndrome-a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patient. Arch Dermatol 1999; 135:182-186.

Copyrighted Material

Inherited Hypomelanotic Disorders

35.

36.

37.

38.

39.

40.

41.

42.

43. 44.

45. 46.

47. 48. 49

445

De long G, Fryns lP. Oculocerebral syndrome with hypopigmentation (Cross syndrome): the mixed pattern of hair pigmentation as an important diagnostic sign. Genet Couns 1991; 2:151-155 Lerone M, Pessagno A, Taccone A, Poggi G, Romeo G, Silengo Me. Oculocerebral syndrome with hypopigmentation (Cross syndrome): report of a new case. Clin Genet 1992; 41 :87-89. Tezcan I, Demir E, Asan E, Kale G, Muftuoglu SF, Kotiloglu E. A new case of oculocerebral hypopigmentation syndrome (Cross syndrome) with additional findings. Clin Genet 1997; 51:118-121. Yici CD, Sabetta G, Gambarara M, Yigevano F, Bertini E, Boldrini R, Parisi SG, Quinti I, Aiuti F, Fiorilli M. Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigrnentation in two brothers. Am 1 Med Genet 1988; 29:1-8. del Campo M, Hall BD, Aeby A, Nassogne MC, Yerloes A, Roche C, Gonzalez C, Sanchez H, Garcia-Alix A, Cabanas F, Escudero RM, Hernandez R, Quero 1. Albinism and agenesis of the corpus callosum with profound developmental delay: Yici syndrome, evidence for autosomal recessive inheritance. Am 1 Med Genet 1999; 85:479-485. Shemer R, Hershko AY, Perk 1, Mostoslavsky R, Tsuberi B, Cedar H, BuitingK, Razin A. The imprinting box of the Prader- WillijAngelman syndrome domain. Nat Genet 2000; 26:440-443. Cassidy SB, Forsythe M, Heeger S, Nicholls RD, Schork N, Benn P, Schwartz S Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15. Am 1 Med Genet 1997; 68:433-440. Saitoh S, Buiting K, Cassidy SB, Conroy 1M, Driscoll Dl, Gabriel 1M, GillessenKaesbach G, Glenn CC, Greenswag LR, Horsthemke B, Kondo I, Kuwajima K, Niikawa N, Rogan PK, Schwartz S, Seip 1, Williams CA, Nicholls RD. Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation. Am 1 Med Genet 1997: 68:195-206. King RA, Wiesner GL, Townsend D, White lG. Hypopigrnentation in Angelman syndrome. Am 1 Med Genet 1993; 46:40-44. Webb T, Clarke D, Hardy CA, Kilpatrick MW, Corbett 1, Dahlitz M. A clinical cytogenetic, and molecular study of 40 adults with the Prader-Willi syndrome. 1 Med Genet 1995; 32181-185. Rougeulle C, Lalande M. Angelman syndrome: how many genes to remain silent? Neurogenetics 1998; 1:229-237. limbow K, Fitzpatrick TB, Szabo G, Hori Y. Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. 1 Invest Dermatol 1975; 64:5062. Herranz P, Borbujo 1, Martinez W, Vidaurrazaga C, Diaz R, Casado M. Rubinstein-Taybi syndrome with piebaldism. Clin Exp Dermatol1994; 19:170-172. Spritz RA, Beighton P. Piebaldism with deafness: molecular evidence for an expanded syndrome. Am 1 Med Genet 1998; 75:101-103. Angelo C, Ciancbini G Grosso MG, Zambruno G, Cavalieri R, Paradisi M.

Copyrighted Material

Cassano and Vena

446

50.

51. 52.

53.

54. 55. 56.

57. 58.

59. 60.

61. 62. 63.

64.

Association of piebaldism and neurofibromatosis type 1 in a girl. Pediatr Dermato12001; J8:490-493. Richards KA, Fukai K, Oiso N, Paller AS. A novel KIT mutation results in piebaldism with progressive depigmentation. 1 Am Acad Dermatol200 I; 44:288292. Chang T, Hashimoto K, Bawle EV. Spontaneous contraction of leukodermic patches in Waardenburg syndrome. 1 Dermatol 1993; 20:707-711. Pusch C, Hustert E, Pfeifer D, Sudbeck P, Kist R, Roe B, Wang Z, Balling R, BEn N, Scherer G. The SOXIO/SoxIO gene from human and mouse: sequence, expression, and transactivation by the encoded HMG domain transcription factor. Hum Genet 1998; 103:115-123. Tekin M, Bodurtha IN, Nance WE, Pandya A. Waardenburg syndrome type 3 (Klein-Waardenburg syndrome) segregating with a heterozygous deletion in the paired box domain of PAX3: a simple variant or a true syndrome? Clin Genet 2001; 60:301-304 McCallion AS, Chakravarti A. EDNRB/EDN3 and Hirschsprung disease type II. Pigment Cell Res 2001; 14:161-169. Tachibana M. A cascade of genes related to Waardenburg syndrome. 1 Invest Dermatol Symp Proc 1999; 4:126-129. Potterf SB, Furumura M, Dunn Kl, Arnheiter H, Pavan Wl. Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOXIO and PAX3. Hum Genet 2000; 107:1-6. Smith SD, Kelley PM, Kenyon lB, Hoover D. Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF. J Med Genet 2000; 37:446-448. Bondurand N, Kuhlbrodt K, Pingault V, Enderich J, Sajus M, Tommerup N, Warburg M, Hennekam RC, Read AP, Wegner M, Goossens M. A molecular analysis of the yemenite deaf-blind hypopigmentation syndrome: SOXJ 0 dysfunction causes different neurocristopathies. Hum Mol Genet 1999; 8: 17851789. Ziprkowski L, Krakowski A, Adam A, Costeff H, Sade l. Partial albinism and deaf mutism. Arch Dermatol 1962; 86:530-539. Roach ES, Smith M, Huttenlocher P, Bhat M, Alcorn D, Hawley L. Diagnostic criteria: tuberous sclerosis complex. Report of the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association. 1 Child Neural 1992; 7:221224. Jimbow K. Tuberous sclerosis and guttate leukodermas. Semin Cutan Med Surg 1997; 1630-35. Rowley SA, O'Callaghan Fl, Osborne lP. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br J Ophthalmol 200 I; 85:420-423. Chudnow RS, Wolfe GJ, Sparagana SP, Delgado MR, Batchelor L, Roach ES. Abnormal sudomotor function in the hypomelanotic macules of tuberous sclerosis complex. 1 Child Neurol 2000; ] 5:529-532. Hodges AK, Li S, Maynard J, Parry L, Braverman R, Cheadle lP, DeClue JE, Sampson lR. Pathological mutations in TSCI and TSC2 disrupt the interaction between hamartin and tuberin. Hum Mol Genet 2001; 10:2899-2905.

Copyrighted Material

Inherited Hypomelanotic Disorders 65.

66.

67.

68.

69.

447

Miloloza A, Kubista M, Rosner M, Hengstschlager M. Evidence For separable Functions of tuberous sclerosis gene products in mammalian cell cycle regulation. J Neuropathol Exp Neuro12002; 61:154-163. Farishian RA, Whittaker JR. Phenylalanine lowers melanin synthesis in mammalian melanocytes by reducing tyrosine uptake: implications for pigment reduction in phenylketonuria. J Invest Dermatol 1980; 74:85-89. Lidsky AS, Law ML, Morse HG, Kao FT, Rabin M, Ruddle FH, Woo SLC. Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome. Proc Natl Acad Sci 1985; 82:6221-6225. Scriver CR, Kaufman S, Woo SLC. The hyperphenylalaninemias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Diseases. 6th ed. New York: McGraw-Hili, 1989:495-546. Guttier F, Guldberg P. Mutations in the phenylalanine hydroxylase gene: genetic determinants for the phenotypic variability of hyperphenylalaninemia. Acta Paediatr Suppl 1994; 407:49-56

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44 Piebaldism Giovanni Maria Palleschi University of Florence, Florence, Italy

Piebaldism or partial albinism is a rare congenital stable leukoderma with autosomal dominant inheritance, characterized by the presence at birth of achromic skin vitiligo-like patches with islands of normal or hyperpigmented skin, associated with frontal poliosi. The disease is rare, with an incidence of I in 20,000, but it is widely distributed and there is no any sex prevalence. Piebaldism was well known by the Greek and Romans but its familiar nature was only described by Morgan in 1786 (J ,2). CLINICAL FEATURES

Typically the macules or patches of piebaldism are present at birth and do not modify during life. Cases that arise after the first sun exposure are reported, but probably this depends on tanning, which shows up the lesions. The color is matte chalk-white, the border can be feathered, normally containing smal] macules of normal or hyperpigmented skin (Fig. ]). The disorder is classically associated with poliosis due to locahzed loss of hair pigment (Fig. 2). The patches are bilateral but not symmetrical (Fig. 3). The distinctive localization that represents the typical pattern in 90% of the cases is on the frontal region median or paramedian with a white forelock (Figs. 4 and 5). This characteristic path is triangular and is extended to the eyebrows but rarely to the eyelashes, which can be white. Occasionally on the face the chin can be affected. The areas affected on the trunk are the lateral regions, the abdomen extending to the upper chest (Fig. 6), and the back, although normally the paravertebral Copyrighted Material 449

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FIGURE 1 Classical matte chalk-white leukodermic area, with feathered border containing small macules of normal or hyperpigmented skin.

region is spared. The four limbs are affected in the upper areas (Figs. 7 and 8). The periorificial regions are spared (1-5). Mucosae are normally spared, and their involvement is rarely reported (6). The areas of hyperpigmented skin within the amelanotic macules or patches and less often on normal skin appear during life. They do not have a uniform color and may be more evident after sun exposure. Some cases of depigmentation during life are reported (1,6). Piebaldism is occasionally related to mental retardation. In two cases reported in the literature it is associated with the interstitial deletion of chromosome 4 (I). Other rare associations are heterochromic irides or sensorineural deafness. The association of piebaldism with perceptive deafness is named Woolf syndrome, and it represents a distinct autosomal recessive syndrome (1,7). The X-linked occipital white forelock is a variant of piebaldism.

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FIGURE 2 Detail of leukodermic patch with hyperchromic maculae within and outside of the border and leukotrichia.

The association of piebald-like maculae with sensorineural deafness, congenital megacolon, a characteristic face, and ocular abnormalities is known as Waardenburg syndrome (Table 1 and Box I) (8,9).

PATHOLOGY In lesional skin the epidermis appears normal but melanocytes and melanosomes are totally absent or greatly reduced. In one case mast cells have been identified in the epidermis. Atypical large melanocytes are sometimes visible

FIGURE

3

Bilateral but not symmetrical patches on the calves.

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FIGURE 4

Typical localization on the median frontal region with white forelock.

in hair follicles. In the hyperpigmentated maculae the melanocytes produce abnormal melanosomes (large, spherical, and granular), which are fused into the keratinocytes (6,9~11).

PATHOGENESIS Studies on animals, dominant white-spotting (Ws) mice (equivalent to human piebaldism), and humans revealed that piebaldism is due to several genetic

FIGURE 5

White forelock on forehead.

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6 Large patch localized on abdomen, with feathered margins, containing numerous hyperchromic maculae.

FIGURE

mutations of the proto-oncogene (c-kit). This gene is implicated in the encode of tyrosine kinase transmembrane receptor of melanocytes, mast cells, and other cells. The ligand of this receptor is represented by the steel factor, also called mast stem cell growth factor or stem cell growth factor (12-14). The result is a modification of the normal migration or differentiation during em briogenesis of melanoblasts from the neural crest to the skin and other organs such as the inner ear (15).

FIGURE 7

Leukodermic

rrf3opj¥~rM3~fJf with

figurated border.

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454

FIGURE

8

Large leukodermic patch on lower limb with widespread leukotrichia.

In the Ws mouse the proto-oncogene c-kit is mapped on chromosome 5, and in humans on chromosome 4. There are 14 known types of mutation of ckit on chromosome segment 4q 12. Point mutation, frame-shift and splicejunction are the most frequent in humans (16-19). Piebaldism is an autosomal dominant disorder, and the mutation in one of the two copies of the gene produces the disease. For the dominant-negative effect there is no relation between a mild or severe phenotype and the grade of genetic mutation (9). The association of piebaldism with mental retardation is related to a deletion of chromosome segment 4q 13. DIFFERENTIAL DIAGNOSIS The most important differential diagnosis is vitiligo (Table I) in which macules appear during life with generally symmetrical, acroloca ted, and/or periorificial distribution, with a hyperpigmented border and with little perifollicular pigmented maculae within the patches. The lesions can also arise following scratching (Koebner phenomenon) or have a unilateral dermatomal arrangement in segmental form. The involvement of mucosae is possible. The course is chronic, with temporary partial remission, but is generally

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TABLE 1

Differential Diagnosis Piebaldism

Age of onset Course

Congenital autosomal dominant Chronic stable

Shape and dimension of maculae Disposition () Distribution

From a few millimeters to many centimeters; irregular, feathered margins Symmetrical Forehead, trunk with sparing of paravertebral regions, upper arms and legs Hyperpigmented macules in leukodermic macules or, rarely, on normal skin Poliosi, leukotrichia

0

~~,


0..

~

CD

~

Characteristic features Other skin alterations Pathology

Extracutaneous manifestations

Diagnostic evaluation

Absent melanocytes, atypical large melanocytes, spherical atypical melanosomes in hyperpigmented macules Deafness in S Woolf

Audiometry

Vitiligo

Waardenburg syndrome

All ages acquired Chronic progressive, temporary regression Rounded, oval, figurate segmental

Congenital autosomal dominant Chronic stable (regressed in two cases) From some millimeters to many centimeters; irregular

Symmetrical Eyelids, genital and periorificial areas, extensor limbs, terminal digits Hyperpigmented border pigmented perifollicular spots, segmental Halo nevus or Sutton nevus, scattered leukotrichia, areata alopecia Absent melanocytes, lymphocytic infiltrate in early lesions

Asymmetrical Forehead, face, neck, trunk, limbs, dorsal hands

Diabetes, autoimmune thyroiditis, Addison's disease, myasthenia gravis, pernicious anemia Glycemia, thyroid function, autoantibody ophthalmological examination, audiometry

"ll (ii' C" III

0:

iii'

3

Piebald-like

Synophrys, graying of hair, leukotrichia Absent melanocytes

Heterochromic iridies, broad nasal root, deafness, congenital megacolon, Hirschsprung disease, dystopia canthorum Audiometry

.j:o

U1 U1

456

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BOX 1

Waardenburg Syndrome

Rare disorder due to abnormal development of neural crest, with autosomal dominant inheritance and variable penetrance (formes frustes). The incidence is 1 in 42,000. It represents approximately 0.9-2.8% of people with perceptive deafness (1,6). The syndrome is based on the original description of dystopia canthorum, broad nasal root, synophrys (confluent thick eyebrows), massive jaw, heterochromia and/or hypopigmentation of the iris, which determine a characteristic face, associated with congenital deafness and piebaldism (8). In about half of the cases a depigmentation of the ocular fundal is present without any alteration of visual acuity (1). Leukoderma is similar to piebaldism, but the forehead, neck, and dorsum of the hands are affected and a premature graying of the hair is present. Two cases with spontaneous remission were reported by Chang in 1993 (24). The syndrome is divided into Types I, II, and III [also known as Klein-Waardenburg syndrome, a result of association with other anomalies described by Klein (25)]. Type I: presence of dystopia canthorum, white forelock, leukoderma, synophrys, broad nasal root. Type II: absence of dystopia canthorum, increased frequency of deafness, heterochromia irides. Type III: characterized by presence of musculoskeletal abnormalities of the upper limbs, such as fusion or hypoplasia of carpal bones, contractu res, syndactyly (26) In Types I and III mutations of the PAX-3 gene on chromosome 2q35-37 are described. In Type II, a mutation of the MITF (microphthalmia transcription factor) gene on chromosome 3p13 (cc) has been reported (9,27).

progressive. Life stress events can cause the illness to break out. Another differential diagnosis is the rare Waardenburg syndrome suggested by heterochromic irides, neurosensorial deafness, and facial dysmorphism (Table land Box 2).

TREATMENT There is no specific therapy. Sunscreen should be applied on the area of leukoderma. There are reports of successful transplantations of unaffected skin into areas ofJeukoderma (20-22). PUVA therapy has been used with poor reults (23).

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BOX 2

457

Deafness and Leukodermic Syndromes

The relationship between leukodermic syndromes and deafness can be explained by the importance of melanocytic cells for inner ear development and function. In the inner ear, melanocytes were observed in the vestibular dark cells, endolymphatic sac, and stria vascularis of the mammalian cochlea (28). The stria vascularis is composed of three types of cell. Marginal cells line the lumen of the cochlear duct and are of ephithelial origin. Basal cells that form a continuous layer derive from the neural crest or from the mesoderm. Intermediate cells derive from the neural crest and show cytological characteristics almost identical to those of melanocytes (29). The marginal cells form extensive interdigitations with the intermediate (melanocyte-like cells) and basal cells. Alteration of the melanocytes could be responsible for ear function defects. Melanocytes appear to be vital for normal stria vacularis development and functioning. In mutant mice with an absence of melanocytes and in albino mice, there is a lack of interdigitation between basal cells and marginal cells. The stria vascularis is abnormally thin and lacking intermediate cells. This morphological aspect is correlated to stria dysfunction evaluated by electrophysiological studies (28-30). A relationship between the production of melanosomes and the process of interdigitation of melanocytes with the marginal cells was demonstrated comparing pigmented rats with albino rats (15). The functioning of stria vascularis depends on melanocytes or melanosomes, which prevent damage to the hair cells by ototoxic agents (15,31). These data are supported by the finding that black-skinned persons are less commonly affected by noise-induced hypoacusis than are white-skinned persons.

REFERENCES J.

2. 3.

4. 5.

6.

Mosher DB, Fitzpatrick TB, Hori Y, Ortonne JP Disorders of Melanocites. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg 1M, Austen KF, eds. Dermatology in General Medicine. 4th ed. New York: McGraw-Hili Inc., 1993:903995. Braun Falco 0, Plewig G, Wolf HH, Winkelmann RK. Disorders of melanin pigmentation. Dermatology. 3rd ed. Berlin: Springer-Verlag, 1984:686-709. Falcos D, Giacomelli A, Caproni M, Palleschi GM. Piebaldismo: descrizione di un caso. Abstracts of Riunione Annuale Congiunta SIDEV-GIRDCA November 12-13, 1993. Palleschi GM, Cipollini EM, Mei S. Piebaldismo: descrizione di un caso. Abstracts. XIII Giornate di Dermatologia Clinica, Roma June 23-25, 1998. Palleschi GM, Cipollini EM. II piebaldismo. In: Lotti TM, ed. La Vitiligine Nuovi Concetti e Nuove Terapie. Milan: UTET Periodici Scientifici, 2000: 152158. Bleehen SS, Ebling FJG, Champion RH. Hypomelanosis. In: Rook-Wilkinson-

Copyrighted Material

Palleschi

458

Ebling, ed. Textbook of Dermatology. 5th ed. Oxford: Blackwell Scientific Pub, 1992:1603-1615. 7. Spritz RA, Beighton P. Piebaldism with deafness: molecular evidence for an expanded syndrome. Am J Med Genet 1998; 75(1):101-103 8. Waardenburg PJ. A new syndrome combining developmental anomalies of the eyelids,eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness Am J Hum Genet 1951; 3:195-253. 9 Bolognia JL. Disorders of hypopigmentation. In: Harper J, Oranje A, Prose N, eds. Textbook of Pedriatic Dermatology. Oxford: Blackwell Science Ltd, 2000: 842-847. 10. Spielvogel RL, Kantor GR. Pigmentary disorders of the skin. In: Elder D, ed. Lever's Histopathology of the Skin. Philadelphia: Lippincott-Raven, 1977:617623. II. Kwan TH. Hypomelanoses. In: Farmer ER, Hood AF, eds. Pathology of the Skin. London: Prentice-Hall International Inc., 1990:498-502. 12. Spritz RA, Holmes SA, Ramesar R, et al. Mutation of the kit (mast/stem cell growth factor receptor) proto-oncogene account for a continuous range of phenotypes in human piebaldism. Am J Hum Genet 1992; 51(5):1058-1065. 13. Spitz RA. Molecular basis of human piebaldism. J Invest Dermatol 1994; 103(suppI5)137s-140s. 14. Yasushi T. The molecular basis of albinism and piebaldism. Arch Dermatol 1994; 130:355-358. 15. Peters TA, Kuijpers W, Tonnaer EL, van Muijen GN, Jap PH. Distribution and features of melanocytes during inner ear development in pigmanted and albino rats. Hear Res 1995; 85(1-2):169-180. 16. Ward KA, Moss C, Sanders DS. Human piebaldism: relationship between phenotype and site of kit gene mutation Br J Dermatol 1995; 132(6):929-935. 17. Fleischman RA, Gallardo T, Mi X. Mutations in the ligand-binding domain of the kit receptor: an uncommon site in human piebaldism. J Invest Dermatol 1996; 107:703-706. 18. Schinzel A, Braegger CP, Brecevic L, et al. Interstitial deletion, del(4) (q 12q21.1), owing to de novo unbalanced translocation in a 2 year old girl: further evidence that the piebald trait maps to proximal 4q 12. J Med Genet 1997; 34(8):692-695. 19. Ezoe K, Holmes SA, Ho L, et al. Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism. Am J Genet 1995; 56(1):5866. 20. Olsson MJ, Juhlin L. Epidermal sheet grafts for repigmentation of vitiligo and piebaldism, with a review of surgical techniques. Acta Derm Venereol 1997; 77(6)463--466. 21. Falabella R. Repigmentation of leukoderma by minigrafts of normally pigmented skin. J Dermatol Surg Oncol 1978; 4:916-919. 22. Njoo MD, Nieuweboer-Krobotova L, Westerhof W. Repigmentation of leucodermic defects in piebaldism by dermabrasion and thin split-thickness skin grafting in combination with minigrafting. Br J Dermatol 1998; 139(5):829-833. 23. Bolognia JL. Therapeutics in pigmentary disorders-medical, surgical, and phys-

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24. 25.

26. 27. 28.

29.

30.

31.

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ical approaches. In: Levine N, Maibach H, eds. Pigmentation and Pigmentary Disorders. Boca Raton, FL: CRC Press, 1993:491-524. Chang T, Hashimoto K, Bawle EV. Spontaneous contraction of leukodermic patches in Waardenburg syndrome. J Dermatol 1993; 20(11):707-711. Klein D. Albinisme partiel (Ieucisme) accompagne de surdi-mutite, d'osteomyodysplasie, de raideurs articularies congenitales multiples et d'autres malformations congeenitales. Arch Jul Klaus-Stiftg 1947; 22:336-342. Goodman RM, Lewithal I, Solomon A, Klein D. Upper limb involvement in the Klein- Waardenburg syndrome. Am J Med Genet 1982; 11 :425-433. Asher JH Jr, Friedman TB. Mouse and hamster mutants as models for Waardenburg syndromes in humans. J Med Genet 1990; 27:618-626. Kitamura K, Sakagami M, Umemoto M, Takeda N, Doi K, Kasugai T, Kitamura Y. Stria I dysfunction in a melanocyte deficient mutant rat (Ws/Ws rat). Acta Otolaryngol 1994; 114(2):177-181 Motohashi M, Hozawa K, Oshima T, Takeuchi T, Takasaka T. Dysgenesis of melanocytes and cochlear dysfunction in mutant microphthalmia (mi) mice. Hear Res 1994; 80( 1): 10-20. Steel KP, Barkway C. Another role for melanocytes: their importance for normal stria vascularis development in the mammalian inner ear. Development 1989; 107(3):453-463. Tosti A, Bardazzi F, Tosti G, Monti L. Audiologic abnormalities in cases of vitiligo. J Am Acad Dermatol 1987; 17:230-233.

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45 Albinism

Evridiki Tsoureli-Nikita University of Siena, Siena, Italy

Giovanni Menchini and Torello M. Lotti University of Florence, Florence, Italy

H. Grossman Regional Dermatology Training Center, Moshi, Tanzania

INTRODUCTION Albinism includes a heterogeneous group of genetically determined diseases characterized by diffuse skin hypopigmentation and ocular disorders, resulting in oculocutaneous albinism (OCA). If the skin and hair are normally pigmented and just the eye pigmentation is affected, the condition is called ocular albinism (OA). The word "albino" derives from the Latin albus, which means white, used once by African populations to describe white people. The prevalence of albinism is approximately I :20,000 in the world population and rises in Africans. Nine different types of clinical and genetic variants of oculocutaneous albinism are inherited as autosomal recessive and one only rare type as autosomal dominant (Table I). In OCA there is partial or complete failure of melanin production, leading to a marked dilution of the pigmentation of the skin, hair, and eyes (1). The melanocytes that originate in the neural crest produce melanin, providing pigment for the skin (including eyelids, hair, uvea, conjunctiva, stroma of the iris, ciliary body, and choroids), which act as a photoprotective pigment. The biosynthesis of melanin begins with the hydroxylation of the amino Copyrighted Material 461

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462 TABLE 1 Hypomelanotic Disorders Due to Genetic and Nevoid Factors

Oculocutaneous albinism Tyrosinase negative (type IA) Yellow mutant (type IB) Platinum Tyrosinase positive (type II) Brown Rufous (type III) Chediak-Higashi Hermansky-Pudlak Minimal pigment Autosomal dominant Ocular albinism With deafness

Albinoidism Cross syndrome Piebaldism Waardenburg syndrome Vitiligo Phenylketonuria Tuberous sclerosis Achromic nevus Incontinentia pigmenti achromians

Recessive Recessive Recessive Recessive Recessive Recessive Recessive Recessive Recessive Dominant X-linked X-linked Recessive Dominant Recessive Dominant Dominant Polygenic Recessive Dominant

acid L-tyrosine to dihydroxylphenylalanine (DOPA) and the oxidation of DOPA to DOPAquinone by the copper-containing enzyme tyrosinase, resulting in either black-brown eumelanin or the presence of sulf11ydryl compounds, red-yellow pheomelanin. The resulting pigment polymer is deposited on a protein matrix within the melanosome. In the skin and hair follicles, the melanosome is then transferred to keratinocytes via the dendrites of the melanocyte. In white persons, the synthesis of pheomelanin derives from the ammino acids tyrosine and cysteine, while in blacks, tyrosine is the only precursor for the biosynthesis of eumelanin (Fig. I). Skin color depends on the dimensions and not on the number of the melanocytes. In fact, blacks have larger melanosomes than whites. The gene encoding tyrosinase has been localized in chromosome 11, and many different mutations are connected to the variants of oculocutaneous albinism. The majority of these mutations lead to the production of tyrosinase enzyme that is inactive ("null" mutations), so the two initial conversions in

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OCA1

OCA3 Eumelanins FIGURE 1 Melanogenesis pathway. OCA1 is due to "null" or "leaky" mutations of the tyrosinase gene leading, respectively, to complete or partial inactivity of tyrosinase (ty-ve albinism). In OCA3, the mutation involves tyrosinase-related protein 1, and only the production of eumelanins is blocked ("rufous," or red phenotype).

the melanin pathway (tyrosine---+dopa---+dopaquinone) (Fig. 1) are not made and no melanin forms. Other tyrosinase gene mutations called "leaky" mutations lead to the production of a tyrosinase enzyme that has some activity not approaching normal. Some melanin is formed, for example, in OCAIB "yellow albinism" and in the minimal pigment type ofOCA. OCA has been divided into two different groups according to the underlying biological defect. When a mutated tyrosinase gene produces inactive, less active, or temperature-sensitive tyrosinase, its phenotype is described as tyrosinase-negative (ty-ve) (type IA), yellow-mutant (type lB), or temperature-sensitive (type I-TS) OCA, respectively. Mutation of the P gene that encodes the tyrosine-transporting membrane protein may occur in tyrosinasepositive (ty + ve) OCA (type 2). In this case, the enzyme is present but the production of type III and type IV melanins is insufficient. Tyrosinase-

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2

Genes Related to Different Phenotypes

of Albinism Gene Tyrosinase gene P gene TRP1 gene HPS gene CHS gene OA1 gene

Type of albinism OCA1 (OCA1A and OCA1B) OCA2 OCA3 Hermansky-Pudlak syndrome Chediak-Higashi syndrome X-linked ocular albinism

positive albinism is characterized by hair bulbs which, after plucking and incubation with tyrosine, produce darkening. In tyrosinase~negative albinism, the hair bulbs do not darken, although the precise metabolic defects have yet to be ascertained (2). Ultrastructural studies of the skin and hair of tyrosinase-negative types show that most of the melanosomes are in stage I or stage 2, without any melanization (2,3). Albinism is found in all races with variable prevalence. The incidence in the United Kingdom is estimated at I in 20,000. In some countries it is more common, especially where there is a tendency towards inbreeding and in isolated comunities. The highest incidence (63 per 10,000) of albinism in the world is found on the coast of Panama, in the Cuba Indians nation on the San Bias islands. Table 2 summarizes the genes related to various types of albinism. CLINICAL FEATURES OCA1A

OCAlA (ty-ve), occurs in approximately I in 40,000 individuals in most populations. It is an autosomal recessive disorder characterized by absence of pigment in hair, skin, and eyes and does not vary with race or age. The most important distinguishing characteristic of OCA I is the presence of marked hypopigmentation at birth. The skin appears pink, the hair white, and patients show a red reflex and blue eyes at birth (4,5). The irides are usually very light blue and translucent, so that the whole iris can appear pink or red in ambient or bright light. During the first two decades of life, the irides usually become a darker blue. Sun exposure produces erythema and a burn if the skin is unprotected. The eyes need melanin to develop normal vision. People with albinism have vision defects because the eyes do not have a normal amount of melanin pigment during development. Hence, the albinotic macula is always hypoCopyrighted Material

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plastic and the albinotic patient has reduced acuity. This maldevelopment of the macula explains the pendular nystagmus of the albino patient, as the albino eye constantly searches for a clear image. Research indicates that there is a disorganization of reticulogeniculate projections in the albino patient, with 20% of temporal fibers decussating at the optic chiasm. The abnormal crossings of the temporal fibers in the optic chiasm can also cause errors of refraction, head nodding, photophobia, variable visual acuity, and, frequently, strabismus in both oculocutaneous and ocular albinism. Foveal hypoplasia can also occur. In contrast, the lack of pigmentation does not obstruct the normal growth and development of the skin or hair. In OCAIB (yellow mutant type), the patient resembles a tyrosinasenegative type at birth, but at the age of I year the hair becomes yellow-red. It is now known that the hair color is the result of pheomelanin synthesis, related to the reduced tyrosinase function. The incubation of tyrosine plus cysteine in the hair bulbs of these patients produces an intensification of the yellowred pheomelanin. This type is common in Amish communities in the United States (7). Another type ofOCAIB is temperature-sensitive OCA, which is caused by a mutation of the tyrosinase gene that produces an enzyme that does not work at regular body temperature (scalp and under the arms) but does work in cooler parts of the body (arms and legs). During development, some of the body hair becomes darker. The hair under the arms and the scalp hair remain white, and with time may develop a slight yellow tint. Hair on the arms and legs slowly develops light to dark pigment. The eyes remain blue and the skin white without tanning. OCA2

OCA2 (ty + ve) is the most common type of albinism, especially frequent among African Americans and Africans. The estimated frequency ofOCA2 in the African American population is 1 in 10,000, in contrast to a frequency of I in 36,000 in Caucasian Americans (6), whereas in certain isolated communities, such as the Hopi Indians in Arizona, it is I in 277 (5). The tyrosinasepositive type tends to be a little darker with straw-colored hair. Some pigment is formed which can be found in the iris (which appears less translucent), skin, and hair with increasing age. Localized (nevi, freckles, and lentigines) skin pigment can develop, often in sun-exposed regions of the skin, but tanning is usually absent. Since the eyes are slightly pigmented, the affected subjects' eyesight is not as severely compromised. In Caucasian individuals with OCA2, the amount of pigment present at birth varies from minimal to moderate. The hair can be very lightly pigmented at birth, having a light yellow or blond color, or more pigmented with a blond, Copyrighted Material

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golden blond, or even red color. With time, pigmented nevi and lentigines may develop and some pigmented freckles can be seen in exposed areas after repeated sun exposure. The hair in these individuals may slowly turn darker through the first two decades of life. African individuals have white skin but the hair is blonde or yellow. Some affected individuals develop lentigoes and pigmented moles, especially in the sun exposed areas. Almost all albinos in Tanzania belong to this group. The irides of these patients are blue/grey, green, or hazel (17). Interestingly, the hair of these subjects can turn lighter in older individuals; this probably represents the normal graying with age. This phenotypic pigment variation probably reflects genetic admixture in this population and may result from different mutations of the P gene and their effects on the function of the P protein. In tyrosinase-positive individuals, the visual acuity may improve as they get older and nystagmus may become less severe. Brown OCA

Brown OCA is a type of albinism that is recognized, for the time being, only in the African and the African American populations. In these individuals, the hair and skin color are light brown, and the irides are gray to tan at birth. Affected individuals are recognized because they have all the ocular defects of albinism. The iris is punctated translucent, and moderate retinal pigment is present. The skin can tan modestly with sun exposure (6,7). Brown OCA is part of the spectrum ofOCA2, resulting from alterations of the P gene associated with the development of yellow or red pheomelanin and a lack of development of brown or black eumelanin. Brown OCA, like OCA 1B, probably arises from a "leaky" mutation, which reduces the function of the P gene product. OCA3 TRP1-Related OCA

The first connection between mutations of the TRP 1 (tyrosinase-related protein 1) gene and variations in human pigmentation came from the description of an African American newborn twin boy with light brown skin, light brown hair, and blue irides, while his fraternal twin brother had normal pigmentation. This and other similar cases have been described from then on in the literature as "red," "rufous," or "xanthous" albinism. The pigment phenotype in South African individuals includes red or reddish-brown skin, ginger or reddish hair, and hazel or brown irides. The ocular features are not fully in accordance with the diagnosis ofOCA; many subjects do not have iris translucency, strabismus, nystagmus, or foveal hypoplasia or misrouting of the optic nerves. This suggests either that this is not a true type of albinism or

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that the hypopigmentation is not sufficient to alter the development of the optic nerve (7,8). Presently, the phenotype for TRP1-related OCA in Asian and Caucasian populations is unknown. Ocular Albinism

In ocular albinism, only the eyes are clinically involved, although melanocytes of the skin seem to show some changes. Four different types exist: two are Xlinked, one dominant and one recessive. The X-linked and recessive types present an association with deafness, since the melanocytes apparently fail to playa protective role in the ear. Ocular albinism type I, also known as Nettleship-Falls type, is the most common X-linked form of ocular albinism. Affected males show all the ocular typical defects of albinism, including reduction in visual acuity, strabismus, nystagmus, retina hypopigmentation, foveal hypoplasia, and loss of stereoscopic vision due to misrouting of the optic tracts. Eye color may be normal, but examination of the back of the eye (retina) through the pupil shows that there is no pigment in the retina. Female carriers, on the contrary, have normal vision but may show after examination a patchy hypopigmentation of the retinal pigment epithelium due to a mosaic inactivation of the affected X chromosome. The clinical severity of ocular albinism type I is believed to depend on the race of the patient, being more severe in those of racial groups exhibiting very light constitutive pigmentation than in those more darkly pigmented (1). Although this type of albinism is categorized as a type of ocular albinism, the melanocytes in the skin and hair follicles are also involved and contain abnormally large melanosomes (9). HERMANSKY-PUDLAK SYNDROME

The Hermansky-Pudlak syndrome is very rare. Only 250 cases have been reported so far, mostly of Puerto Rican origin (11). Tyrosinase-positive oculocutaneous albinism occurs in association with bleeding tendency and deposits of ceroid-like pigment in the reticuloendothelial cells. The bleeding is attributed to a storage-pool platelet defect. No defect has been found in circulating lymphocytes or neutrophils. Association with lupus nephritis, granulomatous colitis, and pulmonary fibrosis has been posited. The primary genetic defect is still unknown. CHEDIAK-HIGASHI SYNDROME

In this rare syndrome, inherited as an autosomal recessive disorder, there is hypopigmentation of the skin and eyes, and abnormal inclusions are found in Copyrighted Material

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many cell types, including melanocytes, leukocytes, and platelets (12). Giant pigment granules, arising by autophagocytosis and fusion of large degraded melanosomes, are present in melanocytes. Similar granule defects can be also seen in leukocytes and platelets. These patients demonstrate a high susceptibility to infections.

CROSS SYNDROME

This syndrome, probably determined by an autosomal recessive gene, is characterized by albinism-like hypopigmentation, ocular defects, and mental retardation. Blood tyrosine levels are normal and light-colored hair pigment poorly in tyrosine solution. Microphthalmos, smal1 opaque cornea, and coarse nystagmus are the major clinical defects at birth, while spacicity and mental retardation become evident soon (13).

ALBINOIDISM

The term "albinoidism" is used to describe families in whom are found partial defects in melanin production in the skin, but only minimal changes in the eyes (5). Slight tanning may occur, while the hair bulb test is positive. A punctate pattern of iris translumination is seen. Although the eyes are usual1y normal, there may be photophobia. The disorder seems to be transmitted as an autosomal dominant. Its biochemical basis remains unknown (14).

ALBINISM-GRISCELLI SYNDROME

Griscelli syndrome is a form of partial albinism associated with immunodeficiency. It is a rare disorder that involves a lack of pigment production and a variable degree of immunodeficiency. Mature melanosomes appear in skin and hair follicle melanocytes, with sparse pigmentation of adjacent keratinocytes. The associated immunodeficiency often involves impaired natural killer cell activity, absent delayed-type hypersensitivity, and poor cell proliferation response to antigenic challenge. Bone marrow transplantation from a compatible donor seems to be the only treatment with some success (15). Recent studies have begun to reveal the molecular links between immunodeficiency and albinism. Chediak-Higashi, Griscelli, and HermaskyPudlak syndromes are all characterized by a combination of immunological and pigmentation defects. New key proteins, such as Rab27a protein, have been recently identified as responsible for the secretion of specialized granules found in immune cells and in melanocytes. These granules, believed to be

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modified Iysosomes ("secretory Iysosomes"), are not found in any other cell type, which explains the selective effects present in these diseases (16). QUALITY OF LIFE OF PERSONS AFFECTED WITH ALBINISM

In temperate climates, the quality of life and the prognosis for albinos is better than in tropical regions, with visual defects being the greatest disability. In the tropics, by contrast, the fate of albinos is inversely related to the distance from the equator, exposing them to more or less intense sunlight and putting them at risk of sun damage and developing skin cancer. The most frequent form of albinism in sub-Saharan Africa is tyrosinase-positive oculocutaneous albinism (OCA2). The estimated frequency of OCA2 in Dar-Es-Salaam (Tanzania) was I in 1429. In Zimbabwe the prevalence in schoolchildren in Harare was found to be 1 in 2833, and nationwide 1 in 4728. In Soweto, South Africa, the prevalence of OCA2 among the black population was estimated to be I in 3900 and in schoolchildren in Swaziland I in 1634 (J 9). Albinos is sub-Saharan Africa are often not accepted by their families. In Tanzania they are sometimes called Zeru zeru (ghost) or I17zungu (white European). In East Africa albino babies have been known to be killed at birth. Although 50% of albinos have another albino in the family, many local people still do not realize that it is hereditary disease (20). This situation contributes to the prevailing stigmatization, alienation, and discrimination. The continuous and inevitable solar exposure provokes precocious skin photoaging, with solar elastosis and formation of many actinic keratoses from an early age and development of basal and squamous cell carcinomas. Malignant melanomas are extremely rare in patients with albinism (J 7). Albinos have a lack of melanin and therefore no suitable protection against UV irradiation. The most frequently observed malignant tumor that occurs in albinos is squamous cell carcinoma, which is often very disfiguring and finally leads to death. Many studies have shown that few albinos in subSaharan Africa survive beyond the third decade (17). Another major problem of albinos in sub-Saharan Africa is poor eyesight. The reduction of melanin in the iris, the poor retinal pigment, and the existing hypoplastic fovea lead to a marked reduction in visual acuity. Albino patients may therefore suffer from poor central vision and refractive errors like myopia or hyperopia, nystagmus, strabismus (squint), and photophobia. A misrouting of the optic fibers results in loss of stereoscopic perception and nystagmus (19). The International Society Dermatology (lSD) has recently taken up a project supporting the albinos of Africa by cooperating with the Regional Dermatology Training Centre (RDTC) in Moshi, Tanzania, a joint venture by the Ministry of Health of Tanzania in collaboration with the International Copyrighted Material

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Foundation For Dermatology (IFD), which serves under the aegis of the International League of Dermatological Societies (ILDS) and the Kilimanjaro Christian Medical Centre (KCMC). The primary aim of this project, which is financially supported by the Italian Rotary Clubs, is to support the Mobile Albino Skin Care Clinic, initially launched by Lookingbill and Leppard in 1993 to provide a clinical advisory service to albinos in the Kilimanjaro region (I7). This project seeks to prevent skin cancers and subsequent early death by providing health education such as sun protection counseling, and guidance to persons affected with albinism, their relatives, community leaders and teachers, and by regular examination and monitoring of those affected with treatment of early and/or advanced lesions. Patients are provided with sunscreens, protective broad-brimmed hats, long-sleeved shirts, and sunglasses and are constantly reminded that only by strict adherence to a protective lifestyle can UV damage be confined. To overcome prejudice, stigmatization, and discrimination, large-scale educational programs for the community at large by means of radio, television, newspapers, and magazines are in the planning phase.

REFERENCES I. 2. 3. 4.

5.

6. 7. 8. 9. 10. II.

Shen B, Samaraweewa P, Rosenberg B, Orlow Sl. Ocular albinism type I: more than meets the eye. Pigment Cell Res 2001; 14:243-248. Bologna lL, Pawelwk 1M. Biology of hypopigmentation. 1 Am Acad Dermatol 1988; 19:217-255. Boissy RE, Nordlund JJ. Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res 1997; 10(1-2):12-24. King RA, Hearing Vl, Creel DJ, Oetting WS. Albinism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill, 1995:4353-4392. Witkop CJ, Quevedo WC, Fitzpatrick TB, et a!. Albinism. In: Scriver CR, et aL eds. The Metabolic Basis ofInherited Disease. 6th ed. New York: McGraw-Hill, 1989. Bleehen SS. Albinism. In: Champion RH, el a!., eds. Disorders of Skin Color. 6th ed. Oxford: Blackwell Science, J998. Ortonne J-P, Mosher DB, Fitzpatrick TB. Vitiligo and Other Hypomelanosis of Hair and Skin. New York: Plenum Medical, 1983:129-310. Lyle WM, Sangster 10, Williams TD. Albinism: an update and review of the literature. J Am Optom Assoc 1997; 68(10):623-645. Garner A, lay BS. Macromelanosomes in X-linked ocular albinism. Histopathology 1980; 4:243-254. Russel-Riggel I. Albinism. Ophthalmol Clin North Am 200J; 14(3):533-546. Shanahan F, Randolph L, King R, et a!. Hermansky-Pudlak syndrome and immunologic asseSSment of IS cases. Am 1 Med 1988; 85:823-828.

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16. 17.

18. 19.

20.

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Acquiron L. Human albinism: clinical, genetic, cellular, biochemical and molecular aspects. Med Trop 2000; 60(4):331-341. Cross HE, McKusick VA, Breen W. A new oculocerebral syndrome with hypopigmentation. J Pediatr 1967; 70:398-406. Guarera M. Albiniso e Albinoidismo. In: Lotti T, ed. UTET Periodici Scientifici 2000; 159-162. Mancini AJ, Chan LS, Paller AS. Partial albinism with immunodeficiency: Griscelli syndrome: report of a case and review of the literature. J Am Acad Dermatol 1998; 38(2 pt 2):295-300. Griffiths GM. Albinism and immunity: what's the link? Curr Mol Med 2002; 2(5):479--483. Lookingbill DP, Lookingbill GL, Leppard B. Actinic damage and skin cancer in albinos in northern Tanzania: Findings in 164 patients enrolled in an outreach skin care programme. J Am Acad Dermatol 1995; 32:653-658. Leppard B. Management of albino children in a tropical climate. Postgrad Doctor 1998; 20:112-116. Doe PT. Educational and social problems of albinism in the Kilimanjaro region of Tanzania-a community-based case study of educational and social problems facing patients with albinism in Kilimanjaro region. Dissertation for the Degree of Masters of Medicine by the TUMAINI University, April 2000 Simona B. Albinism in Africans as seen at the Regional Dermatology Training Centre, Kilimanjaro Christian Medical Centre, Moshi, Tanzania. Personal communication, 2001.

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46 Chediak-Higashi Syndrome Benedetta Brazzini and lIaria Ghersetich University of Florence, Florence, Italy

DEFINITION Chediak-Higashi syndrome (CHS), described for the first time in 1943 by Begnez, is a rare autosomal recessive disorder characterized by partial oculo-cutaneous albinism, recurrent infections with neutropenia, abnormal natural killer cell function, impaired chemotaxis and phagocyte bactericidal activity, easy bleeding due to deficiency of storage, and/or release of platelet dense bodies, and neurological abnormalities (I). A similar disorder occurs in the beige mouse, the Aleutian mink*, and albino Hereford cattle. Parental consanguinity is often reported. CHS affects all races. Symptoms ofCHS usually appear soon after birth or in children before the age of 5. Most children die during infancy (first decade) as a result of infections, bleeding, or the development of the accelerated lymphoma-like phase. Survival into the second and third decades has been reported; these patients usually die from a malignant lymphoma.

*

Aleutian mink disease is a slow progressive disease of mink caused by the Aleutian mink disease virus, characterized by poor reproduction, weight loss, autoimmunity. hypergammaglobulinemia, increased susceptibility to bacterial infections, and death from renal failure. Mink that are homozygous recessive for the Aleutian gene for light coat color are particularly susceptible.

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In 1996 Nagle et al. (2) identified the CBS locus as the LYST or CHSI on chromosome lq42-43 and performed a mutation analysis (Table 1). The CBS locus encodes a lysosomal trafficking regulator expressed in the cytoplasm of many tissues. The CBS gene mutation causes an abnormal membrane fluidity with a consequent uncontrolled granule membrane fusion and the formation of giant cytoplasma tic granules in various types of cells. During the early stage of neutrophil maturation (myelopoiesis in the bone marrow), azurophilic and specific granules tend to coalescence forming megagranules, while in the later stage (myelocyte stage) normal granules are formed. The formation of megagranules results in death of the myeloid precursors in the bone marrow (neutropenia), defective chemotaxis, degranulation and bactericidal activity of the remaining neutrophils with increased susceptibility to infections (especially gram-positive and gram-negative bacteria). A similar phenomenon occurs in lymphocytes, monocytes, macrophages, platelets, and melanocytes. Lymphocytes become defective in antibodydependent cell-mediated cytolysis of tumor cells, while platelets become unable to concentrate serotonin and ADP, resulting in platelet aggregation defect with normal platelet concentration but prolonged bleeding time. Melanosomes in melanocytes are larger in size and irregular in morphology due to a failure to dispense pigment, which causes partial albinism of the hair and skin. In melanocytes, autophagocytosis of melanosomes also occurs (3,4). Other affected cells are Schwann cells with consequent central and peripheral neuropathies and retinal cells with sequelae like photophobia, nystagmus, and altered red reflex.

CLINICAL FEATURES

In CBS the skin is very pale (similar to albinos, but with dyschromic lesions in patchy distribution) and slate-colored areas may be present. Sunlight expo-

TABLE

1

Mutation Analysis of the CHS Gene

Phenotype CHS CHS CHS

Mutation

Basechange

Classification

Ala 40 insG Arg 1103 ter Glu 489 delG

GCA-GGCA CGA-TGA GAGCAA-GA_CAA

Homozygous Homozygous Homozygous

Source: Ref. 1.

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sure may stimulate a slight tanning, but usually causes severe sunburns. The hair is light blond or silvery grey and frizzy. The irides are translucent, bluish, gray, or light brown. Usually the patients present with extreme photophobia, rotary nystagmus, and increased red reflex (5). Recurrent infections occur frequently and involve the skin, the mucous membranes (severe gingivitis, oral ulcerations, and periodontal disease), and the respiratory tract. Skin infections range from superficial pyoderma to deep subcutaneous abscesses and ulcers that heal slowly, leaving atrophic scars. Staphyloeo eus aureus is the most frequently involved agent (6). Neurological manifestations usually have their onset in adulthood and consist of abnormal gait, clumsiness, seizures, ataxia, muscular weakness, paresthesia, mental retardation, and peripheral neuropathy. In most cases neurological dysfunctions appear in the Iymphoproliferative lymphoma-like phase. Progressive neurological deterioration is common in patients who survive early childhood. Generally, these patients enter the acceleration phase of the disease, which is characterized by a lymphoma-like picture with fever, generalized lymphoadenopathy, hepatosplenomegaly, pancytopenia, and sepsis (7). The adult form ofCRS is characterized by onset in early adulthood and marked by neurological sequelae such as parkinsonism, dementia, spinocerebellar degeneration, and peripheral neuropathy (8).

LABORATORY INVESTIGATIONS Laboratory findings include neutropenia, hypergammaglobulinemia, normal platelet count, but prolonged bleeding time. Pancytopenia is present in the accelerated phase. Light microscopy of a routine blood smear reveals the characteristic giant granules in neutrophils and eosinophils, while bone marrow smears reveal giant inclusion bodies in leukocyte precursors. Granules are peroxidase posi tive and contain lysosomal enzymes. Cytochemistry (Wright stain) of cellular granularity and surface molecules offers useful diagnostic information. A prena tal diagnosis can be made by examining hair from fetal scalp biopsies or leukocytes from fetal blood.

TREATMENT A multidisciplinary approach is important (pediatrics, dermatologists, neurologists, ophthalmologists, etc.). Regular monitoring is necessary. The skin must be washed two times a day with disinfectants to avoid infection. Bone marrow transplantation (BMT) (9, lO) is the treatment of choice and is

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indicated before the accelerated phase of the disease develops. However, BMT corrects the immunological status but does not affect the pigment disorder. In the stable phase ascorbic acid may improve the clinical status and phagocytic function; management of infections and seizures is important, but prophylactic antibiotics are not indicated. In the accelerated phase, administration of corticosteroids and microtubulytic drugs (vincristine, vin blastine, and colchichine) and cyclophosphamide seem to partially arrest the Iymphohistiocytic infiltration of the reticuloendothelial system but is not effective in arresting the progression of the disease. Acyclovir (II), high doses of gammaglobulins (12), and methylprednisolone provide a temporary improvement in fever and pancytopenia and decrease the bleeding time. Interferon-ex 2a and 2b has been demonstrated to partially restore the function of natural killer cells.

REFERENCES 1.

2.

3. 4.

5.

6. 7.

8.

9.

10.

Braun-Falco 0, Plewig G, Wolff HH, Burgdorf WHC. Chediak-Higashi syndrome. Dermatology. 2d ed. Berlin: Springer-Verlag, 2000: I029. Nagle DL, Karim MA, Woolf EA, Holmgren L, Bork P, Musini D1. McGrail SH, Dussault B1, Perou CM, Boissy RE, Duyk GM, Spritz RA, Moore KJ. Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet 1996; 14:307-311. Introne W, Boissy RE, Gahl WA. Clinical, molecular and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab 1999; 68(2):283-303. Zhao H, Boissy YL, Abdel-Ma1ek Z, King RA, Nordlund 11, Boissy RE. On the analysis of the pathophysiology of Chediak-Higashi syndrome. Defects expressed by cultured melanocytes. Lab Invest 1994; 7l( I):25-34. Carnide EM, 1acob CM, Pastorino AC, Bellinati-Pires R, Costa MB, Grumach AS. Chediak-Higashi syndrome: presentation of seven cases. Rev Paul Med 1998; 116(6):1873-1878. Kapoor A, Munjal S, Arya R. Chediak-Higashi syndrome: a case report. Indian 1 Pathol Microbiol 2000; 43(3):373-375. Rubin CM, Burke BA, McKenna RW, McClain KL, White JG, Nesbit ME 1r, Filipovich AH. The accelerated phase of Chediak-Higashi syndrome: an expression of the virus-associated hemophagocytic syndrome? Cancer 1985; 56: 524. Hauser RA, Friedlander 1, Baker M1, Thomas 1, Zuckerman KS. Adult Chediak-Higashi parkinsonian syndrome with dystonia. Mov Disord 2000; 15(4): 705-708. Haddad E, Le Deist F, Blanche S, Benkerrou M, Rohrlich P, Vilmer E, Griscelli C, Fischer A. Treatment of Chediak-Higashi syndrome by allogenic marrow transplantation: report of 10 cases. Blood 1995; 85(11):3328-3333. Liang 1S, Lu MY, Tsai M1, Lin DT, Lin KH. Bone marrow transplantation

Copyrighted Material

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11. 12.

477

from HLA-matched unrelated donor for treatment of Chediak-Higashi syndrome. J Formos Med Assoc 2000; 99(6):499-502. Conley ME, Henle W. Acyclovir in accelerated phase of Chediak-Higashi syndrome. Lancet 1987; 1:212. Kinugawa N, Ohtani T. Beneficial effects of high-dose intravenous gammaglobulin on the accelerated phase of Chediak-Higashi syndrome. Helv Pediatr Acta 1985; 40: 169

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47 Melanoma and Vitiligo Dan Forsea University of Bucharest, Bucharest, Romania

Vitiligo or vitiligo-like leukoderma associated with melanoma has been observed by several investigators in the past. Melanoma and vitiligo also have been observed together in animals. The association in some ways is a paradox, because melanoma is an uncontrolled proliferation of malignant melanocytes, and vitiligo is the result of destruction of normal pigment cells (1). The worldwide prevalence of vitiligo has been estimated as 1-2%. The relative rates of association between vitiligo and melanoma have been quite controversial, ranging from 1.4 to 20% (2). Genetic factors have been discussed for both disorders (4). There is considerable evidence that vitiligo and melanoma involve a genetic predisposition. About half of the patients with ordinary vitiligo have a family history of vitiligo that suggests an autosomal dominance for a few families with the disorder and a polygene for others. Approximately 6% of patients with melanoma have one or more family members with melanoma. Lerner et al. (4) reported 12 families with melanoma who had close family members with halo nevi, early graying of hair, a halo primary melanoma, or ordinary vitiligo. It is known that the most common condition associated with halo nevus is vitiligo, occurring in 18-26% of cases (8). A number of clinical observations suggest the relationship between vitiligo and melanoma (3): Patients with melanoma have been observed to develop vitiligo or depigmented spots on the skin.

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The appearance of vitiligo improves the prognosis of melanoma in both animals and humans. The association of the two disorders has been well documented in animals. Several animal models have been studied in which genetic factors, presumably oncogenes, influence the development of vitiligo and melanoma. All gray Arabian horses develop melanocytic tumors, and independent of whether these tumors are malignant or benign, the horses always develop loss of pigment that resembles vitiligo. It is not known whether loss of pigment or development of tumor occurs first, but the horses survive for many years with their tumors. These animals sometimes develop total vitiligo in conjunction with a dramatic regression of their tumors. It has also been postulated that melanoma patients with vitiligo have a better prognosis. It is possible that the melanocytes of people with vitiligo or with a genetic background for vitiligo are predisposed to undergo a malignant transformation, but that presence of vitiligo suppresses the growth of malignant melanocytes. It is knows that patients with metastatic melanoma who develop vitiligo tend to survive longer than those who do not have depigmentation. Immunization of animals to melanoma cells can induce vitiligo. It is important to know the clinical aspects of vitiligo and the kinds of pigment loss that occurs in patients with melanoma (4). Although some observers have termed the widespread leukoderma seen in melanoma patients as vitiligo, this condition is not strictly identical to vitiligo in terms of epidemiology, clinical appearance, body distribution, or histological features. The age range is 30-61 years, whereas classical vitiligo occurs in patients 10-30 years of age with a positive family history of 30-50%. The onset and course of depigmentation in patients with melanoma differ from those of classical vitiligo not associated with melanoma. In the latter, depigmentation most often begins on the hands, face, and feet and spreads centripetally to the trunk. In patients with melanoma, depigmentation begins more commonly on the trunk and spreads centrifugally to involve the neck, face, and extremities. Four patterns of hypomelanosis have been observed in melanoma patients: (a) areas of depigmentation confined to the primary lesion, suggesting spontaneous regression; (b) halos of depigmentation about the primary tumor; (c) coexistent halo nevi; and (d) widespread hypomelanosis occurring at sites distant from the primary site (5). It is of special interest to examine the time of onset of vitiligo in relation to the onset of melanoma, since the development of vitiligo in patients with this malignancy has been claimed to be of prognostic significance by several investigators (2). Most authors have published case reports describing the onset of vitiligo: (a) after first diagnosis of melanoma, (b) after tu-

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mor progression into regional lymph nodes with some cases of widespread metastatic disease, (c) after chemotherapy, irradiation, or immunotherapeutic approaches, and (d) preceding the diagnosis of melanoma. Onset broadly extends over a period of 2-60 years, whereas vitiligo following melanoma occurs in the majority of cases in the first few years after tumor diagnosis; therefore, premelanoma vitiligo may indeed present as a distinct disorder and may be, after all, of different etiology than postmelanoma vitiligo. The mechanism responsible for the association between melanoma and vitiligo is not known. Since both vitiligo and melanoma represent disorders involving melanocytes, more recently there has been much speculation as to the possible clinical connections, especially in regard to immunological factors. In both diseases, researchers have implicated the immune system responses. Clinicopathological support for the immune implication for vitiligo includes the presence of lymphocytes in the dermis of early lesions, the presence of circulatory autoantibodies in many patients, the association with halo nevi and certain autoimmune diseases, and the therapeutic effect of PUYA, which is known to act on T lymphocytes (8). Abnormalities of both humoral and cell-mediated immunity have been also described. The presence of circulatory melanoma-specific cytotoxic T lymphocytes (CTLs) and the small but reproducible incidence of regression of disseminated disease, either spontaneous or after treatment with cytokines such as interleukin-2 (IL-2), are the clinicopathological evidence for the relevance of cell-mediated immunity in melanoma. The rationale for an autoimmune connection between vitiligo and melanoma has emerged from the animal models where melanoma precedes vitiligo followed by tumor regression (2). Sinclair pigs may provide an animal model because melanocytic tumor associated with metastatic disease in these animals is similar to human melanoma, and regression to tumors is associated with surrounding depigmentation as a concomitant event that follows an inflammatory cellular infiltrate in tumors. The mechanism of regression of melanocytic nevi and the depigmentation of halo nevi has been shown to be related to an immunological action mediated by cytotoxic T lymphocytes. Approximately 80% of patients with generalized vitiligo were found to have circulating antibodies to cell surface antigens on normal human melanocytes; these antibodies were cytotoxic to normal melanocytes and melanoma cells in tissue culture (8). Both types of T lymphocytes, CD8 + and CD4 +, appear to playa major role in antitumor response; the tumor antigen-specific CTL (CD8 +) is the important effector cell involved in recognition of tumor rejection antigen. On recognition of the peptide MHC complex, CTLs (CD8 +) can secrete IL-2, IF-)', or TNF or can kill a tumor cell directly. Precursors of mature CD 4 + lymphocytes can differentiate into two types of cytokine-secreting cell: Copyrighted Material

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one produces cytokines important for generating CD8 + cellular response (CD8 + T HI)' the other produces cytokines that help prime B cells for antibody production (CD4 + T H2) (6). The induction of vitiligo in the setting of immunotherapy for melanoma has been observed (9). In a small series of patients treated with sequential chemotherapy (combination chemotherapy with carmustine, dacarbazine, cisplatin, and tamoxifen followed by IL-2 and interferon-ex immunotherapy) for metastatic melanoma, 56% developed extensive de novo vitiligo, particularly on the trunk. This phenomenon, when it occurs spontaneously in patients with metastatic melanoma, may be an example of autoimmunity complicating antitumor immunity. Presumably, the mechanism of vitiligo in this setting may represent an immune response against melanoma antigens that are shared by normal melanocytes, with cytotoxic T lymphocytes and/or antibodies being the effector mechanism. Circulating antibodies in vitiligo patients with active disease are directed to melanocyte antigens with molecular weights of approximately 40-45, 75, and 90 kDa. Likewise, patients with melanoma can develop antibodies to melanoma antigens of similar size. These observations suggest that the clinical links between vitiligo and melanoma result from the presence of immune responses to common pigment cell antigens in both diseases. Management of melanoma continues to present a challenge to dermatologists, particularly in advanced cases. Immunotherapy remains of interest because of the minimal toxicity and improved prognosis correlated with specific humoral and cellular immune responses. Based on the idea that vitiligo may be an autoimmune disorder, much more clinical interest was focused on the possibility that antibodies to melanocytes in vitiligo may be important to the immune defense system in metastatic melanoma (2). Whether clinical links between these two diseases are simply by chance or an interplay between genetics and immunological factors remains to be determined, but it is of note that both vitiligo and melanoma are associated with immune responses to identical antigens expressed by melanocytes and melanoma cells. Metastatic spread of melanoma may provoke an immune response that proceeds to attack both normal pigment cells and tumor cells, e.g., by the action of cytokines, and leading to leukoderma. The selective destruction of pigment cells that occurs in vitiligo is the therapeutic goal sought in melanoma.

REFERENCES I.

Nordlund JJ, Kirkwood 1M, Forget BM, Milton G, Albert OM, Lerner AB. Vitiligo in patients with metastatic melanoma: A good prognostic sign? 1 Am Acad Dermatol 1983; 9:689-696.

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5.

6. 7. 8

9.

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Schallreuter KU, Levenig C, Berger J. Vitiligo and cutaneous melanoma. Dermatologica 1991; ] 83:239-245. Cui J, Bystryn Jc. Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol 1995; 131 :314-318. Lerner AB, Kirkwood JM. Vitiligo and melanoma: Can genetically abnormal melanocytes result in both vitiligo and melanoma within a single family? J Am Acad Dermatol 1984; 11:696-70l. Koh HK, Sober AJ, Nakagawa H, Albert DM, Mihm MC, Fitzpatrick TB. Malignant melanoma and vitiligo-like leukoderma: an electron microscopy study. J Am Acad Dermatol 1983; 9:696-708. Curiel-Lewandrowski C, Demierre MF. Advances in specific immunotherapy of malignant melanoma. J Am Acad Dermatol 2000; 43: 167-185. Kovacs SO. Vitiligo. J Am Acad Dermatol 1998; 38:647-666. Mosher DB, Fitzpatrick TB, Ortonne JP, Hori Y. Hypomelanosis and hypermelanosis. In: Freedberg 1M, Eises AZ, Wolff K, et a!., eds. Dermatology in General Medicine. 5th ed. New York: McGraw-Hili, 1999:949-960. Gaspari AA. Autoimmunity as a complication of interleukin-2 immunotherapy. Arch Dermatol 1994; 130:894-897.

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48 Vaccines and Vitiligo

Silvia Moretti and Paolo Fabbri University of Florence, Florence, Italy

Several findings support the concept of vitiligo as an autoimmune disease in which destruction of melanocytes occurs. Most patients with active vitiligo have cytolytic antimelanocyte antibodies (1-3), and accumulation of activated T cells at the margin of the depigmented lesions has been demonstrated (4). Vitiligo is associated with other autoimmune diseases such as primary hypothyroidism or type 1 diabetes mellitus (5). Therefore, humoral and cellular immune mechanisms as well as a genetic predisposition (so that susceptibility of melanocytes is enhanced toward apoptotic stimuli) may play an important role in vitiligo pathogenesis. An increased frequency of vitiligo in patients with metastatic melanoma has been described by several authors (6). In addition, the presence of vitiligo in melanoma patients seems to correlate with a better prognosis (7,8). In fact, it was speculated that an immune reactivity against a growing melanoma resulted in some destruction of tumor cells as well as normal melanocytes. With the advent of immunotherapy, in which the regression of the tumor is associated with a stimulation of the immune system against the tumor itself, this association was observed more specifically. In fact, upon treatment with interleukin-2 (IL-2, T-lymphocyte growth factor), approximately 20% of responding melanoma patients developed vitiligo, and the relationship between vitiligo and melanoma regression was considered highly significant (9). Although melanoma regression could be observed without vitiligo, every patient who developed vitiligo showed at least a partial tumor regression (9). In addition, no renal cancer patient treated with IL-2 developed vitiligo, suggesting

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that tumor-derived "self" antigens were required for the induction of vitiligo (9). These results suggest that "normal" antigens expressed on both melanocytes and melanoma cells could be the targets of the immune response. In fact, T lymphocytes specific for melanoma cells were able to recognize antigens expressed by normal melanocytes (10). Techniques of biochemistry and molecular biology have made it possible to identify peptides that can be considered tumor-associated antigens. Among tumor antigens, one large class is represented by the so-called shared tumor antigens that, unlike mutated proteins, are expressed in unaltered form on cancer cells from many patients (11,12). One group of these antigens consists of the cancer testis antigens, exclusively expressed in tumors of different histologies as well as normal testis. The main proteins of this group belong to the MAGE family, some antigens of which are found also in melanoma (11). A second group of shared antigens includes the melanocyte differentiation antigens (MDA), mostly enzymes of the cascade of the synthesis of melanin pigment (12). These antigens are expressed by melanoma cells as well as by normal melanocytes and include gpJOO/pmel-17, MART-I, tyrosinase, tyrosinase-related protein (TRP)-I/gp75, and TRP-2 (12-15). Tyrosinase and TRP-I have been identified as targets for antibodies in autoimmune vitiligo (2, I6). In addition, most melanoma-reactive T lymphocytes obtained from tumors recognize MDA, and in many melanoma patients antibodies and/or T lymphocytes that are specific for one or more of these five antigens have been found (17). These findings suggest that autoreactive T cells escape thymic deletion and reach the periphery, where they can in some instances be activated and involved in antitumor immune responses (18). It is generally believed that these autoreactive T cells display relatively low avidity (9) but can be effective when activated under the proper circumstances (10,12). The understanding of the requirements for proper T-cell activation has provided possible explanations for the absence of tumor-specific immunity. Full activation of naive T cells requires stimulation of the T-cell receptors by corresponding peptide-major histocompatibility complex (MHC) complexes as well as co-stimulation through engagement of CD28 molecule by B7.1 or B7.2 molecules on the antigen-presenting cells (19). Stimulation of T cells by antigen in the absence of co-stimulatory signals can result in unproductive T-cell stimulation or T-cell toleration (20). The lack of expression of B7 molecules by tumor cells seems to be one factor that can contribute to their failure to elicit productive immune responses (21,22). It seems important to identify the antigens in cancer patients for which specific T cells are present and to activate these cells and expand them to the point where they can affect tumor regression. As for the supposed lack of immunogenicity of self tumor antigens, such as MDA, lymphocytes isolated from melanoma specimens and grown in vitro with no other stimulation than

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autologous whole melanoma cells and IL-2 consistently recognize MDA in a great majority of cases (23). For these reasons, various attempts have been made to target MDA with cancer vaccines in melanoma, both in animal models and in humans. More recently, the immunogenicity of self antigens was studied and the therapeutic effect of autoimmune responses to these proteins in mouse melanoma models was explored (24). Such studies on mouse models revealed a clear antitumor effect of autoimmunity against mouse TRP-I, and evaluating the contribution of MHC class I and II, using knockout mice as well as in vivo depletion ofCD8 + and CD4 + T lymphocytes, it was found that both mouse TRP-I-induced vitiligo and melanoma destruction relied cri tically on CD4 + T lymphocytes (24). The understanding of the role of CD4 + lymphocytes in antitumor immunity was accompanied by the identification of new molecular mechanisms through which CD4 + T lymphocytes help the initiation and maintenance of the antitumor immune response (24-26). CD4 + T lymphocytes can activate antigen-presenting cells through engagement of CD40, secrete proinftammatory cytokines such as tumor necrosis factor (TNF)-~, interferon (IFN)-'Y, and IL-2, and induce the production of chemokines to attract and activate a large number of other cells to the site of inunune reaction (27,28). Such cells are represented by CD4 + and CD8 + T lymphocytes, B cells, and nonspecific leukocytes (eosinophils and macrophages) (29,30). Furthermore, some melanoma patients also exhibit significant levels ofIgG-type antibodies against melanosomal proteins in the serum, suggesting activation of melanocyte-specific CD4 + T lymphocytes in humans (31,32). MDA, frequently identified as the principal targets of T lymphocytes grown from melanoma lesions in melanoma-bearing mice and patients (17) and ofT lymphocytes in vitiligo lesions in spontaneous vitiligo patients (33), reside in the melanosome. Various observations suggest a close relationship between melanosomes and endosomes/lysosomes, indicating that the endocytic compartment may well intersect with the transport routes of proteins targeted to the melanosome, so that a fraction of MDA may localize to the endocytic compartment (34) and be transported along with proteins destined for the dense endocytic compartment for peptide loading, to the site where MHC class II molecules associate with peptides in melanoma or antigen-presenting cells (34-36). The results of this process may be the availability of high levels of melanosomal proteins for processing and loading on MHC class II molecules when the expression of MHC class II is induced on melanoma cells or melanocyte, e.g., for some stimuli such as IFN-'Y (37). These data suggest that MDA are antigens expressed in a relatively small cell population (i.e., melanocytes). resulting in low levels of antigen during central and peripheral T-cell selection and thus affecting relatively mild tolerization (38). Large amounts of MDA Copyrighted Material

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can be presented together with MHC class I and class II by melanocytes or melanoma cells stimulated by inflammatory cytokines such as IFN--y, allowing recognition by those T cells that escaped tolerance (l7). Induction of vitiligo in metastatic melanoma patients undergoing specific vaccina tion has been reported associa ted wi th vaccine made of allogeneic genetically modified IL-2-producing melanoma cell line (39) or of autologous IL-2-transfected melanoma cells (40), but in both cases it concerned very few patients and was not clearly correlated with good clinical response. In these cases IL-2 probably acts by evoking an inflammatory tissue response at the injection site, which leads to the fragmentation of melanoma cells and subsequent presentation of tumor antigen released (41,42). In human malignant melanoma the cloning and characterization of melanoma-associated antigenderived peptides, such as MDA, recognized by cytotoxic T lymphocytes in a MHC class-I-restricted fashion, has opened new possibilities for vaccine approach, particularly using antigenic peptides, plasmid DNA, or recombinant viruses encoding tumor-associated antigens (43--45). However, several such approaches have thus far met with little or no success in the clinic (46--48). In the induction of peptide-specific cytotoxic T lymphocytes, the dominant role of antigen-presenting cells has been demonstrated (49), and it was shown that the in vivo cytotoxic T Iymphocyte-tolerizing potential of some peptides can be converted to specific immunostimulation depending on the nature of antigen-presenting cells (50). Dendritic cells (DC) are antigen-presenting cells specialized to initiate and regulate immune responses (51). They were used in human melanoma vaccines by the development of methodologies to generate large numbers of these cells in culture from blood monocytes of CD34 + progenitors (52,53). Two recent vaccine trials carried out in stage IV melanoma patients were based on antigen-bearing CD34-derived DC pulsed with a mixture of MDA-derived peptides (MetanA, gp I00, tyrosinase) and/or with peptides of the MAGE family (54,55). Progressing vitiligo was described in I of 14 patients and in 2 of 18 patients, respectively. This clinical effect is a demonstration that the DC vaccine may enhance immunity to MDA, although no clear correlation with clinical response was observed, because only temporary good prognostic serum markers were described in one patient (54). In conclusion, we can say that in melanoma patients responding to specific vaccines, the same mechanism can media te both regression of melanoma cells and development of vitiligo. In fact. based on the concept that normal self proteins such as MDA can function as tumor antigen (12), specific T lymphocytes and antibodies may be able to recognize both melanocytes and melanoma cells. The whole mechanism acting in this process needs to be further elucidated, especially in humans, and new insights into the immune mechanisms concerning MDA in both vitiligo and melanoma will possibly suggest more specific immunotherapeutic approaches in melanoma patients.

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REFERENCES 1. 2. 3.

4. 5. 6. 7. 8. 9.

10.

11. 12. 13.

14.

15.

16. 17.

18.

Cui J, Harning R, Henn M, et al. Identification of pigment cell antigens defined by vitiligo antibodies. J Invest Dermatol 1992; 98:162-165. Cui J, Arnita Y, Bystryn JC. Cytolytic antibodies to melanocytes in vitiligo. J Invest Dermatol1993; 100:812-815. Harning R, Cui J, Bystryn Jc. Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Dermatol 1991; 97: 1078-1080 Badri AM, Todd PM, Garioch 11, et al. An immunohistological study of cutaneous lymphocytes in vitiligo. J Pathol 1993; 170: 149-155. Macron C, Winter KI, Traisman HS. Vitiligo and juvenile diabetes mellitus. Arch Dermatol 1977; 113:1515-1519. Schallreuter KU, Levenig C. Berger J, et al. Vitiligo and cutaneous melanoma. A case study. Dermatologica 1991; 183:239-245. Bystryn JC, Rigel D, Friedman RJ, Kopf A. Prognostic significance of hypopigmentation in malignant melanoma. Arch Dermatol 1987; 123: 1053-1 055. Spallanzani A, Pinci C, Brizzi P, Chiarugi A, Moretti S. Melanoma e vitiligine. G It Dermatol Venereol1996; 131:231-234. Rosenberg SA, White DE. Vitiligo in patients with melanoma: normal tissue antigens can be targets for cancer immunotherapy. J Immunother Emphasis Tumor ImmunolI996; 19:81-84. O'Neil BH, Kawakami Y, Restifo NP, et al. Detection of shared MHC-restricted human melanoma antigens after vaccinia virus-mediated transduction of genes coding for HLA. J Immunol 1993; 151:1410-1418. Boon T, CouJie PG, Van DE. Tumor antigens recognised by T cells. Immunol Today 1997; 18:267-268 Rosenberg SA. Cancer vaccines based on the identification of genes encoding cancer regression antigens. lmmunol Today 1997; 18:175-182. Kawakami Y, Eliyahu S, Delgado CH, et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci USA 1994; 91 :3515-3519. Bakker SB, Schreus MW, Kawakami BA, et al. Melanocyte lineage-specific antigen gplOO is recognised by melanoma-derived tumor-infiltrating lymphocytes. J Exp Med 1994; 179:1005-1009. Wang RF, Parkhurst MR, Kawakami Y, et al. Utilization of an alternative open reading frame of a normal gene in generating a novel human cancer antigen. J Exp Med 1996; 183:1131-1140 Song YH, Connor E, Li Y, et al. The role of tyrosinase in autoimmune vitiligo. Lancet 1994; 344:1049-1052. Overwijk WW, Restifo NP. Autoimmunity and the immunotherapy of cancer: targeting the "self" to destroy the "other." Critic Rev Immunol 2000; 20:433450. Van Elsa A, Hurwitz AA, Allison JP. Combination immunotherapy of BI6 melanoma using anti-cytotoxic T lymphocyte-associated antigen4(CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vac-

Copyrighted Material

Moretti and Fabbri

490

19. 20. 21. 22.

23.

24.

25. 26.

27. 28.

29.

30. 31.

32.

33.

34.

cines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 1999; 190:355-366. Allison JP. CD28-B7 interactions in T-cell activation. Curr Opin Immunol1994; 6:414-419. Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science 1990; 248: 1349-1356. Townsend S, Allison JP. Tumor rejection after direct costimulation of CD8 + T cells by B7-transfected melanoma cells. Science 1993; 259:368-370. Chen L, Ashe S, Brady WA, et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocytes molecules CD28 and CTLA-4. Cell 1992; 71: 1093-11 02. Curtsinger JM, Schmidt CS, Mondino A, et al. Inflammatory cytokines provide a third signal for activation of naive CD4 + and CD8 + T cells. J Immunol 1999; 162:3256-3262 Overwijk WW, Lee DS, Surman DR, et al. Vaccination with a recombinant vaccinia virus encoding a "self' antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4 + T lymphocytes. Proc Natl Acad Sci USA 1999; 96:2982-2987 Pardoll DM, Topalian SL. The role of CD4+ T-cell responses in antitumor immunity. Curl' Opin Immunol 1998; 10:588-594. Ossendorp F, Mengede E, Camps M, Filius R, Melief CJ. Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors. J Exp Med 1998; 187:693702. Lu Z, Yuan L, Zhou X, et al. CD40-independent pathways of T-cell help for priming of CD8 + cytotoxic T lymphocytes. J Exp Med 2000; 191:541-550. Schoenberger SP, Toes RE, van del' Voort EI, et al. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions Nature 1998; 393:480483. Naftzger C, Takechi Y, Kohda H, et al. Immune response to a differentiation antigen induced by altered antigen: a study of tumor rejection and autoimmunity. Proc Natl Acad Sci USA 1996; 93:14809-14814. Hung K, Hayashi R, Lafond-Walker A, et al. The central role ofCD4 + T cells in the antitumor immune response. J Exp Med 1998; 188:2357-2368. Chen YT, Gure AO, Tsang S, et al. Identification of multiple cancer/testis antigens by allogenic antibody screening of a melanoma cell library. Proc Natl Acad Sci USA 1998; 95:6919-6923. Stocker E, Jager E, Chen YT, et al. A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J Exp Med 1998; 187: 13491354. Ogg GS, Rod DP, Romero P, et al. High frequency of skin-homing melanocytespecific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med 1998; 188: 1203-1208. Calvo PA, Frank DW, Bieler BM, Berson JF, Marks MS. A cytoplasmic sequence in human tyrosinase denies a second class of di-leucine-based sorting

Copyrighted Material

Vaccines and Vitiligo

35.

36. 37.

38. 39.

40.

41.

42.

43. 44.

45.

46. 47. 48. 49.

50.

51.

491

signals for late endosomal and lysosomal delivery. J BioI Chern 1999; 274: 1278012789. Nijman HW, Kleijmeer MJ, Ossevoort MA, et al. Antigen capture and major histocompatibility class II compartments of freshly isolated and cultured human blood dendritic cells. J Exp Med 1995; 182:163-174. Rudensky AY, Maric M, Eastman S, et al. Intracellular assembly and transport of endogenous peptide-MHC class LI complexes. Immunity 1994; 1:585-594. Brady MS, Eckels DD, Ree SY, et al. MHC class II-mediated antigen presentation by melanoma cells. J Immunother Emphasis Tumor Immunol 1996; 19: 387-397. Ohashi PS. T-cell selection and autoimmunity: flexibility and tuning. Curr Opin Immunol 1996; 8:808-814. Osanto S, Schiphorst PP, Weijl NL, et al. Vaccination of melanoma patients with an allogeneic, genetically modified interleukin 2-producing melanoma cell line. Hum Gene Ther 2000; 11:739-750. Schreiber S, Kampgen E, Wagner E, et al. Immunotherapy of metastatic malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: outcome of a phase I study. Hum Gene Ther 1999; 10:983-993. Maass G, Schmidt W, Berger M, et al. Priming of tumor-specific T cells in the draining lymph nodes after immunization with IL-2-secreting tumor cells: three consecutive stages may be required for successful tumor vaccination. Proc Natl Acad Sci USA 1995; 92:5540-5544. Zatloukal K, Schneeberger A, Berger M, et al. Elicitation of a systematic and protective antimelanoma immune response by interleukin-2 based vaccine: assessment of critical and molecular parameters. J Immunol 1995; 154:3406-3419. Van den Eynde BJ, Van Der Bruggen P. Tcell defined tumor antigens. CUff Opin Immunol 1997; 9:684-693 Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998; 4:321-327. Rosenberg SA, Zhai Y, Yang JC, et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-lor gplOO melanoma antigens. J Natl Cancer Inst 1998; 90:1894-1900. Gilboa E. The makings ofa tumor rejection antigen. Immunity 1998; 9:757-763. Pardoll DM. Cancer vaccines. Nat Med 1998; 4:525-531. Fong L, Englemann EG. Dendritic cells in cancer immunotherapy. Annu Rev Imrnunol 2000; 18:245-273. Iwasaki A, Torres CA, Ohashi PS, et al. The dominant role of bone marrowderived cells in CTL induction following plasmid DNA immunization at different sites. J Immunol 1997; 159:11-14. Toes RE, Van Der Voort, Schoenberger SP, et al. Enhancement of tumor outgrowth through CTL tolerization after peptide vaccination is avoided by peptide presentation on dendritic cells. J Immunol 1998; 160:4449-4456. Bancehereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18:767-811.

Copyrighted Material

492 52. 53.

54.

55.

Moretti and Fabbri Romani N, Gruner S, Brang D, et al. Proliferating dendritic cell progenitors in human blood. J Exp Med 1994; 180:83-93. Calix C, Dezutter-Dambuyant C, Schmitt D, Bancherau J. GM-CSF and TNF-a cooperate in the generation of dendritic Langerhans cells. Nature 1992; 360:258261. Mackensen A, Herbst B, Chen JL, et al. Phase 1 study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34 + hematopoietic progenitor cells. Int J Cancer 2000; 86:385-392. Bancherau J, Palucka AK, Dhodapkar M, et al. Immune and clinical responses in patients with metastatic melanoma to CD34 + progenitor-derived dendritic cell vaccine. Cancer Res 2001; 61:6451-6458.

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Index

Acquired hypomelanoses, 381-388 chemical substance-induced, 383-384 in internal disease/disorders, 386 postinfectious, 382-383 postinftammatorY,382-383 as sequelae of physical effects, 384-386 therapy, 386-387 Adrenergic system, calcium and, 128 Albinism, 433-436, 461-472 albinism-Griscelli syndrome, 468-469 albinoidism,468 brown OCA, 466 Chediak-Higashi syndrome, 467-468 clinical features of, 464-467 Cross syndrome, 468 Hermanski-Pudlak syndrome, 467 OCA 1A, 464-465 OCA2, 465-466 OCA3 tyrosinase-related protein-Irelated OCA, 466-467 ocular, 436, 467 oculocutaneous, 434-436 partial, with immunodeficiency. See Griscelli-Prunieras syndrome phenotypes, 464 quality of life with, 469-470 Albinoidism, 436, 468 Alezzandrini's syndrome, 377-380

Alternative treatments for vitiligo, 285-292 Ayurvedic medicine, 289-290 balneological therapy, 290-291 climatological therapy, 290-291 homeopathy, 289 khellin, 286-288 L-phenylalanine, 285-286 melagenina, 288 minoxidil, 288-289 ultraviolet A, 286-288 Analytical epidemiology, vitiligo, 28-29 Ancient references to vitiligo, 15-17 Ancient treatments of vitiligo, 18-19 Angelicine, 267 Angelman syndrome, 439 Anthropological aspects of vitiligo implications of, 22-23 self-image, 20-22 Antibody action in vitiligo, 81-82 Antigens, targeted by autoimmune reactions in vitiligo, 83-86 Antioxidant system, components of, 125 biopterin metabolism, 126-127 calcium, adrenergic system, 128 catecholamine synthesis, 128 epidermal behavior modification, 129 H202 in epidermis, 126

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493

Index

494 [Antioxidant system, components of] MSH, 128-129 thioredoxin red uctase, 126 Anti-pigment cell immune responses, melanocytes and, 86-87 Application methods, cover-ups, 356-357 Audiological disorders in vitiligo, 201-206. See also Deafness A utocytotoxic hypothesis, 103-105 factors supporting, 103 Autoimmunity, 79-92, 189-200 autoimmune disease, 191-194 cutaneous abnormalities, 180-190 endocrine disorders, autoimmune, in healthy relatives of vitiligo patients, 56 genetic susceptibility to autoimmune disorders, 53-54 hypothesis of pathogenesis of vitiligo, 7-8, 46-47, 99-102.138 organ disorders, 190-191 rare associations, 194-195 Autologous transplantation, 241-244 Ayurvedic medicine, 289-290 Balneological therapy, 290-291 Biblical references to vitiligo, 18 Bilateral segmental vitiligo, 163-165 Biology of hypopigmentation, 33-50 congenital alteration of pigmentation, 33-42 etiological factors, 34-35 melanocyte development, disorders of,40 melanosome biogenesis, disorders oC 38 melanosome melanization, disorders of,39 melanosome transport/transfer, disorders of, 37 110ncongenital alteration of pigmentation, 42 vitiligo, 42-43 immunological abnormalities in, 47 metabolic abnormalities in, 43

[Biology of hypopigmentation] pathogenesis. See Pathogenesis white patches, dermatological diseases characterized by, 36-37 Biopterin metabolism, 126-127 Bleaching agents, 244-245 Blue vitiligo, 171 Broadband ultraviolet-B, 238-239 Calcium, adrenergic system and, 128 Camouflage, skin, 352-354. See also Cover-ups permanent, 352 temporary, 352, 354-356 cover-ups for, 354-356 Cancer risk, with phototherapy, 239-240 Catecholamine metabolism, 70 Catecholamine synthesis, 128 Cellular immunity, 111 pathogenesis of vitiligo, 83 Chediak-Higashi syndrome, 437-438, 467-468,473-478 clinical features, 474-475 definition, 473 genetic mutation analysis, 474 laboratory investigations, 475 pathogenesis of vitiligo, hypotheses, 473 treatment, 475-476 Chemical agents for depigmentation, 360-362 4-methoxyphenol, 362 monobenzylether of hydroquinone, 360 Chemical leukoderma, in differential diagnosis for vitiligo, 211-213 Chemical substance-induced hypomelanoses, 383-384 Children, vitiligo in, 173-178 clinical features, 174 differential diagnosis, 174 prognosis, 177 trea tmen t, 174-177 Cleansers, 356 Climatological therapy, 290-291

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Index

495

Clinical variants of vitiligo, 159-172 bilateral segmental vitiligo, 163-165 blue vitiligo, 171 raised borders, vittligo with, 170-171 segmental vitiligo, 160-163 trichrome vitiligo, 165-170 "Cobblestoning," 308 Compact foundation, use as cover-up, 355 Congenital alteration of pigmentation, 33-42 Corticosteroids, 240-241, 271-280, 336-337 combination therapies, 277 intralesional steroids, 274 systemic steroids, 274-277 topical, 271-274, 336-337 Cosmetologist view of cover-ups, 347-350 Cover creams, 348 Cover-ups application methods, 356-357 cleanser, 356 compact foundation, 355 cosmetologist view, 347-350 cover creams, 348 dermatologist View, 351-358 fixing spray, 355 liquid foundation, 355 pressed powder, 355 self-tanning products, 348-349, 355-356 side effects, 357-358 skin camouflage, 352-354 permanent, 352 temporary, 352, 354-356 stick foundation, 355 Cross syndrome, 438, 468 Cryotherapy, for depigmentation, 363 Cutaneous diseases, vitiligo and, 182-183 Cutaneous oxidative stress in vitiligo, 124-129 Cutaneous scleroderma, in differential diagnosis for vitiligo, 216-217

Deafness, 457 Definitions of vitiligo, 18 Depigmentation, 80, 244-245, 359-364 chemical agents, 360-362 4-methoxyphenol, 362 monobenzylether of hydroquinone, 360 cryotherapy, 363 indications for, 359-360 methods, 360-363 pattern, in vitiligo, 4-7 Q-switched ruby laser, 362-363 Dermatologist view of cover-ups, 351-358 Differential diagnosis for vitiligo, 207-224 chemical leukoderma, 211-_13 cutaneous scleroderma, 216-217 halo nevus, 213-214 idiopathic guttate hypomelanosis, 213 leprosy, 217-219 lichen sclerosus et atrophicus, 217 mycosis fungoides, 217 nevus anemicus, 215-216 nevus depigmentosus, 214-215 piebaldism, 221 pinta, 219-220 pityriasis alba, 211 postinflammatory hypopigmentation, 209-210 sarcoidosis, 217 tinea versicolor. 209 Doppler flowmetry, 94-95 use of in vitiligo, 95-98 Ear, in vitiligo, 204-205 Ear melanocytes, 204 Eclectic hypothesis, 106-114 pathogenesis of vitiligo, 106-114 8-MOP, topical, systemic, 266 Elejalde syndrome, 438 Emotions in vitiligo, 225-234 Endocrine disorders, vitiligo and, 180-182 polyglandular syndrome, 181

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Index

496 [Endocrine disorders, vitiligo and] thyroid disease, 180-181 Epidemiology of vitiligo, 20-30, 27-32 analytical epidemiology, 28-29 clinical epidemiology, 20-30 descriptive epidemiology, 27-28 pathological conditions associated with, 29 Epidermal behavior modification, 129 Epidermal calcium homeostasis, 71-72 Epidermal catalase, H 2 0 2 accumulation in vitiligo, 66-67 Epidermal cytokines in achromic lesional skin, semiquantitative expression of, 108 in perilesional skin, semiquantitative expression of, 108 Epidermal metabolic abnormalities in vitiligo, 43 Epidermal receptors, expression of, 109 Etiological factors in hypopigmentary disorders, 34-35 Excimer laser, 263 Experimental evidence, systemic oxidati ve stress, 129-130 Eye, in vitiligo, 202-204 Family history of vitiligo, 51, 54-57. See also Genetics 5-MOP, topical, systemic, 266 Fixing spray, 355 Fluticasone propionate, with ultraviolet-A therapy, 245-246 Focused microphototherapy, 246. See also Microphototherapy Free radical damage, 123-136 antioxidant system, components of, 125 biopterin meta bolism, 126-127 calcium, adrenergic system, 128 catecholamine synthesis, 128 epidermal behavior modification, 129 H 2 0 2 in epidermis, 126 MSH,128-129 thioredoxin red uctase, 126

[Free radical damage] cutaneous oxidative stress in vitiligo, 124-129 systemic oxidative stress, experimental evidence, 129-130 Genetics, vitiligo, 51-64, 73-74, 102-103 Grafting cultured autologous melanocytes, 243-244 epidermal blisters, 243 follicular melanocytes, 247 noncultured melanocyte suspension, 244 tissue-engineered skin, 315-317 Griscelli-Prunieras syndrome, 438 Guttate hypomelanosis, idiopathic, 389-392 clinical features, 389 pathology, 390-391 treatment, 391 vitiligo pathogenesis, hypotheses, 391 H 20 2 accumulation in vitiligo, 44-46, 126 consequences of, 66-72 epidermal catalase, 66-67 glutathione peroxidase, 66-67 pterins, 67-70 Halo nevus, 369-376 clinical picture, 369-371 differential diagnosis, 373 in differential diagnosis for vitiligo, 213-214 epidemiology, 369-371 histology, 371-373 pathophysiology, 371-373 Hansen's disease. See Leprosy in differential diagnosis of vitiligo Healthy relatives of vitiligo patients, disorders in, 51-64 association of vitiligo with other disorders, 51-53 autoimmune disorders, genetic susceptibility to, 53-54

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Index

497

[Healthy relatives of vitiligo patients, disorders in] autoimmune endocrine disorders in, 56 family history, 51,54-57 incidence of various disorders in, 55 laboratory findings, 57-58 Hematological diseases, vitiligo and, 182 Hermanski-Pudlak syndrome, 436-437, 467 Histopathology, vitiligo, 145-158 Historical overview of vitiligo, 15-26 achromic disorder, knowledge of, 3 ancient references to vitiligo, 15-17 ancient treatments of vitiligo, 18-19 biblical references to vitiligo, 18 definitions of vitiligo, J8 nineteenth century, knowledge of vitiligo, 19 Homeopathy, 289 Hydrosoluble vitamins, 282 Hyperpigmentation, 308 of nonaffected skin, during treatment, 336~337 Hypomelanosis, 419-432. See also Hypomelanotic disorders, inherited acquired, 381-388 chemical substance-induced, 383-384 in internal disease/disorders, 386 postinfectious, 382-383 postinfiammatorY,382-383 as sequelae of physical effects, 384-386 therapy, 386-387 diagnostic features, 420 genetics, 419-420 hypomelanotic macules, differential diagnosis of, 429 treatment, 429 Hypomelanosis ofIto, 415 Hypomelanotic disorders, inherited, 433-448 albinism, 433-436

[Hypomelanotic disorders, inherited] ocular, 436 oculocutaneous,434-436 variants of, 434 albinoidism,436 Angelman syndrome, 439 Chediak-Higashi syndrome, 437-438 Cross syndrome, 438 Elejalde synd rome, 438 Griscelli-Prunieras syndrome, 438 Hermanski-Pudlak syndrome, 436-437 piebaldism, 439 Prader-Willi syndrome, 439 Tietz syndrome, 442 Vici syndrome, 439 Waardenburg's syndrome, 440-442 variants of, 440 Yemenite deaf-blind hypopigmentation syndrome, 443 Ziprkowski-Margolis syndrome, 443 Hypomelanotic macules clinical features of, 42J-429 histopathology of, 429 morphology, 424 number, 429 shape, 4_4 site, 424-428 size, 424 Hypopigmentation biology of, 33-50 congenital alteration of pigmentation, 33-42 etiological factors, 34-35 etiological factors of, 34-35 melanocyte development, disorders of,40 melanosome biogenesis, disorders of, 38 melanosome melanization, disorders of, 39 melanosome transport/transfer, disorders of, 37 noncongenital alteration of pigmentation, 42

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Index

498 [Hypopigmentation] vitiligo, 42-43 autoimmune pathogenesis, 46-47 hypothesized pa thogenetic mechanisms, 43 immunological abnormalities in, 47 metabolic abnormalities in, 43 metabolic pathogenesis of, 43-46 white patches, dermatological diseases characterized by, 36-37 Hypotheses regarding pathogenesis of vitiligo. See Pathogenesis of vitiligo Hypounpigmented alterations, with ocular diseases, 203 Idiopathic guttate hypomelanosis, 389-392 clinical features, 389 in differential diagnosis for vitiligo, 213 pathology, 390-391 treatment, 391 vitiligo pathogenesis, hypotheses, 391 Immune system. See also Autoimmunity; under specific disorders of abnormalities of, with vitiligo, 47, 83, 87 immunoneuroendocrine system involvement, 93-94 mechanisms of, in vitiligo, 86-88 Immunoneuroendocrine system involvement in vitiligo, 93-94 Infection with surgery, 308 Infectious diseases, vitiligo and, 183-184 Inherited hypomelanotic disorders, 433-448 albinism, 433-436 ocular, 436 oculocutaneous,434-436 variants of, 434 albinoidism,436 Angelman syndrome, 439

[Inherited hypomelanotic disorders] Chediak-Higashi syndrome, 437-438 Cross syndrome, 438 Elejalde syndrome, 438 Griscelli-Prunieras syndrome, 438 Hermanski-Pudlak syndrome, 436-437 piebaldism, 439 Prader-Willi syndrome, 439 Tietz syndrome, 442 Vici syndrome, 439 Waardenburg's syndrome, 440-442 variants of, 440 Yemenite deaf-blind hypopigmentation syndrome, 443 Ziprkowski-Margolis syndrome, 443 Internal disease/disorders, hypomelanoses in, 386 Internet, vitiligo resources available, 365-368 Intralesional steroids, 274 Intrinsic/genetic hypothesis, pathogenesis of vitiligo, 102-103 Keloids, 308 Khellin, 286-288 topical, oral, 266-267 Laser-doppler ftowmetry, 94-95 in vitiligo, 95-98 Laser therapy, 245 LDF. See Laser-doppler ftowmetry Leprosy in differential diagnosis of vitiligo, 217-219 Leukodermic syndromes, 457 Leukonychia, 393-402 Lichen sclerosus et atrophicus, in differential diagnosis for vitiligo, 217 Liposoluble vitamins, 282 Liquid foundation, use as cover-up, 355 L-phenylalanine, 72, 285-286 LS&A. See Lichen sclerosus et atrophicus Melagenina, 288 infrared and/or ultraviolet radiation with,247

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Index Melanization, disorders of, 39 Melanocyte anti-pigment cell immune responses, 86-87 development, disorders of, 40 ear, 204 growth, factors modulating, 107 immune damage to, 87-88 Melanocyte antibodies, association with, 81 Melanoma, vitiligo and, 479-484 Melanosome biogenesis of, disorders, 38 melanization of, disorders, 39 transport/transfer of, disorders, 37 Metabolic pathogenesis of vitiligo, 43-46 H 2 0 2 accumulation, 44-46 Methoxyphenol, 362 Microphototherapy, 263, 337 Microvessels, 93-98 immunoneuroendocrine system involvement, 93-94 Minigrafting, 241-242 Minoxidil, 288-289 Monobenzone. See Monobenzylether of hydroquinone Monobenzylether of hydroquinone, 360 MSH,128-J29 Mycosis fungoides, in differential diagnosis for vitiligo, 2 I7

499 [Nevus depigmentosus] clinical diagnosis, 416-417 in differential diagnosis for vitiligo, 214-215 differential features, 415 hypomelanosis of Ito, differential features, 415 segmental vitiligo, differential features, 415 treatment, 418 tuberous sclerosis, differential fea tures, 4 I 5 Nineteenth century knowledge of vitiligo during, 19 Nitric oxide in pathogenesis of vitiligo, 137-144 Noncongenital alteration of pigmentation, 42 Ocular albinism, 436, 467 Ocular disorders in vitiligo, 201-206 Ocular melanocytes, 20 I-202 Oculocerebral syndrome with hypopigmentation. See Cross syndrome Oculocutaneous albinism, 434-436 Organ disorders with vitiligo, 190-191 Oxidative stress, 71-72 Oxygen burst, 70-7 I Partial albinism with immunodeficiency. See Griscelli-Prunieras syndrome Pathogenesis of vitiligo autocytotoxic hypothesis, 9,103-105 factors supporting, 103 autoimmune hypothesis, 7-8, 99-102, 138 factors supporting, 100 confusion regarding, 1-3 eclectic hypothesis, 106-114 epidermal cytokines in achromic lesional skin, semiquantitative expression of, 108 epidermal cytokines in perilesional skin, semiquantitative expression of, 108 epidermal receptors, expression of,

NADPH oxidase, 70-71 Narrowband ultraviolet-B, 235-237, 262-263, 325-334 doses, 327 equipment,327-328 microphototherapy, 329-333, 337 Natural history of vitiligo, 20-30 Neural hypothesis, 105-106 factors supporting, 105 pathogenesis of vitiligo, 105-106 Neurological diseases, vitiligo and, 182 Nevus anemicus, in differential diagnosis for vitiligo, 2 15-216 Nevus depigmentosus, 413-4 I8 Copyrighted MatelMJ

Index

500 [Pathogenesis of vitiligo] free radical damage in, 123-136 idiopathic guttate hypomelanosis hypothesis, 391 intrinsic/genetic hypothesis, 8-9, 102-103 mechanisms of, 43 melanocyte growth, factors modulating, 107 metabolic, 43--46 H 2 0 2 accumulation, 44--46 neural hypothesis, 9-10, 105~106 factors supporting, 105 nitric oxide in, 137-144 present knowledge of, 3 surgical solutions, 294 Pathological conditions associated with vitiligo, 29 Perilesional skin, epidermal cytokines in, semiquantitative expression of,108 Permanent skin camouflage, 352 Personality in vitiligo, 225-234 Phenylketonuria, characteristics of, 441 Phenylalanine, oral, 267-268 Phototherapy, 240, 246, 262-265, 325334,337. See also Ultraviolet; specific type of phototherapy agents used in, 264 cancer risk with, 239-240 psoralen, 253-260 Piebaldism, 439, 449--460 clinical features, 449--451 in differential diagnosis, 221,454--456 pathology, 451--452 treatment, 456-457 Pigmentation congenital alteration of, 33--42 noncongenital alteration of, 42 Pinta, in differential diagnosis for vitiligo, 219-220 Pityriasis alba, in differen tial diagnosis for vitiligo, 211 Postinfectious hypomelanoses, 382-383 Postinflammatory hypomelanoses, 382-383 C ' ht d

opyng e

Postinflammatory hypopigmentation, in differential diagnosis for vitiligo, 209-210 Prader-Willi syndrome, 439 Present knowledge of pathogenesis of vitiligo, 3. See also Pathogenesis of vitiligo Pressed powder, use as cover-up, 355 Prognosis of vitiligo, 20-30 in children, 177 Pseudocatalase, ultraviolet-B therapy and,246 Psoralen photochemotherapy, 253~260 combination therapy, 255-256 efficacy of, 256-258 pretreatment assessment, 254 side effects, 258-259 treatment protocols, 254-255 ultraviolet-A,237-238 Psycho-anthropological aspects of vitiligo implications of, 22-23 self-image, 20~22 Pterins, H 2 0 2 accumulation in vitiligo, 67-70 QSR. See Q-switched ruby laser Q-switched ruby laser, for depigmentation, 362-363

M

Raised borders, vitiligo with, 170-171 Research studies, 65-78 catecholamine metabolism, 70 epidermal calci um homeostasis, 71-72 H 2 0 2 accumulation in vitiligo, 66 consequences of, 66-72 epidermal catalase, 66~67 glutathione peroxidase, 66-67 pterins, 67-70 L-phenylalanine turnover, 72 NADPH oxidase, 70-71 oxidative stress, 71-72 oxygen burst, 70-71 skin cancer, 73 tyrosinase-related protein- I, 71 viral infections, 72-73 t vitijigo gene, 73-74

a ena

Index

Sarcoidosis, in differential diagnosis for vitiligo, 217 Scan'i ng, 308 Scientific publications, dedicated to vitiligo. 366 Segmental vitiligo, 160-163,415 Self-image, vitiligo and, 20-22 Self-tanning products, 348-349, 355-356 Skin camouflage, 352-354. See also Cover-ups permanent, 352 temporary, 352, 354-356 Skin cancer, 73 Steroids. See also Corticosteroids intralesional, 274 systemic, 274-277 Stick foundation, use as cover-up, 355 Substance-induced hypomelanoses, 383-384 Surgical treatment of vitiligo. See also under specific surgical procedure artificial ultraviolet exposure, following treatment, 306-307 candidate selection, 295-299 difficult-to-treat areas. 299 methods, 299-306 repigmentation process, 295 side effects, 307-308 sunlight exposure, following treatment, 306-307 surgical combination therapy, 299 Systemic antioxidant therapy, -47 Systemic steroids, 274-277

501

(Therapeutic guidelines] cultured autologous melanocytes, 243-244 epidennal bJisters, 243 follicular melanocytes, 247 noncul tured melanocyte suspension, 244 laser therapy, 245 melagenina, infrared and/or ultraviolet radiation with, 247 minigrafting, 241-242 narrowband ultraviolet-B, 235-237 nonsurgical repigmentation therapies, 235-241 novel therapeutic approaches, 245-247 phototherapy. 240 cancer risk of, 239-240 pseudocatalase, ultraviolet-B therapy and, 246 psoralen plus ultraviolet-A, 237-238 systemic antioxidant therapy, 247 thin split-thickness skin grafting, 242-243 Thin split-thickness skin grafting, 242-243 Thioredoxin reductase, 126 Tietz syndrome, 442 Tinea versicolor, in differential diagnosis for vitiligo, 209 Tissue-engineered skin. 313-322 cultures, 314-315 grafting procedure, 315-317 TMP, 265-266 Temporary skin camouflage, 352 Topical corticosteroids, 271-274, cover-ups for, 354-356 336-337 Therapeutic guidelines, 235-252 Trichrome vitiligo, 165-J 70 autologous transplantation methods, TRP-I. See Tyrosinase-related protein-I Tuberous sclerosis, 415, 419-432 241-244 bleaching agents, 244-245 characteristics of, 441 broadband ultraviolet-B, 238-239 clinical features of, 420-42J corticosteroids, 240-241 diagnostic criteria, 421 depigmentation therapy, 244-245 diagnostic features, 420 differential features, 415 fluticasone propiona te, with ultraviolet-A therapy, 245-246 genetics, 419-420 focused micro phototherapy, 246 treatment. 429 grafting CopyrighteJM~llf?1tm-relatedprotein-I, 71

Index

502 Ultrastructural features of vitiligo, 145-158 Ultraviolet A, 286-288 Ultraviolet B, 341-346 Vaccines, 485-492 Vici syndrome, 439 Viral infections, 72-73 Vitamins, 281-284 Vitiligo, 42-43 alternative treatments, 285-292 audiological disorders in, 201-206 autoimmunity, 79-92, 189-200 in children, 173-178 clinical associations, 179-188 clinical varia nts, 159-172 corticosteroids, 271-280 cover-ups for, 347-350, 351-358 depigmentation, 359-364 differential diagnosis, 207-224 disorders in healthy relatives, 51-64 emotional aspects of, 225-234 epidemiology, 27-32 free radical damage, 123-136 histopathology, 145-158 historical overview of, 15-26 immunological abnormalities in, 47 internet, 365-368 melanoma and, 479-484 metabolic abnormalities in, 43 microvessels, 93-98 narrowband, 235-237, 262-263, 325-334, 337 nature of, as disease, symptom, 1-15 nitric oxide in, 137-144 nonsurgical solutions, 335-340 ocular disorders in, 201-206 pathogenesis of. See Pathogenesis of vitiligo

[Vitiligo] personality and, 225-234 photosensitizing substances, 261-270 prognosis, 20-30 in children, 177 psoralen photochemotherapy in, 253-260 psycho-anthropological aspects of, 15-26 rare associations, 189-200 surgery, 293-312 therapeutic guidelines, 235-252 tissue-engineered skin treatment, 313-322 ultrastructural, 145-158 ultraviolet, 261-270 ultraviolet A, 286-288 ultraviolet B, 325-334, 341-346 vaccines and, 485-492 vitamins, 281-284 Vitiligo gene, 73-74 Vogt-Koyanagi -Harada synd rome, 403-412 diagnostic criteria, 406 revised, 407-408 Waardenburg's syndrome, 440-442, 456 variants of, 440 Warburg's syndrome. See Yemenite deaf-blind hypopigmentation syndrome Web pages, dedicated to vitiligo, 366 White patches, dermatological diseases characterized by, 36-37 Yemenite deaf-blind hypopigmentation syndrome, 443 Ziprkowski-Margolis syndrome, 443

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