Digestive Involvement in Systemic Autoimmune Diseases (Handbook of Systemic Autoimmune Diseases, Volume 8)

Handbook of Systemic Autoimmune Diseases Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Handbook of ...

Author: Manel Ramos-Casals | Joan Rodes | Josep Font | Ronald Asherson

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Handbook of Systemic Autoimmune Diseases Volume 8

Digestive Involvement in Systemic Autoimmune Diseases

Handbook of Systemic Autoimmune Diseases Series Editor: Ronald A. Asherson

Volume 1

The Heart in Systemic Autoimmune Diseases Edited by: Andrea Doria and Paolo Pauletto

Volume 2

Pulmonary Involvement in Systemic Autoimmune Diseases Edited by: Athol U. Wells and Christopher P. Denton

Volume 3

Neurologic Involvement in Systemic Autoimmune Diseases Edited by: Doruk Erkan and Steven R. Levine

Volume 4

Reproductive and Hormonal Aspects of Systemic Autoimmune Diseases Edited by: Michael Lockshin and Ware Branch

Volume 5

The Skin in Systemic Autoimmune Diseases Edited by: Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni and Annegret Kuhn

Volume 6

Pediatrics in Systemic Autoimmune Diseases Edited by: Rolando Cimaz and Thomas Lehman

Volume 7

The Kidney in Systemic Autoimmune Diseases Edited by: Justin C. Mason and Charles D. Pusey

Volume 8

Digestive Involvement in Systemic Autoimmune Diseases Edited by Josep Font, Manuel Ramos-Casals, and Juan Rode´s

Handbook of Systemic Autoimmune Diseases Volume 8

Digestive Involvement in Systemic Autoimmune Diseases Edited by:

Josep Fontw Department of Autoimmune Diseases, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

Manuel Ramos-Casals Laboratory of Autoimmune Diseases ‘‘Josep Font’’, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

Juan Rode´s Liver Unit, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain Series Editor

Ronald A. Asherson

Amsterdam – Boston – Heidelberg – London – New York – Oxford Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands Linacre House, Jordan Hill, Oxford OX2 8DP, UK

First edition 2008

Copyright r 2008 Elsevier B.V. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [email protected]. Alternatively you can submit your request online by visiting the Elsevier web site at http://www.elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent veriﬁcation of diagnoses and drug dosages should be made Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-444-53168-1 ISSN: 1571-5078 For information on all Elsevier publications visit our website at books.elsevier.com

Printed and bound in The Netherlands 08 09 10 11 12

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Dedication

This book is one of the last projects led by Josep Font before his unexpected death, and the remaining Editors wish to dedicate these lines as a means of paying a deeply felt homage. Dr. Josep Font (Barcelona, 1953–2006) devoted his professional career to the care of patients with systemic autoimmune diseases (SAD). Dr. Font trained in Internal Medicine at the Hospital Clinic of Barcelona from 1978 to 1982 and obtained his PhD in 1984 for his thesis on systemic lupus erythematosus (SLE). His post-doctoral experience was closely linked with the Lupus Research Unit at St. Thomas’ Hospital in London. His research output was prodigious, with a total of over 500 scientiﬁc articles published in 25 years. In addition, he designed and coordinated many international projects including the Eurolupus, Europhospholipid, CAPS Registry, SS-HCV Registry, and HISPAMEC, and was an active member of some of the most prestigious international research groups such as the Eurolupus Nephritis Trial and the SLICC. In 1995, Josep Font created the Department of Autoimmune Diseases at the Hospital Clinic, a pioneering unit in Europe speciﬁcally dedicated to the clinical management of patients with SAD. Dr. Font played a leading role in creating a network of different specialists at the Hospital Clinic dedicated to the care of these patients. A key characteristic of his clinical research was its multidisciplinary design and the close collaboration between different medical specialities, of which this book is an excellent example. Josep Font was working actively until the last days of his life, and died like a soldier ‘‘with his boots on’’. His integrity, intelligence, and loyalty made him a formidable physician and a wonderful colleague and friend. He was undoubtedly one of the foremost ﬁgures in the ﬁeld of autoimmune diseases in recent decades, and the immense human and professional legacy that he leaves must be maintained and continued by all who had the great fortune to know and work with him. Manuel Ramos-Casals and Juan Rode´s

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Foreword I was pleased to be asked to write the Foreword for this new volume which aims to bring together knowledge on a group of auto-immune disorders involving the digestive tract with systemic involvement. It is surely going to be an important volume and one fulﬁlling a long-felt need by intensivists, rheumatologists, as well as hepatologists and gastroenterologists who are involved in the care of patients suffering from this fascinating group of disorders. Much is known about the nature of immunological reactions that underlie auto-immune disorders, with cytoxic CD8 T cells, NK cells, and b-cell auto-antibody production interacting in the disease process. However, what initiates these processes and gives rise to a particular organ or system involvement is still in most instances uncertain, involving as it may infectious agents, environmental toxins, and with an underlying constitutional predisposition. The overlap syndromes between them are particularly fascinating. Thus PBC and auto-immune hepatitis are usually quite distinct disorders in terms of clinical manifestations and in response to immunosuppressive therapy—highly effective in auto-immune hepatitis, little effect in primary biliary cirrhosis, yet occasional cases have features of both disorders. Primary sclerosing cholangitis in adults is characterised by a progressive ﬁbrosing obliteration of intra and extrahepatic bile ducts but in children there is often an initial phase of an auto-immune hepatitis-like picture with a response to corticosteroids. Arthropathies are common in auto-immune hepatitis and rheumatoid arthritis in primary biliary cirrhosis. Sjo¨gren’s syndrome too is a feature of PBC and there are many other overlap associations. However, lupid hepatitis which was the term applied—because of the ﬁnding of LE cells in the serum to what later became known as active chronic hepatitis and then presently auto-immune hepatitis, is not part of disseminated lupus erythematosus in which hepatic involvement is mild or non-existent. Separate chapters in the volume are devoted to the extrahepatic manifestations of chronic hepatitis consequent on HBV and HVC infection, including glomerulonephritis, thyroiditis, arthropathies, and attributable to the development of an auto-immune reactivity. One of the mechanisms involved maybe molecular mimicry in which antigens of external organisms, bacterial or viral which show homology with self-molecules trigger auto-immunity in an attempt to neutralise the infectious organisms. With outstanding editorship and the acknowledged expertise of the writing contributors this will be an exciting volume to read. Professor Roger Williams, CBE

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List of Contributors

Rupert Abdalian Division of Gastroenterology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, Ont., Canada

Salvatore De Vita Rheumatology Clinic, Azienda OspedalieroUniversitaria ‘‘S. Maria della Misericordia’’, DPMSC, University of Udine, Udine, Italy

Graciela S. Alarco´n Department of Medicine, Division of Clinical Immunology and Rheumatology, 510 20th Street South, FOT 830, The University of Alabama at Birmingham, Birmingham, AL 35294, USA

Luis Donoso Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain

Carmen Ayuso Radiology Department, Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, Abdomen Unit (CT and MRI), IDIBAPS, Villarroel 170, 08036 Barcelona, Spain John M. Cafardi Department of Medicine, Division of Clinical Immunology and Rheumatology, 510 20th Street South, FOT 830, The University of Alabama at Birmingham, Birmingham, AL 35294, USA Ricard Cervera Department of Autoimmune Diseases, Hospital Clı´ nic, Villarroel 170, 0836 Barcelona, Catalonia, Spain Roger Chapman Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK Albert J. Czaja Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA Lara Dani Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden

Gerard Espinosa Department of Autoimmune Diseases, Hospital Clı´ nic, Villarroel 170, 0836 Barcelona, Catalonia, Spain Gianfranco Ferraccioli Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy Xavier Forns Liver Unit, ICMD, Ciberehd, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain Elisa Gremese Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy Loı¨ c Guillevin Department of Internal Medicine, National Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Hoˆpital Cochin, Universite´ Paris 5 – Rene´ Descartes, 27 rue du faubourg Saint-Jacques, 75679 Paris cedex 14, France Jenny Heathcote Division of Gastroenterology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, Ont., Canada Iain R.L. Kean Biomedical Research Centre, Shefﬁeld Hallam University, Shefﬁeld S1 1WB, England, UK ix

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List of Contributors

Walter F. Kean Department of Medicine, McMaster University Faculty of Health Sciences, Suite #401, 1 Young Street, Hamilton, Ont., Canada L8N 1T8 Dinesh Khanna Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, 1000 Veterans Avenue, Rm 32–59, Rehabilitation Building, Los Angeles, CA 90095, USA Ingrid E. Lundberg Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden Michael P. Manns Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Giorgina Mieli-Vergani Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London SE5 9RS, UK Heiko Mix Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Josep Ordi-Ros Internal Medicine Department, Vall D’Hebron General Hospital, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain Mario Page´s Radiology Department, Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, Abdomen Unit (CT and MRI), IDIBAPS, Villarroel 170, 08036 Barcelona, Spain Christian Pagnoux Department of Internal Medicine, National Referral Center for Necrotizing Vasculitides and Systemic

Sclerosis, Hoˆpital Cochin, Universite´ Paris 5 – Rene´ Descartes, 27 rue du faubourg Saint-Jacques, 75679 Paris cedex 14, France Neophytos P. Papageorgiou Center for Autoimmune Diseases, Department of Medicine B, Chaim Sheba Medical Center (Afﬁliated to Tel-Aviv University), Tel-Hashomer 52621, Israel Luca Quartuccio Rheumatology Clinic, Azienda Ospedaliero-Universitaria ‘‘S. Maria della Misericordia’’, DPMSC, University of Udine, Udine, Italy K.D. Rainsford Biomedical Research Centre, Shefﬁeld Hallam University, Shefﬁeld S1 1WB, England, UK Herbert Rakatansky Department of Medicine, Division of Gastroenterology, Warren Alpert School of Medicine, Brown University Providence, RI, USA Manuel Ramos-Casals Laboratory of Autoimmune diseases ‘‘Josep Font’’, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain Juan Rode´s Liver Unit, ICMD, Ciberehd, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain Juanita Romero-Dı´ az Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Me´xico City, Me´xico Jorge Sa´nchez-Guerrero Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Me´xico City, Me´xico

List of Contributors

Jose-Maria Sanchez-Tapias Liver Unit, ICMD, Ciberehd, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

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Athanasios G. Tzioufas Department of Pathophysiology, School of Medicine, University of Athens, Greece

Albert Selva-O’Callaghan Internal Medicine Department, Vall D’Hebron General Hospital, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain

Diego Vergani Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London SE5 9RS, UK

Yehuda Shoenfeld Center for Autoimmune Diseases, Department of Medicine B, Chaim Sheba Medical Center (Afﬁliated to Tel-Aviv University), Tel-Hashomer 52621, Israel

Miquel Vilardell-Tarre´s Internal Medicine Department, Vall D’Hebron General Hospital, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain

Elke Theander Department of Rheumatology, Malmo University Hospital, Malmo, Sweden

Claudio Vitali Department of Internal Medicine and Rheumatology, Ospedale Villamaria, Piombino, Italy

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Contents Dedication Foreword List of Contributors

v vii ix

I Introduction Digestive System and Autoimmunity Heiko Mix, Michael P. Manns Imaging Techniques in Digestive Diseases Carmen Ayuso, Mario Page´s, Luis Donoso

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15

II Systemic Autoimmune Diseases Systemic Lupus Erythematosus Miquel Vilardell-Tarre´s, Albert Selva-O’Callaghan, Josep Ordi-Ros

31

Antiphospholipid Syndrome Gerard Espinosa, Ricard Cervera

39

Gastrointestinal Involvement in Systemic Sclerosis Dinesh Khanna

51

Inﬂammatory Myopathies Lara Dani, Ingrid E. Lundberg

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Digestive Involvement in Primary Sjo¨gren’s Syndrome Manuel Ramos-Casals, Elke Theander, Athanasios G. Tzioufas, Claudio Vitali

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Gastrointestinal Involvement in Systemic Vasculitis Salvatore De Vita, Luca Quartuccio, Elisa Gremese, Gianfranco Ferraccioli

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Mixed Connective Tissue Disease Juanita Romero-Dı´az, Jorge Sa´nchez-Guerrero

101

Gastrointestinal Manifestations of Rheumatoid Arthritis John M. Cafardi, Herbert Rakatansky, Graciela S. Alarco´n

109

III Autoimmune Liver Diseases Immunopathogenesis of Autoimmune Liver Damage Albert J. Czaja

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Contents

Primary Biliary Cirrhosis Rupert Abdalian, Jenny Heathcote

141

Autoimmune Hepatitis Diego Vergani, Giorgina Mieli-Vergani

153

Primary Sclerosing Cholangitis Roger Chapman

169

IV Autoimmunity and Viral Hepatitis Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection Christian Pagnoux, Loı¨c Guillevin

191

Extrahepatic Manifestations in Patients with Chronic Hepatitis C Virus Infection Manuel Ramos-Casals, Xavier Forns, Jose-Maria Sanchez-Tapias, Juan Rode´s

209

V Other Conditions Autoantibodies in Gastrointestinal Autoimmune Diseases Neophytos P. Papageorgiou, Yehuda Shoenfeld

231

Gastrointestinal Complications of Anti-Rheumatic Drugs K.D. Rainsford, Iain R.L. Kean, Walter F. Kean

243

Subject Index

277

Colour Plate Section

PART I:

Introduction

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 1

Digestive System and Autoimmunity Heiko Mix, Michael P. Manns Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

1. The digestive system and gut-associated immunity Mammals depend on feeding and digestion. While single-celled organisms can directly take in nutrients from their outside environment, multi-cellular organisms, with most of their cells removed from direct contact with the outside environment, have developed specialized structures for obtaining and breaking down their food. Large, complex molecules must be broken down into monomers that can then be distributed throughout the body to every cell. This vital function is accomplished by a series of specialized organs that comprise the digestive system. The human digestive system is a coiled, muscular tube about 6–9 m in length when fully extended, stretching from the mouth to the anus. Several specialized compartments occur along this length: mouth, pharynx, esophagus, stomach, small intestine, large intestine, and anus. Accessory digestive organs are connected to the main system by a series of ducts, including salivary glands, the pancreas, and the liver with the biliary system. Like the skin, the digestive tract is situated at the interface between external and internal milieus. In order to maintain homeostasis, physical and chemical mechanisms as elements of the innate immune response are utilized to protect against exogenous, potentially noxious agents. The

Corresponding author.

Tel.: +49-511-532-3305; Fax: +49-511-532-4896 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00001-3

membranes of the digestive tract provide a physical barrier against invading pathogens. A huge number of chemical factors, including low pH in the stomach, pepsin, lysozyme, anti-microbial substances like cryptidins and defensins, limit the growth and invasion of microorganisms (Dann and Eckmann, 2007) (Table 1). In addition to innate defense mechanisms, the digestive system is lined by mucosal lymphatic tissues. It consists of diffuse lymphocytic inﬁltrates throughout the epithelium and lamina propria of the mucosa or nonencapsulated lymphoid nodules in the submucosa of the intestinal tract. Peyer’s patches are the prototypical mucosal lymphatic tissue, specialized to sample environmental antigens. The Peyer’s patches contain lymphoid compartments that are analogous to the cortex and follicles of lymph nodes. Each follicle is covered by a single-layered follicle-associated epithelium, and a more diffuse area immediately below, called subepithelial dome. The follicle-associated epithelium is interrupted by specialized membraneous cells (M cells) that have luminal microfolds instead of microvilli and lack the normal thick layer of mucus. The M cells differentiate from enterocytes under the inﬂuence of membranebound lymphotoxin-a1b2 present on local lymphoid cells (Debard et al., 2001; Kerne´is et al., 1997; Golovkina et al., 1999). These cells endocytose and transport various materials (Nicoletti, 2000). Antigen is delivered to lymphocytes, mononuclear phagocytes, and dendritic cells immediately beneath M cells. The germinal centers contain B cell blasts, follicular dendritic cells, macrophages, and

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Table 1 Mechanisms to minimize self-reactive lymphocyte differentiation and activation Clonal deletion

Induction of apoptosis by inhibition of pro-survival pathways (BIM induction) or by activation of death receptors (FAS activation)

Receptor editing

Receptor editing through V(D)J recombination in primary lymphatic tissues (in T cells and B cells) or by somatic hypermutation in secondary lymphatic tissues (in B cells)

Clonal anergy and tuning

Intrinsic regulation by B or T cell receptor downregulation Induction of inhibitory receptors (CD5, CTLA4) Induction of phosphatases (SHP1, SHIP) Induction of ubiquitin ligases (cbl, GRAIL, Itch, Roquin)

Extrinsic regulation

Limitation of survival factors (BAFF, IL-7) Limitation of costimulation (CD40L, TLR ligands, B7 molecules) Active suppression (regulatory T cells)

unique T cells. B cells undergo immunoglobulin class switching from expression of IgM to IgA under the inﬂuence of several local factors, including transforming growth factor-b (TGF-b), interleukin-10 (IL-10), and other cellular signals that are delivered by dendritic cells and T cells (McIntyre and Strober, 1999). Lymphocytes exit the Peyer’s patches through the draining lymphatics to the mesenteric lymph nodes, from where they migrate into the bloodstream and ﬁnally home to the mucosa. The exit of lymphocytes from the bloodstream into the mucosa is mediated by loss of L-selectin expression and selective upregulation of a4b7 integrin. The ligand for a4b7 integrin, mucosal addressin cell-adhesion molecule 1 (MADCAM1), is highly expressed by the vasculature of mucosal surfaces and mediates the emigration from the bloodstream (Butcher et al., 1999). In addition, expression of the chemokine receptor CCR9 is induced in gut-derived T cells, allowing them to respond to the chemokine CCL25, which is exclusively expressed by small-bowel epithelial cells (Bowman et al., 2002; Campbell and Butcher, 2002). In contrast, T cells primed in peripheral lymphoid organs acquire the a4b1 integrin very late antigen 4 (VLA4) and the chemokine receptor CCR4 and do not migrate to mucosal surfaces (Campbell and Butcher, 2002). Lymphocytes that home into the mucosa of the gut redistribute into distinct compartments. IgAproducing plasma cells remain in the lamina propria. CD4+ T cells are distributed more evenly

throughout the villus–crypt unit within the lamina propria. CD8+ T cells preferentially reside in the epithelium. A memory phenotype of CD4+ and CD8+ T cells predominates in both the epithelium and the lamina propria, indicating that the cells have been exposed to antigen. CD4+ T cells in the lamina propria are of particular importance to local immune regulation. They produce large amounts of cytokines, particularly interferon-g (IFN-g), but also IL-4 and IL-10 (Braunstein et al., 1997; Carol et al., 1998; Hurst et al., 1999). Lamina propria CD8+ T cells can have potent cytotoxic T lymphocyte (CTL) activity (Lefranc- ois et al., 1999). Many of the properties of the lamina propria CD4+ T cells are similar to those of regulatory T cells in other systems (Read and Powrie, 2001; Shevach, 2002). The unresponsiveness of lamina propria T cells to commensal bacteria can be reversed by the depletion of IL-10 or TGF-b (Khoo et al., 1997). Mesenteric lymph nodes have a crucial role in the induction of mucosal immunity and tolerance. Antigen recognition in the mesenteric lymph nodes occurs within a few hours of feeding protein antigen (Gu¨tgemann, 1998; Van Houten and Blake, 1996; Blanas et al., 2000; Lee et al., 2000). More importantly, induction of oral tolerance is not possible in lymphotoxin-a-deﬁcient or lymphotoxin-a-deﬁcient TNF-deﬁcient mice, which lack mesenteric lymph nodes (Spahn et al., 2002). Furthermore, total and speciﬁc IgA-antibody responses are absent in mice lacking mesenteric

Digestive System and Autoimmunity

lymph nodes, while responses to parenterally administered antigens are preserved in these mice (Kang et al., 2002; Yamamoto et al., 2000). Generally, immune responses to most tissue antigens are initiated in the draining lymph nodes. Recent evidence has suggested that naı¨ ve intestinal T cells ﬁrst encounter antigen in the mesenteric lymph nodes and not in Peyer’s patches (MacPherson and Liu, 1999; Huang et al., 2000). While priming of T cells selectively in Peyer’s patches would lead to efﬁcient local immune responses or tolerance, priming of T cells in the mesenteric lymph nodes could explain the fact that intestinal antigens are able to induce systemic immunity or tolerance. Peyer’s patches harbor distinctive subsets of dendritic cells, which have unusual phenotypic and functional characteristics (Ruedl et al., 1996). Conventional subsets of CD8a CD11b+ (myeloid) and CD8a+CD11b (lymphoid) dendritic cells are present next to a large number of CD8a CD11b dendritic cells. Currently, little information is available about this subset of dendritic cells. They can be found outside the organized lymphoid areas, especially in the dome region, which is immediately beneath the follicle-associated epithelium, together with CD8a CD11b+ dendritic cells. Their presence is dependent on the production of macrophage inﬂammatory protein 3a (MIP3a), or CCL20, by local epithelial cells (Iwasaki and Kelsall, 2000, 2001). The predominant CD8a CD11b+ dendritic cell subset is distinctive in that it secretes IL-10. Interestingly, after ligation of the costimulator molecule receptor activator of NF-kB (RANK), the dentritic cells of Peyer’s patches respond by secretion of IL-10. Outside Peyer’s patches, i.e. in the spleen, the same conditions result in the production of IL-12 (Williamson et al., 2002). Dendritic cells in Peyer’s patches are also able to stimulate antigen-speciﬁc T cells to produce T helper type 2 (TH2) cytokines and IL-10. Collectively, these observations underscore an important role of Peyer’s patch dendritic cells in maintaining a state of tolerance against food antigens and commensal bacteria in the digestive system. In addition, intestinal epithelial cells (IECs) have recently been identiﬁed as key elements in the development and regulation of mucosal

5

immunity (Zaph et al., 2007). These cells have been implicated in the regulation of innate immunity and chronic inﬂammation before (Neish et al., 2000; Rimoldi et al., 2005); however, supporting data from in vivo experiments were lacking. The authors could show that mice, deﬁcient in IkB kinase-b (IKK-b), produce reduced levels of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin. The mice were unable to mount an efﬁcient CD4+ TH2 response against the parasite Trichuris. Severe intestinal inﬂammation was the result of exacerbated dendritic-cell-derived IL-12/23p40 and tumor necrosis factor-a production, as well as increased levels of CD4+ T-cell-derived IFN-g and IL-17. The results were proof that the balance of IKK-bdependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis in addition to established pathways involved in pathogen recognition and initiation of immune responses in the gastrointestinal tract, which include M cells and specialized dendritic cell subsets that directly sample the luminal environment. The nervous innervation of the gastrointestinal tract is extensive, including Peyer’s patches, and the diversity of adrenergic, cholinergic, and peptidergic nerve endings in patches is greater than for any other peripheral lymphatic tissue. Noradrenergic ﬁbers form interfollicular plexuses that ramify through the diffuse T-dependent areas near high endothelial venules (HEV). It is likely that the extensive innervation of Peyer’s patches is involved in regulating trafﬁc and reactivity of mucosal immune cells. The nervous system, through the vagus nerve, was shown to signiﬁcantly and rapidly inhibit the release of macrophage-derived tumor necrosis factor-a, thereby attenuating systemic inﬂammatory responses (Borovikova et al., 2000; Bernik et al., 2002; Tracey, 2002). It could be demonstrated that this cholinergic anti-inﬂammatory pathway of acetylcholine-mediated vagus nerve signals was mediated via the nicotinic acetylcholine receptor a7 subunit (Wang et al., 2003). The liver as a member of the accessory digestive organs plays an important role in systemic immunity (Racanelli and Rehermann, 2006). It contains large amounts of professional antigen-presenting

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cell, including liver sinusoidal endothelial cells, Kupffer cells, and dendritic cells. Potential antigen-rich blood is ﬁltered and pathogens are quickly eliminated by phagocytes or by the huge population of natural killer cells or natural killer T cells present in liver. The liver has a high capacity to induce antigen-speciﬁc tolerance. It acts as a central regulator in systemic immune responses by synthesizing and secreting acute-phase proteins and other mediators.

2. Self-tolerance and autoimmunity Adaptive immune responses are essential for normal health. In some cases, adaptive immune responses are elicited by antigens not associated with infectious agents. The responses are essentially identical to adaptive immune responses to infectious agents; however, the antigens are different. Autoimmunity is the response to selfantigens in the absence of infection. The mammalian immune system is able to mount a response to any chemical structure imaginable. B cells and T cells express receptors with huge receptor diversity able to achieve speciﬁcity that differentiates molecules at the atomic level. This huge receptor diversity is encoded in the mammalian genome and is possible through two processes of somatic genome modiﬁcation that occurs selectively in lymphocytes. In central lymphoid organs, i.e. bone marrow for B cells and the thymus for T cells, V(D)J recombination assembles unique receptor genes for B and T cells. In peripheral lymphoid tissues, B cell receptor genes can further be modiﬁed by singlenucleotide substitutions through somatic hypermutation. The random processes of V(D)J recombination and somatic hypermutation generate huge amounts, i.e. between 20 and 50%, of self-reactive B cells and T cells (Ignatowicz et al., 1996; Zerrahn et al., 1997; Laufer et al., 1996; Wardemann et al., 2003). Remarkably, only 3–8% of the population develops an autoimmune disease (Jacobson et al., 1997). Currently, four mechanisms have been identiﬁed that limit the number of self-reactive lymphocytes.

First, clonal deletion is used to trigger apoptosis of cells with self-reactive receptors. Second, cells with self-reactive receptors can edit their speciﬁcity by further V(D)J recombination or somatic hypermutation until the receptor does not bind to selfantigens (Nemazee and Hogquist, 2003). Third, clonal anergy or tuning is the unresponsiveness of cells to signals from self-reactive receptors by changes in intrinsic biochemical processes and gene expression (Healy and Goodnow, 1998; Schwartz, 2003; Grossman and Paul, 2000). Collectively, these ﬁrst three mechanisms are called immunologic ignorance. When cells have evaded all the three mechanisms, extrinsic controls can limit the potential of an autoimmune response by limiting the supply of growth factors, costimuli, pro-inﬂammatory mediators and other factors, or through active suppression by regulatory T cells.

3. Tolerance mechanisms for autoreactive B cells in the bone marrow A series of events has been identiﬁed that occurs if an immature B cell displays a self-reactive receptor in the bone marrow. The immature B cell internalizes the self-reactive receptor when the strength of receptor crosslinking and intracellular signaling exceeds a certain threshold (Hartley et al., 1993; Fields and Erikson, 2003). As a result, homing receptors like CD62 ligand (CD62L), required to enter the lymph nodes, are not expressed (Hartley et al., 1993). In addition, B-cell-activating factor (BAFF) receptors are only poorly induced (Mackay et al., 2003). BAFF is required to sustain peripheral B cell survival. Furthermore, recombination-activating gene 1 (RAG1) and RAG2, which encode the core enzymes for V(D)J recombination, continue to be expressed, allowing further editing of B cell receptors by rearranging a replacement B cell receptor light chain (Jankovic et al., 2004). If the receptor cannot be edited to be less self-reactive, cell death is induced, either by withdrawal of growth factors and/or through increasing levels of BCL-2-interacting mediator of cell death (BIM), a pro-apoptotic factor that inhibits essential B cell

Digestive System and Autoimmunity

survival proteins of the BCL-2 family (Strasser and Bouillet, 2003). Interestingly, BIM-deﬁcient mice spontaneously produce anti-DNA autoantibodies (Strasser and Bouillet, 2003).

4. Tolerance mechanisms for autoreactive T cells in the thymus While B cells are designed to recognize native antigen, T cell receptors bind to peptide fragments of antigen displayed on MHC molecules. An array of self-peptides is displayed on cortical thymic epithelial cells, and T cells that weakly bind to these ligands receive maturation signals that inhibit further RAG gene expression. They increase the level of surface receptor expression and upregulate homing receptors for chemokines found in the thymic medulla and the peripheral lymphoid tissues. This so-called positive selection is unique to the thymic cortical epithelium. Selfreactive T cells are further edited by downregulating the self-reactive receptor, and RAG expression continues until the self-reactive T cell receptor a-chain is replaced with another, less self-reactive chain. In the thymic medulla, the process of testing for self-reactivity continues with the help of medullary thymic epithelial cells and dendritic cells. The cells in the medulla express costimulatory molecules, including CD80 (B7.1) and CD86 (B7.2), the ligands for CD28. Here, T cell receptors that bind strongly to self-peptide-MHC complexes are triggered to induce cell death (negative selection). In animals, deﬁcient in this process either through lack of medullary MHC expression or B7 expression, huge amounts of self-reactive T cells reach the periphery, causing pathologies resembling graft-versus-host disease (Gao et al., 2002). It can be speculated that the well-established association between particular MHC molecules and susceptibility to speciﬁc autoimmune diseases may stem from inefﬁcient presentation of particular selfpeptides during this phase of T cell receptor deletion (Kanagawa et al., 1998; Wicker et al., 1995).

7

Negative selection requires the tyrosine kinase x-chain-associated protein kinase of 70 kDa (ZAP70). Mice deﬁcient in ZAP70 develop a systemic inﬂammatory disorder resembling rheumatoid arthritis (Sakaguchi et al., 2003). In addition, the following factors have been identiﬁed as being essential for negative selection: growthfactor-receptor-bound (GRB) protein 2 (Gong et al., 2001), misshapen-Nck-interacting kinase (NIK) related kinase (MINK) (McCarty et al., 2005), extracellular signal-regulated kinase (ERK), and p38 and Jun kinase (JNK) activation (Palmer, 2003). Induction of cell death of autoreactive T cells requires BIM expression, which antagonizes BCL-2 and related proteins to release proapoptotic BAX and BAK. Furthermore, members of the Nur77 family of orphan nuclear receptors are induced during negative selection. T cell receptor-induced thymocyte death is blocked in the absence of Nur77 (Zhou et al., 1996).

5. Clonal anergy and tuning The intrinsic cellular mechanisms of anergy are particularly well studied in B cells with selfreactive receptors (Benschop et al., 2001). Selfreactive B cell receptors can be internalized through accelerated endocytosis, resulting in reduction of up to 99% of the initial surface expression of a self-reactive receptor. Similarly, the transport of new receptors to the surface can be blocked (Bell and Goodnow, 1994). It has been reported that self-reactive B cell receptors activate tyrosine kinase signaling poorly, which limits cell survival because of weak NF-kB1 activation. In parallel, weak signaling induces BIM expression to promote cell death (Lesley et al., 2004) and ERK pathways that block Toll-like receptor 9 (TLR9)-induced differentiation into plasma cells (Rui et al., 2003). So-called biochemical tuning can be achieved by increasing the threshold of B cell receptor activation, regardless of its speciﬁcity. Recruitment of the SH2-domain-containing protein tyrosine phosphatase 1 (SHP1) through the surface proteins CD22 and PD1 to the activated B cell receptors

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increases its threshold for signaling (Healy and Goodnow, 1998). Another example is the recruitment of the lipid phosphatase SH2-domaincontaining inositol-5-phosphatase (SHIP) to the activated B cell receptor through Fc receptor-g (Ravetch and Lanier, 2000). Spontaneous autoantibody production can occur if either one of these mechanisms is defective. Tuning of self-reactive T cells is achieved by increased expression of the inhibitory receptor CD5 (Wong et al., 2001; Smith et al., 2001). Cytotoxic T-lymphocyte antigen 4 (CTLA4) is another inhibitory receptor that acts through competition with CD28 for ligation with B7 molecules and transmitting inhibitory signals. CTLA4 was found to be upregulated in selfreactive T cells (Sharpe and Freeman, 2002; Walker and Abbas, 2002). Massive accumulation of self-reactive T cells occurs in peripheral lymphoid and nonlymphoid tissues in the absence of CTLA4. Functional variants of the CTLA4 gene can lead to thyroid autoimmunity and type 1 diabetes in humans and mice (Ueda et al., 2003). The ubiquitin ligases cbl-b, GRAIL and Itch have been identiﬁed to be highly expressed in chronic T cell receptor signaling in vitro (Heissmeyer et al., 2004; Anandasabapathy et al., 2003; Jeon et al., 2004). Ubiquitinylation of T cell receptors, CD28 and cytokine receptor signaling molecules can alter intracellular trafﬁcking, promote proteolytic degradation or can allosterically interfere with signaling (Naramura et al., 2002; Liu, 2004). Their importance for preventing autoimmunity in rodents has been clearly demonstrated: cbl-b deﬁciency coupled with a particular MHC haplotype causes type 1 diabetes in the Komeda diabetes prone (KDP) rat strain (Yokoi et al., 2002). Large numbers of activated T cells and high titers of autoantibodies can be found in mice lacking Itch, or cbl-b and its close relative c-cbl (Naramura et al, 2002; Liu, 2004).

6. Extrinsic controls of self-reactive lymphocytes A well-documented extrinsic control mechanism of autoreactive B cells is their dependence on BAFF,

which is produced in limiting quantities by lymphoid stromal cells (Mackay et al., 2003). Binding of BAFF to its receptor increases NF-kB2 activity maintaining peripheral B cell survival through induction of BCL-2 expression (Claudio et al., 2002). It also induces the expression of PIM2, a serin-threonie kinase, which has pro-survival effects by interfering with the pro-apoptotic protein BAD (Fox et al., 2003). On the one hand, given the large numbers of circulating B cells with strong receptor signaling through high afﬁnity to antigen, the selfreactive B cells do not receive enough BAFF and are competitively deleted (Thien et al., 2004). On the other hand, in states of B cell lymphopenia or in phases when BAFF synthesis is high, i.e. during infection, self-reactive B cells are more likely to survive (Mackay et al., 2003; Lesley et al., 2004). As with B cells, T cell survival in the periphery depends on continuous signaling through contact with MHC ligands and exposure to IL-7 (Sprent and Surh, 2002; Marrack and Kappler, 2004; Barthlott et al., 2003). Under normal circumstances, IL-7 levels are low and maintain T cells in interphase. However, in lymphopenia, IL-7 levels rise and amplify T cell receptor signaling and proliferation. This so-called homeostatic proliferation may also activate self-reactive T cells causing autoimmune diseases in extralymphatic sites, a common feature seen in people after T lymphopenia. Lymphopenia and defective T cell function in Wiskott–Aldrich syndrome is leading to an array of autoimmune and inﬂammatory conditions (Dupuis-Girod et al., 2003).

7. Limitation of costimuli In order to secrete antibodies, B cells must receive two signals: First, an antigen must bind to the B cell receptor; second, T helper cells must signal through CD40 ligand (CD40L) and cytokines IL-2, IL-4, IL-5, and IL-21 to initiate B cell proliferation and differentiation into plasma cells (Foy et al., 1996; Kovanen and Leonard, 2004). Since negative selection in the thymus should have reduced the number of self-antigen-speciﬁc T cells, the latter signal to self-reactive B cells is limited.

Digestive System and Autoimmunity

However, self-reactive B cells may receive signals from T helper cells responding to foreign antigens during infections, so-called bystander activation. More importantly, infections only rarely trigger autoantibody diseases, like Guillain–Barre´ syndrome. Efﬁcient B cell intrinsic tolerance mechanisms must be responsible for the fact that only 1 in 1000 people infected with Campylobacter pylori develops autoantibodies that cross-react with components of peripheral nerves (Ang et al., 2004). Interestingly, antibody production can be partially independent of T cell help, when B cells receive stimulatory signals from bacterial ﬂagellins, cell-wall lipopolysaccharides, and unmethylated CpG dinucleotides, which are recognized by Toll-like receptors (TLR) (Beutler, 2004). How this potentially dangerous pathway is dampened is not known in detail. Dysregulated activity of the TLR9 pathway leads to pathological accumulation of circulating IgG–self-DNA complexes, and is a potent driver of the production of autoantibodies against IgG and DNA (Leadbetter et al., 2002). Inadequate clearance of apoptotic cells with exposed CpG DNA and other nuclear antigens may account for the striking association between systemic lupus erythematosus (SLE) and genetic deﬁciencies in classical complement pathway components (Taylor et al., 2000). Mature T cells are activated by T cell receptor ligation and costimulation. Without costimulation, tolerance is favored. The most important costimulus is the interaction of CD28 on T cells and the B7 proteins CD80 and CD86 on antigen-presenting cells. TLR signaling induces expression of B7 molecules and enhances the survival and clonal expansion of T cells. Therefore, blocking B7–CD28 interactions may be an attractive way to induce tolerance. However, this treatment may also decrease thymic deletion and interfere with regulatory T cell function and intrinsic T cell regulation by CTLA4.

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organs (Radic and Weigert, 1994; Ray et al., 1996). Antibodies created by this process can have markedly increased afﬁnities for self-antigens. Follicular B cell differentiation generates longlived plasma and memory cells, which are able to secret antibodies indeﬁnitely (Slifka et al., 1998). Autologous DNA, an important self-antigen target in systemic lupus erythematosus (SLE), is abundantly presented by numerous apoptotic cells in germinal centers (Rosen and Casciola-Rosen, 2001), where it represents a powerful potential stimulus for autoantibody production. It has been found that anti-double-stranded DNA antibodies are somatically mutated in animal models of SLE (Radic and Weigert, 1994). In addition to CD40L, follicular T cells display high levels of ICOS, which is required for germinal center antibody responses in mice and humans (Sharpe and Freeman, 2002; Kroczek et al., 2004). Follicular T cells are also dependent on costimulation through OX40L (Walker et al., 2000). T cell entry into follicles is not induced in the absence of microbial TLR agonist (Kearney et al., 1994). Since self-antigens usually do not stimulate TLR signaling, this strict regulation of follicular T helper cell differentiation may block self-reactive T cells from delivering help to germinal center B cells.

9. Tolerance at the effector phase The mechanisms involved in preventing autoimmunity at target organs are only just beginning to be elucidated. Often pathology is limited to focal areas, like circumscribed skin lesions in pemphigus or single-joint inﬂammation in rheumatoid arthritis. Pathology depends on multiple factors, including immunologic cascades involving Fc receptors, mast cells, neutrophils, and complement (Wipke et al., 2004; Monach et al., 2004).

8. Regulation of self-reactive lymphocytes in follicles

10. Conclusions

Somatic hypermutation occurs in the periphery in germinal center follicles of secondary lymphoid

The mucosa of the gastrointestinal tract is a major site of pathogen entry. The gut-associated immune

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system needs to remain hyporesponsive to food antigens and commensal bacteria while mounting an efﬁcient response against pathogens. Immune responses must be exactly coordinated and regulated in order to effectively cure an infection and to avoid chronic inﬂammation. Autoimmune diseases can be considered as immune responses with defects in mechanisms that control selftolerance. Every organ of the digestive system can be the target of an autoimmune response, either in systemic or in organ-speciﬁc autoimmune diseases. Although many self-tolerance mechanisms exist, defects in a single checkpoint can lead to autoimmune disease. Clinical manifestations of autoimmune diseases are often seen only after a latent period of many years and then only against a few proteins or organs. There seems to be hundreds of genes involved in the checkpoints of self-tolerance. Common analysis of DNA polymorphisms will not be effective in identifying predisposing defects, rather exon resequencing of individuals with autoimmune disease will be required.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 2

Imaging Techniques in Digestive Diseases Carmen Ayusoa, Mario Page´sa, Luis Donosob, a

Radiology Department, Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, Abdomen Unit (CT and MRI), IDIBAPS, Villarroel 170, 08036 Barcelona, Spain b Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain

1. Introduction Gastrointestinal (GI) manifestations are common in patients with autoimmune diseases and can involve any part of the GI tract or the hepatobiliary system. Furthermore, abdominal symptoms may overlap those due to other factors related to the special circumstances of autoimmune disease, such as sideeffects of medication. Imaging techniques have an important role in the diagnosis and management of pathologic abdominal conditions in these patients. Recent technological advances have brought about considerable improvement in abdominal imaging. This chapter provides an overview of the imaging modalities available in the diagnosis of GI involvement in the context of autoimmune diseases. A brief description of the basic principles underlying each technique is provided and the advantages and limitations of the different imaging techniques, including the newest contrast agents for ultrasound (US) and magnetic resonance (MR), are discussed.

2. Imaging modalities 2.1. Plain abdominal film and barium studies Plain abdominal ﬁlms are currently mostly indicated in the clinical context of acute abdominal Corresponding author.

Tel.: +34-93-227-5412; Fax: +34-93-227-9323 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00002-5

disorders. Plain ﬁlms can depict bowel distension or abnormalities in the distribution of abdominal gas, such as free intraperitoneal air, pneumatosis intestinalis, ileus or pseudo-obstructive pattern, or pylephlebitis. Although the imaging examination based on plain ﬁlms of the abdomen sometimes provides enough deﬁnitive information to indicate a particular surgical or conservative treatment, it more often represents the ﬁrst step in a more complex diagnostic imaging process. Endoscopic procedures for the study of the GI pathology have dramatically decreased the indications for contrast-enhanced bowel radiographs. However, barium studies carried out using dynamic techniques such as videoﬂuoroscopy are increasingly used to study the functional disorders of the pharynx and esophagus.

2.2. Ultrasound or ultrasonography The commercial availability of high-resolution ‘gray scale’ equipment since 1974 has made US one of the mainstays in the study of the abdomen and particularly the hepatobiliary system. The basic principle underlying US is the transmission of sound waves into the abdominal organs from a transducer, which converts electrical energy into sound waves and vice versa. As the US wave passes through the abdominal tissues, it is affected by changes in tissue type and is refracted and reﬂected at interfaces between tissues with

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differing acoustic impedance. The transducer is able to detect the reﬂected sound waves and uses the time delay from the transmission to calculate depth within the body. The incoming vibrations are converted into electrical pulses and transformed into images by the US scanner. Current standard US of the abdomen uses state-of-the-art hardware and software together with a 3.5 or 5 MHz transducer and optional Doppler facilities. The general availability and relatively low cost of US, together with the fact that it does not employ ionizing radiation, have ensured that it is widely used to rule out abdominal pathology. US is often performed as the ﬁrst step in the evaluation of abdominal emergencies. Moreover, it is the imaging technique of choice for screening patients with suspected focal liver lesions and also for evaluating gallbladder and biliary tree pathology. US enables real-time studies, and the radiologist can select the most appropriate cross-sectional plane to obtain the desired information. This property enables US to guide a wide range of interventional procedures, such as aspiration biopsies, drainage of abdominal collections, or percutaneous ablative treatments of primary tumors and metastases. There are no contraindications for US, although its effectiveness decreases in obese patients and in those with air-distended bowel loops, which make it difﬁcult to evaluate the underlying tissues. In fact, air interposed between the transducer and the pancreas often limits the assessment of this organ. Color, spectral, and power Doppler imaging provide a non-invasive method of measuring ﬂow in the abdominal vessels and assessing vascularity within a lesion. Spectral Doppler provides a tracing of the Doppler wave from which it is possible to calculate various indices, including peak systolic velocity and resistive indices. Color Doppler enables the direction of blood ﬂow to be determined. Power Doppler displays the integrated power of the color signal to depict the presence of blood ﬂow. The pulsed Doppler technique can provide Doppler shift data selectively from a small segment along the US beam, enabling us to select a small vessel and quantify the velocity of ﬂow through it (Fig. 1).

Tissue harmonic imaging uses secondary frequencies which are multiples of the fundamental transmitted frequency. The resulting harmonic images have fewer artifacts and better space resolution. Harmonic imaging is especially useful when contrast agents are used. US contrast agents consist of very small gasﬁlled microbubbles, which are supported by a shell of biologically inert material. Microbubbles produce unique acoustic signatures that allow their signal to be separated from tissue echoes. The US system takes advantage of the strong echogenicity of the contrast agent to create an enhanced image of the area of interest. US contrast agents are especially useful for characterizing liver lesions (von Herbay et al., 2004; Burns and Wilson, 2007) and assessing the efﬁcacy of percutaneous treatments.

2.3. Computed tomography (CT) CT shows cross-sectional views of patient anatomy. CT involves multiple X-ray transmission measurements through the patient. The information acquired is processed by a computer, which uses mathematical techniques to generate a picture of the internal structures in cross-section. Body CT was introduced in 1974. Rapid development led to the early abandonment of the initial dual-slice scanner in favor of single-detector row scanners and incremental technology. At the end of 1980s, improvements in tube technology and computing led to the advent of helical CT. This faster volumetric acquisition allowed better quality image reconstructions to be obtained in different planes. The development of multidetector CT (MDCT) began in earnest in 1998 when four-slice scanners were introduced. Systems with 6-, 8-, 10-, 16-, 40-, and 64-detector arrays have since become available. The simultaneous acquisition of multiple (16, 64, or even more) continuous slices during one sub-second gantry rotation has improved acquisition speed, resulting in faster imaging protocols. Furthermore, improvements in the z-axis coverage speed have enabled nearly isotropic

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Figure 1. Doppler ultrasound demonstrates patency of portal vein. Doppler is displayed in images (Color Doppler) and graphically (Spectral Doppler). (See Colour Plate Section.)

image acquisition, providing high-resolution multiplanar reformations (MPR) and making excellent three-dimensional (3-D) displays possible (Prokop 2005). The advantages of MDCT are a consequence of (1) shorter scan duration, which reduces motion artifacts and enables a well-deﬁned solid parenchymal phase of contrast enhancement and thus better adjustment of contrast medium injection rate, volume, and concentration; (2) longer scan ranges that permit very good quality CT angiographic studies of the whole body; and (3) thinner sections that permit arbitrary imaging planes, MPR (Fig. 2), and 3-D rendering (Fig. 3). A challenge presented by multidetector-row CT is posed by the substantial increase in the number of reconstructed cross-sections (easily more than 1000 axial images) that are rapidly created and in need of analysis. This situation requires more sophisticated visualization techniques for the assessment of volumetric data, not only in terms

of 3-D workstations but also in fast automated processing and user interfaces to replace the analysis of transverse reconstructions by other alternatives. The large data load means that new ways of viewing, processing, archiving, and displaying images are necessary, and more time is needed to analyze the data than with single-slice helical CT. Images obtained with MDCT show increased image noise as the section collimation is reduced. To keep the noise low, thicker sections have to be reconstructed. Special attention has to be paid to avoid a dramatic increase in the radiation dose to the patients using MDCT protocols, and acquisition protocols must be carefully adjusted to reduce the radiation dose. The indications for abdominal CT in patients with autoimmune diseases cover a wide spectrum ranging from inﬂammatory conditions, such as abdominal sepsis or acute pancreatitis, to

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Figure 2. Computed tomography angiogram. (a) Arterial phase: MPR in a sagittal view shows the normal anatomy of the abdominal aorta and the superior mesenteric artery. (b) Portal phase: MPR in an oblique-coronal plane shows the regular patency of the portal, and superior mesenteric veins.

Imaging Techniques in Digestive Diseases

Figure 3. Computed tomography angiogram provides exquisite detail of the anatomic distribution of the celiac artery and superior mesenteric artery. The hepatic artery and its segmental branches are also displayed. (a) Maximum intensity projection image. (b) Volume-rendered image.

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neoplastic diseases, such as lymphoma or other solid tumors, where CT is a useful tool to deﬁne the tumor extension. One of the most important indications for CT is to rule out vascular complications that are fairly common in this context, such as Budd–Chiari syndrome; however, the most common and most challenging diagnostic and therapeutic problem is acute abdominal pain. Ischemic bowel disease is a very common and severe complication in patients with autoimmune diseases, and it has a very poor prognosis when the diagnosis is delayed. CT can also be used to direct percutaneous interventional diagnostic procedures such as ﬁne-needle biopsy of solid focal lesions (Fig. 4), tru-cut biopsies of solid organs (liver, kidney) to rule out diffuse parenchymal disease, or percutaneous therapeutic procedures such as the drainage of abdominal ﬂuid collections. Low-dose CT ﬂuoroscopy allows continuous control of the tip of the needle in real-time mode to avoid damage to vital structures during interventional procedures. MDCT angiography has become a valuable minimally invasive tool for the visualization of normal vascular anatomy and its variants, as well as pathologic conditions of abdominal vessels. As abdominal pain is a frequent clinical problem in patients with autoimmune diseases and bowel ischemia has to be ruled out, the discussion of MDCT angiography in this chapter will focus on the mesenteric vessels. Although mesenteric MDCT angiography can be speciﬁcally performed as a single study, it is often carried out in combination with studies of solid organs or more generalized abdominal imaging. In patients with suspected mesenteric ischemia, CT may help detect ischemic changes in the affected small bowel loops and mesentery, such as bowel wall thickening, submucosal hemorrhage, increased or decreased enhancement of the bowel wall, or even pathologic changes in the mesenteric vasculature like atherosclerotic stenosis, thrombosis, or occlusion (Fig. 5). To depict these ﬁndings, both unenhanced and biphase CT abdominal studies (arterial and venous phases) are usually performed. Bowel opaciﬁcation should be avoided to improve vascular visualization in 3-D imaging post-processing. A total of

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Figure 4. CT-ﬂuoroscopy-guided ﬁne-needle biopsy. Irregular thickening of the bladder wall can be seen secondary to a primary bladder neoplasm. A 20-gauge needle is placed in an enlarged left iliac lymph node. Metastatic tumor nests were found in the pathologic study of the sample.

100–150 ml of non-ionic iodinated contrast material (300–370 mg of iodine per milliliter) is usually administered with a power injector at a rate of 2–4 ml/s. Three-dimensional imaging postprocessing of data sets from the arterial and venous phases in the workstation allows real-time viewing of axial and multiplanar images and provides additional sophisticated rendering options, such as thick and curved MPR, thin-slab maximum intensity projection (MIP), and volume rendering (VR) reconstructions (Fig. 6). The sensitivity of CT in detecting bowel ischemia has reached 82% (Klein et al., 1995) and is comparable to that of angiography. For this reason, the indications for angiography are moving from diagnostic to therapeutic aspects. Angiography enables endovascular treatment, such as percutaneous transluminal angioplasty or stent placement, in selected patients with acute mesenteric ischemia caused by vascular occlusion (Resch et al., 2005).

2.4. Magnetic resonance MR is based on the relaxation properties of hydrogen atoms when they are subjected to a strong magnetic ﬁeld, and the power of MR equipment is quantiﬁed by Teslas (T), a measurement of magnetic ﬂux density. The ﬁrst commercial MR scanners became available in the early 1980s. MR applications in relatively motionless body parts, such as the brain, spine, or musculoskeletal system, quickly took hold in the ﬁeld of medical diagnosis, because high-quality images not conditioned by artifacts due to bone structures were obtained, with far better contrast resolution than CT. However, abdominal MR imaging was limited by long acquisition times that produced severe motion artifacts due to respiratory and peristaltic movements. These limitations were overcome through technical advances such as the development of ultrafast single-shot sequences, and images providing excellent anatomic detail can

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Figure 5. Acute intestinal ischemia due to nearly total occlusion of the superior mesenteric artery (SMA). (a) Axial CT section at the level of the SMA origin shows a very signiﬁcant reduction in the patent lumen of the artery. (b) A small amount of gas can be seen in the superior mesenteric vein. (c) There is some gas collection in the wall of the right colon and also in the wall of the terminal ileum due to intestinal pneumatosis.

now be obtained routinely. Abdominal MR is currently a widely accepted imaging technique for the study of multiple pathologies of the GI, including pancreatic and hepatobiliary diseases. Technical improvements have led to the development of new MR techniques, such as MR cholangiopancreatography (MRC) or MR angiography.

2.4.1. MR technique MR abdominal studies are routinely obtained with a torso phased-array surface coil. MR examinations

consist of the acquisition of different sequences according to particular study protocols, depending on the abdominal organ studied or the suspected pathology. However, most of the abdominal protocols include T1-weighted sequences (in-phase/ opposed phase to detect fatty inﬁltration, and/or fat-suppressed sequences), T2-weighted sequences (useful in tumor characterization), and a dynamic contrast-enhanced sequence (to demonstrate the enhancing vascular pattern of the lesions). MR’s multiplanar capacity is one of the most interesting characteristics of this imaging

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Figure 6. Acute embolic intestinal ischemia. (a) CT topogram shows dilated small bowel loops. (b) MPR demonstrates multiple ﬁlling defects into the SMA. (c) Volume-rendered image of the same patient showing an almost complete occlusion of the SMA.

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modality: MR images can be acquired in any sectional plane. This property was initially one of the main advantages of MR over CT, although currently MDCT also allows high-quality reconstructions in any orientation. MR has higher contrast resolution than CT, although it has less spatial resolution. In other words, there are more signal intensity changes between tissues, although less deﬁnition in limiting structures.

2.4.2. Contrast agents The most common MR contrast agents are the chelates of gadolinium, which are non-speciﬁc extracellular contrast agents. After intravenous administration, they are initially distributed in the intravascular space, but they are rapidly cleared into the interstitial space, ﬁltered through the capillaries into the extracellular space, and are eventually excreted by the kidneys. The main indications of contrast-enhanced MR include the study of neoplastic lesions to assess tumor vascularity, vascular pathologies, and MR angiography. One advantage of these contrast agents versus the iodinated contrast media used in CT examinations is their lower or non-existent nephrotoxicity, and gadolinium contrast-enhanced

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MR studies have long been a viable alternative in patients with renal failure or iodine allergy. However, a new severe entity which seems to be related to some gadolinium chelates has recently been reported in patients with renal failure: nephrogenic systemic ﬁbrosis (Marckmann et al., 2006). Thus, the chelates of gadolinium should only be administered in these patients when it is essential. Hepatobiliary contrast agents partially pass from blood through the hepatobiliary system with partial excretion through the kidneys and the bile ducts. These liver-speciﬁc contrast agents are selectively uptaken by the hepatocytes, leading to an increase in signal intensity on T1-weighted sequences of the normal liver parenchyma and also of the focal hepatocellular liver lesions. Some of the hepatobiliary contrast agents can be rapidly injected and dynamic hepatic studies can be performed to assess the anatomy of the biliary tree, to detect bile leaks, and also to detect and characterize hepatic tumors (Fig. 7). Reticuloendothelial contrast agents are removed from the blood by the reticuloendothelial cells of the liver and the spleen. These tissue-speciﬁc contrast agents consist of small particles of iron oxide. They are injected intravenously and cleared by the reticuloendothelial system, located

Figure 7. Focal nodular hyperplasia studied by MR imaging. (a) T1-weighted gradient-echo MR image with fat suppression. The lesion exhibits homogeneous intense enhancement in the arterial phase (20 s following the injection of hepatobiliary contrast agent). (b) 20 min after injection (same sequence as (a)), the lesion is slightly hyperintense in comparison to normal liver parenchyma due to its hepatocellular nature.

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predominantly in the Kupffer cells of the liver. Reticuloendothelial contrast agents produce a negative enhancement by decreasing signal intensity in T2-weighted sequences. Iron is added to the iron pool and excreted by the kidneys. These contrast agents are useful in characterizing some focal hepatic lesions, such as focal nodular hyperplasia.

2.4.3. Indications and limitations Absolute contraindications for MR studies are pacemakers and other ferromagnetic implants, such as cochlear implants, vagus nerve stimulators, or insulin pumps. Although other modern medical devices are mainly manufactured without ferromagnetic materials, the magnetic properties of valvular prostheses and stents must be evaluated before a patient can undergo MR. Patients must be queried about possible ferromagnetic foreign bodies, and a plain ﬁlm X-ray is sometimes necessary to rule out their presence. Liver MR is an excellent imaging technique to characterize non-speciﬁc focal lesions previously detected in US or CT studies. Among other indications, hepatic MR is widely used to stage primary hepatic tumors, to evaluate potential living liver donors, and to evaluate complications after liver transplantation. It is also usually performed in patients with liver metastasis prior to surgical resection. MRC is a non-invasive technique to depict the biliary tree and the pancreatic ducts. The images obtained are comparable to endoscopic retrograde cholangiography (ERC). MRC is performed using heavily T2-weighted sequences that demonstrate the ﬂuid-containing bile ducts as high-signal-intensity structures. This technique has demonstrated high sensitivity and speciﬁcity in the diagnosis of the location and etiology of biliary obstruction (Fig. 8) to the extent that ERC is usually indicated only when a therapeutic approach is needed. MR enteroclysis is an emerging technique for the evaluation of small bowel diseases. It combines the study of luminal, mural, and extramural abnormalities. It can evaluate not only bowel wall ulcers but also transmural complications in inﬂammatory bowel disease (Wiarda et al., 2006). (Fig. 9)

Figure 8. MR cholangiography depicts the biliary tree and pancreatic ducts. Multiple ﬁlling defects typical of stones are shown in the lumen of the common bile duct.

Figure 9. MR enteroclysis shows anatomic demonstration of the small bowel. Coronal MR image clearly depicts ﬂuid-ﬁlled bowel loops and provides excellent contrast between the bowel wall and surrounding structures.

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Figure 10. Images for staging an anaplastic lymphoma. PET/CT images. (a) Axial CT image at the pelvis shows an enlarged external iliac lymph node. (b) Corresponding axial maximum intensity projection image showing intense FDG uptake in the external iliac lymph node. (c) PET/CT fused image at the same pelvic level conﬁrms the coincidence of both pathologic images. (See Colour Plate Section.)

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MR angiography provides high-quality arterial and venous images without ionizing irradiation. MR angiography is an alternative to CT angiography in patients with allergies to iodinated contrast media.

2.5. Positron emission tomography Positron emission tomography (PET) is an operator-independent, non-invasive metabolic imaging modality based on the regional distribution of 18 F-ﬂuorodeoxyglucose ([18F]FDG); PET plays a major role in the management of oncology patients (Endo et al., 2006; Rao et al., 2006). Furthermore, activated inﬂammatory cells have also been shown to overexpress glucose transporters and to accumulate increased amounts of glucose and structurally related substances such as [18F]FDG. Some authors have reported the usefulness of this imaging technique in assessing the activity and the extent of large-vessel vasculitis (Meller et al., 2003; Walter et al., 2005). Recently, functional PET images have been used in combination with CT to enable the anatomic or morphologic features of tumors to be assessed as well. PET and CT images obtained at the same position provide the precise localization of lesions with increased glucose metabolism over the whole body in a single session (Fig. 10). PET and/or PET/CT using FDG is now widely employed as an advanced clinical imaging tool for the diagnosis, staging, and restaging of cancer, as well as for the assessment of tumor therapy.

3. Future prospects Recent years have witnessed enormous technological advances in abdominal imaging techniques as well as the development or improvement of different contrast media for use with US, CT, and MRI. Consequently, a wide variety of high-quality diagnostic images can quickly be obtained and more functional protocols can be applied with non-invasive or minimally invasive procedures, while classic invasive imaging techniques have

moved toward therapeutic indications. On the other hand, many percutaneous diagnostic and therapeutic procedures can be guided by imaging techniques, especially US and CT ﬂuoroscopy, leading to faster diagnosis and treatment of abdominal pathologic conditions. In the near future, the development of hybrid technology might allow high-resolution images, functional images, and metabolic information to be combined. This ‘one store shop’ would contribute to a quicker and earlier speciﬁc diagnosis leading to improved management of abdominal diseases and thus improved prognoses.

References Burns, P.M., Wilson, S.R. 2007. Focal liver masses: enhancement patterns on contrast-enhanced images–concordance of US scans with CT scans and MR images. Radiology 242 (1), 162–174. Endo, K., Oriuchi, N., Higuchi, T., Iida, Y., Hanaoka, H., Miyakubo, M., Ishikita, T., Koyama, K. 2006. PET and PET/CT using 18F-FDG in the diagnosis and management of cancer patients. Int. J. Clin. Oncol. 11, 286–296. Klein, H.M., Lensing, R., Kiosterhalfen, B., Tons, Ch., Rolf, W.G. 1995. Diagnostic imaging of mesenteric infarction. Radiology 197, 79–82. Marckmann, P., Skov, L., Rossen, K., Dupont, A., Damholt, M.B., Heaf, J.G., Thomsen, H.S. 2006. Nephrogenic systemic ﬁbrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J. Am. Soc. Nephrol. 17 (9), 2359–2362. Meller, J., Strutz, F., Siefker, U., Scheel, A., Sahlmann, C.O., Lehmann, K., Conrad, M., Vosshenrich, R. 2003. Early diagnosis and follow-up of aortitis with [18F]FDG-PET and MRI. Eur. J. Nucl. Med. Mol. Imaging 30, 730–736. Prokop, M. 2005. MDCT: technical principles and future trends. In: G. Marchal, T.J. Vogl, J.P. Heiken, G.D. Rubin (Eds.), Multidetector-Row Computed Tomography. Scanning and Contrast Protocols. Springer Milan, pp. 5–12. Rao, K.V., Carrasquillo, J.A., Dale, J.K., Bacharach, S.L., Whatley, M., Dugan, F., Tretler, J., Fleisher, T., Puck, J.M., Wilson, W., Jaffe, E.S., Avila, N., Chen, C.C., Straus, S.E. 2006. Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS). Am. J. Hematol. 81, 81–85. Resch, T., Lindh, M., Dias, N., Sonesson, B., Uher, P., Malina, M., Ivancev, K. 2005. Endovascular recanalisation in occlusive mesenteric ischemia, feasibility and early results. Eur. J. Vasc. Endovasc. Surg. 29, 199–203. von Herbay, A., Vogt, C., Willers, R., Haussinger, D. 2004. Real-time imaging with the sonographic contrast agent

Imaging Techniques in Digestive Diseases SonoVue: differentiation between benign and malignant hepatic lesions. J. Ultrasound Med. 23, 1557–1568. Walter, M.A., Melzer, R.A., Schindler, Ch., Mu¨ller-Brand, J., Tyndall, A., Nitzsche, E.U. 2005. The value of [18F]FDG-PET in the diagnosis of large-vessel vasculitis

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and the assessment of activity and extent of disease. Eur. J. Nucl. Med. Mol. Imaging 32, 674–681. Wiarda, B.M., Kuipers, E.J., Heitbrink, M.A., van Oijen, A., Stoker, J. 2006. MR enteroclysis of inﬂammatory smallbowel diseases. AJR 187 (2), 522–531.

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PART II:

Systemic Autoimmune Diseases

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 3

Systemic Lupus Erythematosus Miquel Vilardell-Tarre´s, Albert Selva-O’Callaghan, Josep Ordi-Ros Internal Medicine Department, Vall D’Hebron General Hospital, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain

1. Introduction Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a broad range of clinical manifestations. It is characterized by an immune dysregulation resulting in the production of various autoantibodies (D’Cruz et al., 2007). Different organ systems are involved, with the result that morbidity and mortality are signiﬁcant. Gastrointestinal (GI) manifestations are common in SLE patients due to the disease itself or due to aggressive treatment regimens (Sultan et al., 1999). However, they are seldom reported, probably because they are often masked by other more relevant clinical features such as renal or central nervous system involvement. The incidence of GI manifestations attributable to the disease itself varies widely and ranges from 1.3 to 27.5% in the literature. These manifestations appear to be more frequent in patients of Oriental ethnicity. In this chapter, we present the different GI manifestations of SLE patients.

2. General symptoms Almost half of all SLE patients suffer from anorexia, nausea, and vomiting. These symptoms can be caused by the disease itself, by uraemia in the Corresponding author.

Tel.: 93-274-62-00, 93-489-40-47; Fax: 93-489-40-45 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00003-7

context of renal failure, and by cytostatic therapies such as azathioprine and intravenous pulses of cyclophosphamide or the more recently used immunosuppressive drug, mycophenolate mofetil. Serositis—pleuritis, pericarditis, and less frequently, ascites—is a well-known diagnostic criterion of SLE. It is present in 8–11% of patients with SLE and can be differentiated as inﬂammatory— true serositis—or non-inﬂammatory, due mainly to hypoalbuminemia (nephrotic syndrome, liver cirrhosis, protein-losing enteropathy) (Mok, 2005).

3. Oral cavity, oesophagus, and gastric abnormalities Oral ulcers are frequent in patients with SLE and affect between 6 and 52% of patients (Sultan et al., 1999). They are usually painless and involve the hard palate, nasal cavity, and pharyngeal wall. The fact that most SLE patients receive immunosuppressive therapy means that infection as a cause of oral ulcers should not be overlooked. Candidiasis, herpes virus, and oral leucoplakia can be recognized as oral ulcers or plaque-like lesions. The presence of a secondary sicca syndrome with dry mouth and dry eyes is not uncommon in SLE patients; almost 20% of cases develop this manifestation (Andonopoulos et al., 1990). Dry mouth favours periodontal disease and aphthous ulcers, erythema, haemorrhage, and gingival overgrowth. Treatment with cyclosporine A usually exacerbates gingival hypertrophy. Tissue biopsy

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might show lupus-speciﬁc histopathology similar to that of the skin. The histology and immunopathology of oral lesions in these patients include an inﬂammatory perivascular lymphohistiocytic inﬁltrate, spongiosis, hyperkeratosis, and IgG/ IgM, complement, and ﬁbrinogen deposition at the dermal–epidermal junction. These lesions are sometimes difﬁcult to distinguish from lichen planus or leucoplakia. Anti-malarials (chloroquine and hydroxychloroquine) and topical corticosteroids are the treatment of choice. Systemic steroids and/or azathioprine are generally used in severe cases. Thalidomide and cyclosporine A in Europe and methotrexate in the USA are also used as second-line agents in the most refractory cases. To date, there are no evidencebased guides to systemic therapy of oral lesions in SLE patients. Sugar-free gum, artiﬁcial saliva, and systemic therapy with pylocarpine hydrochloride to increase salivation can be useful in cases of secondary Sjo¨gren syndrome. Oesophageal symptoms in SLE patients include dysphagia and heartburn, but it is difﬁcult to assume that these are due to the disease and not the therapy. The introduction of proton pump inhibitors has lessened the relevance of oesophageal symptoms. Manometry abnormalities, especially hypoperistalsis in the upper one-third, have been reported in almost two-thirds of patients— even in asymptomatic patients—and can be associated with chronic intestinal pseudo-obstruction (CIPO), an uncommon GI complication examined below. Involvement of the lower oesophageal sphincter is rare, and oesophageal symptoms do not seem to correlate well with manometry results. Conventional and symptomatic therapy—proton pump inhibitors and small and frequent meals—is probably a better approach than immunosuppressive or anti-inﬂammatory treatment. Nevertheless, if vasculitis or inﬂammation is documented by biopsy studies, treatment of lupus itself is warranted, especially if serologically and clinically systemic disease is recognized. Gastric disease is more frequently related to treatment complications [non-steroidal antiinﬂammatory drugs (NSAID) and corticosteroids] than to the disease itself. Therefore, patients on long-term NSAIDs may need to be maintained on

a gastroprotective agent such as a proton pump inhibitor. Cytomegalovirus infection of gastric mucosa should be borne in mind, particularly in SLE patients receiving long-term treatment with mycophenolate mofetil, as is well known in renal transplantation (Mathew, 1998). Gastric antral vascular ectasia, the so-called watermelon stomach, is a rare vascular malformation which has been described in SLE. It can cause acute or chronic bleeding which in turn leads to persistent iron deﬁciency anaemia. Moderate doses of prednisone are recommended, although transendoscopic treatment or antrectomy may occasionally be needed (Hallegua and Wallace, 2000). A possible protective role for Helicobacter pylori against the development of SLE has recently been reported in some ethnic groups (Sawalha et al., 2004).

4. Main gastrointestinal syndromes 4.1. Abdominal pain Abdominal pain is usually a non-speciﬁc symptom but can be particularly important in SLE patients. It is not an uncommon complaint in patients with lupus (Mok, 2005), or in children (Richer et al., 2007). Acute abdomen is always a challenging diagnostic and therapeutic problem—even more so in SLE (Kishimoto et al., 2007)—and abdominal pain in these patients could also be caused by complications of therapy and of the disease itself (Table 1). Immunosuppressive treatment and corticosteroids are the usual medications in SLE patients and mainly serve to mask the classical manifestations of perforation and ischemia, two of the main causes of acute abdomen. Non-steroidal anti-inﬂammatory drugs, azathioprine, calcineurin antagonists such as cyclosporine and tacrolimus, and mycophenolate mofetil, can all cause abdominal pain to a greater or lesser extent. Evaluation of the activity of the disease by means of the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) helps physicians to decide the correct approach. It seems that intra-abdominal vasculitis and mesenteric thrombosis—both severe

Systemic Lupus Erythematosus

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Table 1 Abdominal pain in systemic lupus erythematosus SLE related

Treatment related

Non-SLE causes

Renal vein thrombosis Mesenteric thrombosis Acalculous cholecystitis Bowel perforation Vasculitis Ectopic pregnancy Pancreatitis Serositis Splenic infarction Ischemic bowel disease Angioedema

Gastritis, duodenitis Pancreatitis (azathioprine) Sepsis Peptic ulcer Perforation Enterocolitis Salmonella infection

Appendicitis Viral hepatitis Biliary pancreatitis Diverticulitis Surgical adhesions

abdominal SLE complications—are clearly associated with a higher SLEDAI. Radiological explorations such as ultrasound and CT scanning are essential to achieve a correct diagnosis, although in some cases—especially acute abdomen with active SLE and when the clinical presentation is severe—early laparotomy is preferred because the mortality in this subgroup is very high (Medina et al., 1997). Middle serositis, small bowel bacterial overgrowth, and non-SLE-related causes are the most frequent manifestations in outpatients. Mesenteric insufﬁciency (Mok, 2005), the socalled intestinal angina, deserves special attention. It is well known that SLE patients are prone to premature atherosclerosis which can affect different territories. Besides cerebral and coronary vessels, splanchnic arteries may also be involved, causing chronic intermittent abdominal pain which should not be overlooked. Symptoms usually start after lunch and persist for 1–3 h. Weight loss and fear of eating are usually reported in patients with mesenteric insufﬁciency. Conventional angiography is the gold standard for a correct diagnosis, but MRI or abdominal CT scan with angiography is also useful and less invasive. Long-standing disease, renal insufﬁciency, longterm corticosteroid therapy, and the presence of classical cardiovascular risk factors such as hypertension, smoking, hyperlipidemia, and diabetes favour the development and progression of atherosclerosis, also in SLE patients. Healthy habits and drugs (statins) to control or minimize these factors

are strongly recommended. Therapeutic options include surgical revascularization or, in selected cases, percutaneous transluminal mesenteric angioplasty with or without stent placement. Platelet antiaggregants with aspirin and/or clopidogrel or anticoagulation therapy must be chosen on an individual basis.

4.2. Lupus enteritis (gastrointestinal vasculitis) Lupus enteritis, also called gastrointestinal vasculitis due to the characteristic histopathological ﬁndings in nearly all the cases studied, is one of the most serious complications of SLE (Lee et al., 2002). Although some authors believe that the presence of antiphospholipid antibodies (aPL) is associated with lupus enteritis, most are of the opinion that these antibodies are largely related to arterial or venous thrombotic events, but not to vasculitis. Thus, there seems to be a link between mesenteric thrombosis and aPL, but not between vasculitis and aPL. Lupus enteritis is generally accompanied by bowel ischemia, and the CT scan shows dilated bowel, focal or diffuse bowel thickening with bowel wall enhancement, mesenteric oedema, and ascites (Ko et al., 1997). Nevertheless, it is known that most of these signs are highly non-speciﬁc. A clue to the diagnosis of intestinal vasculitis is the involvement of several different vessels simultaneously. The anatomical areas most frequently involved are the jejunum and

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ileum, whereas rectal involvement is fairly uncommon, even though this area is well supplied with blood. Improvement after intravenous glucocorticoid therapy (pulses of 1 gr/d of prednisolone for three days) may favour a diagnosis of reversible ischemic bowel disease caused by intestinal vasculitis. A differential diagnosis with inﬂammatory bowel disease is sometimes required. Besides abdominal pain, there is usually evidence of active disease in other organs, with fever and acute-phase proteins, occult blood in stool, or even frank GI haemorrhage. Glucocorticoids remain the therapy of choice and can be combined with immunosuppressive agents such as cyclophosphamide. Surgery is recommended when the general condition deteriorates (Grimbacher et al., 1998).

4.3. Intestinal pseudo-obstruction This is a rare and poorly understood GI complication of SLE. It has been deﬁned as the presence of clinical features of intestinal obstruction without an identiﬁable organic obstructive lesion

(Mok et al., 2000). CIPO reﬂects a dysfunction of the visceral smooth muscle or the visceral autonomic nervous system. Ureterohydronephrosis and biliary tract involvement have been reported with CIPO, which indicates the existence of a smooth muscle motility problem (Pardos-Gea et al., 2005) (Figs. 1 and 2). Nearly half of the patients described are Oriental, which implies a genetic component, although studies to identify a speciﬁc HLA have not been carried out. Clinical presentation is subacute, with slight abdominal pain and abdominal distension accompanied by very sluggish or absent peristalsis. Rebound tenderness is uncommon. CIPO can be the ﬁrst manifestation of SLE in some patients, but it usually represents a GI complication which appears during the course of the disease. Mortality is not related to CIPO itself but to sepsis from immunosuppressive treatment or other major organ involvement attributed to SLE. Most patients have an undulant course with recurrent attacks and GI clinical relapses. The small bowel is more commonly involved than the large bowel (Narvaez et al., 2003).

Figure 1. Abdominal magnetic resonance imaging with dilated urinary pelvicaliceal system and bilateral ureterohydronephrosis.

Systemic Lupus Erythematosus

35

Figure 2. Magnetic resonance cholangiopancreatography showing dilatation of the extra hepatic common biliary tract and the pancreatic duct without extrinsic or intrinsic obstruction.

Radiological examination—mainly ultrasonography and enhanced contrast abdominal CT scan—frequently reveals bilateral ureteral dilatation with a reduced urinary bladder capacity. Chronic interstitial cystitis, a condition associated with immune complex deposition and a wellrecognized complication of SLE, has been documented in some cases of CIPO (Kim and Park, 1996; Narvaez et al., 2003). Clinical suspicion is typically conﬁrmed by antroduodenal manometry, which generally demonstrates oesophageal aperistalsis and intestinal hypomotility that may be neurogenic or myogenic. Immune complexmediated vasculitis or a common autoantibody against the enteric nervous system or the smooth muscle could be responsible for CIPO manifestations. Serositis, vasculitis, and bowel wall ﬁbrosis

have occasionally been reported as histopathological ﬁndings. No speciﬁc autoantibodies have been regularly associated with CIPO, even though most of these patients had positive antinuclear antibodies, serology suggestive of active disease and anti-Ro antibodies. Nevertheless, antibodies against the proliferative cell nuclear antigen have been reported in two SLE patients with chronic CIPO (Nojima et al., 1996), although the clinical value of this ﬁnding remains elusive. Treatment of CIPO includes high doses of intravenous prednisone, considered the treatment of choice for this rare GI complication in SLE patients. Other immunosuppressive agents— azathioprine, cyclosporine A, and cyclophospha mide—have been successfully used as initial treatment and for maintenance therapy in

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non-responders. Broad-spectrum antibiotics employed to diminish bacterial overgrowth or promotility drugs such as erythromycin are usually effective when combined with the immunosuppressive regimen. Octreotide, a long-acting somatostatin analogue, and rituximab, an anti-CD20 monoclonal antibody, have been used successfully in isolated cases and may prove useful for refractory or severely ill patients. Early recognition of this GI manifestation is important because of the reversibility of the condition with immunosuppressive agents. Surgery should be avoided whenever possible.

human serum albumin scanning is the gold standard and best quantitative study. Other explorations such as endoscopy, barium studies, abdominal CT scan, or the absorption test (D-xylose) may be necessary. Most PLGE patients respond well to corticosteroid therapy, although intravenous pulse cyclophosphamide might be necessary in refractory cases. Recently, the combination of prednisolone and azathioprine has proven to be effective and well tolerated in the treatment and outcome of PLGE in SLE patients (Mok et al., 2006).

4.5. Pneumatosis cystoides intestinalis 4.4. Protein-losing gastroenteropathy Protein-losing gastroenteropathy (PLGE) is a clinical syndrome characterized by hypoalbuminemia due to a loss of protein from the GI tract in the absence of a signiﬁcant loss of protein from the kidneys, reduced protein intake, malnutrition, or severe liver disease (Mok, 2005). Therefore, a diagnosis of PLGE relies mainly on the exclusion of other conditions. Moreover, it should not be regarded as a ﬁnal diagnosis, because several GI alterations, e.g. intestinal lymphoma, lymphatic obstruction or lymphangiectasia, or malabsorption, could be responsible for a loss of protein. The main symptoms of this disorder include generalized oedema, abdominal pain, and severe diarrhoea. It is a well-known, but uncommon, manifestation of SLE and can be the initial manifestation of the disease. Moreover, as CIPO is also more frequent in Oriental patients, speciﬁc genetic or environmental factors may play a role (Meulders et al., 1992). The pathogenesis of PLGE is not well known. Mesenteric vasculitis could be a likely mechanism, but it has not been found in mucosal biopsies. Although no speciﬁc autoantibodies have been associated with this GI manifestation, it seems that an increase in mucosal capillary permeability as a result of complement deposition or cytokine-mediated damage could play a role in the pathogenesis of PLGE (Yazici et al., 2002). Diagnosis of PLGE must be conﬁrmed by complementary explorations. Technetium 99m-labelled

Pneumatosis cystoides intestinalis is an uncommon but important condition in which gas is found in a linear or cystic form in the submucosa or subserosa of the bowel wall (Heng et al., 1995). The left colon and the ileum are the segments of the bowel most likely to be involved. There are few reports of pneumatosis cystoides intestinalis in adult patients with systemic autoimmune diseases, especially systemic sclerosis and dermatomyositis, but it has been described in SLE patients (Cabrera et al., 1994). Several mechanisms have been proposed for its development, including breaks in the intestinal mucosa, infection, and ischemia due to vasculitis. Pneumatosis cystoides intestinalis is often asymptomatic and may occur with pneumoperitoneum, which is sterile and must be distinguished from a perforated viscus. It should be considered as a sign, not a disease; therefore, its relevance should be interpreted within the whole clinical context. Differentiation between the benign variety, in which no intervention is indicated, and the lifethreatening form, in which immediate surgery is necessary, is extremely important and sometimes challenging for the clinician. Radiology—mainly contrast-enhanced CT scan of the abdomen— usually assists diagnosis. Bowel biopsies are not indicated as a rule, given the benignancy of the picture, although ischemic necrosis of the bowel wall due to vasculitis or thrombosis due to aPL has been reported in SLE patients (Alcocer-Gouyonnet et al., 2000). Once life-threatening illnesses such as bowel necrosis, perforation, and infections are

Systemic Lupus Erythematosus

excluded, patients whose symptoms are due to the cysts themselves may be treated with oxygen and/ or antibiotics. Because reports of treatment of pneumatosis cystoides intestinalis are at best anecdotal, the decision to treat and the treatment chosen should be carefully balanced against the risks. In the absence of sepsis or peritonitis, treatment remains highly conservative (Boerner et al., 1996).

5. Lupus-associated pancreatitis This is a rare complication of SLE. In the general population, common causes of pancreatitis include choledocholithiasis, alcohol intake, and certain drugs. Nevertheless, some SLE patients develop pancreatitis of uncertain origin, which can be attributed to the disease itself. The clinical approach to a patient with SLE-associated pancreatitis includes a ﬁrst step in order to rule out the most common causes, which may explain half of all cases (Pascual-Ramos et al., 2004). The relationship between azathioprine and corticosteroids, which can cause drug-induced pancreatitis, is difﬁcult to prove and remains elusive. Although SLE-associated pancreatitis can be the presenting symptom of SLE, this is usually a complication of the disease and is mostly related to SLE activity. Its aetiology is unknown, but different causes have been suggested and include an autoimmune origin, vasculitis, aPL-related thrombosis, or exocrinopathy when sicca syndrome accompanies SLE. Autopsy reports favour inﬂammation of possible autoimmune origin as the most frequent aetiology, but it is difﬁcult to draw deﬁnite conclusions because data are scarce. Clinical manifestations are standard, with severe abdominal pain, nausea and vomiting, but mortality appears to be higher than in non-SLE-associated pancreatitis (Nesher et al., 2006). Some authors have used serum immunoreactive cationic trypsinogen to identify a subclinical pancreatic dysfunction in children with SLE. The clinical relevance of this ﬁnding remains elusive (Eberhard et al., 1992). Treatment with steroids combined with supportive measures seems to improve the prognosis of these patients.

37

References Alcocer-Gouyonnet, F., Chan-Nunez, C., Herna´ndez, J., et al. 2000. Acute abdomen and lupus enteritis: thrombocytopenia and pneumatosis intestinalis as indicators for surgery. Am. Surg. 66, 193–195. Andonopoulos, A., Skopouli, F., Dimou, G., Drosos, A., Moutsopoulos, H. 1990. Sjo¨gren’s syndrome in systemic lupus erythematosus. J. Rheumatol. 17, 202–204. Boerner, R.M., Fried, D.B., Warshauer, D.M., Isaacs, K. 1996. Pneumatosis intestinalis. Two case reports and a retrospective review of the literature from 1985 to 1995. Dig. Dis. Sci. 41, 2272–2285. Cabrera, G.E., Scopelitis, E., Cuellar, M.L., Silveira, L.H., Mena, H., Espinoza, L.R. 1994. Pneumatosis cystoides intestinalis in systemic lupus erythematosus with intestinal vasculitis: treatment with high dose prednisone. Clin. Rheumatol. 13, 312–316. D’Cruz, D.P., Khamashta, M.A., Hughes, G.R. 2007. Systemic lupus erythematosus. Lancet 369, 587–596. Eberhard, A., Couper, R., Durie, P., Silverman, E. 1992. Exocrine pancreatic function in children with systemic lupus erythematosus. J. Rheumatol. 19, 964–967. Grimbacher, B., Huber, M., von Kempis, J., et al. 1998. Successful treatment of gastrointestinal vasculitis due to systemic lupus erythematosus with intravenous pulse cyclophosphamide: a clinical case report and review of the literature. Br. J. Rheumatol. 37, 1023–1028. Hallegua, D.S., Wallace, D.J. 2000. Gastrointestinal manifestations of systemic lupus erythematosus. Curr. Opin. Rheumatol. 12, 379–385. Heng, Y., Schuffer, M.D., Haggitt, R.C., Rohrmann, C.A. 1995. Pneumatosis intestinalis: a review. Am. J. Gastroenterol. 90, 1747–1758. Kim, H.J., Park, M.H. 1996. Obstructive uropathy due to interstitial cystitis in a patient with systemic lupus erythematosus. Clin. Nephrol. 45, 205–208. Kishimoto, M., Nasir, A., Mor, A., Belmont, H.M. 2007. Acute gastrointestinal distress syndrome in patients with systemic lupus erythematosus. Lupus 16, 137–141. Ko, S.F., Lee, T.Y., Cheng, T.T., et al. 1997. CT ﬁndings at lupus mesenteric vasculitis. Acta Radiol. 38, 115–120. Lee, C.-K., Ahn, M.S., Lee, E.Y., et al. 2002. Acute abdominal pain in systemic lupus erythematosus: focus on lupus enteritis (gastrointestinal vasculitis). Ann. Rheum. Dis. 61, 547–550. Mathew, T.H. 1998. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental mycophenolate mofetil renal transplantation study group. Transplantation 65, 1450–1454. Medina, F., Ayala, A., Jara, L.J., et al. 1997. Acute abdomen in systemic lupus erythematosus: the importance of early laparotomy. Am. J. Med. 103, 100–105. Meulders, Q., Michel, C., Marteau, P., et al. 1992. Association of chronic interstitial cystitis, protein-losing enteropathy and paralytic ileus with seronegative systemic lupus

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erythematosus: case report and review of the literature. Clin. Nephrol. 37, 239–244. Mok, C.C. 2005. Investigations and management of gastrointestinal and hepatic manifestations of systemic lupus erythematosus. Best Pract. Res. Clin. Rheumatol. 19, 741–766. Mok, C.C., Ying, K.Y., Mak, A., To, C.H., Szeto, M.L. 2006. Outcome of protein-losing gastroenteropathy in systemic lupus erythematosus treated with prednisolone and azathioprine. Rheumatology 45, 425–429. Mok, M.Y., Wong, R.W.S., Lau, C.S. 2000. Intestinal pseudoobstruction in systemic lupus erythematosus: an uncommon but important clinical manifestation. Lupus 9, 11–18. Narvaez, J., Perez-Vega, C., Castro-Bohorquez, F.J., et al. 2003. Intestinal pseudo-obstruction in systemic lupus erythematosus. Scan. J. Rheumatol. 32, 191–195. Nesher, G., Breuer, G.S., Temprano, K., et al. 2006. Lupusassociated pancreatitis. Semin. Arthritis Rheum. 35, 260–267. Nojima, Y., Mimura, T., Hamasaki, K., et al. 1996. Chronic intestinal pseudoobstruction associated with autoantibodies against proliferating cell nuclear antigen. Arthritis Rheum. 39, 877–879.

Pardos-Gea, J., Ordi-Ros, J., Selva, A., Perez-Lopez, J., Balada, E., Vilardell, M. 2005. Chronic intestinal pseudo-obstruction associated with biliary tract dilatation in a patient with systemic lupus erythematosus. Lupus 14, 328–330. Pascual-Ramos, V., Duarte-Rojo, A., Villa, A.R., HernandezCruz, B., Alarcon-Segovia, D., Alcocer-Varela, J., et al. 2004. Systemic lupus erythematosus as a cause and prognostic factor of acute pancreatitis. J. Rheumatol. 31, 707–712. Richer, O., Ulinski, T., Lemelle, I., et al. 2007. Abdominal manifestations in childhood-onset systemic lupus erythematosus. Ann. Rheum. Dis. 66, 174–178. Sawalha, A.H., Schmid, W.R., Binder, S.R., Bacino, D.K., Harley, J.B. 2004. Association between systemic lupus erythematosus and Helicobacter pylori seronegativity. J. Rheumatol. 31, 1546–1550. Sultan, S.M., Ionnaou, Y., Isenberg, D.A. 1999. A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology 38, 917–932. Yazici, Y., Erkan, D., Levine, D.M., et al. 2002. Protein-losing enteropathy in systemic lupus erythematosus: report of a severe, persistent case and review of pathophysiology. Lupus 11, 119–123.

Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 4

Antiphospholipid Syndrome Gerard Espinosa, Ricard Cervera Department of Autoimmune Diseases, Hospital Clı´nic, Villarroel 170, 0836 Barcelona, Catalonia, Spain

1. Introduction The antiphospholipid syndrome (APS) is an autoimmune prothrombotic condition characterized by venous and/or arterial thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL) [positive lupus anticoagulant (LA) test, anticardiolipin antibodies (aCL) and/or anti-b2-glycoprotein-I antibodies] (Miyakis et al., 2006). This syndrome is considered primary if it is not associated with any other underlying disease (Asherson et al., 1989), but it can appear in association with other autoimmune disorders, mainly systemic lupus erythematosus (SLE) (Font et al., 1989). It is known that aPL are directed against phospholipid binding proteins expressed on, or bound to, the surface of vascular endothelial cells or platelets (Roubey, 1996). The main protein associated with aCL activity is b2-glycoprotein-I (b2GPI) bound to phospholipids (Galli et al., 1990; Matsuura et al., 1990; McNeil et al., 1990). Despite the strong association between aPL and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated. Several pathogenic mechanisms have been proposed, including inhibition of endothelial release of prostacyclin, alterations in protein C–protein S pathway, a direct procoagulant effect on platelets, and impairment of ﬁbrinolysis

Corresponding author.

Tel./Fax: +34-93-2275774 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00004-9

(Espinosa et al., 2003) The aPL appear to play a direct pathogenic role, and the APS is now widely accepted as an example of an autoantibody-mediated disease. Given the heterogeneity of clinical manifestations in APS, it is likely that more than one pathophysiological process may play a role. The classic clinical picture of the APS is characterized by venous and arterial thromboses, fetal losses, and thrombocytopenia, in the presence of aPL. Single-vessel involvement or multiple vascular occlusions may give rise to a wide variety of presentations. Deep venous thrombosis, sometimes accompanied by pulmonary embolism, is the most frequently reported manifestation (38.9%), followed by cerebrovascular accidents, either stroke (19.8%) or transient ischemic attacks (11.1%). Early fetal loss (35.4%), late fetal loss (16.9%), premature birth (10.6%), and pre-eclampsia (9.5%) are the most frequent fetal and obstetric manifestations. However, several other manifestations are also frequently found, including thrombocytopenia (29.6%), livedo reticularis (24.1%), heart valve lesions (14.3%), hemolytic anemia (9.7%), epilepsy (7.0%), leg ulcers (5.5%), myocardial infarction (5.5%), and amaurosis fugax (5.4%), among others (Cervera et al., 2002). Long-term oral anticoagulation was identiﬁed as the best treatment for prevention of recurrent thrombosis in patients with classic APS (Bertolaccini and Khamashta, 2006). A minority of APS patients develop life-threatening multiple organ thromboses, which has been recognized as catastrophic APS (Cervera et al., 2006).

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In 2003, the eponym ‘Asherson’s syndrome’ was attached to the condition (Piette et al., 2003) This is a condition characterized by multiple vascular occlusive events, usually affecting small vessels, presenting over a short period of time, and poor prognosis (almost 50% mortality) despite multimodal treatment (Bucciarelli et al., 2006). In contrast to the classic APS, single venous or arterial medium-to-large blood vessel occlusions are uncommon. Due to the diversity of the clinical and serological presentations, an international consensus on classiﬁcation criteria for catastrophic APS has been developed (Asherson et al., 2003). Combined treatment with anticoagulants plus corticosteroids plus plasma exchange and/or intravenous immunoglobulins has been associated with a higher recovery rate. In contrast, concomitant treatment with cyclophosphamide did not demonstrate additional beneﬁt (Bucciarelli et al., 2006).

2. Digestive involvement in APS The digestive manifestations of the APS have received scarce attention. In this sense, the APS presenting with digestive involvement has been rarely reported and very often has a poor outcome (Von Landerberg et al., 2002). Furthermore, it has become obvious that there is an inordinately high frequency of digestive involvement in catastrophic APS, which is not seen with the simple or ‘classic’ APS (Erkan et al., 2003) (Table 1). In catastrophic APS, severe multiple organ dysfunction characterized by diffuse small-vessel ischemia and thromboses predominantly affecting the parenchymal organs dominates the clinical picture (Meroni et al., 2000). This fact may explain the higher frequency of digestive involvement that appears in patients with catastrophic APS.

3. Gastrointestinal involvement 3.1. Gastrointestinal ischemia The esophageal and gastric involvement has been infrequently reported in patients with aPL. Until

Table 1 Digestive involvement in patients with classic and catastrophic APS Type of digestive involvement

Classic APSa Catastrophic APSb (n=1000), n (%) (n=255), n (%)

Gastrointestinal involvement Splenic involvement Hepatic involvement Pancreatic involvement

15 (1.5)

60 (23.5)

11 (1.1) 7 (0.7) 5 (0.5)

48 (18.8) 85 (33.3) 19 (7.5)

a

Data from ‘Europhospholipid’ cohort (Cervera et al., 2002). Data from ‘Catastrophic Antiphospholipid Syndrome (CAPS) Registry’ (Bucciarelli et al., 2006) including clinical features and ﬁndings of autopsy when described. b

now, only two cases have been published (Cappell, 1994; Kalman et al., 1996); both were patients with known APS (prior venous and arterial thromboses). The former suffered from esophageal necrosis and perforation (Cappell, 1994) and the latter from giant gastric ulceration (Kalman et al., 1996). The histopathological studies in the two cases revealed organized thrombi in esophageal and gastric vessels, respectively, with no cholesterol plaques or evidence of vasculitis. The true incidence of intestinal ischemia and infarction associated with classic APS may be underestimated because of a lack of general awareness of bowel complications in patients with classic APS. Presentation may vary from symptoms of acute bowel infarction to chronic mesenteric angina, including gastrointestinal bleeding. Ischemia may involve any part of intestine, including duodenum, jejunoileum, and colon. In a recent paper, 97 APS patients (37 patients with classic APS and 60 with catastrophic APS) were retrospectively reviewed for the evidence of intestinal involvement (Cervera et al., 2007). The prevalence of abdominal pain as the presenting manifestation of intestinal ischemia was higher in patients with classic APS compared with those with catastrophic APS (76 versus 37%; Po0.005). Other clinical manifestations present in patients with classic APS were nausea or vomiting (16%), gastrointestinal hemorrhage (14%), abdominal distension (11%), weight loss (8%), diarrhea (8%),

Antiphospholipid Syndrome

and chronic intestinal angina (5%). More than a half of patients with classic APS had an acute clinical presentation of intestinal ischemia, whereas 14% had subacute, and 22% had chronic. The prevalence of patients without abdominal clinical symptoms was higher in the group of catastrophic APS compared with those with classic APS (38 versus 14%; Po0.02). In the latter, the diagnosis of intestinal involvement was made during a diagnostic procedure for nephrotic syndrome, splenomegaly, fever of unknown origin, kidney transplantation, and postsurgical control of gastric perforation due to a gastric ulcer. With regard to the type of vessel involved, the rate of venous involvement was higher in patients with classic APS (43 versus 7%; Po0.002). Furthermore, the prevalence of large-to-mediumvessel (both venous and arterial) involvement was higher in patients with classic APS compared with those with catastrophic APS (81 versus 30%; Po0.0005). The main difference in the histopathological ﬁndings between the two groups was the higher rate of microthrombosis in patients with catastrophic APS (75 versus 4%; Po0.0005). In fact, microthrombosis is the histopathological hallmark encountered in these patients (Bucciarelli et al., 2006). This is one of the features that differentiate classic APS from catastrophic APS. As we indicated above, this fact may explain the higher frequency of intestinal involvement that we found in patients with catastrophic APS. Anticoagulation (usually heparin followed by oral anticoagulation) was the most frequent treatment. Independent of medical management, 67% of patients with classic APS were treated with abdominal surgery. The mortality rate was higher in patients with catastrophic APS (55 versus 17%; Po0.0005), septic shock being the major cause of death in both groups. In the light of the results of this study, it is necessary to consider that intestinal involvement, although infrequent, is an important complication in patients with APS, especially in those with catastrophic APS. This would support the need for systematic screening for aPL in all cases of mesenteric thrombosis or

41

ischemic colitis without clear underlying predisposing factors. Another cause of intestinal ischemia is the mesenteric inﬂammatory veno-occlusive disease (MIVOD). The mesenteric veins can become occluded from causes other than venous thrombosis, such as phlebitis and venulitis, which have occasionally been described in association with SLE (Bando et al., 2003). This term has recently been used to describe ischemic injury resulting from phlebitis or venulitis affecting either the bowel or the mesentery, without any evidence of coexisting arterial inﬂammatory involvement or an obvious predisposing cause. At present, one case of APS associated with MIVOD has been described (Gu¨l et al., 1996). This was a 24-year-old Caucasian man with gangrene of small bowels and intestinal resection due to MIVOD, who later developed deep vein thrombosis in his left leg. An IgG aCL titer above 60 GPL unit/mL and thrombocytopenia conﬁrmed the diagnosis of primary APS.

3.2. Inflammatory bowel disease Patients with inﬂammatory bowel disease (IBD) rarely experience vascular complications. When present, these mainly take the form of thromboembolic disease (Solem et al., 2004). The reported prevalence of thromboembolic disease in IBD patients ranges from 1 to 8% (Koutroubakis, 2000). At present, the pathogenic mechanism of the development of thrombosis is not fully known. Recent studies have investigated the possible role of aPL in the thrombotic manifestations of IBD (Koutroubakis et al., 1998; Aichbichler et al., 1999; Gue´don et al., 2001). In most of them, aCL titers were signiﬁcantly increased in patients with IBD, but their levels are associated neither with the pathogenesis of thromboembolic events nor with clinical activity of the disease (Koutroubakis et al., 1998; Aichbichler et al., 1999). Therefore, the presence of aPL in IBD patients would be secondary solely to local inﬂammation, and they are only markers of endothelial lesions in IBD.

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4. Hepatic involvement 4.1. Budd-Chiari syndrome Budd-Chiari syndrome (BCS) is characterized by structural and functional abnormalities of the liver, caused by obstruction to the outﬂow of hepatic venous blood (Dilawari et al., 1994). The consequent liver dysfunction depends on the extension and velocity of instauration of the obstruction. BCS is clinically characterized by abdominal pain, hepatomegaly, and ascites, and the clinical presentation may range from nearly asymptomatic to fulminant liver failure (Hadengue et al., 1994; Blum et al., 1995). The etiology is unknown in a limited proportion of patients, and several myeloproliferative disorders and hypercoagulable states have been implicated, including polycythemia vera, essential thrombocythemia, paroxysmal nocturnal hemoglobinuria, antithrombin, protein C and protein S deﬁciency, resistance to activated protein C, factor V Leiden, G20210A factor II gene mutation, use of oral contraceptives, pregnancy, and postpartum state (Denninger et al., 2000). In some studies (Pomeroy et al., 1984; Shimizu et al., 1993), a relationship between BCS and elevated levels of aPL has been suggested. However, according to other authors, the pathogenic role of these antibodies is controversial (Aggarwal et al., 1998). Some authors suggest that the liver abnormalities caused by the venous outﬂow obstruction could be involved in the production of these antibodies, which would then be just an epiphenomenon secondary to the liver damage (Aggarwal et al., 1998). However, in some cases aPL were detected before the onset of BCS; this strongly suggests that the production of aPL was not a consequence of the liver abnormalities. At present, APS is considered to be the second leading cause of non-tumor-related BCS, after myeloproliferative syndromes (Zeitoun et al., 1999; Braham et al., 2001). Recently, the clinical and immunologic characteristics of 43 previously reported patients with BCS and APS (from 1983 through September 2000) have been described (Espinosa et al., 2001). Sixty-seven per cent of patients were female and 33% were male. Mean age at presentation of BCS

was 30.8712.3 years. Thirty-two (74%) patients had primary APS, and eight (19%) had deﬁned SLE. In more than half of patients, BCS was the ﬁrst clinical manifestation of APS, whereas 23% patients had a previous history of major vascular occlusion, and spontaneous fetal losses had occurred in 35% of the female patients. Anticoagulation was the most frequent treatment, followed by steroids. Different types of surgical derivative procedures were performed in a third of patients, and percutaneous transluminal angioplasty in 11%. Interestingly, of nine patients who presented with vascular occlusions before the development of BCS, only one was on prolonged anticoagulant treatment. Of seven patients who did not receive prolonged anticoagulant therapy after being diagnosed with BCS, four had new thrombotic events. Nineteen of 25 (76%) patients with prolonged anticoagulant therapy were in good health at a mean follow-up of 24 months (range, 1–96 months). The results of this review stress the clinical importance of searching for the presence of LA and aCL in all patients with hepatic vein thrombosis. In these patients, long-term highintensity anticoagulation is mandatory to prevent recurrent thrombosis. At least 20 new patients with BCS associated with APS have been described since the publication of this review.

4.2. Hepatic sinusoidal obstruction syndrome Hepatic sinusoidal obstruction syndrome (HSOS) is the new name given to hepatic veno-occlusive disease (HVOD), an unusual disorder of the liver that presents classically with tender hepatomegaly, hyperbilirubinemia, and ascites (DeLeve et al., 2002). The most frequent cause of HSOS in Western Europe and the United States is the use of high-dose chemotherapy in recipients of hematopoietic stem cell transplantation (Kumar et al., 2003), a procedure used to manage solid tumors, hematologic diseases, and autoimmune disorders (Praprotnik et al., 2005). In this setting, HSOS is caused by toxicity from high-dose chemotherapy

Antiphospholipid Syndrome

regimens, with or without total-body irradiation (conditioning therapy), and is responsible for considerable morbidity and mortality (Wadleigh et al., 2003). Endothelial damage due to pretransplant chemo-radiation and activation of hemostasis are considered to be early events in the development of HVOD with the end result being ﬁbrous obliteration of hepatic vessels. At present, very few cases with aPL as a possible causative agent for HVOD have been described (Hughes et al., 1984; Pappas et al., 1984; Morio et al., 1991). As an example, in one of them, a 37-year-old man with acute myeloblastic leukemia in ﬁrst remission underwent a bone marrow transplant following conditioning with high-dose cytarabine and total-body irradiation. The donor was an HLA-identical brother. Graft rejection occurred, and a second bone marrow transplant was performed from the same donor following conditioning with cyclophosphamide. Engraftment was achieved, but the patient developed severe jaundice and died of respiratory failure on Day 46 after the second transplant. Liver biopsy revealed luminal narrowing of the central veins, and a diagnosis of HVOD was made. The coagulation studies showed a LA, which may have contributed to HVOD (Morio et al., 1991). Recently, the causal association between aPL and HVOD following bone marrow transplantation has not been conﬁrmed (Fastenau et al., 1998). These authors have demonstrated that the incidence of aPL before conditioning was not greater in patients who developed HVOD following bone marrow transplantation.

4.3. Hepatic infarction The rarity of hepatic infarction has been explained by the protection from ischemia provided by the double arterial and portal inﬂow. In this sense, only few cases have been described in patients with ‘classic’ APS (Mor et al., 1989; Kaplan et al., 1995), and histopathological features of hepatic infarction have been described in 16% of patients with catastrophic APS (Bucciarelli et al., 2006). Of a series of 42 ‘classic’ APS patients with abdominal

43

thrombotic and ischemic manifestations evaluated with computed tomography, only one patient had hepatic infarction (Kaushik et al., 2001), and in one study of the computed tomographic appearance of hepatic infarctions in 10 patients, one had APS. She was a 43-year-old-woman with APS associated with SLE, who complained of acute severe abdominal pain. She had celiac, common hepatic, proper hepatic, and splenic arteries thrombosis. Moreover, a high prevalence of hepatic infarctions has been described during pregnancy associated with APS in the context of HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. In a review of 28 patients who had 30 pregnancies with concomitant hepatic infarction, aPL were assessed in 16 patients, 15 out of whom were found to be positive (Pauzner et al., 2003). APS was diagnosed prior to infarction in nine pregnancies. Clinically, all the patients presented with right abdominal pain, abnormal liver function tests, usually accompanied by fever, and hypertension. Even though many of these patients with hepatic infarction suffer from a disease that resembles HELLP syndrome, they do not fulﬁll the classiﬁcation criteria for HELLP. In a retrospective analysis of 16 episodes of HELLP syndrome complicating APS in 15 women, Le Thi Thuong et al. (2005) did not ﬁnd any case of liver infarction.

4.4. Nodular regenerative hyperplasia of the liver Nodular regenerative hyperplasia (NRH) of the liver is a local hyperplastic response of hepatocytes, probably due to vascular abnormalities. It is characterized by transformation of the hepatic parenchyma into hyperplastic nodules without signiﬁcant ﬁbrosis. NRH has been described associated with hematologic (Al-Mukhaizeem et al., 2004) and autoimmune disorders (Abraham et al., 2004; Sekiya et al., 1997) including patients with APS (Pe´rez Ruiz et al., 1991). The possible relationship between NRH and aPL was demonstrated by Klein et al. (2003). These authors tested

44

G. Espinosa, R. Cervera

the sera from 13 patients with histologically deﬁned NRH for aPL. Patients with serologically and histologically deﬁned primary biliary cirrhosis (PBC) and autoimmune hepatitis and healthy blood donors were used as controls. The prevalence of aCL was signiﬁcantly higher in patients with NRH compared with patients with autoimmune liver diseases and blood donors (77% versus 14%; po0.05). The pathophysiology of NRH is believed to result from altered vascular ﬂow through the liver, leading to relative sublethal ischemia, with subsequent reactive hepatocyte hyperplasia and nodule formation. This theory would explain that subclinical thromboses in the hepatic microcirculation, as a consequence of acquired thrombophilia in the form of APS, should provide the stimulus for NRH production. At present, up to 10 patients with NRH associated with aPL have been described (Cancado et al., 2006; Gaya et al., 2005; Austin et al., 2004; Klein et al., 2003; Morla` et al., 1999; Cadranel et al., 1996; Keegan et al., 1994; Pe´rez Ruiz et al., 1991).

4.5. Portal hypertension Portal hypertension has been described in three cases of post-sinusoidal hepatic blood ﬂow obstruction as the main feature of APS (Velasco et al., 1993). Clinically, these patients developed jaundice, malaise, ascites, and hepatomegaly. Doppler ultrasonography and hepatic venography showed small hepatic vein disease in two patients and partial occlusion in the suprahepatic segment of inferior vena cava in the remaining patients. In all, aCL were positive and activated partial thromboplastin time was prolonged. Other cases of portal hypertension secondary to APS associated with SLE (Inagaki et al., 2000; Takahashi et al., 1995) and rheumatoid arthritis (Hirohata et al., 2001) were reported. In the former, the authors suggested that the portal hypertension could have been caused by microthrombosis at the level of the portal vein radicles causing stenosis and obstruction. Recently, 36 patients with portal vein thrombosis have been screened for occult myeloproliferative disorders and classic

prothrombotic disorders including protein C, protein S, and antithrombin deﬁciency, factor V Leiden, factor II mutation, and aPL. Patients with a tumorous obstruction and patients with cirrhosis were excluded. aPL were found in four (11.1%) patients (Denninger et al., 2000). All these cases suggest that aPL should be investigated in patients with portal vein thrombosis of unexplained etiology. Only a few reports in the literature describe APS (primary and associated with SLE) coexistent with the combination of pulmonary and portal hypertension (Mackworth-Young et al., 1984; De Clerck et al., 1991; Bayraktar et al., 2001).

4.6. Autoimmune hepatitis and autoimmune cholestatic liver diseases Recently, 24 patients with well-deﬁned autoimmune hepatitis were investigated for the presence of aPL and for a correlation with clinical, biologic, or histological characteristics (Branger et al., 2007). The frequency of aPL was 70.8% in this series, and four patients had well-deﬁned APS. Seven patients had SLE in the aPL group whereas none in the aPL negative group. There was no correlation between hypergammaglobulinemia and the presence or the isotype of aPL. Clinical presentation and outcome as biologic and histological parameters were similar between patients with aPL compared with those without aPL. Although the frequency of aPL in autoimmune hepatitis patients was high, the authors were not able to ﬁnd clinical, biologic, or histological correlation with the presence of aPL. These results are in accordance with those described by Liaskos et al. (2005). With regard to autoimmune cholestatic liver diseases (PBC and primary sclerosing cholangitis), Zachou et al. (2006) demonstrated a signiﬁcantly higher prevalence of aCL in both compared to other liver diseases and healthy individuals. Moreover, aCL were associated with more severe disease in PBC and biochemical activity in primary sclerosing cholangitis, but they are co-factor(b2GPI) independent. The same conclusion in patients with PBC was achieved by von

Antiphospholipid Syndrome

Landerberg et al. (2005). These authors demonstrated that aPL were present in PBC patients with a higher level of the disease or more intense liver damage than in patients without aPL. Further studies on larger cohorts should clarify the association between aPL and autoimmune hepatitis and whether aCL in autoimmune cholestatic liver diseases may contribute to APS development or the progression of hepatic disease.

45

secondary phenomenon and its role in the development of portal vein thrombosis need further evaluation. The association between hepatitis C virus infection and APS is controversial (Ramos-Casals and Font, 2005), and is extensively reviewed in another chapter.

5. Splenic involvement 4.7. Antiphospholipid antibodies and cirrhosis The results of the studies that have analyzed the relationship between cirrhosis, aPL, and thrombotic events are contradictory. On the one hand, there are studies that do not support a causal relationship between them. Mangia et al. (1999) found that aCL were more frequent in patients with an advanced cirrhosis, mainly due to alcohol abuse, compared with healthy controls. However, they were not associated with thrombotic complications. For these authors, in patients with non-autoimmune liver disease, aCL production was an epiphenomenon of liver damage. The same conclusion was achieved by Gervais et al. (1996). These authors described a high prevalence of aCL in patients with alcohol cirrhosis, mainly related to the degree of liver failure but not to portal obstruction. In the study of Amitrano et al. (2004), aPL were not related either to the portal thrombosis in spite of their high prevalence [IgG aCLW10 U/mL (39%) and IgM aCLW10 U/mL (13%)]. On the other hand, Violi et al. (1994) and Quintarelli et al. (1994) described a signiﬁcant association between aPL and previous venous thrombotic events in patients with cirrhosis. The same result was described in patients with hepatocellular carcinoma due to cirrhosis related with chronic hepatitis B virus infection (Elefsiniotis et al., 2003). Recent studies have supported the causal relationship between aPL and portal vein thrombosis in cirrhotic patients (Oksuzoglu et al., 2003; Romero Go´mez et al., 2000). Therefore, patients with cirrhosis have a high prevalence of aPL. Whether it is a primary or a

5.1. Splenic infarction Although rare, and usually not isolated, splenic infarction is described in patients with aPL in SLE and in non-SLE settings (Arnold and Schrieber, 1988; Obarski et al., 1989; Cappell et al., 1993; Salcedo et al., 2000; Choi et al., 2002; Kara and Ayden, 2004). This does not usually seem to occur in classic APS but is generally described in patients with catastrophic APS (Table 1).

5.2. Autosplenectomy or functional asplenia Functional asplenia or autosplenectomy is a rare but well-recognized complication in patients with SLE and exposes these patients to the risk of life-threatening infections. At present, only two cases of functional asplenia have been reported in association with APS (Pettersson and Julkunen, 1992; Santilli et al., 2003). The former was a woman with APS associated with SLE, who presented with an unexplained thrombocytosis, and schystocytes, ovalocytes, burr cells, and Howell-Jolly bodies in the red blood cell smear. The second was an SLE patient, who presented with cutaneous vasculitis and an unexpected thrombocytosis that resulted from autosplenectomy. Subsequently, she developed full-blown APS. Unfortunately, in the other reports of patients with asplenia and SLE, the aPL status was not reported (Santilli et al., 2003). The authors hypothesize that the coagulopathy related to aPL could lead to repeated splenic microthrombotic events.

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6. Pancreatic involvement As we have described above in the splenic involvement, pancreatic involvement does not usually seem to occur in classic APS but is generally described in patients with catastrophic APS (Table 1). Unlike SLE, where the primary abnormality is vasculitis, in APS, vascular occlusion is due to thromboembolism. In this sense, the post-mortem pathological examination of pancreatitis due to APS showed generalized arterial thrombi within the pancreas (Bird et al., 1987; Wang et al., 1992). At present, three cases of pancreatitis associated with classic APS have been described (Yeh et al., 1993; Gaspari et al., 1995; Spencer, 2004). Two of them suffered from primary APS and the third was associated with SLE. In addition, two of them had a good recovery with anticoagulant treatment (Gaspari et al., 1995; Spencer, 2004). It has been suggested that the investigation of patients with idiopathic pancreatitis should include checking for aPL (Spencer, 2004).

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Hughes, G.R.V., Mackworth-Young, C.G., Harris, E.N., Gharavi, A.E. 1984. Veno-occlusive disease in systemic lupus erythematosus: possible association with anticardiolipin antibodies? Arthritis Rheum. 27, 1071. Inagaki, H., Nonami, T., Kawagoe, T., Miwa, T., Hosono, J., Kurokawa, T., Harada, A., Nakao, A., Takagi, H., Suzuki, H., Sakamoto, J. 2000. Idiopathic portal hypertension associated with systemic lupus erythematosus. J. Gastroenterol. 35, 235–239. Kalman, D.R., Khan, A., Romain, P.L., Nompleggi, D.J. 1996. Gaint gastric ulceration associated with antiphospholipid antibody syndrome. Am. J. Gastroenterol. 91, 1244–1247. Kaplan, B., Cooper, J., Lager, D., Abecassis, M. 1995. Hepatic infarction in a hemodyalisis patient with systemic lupus erythematosus. Am. J. Kidney Dis. 26, 785–787. Kara, E., Ayden, H. 2004. Antiphospholipid antibody syndrome (APS) presenting as splenic thrombosis and acute acalculous cholecystitis. Acta Chir. Belg. 104, 733–735. Kaushik, S., Federle, M.P., Schur, P.H., Krishnan, M., Silverman, S.G., Ros, P.R. 2001. Abdominal thrombotic and ischemic manifestations of the antiphospholipid antibody syndrome: CT ﬁndings in 42 patients. Radiology 218, 768–771. Keegan, A.D., Brooks, L.T., Painter, D.M. 1994. Hepatic infarction and nodular regenerative hyperplasia of the liver with associated anticardiolipin antibodies in a young woman. J. Clin. Gastroenterol. 18, 309–313. Klein, R., Goller, S., Bianchi, L. 2003. Nodular regenerative hyperplasia (NRH) of the liver – a manifestation of ‘organspeciﬁc antiphospholid syndrome’? Immunobiology 207, 51–57. Koutroubakis, I.E. 2000. Role of thrombotic risk factors in inﬂammatory bowel disease. Dig. Dis. 18, 161–167. Koutroubakis, I.E., Petinaki, E., Anagnostopoulou, E., Kritikos, H., Mouzas, I.A., Kouroumalis, E.A., Manousos, O.N. 1998. Anti-cardiolipin and anti-beta2-glycoprotein I antibodies in patients with inﬂammatory bowel disease. Dig. Dis. Sci. 43, 2507–2512. Kumar, S., DeLeve, L.D., Kamath, P.S., Tefferi, A. 2003. Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin. Proc. 78, 589–598. Le Thi Thuong, D., Tieulie, N., Costedoat, N., Andreu, M.R., Wechsler, B., Vauthier-Boruzes, D., Aumaitre, O., Piette, J.C. 2005. The HELLP syndrome in the antiphospholipid syndrome: retrospective study of 16 cases in 15 women. Ann. Rheum. Dis. 64, 273–278. Liaskos, C., Rigopoulou, E., Zachou, K., Georgiadou, S., Gatselis, N., Papamihali, R., Dalekos, G.N. 2005. J. Autoimmun. 24, 251–260. Mackworth-Young, C.G., Gharavi, A.E., Boey, M.L., Hughes, G.R. 1984. Portal and pulmonary hypertension in a case of systemic lupus erythematosus: possible relationship with a clotting abnormality. Eur. J. Inﬂam. 7, 71–74. Mangia, A., Margaglione, M., Cascavilla, I., Gentile, R., Cappucci, G., Facciorusso, D., Grandote, E., Di Minno, G., Rizzeto, M.,

Andriulli, A. 1999. Anticardiolipin antibodies in patients with liver disease. Am. J. Gastroenterol. 94, 2983–2987. Matsuura, E., Igarashi, Y., Fujimoto, M., Ichikawa, K., Koike, T. 1990. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 336, 177–178. McNeil, H.P., Chesterman, C.N., Krilis, S.A. 1990. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: b2-glycoprotein I (apolipoprotein H). Proc. Natl. Acad. Sci. USA 87, 4120–4124. Meroni, P.L., Raschi, E., Camera, M., Testoni, C., Nicoletti, F., Tincani, A., Khamashta, M.A., Balestrieri, G., Tremoli, E., Hess, D.C. 2000. Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome. J. Autoimmun. 15, 237–240. Miyakis, S., Lockshin, M.D., Atsumi, T., Branch, D.W., Brey, R.L., Cervera, R., Derksen, R.H., de Groot, P.G., Koike, T., Meroni, P.L., Reber, G., Shoenfeld, Y., Tincani, A., Vlachoyiannopoulos, P.G., Krilis, S.A. 2006. International consensus statement on an update of the classiﬁcation criteria for deﬁnite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306. Mor, F., Beigel, Y., Inbal, A., Gore, M., Wysenbeck, A.J. 1989. Hepatic infarction in a patient with the lupus anticoagulant. Arthritis Rheum. 32, 495. Morio, S., Oh, H., Hirasawa, A., Aotsuka, N., Nakamura, H., Asai, T., Yoshida, S., Ito, M. 1991. Hepatic veno-occlusive disease in a patient with lupus anticoagulant after allogeneic bone marrow transplantation. Bone Marrow Transplant. 8, 147–149. Morla`, R.M., Ramos-Casals, M., Garcı´ a-Carrasco, M., Cervera, R., Font, J., Bruguera, M., Rojas-Rodriguez, J., Ingelmo, M. 1999. Nodular regenerative hyperplasia of the liver and antiphospholipid antibodies: report of two cases and review of the literature. Lupus 8, 160–163. Obarski, T.P., Stoller, J.K., Weisntein, C., Hayden, S. 1989. Splenic infarction: a new thrombotic manifestation of the circulating lupus anticoagulant. Cleveland Clin. J. Med. 56, 174–176. Oksuzoglu, G., Bayraktar, Y., Arslan, S., Celik, I., Arslan, M., Sivri, B., Kirazli, S., Kayhan, B. 2003. Portal vein thrombosis in cirrhotics: related with anticardiolipin antibodies? Hepatogastroenterology 50, 1527–1530. Pappas, S.C., Malone, D.G., Rabin, L., Hoofnagle, J.H., Jones, E.A. 1984. Hepatic veno-occlusive disease in a patient with systemic lupus erythematosus. Arthritis Rheum. 27, 104– 108. Pauzner, R., Dulitzky, M., Carp, H., Mayan, H., Kenett, R., Farfel, Z., Many, A. 2003. Hepatic infarctions during pregnancy are associated with the antiphospholipid syndrome and in addition with complete or incomplete HELLP syndrome. J. Thromb. Haemost. 1, 1758–1763. Pe´rez Ruiz, F., Orte Martinez, F.J., Zea Mendoza, A.C., Ruiz del Arbol, L., Moreno Caparros, A. 1991. Nodular regenerative hyperplasia of the liver in rheumatic disorders: report of seven cases and review of the literature. Semin. Arthritis Rheum. 21, 47–54.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 5

Gastrointestinal Involvement in Systemic Sclerosis Dinesh Khanna Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, 1000 Veterans Avenue, Rm 32-59, Rehabilitation Building, Los Angeles, CA 90095, USA

Disease of the gastrointestinal tract (GIT) occurs in approximately 90% of patients with systemic sclerosis (SSc) (Sjogren, 1996; Sallam et al., 2006) and has a major impact on their quality of life. Every part of the GIT can be involved in SSc, including the mouth (xerostomia), esophagus (dysmotility, acid reﬂux), stomach (vascular ectasia, gastroparesis), intestines (vascular lesions, hypomotility, bacterial overgrowth, toxic megacolon), and anorectal system (fecal incontinence) (Sjogren, 1996; Sallam et al., 2006). This chapter provides practical guidance in the diagnosis and treatment of SSc-associated GIT involvement.

1.1. Vascular hypothesis

1. Pathogenesis of GIT dysmotility

1.2. Autoimmune hypothesis

Although different GI organ systems may manifest GIT involvement in a variety of ways, the underlying pathophysiology is the same (Clements et al., 2003). Dysmotility of the smooth muscles of the GIT is the primary abnormality. Different hypotheses have been put forward to explain the pathophysiology of GIT involvement.

A second possibility is autoimmune-mediated injury. In one study, high-titer antibodies directed against myenteric neurons were detected in 19 of 41 patients with SSc, but not in patients with idiopathic gastrointestinal dysmotility (Howe et al., 1994). In another study, rats were immunized with puriﬁed immunoglobulin G from the serum of patients with SSc who had anti-myenteric neuronal antibodies, and intestinal motility effects in rats were assessed (Eaker et al., 1999). Passive immunization led to the prolongation and disruption of rat intestinal myoelectric activity; there was no effect on the myoelectric activity when the rats were immunized by immunoglobulin G of normal healthy controls.

Corresponding author.

Tel.: (310) 825-3061; Fax: (310) 206-8606 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00005-0

Sjogren (1994) proposed that the initial GIT lesion in SSc is neural dysfunction, which is caused by arteriolar changes in the vaso nervosum or by collagen deposits. During this phase, the smooth muscle is still functional; patients are generally asymptomatic and respond to prokinetic agents. In the second phase, there is atrophy of the smooth muscle, which results in GIT-related symptoms with some response to prokinetic agents. The last phase consists of complete muscle ﬁbrosis, and the smooth muscle does not respond to prokinetic agents.

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2. Esophagus Esophageal involvement occurs in 50–90% of patients with SSc (Sjogren, 1994). Esophageal dysmotility in SSc is caused by a decrease in, or complete absence of, lower esophageal sphincter (LES) pressures, and by decreased amplitude of distal esophageal peristalsis (Sjogren, 1996), resulting in gastroesophageal reﬂux disease (GERD). SSc primarily affects the distal twothirds of the esophagus; the motility of the esophageal sphincter and proximal esophagus is generally normal.

2.1. Gastroesophageal reflux disease Although heartburn is the most common symptom of GERD, other symptoms may include odynophagia, mouth ulcers, substernal chest pain, chronic laryngitis, chronic nocturnal cough, and asthma (Weinstein and Kadell, 2004). In addition, an association between GERD and interstitial lung disease has been proposed in SSc (Troshinsky et al., 1994; Lock et al., 1998; Marie et al., 2001a). The goals of GERD treatment include (1) relieving symptoms, (2) preventing distal esophageal scarring, and (3) reducing the incidence of Barrett’s esophagus.

out other causes of esophagitis (Hendel et al., 1988). Some authors have suggested barium radiography and upper endoscopy as a baseline test before treatment is initiated (Weinstein and Kadell, 2004). Esophageal manometry can document hypomotility but is usually not performed routinely since a barium swallow has a good correlation with manometry (Clements et al., 1979). In addition, many structural abnormalities not demonstrated by manometry are identiﬁed by barium radiography. Manometry is helpful in patients who are considering surgery for intractable GERD symptoms or patients undergoing evaluation for a heart–lung transplant for advanced lung involvement. Similarly, although 24-h pH monitoring is helpful to document the GERD, it is cumbersome for the patient and is technically difﬁcult to do. It can be used to assess if there is complete suppression of acid production on therapy before elective surgery is considered. In addition, 24-h pH monitoring is helpful to assess if there is a correlation between acid reﬂux and continuing symptoms in patients receiving maximum therapy for their GERD (Weinstein and Kadell, 2004). Reﬂux (pHo4) for greater than 4% of the 24-h period is considered abnormal (Weinstein and Kadell, 2004).

2.2. Barrett’s esophagus 2.1.1. Treatment approach Treatment consists of anti-reﬂux measures and medications as detailed in Tables 1 and 2. I usually start empirical therapy with a proton-pump inhibitor (PPI) twice a day (Sjogren, 1994) and then sequentially increase the dose (Table 2) (Sallam et al., 2006; Hendel et al., 1992). The goal of the therapy is to completely eliminate the symptoms of GERD. If the symptoms continue on high doses of PPI, I add a prokinetic agent 30–60 min before each meal and a histamine type-2 receptor blocker at bedtime. If the patient continues to complain of heartburn and other GERDrelated symptoms after 2–3 weeks, I do a complete evaluation, such as a barium swallow (Fig. 1) and upper endoscopy, to assess for strictures and rule

Barrett’s esophagus is a complication of longstanding GERD (Chang and Katzka, 2004; Shaheen and Ransohoff, 2002) and was present in approximately 13% of 110 consecutive patients with SSc (Wipff et al., 2005) receiving chronic therapy with PPI (an incidence similar to that seen in patients with GERD) (Chang and Katzka, 2004; Shaheen and Ransohoff, 2002). Barrett’s esophagus is associated with adenocarcinoma in SSc (Recht et al., 1988). In a large retrospective study of 110 patients with SSc (Wipff et al., 2005), there were no clinical or biological differences in patients who developed Barrett’s esophagus vs. those who did not. The American College of Gastroenterology (Chang and Katzka, 2004; Sampliner, 2002) has developed guidelines for the management of

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Table 1 GIT involvement with recommended testing and treatment Problem

Test

Treatment

Gastroesophageal reﬂux disease

Barium swallow, upper endoscopy, esophageal manometrya, 24-h pH monitoringa

Anti-reﬂux measures Head of the bed elevated using wooden blocks under the feet at the head of bed or using wedge pillow. Take frequent small meals (5–6 per day). Avoid eating or drinking ﬂuids 2 h before bedtime. Stop smoking (if currently smoking). Avoid or minimize acid producing foods (fat, chocolate, and coffee). Do not wear tight belts as they put pressure on the abdomen and the lower esophageal pressure sphincter. Medications Anti-secretory Proton-pump inhibitors (may require 2–4 times the FDA-approved doses), H2 blockers Promotility (take 30–60 min before meals) Metoclopramide, erythromycin, domperidoneb, cisapridec Surgical procedures Endoscopic dilatation of strictures, fundoplication

Gastroparesis

Gastric radionuclide emptying study, upper endoscopya

Anti-reﬂux measures Take frequent small meals (5–6 per day). Avoid eating or drinking ﬂuids 2 h before bedtime. Medications Anti-secretory and promotility agents (see GERD section) Gastric electric stimulationd, jejunal feeding tube

Watermelon stomach (iron deﬁciency anemia)

Upper endoscopy, colonoscopya, push enteroscopya, radiolabeled red blood scana, video capsule endoscopya

Medications Anti-secretory agents Endosocopic procedures Argon laser ablation, argon plasma coagulation, Nd:YAG laser Surgical Antrectomy

Bacterial overgrowth syndrome

Serum iron, calcium, magnesium, alkaline phosphatase, serum carotene, vitamin B12 and methylmalonic acid, vitamin D, and prothrombin time, bone density measurement, glucose hydrogen breath testa, lactulose hydrogen breath testa, 14C-D-xylose breath testa, fecal fat quantiﬁcationa, bacterial and fungal culture from jejunal aspiratea

Medications Antibiotic therapy Amoxicillin, ciproﬂoxacin, metronidazole, doxycycline, neomycine, rifaximine (monthly rotating, intermittent, or continuous therapy) Vitamins Adequate calcium/vitamin D daily

Intestinal pseudoobstruction

Plain radiographs of the chest (to rule out free air) and abdomen, CT of the abdomen

Bowel rest and intravenous nutrition support, total parenteral nutrition Medications Promotility agents Octreotide, metoclopramide, erythromycin, domperidoneb, cisapridec

D. Khanna

54 Table 1 (continued ) Problem

Test

Treatment

Constipation

Plain radiographs of the abdomen

Diarrhea

Work-up as recommended for bacterial overgrowth syndrome

Rectal incontinence

Anorectal manometry, endoscopic ultrasounda

Medications Stimulant laxatives Senna, lactulose, bisacodyl, polyethylene glycol (Golytelys) Medications Bulking agents Citrucel Antidiarrheal agents Loperamide Medications Bulking agents Citrucel Antidiarrheal agents Loperamide Other modalities Biofeedback Sacral nerve stimulation Surgery Repair for rectal prolapse

Adapted from (Sallam et al., 2006; Jaovisidha et al., 2005; Khanna and Furst, 2007). a Recommended only if symptoms do not improve after initial treatment. b Not FDA-approved in US. c Available in US on compassionate basis (call 1-800-JANSSEN). d Not approved/studied for SSc. e Minimal systemic absorption.

Table 2 Proton pump inhibitors, prokinetic agents used in the treatment of GIT involvement Generic name

Oral dose

Dose adjustment

a

Proton pump inhibitors Esomeprazole Lansoprazole Omeprazole Pantoprazole Raberprazole

20–80 mg 15–60 mg 20–80 mg 40–80 mg 20–40 mg

Prokinetic agentsd Cisapridee Domperidonef Erythromycinb,g Metoclopramideb Octreotideb,h

10–20 mg, 4 times a day 10–20 mg, 4 times a day 250 mg, 3 times a day 5–10 mg, 4 times a day 50 mg, 1–2 times a day

a

per per per per per

dayb dayb,c day dayb day

Severe hepatic impairment Severe hepatic impairment Caution during severe hepatic impairment No adjustment for renal or hepatic disease Caution during severe hepatic impairment Decrease Decrease Decrease Decrease Decrease

dosage dosage dosage dosage dosage

in in in in in

All administered daily before breakfast. Second dose, if necessary, should be given before evening meal. Available for intravenous therapy. c Available as soluble tablet. d 30 to 60 min before each meal and at bedtime. e Available in US on compassionate basis (1-800-JANSSEN). f Not available in US. g Available for intravenous and intramuscular use. h Usually given subcutaneously. b

hepatic impairment renal impairment renal impairment renal impairment renal impairment

Gastrointestinal Involvement in Systemic Sclerosis

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demonstrated in patients with SSc (Sjogren, 1994). In a study of 22 consecutive patients with SSc, gastric impairment was seen in approximately 80% of patients on electrogastrography, and 50% had delayed gastric emptying (Marie et al., 2001b). As a result, patients with SSc develop clinical symptoms of gastroparesis, including bloating, nausea and vomiting, abdominal pain, and excessive ﬂatulence; these symptoms may contribute to signiﬁcant weight loss.

3.1.1. Treatment approach

Figure 1. Barium swallow showing characteristic patulous esophagus.

Barrett’s esophagus: In patients with Barrett’s esophagus with no dysplasia on biopsy, surveillance endoscopy is recommended every 3 years; in patients with low-grade dysplasia, surveillance endoscopy is recommended every 1 year; and in patients with high-grade dysplasia, surveillance endoscopy is recommended every 3 months, along with an esophagectomy or endoscopic ablation.

3. Stomach 3.1. Gastroparesis Like the esophagus, the stomach is also affected by SSc. Alterations in gastric motility, myoelectric activity, and gastric emptying have been

In addition to advising patients to take small meals and avoid lactose-containing products (e.g. milk), I initiate prokinetic therapy (Table 2). Based on small studies, different authors recommend metoclopramide and erythromycin as initial prokinetic agents (Sallam et al., 2006); octreotide inhibits antral motility and is not helpful for gastric dysmotilty (Sallam et al., 2006). I start empirical treatment, although an initial gastric emptying study can be performed because symptoms of gastroparesis and small bowel bacterial overgrowth overlap. In patients who continue to have symptoms on prokinetic therapy, I perform a gastric emptying study to conﬁrm the diagnosis. If the gastric emptying study is normal or near normal on prokinetics, further work-up to assess small bowel involvement is done (detailed in the next section). Some experts do a baseline gastric emptying study (before initiating prokinetic therapy) to document gastroparesis, and repeat the procedure if symptoms do not improve after treatment (Daniel E. Furst, MD, personal communication). For patients who do not improve with prokinetic therapy but have acceptable intestinal transit, a jejunal tube may be an option. Gastric electric stimulation is a novel therapy for refractory symptoms. A recent systematic review (Zhang and Chen, 2006) showed the beneﬁcial effects of gastric electric stimulation (Enterra Therapys) for upper GIT symptoms, including reduced nausea/vomiting, decreased duration of gastroparesis-related hospitalizations, and improved quality of life in patients with diabetes, surgery, or gastroparesis due to idiopathic causes. Gastric

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electric stimulation has not been evaluated in SSc. Some data support the use of acupuncture (Sallam et al., 2007).

3.2. Gastric antral vascular ectasia (watermelon stomach) Gastric antral vascular ectasia (GAVE) is an important cause of iron deﬁciency anemia in patients with SSc. Because its characteristic appearance on the upper endoscopy resembles the stripes of a watermelon, it is also termed ‘watermelon’ stomach (Fig. 2). The prevalence of GAVE in SSc ranges from 9 to 14% in different published series (Marie et al., 2001b; Gostout et al., 1992; Duchini and Sessoms, 1998), with a higher likelihood in patients with limited disease (Marie et al., 2001b). The presenting symptoms may be fatigue and tiredness, and a complete blood count may show moderate-to-severe iron deﬁciency anemia. In some patients, repeated blood transfusions are necessary (Elkayam et al., 2000).

3.2.1. Treatment approach Treatment consists of endoscopic therapy with argon plasma coagulation, argon laser, or Nd:YAG

laser (Sebastian et al., 2003), the choice of therapy depending on the person performing the endoscopy (Calamia et al., 2000; Sebastian et al., 2004). Most of the patients require more than one session, and long-term outcomes are generally good. If everything else fails, an antrectomy may be necessary (Sherman et al., 2003).

4. Small bowel Intestinal dysmotility has been reported in 40–88% of patients with SSc (Sallam et al., 2006; Clements et al., 2003). The dysmotility can lead to bacterial overgrowth syndrome, intestinal pseudoobstruction, and pneumatosis cystoides intestinalis (Sallam et al., 2006).

4.1. Bacterial overgrowth syndrome Bacterial overgrowth syndrome is caused by stasis of the intestinal contents, resulting in migration and colonization of bacteria from the colon (Sjogren, 1994). The symptoms include bloating, nausea, vomiting, abdominal pain, diarrhea (with pale, greasy, voluminous, foul-smelling stools), excessive ﬂatulence, and inability to gain or

Figure 2. Gastric antral venous ectasia or ‘‘watermelon’’ stomach on upper endoscopy.

Gastrointestinal Involvement in Systemic Sclerosis

maintain body weight with good oral intake; the symptoms overlap with that of gastroparesis. Low serum carotene, a marker of vitamin A absorption, is associated with bacterial overgrowth and can be used as a screening test (Clements et al., 2003; Weinstein and Kadell, 2004). Since bacterial overgrowth syndrome can cause deﬁciency of fatsoluble vitamins, vitamin B12, and iron, I get serum B12, methylmalonic acid, iron, calcium, magnesium, albumin, vitamin D, alkaline phosphatase, and prothrombin time baseline readings. Because bacterial overgrowth is associated with low bone mineral density when compared to ageand sex-matched controls (Di Stefano et al., 2001; Stotzer et al., 2003), a bone density scan can be done to get a baseline value.

4.1.1. Treatment approach My treatment approach includes an empirical trial of a broad-spectrum antibiotic (Table 1) for 2–4 weeks to assess the improvement in symptoms, especially of bloating and diarrhea (Attar et al., 1999). I choose this approach rather than doing a breath test because the sensitivity and speciﬁcity of the lactulose hydrogen breath test in detecting bacterial overgrowth are only 68 and 44%, respectively, and for the glucose breath test only 62 and 83%, respectively (Romagnuolo et al., 2002; Corazza et al., 1990). If there is a subjective improvement in the symptoms, the patients can be followed closely to see if the symptoms reoccur (in the majority they do), or can continue cyclic antibiotic therapy for 2 weeks on and then 2–4 weeks off. Some physicians use different antibiotics to prevent bacterial resistance. All patients should receive standard doses of a multivitamin, 1500 mg/day of calcium and 800 IU of vitamin D. Additional replacement of multivitamins is guided by the laboratory tests described above. Probiotic therapy may have a role in the treatment of bacterial overgrowth syndrome, but there is a lack of well-designed trials. I recommend yogurt with live-active cultures to be taken everyday because it provides 15–20% of daily required calcium and lacks side-effects. Total parenteral nutrition is required if weight loss continues despite therapy.

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If patients show no symptomatic improvement with antibiotic therapy, they should get a complete work-up to assess gastric and small intestine dysmotility as detailed in Table 1.

4.2. Intestinal pseudo-obstruction Intestinal pseudo-obstruction is common in patients with SSc and usually presents as abdominal pain and distention, nausea, vomiting, and inability to pass ﬂatulence.

4.2.1. Treatment approach I usually admit patients to the hospital, and all of them undergo plain radiographs of the abdomen, a barium radiographic study, and a computer tomography scan of the abdomen to rule out mechanical obstruction. The initial treatment includes bowel rest, intravenous ﬂuids, and correction of electrolyte imbalances. In addition, I prescribe prokinetic therapy and broad-spectrum antibiotics to decrease the bacterial load in the small intestine. Different case series have reported the effectiveness of metoclopramide, cisapride, and domperidone in relieving pseudo-obstruction; erythromycin has no effect on intestinal dysmotility in patients with SSc (reviewed in Sallam et al., 2006). Octreotide, a somatostatin analogue, improves intestinal motility and has been studied in SScrelated pseudo-obstruction with favorable results (Soudah et al., 1991; Perlemuter et al., 1999; Marie et al., 2007). I start with octreotide at 50 mg subcutaneously twice a day during an acute attack, and clinical improvement (apparent by the presence of bowel sounds, passing of ﬂatulence, and decreasing abdominal pain) is usually seen within 48–72 h. The dose is increased up to 200 mg if a satisfactory response is not observed. It is imperative to rule out bowel obstruction, as a trial of octreotide may lead to perforation. Total parenteral nutrition is usually required while the patient is recovering. For patients with recurrent episodes of pseudo-obstruction, 50 mg of octreotide at bedtime is usually therapeutic and depot octreotide is available that can be prescribed on a monthly basis. A combination of octreotide and erythromycin can be tried in resistant cases (Verne et al., 1995). Surgery

D. Khanna

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should be avoided but may be needed for venting (decompression to relieve symptoms) and feeding, and to exclude intestinal obstruction.

4.3. Pneumatosis cystoides intestinalis Pneumatosis cystoides intestinalis, or air in the bowel wall, has been reported in SSc. It is usually of no consequence, but rarely the air-ﬁlled cysts in the bowel may rupture, leading to benign pneumoperitoneum (Weinstein and Kadell, 2004). As the cysts do not require surgery, physicians should be aware of this.

5. Colon and anorectal disorders Colonic involvement is seen in 20–50% of patients with SSc and usually presents as constipation or diarrhea. Colonic contractions are usually reduced or absent in patients with SSc, resulting in prolonged colonic transit (Sallam et al., 2006) which can cause pseudo-sacculations (Fig. 3) and symptoms of constipation. Diarrhea usually results from bacterial overgrowth syndrome or fecal incontinence seen with anorectal involvement. Anorectal involvement is common and reported in 50–70% of patients with SSc. The patients present with chronic diarrhea, fecal incontinence,

Figure 3. Barium study showing pseudo-sacculations.

Gastrointestinal Involvement in Systemic Sclerosis

and rectal prolapse. The most common manometric abnormality is an absent or diminished rectoanal inhibitory reﬂex (Massone et al., 2002; Hamel-Roy et al., 1985). The response of the internal anal sphincter is diminished or absent, and the response of the external sphincter is either normal or increased.

5.1. Treatment approach For patients with constipation, I avoid a high-ﬁber diet and bulk-forming laxatives since these can make the constipation worse. I recommend liberal ingestion of ﬂuids and use stimulant and osmotic laxatives such as senna, lactulose, bisacodyl, and polyethylene glycol (Golytelys). These laxatives exert their effects primarily via alteration of electrolyte transport by the intestinal mucosa, and by increasing intestinal motor activity. There is no convincing evidence that chronic use of stimulant laxatives causes structural or functional impairment of the colon, nor do they increase the risk for colorectal tumors (Weinstein and Kadell, 2004; Wald, 2003). I advise patients to take their laxatives every 2–3 days to maintain a healthy bowel regimen. Patients with diarrhea are treated with antibiotics (for bacterial overgrowth syndrome) and with judicious use of anti-diarrheal agents. For anorectal involvement, biofeedback therapy has been used. Sacral nerve stimulation has been successful in people with fecal incontinence (Keneﬁck et al., 2002; Hetzer et al., 2007); it requires insertion of an implantable pulse generator under local anesthesia by a surgeon. The short- and longterm effects have been very encouraging, with a decrease in episodes of fecal incontinence and marked improvement in quality of life (Keneﬁck et al., 2002; Hetzer et al., 2007), and the procedure is associated with minimal morbidity. A surgical procedure is usually required for rectal prolapse.

6. Patient-reported outcome measure The majority of patients with SSc have multiple types of GIT involvement with overlapping

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symptoms, making quantiﬁcation of GIT in SSc extremely challenging. In addition, the correlation between histological or physiological severity and GIT symptoms has been poor in recent studies (Sallam et al., 2006; Sjogren, 1994; Marie et al., 2001b), stressing the need for a validated patientreported instrument. Our group recently developed a patient-reported outcome measure, the Scleroderma Gastrointestinal Tract 1.0 (SSC-GIT 1.0) instrument (Khanna et al., 2007), to capture GIT involvement in patients with SSc. SSC-GIT 1.0 is a 52-item self-administered instrument that is speciﬁcally developed for people with SSc and GIT involvement. SSC-GIT 1.0 is feasible—the 52-item instrument takes approximately 11 min to complete and covers the whole range of GIT involvement. SSCGIT 1.0 has six scales—reﬂux/indigestion, diarrhea, constipation, pain, emotional well-being, and social functioning—that measure different aspects of GIT involvement. In a cross-sectional study of 88 subjects with SSc and GIT involvement, the instrument showed acceptable test–retest reliability, internal consistency reliability, and construct validity. SSC-GIT 1.0 was able to discriminate between GIT severity; participants who rated their GIT disease as ‘mild’ had the highest scores (indicating better health) on all of the six scales, whereas participants who rated their GIT as ‘severe’ had the lowest scores (indicating poor health). The instrument is available free of charge from the author ([email protected]).

7. Conclusion GIT involvement in SSc is very common and has a major impact on quality of life (Nietert et al., 2005). A proactive approach is suggested (Weinstein and Kadell, 2004). The cornerstones of GIT examination are imaging studies and laboratory tests; physical examination of the GIT system yields little information (Weinstein and Kadell, 2004). For motility disorders, a barium contrast study is the preferred radiographic procedure, and for assessment of mucosal disease, endoscopy is the preferred test.

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D. Khanna

Acknowledgment Dr. Khanna was supported by the Scleroderma Foundation (New Investigator Award) and a National Institutes of Health Award (NIAMS K23 ARO53858-01A1).

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Gastrointestinal Involvement in Systemic Sclerosis Perlemuter, G., Cacoub, P., Chaussade, S., Wechsler, B., Couturier, D., Piette, J.C. 1999. Octreotide treatment of chronic intestinal pseudoobstruction secondary to connective tissue diseases. Arthritis Rheum. 42 (7), 1545–1549. Recht, M.P., Levine, M.S., Katzka, D.A., Reynolds, J.C., Saul, S.H. 1988. Barrett’s esophagus in scleroderma: increased prevalence and radiographic ﬁndings. Gastrointest. Radiol. 13 (1), 1–5. Romagnuolo, J., Schiller, D., Bailey, R.J. 2002. Using breath tests wisely in a gastroenterology practice: an evidencebased review of indications and pitfalls in interpretation. Am. J. Gastroenterol. 97 (5), 1113–1126. Sallam, H., McNearney, T.A., Chen, J.D. 2006. Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma). Aliment. Pharmacol. Ther. 23 (6), 691–712. Sallam, H., McNearney, T.A., Doshi, D., Chen, J.D. 2007. Transcutaneous electrical nerve stimulation (TENS) improves upper GI symptoms and balances the sympathovagal activity in scleroderma patients. Dig. Dis. Sci. 52 (5), 1329–1337. Sampliner, R.E. 2002. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am. J. Gastroenterol. 97 (8), 1888–1895. Sebastian, S., McLoughlin, R., Qasim, A., O’Morain, C.A., Buckley, M.J. 2004. Endoscopic argon plasma coagulation for the treatment of gastric antral vascular ectasia (watermelon stomach): long-term results. Dig. Liver Dis. 36 (3), 212–217. Sebastian, S., O’Morain, C.A., Buckley, M.J. 2003. Review article: current therapeutic options for gastric antral vascular ectasia. Aliment. Pharmacol. Ther. 18 (2), 157–165. Shaheen, N., Ransohoff, D.F. 2002. Gastroesophageal reﬂux, Barrett esophagus, and esophageal cancer: scientiﬁc review. JAMA 287 (15), 1972–1981.

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Sherman, V., Klassen, D.R., Feldman, L.S., Jabbari, M., Marcus, V., Fried, G.M. 2003. Laparoscopic antrectomy: a novel approach to treating watermelon stomach. J. Am. Coll. Surg. 197 (5), 864–867. Sjogren, R.W. 1994. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum. 37 (9), 1265–1282. Sjogren, R.W. 1996. Gastrointestinal features of scleroderma. Curr. Opin. Rheumatol. 8 (6), 569–575. Soudah, H.C., Hasler, W.L., Owyang, C. 1991. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N. Engl. J. Med. 325 (21), 1461–1467. Stotzer, P.O., Johansson, C., Mellstrom, D., Lindstedt, G., Kilander, A.F. 2003. Bone mineral density in patients with small intestinal bacterial overgrowth. Hepatogastroenterology 50 (53), 1415–1418. Troshinsky, M.B., Kane, G.C., Varga, J., Cater, J.R., Fish, J.E., Jimenez, S.A., et al. 1994. Pulmonary function and gastroesophageal reﬂux in systemic sclerosis. Ann. Intern. Med. 121 (1), 6–10. Verne, G.N., Eaker, E.Y., Hardy, E., Sninsky, C.A. 1995. Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction. Dig. Dis. Sci. 40 (9), 1892–1901. Wald, A. 2003. Is chronic use of stimulant laxatives harmful to the colon? J. Clin. Gastroenterol. 36 (5), 386–389. Weinstein, W., Kadell, B.M. 2004. The gastrointestinal involvement in systemic sclerosis. In: P.J. Clements, D.E. Furst (Eds.), Systemic Sclerosis. Lippincott Williams and Wilkins, Philadelphia, pp. 293–308. Wipff, J., Allanore, Y., Soussi, F., Terris, B., Abitbol, V., Raymond, J., et al. 2005. Prevalence of Barrett’s esophagus in systemic sclerosis. Arthritis Rheum. 52 (9), 2882–2888. Zhang, J., Chen, J.D. 2006. Systematic review: applications and future of gastric electrical stimulation. Aliment. Pharmacol. Ther. 24 (7), 991–1002.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 6

Inﬂammatory Myopathies Lara Dani, Ingrid E. Lundberg Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden

1. Introduction Polymyositis and dermatomyositis are autoimmune inﬂammatory connective tissue diseases that are characterized by chronic inﬂammation of striated muscle and, in the case of dermatomyositis, also by skin involvement. They are rare diseases with an annual incidence of 5–10 new cases per million people (Medsger et al., 1970). The peak age at onset of polymyositis or dermatomyositis in adults is between 50 and 60 years. Both polymyositis and dermatomyositis are more frequent in women than in men (women:men, 2:1). Dermatomyositis, but rarely polymyositis, also occurs in children, in which case it is called juvenile dermatomyositis (Klippel and Dieppe, 2000). The disease mechanisms that cause muscle weakness are not fully understood, but both immune-mediated muscle ﬁber necrosis as well as non-immune mechanisms are likely to be involved, such as cytokine-mediated muscle weakness, endoplasmic stress that could lead to an acquired metabolic myopathy (Grundtman et al., 2007). Moreover, disuse of muscle as well as glucocorticoids treatment may lead to muscle atrophy. The most important clinical signs commonly seen in both polymyositis and dermatomyositis are proximal, symmetrical, and often painless progressive muscle weakness and reduced muscle

Corresponding author.

Tel.: +46-8-5177-3020; Fax: +46-8-5177-3080 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00006-2

endurance. The muscle groups mainly involved are the shoulder and pelvic girdles, but neck ﬂexor weakness and thoracic and pharyngeal muscle weakness can also occur. The onset of muscle impairment is typically insidious over weeks to months. In dermatomyositis the skin involvement results most often in a heliotrope rash of eyelids and in Gottron’s papulae, which are erythematous plaques over dorsal aspects of joints. Extramuscular symptoms besides skin rash are common in polymyositis and dermatomyositis, such as fever, weight loss, arthritis, arthralgia, pulmonary symptoms due to thoracic muscle weakness, interstitial lung disease or aspiration pneumonia, and cardiac symptoms such as atrioventricular conduction defects, myocarditis, and more rarely congestive heart failure. In children with juvenile dermatomyositis calcinosis in skin, subcutaneous tissue or muscle may impose a particular problem. Laboratory abnormalities including elevated levels of serum muscle enzymes (especially creatine kinase) are present in most patients, and abnormal electromyography is frequent (ﬁbrillation potentials in 90% of patients). Muscle biopsy ﬁndings that support polymyositis or dermatomyositis diagnosis are endomysial and/or perivascular inﬁltrates of mononuclear inﬂammatory cells and signs of myopathy including muscle ﬁber degeneration and necrosis of myoﬁbrils and expression of major histocompatibility complex (MHC) class I in muscle ﬁbers. The inﬂammatory inﬁltrates are mainly characterized by T lymphocytes and macrophages. A muscle biopsy is also important in the diagnostic evaluation to exclude other

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myopathies. Autoantibodies are common and present in approximately 60–70% of the patients. Some autoantibodies are speciﬁc for myositis, so-called myositis-speciﬁc autoantibodies, the most frequent being anti-Jo-1 autoantibodies present in 20–30%, and anti-Mi-2 present in 6% (Hengstman et al., 2002). Myositis-associated autoantibodies include anti-PM-Scl and anti-RNP autoantibodies that are often present in overlap syndromes where two inﬂammatory systemic diseases coexist in the same patient, especially polymyositis and systemic sclerosis with anti-PM-Scl and mixed connective tissue disease (MCTD) with anti-RNP antibodies. None of these autoantibodies have been reported to confer risk to develop involvement of the gastrointestinal (GI) tract. Inclusion body myositis (IBM) is a special subtype of myositis, which is characterized by vacuoles and intranuclear and intracytoplasmatic inclusions in muscle ﬁbers in addition to inﬂammatory inﬁltrates resembling polymyositis. Clinically distinct features are slowly progressive onset, over months to years, weakness in both proximal and distal muscle often together with evident muscle atrophy, and furthermore, usually resistance to glucocorticoid and other immunosuppressive treatment. The most often recommended therapy today for patients with polymyositis or dermatomyositis is based on a combination of high-dose glucocorticoids (0.75–1 mg/kg/day) with another immunosuppressive drug like azathioprine or methotrexate. There are anecdotal reports that cyclosporine A, mycophenolite mofetile, or cyclophosphamide may be effective, but controlled trials are missing. There is conﬂicting data as to whether high-dose intravenous globulin is effective in polymyositis and dermatomyositis (Dalakas, 2006; Barbasso Helmers et al., 2007). Despite the use of these immunosuppressive therapies, many patients are left with muscle impairment and some do not respond at all. Thus, there is a need for improved therapy. The overall prognosis is hard to estimate because of the rarity of the disease, but nowadays the expected survival with the use of glucocorticoids in combination with immunosuppressive drugs, excluding paraneoplastic polymyositis/ dermatomyositis, is over 90% ﬁve-year survival

(Klippel and Dieppe, 2000). Factors associated with poorer survival are dysphagia with aspiration pneumonia, lung or heart involvement, and side effects of treatment. There are several mechanisms that may cause GI-tract involvement in patients with inﬂammatory myopathies. First, striated muscle in the GI tract could be affected by inﬂammation and could lead to weakness and cause disturbance of motility at various levels of the GI tract. The inﬂammation in dermatomyositis is often perivascular, and in occasional cases, vasculitis in the GI tract could be seen. The latter has mainly been reported in juvenile dermatomyositis. Other autoimmune reactions than muscle inﬂammation localized to the GI tract have been observed in patients with myositis, such as celiac disease and autoimmune hepatitis. Finally, the mucosal membrane may be affected due to decreased salivation as a result of a secondary Sjo¨gren’s syndrome. These manifestations are in focus of this review and will be discussed in relation to different parts of the GI tract.

2. Oral cavity Very few reports about patients with myositis include problems of the oral cavity. In one recent retrospective report including 34 Hungarian patients, several problems of the oral cavity were observed, however (Ma`rton et al., 2005). Although facial muscles are rarely involved in myositis patients, weakness of masticatory muscle was reported as one problem of the oral cavity in myositis patients (Ma`rton et al., 2005). The most prominent symptom of the oral cavity was dryness of mouth with objectively reduced saliva ﬂow rate and labial biopsies with ﬁbrosis and interstitial perivascular inﬁltration (Ma`rton et al., 2005). Increased caries prevalence was also seen compared to the general population (Ma`rton et al., 2005). An unusual manifestation of oral cavity is macroglossia with dysartria, swallowing difﬁculties, and noisy breathing, reported in one patient with polymyositis. EMG and biopsy conﬁrmed changes compatible with myositis in the tongue,

Inflammatory Myopathies

and no other cause of macroglossia was found. Symptoms resolved quickly with glucocorticoids and infusions with high-dose intravenous immunoglobulins (Chauvet et al., 2002).

3. Dysphagia The most frequently occurring symptom in the GI tract in myositis patients is difﬁculties with swallowing. Difﬁculty in swallowing has been reported in 12–54% of patients with polymyositis or dermatomyositis, and it is more frequent in the acute than in the late chronic phase of the disease (Sonies, 1997). In IBM, dysphagia is even more prevalent and is reported in up to 60% of patients (Litchy and Engel, 1992; Dalakas et al., 1997). However, of the total number of cases with dysphagia, myositis accounts only for approximately 3%. Still, myositis diagnosis is worth to be considered since it can be treated with immunosuppressive medical therapy and not only by surgery. The clinical signs of dysphagia range from mild swallowing problems of dry food or reﬂux-like symptoms to severe problems that confer risk of aspiration and may require naso-gastric feeding or parental nutrition. A number of patients complain of difﬁculties when starting to swallow. Nasal regurgitations may also occur. One consequence of dysphagia could be malnutrition and weight loss. The presence of dysphagia is associated with poorer prognosis because of risk of aspiration pneumonia, septicemia, and cachexia (Klippel and Dieppe, 2000). The explanation for dysphagia in myositis is inﬂammation of striated muscle in the GI–tract, leading to dysmotility of both oropharyngeal structures and esophagus (Dietz et al., 1980). Muscle biopsy specimen from the cricopharyngeal muscle has conﬁrmed inﬂammatory changes. Moreover, disturbed motility was demonstrated in a Turkish study including 19 patients with polymyositis or dermatomyositis and dysphagia with 1–10 month duration. The patients were investigated by electrophysiological methods analyzing oropharyngeal muscles: The pharyngeal

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transit time of the bolus from the oral cavity to the upper esophageal sphincter was signiﬁcantly prolonged (Ertekin et al., 2004). It had previously been reported that there could be a kind of achalasia in the cricopharyngeal sphincter (Kagen et al., 1985). In this Turkish study, 50% of the patients also had an abnormal cricopharyngeal sphincter activity, some of them had hyper-reﬂexity (possible muscle edema in the acute phase), and some had hyporeﬂexity (possibly due to muscle ﬁbrosis in chronic phase and in IBM). Electrophysiological investigations may differentiate the hyper-reﬂexity, which is also more suitable to myotomy (Ertekin et al., 2004). Dysphagia in patients with myositis compared to neurological diseases and healthy controls was more often characterized by more prevalent cricopharyngeal restrictive problems, reduced upper esophageal sphincter opening, and elevated hypopharyngeal intrabolus pressure when tested with pharyngeo-esophageal videomanometry (Williams et al. 2003). There were other discrepancies also when laboratory ﬁndings, EMG, and muscle biopsy data were compared. The mean time between dysphagia onset and diagnosis of myositis was 55 months. Notably in this study, one-third of myositis patients did not have any other signs of muscle weakness except dysphagia. Only 75% of myositis patients had abnormal CPK and EMG, and muscle biopsy was mandatory for myositis diagnosis. Prognosis was poor with 31% 12-month mortality due mainly to respiratory complications; despite that, the presence of dysphagia made immunosuppressive therapy mandatory. The fact that only two-third of the patients with dysphagia had other muscle involvement induces the hypothesis that there might be a local involvement of cricopharyngeal muscles with a chronic inﬂammation that reduces the cricopharyngeal compliance with time (Shapiro et al., 1996; Williams et al., 2003). This study also reported an unexpected high prevalence of Zenker’s diverticula in myositis patients. Zenker’s diverticula is associated with a restrictive disorder of the cricopharyngeal secondary to myonecrosis and ﬁbrous tissue replacement. The ﬁbrous replacement in myositis can therefore lead to Zenker’s diverticula in susceptible patients with myositis.

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In clinical practice, the easiest way to investigate complaints of dysphagia is an esophagus radiography with bolus contrast, but in doubtful cases, investigations can be completed with videoradiography or manometric measures such as videomanometry. Treatment of dysphagia in myositis is based on conventional immunosuppressive treatment as for the skeletal muscle weakness in general and, in addition, on symptomatic drugs when the disease still allows a normal nutrition (mainly proton pump inhibitors). A more deﬁnitive treatment is surgical by cricopharyngeal disruption. This could be done either by dilatation or by myotomy (Venkovsky et al., 1988). Of these, the cricopharyngeal myotomy is the only validated method for treatment of severe dysphagia in patients with IBM (Verma et al., 1992). There is no clear evidence that immunosuppressive treatment could improve dysphagia and ﬁnally avoid surgery in IBM cases. Interestingly, in a small case series including four patients with life-threatening dysphagia in IBM, swallowing problems in patients dramatically improved after the administration of high-dose intravenous immunoglobulin in combination with glucocorticoids (Cherin et al., 2002). Two other patients who were affected by IBM were successfully treated with injection of botulinum toxin A (Liu et al., 2004).

Theoretically also, the lower level of GI tract could be involved, e.g. the sphincter anus being a striated muscle. However, in the literature we only found one case report with a dermatomyositis patient who presented with rectal incontinence due to external sphincter myositis (Vitali et al., 1991). Muscle disorders in patients with inﬂammatory bowel disease are rare, but there are some reported cases that have either ulcerative colitis or Crohn’s disease and myositis (Leibowitz et al., 1994; Chugh et al., 1993; Kaneoka et al., 1990; Kulkarni et al., 1997). All patients had involvement of the colon, and it is already known that patients with colonic involvement have more extraintestinal manifestations. Some patients did not have any clinical muscle symptoms that indicated myositis but had elevated creatine kinase values. One important observation is that patients with inﬂammatory bowel diseases are often treated with high doses of glucocorticoids that by themselves can lead to a myopathy that clinically resembles polymyositis, namely steroid myopathy. Muscle biopsy is sometimes helpful in differentiating these two entities, as in glucocorticoid-induced myopathy there is no sign of inﬂammation, which is typically seen in myositis patients. Moreover, they respond in different ways to tapering of glucocorticoids, as steroid myopathy will improve by tapering the glucocorticoid dose.

4. Bowel 5. Liver Already in 1982 there was a suggestion of an association between celiac disease and myositis due to increased levels of anti-gluten autoantibodies (in patients with inﬂammatory myopathies) (Henriksson et al., 1982). Recently, this was conﬁrmed, as 31% of myositis patients were positive for IgA-class anti-gliadin (AGA) autoantibodies, especially patients with IBM. Only few patients underwent conﬁrming biopsy, but some of them had villous atrophy and crypt hyperplasia representing 6% of all myositis patients (Selva-O’Callaghan et al., 2007). Mucosal recovery occurred in all biopsy positive patients after three months with gluten-free diet, but their muscle symptoms did not improve.

Liver involvement is unusual in myositis patients. In the literature, there are a few reports referring to an association between polymyositis and primary biliary cirrhosis (PBC) (Bondeson et al., 1998; Ahn et al., 1993; Rain et al., 1996; Boki and Dourakis, 1995; Yasuda et al., 1993). However, one of these reports refers to a patient already affected by PBC, who developed polymyositis after treatment with D-penicillamine. As it is known that this drug may cause polymyositis, an association between PBC and myositis in this particular case is uncertain. In a review of the literature, 10 more cases were found with an association between proven diagnosis of both PBC and

Inflammatory Myopathies

polymyositis/dermatomyositis. This raises the hypothesis of a possible mitochondrial dysfunction also in the muscles and makes mitochondrial dysfunction a possible inducing factor for polymyositis and dermatomyositis patients. On the other hand, an immunological study comparing different rheumatic diseases for presence of antimitochondrial antibodies found that they were often present in patients with Sjo¨grenus syndrome, systemic lupus erythematosus, systemic sclerosis and rheumatoid arthritis, whereas none of the polymyositis/dermatomyositis patients were positive in that study (Zurgil et al., 1992). One interesting case report tells about a patient who had Crohn’s disease and within a period of six years developed a series of autoimmune diseases, starting with sclerosing cholangitis, then alopecia universalis, and ﬁnally polymyositis. Polymyositis improved with glucocorticoids and azathioprine treatment. In this case it seems more likely that the liver disease was associated with Crohn’s disease rather than with polymyositis (Seibold et al., 1996).

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and one of them also had hepatitis (See et al., 1997); one of them had a good response from treatment with high-dose glucocorticoids, the other responded only after immunosuppressive drugs and plasmapheresis. Their good response to glucocorticoids in some cases is interesting because during the 1950s and 1960s, cortisone was considered a potential cause of pancreatitis (Riemenschneider et al., 1968). Pancreatitis itself has to be treated urgently because of the risk of cardiovascular collapse, respiratory distress, or renal failure. Three cases of juvenile dermatomyositis and cholestasis were reported (Russo et al., 2001). They all developed a biopsy-veriﬁed cholestasis during the ﬁrst months of disease, and two of them improved with glucocorticoids. The third patient was treated from the beginning with glucocorticoids and cyclophosphamide but died from a pulmonary infection. The potential relationship between juvenile dermatomyositis and cholestasis is still uncertain as the reported cases are few. Children with dermatomyositis may also develop malabsorbtion, probably because of inﬂammatory inﬁltration of the intestinal mucosa (Pachman, 1995; Laskin et al., 1999).

6. Juvenile dermatomyositis Particular attention must be paid to juvenile dermatomyositis, which is also characterized by proximal muscle weakness and rash, and in contrast to adult dermatomyositis, it is not associated with malignancy. Juvenile dermatomyositis has more frequent digestive tract involvement compared to dermatomyositis or polymyositis in adults. In juvenile dermatomyositis, the GI-tract manifestations range from dysphagia to life-threatening ulceration, perforation, and hemorrhage of the whole GI tract as a consequence of vasculitis or thromboses. A particularly serious situation is a late diagnosis of distal duodenum perforations (Schullinger et al., 1985). Vasculitis can also cause pancreatitis, hepatitis, and renal vessel occlusion. There are a few reported cases including children with diagnosed juvenile dermatomyositis and rare digestive complications of the disease. Two children presented with bowel vasculitis together with pancreatitis,

7. Summary In summary, the whole GI tract may be involved in patients with inﬂammatory myopathies. In particular, dysphagia is common and may, in some patients, become severe and life threatening. However, there are only a few studies in which GI-tract involvement has been systematically investigated in myositis patients; thus, the true prevalence of GI-tract involvement and likewise how it affects prognosis and health-related quality of life are uncertain.

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Barbasso Helmers, S., Dastmalchi, M., Alexanderson, H., Nennesmo, I., Esbjornsson, M., Lindvall, B., Lundberg, I.E. 2007. Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inﬂammatory myopathies. Ann. Rheum. Dis. 66, 1276–1283. Boki, K.A., Dourakis, S.P. 1995. Polymyositis associated with primary biliary cirrhosis. Clin. Rheumatol. 14 (3), 375–378. Bondeson, J., Veress, B., Lindroth, Y., et al. 1998. Polymyositis associated with asymptomatic primary biliary cirrhosis. Clin. Exp. Rheumatol. 16 (2), 172–174. Chauvet, E., Sailler, L., Carreiro, M., et al. 2002. Symptomatic macroglossia and tongue myositis in polymyositis. Arthritis Rheum. 46, 2762–2764. Cherin, P., Pelletier, S., Teixeira, A. 2002. Intravenous immunoglobulin for dysphagia of inclusion body myositis. Neurology 58, 326–327. Chugh, S., Dilawari, J.B., Sawhney, I.M.S., et al. 1993. Polymyositis associated with ulcerative colitis. Gut. 34, 567–569. Dalakas, M.C., Sonies, B., Dambrosia, J., et al. 1997. Treatment of inclusion body myositis with IVIg: a double blind, placebo controlled study. Neurology 48, 712–716. Dalakas, M.D. 2006. The role of high-dose immune globulin intravenous in the treatment of dermatomyositis. Int. Immunopharmacol. 6 (4), 550–556. Epub 2005 Dec 20. Review. Dietz, F., Logeman, J.A., Sahgal, V., et al. 1980. Cricopharyngeal muscle dysfunction in the differential diagnosis of dysphagia in polymyositis. Arthritis Rheum. 23 (4), 491–495. Ertekin, C., Secil, Y., Yuceyar, N. 2004. Oropharyngeal dysphagia in polymyositis/dermatomyositis. Clin. Neurol. Neurosur. 107 (1), 32–37. Grundtman, C., Malmstrom, V., Lundberg, I.E. 2007. Immune mechanisms in the pathogenesis of idiopathic inﬂammatory myopathies. Arthritis Res. Ther. 9 (2), 208. Hengstman, G.J., Brouwer, R., Egberts, W.T., et al. 2002. Clinical and serological characteristics of 125 Dutch myositis patients. Myositis speciﬁc autoantibodies aid in the differential diagnosis of the idiopathic inﬂammatory myopathies. J. Neurol. 249 (1), 69–75. Henriksson, K.G., Hallert, C., Norrby, K., Walan, A. 1982. Polymyositis and adult coeliac disease. Acta Neurol. Scand. 65, 301–319. Kagen, L.J., Hochman, R.B., Strong, E.W. 1985. Cricopharyngeal obstruction in inﬂammatory myopathies (polymyositis/dermatomyositis). Report of three cases and review of the literature. Arthritis Rheum. 28, 630–636. Kaneoka, H., Iyadomi, I., Hiida, M., et al. 1990. An overlapping case of ulcerative colitis and polymyositis. J. Rheumatol. 17, 274–276. Klippel, J.H., Dieppe, P.A. 2000. Rheumatology. Mosby, London. Kulkarni, A., Ravi, T.J., Brodmerkel, G.J., Jr., et al. 1997. Inﬂammatory myositis in association with inﬂammatory bowel disease. Dig. Dis. Sci. 42 (6), 1142–1145.

Laskin, B.L., Choyke, P., Keenan, G., et al. 1999. Novel gastrointestinal tract manifestations in juvenile dermatomyositis. J. Pediatr. 135, 371–374. Leibowitz, G., Eliakim, R., Amir, G., et al. 1994. Dermatomyositis associated with Crohn’s disease. J. Clin. Gastroenterol. 18, 48–52. Litchy, W.J., Engel, A.G. 1992. Inclusion body myositis with cricopharyngeus muscle involvement and severe dysphagia. Muscle Nerve 15 (1), 115. Liu, L.W., Tarnopolsky, M., Armstrong, D. 2004. Injection of botulinum toxin A to the upper esophageal sphincter for oropharyngeal dysphagia in two patients with inclusion body myositis. Can. J. Gastroenterol. 18 (6), 397–399. Ma`rton, K., Hermann, P., Danko`, K., et al. 2005. Evaluation of oral manifestation and masticatory force in patients with polymyositis and dermatomyositis. J. Oral Pathol. Med. 34, 164–169. Medsger, T.A., Jr., Dawson, W.N., Jr., Masi, A.T. 1970. The epidemiology of polymyositis. Am. J. Med. 48 (6), 715–723. Pachman, L.M. 1995. Juvenile dermatomyositis: pathophysiology and disease expression. Pediatr. Clin. North Am. 42, 1071–1097. Rain, F., Durieu, I., Mackiewitz, R., et al. 1996. Dermatopolymyositis and primary biliary cirrhosis. A rare association. Presse Med. 25 (12), 581–582. Riemenschneider, T.A., Wilson, J.F., Vernier, R.L. 1968. Glucocorticoid induced pancreatitis in children. Pediatrics 41, 428–437. Russo, R.A.G., Katsicas, M.M., Da´vila, M., et al. 2001. Cholestasis in juvenile dermatomyositis. Arthritis Rheum. 44 (5), 1139–1142. See, Y., Martin, K., Rooney, M., et al. 1997. Severe juvenile dermatomyositis complicated by pancreatitis. British J. Rheum. 36, 912–916. Seibold, F., Klein, R., Jacob, F. 1996. Polymyositis, alopecia universalis, and primary sclerosing cholangitis in a patient with Crohn’s disease. J. Clin. Gastroenterol. 23 (2), 121–124. Selva-O’Callaghan, A., Casellas, F., de Torres, I., et al. 2007. Celiac disease and antibodies associated with celiac disease in patients with inﬂammatory myopathy. Muscle Nerve 35 (1), 49–54. Shapiro, G., Martin, S., De Girolami, U., et al. 1996. Inﬂammatory myopathy causing pharyngeal dysphagia: a new entity. Ann. Otol. Rhinol. Laryngol. 105 (5), 331–335. Schullinger, J.N., Jacobs, J.C., Berdon, W.E. 1985. Diagnosis and management of gastrointestinal perforations in childhood dermatomyositis with particular reference to perforations of the duodenum. J. Pediatr. Surg. 20 (5), 521–524. Sonies, B.C. 1997. Evaluation and treatment of speech and swallowing disorders associated with myopathies. Curr. Opin. Rheumatol. 9 (6), 486–495. Venkovsky, J., Rehak, F., Pafko, P., et al. 1988. Acute cricopharyngeal obstruction in dermatomyositis. J. Rheumatol. 15 (6), 1016–1018.

Inflammatory Myopathies Verma, A., Bradley, W.G., Soule, N.W. 1992. Quantitative morphometric study of muscle in inclusion body myositis. J. Neurol. Sci. 112, 192–198. Vitali, C., Sciuto, M., Rossi, B. 1991. Rectal incontinence due to an unusual localization of the myositis process in the external sphincter of a patient with dermatomyositis. Arthritis Rheum. 34 (10), 1337–1339. Williams, R.B., Grehan, M.J., Hersch, M., et al. 2003. Biomechanics, diagnosis and treatment outcome in

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inﬂammatory myopathies presenting as oropharyngeal dysphagia. Gut 52 (4), 471–478. Yasuda, Y., Nakano, S., Akiguchi, I., et al. 1993. Polymyositis associated with asymptomatic primary biliary cirrhosis. Eur. Neurol. 33 (1), 51–53. Zurgil, N., Bakimer, R., Moutsopoulos, H.M. 1992. Antimitochondrial (pyruvate dehydrogenase) autoantibodies in autoimmune rheumatic diseases. J. Clin. Immunol. 12 (3), 201–209.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 7

Digestive Involvement in Primary Sjo¨gren’s Syndrome Manuel Ramos-Casalsa,, Elke Theanderb, Athanasios G. Tzioufasc, Claudio Vitalid a

Laboratory of Autoimmune diseases ‘‘Josep Font’’, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain b Department of Rheumatology, Malmo University Hospital, Malmo, Sweden c Department of Pathophysiology, School of Medicine, University of Athens, Greece d Department of Internal Medicine and Rheumatology, Ospedale Villamaria, Piombino, Italy

Sjo¨gren’s syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes due to functional impairment of the salivary and lacrimal glands (Fox, 2005). The histological hallmark is a focal lymphocytic inﬁltration of the exocrine glands, and the spectrum of the disease extends from an organspeciﬁc autoimmune disease (autoimmune exocrinopathy) (Kassan and Moutsopoulos, 2004) to a systemic process with diverse extraglandular manifestations (Ramos-Casals et al., 2005d). An estimated 2–4 million persons in the United States have SS, of whom approximately 1 million have an established diagnosis (Kassan and Moutsopoulos, 2004). The prevalence in European countries ranges between 0.60 (Dafni et al., 1997) and 3.3% (Thomas et al., 1998). The incidence of SS has been calculated as 4 cases per 100,000 (Pillemer et al., 2001). SS primarily affects white perimenopausal women, with a female–male ratio ranging from 14:1 (Garcia-Carrasco et al., 2002) to 24:1 (Skopouli et al., 2000) in the largest reported series. The disease may occur at all ages but typically has its onset in the fourth–sixth decades of life, although some cases are detected in younger Corresponding author.

Tel.: +34-93-2275774; Fax: +34-93-2275774 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00007-4

female patients, especially in mothers of babies with congenital heart block (Haga et al., 2005). When sicca symptoms appear in a previously healthy person, the syndrome is classiﬁed as primary SS. When sicca features are found in association with another systemic autoimmune disease, most commonly rheumatoid arthritis (RA), systemic sclerosis (SSc) or systemic lupus erythematosus (SLE), it is classiﬁed as associated SS. The variability in the presentation of SS may partially explain delays in diagnosis of up to nine years from the onset of symptoms (Fox, 2005). Although most patients present with sicca symptoms, various clinical and analytical features may indicate an undiagnosed SS. In addition, SS is a disease that may be expressed in many guises, depending on the speciﬁc epidemiological, clinical or immunologic features. Epidemiologically, a lower immunologic expression is observed in male SS patients and those with an older onset (GarciaCarrasco et al., 2002). Clinically, two main patterns of disease expression are observed: patients with only glandular involvement (siccalimited disease), who have a low frequency of immunologic abnormalities and extraglandular features, and patients with a predominant ‘systemic’ expression in addition to the sicca involvement (Garcia-Carrasco et al., 2002). Patients with positive immunologic features need a closer follow-up, paying special attention to the

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development of extraglandular manifestations. The therapeutic management of SS is mainly centered on the control of sicca features, using substitutive and oral muscarinic agents, while corticosteroids and immunosuppressive agents play a key role in the treatment of extraglandular features. Gastrointestinal involvement has been little studied in primary SS and may include altered esophageal motility, gastroesophageal reﬂux (GER), chronic gastritis and, less frequently, malabsorption. More clinical data are available on pancreatic and liver involvement, which were ﬁrst reported to be part of the extraglandular expression of SS by Bloch et al. (1965).

1. Esophageal involvement Recent studies have analyzed esophageal involvement in patients with primary SS. Because adequate pharyngoesophageal transfer of the alimentary bolus requires saliva (Helm, 1989), its lack might contribute to the development of dysphagia in SS. However, Anselmino et al. (1997) observed no differences in salivary ﬂow rates of primary SS patients with and without dysphagia, while Grande et al. (1993) found no relationship between dysphagia and the parotid saliva ﬂow rate. Dysphagia has also been associated with esophageal motor dysfunction and upper esophageal webs (Volter et al., 2004). Thus, Rosztoczy et al. (2001) described decreased peristaltic velocity in the esophageal body of 11 (44%) out of 25 patients with primary SS. However, the majority of studies have found that SS patients with and without dysphagia have similar function (Anselmino et al., 1997; Grande et al., 1993; Volter et al., 2004; Tsianos et al., 1985) and that dysphagia is independent of esophageal dysmotility (Grande et al., 1993; Kjellen et al., 1986; Palma et al., 1994). Although patients with primary SS may have altered manometric studies, to date, studies have failed to describe any consistent pattern of esophageal dysfunction, and the motor disorders that some patients may present do not correlate with the presence of dysphagia.

A recent study investigated the prevalence and clinical signiﬁcance of GER in patients with primary SS, and its possible association with esophageal dysmotility (Volter et al., 2004), and found abnormalities in motility in 21 patients with SS, which was associated with GER. The study found slow acid clearance in the esophagus of SS patients with GER, suggesting a prolonged duration of reﬂux. This extended exposure of the esophagus to reﬂuxed acid may result either from defective acid neutralization by salivary bicarbonates or from altered esophageal motility (Kahrilas et al., 1986; Schowengerdt, 2001; Geatti et al., 1991; Fitzgerald and Triadaﬁlopoulos, 1997). Ho et al. (2002) described a high frequency of tertiary waves in patients with markedly abnormal pH that were signiﬁcantly associated with the total reﬂux time, suggesting a relationship between these contractions and prolonged exposure of the esophageal mucosa to low pH values.

2. Gastric involvement 2.1. Chronic gastritis Although earlier reports described chronic gastric inﬂammation with mucosal atrophy in nearly 80% of patients with SS (Buchanan et al., 1966; Kilpi et al., 1983; Maury et al., 1985), the prevalence of chronic gastritis has not been evaluated in recent series. In clinical practice, patients frequently complain of gastric pain, although gastroscopic studies often show only mild gastric abnormalities. Two recent studies have analyzed the prevalence and clinical signiﬁcance of anti-parietal cell gastric antibodies (anti-PCA) in primary SS. Nardi et al. (2006) found positive anti-PCA antibodies in 90 (27%) out of 335 patients. These patients showed a higher prevalence of thyroiditis and autoimmune liver involvement, but not gastrointestinal involvement. El Miedany et al. (2005) found anti-PCA antibodies in one-third of SS patients and controls. However, all SS patients with anti-PCA antibodies had Helicobacter pylori infection, in comparison with less than half of the autoantibodypositive controls. Likewise, only 22% of the autoantibody-positive controls had atrophic changes in gastric mucosa compared with 86% of

Digestive Involvement in Primary Sjo¨gren’s Syndrome

those with SS. This study found a close association between anti-PCA antibodies and H. pylori infection, suggesting that this bacterium may induce a local hyperreactive/autoimmune response that might facilitate the induction of autoantibodies against the gastric mucosa of SS patients. Although anti-PCA antibodies have been associated with chronic atrophic gastritis and pernicious anemia, the two processes are only rarely described in patients with primary SS. Two cases were described in a recent review of hematologic manifestations in a cohort of 380 SS patients (Ramos-Casals et al., 2002), with only four additional cases being reported (Pedro-Botet et al., 1993; Wegelious et al., 1970; Williamson et al., 1970), suggesting that chronic atrophic gastritis and pernicious anemia are very infrequent in primary SS.

2.2. Helicobacter pylori infection A number of studies have analyzed the prevalence and clinical signiﬁcance of H. Pylori infection in primary SS, searching for a possible association with dyspepsia, gastritis, gastric ulcers or lymphoma, with controversial results. Theander et al. (2001) found that SS patients have a similar H. pylori seroprevalence rate to controls, while Collin et al. (1997) found that the seroprevalence of H. pylori infection in dyspeptic SS patients was similar to that of dyspeptic patients without SS. In contrast, other studies have described a higher prevalence of H. pylori antibodies in primary SS compared with controls (De Vita et al., 1996; Ostuni et al., 1993; Sugaya et al., 1995). El Miedany et al. (2005) found both a signiﬁcantly higher prevalence and higher serum titers of IgG and IgM anti-H. pylori antibodies in SS patients compared with both patients with other autoimmune diseases without sicca syndrome and healthy controls. This might reﬂect geographic differences in the prevalence of H. pylori infection, which is reported to be lower in Sweden than in other countries. Moreover, a recent study has shown that H. pylori was detected in gastric biopsies in 71% of Italian SS patients in comparison with 31% of Scandinavian patients (Theander et al., 2001).

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Histologically, the severity of gastritis has been closely associated with the presence of H. pylori in primary SS. However, a recent study showed that eradication of H. pylori caused a signiﬁcant regression of gastric MALT and atrophy in controls but not in SS patients (Witteman et al., 1995). In addition, dyspepsia did not improve following bacterial eradication in the majority of SS patients, suggesting that H. pylori does not seem to play a role in the dyspeptic symptoms found in SS. A possible relationship between H. pylori and gastric lymphomagenesis in SS has recently been postulated. Lymphoid accumulation in the gastric mucosa is common in SS, but full evidence for an antigen-driven B-cell expansion has not been demonstrated. De Vita et al. (1996) described a low-grade gastric lymphoma concomitantly with H. pylori infection in a patient with SS. After H. pylori eradication, a dramatic regression of gastric lymphoma into chronic gastritis was observed, but no amelioration occurred in the parotid and nodal involvement. Multiple molecular analyses showed the expansion of the same B-cell clone in synchronous and metachronous lymph node, parotid and gastric lesions before and after H. pylori eradication. Ferraccioli et al. (1996) studied the gastric tissue in SS in order to deﬁne whether the presence of MALT in the stomach is associated with several infectious agents, and showed that H. pylori infection is not more frequent among patient with SS than in controls and that the abnormal accumulation of MALT may occur in the stomach even in the absence of H. pylori infection. Other studies performed on a limited number of SS patients with simple dyspepsia indicate that clonality may persist for up to six months after the eradication of H. pylori (Al-Saleem, 1993). Thus, although H. pylori may play a crucial role in the local boosting of B-cell lymphoproliferation, the underlying B-cell disorder seems to be a nonmalignant process (De Vita et al., 1996).

3. Intestinal involvement Intestinal involvement should be considered as one of the less-frequent extraglandular manifestations

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of primary SS, with isolated cases of malabsorption or vasculitis being reported. However, recent studies have analyzed the association of celiac disease (CD) in small series of patients with primary SS. Iltanen et al. (1999) found that 5 (15%) out of 34 SS patients had CD, while Szodoray et al. (2004) diagnosed CD in 5 (4.5%) out of 111 patients with SS, whereas the prevalence of CD is estimated to be 0.45% in the general population. In contrast, Lazarus and Isenberg (2005) found 1 (0.9%) out of 114 patients with primary SS, and no case was found in a series including 400 patients (Garcia-Carrasco et al., 2002). In contrast with the opinion of other authors (Roblin et al., 2004), these data suggest that CD should not be routinely evaluated in patients with primary SS. However, the close association of CD with other processes that may also be observed in primary SS, such as primary biliary cirrhosis (PBC) or IgA deﬁciency, suggests that these patients should be tested for antiendomysial antibodies due to the increased risk of small bowel adenocarcinomas and lymphomas in patients with CD. In patients with primary SS, systemic vasculitis only rarely involves the gastrointestinal tract. Of 19 reports of SS patients with systemic necrotizing vasculitis (Ramos-Casals et al., 2004), 13 had gastrointestinal tract involvement (Table 1). In addition, of the 19 reported deaths of SS patients due to vasculitis, the two main causes were CNS involvement in six and gastrointestinal perforation in ﬁve. Cryoglobulins were determined in 12 of these patients and were positive in 10 (83%) cases. In spite of its rarity, gastrointestinal vasculitis, often related to cryoglobulinemia, should be considered as a life-threatening situation in patients with primary SS.

4. Pancreatic involvement In patients with primary SS, pancreatic involvement is usually asymptomatic and is demonstrated by altered pancreatic function tests, although some patients may present chronic pancreatitis. The prevalence of altered pancreatic function tests varies widely according to the tests used (Table 2). Fenster

Table 1 Previous reported cases of vasculitis involving the gastrointestinal tract in patients with primary Sjo¨gren syndrome (Ramos-Casals et al., 2004) Number of cases

Histology

Site of vasculitic involvement

1 2 3 4 5 6 7 8 9 10 11 12 13

Necrotizing Necrotizing Necrotizing Necrotizing Necrotizing Necrotizing Necrotizing Necrotizing Leukocytoclastic Leukocytoclastic Leukocytoclastic Leukocytoclastic Leukocytoclastic

Ileum Gallbladder, spleen CNS, GI, kidney, pancreas Bowel Colonic ulcers Muscle, kidney, CNS, GI Muscle, parotid, bowel Colon ulcers Rectum Bowel Ileum Bowel Gallbladder, appendix, mesentery

CNS: central nervous system, GI: gastrointestinal.

Table 2 Prevalence of altered functional pancreatic tests in patients with SS Author

Pancreatic tests

Prevalence of altered tests

Fenster et al. (1964) Hradsky et al. (1967) Gobelet et al. (1983)

Secretin Secretin-cholecystokinin N-Benzoyl-L-tyrosyl paraamino-benzoic acid (NBT PABA) test, radioimmunoassay trypsinemia NBT PABA test, radioimmunoassay trypsinemia, and stool fat measurements

52% 36% 35%

Coll et al. (1989)

63%

et al. (1964) found a prevalence of altered secretin/ cholecystokinin test of 52% and Hradsky et al. (1967) a prevalence of 36%, while Gobelet et al. (1983) described a prevalence of 35% using the NBT-PABA test and Coll et al. (1989) a prevalence of 63% using NBT-PABA test, serum immunoreactive trypsin levels and stool fat measurement. All these studies, mainly performed in the 1970s and 1980s, suggested a high frequency of altered pancreatic function in primary SS, although no data were presented on the clinical impact of these altered tests in patients with primary SS. In contrast, the frequency of chronic pancreatitis is

Digestive Involvement in Primary Sjo¨gren’s Syndrome

very low in large series of patients with primary SS (lower than 2%), although some patients may present with a cluster of autoimmune diseases including chronic pancreatitis, thyroiditis and sclerosing cholangitis (SC) (Fukui et al., 2005; Montefusco et al., 1984; Nieminen et al., 1997). Autoimmune pancreatitis has recently been considered as an IgG4-related autoimmune disease, a novel group of diseases that includes other organ-speciﬁc autoimmune diseases such as Riedel’s thyroiditis or tubulointerstitial nephritis (Kamisawa, 2006; Takeda et al., 2004). Recent studies have described some Japanese patients with Mikulicz’s disease (MD), a disease closely related to SS (Kamisawa et al., 2003; Tsubota et al., 2000). These patients showed a higher frequency of males, higher levels of serum IgG4, lower titers of ANA, negative anti-Ro and anti-La antibodies, a predominance of IgG4+ cells in the salivary glands and a close association with autoimmune pancreatitis in more than 50% of cases. The lack of reported cases outside Japan suggests that the association between MD and autoimmune pancreatitis might be related to local genetic or environmental factors.

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closer association between SS and PBC than with other types of autoimmune liver disease (AlarconSegovia et al., 1973; Tsianos et al., 1990). However, it not was until the 1990s when the spectrum of liver disease in patients with primary SS, included the evaluation of clinical signs of liver disease, liver function and a complete panel of autoantibodies (Lindgren et al., 1994; Skopouli et al., 1994). Recent studies have shown that liver function tests may be altered in 10–20% of patients with primary SS (Csepregi et al., 2002). After discarding potentially hepatotoxic drugs, the main causes were chronic HCV infection (especially in geographic areas with a high prevalence) and PBC (Ramos-Casals et al., 2005b; Abraham et al., 2004). Some SS patients may present positive AMA with no clinical or analytical evidence of liver involvement, probably reﬂecting an early asymptomatic stage of PBC (Ramos-Casals et al., 2006). Less frequently, SS patients may present type 1 autoimmune hepatitis (AIH) and, even more rarely, autoimmune or SC.

5.1. Chronic viral hepatitis 5. Liver involvement Liver involvement was one of the ﬁrst reported extraglandular manifestations of the systemic expression of SS, although new developments in the ﬁeld of hepatic diseases have changed the diagnostic approach signiﬁcantly. In the ﬁrst studies on SS patients in the 1960s, liver involvement was evaluated by the presence of hepatomegaly, with a prevalence of 20%. In 1965, Bloch et al. found a 27% prevalence of liver involvement (hepatomegaly and/or raised alkaline phosphatase) in the ﬁrst well-described series of patients with SS. In 1970, Golding et al. reported a higher frequency of sicca syndrome in patients with diverse liver diseases including chronic active hepatitis, PBC or cryptogenetic cirrhosis. Antimitochondrial antibodies (AMA) were included as a marker of liver disease in SS patients in the 1970s, with later studies ﬁnding a

Chronic viral liver diseases have recently emerged as an additional cause of liver involvement in patients with SS (especially in some geographic areas), broadening the spectrum of hepatopathies that may affect these patients (Ramos-Casals et al., 2005b). In a recent study, chronic HCV infection was the main cause of liver involvement in patients with SS, with a prevalence of 13%, nearly threefold greater than that observed for autoimmune liver involvement (Ramos-Casals et al., 2006). This underlines the importance of chronic HCV infection as a cause of liver disease in SS patients from regions such as the Mediterranean, with higher prevalence of HCV infection in the general population. Recent experimental (De Vita et al., 1995; Koike et al., 1997), virological (Arrieta et al., 2001; Toussirot et al., 2002) and clinical evidence (De Vita et al., 2002; Jorgensen et al., 1996; Ramos-Casals et al., 2001a) has revealed a close association between HCV and

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SS and, in a recent large multicenter study (Ramos-Casals et al., 2005b), SS-HCV was indistinguishable in most cases from the primary form using the most recent sets of classiﬁcation criteria. Two-thirds of SS-HCV patients presented cryoglobulinemia, which may be considered the key immunologic marker of SS associated with HCV and the main cause of vasculitis in these patients. How then should this SS be classiﬁed? Current evidence suggests that chronic HCV infection should be considered an exclusion criterion for the classiﬁcation of primary SS, not because it mimics primary SS, but because it seems to be directly responsible for the development of SS in a speciﬁc subset of HCV patients (Ramos-Casals et al., 2005b). SS-HCV patients should be considered as a separate subset from the primary form, and it would be more appropriate to classify these patients as having a ‘SS associated with HCV’. The term ‘SS secondary to HCV’ might be used in those cases in which infection of salivary gland epithelium by HCV is directly demonstrated. The association between SS and other types of chronic viral hepatitis is very infrequent. Only one case of chronic HBV infection was found in 475 SS patients, in comparison with 63 patients with chronic HCV infection (Ramos-Casals et al., 2006). Three additional cases (Aprosin et al., 1993; Iakimtchouk et al., 1999; Toussirot et al., 2000) of HBV-related SS have been reported (one associated with HBV vaccination), compared with more than 300 cases of HCV-related SS (Ramos-Casals et al., 2005c). Similarly, chronic HGV infection also plays an insigniﬁcant role in liver disease in SS patients. The predominant etiopathogenic role of HCV is probably due to its speciﬁc lymphotropism and sialotropism (De Vita et al., 1995; Ramos-Casals et al., 2001b), which means it can infect and replicate in both circulating lymphocytes and epithelial cells from the salivary glands (Ramos-Casals and Font, 2005).

5.2. Primary biliary cirrhosis After discarding HCV infection, PBC should be considered as the main cause of liver disease in

patients with primary SS (Lindgren et al., 1994; Ramos-Casals et al., 2006; Skopouli et al., 1994). Although historically these patients have been considered as having a ‘secondary’ SS, it seems more rational to use the term ‘SS associated with PBC’, due to the clinical-based evidence that SS is associated with (and not secondary to) other autoimmune diseases. The inclusion of AMA in the routine immunologic follow-up of SS patients should be recommended, independently of whether the analytical liver proﬁle is altered or not, due to the strong association between AMA and the development of PBC. Several studies have analyzed the prevalence of AMA in patients with primary SS. Csepregi et al. (2002) studied 180 patients and found ﬁve AMA positive patients (two of whom developed symptomatic PBC), three patients with AIH and one with autoimmune cholangitis, while Kaplan (1993) found abnormal liver tests in 29/59 (49%) patients, including ﬁve patients with positive AMA and one with AIH. Nardi et al. (2006) found a prevalence of 8% of AMA, although only 50% of these SS-AMA positive patients had clinical or analytical evidence of liver involvement, suggesting the existence of an incipient or incomplete PBC in some patients with primary SS. A recent study has conﬁrmed the broad spectrum of abnormalities in the analytical liver proﬁle of SS patients with AMA-M2, including three patients with no clinical or analytical data suggestive of liver disease (Ramos-Casals et al., 2006), as has been reported in ﬁve previous cases (Csepregi et al., 2002; Lindgren et al., 1994; Skopouli et al., 1994). Previous studies on non-SS patients have shown that AMA-M2 patients with any clinical or analytical sign of liver involvement have a high risk of developing symptomatic PBC (Prince et al., 2004), underlining the key role of AMA-M2 as an early immunologic marker of PBC (Abraham et al., 2004). Although there are no therapeutic guidelines for these asymptomatic patients, early use of ursodeoxycholic acid may be considered, since some studies on non-SS patients with mild analytical abnormalities have suggested that treatment with ursodeoxycholic acid might prevent a possible evolution to liver cirrhosis (Beswick et al., 1985).

Digestive Involvement in Primary Sjo¨gren’s Syndrome

5.3. Autoimmune hepatitis AIH was another autoimmune liver disease found in SS patients, although less frequently than PBC. There are 51 reported cases of AIH in patients with primary SS (Table 3) and all are type 1 AIH (Coll et al., 2003). An additional characteristic of the AIH associated with primary SS is that most of the reported cases (33 out of 51, 65%) are from oriental countries. There are no reported cases of type 2 AIH in patients with primary SS, a fact consistent with the lack of positive anti-LKM-1 antibodies in SS. The prevalence of anti-LKM-1 antibodies has recently been evaluated in a large series of patients with primary SS, and none of the 335 patients tested had these autoantibodies (Nardi et al., 2006).

5.4. Other autoimmune liver diseases Other autoimmune liver diseases have infrequently been described in patients with primary SS (Table 4), including 13 cases of SC, 7 cases of Table 3 Autoimmune hepatitis and SS: reported cases (Ramos-Casals et al., 2006) Number of cases

Year

Country

1 2 3–9 10–11 12 13 14–19 20 21 22 23 24 25 26–28 29 30 31 32–34 35–42 43–51

1991 1993 1995 1997 1997 1998 1998 1999 2000 2001 2001 2001 2002 2002 2003 2003 2003 2004 2005 2006

Japan France Japan France Italy India China Japan Japan Spain Korea Japan Japan Hungary Japan France Korea Japan Japan Spain

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autoimmune cholangitis and 1 case of nodular regenerative hyperplasia of the liver (Ramos-Casals et al., 2006). Some characteristics of patients with SS and associated SC should be highlighted: a speciﬁc pattern of clinical features at presentation of SC (mainly abdominal pain, jaundice and diarrhea), an overwhelming association with chronic pancreatitis in all but one case (with pancreatic masses demonstrated by CT abdominal scan) and an association with other autoimmune processes such as retroperitoneal ﬁbrosis. These speciﬁc features may aid earlier diagnosis of this rare disease in patients with primary SS.

5.5. Evaluation of altered liver profile in patients with SS Detection of an altered liver proﬁle in a patient with SS requires a sequential diagnosis (Fig. 1). The ﬁrst step is to discard processes not associated with SS, mainly the chronic use of potentially Table 4 Other autoimmune liver disease associated with SS (RamosCasals et al., 2006) Liver disease

Year

Country

Sclerosing cholangitis Sclerosing cholangitis Sclerosing cholangitis Sclerosing cholangitis Sclerosing cholangitis Sclerosing cholangitis Autoimmune cholangitis Sclerosing cholangitis Nodular regenerative hyperplasia of the liver Autoimmune cholangitis Autoimmune cholangitis Sclerosing cholangitis Sclerosing cholangitis Autoimmune cholangitis Autoimmune cholangitis Sclerosing cholangitis Autoimmune cholangitis Autoimmune cholangitis Sclerosing cholangitis Sclerosing cholangitis Sclerosing cholangitis

1975 1975 1984 1986 1989 1989 1989 1991 1994

UK UK USA France Peru Japan Spain Spain Spain

1995 1995 1996 1997 1998 2001 2002 2002 2002 2003 2004 2005

Greece Japan Japan Finland Korea Korea Japan Hungary Rumania Switzerland Germany Japan

M. Ramos-Casals et al.

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Altered liver profile

No SS-related

SS-related

Hepatotoxic drugs Steatosis Chronic ilness

Viral infection

Autoimmune liver disease

-Mediterranean areas -Older and male patients -Cryoglobulins+ -Hypocomplementemia

-Younger and female patients -Hypergammaglobulinemia -Autoantibodies +++

ANA+ SMA+

AMA-M2+

AMA-

Type 1 AIH

PBC

Autoimmune cholangitis Sclerosing cholangitis

HCV infection

Figure 1. Sequential diagnosis of an altered liver proﬁle in a patient with Sjo¨gren syndrome.

hepatotoxic drugs, steatosis and congestive heart failure, all of which are frequently found in the elderly. The second step is to differentiate between autoimmune and viral liver disease. Evaluation of epidemiological factors may be helpful. For example, HCV infection is more frequently found in SS patients from the Mediterranean area than in those from North Europe (Ramos-Casals et al., 2005a). Likewise, HCV diagnosis is more frequent in older and male SS patients, while younger and female SS patients are more likely to have an associated autoimmune liver disease. The third step is the analytical liver proﬁle, although in a recent study, this was not useful in differentiating between HCV- and autoimmune-related liver diseases (Ramos-Casals et al., 2006). The fourth step is the immunologic proﬁle, which plays a key role in differentiating between the main etiologies: Patients with chronic HCV infection have a higher frequency of cryoglobulins and hypocomplementemia, while those with autoimmune liver disease

present hypergammaglobulinemia and autoantibodies (ANA, SMA, Ro and La) more frequently. In SS patients with a suspected autoimmune liver disease, the existence of AMA with a speciﬁc M2 pattern indicates PBC, while high titers of ANA and anti-SMA suggest type 1 AIH. The differential diagnosis of liver disease in patients with primary SS (viral versus autoimmune) is clinically important, since the two processes have a different therapeutic approach and prognosis.

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Ostuni, P.A., Germana, B., DiMario, F., Rugge, M., Plebani, M., DeZambiasi, P. 1993. Gastric involvement in primary Sjogren’s syndrome. Clin. Exp. Rheumatol. 11, 21–25. Palma, R., Freire, A., Freitas, J., Morbey, A., Costa, T., Saraiva, F., Queiros, F., Carvalhinhos, A. 1994. Esophageal motility disorders in patients with Sjogren’s syndrome. Dig. Dis. Sci. 39, 758–761. Pedro-Botet, J., Coll, J., Toma´s, S., Soriano, J.C., Gutie´rrez Cebollado, J. 1993. Primary Sjogren’s syndrome associated with chronic atrophic gastritis and pernicious anemia. J. Clin. Gastroenterol. 16, 146–148. Pillemer, S.R., Matteson, E.L., Jacobsson, L.T., Martens, P.B., Melton, L.J., 3rd, O’Fallon, W.M., Fox, P.C. 2001. Incidence of physician-diagnosed primary Sjo¨gren syndrome in residents of Olmsted County, Minnesota. Mayo Clin. Proc. 76, 593–599. Prince, M.I., Chetwynd, A., Craig, W.L., Metcalf, J.V., James, O.F. 2004. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut. 53, 865–870. Ramos-Casals, M., Anaya, J.M., Garcia-Carrasco, M., Rosas, J., Bove, A., Claver, G., Diaz, L.A., Herrero, C., Font, J. 2004. Cutaneous vasculitis in primary Sjogren syndrome: classiﬁcation and clinical signiﬁcance of 52 patients. Medicine (Baltimore) 83, 96–106. Ramos-Casals, M., Font, J. 2005. Extrahepatic manifestations in patients with chronic hepatitis C virus infection. Curr. Opin. Rheumatol. 17, 447–455. Ramos-Casals, M., Font, J., Garcia-Carrasco, M., Brito, M.P., Rosas, J., Calvo-Alen, J., Pallares, L., Cervera, R., Ingelmo, M. 2002. Primary Sjogren syndrome: hematologic patterns of disease expression. Medicine (Baltimore) 81, 281–292. Ramos-Casals, M., Garcia-Carrasco, M., Cervera, R., Font, J. 2001. Is hepatitis C virus a sialotropic virus? Am. J. Pathol. 159, 1593–1594. Ramos-Casals, M., Garcia-Carrasco, M., Cervera, R., Rosas, J., Trejo, O., de la Red, G., Sanchez-Tapias, J.M., Font, J., Ingelmo, M. 2001. Hepatitis C virus infection mimicking primary Sjogren syndrome. A clinical and immunologic description of 35 cases. Medicine (Baltimore) 80, 1–8. Ramos-Casals, M., Jara, L.J., Medina, F., Rosas, J., Calvo-Alen, J., Man˜a´, J., Anaya, J.M., Font, J., HISPAMEC Study Group. 2005a. Systemic autoimmune diseases co-existing with chronic hepatitis C virus infection (the HISPAMEC Registry): patterns of clinical and immunological expression in 180 cases. J. Intern. Med. 257, 549–557. Ramos-Casals, M., Loustaud-Ratti, V., De Vita, S., Zeher, M., Bosch, J.A., Toussirot, E., Medina, F., Rosas, J., Anaya, J.M., Font, J., SS-HCV Study Group. 2005b. Sjogren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases. Medicine (Baltimore) 84, 81–89. Ramos-Casals, M., Loustaud-Ratti, V., Zeher, M. 2005c. Hepatitis C virus and autoimmune diseases. In: M. Ramos-Casals, M. Garcı´ a-Carrasco, J. Rosas, J. Calvo, J. Font (Eds.), Enfermedades Autoinmunes Siste´micas y Reumatolo´gicas. Masson, Barcelona, pp. 742–758.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 8

Gastrointestinal Involvement in Systemic Vasculitis Salvatore De Vitaa,, Luca Quartuccioa, Elisa Gremeseb, Gianfranco Ferracciolib a

Rheumatology Clinic, Azienda Ospedaliero-Universitaria ‘‘S. Maria della Misericordia’’, DPMSC, University of Udine, Udine, Italy b Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy

1. Introduction Gastrointestinal (GI) manifestations of systemic vasculitides (SVs) are a challenge for the clinician due to the variety and severity of individual vasculitis ranging from isolated involvement (e.g., small mucosal lesions) to life-threatening disease related to massive intestinal disease (e.g., acute mesenteric ischaemia or infarction) (Table 1) (Mosley et al., 1990). When considering the differential diagnosis, it is ﬁrst necessary to distinguish between primary and secondary vasculitis (Mu¨ller-Ladner, 2001). Generally, acute intestinal vasculitis presents as rapidly evolving disease with intensive abdominal pain, followed by signs of peritonitis and ileus, and may progress into a life-threatening shock syndrome with high mortality. At the emergency department admission, it is quite difﬁcult to distinguish between vasculitis-related mesenteric ischaemia from embolic or thrombotic disease in a patient with an acute abdomen presentation. More importantly, the ﬁrst step, after a careful clinical history collection and physical examination, is to evaluate serum concentrations for lactate and coagulation parameters, as well as speciﬁc markers of systemic inﬂammatory disease. Then, when the hypothesis of abdominal ischaemia is Corresponding author. Tel.: 0039 0432 559800; 0039 0432 559808; Fax: 0039 0432 559472 E-mail address: [email protected]

r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00008-6

highly probable, abdominal X-ray and multislice three-dimensional computed tomography (CT) scan and ultrasound Doppler imaging of the mesenteric arteries are mandatory for the diagnosis of ileus, intestinal oedema or perforation. Angiography and surgical intervention may be the subsequent diagnostic and therapeutic step, which should be coordinated with radiologists and vascular surgeons (Mu¨ller-Ladner, 2001). Chronic vascular diseases are related to arteriosclerosis in more than 90% of patients, and in the remaining 10% of patients, they may be due to various chronic intestinal vasculitides. However, chronic vascular diseases can mimic all types of GI disorders; thus, a diagnostic workup should be performed starting from patient’s history. In this regard, abdominal pain 30–60 min after the meal is one of the predominant symptoms. Abdominal Table 1 Gastrointestinal involvement in systemic vasculitis Type of vasculitis

Frequency of gastrointestinal vasculitis

Polyarteritis nodosa Churg-Strauss syndrome Wegener’s granulomatosis Takayasu’s arteritis Giant cell arteritis Scho¨nlein-Henoch purpura Vasculitis in systemic lupus erythematosus Rheumatoid arthritis vasculitis Mixed type II cryoglobulinemia

30–50% 25–50% 5–10% up to 50% 11% 50–90% up to 50% up to 10% Rare

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bruits due to incomplete stenosis of one of the major abdominal arterial vessels are often recorded at physical examination, also in the lack of ultrasound alterations. Gastroscopy and colonoscopy sometimes reveal signs of colitis or multiple petechiae or small mucosal ulcers. Chronic intestinal vasculitides are associated with important morbidity and mortality. In this setting a rare complication, amyloidosis, occurs in the course of hypersensitivity vasculitis, leading to intestinal pseudo-obstruction (Hiramatsu et al., 1998).

2. Large-vessel vasculitis SVs, by nature, can affect any organ or apparatus, and the GI tract falls into the rule. When examining carefully the data of the literature on organ involvement in the various types of systemic vasculitides, the GI tract appears especially affected when the small- and medium-size vessels are involved and much less affected when the large vessels are involved (Tables 1–3), even though we must Table 2 Frequency of the major clinical manifestations of Takayasu’s arteritis (TA) % Fever Asthenia Pulseless Hypertension Carotidodynia Headache Ischemic retinopathy Gastrointestinal (clinical/X-ray)

35 50 50–96 33–76 32 20–42 37–52 47

Table 3 Frequencies (approximate %) of GI organ involvement in largevessel vasculitides

Imaging and/or clinical gastrointestinal (GI) tract involvement

TA

GCA

Chronic peri-aortitis

47

11

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recognize that no vessel size can be, by deﬁnition, ruled out in any of the commonly classiﬁed inﬂammatory vasculitides (Ferraccioli et al., 1998).

3. Takayasu’s arteritis Takayasu’s arteritis (TA) is an acute arteritis affecting the large and medium vessels (aorta and pulmonary arteries in particular) and is characterized by signs and symptoms of stenosis of aortic branches. The typical sign is the pulseless disease that affects young women more than men (60–90 are women). The incidence is 1.2–2.6 cases/ 1,000,000o40 years. Prognosis is essentially linked to the occurrence of catastrophic neurologic events due to hypertension, aneurysms and aortic insufﬁciency. Progression of inﬂammation leads to stenotic occlusion of the involved arteries and to aneurysmatic lesions of ascending aorta, aortic arch, descending aorta and bilateral common carotid arteries. GI symptoms (abdominal pain, cramps, diarrhoea) are among the most frequent manifestations of the disease (Tables 2 and 3).

3.1. Pathogenesis An infectious origin has been hypothesized from the fairly common association with previous mycobacterial infection (tuberculosis) (LupiHerrera et al., 1977). An autoimmune origin was suggested by the association described with other autoimmune diseases (Crohn’s disease, anchylosing spondylitis, systemic lupus erythematosus) and by the association with HLAB5 and more particularly with B52. Moreover, besides an higher expression of HLA class I and II antigens, an higher expression of heat shock protein 65 (HSP-65) was seen in Takayasu’s arteritic lesions, suggesting a possible pathogenetic role of gd T cells (especially Vd1+) cells as well as ab T cells activated by infectious events and inﬁltrating the arterial wall (Seko, 2000; Kerr et al., 1994). Human studies suggesting endothelial cell activation have demonstrated increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in

Gastrointestinal Involvement in Systemic Vasculitis

patients with TA. Humoral immunity is also believed to be involved in this disease; antiaorta antibodies and antiendothelial cell antibodies have been found in patients with TA. Immunoglobulin G, immunoglobulin M and properdin are found in lesions from pathologic specimens.

3.2. Pathology Macroscopically, the aorta appears rigid, thickened and ﬁbrotic. Stenotic lesions can be observed framed with fully normal traits. Microscopically, mononuclear inﬁltration of the adventitia occurs early in the course of the disease, with cufﬁng of the vasa vasorum. Granulomatous changes may be observed in the tunica media with Langerhans cells and central necrosis of elastic ﬁbres and smooth muscle cells. A panarteritis with inﬁltrates of lymphocytes, plasma cells, histiocytes and giant cells is present. Later, ﬁbrosis of the media and a cellular thickening of the intima compromise the vessel lumen. Wrinkling of the intima is visible on gross examination. In chronic phases, the intima presents calciﬁcations.

3.3. Diagnosis Age less than 40, claudication of the extremities, pulselessness in one brachial artery and a pulse pressure difference of more than 10 mm Hg between the upper limbs, clearcut bruits over a subclavian artery, arteriographic lesions of the proximal aortic branches, not linked to arterosclerotic lesions: The presence of three or more criteria suggests the diagnosis with a sensitivity of 90.5% and a speciﬁcity of 97.8%. The arteriographic study allows to distinguish among the ﬁve types of the disease (class I to IIa and IIb: ascending aorta; class III: thoracic and abdominal aorta; class IV: abdominal aorta and renal arteries; class V: class IIb and III).

3.4. Therapy No controlled therapeutic trial is available. Corticosteroids are the mainstay of therapy (0.7–1 mg/kg/day for 1 month, then tapered

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down slowly). In patients who show persistent activity despite 15 mg/day of prednisone, immunosuppressive agents should be employed (Cyclophosphamide, Azathioprine, Methotrexate, Mycophenolate Mofetil). A 12-month treatment is generally necessary before reaching a full control of disease activity. A small series (15 patients) showed that TNF inhibition using etanercept or inﬂiximab was successful in inducing clinical remission and permitting corticosteroid taper in patients who are steroid dependent. The role of TNF inhibition in treating initial disease or relapses is yet to be established, but use of these agents and immunosuppressants, such as mycophenolate or methotrexate (0.3 mg/kg/wk), anticipate regimens in which disease is controlled while minimizing morbidity from steroid. Some very resistant cases to conventional therapies can lead to percutaneous balloon angioplasty and endovascular stenting revascularization. Aneurysm formation occurs in 27% of the cases. While the 5-year survival rates exceed 90%, the disease has a high incidence of residual morbidity (Arend et al., 1990; Arora et al., 1997; Baumgartner et al., 2005; Daina et al., 1999; de Leeuw et al., 2004; Della Rossa et al., 2005; Haberhauer et al., 2001; Hoffman et al., 1994, 2004).

4. Giant cell arteritis Giant cell arteritis (GCA) is a chronic, systemic vasculitis with a distinct localization in large- and medium-sized arteries (aorta and its extracranial branches). The incidence is 9–29 cases/100,000 in patients W50 years, according to geographical studies. Symptoms include headache, jaw claudication, scalp tenderness, muscle aches, weight loss, fatigue, fever and visual complaints. The most serious complications of GCA are persistent and permanent visual loss or neurologic damage. Prognosis depends upon its major localizations. While the prevalence of myocardial infarction is unknown, the risk of abdominal aneurysm is 2.4%, and cerebral infarction has been reported in 7% of consecutive patients with biopsy-proven GCA (Small and Brisson, 1991; Phelan et al., 1993;

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Burke et al., 1995; Srigley and Gardiner, 1980; Smith et al., 1988; Krant and Ross, 1992; Hassan and Daymond, 1993; Trimble and Weisz, 2002; Evans et al., 1995). Abdominal complaints are frequent and strictly related to the ischaemic necrotic lesions occurring in various parts of the vascular net of the GI tract (Table 3).

leukocytes are rare. Thrombosis may develop at the sites of active inﬂammation. These areas with thrombosis may recanalize later. It has been observed that the inﬂammatory process is usually most marked in the inner portion of the media adjacent to the internal elastic lamina.

4.3. Diagnosis 4.1. Pathogenesis The granulomatous histopathology of GCA has suggested the presence of an antigen-driven disease with local T-cell and macrophage activation in or near elastic tissue in the arterial walls with an important role of the proinﬂammatory cytokines. Some familial accumulation and the association with HLA-DR4 suggest a clear immunological genetic predisposition. The CD4+T cells appear to be central in the pathogenesis. In fact, clonal expansion of CD4+T cells presenting identical Ag receptors has been isolated from arteritic lesions. These T cells are thought to derive from vasa vasorum, under the inﬂuence of chemokines such as CCL19 and CCL21 produced by dendritic cells present in the adventitia. Data suggest that endothelial cells and dendritic cells are activated before T-cell recruitment (Weyand and Goronzy, 2003; Nordborg and Nordborg, 2003).

4.2. Pathology Biopsy demonstrates a vasculitis with mononuclear cell inﬁltrates. Collections of lymphocytes are conﬁned to the region of the internal or external elastic lamina or adventitia in early cases or regions of arteries with minimal involvement. Intimal thickening, with prominent cellular inﬁltration, is typically present. In late cases or regions of arteries with marked involvement, there are widespread areas of necrosis of portions of the arterial wall. The elastic laminae are usually involved, and granulomas containing multinucleated histiocytic and foreign body giant cells, histiocytes, predominantly helper T-cell lymphocytes, and some plasma cells and ﬁbroblasts are usually present. Eosinophils may be seen in the specimen section, but polymorphonuclear (PMN)

The American College of Rheumatology criteria (1990) for the diagnosis of GCA are as follows:

Age of 50 years at onset New headache Abnormalities of the temporal arteries Erythrocyte sedimentation rate (ESR) of 50 mm/h Positive results of a temporal artery biopsy (vasculitis characterized by a predominance of mononuclear inﬁltrates or granulomas, usually with multinucleated giant cells) (Table 4).

4.4. Therapy Corticosteroids are central in the therapeutic approach to GCA treatment. The initial dose in the case of impeding visual loss requires boluses of corticosteroids (1 g of 6-methylprednisolone for 3 days) followed by prednisone equivalents of 1 mg/kg/day for 1 month and gradual, slow Table 4 Characteristics of GCA and TA Findings

Giant cell arteritis Takayasu’s arteritis

Female-to-male ratio 3:2 Age at onset W50 years Ethnic ancestry European Histopathology Granulomatous inﬂammation Primary vessels External carotid involved artery branches Abdominal pain Rare Renovascular Rare hypertension HLA association HLA-DR4 Course Self-limited Response to Excellent corticosteroids

7:1 o40 years Asian Granulomatous inﬂammation Aorta and branches Common Common HLA-Bw52 Chronic Excellent

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tapering afterwards. The objective should be to decrease or even stop the steroid as soon as possible in order to avoid all the side effects that occur during a long-term treatment especially in elderly patients. Of crucial importance, no studies have addressed the issue of how to taper the corticosteroids in patients with GCA. One possible approach is to reduce the daily dose of prednisone by 10 mg every month until a dose of 25 mg has been reached, then the daily dose may be decreased by 2.5 mg each month until the patients takes 10 mg/day and then reduce by 2.5 mg on alternate days every 2 wks. These regimens would result in full steroid withdrawal after 13–14 months. However, disease exacerbation is frequent and abdominal symptoms are among the manifestations of recurrence. Of note, abdominal as well as thoracic aneurysms are among the late complications of a poorly controlled GCA and can develop in nearly 20% of the patients (Evans et al., 1995).

5. Chronic periaortitis (Index case) A 16-year-old boy, in perfect shape, suddenly developed cramping abdominal pain, and fever

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a few hours later. The abdominal pain was unusually (for the age) located in the periumbilical and left upper quadrant of the abdomen and did not vanish with spasmolytic drugs nor with paracetamol. The patient at the emergency room of the local hospital underwent a plain abdominal X-ray and an ultrasound examination that revealed a dilated small and large intestine, with large bowel loops and decreased bowel movements, without any sign of paralysis of the intestine. The acute-phase reactants were elevated and the abdomen CT scan showed multiple ﬂuidand gas-ﬁlled loops of the small bowel without a deﬁnite point of obstruction. No appendix or pancreatic or kidney lesions were demonstrated. A suspicion of thickening of the abdominal aorta was raised (aortitis?), and the patients was sent to our unit, where a new CT angiography scan showed periaortitis of the aortic arc, of the abdominal aorta below and above the renal artery, and of the superior mesenteric artery (Figs. 1 and 2). This patient was affected by periaortitis of the supradiaphragmatic and subdiaphragmatic aorta, presenting as abdominal pain. This case underlines once again that largevessel arteritides can present with manifestations at the GI tract level.

Figure 1. Aorta abdominal tract showing thickening of the wall of 2.8 mm.

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Figure 2. Aorta abdominal tract above and below the renal artery, showing thickening of the wall.

5.1. Characteristics of the disease

5.3. Diagnosis

Chronic periaortitis is thought to be the most aggressive manifestation of inﬂammatory atherosclerosis, and is probably an autoimmune process. The estimated annual incidence is 0.2–0.5 per 100,000 persons. It affects middle-aged to elderly men more commonly than females (ratio 2:1–3:1).

Abdominal (or back) pain is the most common presentation (80%). Fever, weight loss, vomiting, malaise, and also testicular pain, ureteral colic and claudication, have been often described. Symptoms and elevated acute-phase reactants raise the suspicion that can be conﬁrmed by contrastenhanced CT scanning (or MRI). These investigations reveal the periaortic tissue mass as a ring of abnormal inﬂammatory (or ﬁbrous tissue) around the aorta and often involving other branches (Hellmann et al., 2007; Jois et al., 2004).

5.2. Pathology The key features are represented by chronic inﬂammatory inﬁltrates in the aortic adventitia, medial thinning in dilated or undilated aorta with different degrees of periaortal ﬁbrosis, extending into the adjacent structures. The striking inﬂammatory reaction in the adventitia consists of plasma cells, many B cells but few T cells, and macrophages. Occasionally, small granulomas and giant cells can be observed (Parums, 1990; Pasquinelli et al., 1993).

5.4. Therapy Even though the relative role of corticosteroids is still undeﬁned, they remain the basic therapeutic approach in this entity. However, there is no standard for dose and duration of steroid treatment.

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When the response is incomplete, azathioprine, methotrexate, mycophenolate mofetil, tamoxifen and cyclophosphamide have all been described as effective in selected case reports or small series (Kardar et al., 2002; Warnatz et al., 2005; Grotz et al., 1998; Marcolongo et al., 2004; Bourouma et al., 1997).

6. Medium-sized vessel vasculitis Polyarteritis nodosa (PAN) and Kawasaki disease (KD) are the two major forms of medium-sized vessel vasculitis (MVV), characterized by necrotizing arteritis (Jennette et al., 1994). Patients with necrotizing arteritis fall into two broad categories: those with vasculitis affecting arteries versus those with vasculitis affecting not only arteries but also vessels smaller than arteries, such as venules and capillaries. The former includes PAN and KD, the latter includes several forms of small-sized vessel vasculitis (SVV) (Hunder et al., 1990).

6.1. Polyarteritis nodosa According to the Chapel Hill Consensus Conference (CHCC), PAN is a necrotizing inﬂammation of small- and medium-sized arteries without glomerulonephritis or arteritis in arterioles, capillaries or venules (1). PAN is a rare form of systemic vasculitis, but there are also organ-limited varieties of PAN, cutaneous PAN being the best recognized. In 1970, Trepo and Thivolet reported on the association of PAN with hepatitis B virus (HBV) infection. HBV infection is included as a diagnostic criterion in the ACR 1990 classiﬁcation, but in the 2006 classiﬁcation proposal for childhood vasculitis, HBV-PAN is classiﬁed as separate from idiopathic PAN (Ozen et al., 2006). The incidence of the disease is rather low, ranging from 5 to 10 per million. The pathologic hallmarks of PAN are transmural ﬁbrinoid necrosis and inﬂammation, which is initially characterized by neutrophil inﬁltration, but later by monocytes, macrophages and lymphocytes. This necrotizing inﬂammation results in aneurysms (pseudoaneurysms), the arterial nodules that prompted the term ‘nodosa’. Biopsy of target

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organ hardly allows the differentiation between MVV (e.g., PAN) and SVV; thus, the diagnosis of PAN should be done only after a reasonable search for clinical and pathologic evidence for SVV is negative, especially including absence of glomerulonephritis or pulmonary capillaritis, while skin and peripheral nerves represent the most frequent involvement (Guillevin and Lhote, 1995a). GI vasculitis is found in up to 25–63% of the patients and may be present at PAN onset (Stone, 2002; Guillevin et al., 1995b). Patients more frequently present with subacute disease onset over many weeks or months (Levine et al., 2002). GI involvement may also present as a perforation of the stomach, small or large bowel; infarction of the stomach, small or large bowel; vasculitic appendicitis; gallbladder infarction and vasculitic cholecystitis; haemorrhagic pancreatitis; nausea and vomiting; bloody and non-bloody diarrhoea; melaena; occult or massive intestinal bleeding and rupture of splenic, hepatic or renal arteries. The diagnosis of PAN is suggested by an angiographic ﬁnding of aneurysms up to 1 cm in diameter within the mesenteric and hepatic vasculature. However, this ﬁnding is not always pathognomonic for PAN, because it is also seen in necrotizing angiitis associated with drug abuse (Halpern and Citro, 1971), Wegener’s granulomatosis (WG) and systemic lupus erythematosus (Travers et al., 1979). Based on a prospective study, the French Vasculitis Study Group determined that the following ﬁve factors (ﬁve-factor score) had signiﬁcantly worse prognostic value in PAN and Churg-Strauss syndrome (CSS): proteinuriaW1 g/day, creatininemiaW158 mg/dl, cardiomyopathy, GI tract involvement and central nervous system involvement. Since 1950s, the introduction of corticosteroids has dramatically improved the outcome, from 87% of a 5-year mortality to 50%, and recent long-term follow-up studies have described 5-year survival of up to 85%. GI tract involvement, HBV infection and ageW65 years are associated with increased mortality (Gayraud et al., 2001). Clinical trials of therapeutic strategies over the last 10 years have optimized the use of cyclophosphamide and the best administration (continuous oral versus pulsed intravenous) or treatment duration (Guillevin et al., 2003).

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6.2. Kawasaki’s disease KD is a MVV affecting children. This is a febrile illness of childhood that usually occurs before 5 years. The most deﬁnite feature is the mucocutaneous lymph node syndrome, which includes fever, polymorphous erythematous skin rash, oropharyngeal erythema, redness or ﬁssuring of the lips, indurative oedema of the extremities, desquamation, conjunctivitis and nonsuppurative lymphadenopathy. Coronary arteries are often involved and represent the most important involvement affecting the morbidity and mortality in this setting. Pathologically, the arteritis of KD shows less ﬁbrinoid necrosis than that observed in PAN and more medial oedema. Involvement of the bowel or gallbladder is relatively uncommon (Falcini et al., 2002). The reported GI manifestations comprise surgically acute abdomen caused by paralytic ileus, vasculitic appendicitis, haemorrhagic duodenitis, or bloody or non-bloody diarrhoea. A course of intravenous immunoglobulins (2 g/kg in total) given in the ﬁrst 10 days in addition to aspirin (50–80 mg/kg) led to a faster resolution of fever and clinical signs and to a shorter hospitalization (Newburger et al., 1991). Corticosteroids may be useful in patients who failed intravenous immunoglobulins (Hashino et al., 2001). Recently, a randomized trial failed to demonstrate an advantage when a single pulsed dose of intravenous methylprednisolone was added to conventional intravenous immunoglobulin therapy for the routine primary treatment of children with KD (Newburger et al., 2007).

7. Small-sized vessels vasculitis Small-sized vessels vasculitis (SVV) has a predilection for capillaries and venules, but arterioles and small arteries may be involved. SVV can be divided in two immunopathologic categories: immune complex-mediated vasculitis, such as HenochScho¨nlein purpura (HSP) and cryoglobulinemia, and pauci-immune SVV, such as ANCA-associated vasculitis.

7.1. Henoch-Scho¨nlein purpura and leukocytoclastic vasculitis HSP is a vasculitis of small vessels, secondary to an immune process that generates circulating immune complexes containing signiﬁcant amounts of IgA, which precipitate in the skin, joints, kidneys and bowel. In fact, clinical features include a palpable purpura, arthritis, acute glomerulonephritis and abdominal pain. The typical histologic lesion in the skin biopsy is leukocytoclastic angiitis affecting postcapillary venules, capillaries and arterioles. The most speciﬁc pathologic ﬁnding for HSP, which can differentiate HSP from other leukocytoclastic vasculitis, such as cryoglobulinemia, WG, CSS or micropolyangiitis, is the deposition of IgA-dominant immune complexes in vessel walls (Baart de la Faille-Kuyper et al., 1973). Although the aetiology is unknown, immunization, insect bites, medications and infections may play a role in its development. HSP occurs predominantly in younger patients, but it can also affect the adult patients. In a Spanish study, more than 30% of children with HSP presented with abdominal pain alone or in association with other manifestations, and during the follow-up, 70.5% developed bowel angina and about 31% GI bleeding (Calvino et al., 2001). There is a wide spectrum of involvement of the bowel in HSP, GI manifestations having been related to oedema and intramural haemorrhage. GI haemorrhage is mostly conﬁned to the mucosa and submucosa, while full-thickness necrosis and perforation of a bowel loop is rare. The GI ﬁndings described in the course of HSP include intussusception (2–5%, the most serious complication), bowel ischaemia and infarction, intestinal perforation, ﬁstula formation, acute appendicitis, massive upper GI haemorrhage, pancreatitis, hydrops of the gallbladder and pseudomembranous colitis. Non-characteristic radiological ﬁndings are seen, although upper GI barium studies as well as CT scans are useful to identify mural thickening, thickened folds and ulcerations (Siskind et al., 1985). Treatment for HSP has been essentially supportive, a benign course being the most frequent outcome. Corticosteroids have been widely and

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successfully used in the acute phase of the disease to treat abdominal pain and arthralgias/arthritis in children (Rosenblum and Winter, 1987). In refractory cases, intravenous immunoglobulins, plasma exchange, immunosuppressive treatment (mainly in leukocytoclastic vasculitis other than HSP) and tonsillectomy have been utilized in open-label study, but the results are controversial. Isolated localized GI vasculitis is a rare entity that is very difﬁcult to distinguish from HSP, and it can occur in association with HSP. The absence of IgA deposits on intestinal biopsy specimen in the context of a leukocytoclastic vasculitis is crucial for the diagnosis. The course of this disease appears more aggressive and difﬁcult to treat than that observed in HSP, requiring immunosuppressors or surgical intervention (Garcia-Porrua et al., 2006).

7.2. ANCA-associated small-vessel vasculitis The antineutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitides (ASV) comprise a group of disorders characterized by necrotizing small-vessel vasculitis with a paucity of immune deposits, in conjunction with autoantibodies directed against neutrophil cytoplasmic constituents, in particular proteinase 3 (PR3) and myeloperoxidase (MPO). A common feature is glomerulonephritis with crescent formation and ﬁbrinoid necrosis (Jennette and Falk, 1997; Bosch et al., 2006). The ASV include WG, microscopic polyangiitis and CSS. ANCA positivity is often observed in WG patients, usually PR3-ANCA, and most patients with microscopic angiitis display MPOANCA, while only 35–50% of CSS patients are positive for ANCA, generally MPO-ANCA (Sinico et al., 2005). These ﬁndings, together with substantial clinical, histologic and biologic differences between these three entities, have opened some debate when considering WG, CSS and microscopic angiitis either as three distinct disorders or, more generally, as different aspects of a unique type of vasculitis. A putative role of ANCA, in particular MPO-ANCA, in the

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pathogenesis of ASV represents the basis of the hypothesis of an ANCA-associated vasculitic syndrome and the rationale of novel B-cell depletion treatment (Falk and Hoffmann, 2007). The ASV often present with malaise, myalgias, arthralgias, fever, rash and neuropathy. WG and microscopic angiitis commonly present with acute renal and pulmonary disease. A hypereosinophilia and history of asthma characterize CSS, while the upper respiratory tract (typically ear, nose, throat) is the common target of WG and the granulomatous inﬂammation is the pathologic hallmark (Jennette and Falk, 2007). GI involvement in the course of CSS is frequent, more common than in the remaining ASV, ranging from 25 to 50%. In a recent French study, about 30% of CSS patients had GI symptoms during the course of their disease and 2/23 died due to mesenteric infarct (Bligny et al., 2004). Other documented manifestations include melaena, haematemesis, oesophageal gastric, small intestine and colonic perforation, cholecystitis, bowel ischaemia, ischaemic colitis and omental haematoma. In some patients, several of the intestinal vessels can be affected causing life-threatening organ failures (Boggi et al., 1997). Recently, an Italian study group retrospectively followed 75 patients after diagnosis: 36 with WG, 23 with CSS, and 16 with microscopic polyangiitis. GI involvement was associated with an increased risk of relapse, mainly in patients with CSS, whereas renal disease and perinuclear antineutrophil cytoplasmic antibody positivity were correlated with a lower risk of relapse. Older age, renal and hepatic involvement, ESRZ100 mm/h and serum creatinine levelsZ1.5 mg/dl were all related to higher risk of death in univariate analysis. However, only cerebral and hepatic involvement and serum creatinine levelZ1.5 mg/dl were independently correlated with an unfavorable prognosis for survival (Pavone et al., 2006). Similarly, French groups found that GI involvement represents a poor prognostic sign in CSS or PAN patients, in particular in those patients with bleeding, perforation, infarction or pancreatitis (Guillevin et al., 1996). Interestingly, microscopic polyangiitis resembles CSS in many aspects, showing a similar spectrum of GI symptoms.

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GI involvement in WG appears to be a rare event, usually resulting in granulomatous colitis and gastritis. WG case reports with bowel infarction, oesophageal ulceration, cholecystitis, gallbladder infarction, pancreatitis and pancreatic mass, bloody diarrhoea, small and large bowel perforation and spontaneous splenic haemorrhage are recorded in the literature. Isolated intestinal vasculitis sometimes occurred as the only manifestation, and with a severe course (Chang and Kerr, 2000). The introduction of cyclophosphamide and corticosteroids in combination has drastically improved the overall survival in ASV, especially in WG, with 85% of patients achieving temporal or persistent remission. Cyclophosphamide, methotrexate, azathioprine and glucocorticoids all have a role in the treatment of ASV. However, despite strong immunosuppressive regimen, many patients do not reach remission and up to 50% relapse; in addition, these regimens may result in high rate of morbidity and mortality. Thus, several randomized controlled trials have been recently published or are now ongoing to optimize the use of immunosuppressants both in the remission induction and in the maintenance regimen. Novel treatment with biological agents, such as TNF alpha blocking agents, as well as anti-CD20 therapy (rituximab), are now under study in randomized controlled trials, after preliminary good results coming from open trials (Kallenberg, 2007). In particular, in one reference study, rituximab induced remission in all patients with active, severe ASV, with resistance or intolerance to cyclophosphamide, allowing steroid tapering (Keogh et al., 2006). A large controlled trial (RAVE) with rituximab in ASV was then started. By contrast, etanercept, a soluble receptor of TNF, proved to be ineffective in the WG etanercept trial (WGET), in addition to the immunosuppressive standard regimen (Wegener’s Granulomatosis Etanercept Trial (WGET) research group, 2005), increasing the risk of cancer (Seo et al., 2005). Finally, more aggressive treatments, such as lymphocyte depletion with anti-thymocyte globulin or alemtuzumab (CAMPATH 1-H), or autologous stem cell transplantation, have been used in very refractory and life-threatening diseases (Jayne, 2007).

8. Mixed cryoglobulinemia, HCV infection and gastrointestinal involvement The cryoglobulinemic vasculitis or syndrome is a systemic vasculitis usually associated with hepatitis C virus (HCV) infection and characterized by non-neoplastic B-cell lymphoproliferation in the large majority of cases, but with an increased risk of B-cell lymphoma development (Gorevic et al., 1980; De Vita et al., 2000a; Dispenzieri, 2000). Among the HCV-negative cryoglobulinemic syndrome group, many cases with type II serum mixed cryoglobulinemia (MC) also present Sjo¨gren’s syndrome, an autoimmune and lymphoproliferative disorder primarily involving the salivary and lachrymal glands, leading to glandular damage, dysfunction and sicca syndrome (Johnsson et al., 2005; Tzioufas et al., 1996; De Vita et al., 2001). MC syndrome may rarely complicate with lifethreatening abdominal vasculitis, possibly involving the stomach and the small and the large bowel (Gorevic et al., 1980; Baxter et al., 1988; Cacoub et al., 2001; Ferri et al., 2004; Ramos-Casals et al., 2006). Vague and diffuse abdominal complaints may be referred at ﬁrst. Thus, this organ manifestation must be primarily suspected and speciﬁcally investigated in its early stages. In a panarteritis-like subset of MC syndrome, necrotizing vasculitis may lead to the small aneurysm ﬁndings (mesenteric, coeliac, hepatic, as well as renal) by abdomen arteriography (Cacoub et al., 2001; CostedoatChalumeau et al., 2002), as seen in classical panarteritis nodosa, while colic mucosa biopsy may show non-speciﬁc pathologic ﬁndings. A picture of acute abdomen and bowel infarctual lesions may then follow, though it may also develop ab initio. Finally, colitis pseudomembranosa may superimpose if the patient has been treated with largespectrum antibiotics in our experience, and this further complicates the diagnostic and treatment approach. Although rare, such severe intestinal vasculitic complications of MC syndrome must be diagnosed and treated promptly, and mortality is high in any case. Therapy includes high-dose steroids and cyclophosphamide. We also protect the patient from superimposed infections with antibiotic plus antifungal therapy in the period

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of high-to-medium-dose steroids combined with cyclophosphamide, and periodically assess Clostridium difﬁcile infection. Plasmapheresis is another treatment option as an induction therapy, while rituximab is currently not recommended for abdomen vasculitis in MC syndrome, as well as in ANCA-associated vasculitis. In fact, the latency for clinical efﬁcacy of rituximab may be too long, usually more than 1 month, despite the usual early B-cell depletion (Zaja et al., 2003; Quartuccio et al., 2006). In addition, MC cases with very delayed B-cell clinical response (W3 months after the ﬁrst drug infusion) or with late B-cell depletion have been observed (De Vita, S., personal communication). However, rituximab may also prove effective in MC-related intestinal vasculitis based on personal preliminary experience, either in the context of induction polytherapy or as maintenance therapy. Thus, additional investigation is required. GI bleeding due to peptic ulcer, MC-unrelated, or due to oesophageal varices associated with portal hypertension in HCV-related cirrhosis (Gorevic et al., 1980) should always be considered in the differential diagnosis. The association of protein-losing enteropathy and cryoglobulinemia was recently reported in one patient (Samarkos et al., 2003). A 79-year-old woman with HCV-related MC syndrome diagnosed in 2001 was successfully treated by our group with combined standard antiviral therapy, with subsequent virus RNA (genotype 5a) clearance from serum and disappearance of systemic vasculitis features and bone marrow low-grade B-cell lymphoma by morphologic analyses. Interferon and ribavirin were however suspended after 1 year, since they were no longer tolerated. Two months after suspension of antiviral therapy, while still HCV RNAnegative, the patient was then admitted to our clinic for the onset of chronic diarrhoea in association with fever. She developed an intractable wasting syndrome concomitantly with MC syndrome reactivation including active nephritis and cutaneous vasculitis. Infectious diseases, lymphoproliferative intestinal diseases and coeliac disease were all excluded by tissue biopsies and radiological studies. High-dose steroid therapy was ineffective and the patient worsened

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developing hepatic failure and, ﬁnally, died because of multiorgan failure syndrome. Another patient with MC syndrome and chronic diarrhoea, possibly due to intestinal vasculitis, has been reported (Jones et al., 1991). Of note, intestinal vasculitis also developed during interferon plus ribavirin therapy (Pompili et al., 2005). Abnormal acquisition of MALT (mucosaassociated lymphoid tissue) in the gastric mucosa represents an additional and much more frequent clinical manifestation both in HCV-related MC syndrome and in chronic HCV infection without MC, as well as in Sjo¨gren’s syndrome with or without MC. This gastric MALT accumulation may lead to different pictures of chronic gastritis lymphoid inﬁltration, i.e., sparse, follicular or lymphoepithelial lesions (Ferraccioli et al., 1996; De Vita et al., 2000b), and might favour gastric lymphoproliferation and eventually the development of low-grade gastric B-cell lymphoma of MALT. Such a subset of MALT lymphoma is usually linked with Helicobacter pylori infection, but in the case of MC syndrome and Sjo¨gren’s syndrome H. pylori infection likely represents only a possible pathogenetic co-factor. By contrast, the ‘background’ of lymphoproliferation is likely linked to the underlying autoimmune disease (De Vita et al., 1996; De Vita et al., 2000b, 2001) (Fig. 3). As a ﬁrst issue, HCV may localize in the gastric mucosa, both in HCV-infected individuals without MC and in HCV-related MC syndrome. HCV gastric localization was shown by strong and unequivocal reactivity of the cytoplasm of glandular cells by immunohistochemistry, while the nuclei were completely negative. Results were concordant with the viral ﬁndings obtained by PCR in whole RNA from the same samples, while HCV in situ hybridization could not be employed (De Vita et al., 2000b). When also considering the possible contribution of autoimmunity in chronic gastritis (Hussell et al., 1993; Negrini et al., 1996) and the evidence of intragastric clonal B-cell expansion in Sjo¨gren’s syndrome also in the absence of H. pylori infection (Ferraccioli et al., 1996), the role of other gastric local triggers (including HCV) and co-factors in the predisposed individual can be hypothesized.

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Figure 3. Low-grade gastric B-cell lymphoma of MALT, H. pylori positive (panel A) occurring in a patient with Sjo¨gren’s syndrome, persistent parotid swelling due to myoepithelial sialadenitis, and non-malignant lymphadenopathy. Gastric lymphoma regressed to chronic gastritis after H. pylori eradication with antibiotics (panel B). However, as shown in panel C (agarose gel stained with ethidium bromide showing VDJ-PCR products) and as conﬁrmed by DNA sequencing, the same B-cell clone Sjo¨gren’s syndrome-related, as detected in the gastric fundus (F0), lymph node (L0) and parotid (P0) at baseline (monoclonal single band), was still present in the gastric fundus chronic gastritis (F1) and in non-malignant lymph node (L1) in repeated biopsies after H. pylori eradication (De Vita et al., 1996). The patient developed a gastric high-grade B-cell lymphoma, H. pylori-negative, in subsequent follow-up. Lanes A0 and A1 in panel C show a polyclonal pattern in the patient’s gastric antrum uninvolved by lymphoma, and in control reactive lymph node from another case (lane R). Lane B: positive control with ampliﬁed B-cell leukaemia DNA; lane M: molecular weight markers; lane N: negative PCR control without DNA. (See Colour Plate Section.)

Secondly, HCV infection appears to increase the risk of gastric lymphoma, since the rate of HCV infection was increased in unselected cases of gastric lymphomas and in HCV-related lymphomas in Sjo¨gren’s syndrome (De Vita et al., 1998; Luppi et al., 1996; Ramos-Casals et al., 2007). This increased occurrence of HCV-positive cases was

also found for what concerns primary hepatic and major salivary gland B-cell lymphomas (De Vita et al., 1998). Strikingly, HCV shows a tropism not only for the liver, but also for the salivary epithelium (De Vita et al., 1995), and a role of HCV as a trigger of MALT lymphoproliferation in the local microenvironment has been hypothesized

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(De Vita et al., 2002). Gene sequence analyses were also consistent with an antigen-driven B-cell proliferation in HCV-positive cases of lymphoma (De Vita et al., 2000b; De Re et al., 2000) in analogy with H. pylori-related gastric B-cell proliferation of MALT. Thirdly, gastric low-grade B-cell lymphoma did not regress despite eradication of local H. pylori infection, as assessed by repeated methacronous gastric biopsies after effective antibiotic therapy, while HCV-RNA was detected by sensitive PCR analyses in the same tissue lesions. Of note, HCV localization in the cytoplasm of the residual glandular epithelium was shown by in situ studies within the lymphomatous lesion, with no substantial differences in staining intensity if compared to results obtained in chronic gastritis in HCV-positive individuals. Frequently, positive cells could be observed within the centre and the invasion front of the tumour, and positive residual glandular cells were found within the homogeneously HCV-negative lymphoma cells. Of note, sequence analyses of the immunoglobulin rearranged genes of the neoplastic B-cell clone in the gastric lymphoma sample obtained after H. pylori eradication still showed the presence of intraclonal heterogeneity, indicating the persistence of antigenic stimulation in the gastric mucosa (De Vita et al., 2000b). This also argues against a fully deregulated B-cell neoplastic proliferation. Lastly, gastric B-cell lymphoproliferation in HCV-related Sjo¨gren’s syndrome and in MC syndrome showed signiﬁcant deduced amino acid sequence homology both with immunoglobulin sequences encoding for rheumatoid factors (RF) and with sequences encoding for anti-HCV antibodies, i.e., antibodies related to HCV infection (De Vita et al., 2000a, b; De Re et al., 2000). These early results led to subsequent studies by our group that better explained a relevant mechanism by which HCV infection may preferentially favour the proliferation of RF-positive B-cell clones, i.e., HCV linking to RF B-cell receptor itself (De Re et al., 2006). For what concerns the acquisition of gastric MALT and vasculitis in HCV-unrelated MC syndrome and Sjo¨gren’s syndrome, it should be

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noticed that among the many extraglandular features that may be observed in the course of Sjo¨gren’s syndrome, MC occurs in a minority of cases (Tzioufas et al., 1996; De Vita et al., 2001), but has been consistently associated with the development of a B-cell lymphoma (Tzioufas et al., 1996), which is in turn a well-known complication in MC syndrome secondary to HCV infection. By integrated clinical, pathologic and molecular studies, we recently highlighted that MC has a different biologic background in Sjo¨gren’s syndrome if compared to chronic HCV infection (De Vita, S., personal presentation and manuscript in preparation). MC is polyclonal in the bone marrow and is associated with salivary MALT lymphoma in SS, consistent with the primary role of salivary MALT chronic inﬂammation and lymphoproliferation as a predisposing factor to lymphoma in this disease, which is rarely associated with HCV infection. By contrast, MC in the course of HCV infection is primarilly a liver and bone marrow autoimmune and lymphoproliferative disorder, and malignant lymphoproliferation of salivary MALT is rarer in this setting. Overlapping features of Sjo¨gren’s syndrome and MC vasculitis may however occur in HCV-positive patients. Interestingly, as reported above, abnormal acquisition of gastric MALT may occur both in Sjo¨gren’s syndrome and in MC syndrome. Thus, the study of the gastric microenvironment, in conjunction with that of the bone marrow, liver and salivary glands, may be relevant for future research aimed to clarify the mechanisms leading to preferential RF-positive B-cell expansion in these diseases, and, in general, to better explain the various components of gastric lymphomagenesis. The therapeutic value of targeting the local trigger of chronic inﬂammation, autoimmunity and lymphoproliferation versus other biologic targets should be better explored as well (Quartuccio et al., 2006; De Vita and Quartuccio, 2006). Besides local antigenic stimulation, the mechanisms by which HCV infection and other local triggers may favour gastric acquisition of MALT and, more generally, chronic inﬂammation and B-cell expansion, remain elusive. With regard to this issue, local cytokine networks are likely implicated. Recent results pointed out the role of

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HCV infection in upregulating the expression of BAFF (Fabris et al., 2007), a relevant growth factor implicated in autoimmunity and B-cell lymphoproliferation.

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Phelan, M.J., Kok, K., Burrow, C., Thompson, R.N. 1993. Small bowel infarction in association with giant cell arteritis. Br. J. Rheumatol. 32, 63–65. Pompili, M., Pizzolante, F., Larocca, L.M., et al. 2005. Ischaemic jejunal vasculitis during treatment with pegylated interferon alpha 2b and ribavirin for hepatitis C virus related cirrhosis. Dig. Liver Dis. 38, 352–354. Quartuccio, L., Soardo, G., Romano, G., et al. 2006. Rituximab treatment for glomerulonephritis in HCVassociated mixed cryoglobulinaemia: efﬁcacy and safety in the absence of steroids. Rheumatology 45, 842–846. Ramos-Casals, M., La Civita, L., De Vita, S., et al. 2007. Characterization of B cell lymphoma in patients with Sjogren’s syndrome and hepatitis C virus infection. Arthritis Rheum. 57, 161–170. Ramos-Casals, M., Robles, A., Brito-Zeron, P., et al. 2006. Life-threatening cryoglobulinemia: clinical and immunological characterization of 29 cases. Semin. Arthritis Rheum. 36, 189–196. Rosenblum, N., Winter, H. 1987. Steroid effects on the course of abdominal pain in children with Henoch-Scho¨nlein purpura. Pediatrics 79, 1018–1021. Samarkos, M., Vaiopoulos, G., Andreopoulos, A., et al. 2003. Association of protein-losing enteropathy and cryoglobulinemia. Scand. J. gastroenterol. 38, 334–336. Seko, Y. 2000. Takayasu arteritis. Jpn. Heart J. 41, 15–26. Seo, P., Min, Y.I., Holbrook, J.T., et al. 2005. Damage caused by Wegener’s granulomatosis and its treatment: prospective data from the Wegener’s Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 52, 2168–2178. Sinico, R.A., Di Toma, L., Maggiore, U., et al. 2005. Prevalence and clinical signiﬁcance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum. 52, 2926–2935. Siskind, B., Burrell, M., Pun, H., et al. 1985. CT demonstration of gastrointestinal involvement in Henoch-Scho¨nlein syndrome. Gastrointest. Radiol. 10, 352–354. Small, P., Brisson, M.L. 1991. Wegener’s granulomatosis presenting as temporal arteritis. Arthritis Rheum. 34, 220–223. Smith, J.A., O’Sullivan, M., Gough, J., Williams, B.D. 1988. Small-intestinal perforation secondary to localized giantcell arteritis of the mesenteric vessels. Br. J. Rheumatol. 27, 236–238. Srigley, J.R., Gardiner, G.W. 1980. Giant cell arteritis with small bowel infarction: a case report and review of the literature. Am. J. Gastroenterol. 73, 157–161. Stone, J.H. 2002. Polyarteritis nodosa. JAMA 288, 1632–1639. Travers, R.L., Allison, D.J., Brettle, R.P., et al. 1979. Polyarteritis nodosa: a clinical and angiographic analysis of 17 cases. Semin. Arthritis Rheum. 8, 184–189. Trepo, C., Thivolet, J. 1970. Hepatitis associated antigen and periarteritis nodosa (PAN). Vox Sang. 19, 410–411.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 9

Mixed Connective Tissue Disease Juanita Romero-Dı´ az, Jorge Sa´nchez-Guerrero Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Me´xico City, Me´xico

Mixed connective tissue disease (MCTD) was ﬁrst described in 1972 by Sharp et al. as a disease with overlapping features of systemic lupus erythematosus, systemic sclerosis, and polymyositis associated with high titers of hemagglutinating antibody to the ribonuclease sensitive component (RNP-ribonucleoprotein) of extractable nuclear antigen (ENA). The combination of these features may occur simultaneously or in sequence (Piirainen and Kurki, 1990), and the diagnosis is based on clinical, pathological, and serological criteria. Three sets of criteria for the classiﬁcation and diagnosis of MCTD have been proposed with a high correlation among them (Alarco´n-Segovia and Cardiel, 1989a, b). Recognition of gastrointestinal manifestation in patients with MCTD is important because they may have special diagnostic, therapeutic, and prognostic implications that require consideration for appropriate management (Pope, 2005). For a long time, this entity had not gained widespread recognition despite having distinct clinical, serological, and immunoregulatory proﬁles (Alarco´nSegovia and Cardiel, 1991; Sharp, 2002; Vanables, 2006). This may explain the scarcity of studies focused on clinical manifestations, particularly gastrointestinal in MCTD patients. The initial descriptions of the disease included as one of its main clinical characteristics an abnormal esophageal motility, similar to that found in

Corresponding author.

Tel.: +5487-0900 x 2600 y 2601; Fax: +56-55-10-76 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00009-8

scleroderma; however, a notable difference with scleroderma esophageal dismotility is the potential beneﬁt of corticosteroids in MCTD (Burdt et al., 1999). Subsequent studies included descriptions of sialoadenitis, malabsorption, colonic, and small bowel perforations due to vasculitis, chronic active hepatitis, acute pancreatitis, protein-loosing enteropathy, and acute pneumatosis intestinalis (PI), reﬂecting that any area of the gastrointestinal tract may be affected in MCTD. On the other hand, some gastrointestinal manifestations may overshadow other aspects of the disease, because they may derive from complications of the initial symptoms or adverse effects of medication (e.g., esophageal structure).

1. Are gastrointestinal features a common manifestation of mixed connective tissue disease? Involvement of the gastrointestinal tract has been reported in most of the rheumatic diseases. Concerning MCTD, radiological evidence of esophageal dysmotility has been recognized as a feature in more than 50% of the patients. The follow-up period, important in a disease with manifestations that tend to drift over time, and the sensitivity of the different tests used vary considerably from report to report, contributing to the variation of the clinical manifestations (Table 1). Gastrointestinal symptoms are common, affecting 66–74% of the patients (Burdt, Marshall, and

J. Romero-Dı´az, J. Sa´nchez-Guerrero

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Table 1 Cumulative gastrointestinal ﬁndings according to length of disease evolutiona Reference

Burdt et al. (1999) Sharp et al. (1972); Nimelstein et al. (1980) Tiddens et al. (1993)

Esophageal dysmotility At onset

At diagnosis

Cumulative (years of follow-up)

9 57 –

47 – –

66 (15) 43 (8)b 100 (9.3)

a

The values are presented as percentage of patients. In this study, evidence of esophageal dysmotility was slightly less frequent. The authors thought that this might be explained by lack of radiographic or manometric studies on reevaluation. b

Table 2 Gastrointestinal symptoms in patients with mixed connective tissue disease Features

Gutierrez et al. (1982)

Marshall et al. (1990)

Doria et al. (1991)

Number of patients Mean of follow-up (years) Dysphagia (%) Heartburn or regurgitation Dyspepsia Vomiting Esophageal dysmotility (abnormal esophageal manometry) Diarrhea Constipation Malabsorption

17 8 53 59 65 – 91a

61 6.3 38 48 20 2 60

21 7.7 19 23.8 – – 85

Other conditions Pancreatitis Chronic active hepatitis Spontaneous perforations associated with vasculitis a b

Tiddens et al. (1993) 14b 9.3 40 20 – – 100

– – –

5 3

– –

– – –

– – –

1 1 1

– – –

– – –

Ten of 11 patients studied had abnormal results. Patients with juvenile onset of MCTD.

Doria). The most frequently reported, heartburn in 48% and dysphagia in 38% of the patients, result from esophageal involvement (Table 2). A review of 80 patients from our department revealed a high frequency of diarrhea (36%) and malabsorption (20%), and in two patients occlusive episodes were observed (Alarco´n-Segovia and Cardiel, 1989a, b).

2. Oral manifestations As in other connective tissue disease, Sjo¨gren’s syndrome may be present in MCTD. According to

Alarco´n-Segovia (1976), 12 out of 25 patients with MCTD had xerostomia and/or ocular symptoms of keratoconjunctivitis sicca. Setty et al. (2002) determined longitudinally the prevalence of clinical and serological features of Sjo¨gren’s syndrome in a cohort of MCTD patients. This study summarized the clinical and serological features of 55 patients followed during 30 years who fulﬁlled criteria for MCTD of whom 23 (42%) had sicca symptoms; no association was found with anti-SSA/Ro antibodies. From 19 patients with MCTD, 17 had focal sialoadenitis determined on clinical manifestations, unstimulated and stimulated whole saliva, and minor salivary gland biopsy. Sixty-one percent

Mixed Connective Tissue Disease

had decreased salivary secretion and 74% had oral symptoms. The mean duration of the disease at the study was 10.6 years and only 11 (58%) patients had positive anti-RNP autoantibodies (Helenius et al., 2001). Konttinen and colleagues (1990) described the signs and symptoms in the masticatory system. All the 10 patients with MCTD included showed clinical dysfunction, and 7 had additional radiographic changes of the temporomandibular joints. Sialopenia was observed in 70% of the patients and sialoadenitis with a focus score >1 in the labial salivary gland biopsy of nine patients. Only one patient had clinically detectable mucosal lesion. In 83% of patients with normal appearing mucosa, histological examination revealed chronic inﬂammation. The authors concluded that as it occurs in other connective tissue disease, MCTD patients should be treated on a multidisciplinary basis (Alfaro-Giner et al., 1992).

3. Esophageal dysfunction Despite the heterogeneity of the rheumatic diseases in terms of symptoms and prognosis, most of them share some gastrointestinal manifestations. According to these observations, several investigators have thought that the features in MCTD are similar to those found in scleroderma but of milder degree. Nonetheless, it is clear that esophageal dysfunction is a much more common feature in scleroderma and MCTD than in the other connective tissue disease (92 and 88%, respectively) (Marshall et al., 1990). The motor disorders affecting the esophagus are found not only in systemic sclerosis, but also in systemic lupus

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erythematosus and other connective tissue diseases. The simultaneous involvement of the esophageal body and the lower esophageal sphincter (LES) is discriminant between scleroderma, MCTD, polymyositis and undifferentiated connective tissue disease, and SLE (Lapadula et al., 1994; Kotajima et al., 1996). A study of esophageal motility in 37 patients with progressive systemic sclerosis, 12 patients with MCTD, and 40 healthy controls without rheumatologic symptoms reported that MCTD patients were similar to PSS patients. Half of the MCTD patients had dysphagia, four patients had abnormal motility, and in only two patients motility was normal. LES pressure was low in seven patients, and in only one patient the pressure was similar to that of the controls. Involvement of the upper esophagus was unusual (Dantas et al., 1985). Manometry and radiological examinations have also been used to evaluate the esophageal disorders. Lapadula and colleagues studied the performance of these methods in the evaluation of esophageal motility; their data showed a higher sensitivity of esophageal manometry (EM) over the usual radiographic examination of the esophagus (ERE)—72.7 vs. 40.7. Manometry was able to detect early motility disorders, such as a lower LES pressure and reductions in peristaltic waves amplitude, which are difﬁcult to recognize by ERE (Table 3). Dinsmore et al. (1966) described the presence of air on conventional chest roentgenograms within the intrathoracic portion of the esophagus in 12 out of 16 patients with systemic sclerosis, proposing that an air esophagogram is strongly suggestive of systemic sclerosis. In 1998, Lock et al. assessed systematically the diagnostic signiﬁcance of an air esophagogram in 51 patients with connective tissue diseases and esophageal involvement, and 47

Table 3 Esophageal involvement studied by esophageal radiographic examination (ERE) and esophageal manometry (EM) Reference

Patients with abnormal ERE (%)

Patients with abnormal EM (%)

Lapadula et al. (1994) Lock et al. (1998) Stacher et al. (2000) Doria et al. (1991) Gutierrez et al. (1982)

70.6 31.4 – – –

88.2 45.1 83.3 71 94

104

J. Romero-Dı´az, J. Sa´nchez-Guerrero

controls by comparing the ﬁndings in chest roentgenogram with EM as the gold standard of esophageal motility testing. The presence of air in one or more esophageal segments had a sensitivity of 52% and a speciﬁcity of 68% for esophageal dysfunction compared to EM. They concluded that the radiological sign of air in the esophagogram is neither sensitive nor speciﬁc enough to omit esophageal motility studies in patients with connective tissue diseases. Regarding the pathophysiology of esophageal dysmotility, Stevens and colleagues (1994) demonstrated the association between Raynaud’s phenomenon (RP) and aperistalsis, suggesting that the esophageal dysfunction may result from an abnormality of the autonomous nervous system, rather than sclerosis of the esophagus. On the contrary, Lapadula et al.’s (1994) study did not demonstrate a consistent correlation between esophageal motility disorders and RP in 150 patients evaluated, suggesting that esophageal dysfunction and RP do not have the same neurogenic origin. They proposed that RP constitutes a parallel but independent phenomenon.

4. Bowel manifestations PI, an uncommon manifestation in scleroderma, has also been reported in patients with MCTD. These reports included patients between 18 and 77 years of age and variable length of the disease (Lynn et al., 1984; Gessner et al., 2001; Essalah and Eddy, 1999; Wakamatsu et al., 1995; Goulet et al., 1988; Samach et al., 1978). In patients with systemic lupus erythematosus, PI is thought to result from isquemic necrosis of the bowel wall due to vasculitis; however, in systemic sclerosis and MCTD, the mechanism of this manifestation is poorly understood. It is thought that an increase of the intraluminal pressure allows the passing of air within the intestinal wall. The usual clinical manifestations are abdominal pain and diarrhea, but patients can also be asymptomatic. Radiographs show a collection of air within the intestinal wall that delineates it longitudinally and intraperitoneal air

can also be seen. The authors concluded that PI should be suspected in those patients known to have systemic sclerosis-type involvement of the esophagus and the small bowel, and who present with abdominal distension. It may not only occur early in the course of the disease and resolve rapidly through medical intervention, but also has been associated with poor survival. No surgical treatment is recommended unless the condition is complicated by perforation. Malabsorption is another symptom observed in scleroderma and less frequent in MCTD. Sometimes it may constitute a major management problem; several mechanisms have been proposed for its occurrence, but intestinal stasis with secondary bacterial overgrowth appears to be the main factor (Alarco´n-Segovia and Cardiel, 1989a, b). Protein-loosing enteropathy is a rare manifestation, and there is only one case report of this condition associated to MCTD (Nosho et al., 1998). Protein-loosing enteropathy should be suspected when diarrhea and severe hypoalbuminemia without proteinuria are found. Histological ﬁndings include atrophy of villi, polymorphonuclear inﬁltrate, and edema of the submucosa in the absence of vasculitis. The increased protein loss from the bowel can be documented by an increase of fecal excretion with intravenous radiolabeled albumin. Diagnosis is important because most patients improve with corticosteroids therapy. Megacolon is another rare manifestation and is typically manifested radiograﬁcally as wide-mouthed diverticular saculations. Symptoms secondary to this complication are rare but occasionally serious, such as impactation of barium or feces (Ferreiro et al., 1986). Spontaneous perforation associated with vasculitis has also been reported. The gastrointestinal bleeding may be due to ﬁbrinoid necrosis of blood vessels of the small and large intestine (Cooke and Lurie, 1977; Hirose et al., 1993).

5. Other conditions In the group of MCTD patients described by Marshall et al. (1990), only one of them had

Mixed Connective Tissue Disease

identiﬁable pancreatic disease with subsequent pseudocyst and abscess formation. MCTD was presumed to be the cause of the pancreatitis, although a medication-related etiology could not be completely excluded. Also, one patient with chronic active hepatitis is the only instance of clinically signiﬁcant liver disease in the same series of patients.

6. Therapeutic considerations In contrast to scleroderma, esophageal dysfunction was noted to improve following corticosteroid therapy in MCTD patients (Lundberg, 2005). The results from manometry studies carried out in 10 patients before and after treatment suggest that esophageal dysfunction in MCTD may be responsive to corticosteroids. These patients had received a mean of 67 wk of steroid therapy (range 44–154 wk) at the time when the follow-up manometry was performed. Initially, most of the patients received 1 mg/kg of prednisone and the average dose during the course of their treatment was 25 mg/day. The improvement in the LES pressure was statistically signiﬁcant (po0.05). No differences in distal and proximal esophageal peristaltic pressures were found; however, an improvement in upper esophageal sphincter hypotension and a reduction in the frequency of associated aspiration events were observed (Marshall et al., 1990). Similar results were not demonstrated by Gutierrez et al. (1982). They studied 14 MCTD patients who had received steroids for a mean of 6.9 years (range 1–11 years), and esophageal peristalsis was abnormal in all of them; however, this study did not include an evaluation before the corticosteroid treatment. Probably the two series included patients with different degrees of severity of the disease, and probably in patients with less severe disease and predominantly inﬂammatory reaction in the esophageal muscles, steroids may reverse the inﬂammatory reaction, while in patients with ﬁbrosis this response is not possible. According to these results, a course of steroid therapy (15–30 mg/day) may be considered in

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some cases of esophageal dysfunction that are refractory to conventional treatment and have a short disease evolution. The conventional treatment consists of protonpump inhibitors, H2 receptor antagonists, antacids, and lifestyle modiﬁcations. Esophageal pH monitoring in patients who have persistent reﬂux symptoms to determine if high-dose therapy is needed, endoscopic dilatations in severe cases of dysphagia related to structures, and ﬂuids, ﬁber, and exercise in some cases of constipation should be considered. Severe manifestations such as pseudo-obstruction and PI may require hospitalization for bowel rest (Kim and Grossman, 2005). A surgical approach is not recommended since it is associated to a bad prognosis. In some MCTD patients with diarrhea, the cause of this symptom may be unclear and symptomatic treatment may be indicated. Patients with malabsorption may require cyclic broad-spectrum antibiotic treatment to control colonic bacterial overgrowth (Alarco´n-Segovia and Cardiel, 1991). Among 62 patients (46 systemic sclerosis, 8 MCTD, and 8 polymyositis and systemic sclerosis overlap), 12 (19%) required total parenteral or enteral nutrition. This may reﬂect severe gastric or intestinal involvement in systemic sclerosis and related disorders; however, the possibility of tertiary referral bias because the patients needed nutritional support may partially explain these results (Weston et al., 1998).

7. Discussion According to the information available, almost any segment of the gastrointestinal tract can be involved in patients with MCTD, particularly the esophagus. Up to now, few studies have evaluated the gastrointestinal manifestations in this disease. Unfortunately, the few studies available differ in some characteristics that may inﬂuence the results as follows: number of patients included, length of disease duration, diagnostic criteria used, etc. Proof of this is that the largest study (Marshall et al., 1990), which included 61 patients, is the one where rare gastrointestinal manifestations such as

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pancreatitis, chronic active hepatitis, and spontaneous perforations due to vasculitis were described. The single study that assessed gastrointestinal manifestations at varying periods of disease evolution showed the variability in their prevalence (Burdt et al., 1999). Also, although the four sets of criteria available (Sharp, 1987; Kasukawa et al., 1987; Alarco´n-Segovia and Villarreal, 1987; Kahn and Appeboom, 1991 criteria) identify most, MCTD patients, in 80 MCTD patients evaluated in our department, the former three sets of criteria ruled out MCTD in most patients with other connective tissue disease except the criteria for possible MCTD included as part of Sharp’s set of criteria that identiﬁed as such 10 patients with SLE, 36 with scleroderma, 13 with polymyositis/dermatomyositis, and 2 with Sjo¨gren’s syndrome (Alarco´n-Segovia and Cardiel, 1989a, b).

8. Summary Gastrointestinal manifestations in patients with MCTD are frequent, especially those related to esophageal symptoms due to dysmotility described as hypomotility or aperistalsis. The most affected structures are two-thirds of the esophageal body and the LES, as it is seen with high frequency in systemic sclerosis (Marshall et al., 1990). Autoimmune hepatitis, pancreatitis, and gastrointestinal vasculitis have been reported. Some patients with PI and protein-loosing enteropathy have also been informed. To evaluate esophageal dysfunction, manometry is a more sensitive and speciﬁc test than chest X-ray. The initial therapeutic approach includes conventional treatments such as proton-pump inhibitors, H2 receptor antagonists, antacids, lifestyle modiﬁcations, and esophageal pH monitoring in patients who have persistent reﬂux symptoms. A course of steroid therapy (15–30 mg/day) may be considered in some cases of esophageal dysfunction that are refractory to conventional treatment and have a short-time disease evolution.

References Alarco´n-Segovia, D. 1976. Symptomatic Sjo¨gren’s syndrome in mixed connective tissue disease. J. Rheumatol. 3, 191–195. Alarco´n-Segovia, D., Cardiel, M.H. 1989a. Comparisons between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J. Rheumatol. 16, 328–334. Alarco´n-Segovia, D., Cardiel, M.H. 1989b. Connective tissue disease and the bowel. Baillier’s Clin. Rheumatol. 3 (2), 371–392. Alarco´n-Segovia, D., Cardiel, M.H. 1991. Mixed connective tissue disease. In: Current Therapy in Allergy, Immunology and Rheumatology. Nosby Year Book, USA, pp. 202–206. Alarco´n-Segovia and Villarreal M. 1987. Classiﬁcation and diagnostic criteria for mixed connective tissue disease. In: R. Kasukawa, G.C. Sharp (Eds.), Mixed Connective Tissue Disease and Antinuclear Antibodies. Elsevier, Amsterdam, pp. 33–40. Alfaro-Giner, A., Pen˜arrocha-Diago, M., Baga´n-Sebastia´n, J.V. 1992. Orofacial manifestations of mixed connective tissue disease with an uncommon serologic evolution. Oral Surg. Oral Med. Oral Pathol. 73, 441–444. Burdt, M.A., Hoffman, R.W., Deutscher, S.L., et al. 1999. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic ﬁndings. Arthritis Rheum. 42 (5), 899–909. Cooke, C.L., Lurie, H.I. 1977. Case report: fatal gastrointestinal hemorrhage in mixed connective tissue disease. Arthritis Rheum. 20 (7), 1421–1427. Dantas, R.O., Villanova, M.G., de Godoy, R.A. 1985. Esophageal dysfunction in patients with progressive systemic sclerosis and mixed connective tissue disease. Arq. Gastroenterol. 22 (3), 122–126. Dinsmore, R.E., Goodman, D., Dreyfuss, J.R. 1966. The air esophagogram a sign of scleroderma involving the esophagus. Radiology 87, 348–349. Doria, A., Bonavina, L., Anselmino, M., et al. 1991. Esophageal involvement in mixed connective tissue disease. J. Rheumatol. 18 (5), 685–690. Essalah, A.A., Eddy, A.A. 1999. Pediatr. Nephrol. 13 (1), 54–56. Ferreiro, J.E., Busse, J.C., Saldana, M.J. 1986. Megacolon in a collagen vascular overlap syndrome. Am. J. Med. 80 (2), 307–311. Gessner, C., Kaltenhauser, S., Borte, G., Keim, V. 2001. Pneumatosis custodies intestinalis, a rare complication of mixed connective tissue disease. Dtsch. Med. Wochenschr. 126 (40), 1099–1102. Goulet, J.R., Hurtubise, M., Senecal, J.L. 1988. Retropneumoperitoneum and pneumatosis intestinales in 2 patients with mixed connective tissue disease and the overlap syndrome. Clin. Exp. Rheumatol. 6 (1), 81–85. Gutierrez, F., Valenzuela, J.E., Ehresmann, G.R., et al. 1982. Esophageal dysfunction in patients with mixed connective tissue disease and systemic lupus erythematosus. Dig. Dis. Sci. 27 (7), 592–597.

Mixed Connective Tissue Disease Helenius, L.M.J., Hietanen, J.H., Helenius, I., et al. 2001. Focal sialoadenitis in patients with ankylosing spondylitis and spondyloarthropathy: a comparison with patients with rheumatoid arthritis or mixed connective tissue disease. Ann. Rheum. Dis. 60, 744–749. Hirose, W., Nakane, H., Misumi, J., et al. 1993. Duodenal hemorrhage and dermal vasculitis associated with mixed connective tissue disease. J. Rheumatol. 20, 151–154. Kahn, M.F., Appeboom, T. 1991. Syndrome de sharp. In: M.F. Kahn, A.P. Peltier, O. Meyer, J.C. Piette (Eds.), Les Maladies Systemiques, 3rd ed., Flammarion, Paris, pp. 545–556. Kasukawa, R., Tojo, T., Miyawaki, S. 1987. Preliminary diagnostic criteria for classiﬁcation of mixed connective tissue disease. In: R. Kasukawa, G.C. Sharp (Eds.), Mixed Connective Tissue Disease and Antinuclear Antibodies. Elsevier, Amsterdam, pp. 41–47. Kim, P., Grossman, J.M. 2005. Treatment of mixed connective tissue disease. Rheum. Dis. Clin. North Am. 31, 549–565. Konttinen, Y.T., Tuominen, T.S., Piirainen, H.I., et al. 1990. Signs and symptoms in the masticatory system in ten patients with mixed connective tissue disease. Scand. J. Rheumatol. 19, 363–373. Kotajima, L., Aotsuka, S., Sumiya, M., et al. 1996. Clinical features of patients with juvenile onset mixed connective tissue disease: analysis of data collected in a Nationwide collaborative study in Japan. J. Rheumatol. 23, 1088–1094. Lapadula, G., Moulo, P., Semeraro, F., et al. 1994. Esophageal motility disorders in the rheumatic disease: a review of 150 patients. Clin. Exp. Rheumatol. 12, 515–521. Lock, G., Strotzer, M., Straub, R.H., Scholmerih, J., et al. 1998. Air oesophagogram: a frequent, but not a speciﬁc sign of oesophageal involvement in connective tissue diseases. Br. J. Rheumatol. 37, 1011–1014. Lundberg, I.E. 2005. The prognosis of mixed connective tissue disease. Rheum. Dis. Clin. North Am. 31, 535–547. Lynn, J., Gossen, G., Miller, A., Russell, J. 1984. Pneumatosis intestinales in mixed connective tissue disease: two case reports and literature review. Arthritis Rheum. 27 (10), 1186–1189. Marshall, J.B., Krestschmar, J.M., Gerhadt, D.C., et al. 1990. Gastrointestinal manifestations of mixed connective tissue disease. Gastroenterology 98 (5 Pt 1), 1232–1238. Nimelstein, S.H., Brody, S., Mcshane, D., Holman, H.R. 1980. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine 59 (4), 239–248. Nosho, K., Takahashi, H., Ikeda, Y., et al. 1998. A case of protein-losing gastroenteropathy in association with mixed

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connective tissue disease which was successfully treated with cyclophosphamide pulse therapy. Ryumachi 38, 818–824. Piirainen, H.I., Kurki, P.T. 1990. Clinical and serological follow-up of patients with polyarthritis, Raynaud’s phenomenon, and circulating RNP antibodies. Scand. J. Rheumatol. 19, 51–56. Pope, J.E. 2005. Other manifestations of mixed connective tissue disease. Rheum. Dis. Clin. North Am. 31, 519–533. Samach, M., Brandt, L.J., Bernstein, L.H. 1978. Spontaneous pneumoperitoneum with pneumatosis cystoids intestinalis in a patients with mixed connective tissue disease. Am. J. Gastroenterol. 69 (4), 494–500. Setty, Y.N., Pittman, C.B., Mahale, A.S., et al. 2002. Sicca symptoms and anti-SSA/Ro antibodies are common in mixed connective tissue disease. J. Rheumatol. 29, 487–489. Sharp, G.C. 1987. Diagnostic criteria for classiﬁcation of MCTD. In: R. Kasukawa, G.C. Sharp (Eds.), Mixed Connective Tissue Disease and Antinuclear Antibodies. Elsevier, Amsterdam, pp. 23–32. Sharp, G.C. 2002. MCTD: a concept which stood the test of time. Lupus 11, 333–339. Sharp, G.C., Irvin, W.S., Tan, E.M., et al. 1972. Mixed connective tissue disease—an apparently distinct rheumatic disease syndrome associated with speciﬁc antibody to an extractable nuclear antigen (ENA). Am. J. Med. 52 (2), 148–159. Stacher, G., Merio, R., Budka, C., et al. 2000. Cardiovascular autonomic function, antiantibodies, and esophageal motor activity in patients with systemic sclerosis and mixed connective tissue disease. J. Rheumatol. 27, 692–697. Stevens, M.B., Hookman, P., Siegel, C.I., et al. 1964. Aperistalsis of the esophagus in patients with connectivetissue disorders and Raynaud’s phenomenon. N. Engl. J. Med. 270 (23), 1218–1222. Tiddens, H., Van der Net, J., Graeff-Meeder, E., et al. 1993. Juvenile-onset mixed connective tissue disease: longitudinal follow-up. J. Pediatr. 122, 191–197. Vanables, P.J.W. 2006. Mixed connective tissue disease. Lupus 15, 132–137. Wakamatsu, M., Inada, K., Tsutsumi, Y. 1995. Mixed connective tissue disease complicated by pneumatosis cystoids intestinalis and malabsorption: case report and literature review. Pathol. Int. 45 (11), 875–878. Weston, S., Thumshirn, M., Wiste, J., Camilleri, M. 1998. Clinical and upper gastrointestinal motility features in systemic sclerosis and related disorders. Am. J. Gastroenterol. 93, 1085–1089.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 10

Gastrointestinal Manifestations of Rheumatoid Arthritis John M. Cafardia, Herbert Rakatanskyb, Graciela S. Alarco´na, a

Department of Medicine, Division of Clinical Immunology and Rheumatology, 510 20th Street South, FOT 830, The University of Alabama at Birmingham, Birmingham, AL 35294, USA b Department of Medicine, Division of Gastroenterology, Warren Alpert School of Medicine, Brown University Providence, Rhode Island, USA

In this review, the gastrointestinal (GI) pathology and associated clinical manifestations in patients with rheumatoid arthritis (RA) will be examined (Sales, 1970). First, some manifestations described as a direct result of RA will be discussed; this will be followed by the GI manifestations that commonly occur as a complication of RA therapy. Finally, diseases that can mimic the presentation of RA in the GI system will be covered. This outline is depicted in Table 1.

1. Manifestations directly due to rheumatoid arthritis RA is a chronic, systemic, and progressive inﬂammatory condition, mediated by self-reactive T and B lymphocytes. RA occurs worldwide and affects approximately 1% of the North American and European population (Firestein, 2005; Alamanos and Drosos, 2005; Edwards and Cambridge, 2006; Martinez-Gamboa et al., 2006). It is characterized by inﬂammation of the synovium and surrounding structures, which may lead to signiﬁcant joint destruction. The disease is not limited to the joints, however; there are many non-articular complications that are also mediated by the inﬂammatory Corresponding author.

Tel.: 205-934-2799; Fax: 205-934-4602 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00010-4

process (O’Dell, 2004; Muller-Ladner et al., 2005; Huber et al., 2006). RA leads to a predominance of the CD4+ T-helper lymphocyte subset 1 (TH1)-type immune response, with most cytokines secreted from this class type, i.e. TNF-a, IFN-g, and IL-1 (Choy and Panayi, 2001; Smith and Haynes, 2002). Systemic manifestations of RA such as rheumatoid vasculitis and Felty’s syndrome are understood now to originate from progressive inﬂammation, such as that of large and small vessels. Sustained articular and extra-articular inﬂammation may be followed by premature or accelerated atherosclerosis. In turn, accelerated atherosclerosis leads to an increased morbidity and mortality from cardiovascular and cerebrovascular disease (Roman et al., 2006; Kremers and Gabriel, 2006; Gonzalez-Gay et al., 2005). Other GI manifestations such as amyloidosis, secondary Sjo¨gren’s syndrome, and liver dysfunction are also present in RA, but the exact pathophysiology is poorly understood (Editorial, 1973; Fleming et al., 1976; Turesson and Jacobsson, 2004). An overview of GI disease in RA and its pathophysiology can be found in Table 2. Rheumatoid vasculitis, though observed less frequently at this time than in the past, is a nonarticular manifestation of RA in which microvascular lesions develop throughout the body and the GI tract, predominating in the small bowel (Schneider et al., 2006). It can present as upper or lower GI bleeding, ulceration, ischemia or infarction, or intestinal perforation (Babian

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et al., 1998; Achkar et al., 1995). Rheumatoid vasculitis, whether involving the GI tract or not, is not a common presentation of RA; instead, it is frequently associated with a protracted course and a long history of erosive arthritis (Voskuyl et al., 1993). It is less frequent in patients who have had earlier or more intensive therapeutic interventions; ﬂares of rheumatoid vasculitis, however, tend to accompany a more quiescent phase of articular disease (Cruickshank, 1954; Glass et al., 1976). Felty’s syndrome is a recognized complication of RA. The syndrome’s triad consists of splenomegaly, leucopenia in the setting of seropositive, and nodular and destructive RA (Balint and Balint, 2004). As with rheumatoid vasculitis, it is rarely seen nowadays. Portal hypertension with gastroesophageal varices (DeCoux and Achord, 1980; Reisman et al., 1977) and hepatic ﬁbrotic disease (Thorne et al., 1982) such as nodular regenerative hyperplasia (Cohen et al., 1982) can occur as secondary manifestations of this rare syndrome. Secondary amlyoidosis usually occurs in the setting of chronic inﬂammatory conditions such as RA, which leads to the progressive deposition of Table 1 The gastrointestinal system in rheumatoid arthritis (RA): chapter outline Mechanisms of injury in the GI tract Secondary syndromes and how they can injure the GI tract: Amyloidosis Sjo¨gren’s Syndrome Felty’s Syndrome GI toxicities of medications used to treat RA Mimics of GI-RA involvement

protein ﬁbrils of serum amyloid A (SAA) (Falk et al., 1997). These ﬁbrils are deposited throughout the body, but have the most obvious clinical consequences when deposited in renal, GI, or cardiac tissues (Cunnane and Whitehead, 1999; Cunnane, 2001). The distribution of secondary amyloidosis in the context of RA varies worldwide; the majority of cases have been described not in North America or Europe, but rather in other parts of the world such as Central and East Asia (Shimoyama et al., 2003; Alishiri et al., 2006). Secondary amyloidosis of the GI tract may have different clinical presentations such as localized ulcerations, achalasia-type dysmotility, or a protein-wasting enteropathy (Schneider et al., 2006). Although Sjo¨gren’s syndrome is more commonly recognized in its primary form, it can also occur secondary to a pre-existing auto-immune disease, and it is likely that 13 of the 19 patients that Sjo¨gren included in his original case-series deﬁnition had secondary disease due to RA (Fox, 2005). Primary or secondary Sjo¨gren’s syndrome involves lymphocytic inﬁltration and damage of exocrine glands; it has classically been recognized as involving the ocular and salivary glands but GI, cutaneous, renal, vascular, neurologic, and respiratory involvement is also well documented (Mavragani et al., 2006). Pancreatic exocrine deﬁciency has been noted, but is an uncommon complication (Kauppi et al., 2001). Severe sicca manifestations may be observed with secondary Sjo¨gren’s syndrome, leading to problems with deglutition and overall patient comfort (Moutsopoulos et al., 1980), while both Sjo¨gren’s-associated and primary-RA-associated esophageal disease can

Table 2 Secondary GI syndromes in RA: manifestations and pathogenesis Disease manifestation

Pathogenesis

Ulceration of the stomach (peptic ulcer disease), small intestine and colon, with perforation as a possible sequela

Luminal injury as a result of drug toxicity, such as NSAIDs or glucocorticoids, or as a consequence of rheumatoid vasculitis

Dysmotility of the esophagus and lower esophageal sphincter

Secondary Sjo¨gren’s syndrome

Chronic diarrhea and protein-wasting enteropathy

Secondary amyloidosis (SAA) of the small intestine

Hepatic disease––nodular regenerative hyperplasia

Felty’s syndrome

Pancreatic exocrine insufﬁciency and sicca syndrome

Secondary Sjo¨gren’s syndrome

Gastrointestinal Manifestations of Rheumatoid Arthritis

range from primary dysmotility to lower-esophageal sphincter dysfunction (Bassotti et al., 1988; Volter et al., 2004). Primary RA hepatotoxicity, unrelated to any therapeutic intervention, has been noted more often in past years rather than in the current literature. It was often described as a functional pathology, with steatosis and evidence of hepatocellular degeneration and elevated serum transaminase levels, with some cases progressing to impaired synthetic function (Sullivan et al., 1978; Lefkovits and Farrow, 1955; Whaley et al., 1970). Overall, such cases are seen less frequently now, with therapeutic interventions currently occurring earlier in the course of the disease.

2. Gastrointestinal disease resulting from rheumatoid arthritis therapeutics Both glucocorticoids and non-steroidal antiinﬂammatory drugs (NSAIDs) are frequently used in the management of inﬂammation and the symptoms associated with it, pain in particular. Although these drugs are useful for analgesia and improvement of function in cases of signiﬁcant synovitis, NSAIDs have a limited role in altering the course of the disease whereas low-dose glucocorticoids have been recognized to have a signiﬁcant disease-modifying effect (Kirwan, 1995). Both glucocorticoids and NSAIDs can lead to signiﬁcant GI toxicity. GI toxicity in the NSAID-treated patient is a serious problem, with the risk of serious GI complications estimated in one study at 13 per 1000 RA patients treated with these drugs (Singh and Triadaﬁlopoulos, 1999). Of the subset of patients who are hospitalized with upper GI bleeding, secondary to NSAID ulceration, mortality is calculated at 5.6% (Lanas et al., 2005). An estimated 16,500 deaths have occurred each year in North America, secondary to GI toxicity since the mid-1990s (Singh, 1998). NSAIDs act through either the selective (isoenzyme 2) or the non-selective (iso-enzymes 1 and 2) inhibition of cyclooxygenase (COX), leading to either a total inhibition of synthesis of prostanoids

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(PGD2, PGE2, PGH2, PGI2, and TxA2) with the non-selective COX inhibitors or a selective decrement in PGE2 with the COX-2 inhibitors (Steinmeyer, 2000). Although it was originally believed that this selective inhibition would lead to equal analgesic efﬁcacy and reduced risk for gastric toxicity, this original model has been challenged by clinical trial results showing little to no improvement in the rates of gastric ulceration, an increase in the rates of cardiovascular complications, compared to non-selective COX inhibitors, and a loss of any GI protective effects if concurrent aspirin therapy is used (Psaty and Furberg, 2005; Drazen, 2005; Garcia Rodriguez and Barreales Tolosa, 2007). The mechanism for the GI toxicity of both selective and non-selective NSAIDs is incompletely understood, but there is consensus on the basic principles. In the inhibition of the eicosanoid precursors transformed into prostaglandins (the end products of the arachadonic acid pathway), the protective prostaglandin––PGI2––among others inhibited, is thought to be inhibited by only non-selective NSAIDs, while the pro-inﬂammatory prostaglandin PGE2 is inhibited by both. Additionally, inhibition of the COX enzymes appears to have an as-yet-uncharacterized effect on wound healing that prevents already developed ulcers from healing (Newberry et al., 1999). Overall, treatment with NSAIDs increases the risk of developing gastritis and peptic ulcer disease, with the subsequent risks of bleeding and perforation (Wolfe et al., 1999; Raskin, 1999), as mentioned above. Glucocorticoids have multiple, complex mechanisms of action, but are currently understood to act at both the transcriptional level (NF-kB) and through protein–protein inhibitory interactions such as IkB-NF-kB and functional inactivation of cytosolic phospholipase A2 (cPlA2). All of these processes lead to decrease in the production of pro-inﬂammatory cytokines and consequently reduction of inﬂammation (Rhen and Cidlowski, 2005). Additionally, glucocorticoids are associated with gastritis, peptic ulcer disease, and GI bleeding, although not to the same degree as NSAIDs (Messer et al., 1983). Methotrexate is a disease-modifying antirheumatic drug (DMARD), which is frequently

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prescribed as initial therapy for RA. The mechanism of methotrexate is irreversible inhibition of dihydrofolate reductase (DHFR), preventing the formation of reduced folate metabolites and inhibiting the de novo synthesis of purines (Cronstein, 1996, 1997; Furst, 1997). The therapeutic value of methotrexate, however, is often hampered by its various systemic toxicities; we will discuss the hepatic toxicity here. Other drugrelated toxicities, including pulmonary ﬁbrosis and hematopoietic abnormalities, while not discussed here are understood to have as a common underlying mechanism the intracellular accumulation of polyglutaminated methotrexate aggregates (Chabner et al., 1985). Speciﬁc methotrexate hepatotoxicity can result in histological patterns including steatosis, stellate cell hypertrophy, anisonucleosis, and hepatic ﬁbrosis (West, 1997; Farrell, 1997). Exposure to other hepatotoxic drugs, alcohol, and intercurrent hepatic infections can increase the risk of methotrexate liver damage, although the risk for cirrhosis resulting from methotrexate is small (Kremer et al., 1989; Richard et al., 2000). The American College of Rheumatology has published guidelines for the monitoring of patients with RA receiving methotrexate therapy that are designed to minimize the risk of toxicity (Kremer et al., 1994). A newer and less commonly used DMARD is leﬂunomide, the inactive oral prodrug of the active metabolite A77-1726 (Fox et al., 1999). A77-1726 acts as a non-competitive inhibitor of dihydroorotate dehydrogenase, thus inhibiting the de novo synthesis of pyrimidines (Herrmann et al., 2000; Sanders and Harisdangkul, 2002). It is brought to attention here because of concerns of hepatotoxicity. The European Union Medicines Control Agency (EUMCA) undertook a study of leﬂunomide hepatotoxicity and found 296 total and 129 serious events among patients taking leﬂunomide over 104,000 patient-years. Of those 129 serious events, 101 (78%) occurred in patients who were taking ‘other hepatotoxic medications’ (not speciﬁcally deﬁned). Among the conclusions reached was that although confounding factors exist, a causal relationship could not be excluded, and the use of leﬂunomide in patients with pre-existing liver disease was contraindicated. Additionally, the

use of this agent with other potentially hepatotoxic medicines is discouraged, and the commission urges its use to be restricted to experienced specialists (Products EAftEoM, 2001). The vast majority of patients who had presumed leﬂunomide-associated hepatotoxicity had previously received hepatotoxic regimens, including methotrexate. As such, the biochemical and histological patterns of injury that have been documented have been difﬁcult to assign to this single agent. The Food and Drug Administration and the professional rheumatologic societies in North America and Europe have not endorsed these recommendations and have not introduced a black box warning on this product. The mechanism and side-effects of various RA therapeutics modalities are summarized in Table 3.

3. Mimics of gastrointestinal disease in rheumatoid arthritis Although one of the most common associations of bowel disease and inﬂammatory arthritis or spondylitis is found in inﬂammatory bowel disease, it will not be discussed in this chapter because there is a separate chapter in this volume devoted entirely to this topic. Reactive or post-infectious arthritis may have a similar presentation to that of RA GI disease (Toivanen and Toivanen, 2000). Dysentery resulting from infectious agents such as Yersinia enterocolitica, Yersinia pseudotuberculosis, and Chlamydophila spp. (formerly Chlamydia spp.) is associated with reactive arthritis (Hannu et al., 2003, 2006; Taccetti et al., 1994). If the clinical timeline is uncertain, the bloody stools may be seen as a later part of the patients’ illness, rather than the precipitating event. Delineation of the patient’s history can often determine if the underlying issue is primarily GI or rheumatologic in nature. A more complicated, although admittedly rare, disease is Whipple’s disease; although ﬁrst described over 70 years ago, it is still very difﬁcult to diagnose. It consists of progressive wasting, chronic diarrhea, and polyarticular arthritis,

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Table 3 GI toxicities of medications used to treat rheumatoid arthritis Drug or drug class

Mechanism

Manifestations

References

NSAIDs

Differential inhibition of cyclooxygenase isoforms; downregulation of cytoprotective prostaglandins and impaired healing of mucosal ulcerations.

Development and progression of gastric and enteric ulcers. An enhanced likelihood of progression to perforation with frank hemorrhage or infection.

Armstrong and Blower (1987) Singh (1998) Newberry et al. (1999) Wolfe et al. (1999) Steinmeyer (2000)

Glucocorticoids

Pleiotropic actions, including indirect inhibition of the transcription factor NF-kB, cytosolic phospholipase A2a (cPLA2a) and mitogen-activated protein kinase (MAPK), through several pathways. They are antiinﬂammatory/immunosuppressive.

Development and progression of gastric and enteric ulcers.

Messer et al. (1983) Kirwan (1995)

Methotrexate

Polyglutamation of intracellular methotrexate. Accumulation can result in toxicity.

Hepatocellular steatosis, ﬁbrosis, and rarely, cirrhosis.

Chabner et al. (1985) Gispen et al. (1987) Kremer et al. (1989)

Sulfasalazine

Potent inhibitor of the transcription factor NF-kB, with resulting anti-inﬂammatory actions.

Common nausea, vomiting and diarrhea, with uncommon, idiosyncratic hypersensitivity hepatitis. Rechallenge must not be attempted.

Box and Pullar (1997) Smedegard and Bjork (1995) Wahl et al. (1998)

Hydroxychloroquine

Neutralization of acidic lysosomes; modiﬁcation of innate immune response through TLR interaction.

Frequent GI disturbance due to muscular contractions caused by drugs; infrequent hepatocellular damage, which may be worsened in the setting of pre-existing viral hepatitis.

Kyburz et al. (2006) Gladman et al. (1998) Scherbel et al. (1958) Mok et al. (2000)

Gold saltsa

Exact mechanism uncertain; it may involve dissociation of antigenMHC complexes.

Gold preparations rarely cause enterocolitis, with parenteral preparations causing more severe disease than enteral compounds. Gold salts can also cause rare cholestatic jaundice and pancreatitis.

Fam et al. (1980) Eisemann et al. (1989) Conaghan and Brooks (1995)

d-Penicillaminea

Exact mechanism uncertain; it may involve interruption of T-cell– antigen-presenting cell interaction. It also complexes with circulating IgM rheumatoid factor.

Nausea and vomiting are common side-effects. Dysgeusia, gingivostomatitis, and the re-activation of pre-existing ulcers are also a potential.

Stein et al. (1980) Fries et al. (1993)

anti-TNF compounds

Varies by agent; etanercept consists of a soluble p75 TNFaR:Ig fusion molecule that binds to and inactivates free TNFa. Both inﬂiximab and adalimumab are mAb directed against TNFaR (p55 and p75). They differ in Fc and route of administration. Inﬂiximab is human-murine chimeric and is administered IV; adalimumab is a human mAb and is administered subcutaneous.

Etanercept has shown little signiﬁcant GI toxicity. Inﬂiximab has the risk of liver damage, with several cases of idiosyncratic hepatitis reported. Adalimumab has shown potential to cause a hypersensitivity reaction that can affect the GI tract, with the liver most commonly involved.

Menghini and Arora (2001) Michel et al. (2003) REMICADEs PI (Centocor, 2006) HUMIRAs PI (Abbot Laboratories, 2006)

J.M. Cafardi et al.

114 Table 3 (continued ) Drug or drug class

Mechanism

Manifestations

References

Abatacept

A human fusion protein of CTLA4 (CD154) and the Fc portion of IgG1. It inhibits the co-stimulatory signal between CD28 and CD80/ CD86 necessary for T-cell activation.

In 1955 subjects enrolled in placebo-controlled trials and reported by the manufacturer, there were no signiﬁcant GI events. A PubMed-MEDLINE search in April 2007 revealed no reports of GI toxicity resulting from abatacept.

ORENCIAs PI (Bristol Myers Squibb, 2007)

Rituximab

A murine-human chimeric mAb (IgG1k) against CD20, an antigen found on pre B cells, mature B cells and W90% of malignant B cells.

Worsening or unmasking of pre-existing viral hepatitis (B not C).

Tsutsumi et al. (2005) RITUXANs PI (Genentech, 2007)

a

Of historical interest.

followed by neurologic deterioration and, if untreated, death (Fenollar et al., 2007). Long-term treatment with trimethoprim-sulfa appears to be curative, with little risk of a relapse. The etiologic organism Tropheryma whipplei has only been recently identiﬁed, while seropositivity and carriage of the organism appear to be frequent (O’Duffy et al., 1999). The prevalence of Whipple’s disease has been reported as very low, with only approximately 1000 cases reported to date and an autopsy prevalence of less than 0.1%. Due to the wide variability in symptoms, the large seropositive or carrier population, and the difﬁculty in culturing the organism, the true prevalence of the disease is unknown at this time. It is known that misdiagnosis of Whipple’s disease for RA and treatment with corticosteroids can lead to an accelerated course and progression of GI disease and a potentially fatal outcome (Mahnel et al., 2005).

4. Summary and conclusions In summary, GI disease in RA can take on many forms, although the primary cause of GI manifestations at this time is iatrogenic. Physicians should be vigilant in their prescribing habits and carefully monitor patients on NSAIDs and DMARDs.

In addition to this, healthcare providers should remain aware that RA is a chronic, multisystemic disease that does not manifest itself only in the articular surfaces. Bleeding, infarction, and perforation from primarily affected bowel sites should be considered on the differential diagnosis in the care of patients with RA, while hepatotoxicity and esophageal varices and dysmotility can occur either directly as a result of RA or as manifestations of rheumatic syndromes such as Felty’s and Sjo¨gren’s, secondary to RA. Finally, it should be remembered that numerous diseases affect the GI tract and articular surfaces in close temporal relationship, and a careful history remains essential.

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PART III:

Autoimmune Liver Diseases

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 11

Immunopathogenesis of Autoimmune Liver Damage Albert J. Czaja Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA

Autoimmune liver damage implies that an immune attack has been misdirected against self (Czaja, 2001). This loss of self-tolerance may reﬂect deﬁciencies in the mechanisms by which immunocytes distinguish self-antigens from foreign antigens and perturbations in the regulatory networks that inﬂuence immunocyte activation, differentiation, proliferation, and disposal (Czaja, 2002). The predisposing factors can be extrinsic to the individual and represent indigenous environmental, toxic or infectious agents that overwhelm self-tolerance by their absolute number or their repetitive stimulation (Vergani et al., 2002). They may also be intrinsic to the individual and represent genetic or hormonal predispositions that favor protracted or exaggerated immune responses to the triggering antigen (Czaja et al., 1998). Excess antigenic stimulation can relate to the magnitude of antigens with homologous epitopes that bombard the individual, the frequency of antigenic exposure, the responsiveness of the individual to a given antigen, or any combination of these factors (Czaja, 2001; Vergani et al., 2002). Multiple viruses and drugs have been implicated as triggers for autoimmune liver disease, and these reports imply that diverse antigenic stimuli can produce the same clinical result (Czaja, 2001). These diverse antigenic stimuli must have shared peptide sequences that stimulate immune reactivity (molecular mimicry) since the CD4 and CD8 T Corresponding author.

Tel.: +507-284-8118; Fax: +507-284-0538 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00011-6

lymphocytes implicated in the pathogenesis of autoimmune liver disease possess few antigen recognition sites (Ichiki et al., 2005). The frequent concurrence of other autoimmune manifestations in patients with autoimmune liver disease also suggests that the antigen recognition sites on the activated immunocytes are imprecise (Czaja, 2001; Vergani et al., 2002). This imprecision can extend the range of targets to tissues anatomically different and distant from the liver (promiscuous activity) (Vergani et al., 2002; Doherty et al., 1998). The key epitope triggering autoimmune liver disease is likely to be a commonly shared, easily mimicked amino acid sequence that can activate immunocytes with promiscuous activity (Czaja, 2001). The long time lag between the onset of the disease and its clinical detection can obscure the initiating event. Host-dependent, rather than disease-speciﬁc, factors may also override self-tolerance (Czaja and Donaldson, 2000). Genetic predisposition may naturally select individuals from the general population and favor the development of disease. Genetic risk factors for autoimmune hepatitis (Donaldson et al., 1991; Strettell et al., 1997), primary biliary cirrhosis (PBC) (Gores et al., 1987; Manns et al., 1991a, b; Onishi et al., 1994; Jones and Donaldson, 2003; Donaldson et al., 2006), and primary sclerosing cholangitis (PSC) (Donaldson and Norris, 2001, 2002) have been described, and certain genetic factors may also offer protection from these diseases (Doherty et al., 1994; Strettell et al., 1997; Donaldson and Norris, 2002; Donaldson et al., 2006). Autoimmune liver

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diseases are polygenic disorders, and complex alterations in the counter-regulatory networks of immune activation that are based on genetic factors or gender differences may create a complex milieu that promotes or prevents these diseases (Donaldson, 1996, 2002, 2004; Donaldson and Czaja, 2002). In this context, the components of the milieu may vary greatly between individuals despite producing the same clinical consequence. Single disturbances in a highly coordinated, interactive immune system may change order to chaos, and the ability of subtle effects to be magniﬁed into a disease state may explain the difﬁculty in identifying the core defect in autoimmune liver disease. In this review, the multi-factorial nature of autoimmune liver disease is emphasized, and the various theoretical bases for its occurrence are presented. Disturbances in antigen recognition, deﬁciencies in the regulatory networks that control immune reactivity, and differences in the genetic and gender predispositions for autoimmune liver disease are discussed. These diverse factors are interactive and the degree of their involvement can vary among individuals and modify the clinical expression and behavior of the disease.

1. Disturbances in antigen recognition The limited number of antigen recognition sites in CD4 and CD8 T lymphocytes suggests that autoimmune liver disease can be triggered by only a few antigens or that the triggering antigenic sequence is shared by multiple peptides (molecular mimicry) (Vergani et al., 2002; Ichiki et al., 2005). Furthermore, the diversity of immune manifestations in individuals with autoimmune liver disease suggests that the activated immunocytes have imprecise antigen recognition sites and are capable of targeting diverse cell populations (promiscuous activity) (Doherty et al., 1998). Molecular mimicry and promiscuous activity by the activated immunocytes are important pathogenic mechanisms that have been implicated in autoimmune liver disease (Table 1).

1.1. Molecular mimicry Molecular mimicry implies that multiple antigenic targets have the same or similar epitopes against which activated lymphocytes with imprecise

Table 1 Disturbances in antigen recognition Immune disturbance

Pathogenic mechanism

Consequences

Molecular mimicry

Multiple antigenic targets have same or similar peptide sequences or conformational epitopes. Foreign and self antigens are indistinguishable.

Different etiologic agents with homologous epitopes produce same immune response. Anatomically different and distant organs can be targeted in the same individual.

Recognition of cryptic self-antigens or neo-antigens

New antigens are uncovered during primary immune reactions that generate additional immune responses.

Collateral immune responses escalate the primary immune reaction and its outcome.

Loss of self-tolerance

Protracted or repeated exposure to foreign antigens that resemble self-antigens generates cross-reacting humoral and cellular immune responses.

Self-perpetuating immune attack is directed against homologous epitopes in own tissue (autoimmunity).

Promiscuous immunocyte activity

T cell antigen receptor of activated immunocyte has imprecise antigen recognition. Immunocyte is unable to distinguish between closely homologous epitopes in different antigens.

Consequences of molecular mimicry are enhanced. Immune attack is extended against similar selfantigens in diverse tissues favoring development of multiple immune diseases in same individual.

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antigen recognition sites (promiscuous activity) can be directed (Vergani et al., 2002) (Table 1). Molecular mimicry explains autoreactivity (Bogdanos et al., 2001), but it has been difﬁcult to prove in human disease (Albert and Inman, 1999). Humoral cross-reactivity has been well described in autoimmune conditions (Choudhuri et al., 1998; Bogdanos and Vergani, 2006), but cellular cross-reactivity has been difﬁcult to demonstrate (Kammer et al., 1999). Molecular mimicry can occur when there are homologous amino acid sequences within peptides or similar conformational epitopes in structurally dissimilar peptides (Bogdanos et al., 2001; Vergani et al., 2002). The uncovering of cryptic selfantigens or the recognition of neo-antigens can escalate the autoreactive response (Table 1). Molecular mimicry explains how different environmental agents, drugs, and viruses may produce the same disease and how autoimmune hepatitis can recur or develop de novo after liver transplantation (Czaja, 2002). Molecular mimicry also predicts that anatomically distant organs can be targeted in the same individual and that immune diseases involving different organs can occur in the same patient (Vergani et al., 2002). A murine model of autoimmune hepatitis based on DNA immunization against self-antigens has provided strong support for its pathogenic role (Lapierre et al., 2004). In this model, immunized mice developed hepatitis after plasmid injections containing the antigenic regions of human CYP2D6 and human formiminotransferase cyclodeaminase (Lapierre et al., 2004). Affected mice developed antibodies against the human peptides, and cytotoxic T lymphocytes were found within the liver that were sensitized against the antigens in the plasmid constructs. DNA immunization against human antigens appeared to break self-tolerance in this model, and liver injury developed because of molecular mimicry between foreign- and selfantigens that resulted in cross-reacting humoral and cellular responses. Homologies between various viral genomes (hepatitis C virus, cytomegalovirus, and herpes simplex type 1 virus) and recombinant CYP2D6 suggest that multiple exposures to viruses

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mimicking self may be a mechanism by which to break self-tolerance and induce autoimmune liver disease (Manns et al., 1991a, b; Kerkar et al., 2003). Cross-reactivity has also been demonstrated between HCV antigens and host-derived smooth muscle and nuclear antigens (Gregorio et al., 2003). Furthermore, HLA B51 has been associated with cross-reactive immune responses between viral and microsomal antigens (Bogdanos et al., 2004). Geographic differences in the occurrence of certain indigenous viral agents or the frequencies of exposure to structurally similar viruses may explain regional differences in the expression of certain autoantibodies and disease types. Various cytosolic enzymes other than the monooxygenase, CYP2D6, have been implicated as autoantigens in autoimmune hepatitis. They include uridine triphosphate glucuronosyltransferase (Manns and Obermayer-Straub, 1997), glutathione S-transferase (Aguilera et al., 2001), formiminotransferase cyclodeaminase (Muratori et al., 2001; Lapierre et al., 2004), and the transfer ribonucleoprotein complex, tRNP(Ser)Sec (Costa et al., 2000). Each candidate has the potential to generate cross-reacting humoral and cellular immune responses that may overcome selftolerance. Homologies between these molecules have not been investigated, nor have homologies between these candidate autoantigens and various viral agents been demonstrated.

1.2. Promiscuous immunocyte activity The ability of molecular mimicry to generate an autoreactive response depends in part on the promiscuous activity of the sensitized immunocytes (Table 1). Promiscuous immunocyte reactivity implies that the T cell antigen receptor (TCR) of the immunocyte is imprecise in its targeting and that the immunocyte cannot distinguish between closely homologous epitopes in different antigens (Doherty et al., 1998). This deﬁciency promotes and may perpetuate an immune attack against selfantigens that resemble foreign antigens through molecular mimicry.

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Antigenic peptides are displayed in the antigenbinding groove of class II molecules of the major histocompatibility complex (MHC) (Czaja et al., 2002a). These peptides are selected for presentation by the amino acid sequences within the peptide that interact with residues within the antigen-binding groove. Peptide binding to class II MHC molecules is highly degenerate in that each MHC molecule can bind a variety of peptides with varying afﬁnities. Different MHC molecules show a strong bias for particular types of amino acids that are present at peptide positions P1, P4, P6, P7, and P9 from the N-terminal anchor position (Doherty et al., 1998; Corper et al., 2000). The critical contacts that take place between a TCR and its ligand involve residues of the antigenic peptide, the a-helical region of the class II MHC molecule, and the complementaritydetermining regions (CDR) of the a- and b-chains of the TCR (Penzotti et al., 1996; Garboczi et al., 1996; Garcia et al., 1996). The three variable CDR loops of the a-chain and CDR3 of the b-chain are predicted to contact the a-helix of the MHC molecule. The CDR1 and CDR3 loops of both the a- and b-chains contact the bound peptide, but CDR3 displays the greatest degree of diversity within the TCR and it may respond to diverse homologous peptides in the antigen-binding groove. The TCR of liver-inﬁltrating immunocytes tend to be restricted (Hoshino et al., 1995; Arenz et al., 1997, 1998, 2001) and clonally different among various liver diseases (Shimizu et al., 1997; Arenz et al., 1998), but their limited clonal diversity suggests that they are each directed against multiple similar target antigens (Yoshizawa et al., 1999). Since multiple similar peptides can be presented by the same class II MHC molecules and multiple class II MHC molecules can present the same or similar peptides, there is ample opportunity to activate immunocytes against multiple similar peptides and promote molecular mimicry and promiscuous activity (Doherty et al., 1998; Czaja et al., 2002a). Furthermore, this pluri-potential reactivity may be affected by germline polymorphisms that affect the structure of the TCR (Manabe et al., 1994). Homozygosity for the 10-kb Bgl II polymorphism of the TCR constant b gene occurs more commonly in patients with

autoimmune hepatitis than in normal subjects, especially in patients without HLA DRB1*03 and DRB1*04. In patients aged less than 30 years who have HLA DRB1*03, the occurrence of this polymorphism is signiﬁcantly reduced (Manabe et al., 1994). These observations suggest that susceptibility to autoimmune liver disease may relate to the lack of antigenic speciﬁcity of the TCR of the effector cells and to intrinsic hostspeciﬁc genetic factors that subtly modify TCR structure (TCR polymorphisms) and antigen presentation (class II MHC molecules).

2. Deﬁciencies in regulatory networks The immune response is tightly controlled by counter-regulatory molecules that inﬂuence immunocyte activation, cytokine pathways that affect immunocyte differentiation and proliferation, and programs of cell death (apoptosis) that determine the duration of immunocyte reactivity (Czaja, 2001) (Table 2). Deﬁciencies in these regulatory pathways have been demonstrated in autoimmune liver disease, and they may contribute to its occurrence and behavior. Host-speciﬁc genetic factors have been implicated in disturbing this homeostasis, and there are undoubtedly many yet unrecognized interactive genetic polymorphisms inside and outside the MHC that work individually, in clusters, or in synergy (epistasis) with the principal drivers of the disease to modify its clinical phenotype and outcome. The completion of the human genome project and the availability of gene microarray technology and genome-wide DNA microsatellite assessments will undoubtedly clarify the diversity and importance of these interactions.

2.1. Perturbations in activation signals Uncommitted CD4 T helper cells are activated by binding with the antigen-presenting class II MHC complexes on the surface of antigen-presenting cells (APC) (ﬁrst co-stimulatory signal) and after ligation of the CD28 molecules on their surface with B7-1 (CD80) or B7-2 (CD86) on the APC

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Table 2 Deﬁciencies in regulatory networks Immune deﬁciency

Pathogenic mechanism

Consequences

Down-regulation of activation signal

Polymorphism of CTLA-4 gene generates product that fails to compete with CD28 for the B7 ligands on the antigen-presenting cell.

Vigorous or excessive immunocyte activation.

Plethora of interactive polymorphic autoimmune promoters

Polymorphisms outside the major histocompatibility complex work alone or in synergy (epistasis).

Constellations of polymorphic promoters individualize the disease by affecting the clinical phenotype, disease severity and outcome.

Cytokine imbalance favoring type 1 response

Polymorphism of tumor necrosis factor-a gene (TNFA*2) is associated with high levels of TNF-a and HLA DRB1*03.

Increased levels of TNF-a favor clonal expansion of liver-inﬁltrating cytotoxic T cells.

Impaired regulation of apoptosis

Polymorphism of Fas gene promoter at 670 associated with autoimmune hepatitis. Bcl-2 is over-expressed on liver-inﬁltrating CD4 lymphocytes.

Fas gene polymorphism facilitates the early development of cirrhosis. Liver-inﬁltrating immunocytes escape apoptosis and extend autoimmune hepatitis.

Deﬁciencies in regulatory cells with suppressor function

Regulatory CD4+CD25+ T cells (T-reg cells) that suppress proliferation of CD8 lymphocytes are decreased in number and function. Intrahepatic natural killer T cells are decreased in autoimmune hepatitis.

Liver-inﬁltrating CD8 T lymphocytes can proliferate and enhance liver injury. Immune-mediated liver injury is promoted.

surface (second co-stimulatory signal) (Czaja and Donaldson, 2000; Czaja, 2001; Czaja et al., 2002a; Vergani et al., 2002). Cytotoxic T lymphocyte antigen-4 (CTLA-4) is expressed on the surface of activated CD4 T helper cells, and it competes with CD28 for the B7 ligands. CTLA-4 can dampen the activation of CD4 T helper cells by inhibiting the second co-stimulatory signal. In white North American and northern Europeans with autoimmune hepatitis, a polymorphism of the CTLA-4 gene appears to favor disease occurrence (Agarwal et al., 2000a; DjilaliSaiah et al., 2001) (Table 2). The substitution of a guanine for an adenine at position 49 in the ﬁrst exon of the CTLA-4 gene results in a threonine for alanine substitution in the expressed protein, and this variation in the gene product may be sufﬁcient to impair its function (Agarwal et al., 2000a). The same polymorphism of the CTLA-4 gene described in autoimmune hepatitis has been found in PBC, and it may be one of several autoimmune promoter genes that are outside the MHC and not disease speciﬁc (Agarwal et al., 2000b). The CTLA-4 gene polymorphism described in white North American and northern European

patients has not been found in South American patients (Bittencourt et al., 2003). Autoimmune hepatitis has a global occurrence, but its manifestations can vary by geographic region and ethnic group. These phenotypic differences can reﬂect diverse etiologic factors, triggering antigens, genetic predispositions, and pathogenic mechanisms (Czaja et al., 2002b). Observations made in homogenous white populations of North America and northern Europe may not apply to the same disease in another region, and there must be wariness in ‘universalizing’ the ﬁndings. The CTLA-4 polymorphism may be only one example of the type of genetic factors that can inﬂuence disease occurrence in different regions and ethnic groups. The existence and variety of these genetic determinants have been underscored by studies in murine models of autoimmune hepatitis in which mouse strains with different genes inside and outside the MHC have responded differently to the same recipe for the induction of experimental hepatitis (Lapierre et al., 2006). Polymorphisms of the vitamin D receptor (VDR) gene (Vogel et al., 2002), point mutation of the tyrosine phosphatase CD45 gene (Vogel et al., 2003;

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Esteghamat et al., 2005), polymorphisms of the Fas gene [tumor necrosis factor receptor super family (TNFRSF)] (Hirade et al., 2005; Agarwal et al., 2007), mutations of the autoimmune regulator (AIRE) gene (Lankisch et al., 2005), and polymorphisms of the interleukin (IL)-1, IL-6, and IL-10 promoter genes (Fan et al., 2005) are examples of other genetic factors outside the MHC that are not disease speciﬁc but are capable of inﬂuencing the occurrence and manifestations of autoimmune liver disease.

2.2. Perturbations in the cytokine network Cytokines govern differentiation and proliferation of immunocytes through cross-regulatory actions. IL-2, IFN-g, and TNF-a constitute the type 1 (Th1) cytokine pathway that regulates cellular immune mechanisms by facilitating clonal expansion of cytotoxic T lymphocytes (Lucey et al., 1996; Peters, 1996). IL-4, IL-5, IL-6, IL-8, IL-10, and IL-13 constitute the type 2 (Th2) cytokine pathway, and they inﬂuence the humoral immune response by activating B cells and stimulating autoantibody production (Lucey et al., 1996; Peters, 1996). The type 1 cytokine response favors liver injury by expanding sensitized, tissueinﬁltrating, cytotoxic T cells and inducing cellmediated cytotoxicity, and the type 2 cytokine response favors liver cell injury by generating immunoglobulin that can complex with normal constituents of the hepatocyte membrane and be targeted by natural killer (NK) cells in an antibody-dependent, cell-mediated form of cytotoxicity. The type 2 cytokine response also has anti-inﬂammatory effects that counter the type 1 cytokine response. The type 1 and type 2 cytokine pathways constitute a regulatory network that is characterized by redundant action and extensive crossinhibition (Lucey et al., 1996; Peters, 1996) (Table 2). Both cytokine pathways are interactive in autoimmune liver disease and important in modulating disease activity, but neither pattern characterizes a particular autoimmune liver disease (Tilg et al., 1992; Al-Wabel et al., 1993; Schlaak

et al., 1993; Lohr et al., 1994; Maggiore et al., 1995; Trautwein and Manns, 1995; Cacciarelli et al., 1996; Bertoletti et al., 1997). Serum determinations of the cytokine proﬁle in white North American and northern European adults with autoimmune hepatitis show mixed patterns (Czaja et al., 2000). These cytokine patterns change during the course and treatment of the disease. Type 1 cytokines may prevail during periods of active inﬂammation, and type 2 cytokines may prevail during intervals of quiescence. HLA DRB1*03 and the A1-B8-DRB1*03 phenotype occur more commonly in white North American patients with autoimmune hepatitis and mixed type 1 and type 2 cytokine proﬁles than in white patients with pure type 2 cytokine proﬁles (Czaja et al., 2000). This ﬁnding suggests that a genetic predisposition associated with HLA DRB1*03, possibly a genetic polymorphism of the tumor necrosis factor-a gene (Cookson et al., 1999; Czaja et al., 1999), may inﬂuence the cytokine milieu and promote clonal proliferation of liver-inﬁltrating, cytotoxic T cells in white North American patients. Polymorphisms of genes responsible for cytokine production may modify the cytokine milieu in some individuals to favor an autoimmune response (Table 2). The TNFA*2 allele is carried on the 8.1 ancestral haplotype of white northern Europeans, and this linkage disequilibrium with HLA DRB1*03 may modulate the cytokine milieu to favor a cytotoxic immune response. The substitution of an adenine for a guanine at position 308 of the TNF-A gene is associated with high inducible and constitutive levels of TNF-a, and increased levels of this cytokine directs a type 1 cytokine response (Cookson et al., 1999). The polymorphism occurs mainly in young patients with autoimmune hepatitis, especially those who respond less well to corticosteroid therapy (Czaja et al., 1999). These ﬁndings suggest that genetic polymorphisms that affect the cytokine response may work in synergy (epistasis) with HLA DRB1*03 to affect disease severity. IL-2, IL-4, IL-6, IFN-g (Fan et al., 2005) and transforming growth factor-b (TGF-b) (Bayer et al., 1998; Schramm et al., 2003) are also under genetic control, and their role in the occurrence and

Immunopathogenesis of Autoimmune Liver Damage

behavior of autoimmune liver disease requires further study.

2.3. Perturbations in the apoptotic pathways Programmed cell death (apoptosis) is the principal mode of liver cell loss in autoimmune liver disease, and it is also the principal mechanism by which autoreactive immunocytes are eliminated (Fox et al., 2001). Two overlapping signal pathways that stimulate apoptosis affect the extent and the duration of the autoreactive response through intrinsic and extrinsic mechanisms (Bai and Odin, 2003). Perturbations in each pathway have been implicated in the pathogenesis of autoimmune liver disease (Table 2). The intrinsic pathway is characterized by mitochondrial dysfunction that results mainly from oxidative stress and damage to the inner mitochondrial membrane (Bai and Odin, 2003). This injury releases cytochrome c and apoptosisinducing factor (AIF). Caspases are then activated and other factors are released (endo G), which cleave chromosomal DNA and induce cell death. The intrinsic apoptotic pathway is modulated by counter-regulatory proteins that prevent apoptosis (bcl-2) or enhance it (bax, bad). IL-4, IL-7, and IL-15 up-regulate the expression of bcl-2, and they have anti-apoptotic actions. In autoimmune hepatitis, the persistence of activated lymphocytes expressing CD95 (Fas/APO-1) suggests that the intrinsic apoptotic pathway for immunocyte deletion is defective (Ogawa et al., 2000). Activated lymphocytes expressing CD95 (Fas/APO-1) fail to down-regulate the expression of the anti-apoptotic protein, bcl-2, and high concentrations of bcl-2 have been demonstrated in liver-inﬁltrating lymphocytes. Apoptosis of the activated effector cells is inhibited and their persistence within the liver is enhanced. The extrinsic pathway of apoptosis is mediated by the cell surface receptors, Fas and TNF-a receptor-1 (TNF-R1), and by the release of perforin and granzyme B from activated cytotoxic T cells (Bai and Odin, 2003). FasL on the surface

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of the cytotoxic T cells and TNF-a in the cytokine milieu activate the death signals on hepatocytes by binding with their respective ligands, FasL and TNF-a, whereas granzyme B enters the hepatocyte via a membrane pore formed by perforin. The Fas and TNF-R1 complexes cleave procaspase 8 into its active form leading to activation of other downstream caspases, and granzyme B directly cleaves proteins necessary for cell survival. The activated caspases induce cell death directly by cleaving cell proteins or indirectly by releasing cytochrome c from mitochondria. In this fashion, the intrinsic and extrinsic apoptotic pathways can interact in autoimmune liver disease. The cleavage of cell proteins and the fragmentation of DNA can expand the number of autoantigens available to perpetuate the autoimmune response or enlarge the spectrum of autoantibodies associated with the disease. The human Fas gene is a member of the TNFRSF, and it is located on chromosome 10q24.1 (Hirade et al., 2005). Twenty distinct polymorphisms have been described over a span of 26 kb, and four have been associated with the occurrence of autoimmune hepatitis in Japan (Hirade et al., 2005). In white North American and northern European patients with autoimmune hepatitis, an adenosine to guanine single-nucleotide polymorphism in the Fas gene promoter at position 670 (TNFRSF6) has been associated with the early development of cirrhosis (Agarwal et al., 2007). Cirrhosis is more common at presentation in patients with the adenosine/ adenosine or adenosine/guanine genotypes than in those with the guanine/guanine genotype (29 versus 6%, p=0.006; odds ratio=6.4). These ﬁndings suggest that genetic factors can inﬂuence disease progression in autoimmune liver disease through modulation of receptor-mediated programmed cell death (Table 2). Liver-inﬁltrating CD4 T lymphocytes in patients with autoimmune hepatitis are distinguished by their expression of CD28 and the anti-apoptotic protein, bcl-2 (Kurokohchi et al., 2006). In this fashion, the CD4 helper T lymphocytes may escape apoptosis and provide cognate help for the induction of cytotoxic T lymphocytes. These observations highlight the capability of effector

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cells to undergo special modiﬁcations that evade apoptosis and promote autoimmune liver disease.

2.4. Deficiencies in regulatory cells with suppressor functions Counter-regulatory cells have recently been identiﬁed that are likely to reduce the autoreactive response by dampening cytokine pathways that promote the proliferation of cytotoxic T lymphocytes (Table 2). The functions of these cellular regulators have been incompletely described, but they have largely suppressive actions on the pathogenic pathways. Unexplained deﬁciencies in their number and function have been identiﬁed in autoimmune hepatitis, and these deﬁciencies may in turn enhance the development and severity of the liver disease. Regulatory CD4+CD25+ T cells (T-reg cells) modulate CD8 T cell proliferation by exerting a direct suppressive effect on the production of IFN-g while increasing secretion of IL-4, IL-10, and TGF-b (Longhi et al., 2005, 2006; Lan et al., 2006). These cells are decreased in number and function in autoimmune hepatitis, and their failure to modulate CD8 T cell proliferation and cytokine production may facilitate the liver injury (Table 2). T-reg cells do not affect target cell apoptosis, but they exert a direct suppressive effect on the immune response by modifying the cytokine milieu. Recent studies demonstrating deﬁcient T-reg cell function in the siblings and children of patients with PBC suggest that the suppressor activity of this subset may be modulated by genetic factors (Lan et al., 2006). Corticosteroid therapy can re-constitute T-reg cell function and attenuate the cell-mediated cytotoxic response in autoimmune hepatitis (Longhi et al., 2005). Natural killer T (NKT) cells are lymphoid cells derived from the bone marrow, and they are abundant in the liver (Lalazar et al., 2006; Zhang et al., 2006). These cells express surface markers found on monocytes, granulocytes, and lymphocytes, and their co-expression of a TCR characteristic of lymphocytes and a NK1.1 lectin characteristic of NK cells has justiﬁed their

designation as NKT cells. The NKT cells produce cytokines, including IFN-g and IL-4, that can have pro-inﬂammatory and anti-inﬂammatory effects (Table 2). NKT cells are activated by glycolipids that are bound to or presented by the CD1d on APCs or hepatocytes (Lalazar et al., 2006). CD1d-deﬁcient mice lack NKT cells, and they are highly resistant to experimental hepatitis induced by the intravenous injection of concanavalin (Con) A (Takeda et al., 2000). Sensitivity to Con-A-induced liver injury is restored after adoptive transfer of hepatic NKT cells isolated from wild-type mice. In this model, the wild-type hepatic NKT cells rapidly up-regulate cell surface expression of FasL and induce FasL-mediated cytotoxicity before disappearance from the liver by apoptosis. In Con-Ainduced liver disease, NKT cells appear to have deleterious actions (Takeda et al., 2000). Conversely, NKT cells may have a protective function in autoimmune liver disease (Table 2). Recent studies have indicated that the number of intrahepatic NKT cells in autoimmune hepatitis is less than in patients with PBC and that the levels of mRNA encoding soluble CD1d are also lower in these individuals (Takahashi et al., 2006). Patients without intrahepatic NKT cells have higher serum aminotransferase and immunoglobulin G levels and lower mRNA levels for soluble CD1d than patients with intrahepatic NKT cells. These ﬁndings indicate that NKT cells can prevent liver injury in autoimmune liver disease. Their differentiation as protectors or effectors of liver injury may depend on the type of liver disease and host-dependent co-factors, such as CD1d expression and the natural occurrence of glycolipids. Further characterization of the T-reg cells and NKT cells may afford opportunities to increase their suppressor functions in autoimmune liver disease by medication or adaptive transfer.

3. Genetic and gender predispositions Host-dependent factors clearly inﬂuence the nature and severity of autoimmune liver disease (Czaja et al., 1998). Genetic factors have already been

Immunopathogenesis of Autoimmune Liver Damage

implicated in modulating the CTLA-4 pathway of immunocyte activation (Agarwal et al., 2000a, b), altering the structure of the TCR of activated immunocytes (Manabe et al., 1994), enhancing the type 1 cytokine pathway (Cookson et al., 1999; Czaja et al., 1999; Fan et al., 2005), altering the apoptosis of liver cells and immunocytes (Hirade et al., 2005; Agarwal et al., 2007), and possibly affecting the number of T-reg cells in PBC (Lan et al., 2006). The female predisposition for autoimmune hepatitis and PBC as well as autoimmune disease in general is well recognized, and the female gender may be the strongest, single, hostspeciﬁc risk factor for autoimmunity (Czaja et al., 1998). Earlier examples of genetic factors inﬂuencing the occurrence and phenotype of autoimmune liver disease consisted mainly of polymorphisms that were outside the MHC, not disease speciﬁc, and unlikely to be the primary drivers of the autoimmune response. Much has been learned

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regarding the principal susceptibility factors for autoimmune liver disease, and these insights have generated compelling hypotheses regarding the pathogenesis of these disorders. Furthermore, the clariﬁcation of the immune-modulating effects of the various sex hormones, especially estrogen, has allowed speculation as to how gender may contribute to susceptibility.

3.1. Principal genetic risk factors The principal susceptibility alleles for autoimmune hepatitis in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401 (Strettell et al., 1997) (Table 3). In contrast, DRB1*1501 has been associated with protection from the disease (Doherty et al., 1994; Strettell et al., 1997). The key genetic risk factors for PSC are

Table 3 Genetic predispositions Genetic component

Genetic predispositions

Consequences

Principal genetic risk factors

DRB1*0301 and DRB1*0401 in autoimmune hepatitis. DRB3*0101–DRB1*0301 and DRB3*0101– DRB1*1301 in primary sclerosing cholangitis. DRB1*0801–DQB1*0402 in primary biliary cirrhosis.

Susceptibility alleles encode the antigen-binding groove of the class II molecule of the major histocompatibility complex to favor presentation of disease-speciﬁc triggering antigens.

Shared antigenbinding motif

LLEQKR encoded at positions DRb67-72 and lysine at DRBb71 are key factors in autoimmune hepatitis. Arginine is encoded by DRB1*0404 and DRB1*0405 at DRBb71 and similar to lysine. DRB3*0101 and DRB5*0101 encode a leucine at position DRb38 in primary sclerosing cholangitis.

Multiple alleles can encode the same or similar amino acid motif in the antigen-presenting molecule and affect disease occurrence similarly.

Region-speciﬁc genetic risk factors

DRB1*1301 is associated with autoimmune hepatitis in South America. DRB1*07 is associated with antibodies to liver/ kidney microsome type 1 in northern Europe. DQB1*0201 is associated with type 2 autoimmune hepatitis.

Genetic susceptibilities favor indigenous triggering antigens in different geographical regions and ethnic groups. Multiple alleles in a single disease may affect different aspects of its clinical phenotype.

Gene dose effects

Multiple alleles can encode the same antigen recognition sites.

Multiple antigen recognition sites increase immunocyte activation.

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DRB3*0101–DRB1*0301 and DRB3*0101– DRB1*1301, and the haplotype containing DRB1*04–DQB1*0501 has been associated with protection from the disease (Farrant et al., 1992; Donaldson and Norris, 2001, 2002) (Table 3). DRB1*0801 has been weakly associated with PBC in white North American and northern European patients (Gores et al., 1987; Manns et al., 1991a, b; Donaldson et al., 2006), and DRB1*0803 has been associated with PBC in Japan (Onishi et al., 1994) (Table 3). The DRB1*08–DQB1*0402 haplotype may extend weakly to the DPB1*0301 allele in Britain and to the DPB1*0501 allele in Japan (Underhill et al., 1995), whereas HLA DRB1*11 and DRB1*13 may be protective against PBC in diverse ethnic populations (Donaldson et al., 2006). The genetic associations in PBC are within the chromosomes 6p21.3 and 2q, and they include the HLA DRB1*08 haplotypes as well as polymorphisms that may alter the autoimmune response, such as CTLA-4 (Jones and Donaldson, 2003). The alleles of the MHC are the principal drivers of autoimmune liver disease, whereas polymorphisms outside the MHC modify the clinical phenotype and affect disease severity. The MHC alleles encode the amino acid sequences within the antigen-binding groove of the class II MHC molecules that are responsible for antigen presentation and immunocyte activation (Czaja and Donaldson, 2000; Czaja et al., 2002a). In this fashion, they directly affect antigen selection and the immune response. Analyses of amino acid sequence variations encoded by the susceptibility alleles associated with autoimmune hepatitis in white North American and northern European patients indicate that the core susceptibility motif is a six amino acid sequence, LLEQKR, at positions DRb67–72 of the antigen-binding groove of the class II MHC molecule (Doherty et al., 1994; Strettell et al., 1997) (Table 3). Lysine (K) at position DRb71 is at the lip of the antigen-binding groove, and it is at a critical contact point between the antigen, the class II MHC molecule, and the TCR. In white North American and northern European patients with autoimmune hepatitis, the optimal presentation of antigens by the class II MHC molecules depends on lysine at position DRb71 (Doherty et al., 1994; Strettell et al., 1997).

Both DRB1*0301 and DRB1*0401 encode identical sequences at positions DRb67–72 (Doherty et al., 1994; Donaldson and Czaja, 2002). DRB1*0301 is in strong linkage disequilibrium with DRB3*0101, which also encodes a lysine at DRb71, whereas DRB1*0401 is in strong linkage disequilibrium with DRB4*0103, which encodes an arginine at DRb71. Patients with DRB1*0301 have two lysine-encoding DRB alleles per haplotype, whereas those with DRB1*0401 have one. The reduced density of antigen-presenting molecules with lysine at DRb71 in patients with DRB1*0401 may attenuate the immune response and lessen the severity of the disease (Czaja et al., 1997a, b; Strettell et al., 1997). The diversity of class II MHC molecules in patients with DRB1*0401 may confer responsiveness to multiple liver and non-liver antigens. This diversity may in turn favor a more varied clinical phenotype (Czaja and Donaldson, 2002). Clinical studies have supported these concepts by indicating that patients with DRB1*0301 have more severe disease than those with DRB1*0401, whereas patients with DRB1*0401 are more commonly women and they have a higher frequency of concurrent immune diseases than those with DRB1*0301 (Czaja et al., 1993, 1997a, b; Czaja and Donaldson, 2002). Arginine (R) is a polar amino acid that is structurally similar to lysine, and its substitution for lysine at position DRb71 would not greatly alter the steric and electrostatic properties of the class II MHC molecule (Strettell et al., 1997; Czaja and Donaldson, 2000; Czaja et al., 2002a; Donaldson, 2002; Donaldson and Czaja, 2002). Arginine at DRBb71 has been associated with autoimmune hepatitis in Japan (Seki et al., 1992; Yoshizawa et al., 2005), Mexico (Vazquez-Garcia et al., 1998), and mainland China (Qiu and Ma, 2003) where the susceptibility alleles, DRB1*0404 and DRB1*0405, encode an arginine (R) for lysine (K) at the DRb71 position. In contrast, DRB1*1501 protects against type 1 autoimmune hepatitis in white North Americans and northern Europeans, and this allele encodes an isoleucine (I) for leucine (L) at position DRb67 and an alanine (A) for lysine (K) at position DRb71 (Doherty et al., 1994; Strettell et al., 1997). Alanine is a

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neutral, nonpolar amino acid whose substitution for lysine would greatly affect antigen presentation and immunocyte activation. The substitution of a single amino acid at a critical location in the antigen-binding groove of the class II MHC molecule may affect disease occurrence by altering antigen recognition. In PSC, susceptibility and protection relate to amino acid substitutions at position DRb38 (Farrant et al., 1992). Both DRB3*0101 and DRB5*0101 encode a leucine at position DRb38, whereas the DRB4*0101 allele, which encodes DRw53 and may be protective against PSC, encodes an alanine at this position. Maximum relative risk for PSC relates to leucine at position DRb38, and minimum relative risk relates to alanine at DRb38 (Farrant et al., 1992). Multiple alleles of the MHC in addition to the principal susceptibility factors can encode the same critical amino acids at positions DRb71 in autoimmune hepatitis and DRb38 in PSC (Doherty et al., 1994; Strettell et al., 1997). These alleles may increase susceptibility to the disease by enhancing the number of class II MHC molecules with critical amino acids at key positions within the antigen-binding groove to optimize autoantigen presentation (Czaja et al., 1997a, b; Strettell et al., 1997). Alternatively, they may be sufﬁcient to favor development of the disease in the absence of the principal MHC alleles (Czaja et al., 2006; Montano-Loza et al., 2006). The commonality of susceptibility alleles for autoimmune hepatitis in different ethnic regions has generated a ‘shared motif hypothesis’ of pathogenesis. The ‘shared motif hypothesis’ predicts that disease risk relates to amino acid sequences in the antigen-binding groove of the DR molecule and that multiple alleles can encode the same or similar sequence and affect susceptibility similarly (Czaja and Donaldson, 2000, 2002). The various implicated susceptibility alleles for autoimmune hepatitis in different ethnic groups, including the Japanese, mainland Chinese, and Mexicans, each encode a similar six amino acid sequence between positions 67 and 72 of the DRb chain. The only exception has been the association of HLA DRB1*13 with autoimmune hepatitis in South America (Fainboim et al., 1994; Pando

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et al., 1999; Bittencourt et al., 1999; Goldberg et al., 2001).

3.2. Region-specific genetic risk factors Autoimmune liver disease in different geographic regions may have genetic risk factors that are characteristic of that region or ethnic group (Fainboim et al., 1994; Pando et al., 1999; Bittencourt et al., 1999; Goldberg et al., 2001). These susceptibility alleles do not encode similar amino acid sequences within class II MHC molecules and affect susceptibility similarly. Instead, they may encode sequences that favor the presentation of indigenous triggering antigens that in turn cause the disease by protracted exposure and molecular mimicry (Fainboim et al., 2001). The ‘molecular footprint hypothesis’ holds that different individuals within a population have alleles that render them particularly susceptible to an indigenous, region-speciﬁc, etiologic agent that selects them to develop autoimmune liver disease (Donaldson, 2002, 2004; Donaldson and Czaja, 2002). By using the susceptibility allele as a ‘footprint’, it may be possible to deduce the region-speciﬁc, etiologic trigger for the disease. DRB1*1301 is associated with autoimmune hepatitis in Argentine children (Fainboim et al., 1994; Pando et al., 1999) and Brazilian patients (Bittencourt et al., 1999; Goldberg et al., 2001), and it encodes ILEDER at positions DRb67–72 (Czaja et al., 2002a; Donaldson, 2002; Donaldson and Czaja, 2002) (Table 3). Glutamic acid (E), aspartic acid (D), and glutamic acid (E) are at positions DRb69, 70, and 71 in the class II MHC molecules, and these negatively charged amino acid residues favor presentation of antigens different from those accommodated within class II MHC molecules encoded by DRB1*0301 and DRB1*0401. DRB1*1301 is associated with protracted hepatitis A virus infection (Fainboim et al., 2001), and hepatitis A virus has been associated with the development of autoimmune hepatitis (Vento et al., 1991; Huppertz et al., 1995; Tanaka et al., 2005). South Americans, especially children, with DRB1*1301 may be selected to have

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prolonged exposure to viral and hepatic antigens and thereby overcome self-tolerance (TapiaConyer et al., 1999; Fainboim et al., 2001). Other geographic regions may have other susceptibility alleles for the same disease based on the indigenous antigens that can trigger their disease. Type 2 autoimmune hepatitis is characterized by antibodies to liver/kidney microsome type 1 (anti-LKM1), and it has been described mainly in European children (Homberg et al., 1987). Susceptibility to type 2 autoimmune hepatitis has been associated with DRB1*07 in Brazil (Bittencourt et al., 1999), Britain (Ma et al., 2006), and Germany (Czaja et al., 1997a, b) and with DRB1*03 in Spain (Jurado et al., 1997). DQB1*0201 is in strong linkage disequilibrium with DRB1*07 and DRB1*03, and it has been proposed as the principal genetic determinant of the disease (Djilali-Saiah et al., 2006). The association of a single disease with multiple alleles suggests that there may be different determinants for various aspects of the condition. DRB1*07 has been associated with the expression of anti-LKM1 in children with type 2 autoimmune hepatitis (Bittencourt et al., 1999; Djilali-Saiah et al., 2006) and in Italian patients with chronic hepatitis C (Muratori et al., 2007). In contrast, antibodies to liver cytosol type 1 (antiLC1) are associated with DRB1*03 (Djilali-Saiah et al., 2006). Both anti-LKM1 and anti-LC1 occur in type 2 autoimmune hepatitis, and each has genetic associations distinct from each other but occurring in the same disease. This disease in turn is driven mainly by DQB1*0201 (Djilali-Saiah et al., 2006). These ﬁndings suggest that the expression of nonpathogenic autoantibodies controlled by the HLA DR locus in type 2 autoimmune hepatitis and the occurrence of the disease controlled by the HLA DQ locus can be variably associated. The implication is that nonpathogenic antibodies can be expressed in diverse conditions if the host has a suitable haplotype and antigenic stimulus. A corollary to this observation is that the inability to detect certain antibodies in patients with the same disease may reﬂect the rarity of the predisposing haplotype in that population. This corollary has been invoked to explain in part the low occurrence of anti-LKM1 in North American

patients with autoimmune hepatitis (Czaja et al., 1992) or chronic hepatitis C (Reddy et al., 1995; Muratori et al., 2007).

3.3. ‘Gene dose’ effects The number of susceptibility alleles that can encode the same critical amino acid sequence within the binding groove of the class II MHC molecules (‘gene dose’) determines the density of the antigen-binding complexes on the surface of the APC (Czaja and Donaldson, 2000; Czaja et al., 2002a; Donaldson and Czaja, 2002). This density in turn inﬂuences the vigor of immunocyte activation by favoring simultaneous activation of multiple antigen recognition sites within the CD4 T helper cells. The clinical phenotype and severity of autoimmune hepatitis in North American and northern European patients with autoimmune hepatitis are associated with the number of alleles that encode lysine at position DRb71 (Czaja and Donaldson, 2000; Czaja et al., 2002a; Donaldson and Czaja, 2002) (Table 3). This ‘gene dose’ can be variable among individuals with the same principal susceptibility alleles since the critical motif at position DRb71 can be encoded by other alleles within the haplotype. The ability of multiple alleles to encode the same critical motif may also account for the occurrence of autoimmune hepatitis in individuals from the same geographic region who lack DRB1*0301 and DRB1*0401 (Czaja et al., 2006; Montano-Loza et al., 2006). In type 2 autoimmune hepatitis, the proliferative T cell response to the target antigen, CYP2D6, is against multiple antigenic regions (Ma et al., 2006). These antigenic regions differ in patients with and without DRB1*07, presumably because of differences in the peptide-binding afﬁnity of the class II MHC molecules. T and B cell responses can be induced by the same overlapping antigenic sequences, and disease activity relates to the number of epitopes involved in the T and B cell responses and the amount of cytokines produced from these responses (Ma et al., 2006). Gene dosing and its impact on the density of

Immunopathogenesis of Autoimmune Liver Damage

antigen-presenting MHC molecules is probably an important factor that affects the occurrence and severity of autoimmune liver disease.

3.4. Gender effects The strong female predilection for autoimmune liver disease is unexplained (Czaja et al., 1998), but it is an important association that might provide clues to regulatory mechanisms controlled by sex-linked genes or gender-speciﬁc hormones (McFarlane and Heneghan, 2004). Immune cells have two estrogen receptors, and the activation of these receptors relate to the concentrations of estrogen in the microenvironment (Fox et al., 1991; Muller et al., 1995). High estrogen levels, as in pregnancy, inhibit the type 1 cytokine response that favors the proliferation of cytotoxic T cells, and they promote a type 2 cytokine response that favors antibody production and antibodydependent pathogenic pathways. Low estrogen levels favor a type 1 cytokine response and promote cell-mediated pathogenic pathways (Whitacre et al., 1999). Because the female predilection for autoimmune hepatitis is apparent among children (Gregorio et al., 1997) and the elderly (Wang and Czaja, 1989; Czaja and Carpenter, 2006), ﬂuctuations in estrogen levels are insufﬁcient to account for all cases of the disease. Pituitary hormones, such as prolactin and growth hormone (Reber, 1993; Paavonen, 1994), and other sex hormones, such as progesterone and testosterone (Chao et al., 1995; Kimura et al., 1995), counter-regulate the immune response, probably by altering the cytokine milieu and estrogen receptor expression. Interactions between growth hormone, prolactin, testosterone, and estrogen may constitute a changing hormonal milieu that affects immune responsiveness differently at various ages and favors certain antigens during different stages of maturation. The female gender may be the critical determinant affecting the hormonal blend of this interactive network at each age.

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Women may also be exposed to unique triggering antigens that enhance their susceptibility to autoimmune disease or have attributes that favor optimal antigen presentation. Pregnancy is a unique female experience, and fetal cells in the maternal circulation have been associated with the initiation and exacerbation of autoimmune disease. Microchimerism can persist for years after pregnancy, and it may compromise self-tolerance late in life by promoting cross-reactivities in the humoral and cellular immune responses (Nelson, 1999; Lambert et al., 2000). Its importance in autoimmune liver disease has not been established (Tanaka et al., 2000), and the female propensity may better reﬂect gender-related attributes in antigen presentation and the activation of CD4 T helper cells. White North American women with autoimmune hepatitis have HLA DRB1*04 more commonly than men with the same disease (Czaja et al., 1993, 1997a, b; Czaja and Donaldson, 2002), and they have a greater diversity of HLA DRB1*04 alleles (Czaja and Donaldson, 2002). This diversity of HLA DRB1*04 alleles in women implies that they are able to present a greater variety of antigens to CD4 T helper cells than men. This propensity may enhance their ability to trigger an autoimmune response as well as target anatomically distant organs. HLA DRB1*04 has been associated with autoimmune hepatitis and with the concurrence of other immune diseases in the same individual (Czaja et al., 1993, 1997a, b; Czaja and Donaldson, 2002). The mechanisms by which the female gender enables autoreactivity are largely conjectural, but the female predilection for this response across all age groups underscores the importance of host-related predispositions, genetic and otherwise, in the occurrence of autoimmune liver disease. One X-chromosome is normally inactivated in women in a random fashion to achieve equivalent X-linked gene products in each gender. In primary biliary cirrhosis, X-chromosome loss occurs more frequently than in normal women or disease controls, and the inactivation is not random (Miozzo et al., 2007). Genes crucial for immune tolerance are on the X-chromosome, and variations in their inactivation may favor the loss of

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self-tolerance. The preferential X-chromosome loss may be acquired and a basis for the female predilection in some autoimmune diseases.

4. Summary Autoimmune liver disease is the net consequence of an interactive network of stimulatory and inhibitory immune responses that are activated by diverse antigens that probably have a homologous epitope (Czaja, 2001; Vergani et al., 2002). The ﬁnal product of these convergent modiﬁers is dependent on the genetic and hormonal composition of the host (Czaja and Donaldson, 2002; Czaja et al., 2002a). Cell-mediated and antibodydependent cytotoxic mechanisms initiate and extend the injury pattern, and ﬂaws in the apoptotic pathways that deplete autoreactive T cells or prevent excessive hepatocyte loss perpetuate the disease. Autoimmune liver disease has pathogenic mechanisms that are shared by other autoimmune diseases (HLA predispositions and genetic polymorphisms) (Czaja et al., 2001; Alarcon-Segovia, 2005), and its distinction from these other diseases must reﬂect unique antigenic triggers and a constellation of host-dependent modiﬁers that shape the clinical phenotype. Autoimmune liver disease is a human model of autoimmunity, and it has the potential to provide insight into the mechanisms and treatment of other similar conditions. Major strides have already been made in understanding target autoantigens and genetic predispositions that trigger the autoreactive response and perpetuate the disease. A conﬁdent animal model of the human disease is necessary to clarify the critical pathogenic mechanisms and to assess emerging pharmacological agents and molecular interventions that will improve treatment strategies.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 12

Primary Biliary Cirrhosis Rupert Abdalian, Jenny Heathcote Division of Gastroenterology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, Ont., Canada

1. Introduction Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the chronic progressive loss of interlobular bile ducts. An immune-mediated destruction of the bile duct epithelium is thought to mediate its pathogenesis. It is a disease that primarily affects middle-aged women of all races. Histologically, it is characterized by portal inﬂammation comprising aggregates of lymphoid cells and/ or granulomas, which invade and destroy biliary epithelial cells (Fig. 1). This causes secondary duct loss, decreased bile secretion, and cholestasis which promotes hepatic ﬁbrosis, cirrhosis, and, eventually, liver failure. Serologically, the diagnostic hallmark ﬁnding is antimitochondrial antibody (AMA). PBC was ﬁrst described in 1851 by Addison and Gull (1851), and subsequently in 1952 the conﬁrmation of an association with hyperlipidemia and cutaneous xanothomas led to the initial description of ‘xanothomatous biliary cirrhosis’ (McCabe and Thompson, 1952). The label of ‘Primary Biliary Cirrhosis’ was adopted a year later at the Rockefeller Institute, despite opposition from those who argued that not all patients present with cirrhosis at diagnosis. The later description of ‘chronic non-suppurative destructive cholangitis’ was deemed more plausible

Corresponding author.

Tel.: (416) 603-5914; Fax: (416) 603-6281 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00012-8

clinically, yet it never grew to replace the more popular designation of PBC.

2. Epidemiological highlights Initial studies published between 1974 and 1985 described annual incidence rates for PBC ranging between 0.6 and 13.7 cases per million population (Hamlyn and Sherlock, 1974; Lofgren et al., 1985). Subsequent studies from Europe reported incidence rates ranging from 0.7 to 48 cases per million. In North America, the incidence rate of 27 cases per million population with prevalence rates between 160 and 402 cases per million have been reported within speciﬁc regions (Kim et al., 2000; Hurlburt et al., 2002). The age- and gender-adjusted prevalence per 100,000 persons was 65.4 for women and 12.1 for men in a well-deﬁned population from Minnesota (Kim et al., 2000). The concept of a ‘north-south’ gradient as in other autoimmune conditions can also be postulated in PBC. The highest incidence and prevalence rates have been reported in the United Kingdom, Scandinavia, Canada, and the United States, whereas the lowest in Australia. Notably high rates have been reported in clusters of populations such as one large First Nations family near Vancouver Canada (Arbour et al., 2004) as well as a group of individuals living in close proximity to the Nagasaki atomic bomb explosion site in Japan (Ohba et al., 2001). A selection bias as well as variable diagnostic criteria may account for this geographic variability.

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Figure 1. Typical bile duct lesion of primary biliary cirrhosis (center). (See Colour Plate Section.)

The absence of population-based standardized methodology limits the reliability of these ﬁndings. As more sophisticated testing for AMA are developed and diagnostic criteria further reﬁned and universally applied, more cases may be identiﬁed. Little information is available regarding the contribution of race and ethnicity to the pathogenesis of PBC. In a recent report from Australia, the prevalence rates in migrants from Great Britain (41 cases per million), Italy (200 cases per million), and Greece (208 cases per million) were signiﬁcantly higher when compared to the local indigenous population surveyed (Sood et al., 2004). In women older than 40 years, the PBC prevalence in British-born immigrants to Victoria was signiﬁcantly higher than that of Australian-born women. With our current knowledge of genetic susceptibility in PBC, it is difﬁcult to delineate the true interaction between the environment and the host. An interesting case report described development of PBC in a daughter, her mother, and a close unrelated friend who had nursed the daughter through her terminal illness (Douglas and Finlayson, 1979). This suggests that host susceptibility plays a signiﬁcant role in the development of PBC. The peak incidence of PBC occurs in the ﬁfth decade of life, and it is uncommon under the age of

25 years. The onset is usually between the ages of 30 and 65, but it has been reported in women as young as 15 and as old as 93. A 90% female preponderance is observed. A familial predisposition is now well recognized as well. Relatives of patients with PBC are more likely to exhibit immune system derangements. Various reports have estimated prevalence rates of PBC among ﬁrst-degree relatives ranging between 5 and 6% (Jones et al., 1999). This correlation is the strongest among sisters and daughters who are younger at diagnosis compared to index cases (Tsuji et al., 1999). It is noteworthy to mention, however, that family clustering may reﬂect ascertainment bias and shared environmental factors. To this day, speciﬁc HLA associations with PBC have been only weak at best, and reports of speciﬁc inherited alleles altering immune responsiveness have failed to convincingly highlight any disease-speciﬁc associations (Milkiewicz et al., 2006).

3. Pathophysiological insights An immune-mediated destruction of bile duct epithelial cells is thought to drive the pathogenesis of PBC. Chronic inﬂammation and repeated injury

Primary Biliary Cirrhosis

to the small ducts promote a repair mechanism that involves expansion of portal tracts with proliferating bile ductules. The ensuing myoﬁbroblastic response results in the net accumulation of collagen matrix, which, with time, expands to adjacent portal areas, leading to the typical biliary pattern of ﬁbrosis and eventually of cirrhosis. Inﬂammatory responses likely stem from recognition of aberrant expression of mitochondrial self-antigens and/or breakdown of immunologic tolerance, resulting in the generation of speciﬁc T and B lymphocytes that mediate production of proinﬂammatory cytokines and autoantibodies (Kita et al., 2003). The mechanisms that mediate the ﬁbrogenic response to bile duct injury have been recently subjected to considerable investigation. Immature cholangiocytes have been shown to generate autocrine growth factors (e.g., hepatocyte growth factor, epidermal growth factor) as well as cytokines (e.g., platelet-derived growth factor b) that are believed to mediate the proliferation of myoﬁbroblastic cells (Omenetti et al., 2007). Therefore, signaling between biliary epithelial cells and stromal cells may modulate the mechanism whereby bile ducts are damaged. The Hedgehog family of ligands has recently been shown to promote the growth of both of these cell types (Sicklick et al., 2006). They function as viability factors for many types of progenitors, and have been shown to play a pivotal role in tissue morphogenesis during embryological development (Deutsch et al., 2001). They mediate the signaling between mesenchymal and epithelial cells and thus modulate remodeling responses after injury during adult life (Sicklick et al., 2006). Using immunohistochemistry, Jung et al. (2007) demonstrated that proliferating bile ductular cells are a rich source of Hedgehog ligands, further supporting the hypothesis that an epithelial–mesenchymal ‘cross-talk’ promotes the ﬁbroproliferative response to bile duct injury via autocrine and/or paracrine regulation of hepatic progenitor cell populations. An inappropriate upregulation of connective tissue elements in bile-duct-ligated mice with a genetic defect limiting downregulation of the Hedgehog pathway activity has been reported as well, further supporting this hypothesis (Omenetti et al., 2007).

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A more concerted research effort in unraveling the Hedgehog pathway intricacies and that of other systems that modulate progenitor cell proliferation, apoptosis, and differentiation may shed further light into the complex pathogenesis of PBC. PBC is considered an organ-speciﬁc autoimmune disease associated with the presence of wellcharacterized antimitochondrial antibodies. These target at least three components of the M2 family of mitochondrial antigens: the E2 subunit of pyruvate dehydrogenase complex (PDC-E2), the 2-oxoglutarate dehydrogenase complex (OGDC), and branched-chain 2 oxo-acid dehydrogenase complex (BCOADC). Additional targets such as the keto-glutaric acid dehydrogenase complex and the dihydrolipoamide dehydrogenase binding protein have been described (Gershwin et al., 2000). Marked homology exists between these different antigenic targets, all share a lipoic acid moiety and are involved in oxidative phosphorylation. They are located on the inner mitochondrial matrix and play a critical role in the metabolism of keto-acid substrates. These antimitochondrial antibodies are detected in the sera of at least 95% of affected individuals, and have been validated as highly sensitive and speciﬁc tools in the diagnosis of PBC (Kaplan and Gershwin, 2005). PBC seems to be the only disease in which autoreactive T cells and B cells responding to the PDC-E2 are detected. Autoantibodies directed at nuclear antigens have been described in approximately 50% of patients PBC, and often in patients who possess antimitochondrial antibodies (Kaplan and Gershwin, 2005). Their pathogenic role is further supported by reports demonstrating secretory IgA autoantibodies against PDC in the saliva, bile, and urine specimens of patients with PBC (Reynoso-Paz et al., 2000; Tanaka et al., 2000). Examples of antinuclear antibodies include those against the nuclear pore proteins gp210 and p62, both of which are believed to be associated with more active and severe disease (Nakamura et al., 2007). The nuclear body protein sp100 is another identiﬁed target. The nuclear-rim and nuclear-dot antinuclear patterns of these are highly speciﬁc for the disease (Worman and Courvalin, 2003). The main paradox in the above hypothesis, however, is the fact that mitochondrial proteins are

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present in all nucleated cells, yet the targets of autoimmune injury are the biliary epithelium and salivary duct cells. It is believed that cellular apoptosis can increase the exposure of PDC-E2 domain to the immune system via modiﬁcation of its lysine-lipoyl moiety by glutathione (Odin et al., 2001). The immunoreactivity is decreased by glutathionylation, whereas it is sustained by inhibition of glutathionylation. It is speculated that this intricate control of immune expressivity is impaired in cells involved in the pathogenesis of PBC. Cellular apoptosis itself can cause aberrant expression of PDC-E2 on cell surface, which leads to the failure of attachment of this key regulatory glutathione group (Odin et al., 2001). In vitro caspase cleavage of PDC-E2 has been shown to generate immunologically active protein fragments (Macdonald et al., 2004). In addition, speciﬁc xenobiotic modiﬁcations of the inner lysine-lipoyl domain of the PDC-E2 are immunoreactive when tested with the serum of patients with PBC, further supporting this mechanism (Amano et al., 2005). Markers of ongoing apoptosis have been reported within affected portal tracts, including downregulation of the antiapoptotic protein bcl-2 (Matsumura et al., 2002). The T-cell mitochondrial responses also contribute to bile duct injury in PBC. PDC-E2-speciﬁc CD4+ and CD8+ T cells have been identiﬁed in the peripheral blood and liver of PBC patients, mostly during early disease states (Palmer et al., 1999; Kita et al., 2002). Epitope mapping studies have identiﬁed the HLADR40101-restricted T-cell epitope that spans amino acid residues 163 through 176 of the PDC-E2 domain. Also, CD8+ T cells from livers of patients with PBC demonstrate cytotoxicity against PDC-E2 159–167 pulsed autologous cells (Palmer et al., 1999). Recently, a mouse model for PBC has been described. Irie et al. (2006) demonstrated that the NOD.c3c4 mice congenically derived from a nonobese diabetic strain develop an autoimmune biliary disease that models human PBC. These mice develop antibodies to PDC-E2 that are speciﬁc for the inner lipoyl domain. The affected biliary epithelium is inﬁltrated with CD3+, CD4+, and CD8+ T cells, and treatment with monoclonal antibody to CD3 protects further bile duct injury.

Histological analysis reveals destructive cholangitis, granuloma, and eosinophilic inﬁltration as seen in PBC; although, unlike PBC, the extrahepatic biliary ducts are also affected. These have been reports of two other mouse models that are associated with AMA and chronic biliary disease—both have deﬁcient T regulatory cells (Wakabayashi et al., 2006; Oertelt et al., 2006). Potential associations between speciﬁc environmental exposures and the development of PBC have shed some light into its pathogenesis. Molecular mimicry is the most widely proposed mechanism for the initiation of autoimmunity (Selmi and Gershwin, 2004). Its underlying concept is that of cross-reactivity with self-antigens from circulating antibodies developed in response to infection. Several causative culprits have been identiﬁed, including bacteria, viruses, and environmental pollutants. Examples of bacterial pathogens linked to PBC are Escherichia coli, Pseudomonas aeruginosa, Helicobacter pylori, Chlamydia pneumoniae, and Haemophilus influenza. The most intriguing association is Novosphingobium aromaticivorans, a ubiquitous pathogen, whose own PDC-E2 domain contains 12 of 13 contiguous amino acids sequence identical to human PDC-E2 (Selmi and Gershwin, 2004). Two case-control studies describe a greater than expected frequency of previous urinary tract infection in patients with PBC (Gershwin et al., 2005; Howel et al., 2000). There is a report of a human b retrovirus resembling mouse mammarytumor virus (MMTC) in patients with PBC (Mason et al., 2004), although this work has not been reproduced. The potential role of microorganisms in triggering PBC via their interaction with the innate immune system has been proposed (Hartmann and Krieg, 2000). A recent investigation described the association between PBC and residency near superfund toxic waste sites in New York city (Ala et al., 2006). Whether these ﬁndings are mere coincidental associations or etiologically relevant is a matter of ongoing debate. It has been suggested that pregnancy is a risk factor for PBC. Persistence of fetal cells in the maternal circulation may play a role in the pathogenesis of PBC. However, existing data from clinical investigations are quite disparate on this issue (Corpechot et al., 2000a; Schoniger-Hekele

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et al., 2002). The association between oral contraceptive use and PBC is weak, but recent data suggest that current or prior use of hormone replacement therapy is observed at higher than expected rates in patients with PBC compared to unaffected controls (Parikh-Patel et al., 2001). Less well investigated are the impact of diet and lifestyle. Past smoking history was observed in 76% of patients with PBC surveyed in one series from the United Kingdom, compared to 57% of unaffected controls (Howel et al., 2000). A greater than 20 pack-year history of smoking was associated with even a higher prevalence rate of PBC. Such an association is biologically plausible, as toxic compounds found in cigarette smoke activate T lymphocyte cytokine responses that could play a role in the pathogenesis of PBC. The older literature reports a higher frequency of extrahepatic autoimmune diseases among patients with PBC supports the autoimmune basis of the condition (Culp et al., 1982). However, studies documenting prevalence rates for speciﬁc associations have reported divergent data. Both rheumatoid arthritis and thyroid disease were reported as often in PBC as in unaffected controls in one series, whereas the risk of Sjo¨gren syndrome and Raynaud’s phenomenon was approximately fourfold higher (Watt et al., 2004). Classic rheumatoid arthritis develops in 5–10% of patients and approximately 40–65% have symptoms of Sjo¨gren syndrome, including keratoconjunctivitis and/or xerostomia. Clonal expansion of T cells bearing a speciﬁc beta chain variable region (TCRBV3) has been demonstrated in some of these patients, suggesting that patients with PBC and CREST may have a distinct disorder (Mayo et al., 1999). The signiﬁcance of systemic lupus erythematosus (SLE) as risk factor for PBC was also recently conﬁrmed by multivariate analysis (Watt et al., 2004). These associations further support the hypothesis of genetic susceptibility as a predisposing factor for PBC.

4. Clinical presentations PBC is diagnosed much earlier now than previously. Nearly 60% are asymptomatic at diagnosis and underlying liver disease is often identiﬁed just by an elevation in serum ALP in an asymptomatic

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individual. This may be accompanied by two- to fourfold rise in serum aminotranferases levels (Prince et al., 2004). Fatigue and pruritus are the most common presenting complaints (Witt-Sullivan et al., 1990). Fatigue itself has been a reported complaint in up to 78% of patients and can be a cause for signiﬁcant disability (Forton et al., 2005). The cause of this fatigue, which is not refreshed by sleep, remains elusive. Recent data suggest a possible association between the fatigue of PBC with altered autonomic control and daytime somnolence (Newton et al., 2006). It is not necessarily improved by liver transplantation (Goldblatt et al., 2002) and is not associated with liver disease severity (Cauch-Dudek et al., 1998). The pruritus of PBC, whether local or diffuse, can also be severely distressing at times. It may interfere with sleep, as it is usually worst at night. Its onset often precedes the onset of jaundice and lessens with progression of the disease! The precise mechanism that promotes pruritus in chronic cholestasis remains uncertain, but as partial biliary diversion and plasmapheresis alleviate this symptom the pruritigen is obviously present in both bile and blood (Ng et al., 2000; Cohen et al., 1985). Unexplained intermittent right upper quadrant pain is noted in approximately 10% of patients. The severity of liver disease may be discordant from the severity of symptoms. Overt symptomatic disease develops within 2–4 years in the majority of initially asymptomatic patients, although nearly one-third of patients will remain symptom-free for many years (Prince et al., 2004). Additional ﬁndings in PBC include hyperlipidemia, hypothyroidism, metabolic bone disease (with advanced liver disease), and coexisting autoimmune disease such as Sjo¨gren’s syndrome and scleroderma (Watt et al., 2004). Portal hypertension and related complications may occur early in the course of illness due to obliteration of the portal venous radicals probably secondary to the inﬂammatory response within the portal triads causing nodular regeneration hyperplasia (Colina et al., 1992). Once cirrhotic, patients present with ascites, hepatic encephalopathy, and/or esophageal variceal hemorrhage. Fat-soluble vitamin deﬁciency, malabsorption, and steatorrhea occur only once jaundice is present. With longstanding,

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histologically advanced PBC, the risk of hepatocellular carcinoma is signiﬁcantly elevated (Nijhawan et al., 1999). The physical examination is usually normal in patients with asymptomatic PBC. As in all chronic cholestatic diseases increased melanin pigmentation of the skin develops with time, made worse by chronic excoriation caused by pruritus. Xanthelasma are seen in a minority of patients, and xanthomas are rare. Hepatosplenomegaly is another feature predominant in a few. Jaundice is now rarely noted (likely due to current therapy), but ascites and edema suggest onset of liver failure (Prince et al., 2002). Histologically, PBC is divided into four distinct stages. However, the liver is not always uniformly involved, and a single biopsy may demonstrate the presence of all four stages simultaneously. The characteristic lesion of PBC is the asymmetric destruction of the bile ducts within portal triads. Stage 1 is deﬁned by portal inﬂammation. Stage 2 is deﬁned by extension of this inﬂammation beyond portal tracts into the surrounding parenchyma with or without associated duct loss. In stage 3, ﬁbrous septa link adjacent portal triads. Stage 4 represents end-stage liver disease, characterized by frank cirrhosis within regenerative nodules. The diagnosis of PBC is, therefore, based on a constellation of ﬁndings. Current criteria require the presence of detectable AMA, abnormal liver enzymes (mostly alkaline phosphatase) for more than 6 months, and histological ﬁndings in the liver that are compatible with the PBC to make a ‘deﬁnite’ diagnosis. A ‘possible’ diagnosis is made if any two of these ﬁndings are present. Liver biopsy allows the severity of disease to be clariﬁed and may indicate the need for speciﬁc therapeutic regimens. As many as 10% of patients are AMA negative, but their disease course seems identical to that in patients with classic PBC (Michieletti et al., 1994) (Table 1).

5. Natural history and prognostic considerations Historically, the ﬁrst case descriptions of PBC were almost uniformly described in patients who

Table 1 AMA-negative PBC vs. AMA-positive PBC Clinical picture

AMA negative (17)

AMA positive (17)

Female:male Age at diagnosis (mean) Jaundice Fatigue Pruritus Hypothyroidism Polyarthralgias Sicca syndrome Raynaud’s

14:3 51.1 3 8 9 3 5 3 2

14:3 55.0 3 7 11 3 3 7 4

Michieletti et al. (1994).

had presented with jaundice with or without endstage liver disease. Access to routine screening of liver chemistries has since generated a large cohort of asymptomatic patients. Asymptomatic PBC accounts for over 60% of newly diagnosed cases (Prince et al., 2002). In a population-based cohort of 469 patients with asymptomatic PBC, the cumulative 1-year incidence rates for developing fatigue, pruritus, and complications from portal hypertension were 15, 13, and 5%, respectively (Prince et al., 2004). However, 10 years later, only 20% continued to remain asymptomatic. Despite reﬁned diagnostic and clinical tools, unfortunately not all patients with PBC receive their diagnosis when the disease is still in an early histological stage. In a study of 262 patients with PBC, the probability of succumbing to liver failure or requiring a liver transplant in those with advanced disease, as compared with a healthy ageand sex-matched population, was signiﬁcantly increased despite UDCA therapy (relative risk 2.2) (Corpechot et al., 2005). In a large cohort of 770 patients from northern England, the median time until death or liver transplant referral was only 9.3 years (Prince et al., 2002). Patients who were asymptomatic at diagnosis did not live longer than their symptomatic counterparts in stark contrast to other studies ascribing a clear survival advantage to those with early and asymptomatic disease (Pares et al., 2000). This difference is likely related to age—the cohort from the studies in the north of England being at least one decade older at the time of initial diagnosis. Of note, there

Primary Biliary Cirrhosis

is no distinguishing feature that helps predict which patients will remain asymptomatic indeﬁnitely (Springer et al., 1999). Neither the presence nor the AMA titer affects risk of disease progression, survival, or treatment responsiveness (Van Norstrand et al., 1997). But recent data suggest that presence of anti-gp210 antibodies, and particularly when in high titer, may predict those patients with poor outcome (Nakamura et al., 2007). Prospective cohort studies with long followup periods and serial clinical, biochemical, and histological data will prove invaluable in unraveling markers of disease progression in PBC. For symptomatic PBC, advanced age, elevated INR, jaundice, low serum albumin, edema, ascites, and advanced histological stage are strongly correlated with median survival rates less than 5 years from the time of diagnosis. Serum total bilirubin remains the most reliable clinical variable for survival estimates and is a key component in current mathematical predictive models of PBC (Dickson et al., 1989). Liver failure remains the predominant cause of death in patients with PBC. A 60% mortality from liver-related causes is reported in symptomatic patients (Prince et al., 2002). Thirty percent of initially asymptomatic patients will succumb to liver failure as well (Prince et al., 2004). Such numbers, however, are derived from studies in large tertiary referral centers prior to the widespread use of UDCA, and thus ﬁndings may not reﬂect the more current and contemporary experience of PBC therapy. Liver failure has been described in patients without cirrhosis but with severe cholestasis and marked ductopenia (Vleggaar et al., 2001). Non-liver-related mortality risk is nearly doubled in patients with asymptomatic disease (Prince et al., 2002), an observation that may stem from a surveillance bias during the evaluation of more signiﬁcant medical comorbidities, although cigarette smoking is more common in patients with PBC than the general population (Parikh-Patel et al., 2001).

6. Treatment considerations The Food and Drug administration has approved UDCA at 13–15 mg/kg body weight as the

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preferred pharmacological agent of choice for the treatment of PBC. UDCA is an epimer of chenodeoxycholic acid, and comprises 2% of human bile acids. It functions as a choleretic agent. It decreases serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, cholesterol, and IgM. In a study that combined data from three controlled trials, UDCA 13–15 mg/kg/day was found to decrease likelihood of liver transplantation and death after 4 years (Poupon et al., 1997). However, the clinical use and therapeutic beneﬁts of UDCA in PBC remain controversial. Two separate meta-analyses highlighted no clear survival difference between UDCA-treated and placebo-treated patients (Goulis et al., 1999; Gong et al., 2007). However, the surveyed randomized trials had questionable validity, as marked differences in follow-up periods and UDCA doses (at times suboptimal) may have ﬂawed the results. However, no difference was observed even if shortduration trials were analyzed separately than longer-duration ones. A third meta-analysis featuring data from more methodologically sound trials demonstrated that the risk of death and liver transplantation was 32% lower in the UDCAtreated group (Corpechot et al., 2005), but the most recent meta-analysis of randomized clinical trials using Bayesian approach indicated no beneﬁt of UDCA on morbidity, mortality, and need for liver transplantation (Gong et al., 2007). The life expectancy of patients treated with and responding to UDCA was similar to that of age- and sexmatched healthy controls for up to 20 years in another survey; nevertheless, detailed histological studies indicate that UDCA slows disease progression particularly in those with early-stage histological involvement (Angulo et al., 1999; Corpechot et al., 2000b), but no disease regression is observed. The last three decades have seen a variety of adjuvant medications that have been used alone or in combination with UDCA in patients with an incomplete response to UDCA monotherapy. These include systemic corticosteroids, budesonide, azathioprine, mycophenolate mofetil, methotrexate, colchicine, silymarin, and bezaﬁbrate. Neither the larger trials nor the pilot studies have indicated any survival beneﬁt from their agents. Now that serum bilirubin levels remain normal for

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so many years there is no surrogate marker available as an indirect measure of outcome. Hence, therapeutic trials in early PBC are very difﬁcult to conduct as patients are intolerant of prolonged trials and the costs of running same are prohibitive. At the present time, UDCA in combination with various other adjuvant products is not recommended outside of research protocols.

7. Conclusion There is still ongoing debate about the pathophysiology of PBC since its original description in 1851. With the advent of sensitive diagnostic and research tools, it has become a liver disease, which is wellrecognized worldwide; thus, the majority of patients are now diagnosed at an early asymptomatic stage. Epidemiological data indicate that geographic clustering occurs, implicating both genetic and environmental inﬂuences in its pathogenesis. Given a genetically primed host both xenobiotics and viral infections could promote the development of PBC. The recent description of mice models for PBC is exciting and will surely guide further genetic research. The pathophysiological basis of PBC seems to lie in the demonstrated defects in immune tolerance that results in the activation and expansion of self-antigen-speciﬁc T and B lymphocyte clones and the production of circulating autoantibodies, cytokines, and other inﬂammatory mediators. Larger prospective cohort studies with longitudinal clinical, serological, genetical, and histological data will prove invaluable in unraveling new associations, and perhaps highlighting markers of disease progression. The true impact of UDCA on disease course and natural history needs more deﬁnitive scrutiny. Its inadequate efﬁcacy in causing disease regression gives impetus to further studies of the pathogenetic mechanisms of the disease and drives the endless search for new therapies.

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Newton, J.L., Gibson, G.J., Tomlinson, M., Wilton, K., Jones, D. 2006. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology 44 (1), 91–98. Ng, V.L., Ryckman, F.C., Porta, G., Miura, I.K., de Carvalho, E., Servidoni, M.F., Bezerra, J.A., Balistreri, W.F. 2000. Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis. J. Pediatr. Gastroenterol. Nutr. 30 (2), 152–156. Nijhawan, P.K., Therneau, T.M., Dickson, E.R., Boynton, J., Lindor, K.D. 1999. Incidence of cancer in primary biliary cirrhosis: the Mayo experience. Hepatology 29 (5), 1396–1398. Odin, J.A., Huebert, R.C., Casciola-Rosen, L., LaRusso, N.F., Rosen, A. 2001. Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J. Clin. Invest. 108 (2), 223–232. Oertelt, S., Lian, Z.X., Cheng, C.M., Chuang, Y.H., Padgett, K.A., He, X.S., Ridgway, W.M., Ansari, A.A., Coppel, R.L., Li, M.O., Flavell, R.A., Kronenberg, M., Mackay, I.R., Gershwin, M.E. 2006. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J. Immunol. 177 (3), 1655–1660. Ohba, K., Omagari, K., Kinoshita, H., Soda, H., Masuda, J., Hazama, H., Tagawa, M., Hata, T., Nakamura, H., Murata, I., Kohno, S. 2001. Primary biliary cirrhosis among atomic bomb survivors in Nagasaki, Japan. J. Clin. Epidemiol. 54 (8), 845–850. Omenetti, A., Yang, L., Li, Y.X., McCall, S.J., Jung, Y., Sicklick, J.K., Huang, J., Choi, S., Suzuki, A., Diehl, A.M. 2007. Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation. Lab. Invest. 87 (5), 499–514. Palmer, J.M., Diamond, A.G., Yeaman, S.J., Bassendine, M.F., Jones, D.E. 1999. T cell responses to the putative dominant autoepitope in primary biliary cirrhosis (PBC). Clin. Exp. Immunol. 116 (1), 133–139. Pares, A., Caballeria, L., Rodes, J., Bruguera, M., Rodrigo, L., Garcia-Plaza, A., Berenguer, J., Rodriguez-Martinez, D., Mercader, J., Velicia, R. 2000. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCACooperative Group from the Spanish Association for the Study of the Liver. J. Hepatol. 32 (4), 561–566. Parikh-Patel, A., Gold, E.B., Worman, H., Krivy, K.E., Gershwin, M.E. 2001. Risk factors for primary biliary cirrhosis in a cohort of patients from the United States. Hepatology 33 (1), 16–21. Poupon, R.E., Lindor, K.D., Cauch-Dudek, K., Dickson, E.R., Poupon, R., Heathcote, E.J. 1997. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 113 (3), 884–890. Prince, M.I., Chetwynd, A., Newman, W., Metcalf, J.V., James, O.F. 2002. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 123 (4), 1044–1051.

Prince, M.I., Chetwynd, A., Craig, W.L., Metcalf, J.V., James, O.F. 2004. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut. 53 (6), 865–870. Erratum in: Gut. 2004; 53(8), 1216. Reynoso-Paz, S., Leung, P.S., Van De Water, J., Tanaka, A., Munoz, S., Bass, N., Lindor, K., Donald, P.J., Coppel, R.L., Ansari, A.A., Gershwin, M.E. 2000. Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis. Hepatology 31 (1), 24–29. Schoniger-Hekele, M., Muller, C., Ackermann, J., Drach, J., Wrba, F., Penner, E., Ferenci, P. 2002. Lack of evidence for involvement of fetal microchimerism in pathogenesis of primary biliary cirrhosis. Dig. Dis. Sci. 47 (9), 1909–1914. Selmi, C., Gershwin, M.E. 2004. Bacteria and human autoimmunity: the case of primary biliary cirrhosis. Curr. Opin. Rheumatol. 16 (4), 406–410. Sicklick, J.K., Li, Y.X., Melhem, A., Schmelzer, E., Zdanowicz, M., Huang, J., Caballero, M., Fair, J.H., Ludlow, J.W., McClelland, R.E., Reid, L.M., Diehl, A.M. 2006. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am. J. Physiol. Gastrointest. Liver Physiol. 290 (5), G859–G870. Sood, S., Gow, P.J., Christie, J.M., Angus, P.W. 2004. Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations. Gastroenterology 127 (2), 470–475. Springer, J., Cauch-Dudek, K., O’Rourke, K., Wanless, I.R., Heathcote, E.J. 1999. Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis. Am. J. Gastroenterol. 94 (1), 47–53. Tanaka, A., Nalbandian, G., Leung, P.S., Benson, G.D., Munoz, S., Findor, J.A., Branch, A.D., Coppel, R.L., Ansari, A.A., Gershwin, M.E. 2000. Mucosal immunity and primary biliary cirrhosis: presence of antimitochondrial antibodies in urine. Hepatology 32 (5), 910–915. Tsuji, K., Watanabe, Y., Van De Water, J., Nakanishi, T., Kajiyama, G., Parikh-Patel, A., Coppel, R., Gershwin, M.E. 1999. Familial primary biliary cirrhosis in Hiroshima. J. Autoimmun. 13 (1), 171–178. Van Norstrand, M.D., Malinchoc, M., Lindor, K.D., Therneau, T.M., Gershwin, M.E., Leung, P.S., Dickson, E.R., Homburger, H.A. 1997. Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression. Hepatology 25 (1), 6–11. Vleggaar, F.P., van Buuren, H.R., Zondervan, P.E., ten Kate, F.J., Hop, W.C. 2001. Dutch Multicentre PBC study group. Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant. Gut. 49 (2), 276–281. Wakabayashi, K., Lian, Z.X., Moritoki, Y., Lan, R.Y., Tsuneyama, K., Chuang, Y.H., Yang, G.X., Ridgway, W., Ueno, Y., Ansari, A.A., Coppel, R.L., Mackay, I.R.,

Primary Biliary Cirrhosis Gershwin, I.R. 2006. IL-2 receptor alpha( / ) mice and the development of primary biliary cirrhosis. Hepatology 44 (5), 1240–1249. Watt, F.E., James, O.F., Jones, D.E. 2004. Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. QJM 97 (7), 397–406.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 13

Autoimmune Hepatitis Diego Vergani, Giorgina Mieli-Vergani Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London SE5 9RS, UK

1. Deﬁnition Autoimmune hepatitis (AIH) is a progressive inﬂammatory liver disorder, preferentially affecting females, characterized histologically by interface hepatitis (Fig. 1), and serologically by high levels of transaminases and immunoglobulin G (IgG) and presence of autoantibodies, in the absence of a known aetiology. AIH is divided into two main types according to the autoantibody proﬁle: type 1 is positive for anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA); type 2 is positive for anti-liver/kidney microsomal type 1 antibody (anti-LKM-1). AIH responds satisfactorily to immunosuppressive treatment.

the efﬁcacy of immunosuppression was established, untreated severe AIH had a mortality of 50% at 5 years and 90% at 10 years (Soloway et al., 1972; Murray-Lyon et al., 1973). The prevalence of

2. History and epidemiology AIH is a recently recognized disease having been ﬁrst described by Waldenstrom in 1950. Seropositivity for ANA, the hallmark of systemic lupus erythematosus, led Mackay to call it ‘lupoid hepatitis’ (Mackay et al., 1956), a term no longer used. Since the disease frequently presents acutely, similarly obsolete is the term ‘chronic active hepatitis’, which implied that the disease should be chronic, i.e. of at least six months duration, before institution of immunosuppression. Before Corresponding author.

Tel.:+44-(0)-20-3299-3305; Fax:+44-(0)-20-3299-3700 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00013-X

Figure 1. Portal and periportal lymphocyte and plasma cell inﬁltrate, extending to and disrupting the parenchymal limiting plate (interface hepatitis). Swollen hepatocytes, pyknotic necroses and acinar inﬂammation are present. Haematoxylin and eosin staining. (Picture kindly provided by Dr. Alberto Quaglia.) (See Colour Plate Section.)

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AIH is unknown. Prevalences varying from 1/200,000 in the US general population (Manns et al., 1998) to 20/100,000 in females over 14 years of age in Spain (Primo et al., 2004) have been reported, though probably both ﬁgures are underestimates.

3. Clinical features The diagnosis of AIH is based on the presence of positive autoantibodies, elevated transaminase and IgG levels, and interface hepatitis on liver biopsy. The latter is required to conﬁrm the diagnosis and to evaluate the severity of liver damage. The levels of transaminases and of IgG do not reﬂect the extent of the histological inﬂammatory activity, nor indicate presence or absence of cirrhosis. Other hepatic disorders that may share some of the above features need to be considered in the differential diagnosis. These include viral hepatitides (in particular B and C), Wilson disease and drug-induced liver disease (minocycline, nitrofurantoin, isoniazid, propylthiouracil, diclofenac, pemoline, atovastatin and alpha-methyldopa). Female patients outnumber male patients (3:1). A family history of autoimmune diseases is present in some 40% of the patients. Associated autoimmune disorders are present at diagnosis or develop during follow-up in at least one-ﬁfth of the patients and include thyroiditis, ulcerative colitis, insulindependent diabetes, vitiligo, nephrotic syndrome, hypoparathyroidism and Addison’s disease, the last two being observed in particular in antiLKM-1 positive patients or in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder with a variable phenotype that includes AIH in some 20% of the cases. Typically, AIH responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. The onset of AIH is often ill deﬁned, and it frequently mimics acute hepatitis, particularly in young patients. Two main types of AIH are recognized, according to the presence of SMA and/or ANA or anti-LKM-1 (Fig. 2). Major targets of SMA are the microﬁlaments (MFs) of smooth muscle, whereas the

molecular target of anti-LKM-1 is cytochrome P4502D6 (CYP2D6). The distinction in type 1 and type 2 AIH is particularly relevant in paediatrics, since anti-LKM-1 positive disease is quite rare, but not absent, in adults. In paediatrics, anti-LKM-1 positive AIH represents one-third of all cases and has a clinical course similar to ANA/SMA-positive AIH, though anti-LKM-1 positive children present at a younger age, more often with an acute onset, including fulminant hepatitis, and have associated IgA deﬁciency (Gregorio et al., 1997). There are three main patterns of disease presentation: an acute onset, characterized by non-speciﬁc symptoms of malaise, nausea/vomiting, anorexia, and abdominal pain, followed by jaundice, dark urine, and pale stools; an insidious onset, with an illness characterized by progressive fatigue, relapsing jaundice, headache, anorexia, and weight loss; and ﬁnally a presentation with complications of portal hypertension, such as haematemesis from oesophageal varices, bleeding diathesis, chronic diarrhoea, weight loss, and vomiting. The mode of presentation of AIH is therefore variable, and the disease should be suspected and excluded in all patients presenting with symptoms and signs of prolonged or severe liver disease. Some patients, however, are completely asymptomatic and are diagnosed after incidental discovery of abnormal liver function tests. The course of disease can be ﬂuctuating, with ﬂares and spontaneous remissions, a pattern which may result in delayed referral and diagnosis. The majority of the patients, however, on physical examination have clinical signs of an underlying chronic liver disease, i.e. cutaneous stigmata (spider nevi, palmar erythema, leukonikia, striae), ﬁrm liver and splenomegaly; at ultrasound the liver parenchyma is often nodular and heterogenous.

4. Diagnosis and laboratory ﬁndings Diagnosis of AIH is based on a series of positive and negative criteria (Johnson and McFarlane, 1993; Alvarez et al., 1999). Liver biopsy is necessary to establish the diagnosis, the typical histological picture including the following: a dense

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SMA

ANA

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LKM

Figure 2. Immunoﬂuorescence appearance of smooth muscle (SMA), anti-nuclear (ANA) and anti-liver/kidney microsomal type 1 (anti-LKM-1) autoantibodies on renal and liver rodent sections. SMA stains the small artery and the glomeruli in a renal section, ANA the nuclei in a liver section and anti-LKM-1 the cytoplasm of hepatocytes and proximal renal tubules. SMA and/or ANA are the markers of autoimmune hepatitis type 1: Their molecular targets are still unknown. Anti-LKM-1 characterizes autoimmune hepatitis type 2 and its target is cytochrome P4502D6. (See Colour Plate Section.)

mononuclear and plasma cell inﬁltration of the portal areas, which expands into the liver lobule; destruction of the hepatocytes at the periphery of the lobule with erosion of the limiting plate (‘interface hepatitis’); connective tissue collapse resulting from hepatocytes death and expanding from the portal area into the lobule (‘bridging collapse’); and hepatic regeneration with ‘rosette’ formation (Fig. 1). In addition to the typical histology, other positive criteria include elevated serum transaminase and IgG/gammaglobulin levels, and presence of ANA, SMA or anti-LKM-1. The diagnosis of AIH has been advanced by the criteria developed by the International Autoimmune Hepatitis Group (IAIHG) (Johnson and McFarlane, 1993; Vergani et al., 2004), where negative criteria such as evidence of infection with hepatitis B or C virus or Wilson disease, alcohol, etc are taken into account in addition to the positive criteria mentioned above. IAIHG has provided a scoring system for the diagnosis of AIH, mainly used for research purposes (Table 1).

4.1. Autoantibodies A key component of the criteria developed by the IAIHG (Johnson and McFarlane, 1993; Alvarez et al., 1999; Vergani et al., 2004) is detection by indirect immunoﬂuorescence of autoantibodies to constituents of the nuclei (ANA), smooth muscle (SMA) and liver kidney microsome type 1 (antiLKM-1). Autoantibody detection not only assists in the diagnosis, but also allows differentiation of AIH types. ANA and SMA that characterize type 1 AIH and anti-LKM-1 that deﬁnes type 2 AIH are practically mutually exclusive; in those rare instances when they are present simultaneously, the clinical course is similar to that of AIH type 2. Recognition and interpretation of the immunoﬂuorescence patterns is not always straightforward (Vergani et al., 2004). The operator dependency of the technique and the relative rarity of AIH explain the non-infrequent occurrence of errors in reporting, particularly of less frequent speciﬁcities such as anti-LKM-1. Problems do exist

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Table 1 IAIHG scoring system for the diagnosis of autoimmune hepatitis Parameter Principal parameters Sex ALP:AST (or ALT) ratio

Serum globulins or IgG (times above normal)

ANA, SMA or anti-LKM-1 titresa

AMA Viral markers of active infection Hepatotoxic drug history Average alcohol Histological features

Optional additional parameters Seropositivity for other deﬁned autoantibodies HLA Response to therapy Interpretation of aggregate scores Pre-treatment Deﬁnite AIH Probable AIH Post treatment Deﬁnite AIH Probable AIH

Feature

Score

Female W3 1.5–3 o1.5 W2.0 1.5–2.0 1.0–1.5 o1.0 W1:80 1:80 1:40 o1:40 Positive Positive Negative Yes No o25 g/day W60 g/day Interface hepatitis Plasma cells Rosettes None of above Biliary changesb Atypical changesc

+2 2 0 +2 +3 +2 +1 0 +3 +2 +1 0 4 3 +3 4 +1 +2 2 +3 +1 +1 5 3 3

Anti-SLA/LP, actin, LC1, ASGPR, pANCA DR3 or DR4 Remission Relapse

+2 +1 +2 +3

W15 10–15 W17 12–17

IAIHG, International Autoimmune Hepatitis Group; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IgG, immunoglobulin G; ANA, antinuclear antibody; SMA, smooth muscle antibody; LKM-1, liver kidney microsomal antibody type 1; AMA, anti-mitochondrial antibody; SLA/LP, soluble liver antigen/liver pancreas; LC1, liver cytosol type 1; ASGPR, asialoglycoprotein receptor; pANCA, perinuclear anti-neutrophil cytoplasmic antibody; HLA, human leukocyte antigen; AIH, autoimmune hepatitis. a In children, signiﬁcant titres are 1:20 for ANA and SMA, and 1:10 for anti-LKM-1. b Including granulomatous cholangitis, concentric periductal ﬁbrosis, ductopaenia, marginal bile duct proliferation with cholangiolitis. c Any other prominent feature suggesting a different aetiology. Modiﬁed from Alvarez et al. (1999).

between laboratory reporting and clinical interpretation of the results that are partly dependent on insufﬁcient standardization of the tests, but also partly dependent on a degree of unfamiliarity of some clinicians with the disease spectrum of AIH. With regard to standardization, guidelines have been given by the IAIHG serology committee (Vergani et al., 2004). The basic technique for the routine testing of autoantibodies relevant to AIH is indirect immunoﬂuorescence on a freshly prepared rodent substrate that should include kidney, liver and stomach to allow the detection of ANA, SMA, anti-LKM-1 as well as anti-liver cytosol type 1 (anti-LC-1), but also of anti-mitochondrial antibody (AMA), the serological hallmark of primary biliary cirrhosis. Commercially available sections are of variable quality because, to lengthen shelf-life, they are treated with ﬁxatives (acetone, ethanol or methanol), which readily result in enhanced background staining that may hinder the recognition of diagnostic autoantibodies, especially when these are present at low titre. Since healthy adults may show reactivity at the conventional starting serum dilution of 1/10, the arbitrary dilution of 1/40 has been considered clinically signiﬁcant by the IAIHG. In contrast, in healthy children, autoantibody reactivity is infrequent, so that titres of 1/20 for ANA and SMA and 1/10 for anti-LKM-1 are clinically relevant. Positive sera should be titrated to extinction. The laboratory should report any level of positivity from 1/10 in children to 1/40 in adults, and the attending physician should interpret the result within the clinical context. ANA is readily detectable as a nuclear staining in kidney, stomach and liver. On the liver, in particular, the ANA pattern may be detected as homogeneous, or coarsely or ﬁnely speckled. In most cases of AIH, but not in all, the pattern is homogeneous. To obtain a much clearer and easier deﬁnition of the nuclear pattern, HEp2 cells that have prominent nuclei should be used. HEp2 cells, however, should not be used for screening purposes, because nuclear reactivity to these cells is frequent at low serum dilution (1/40) in the normal population (Tan et al., 1997). For ANA, likely molecular targets include nuclear chromatin and

Autoimmune Hepatitis

histones, akin to lupus, but there are probably several others. The advent of new techniques using recombinant nuclear antigens and immunoassays will enable a better deﬁnition of ANA target antigens, an assessment of their speciﬁcity for diagnosis and their possible role in the pathogenesis of AIH type 1. SMA is detected on kidney, stomach and liver, where it stains the walls of the arteries. In the stomach it also stains the muscularis mucosa and the lamina propria. On the renal substrate, it is possible to visualize the V, G and T patterns; V refers to vessels, G to glomeruli, and T to tubules (Bottazzo et al., 1976). The V pattern is present also in non-autoimmune inﬂammatory liver disease, in autoimmune diseases not affecting the liver and in viral infections, but the VG and VGT patterns are more speciﬁc for AIH. The VGT pattern corresponds to the so-called F actin or MF pattern observed using cultured ﬁbroblasts as substrate. Neither the VGT nor the anti-MF patterns are, however, entirely speciﬁc for the diagnosis of AIH type 1. Though the VGT-MF pattern has been suggested to be due to a speciﬁc antibody uniquely found in AIH type 1, it may just reﬂect high-titre SMA. The molecular target of the MF reactivity that is observed in AIH type 1 remains to be identiﬁed. Though ‘anti-actin’ reactivity is strongly associated with AIH type 1, some 20% of SMA-positive AIH type 1 patients do not have the F-actin/VGT pattern. The absence, therefore, of anti-actin SMA does not exclude the diagnosis of AIH (Muratori et al., 2002). Anti-LKM-1 stains brightly the liver cell cytoplasm and the P3 portion of the renal tubules, but does not stain gastric parietal cells. Anti-LKM-1 is often confused with AMA, since both autoantibodies stain liver and kidney. Compared to antiLKM-1, AMA stains the liver more faintly and the renal tubules more diffusely with an accentuation of the small distal ones. In contrast to anti-LKM-1, AMA also stains the gastric parietal cells. In the context of AIH, there can be positivity for AMA in rare cases (Gregorio et al., 1997). The identiﬁcation of the molecular targets of anti-LKM-1, i.e. cytochrome P4502D6 (CYP2D6), and of AMA, i.e. enzymes of the 2-oxo-acid dehydrogenase

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complexes, has led to the establishment of immunoassays based on the use of the recombinant or puriﬁed antigens (Vergani et al., 2004). Commercially available ELISAs are accurate for detection of anti-LKM-1, at least in the context of AIH type 2, and reasonably accurate for the detection of AMA. Therefore, if a doubt remains after examination by immunoﬂuorescence, this can be resolved by the use of molecularly based immunoassays. Other autoantibodies less commonly tested but of diagnostic importance include anti-LC-1, anti– neutrophil cytoplasm antibody (ANCA) and soluble liver antigen (SLA). Anti-LC-1, which can be present on its own, but frequently occurs in association with anti-LKM-1, is an additional marker for AIH type 2 and targets formiminotransferase cyclodeaminase (FTCD) (Lapierre et al., 1999). ANCA can also be positive in AIH (Gregorio et al., 1997; Vergani et al., 2004). There are three types of ANCA, namely cytoplasmic (cANCA), perinuclear (pANCA) and atypical perinuclear, the target of which is a peripheral nuclear and not cytoplasmic perinuclear antigen (hence the suggested name of pANNA, i.e. peripheral anti-nuclear neutrophil antibody). The type found in AIH type 1 is pANNA, which is also found in inﬂammatory bowel disease and sclerosing cholangitis, while it is virtually absent in type 2 AIH. Anti-SLA that was originally described as the hallmark of a third type of AIH in humans (Manns et al., 1987) is also found in some 50% of patients with type 1 and type 2 AIH, where it deﬁnes a more severe course (Ma et al., 2002). Screening of cDNA expression libraries using high-titre antiSLA serum has allowed to identify the molecular target antigen as UGA tRNA suppressor associated antigenic protein (tRNP(Ser)Sec) (Wies et al., 2000; Costa et al., 2000). Molecularly based diagnostic assays have become available, but their full evaluation is still under way. After assessment of all the speciﬁcities described above, there is a small proportion of patients with AIH without detectable autoantibodies. This condition, which responds to immunosuppression like the seropositive form, represents seronegative AIH, and its prevalence and clinical characteristics remain to be deﬁned.

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5. Pathophysiology 5.1. Genetics AIH is a ‘complex trait’ disease, i.e. a condition not inherited in a Mendelian autosomal dominant, autosomal recessive or sex-linked fashion. The mode of inheritance of a complex trait disorder is unknown and involves one or more genes, operating alone or in concert, to increase or reduce the risk of the trait, and interacting with environmental factors. Susceptibility to AIH is imparted by genes within the histocompatibility lymphocyte antigen (HLA) region on the short arm of chromosome 6, especially those encoding DRB1 alleles. These class II major histocompatibility complex (MHC) molecules are involved in peptide antigen presentation to CD4 T cells, suggesting the participation of MHC class II antigen presentation and T cell activation in the pathogenesis of AIH. In Europe and North America, susceptibility to AIH type 1 is conferred by the possession of HLA DR3 (DRB10301) and DR4 (DRB10401), both heterodimers containing a lysine residue at position 71 of the DRB1 polypeptide and the hexameric amino acid sequence LLEQKR at positions 67–72 (Donaldson, 2002, 2004). In Japan, Argentina and Mexico, susceptibility is linked to DRB10405 and DRB10404, alleles encoding arginine rather than lysine at position 71, but sharing the motif LLEQ-R with DRB10401 and DRB10301 (Czaja and Donaldson, 2000). Thus, K or R at position 71 in the context of LLEQ-R may be critical for susceptibility to AIH, favouring the binding of autoantigenic peptides complementary to this hexameric sequence. The lysine-71 and other models for AIH type 1 cannot explain the disease completely, since for example in European and North American patients, presence of lysine-71 is associated with a severe, mainly juvenile, disease in DRB10301positive patients, but with a mild, late-onset, disease in DRB10401-positive patients. Other genes within or/and without the MHC are, therefore, likely to be involved in determining the phenotype. Possible candidates are the MHCencoded complement and tumour necrosis factor

alpha (TNF-a) genes, mapping to the class III MCH region, and the MHC class I chain-related A and B genes. Patients with AIH, whether antiLKM-1 or ANA/SMA positive, have isolated partial deﬁciency of the HLA class III complement component C4, which is genetically determined (Vergani et al., 1985; Doherty et al., 1994). Susceptibility to AIH type 2 is conferred by the possession of HLA DR7 (DRB10701) and DR3 (DRB10301), patients positive for DRB10701 having a more aggressive disease and severe prognosis (Ma et al., 2006). A form of AIH resembling AIH type 2 affects some 20% of patients with APECED, a condition also known as autoimmune polyendocrine syndrome 1. APECED is a monogenic autosomal recessive disorder caused by homozygous mutations in the AIRE1 gene and characterized by a variety of organ-speciﬁc autoimmune diseases, the most common of which are hypoparathyroidism and primary adrenocortical failure, accompanied by chronic mucocutaneous candidiasis (Simmonds and Gough, 2004; Liston et al., 2005). The AIRE1 gene sequence consists of 14 exons containing 45 different mutations, with a 13 bp deletion at nucleotide 964 in exon 8 accounting for more than 70% of APECED alleles in the UK (Simmonds and Gough, 2004). The protein predicted to be encoded by AIRE1 is a transcription factor. AIRE1 is highly expressed in medullary epithelial cells and other stromal cells in the thymus involved in clonal deletion of self-reactive T cells. Studies in a murine model indicate that the gene inhibits organ-speciﬁc autoimmunity by inducing thymic expression of peripheral antigens in the medulla leading to central deletion of autoreactive T cells. Interestingly, APECED has a high level of variability in symptoms, especially between populations. Since various gene mutations have the same effect on thymic transcription of ectopic genes in animal models, it is likely that the clinical variability across human populations relates to environmental or genetic modiﬁers. Of the various genetic modiﬁers, perhaps the most likely to synergize with AIRE mutations are polymorphisms in the HLA region. HLA molecules are not only highly variable and strongly associated with multiple autoimmune diseases, but are also able to affect thymic

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repertoire selection of autoreactive T cell clones. Carriers of a single AIRE mutation do not develop APECED. However, although the inheritance pattern of APECED indicates a strictly recessive disorder, there are anecdotal data of mutations in a single copy of AIRE being associated with human autoimmunity of a less severe form than classically deﬁned APECED (Simmonds and Gough, 2004; Liston et al., 2005). The role of AIRE1 heterozygote state in the development of AIH remains to be established.

5.2. Immune mechanisms The typical histological picture of AIH, interface hepatitis, is characterized by a dense mononuclear cell inﬁltrate eroding the limiting plate and invading the parenchyma (De Groote et al., 1968; Scheuer, 1973). Immunocytochemical studies have identiﬁed the phenotype of the inﬁltrating cells. T lymphocytes mounting the alpha/beta T-cell receptor predominate. Among the T cells, a majority are positive for the CD4 helper/inducer phenotype, and a sizable minority are positive for the CD8 cytotoxic phenotype. Lymphocytes of non–T-cell lineage are fewer and include (in decreasing order of frequency) natural killer cells (CD16/CD56 positive), macrophages and B lymphocytes (Senaldi et al., 1992). The recently described natural killer T cells, which express simultaneously markers of both natural killer (CD56) and T cells (CD3), are involved in liver damage in an animal model of AIH (Takeda et al., 2000). A powerful stimulus must be promoting the formation of the massive inﬂammatory cell inﬁltrate present at diagnosis. Whatever the initial trigger, it is most probable that such a high number of activated inﬂammatory cells cause liver damage. There are different possible pathways that an autoimmune attack can follow to inﬂict damage on hepatocytes (Fig. 3). It is believed that liver damage is orchestrated by CD4+ T lymphocytes recognizing a self-antigenic peptide on hepatocytes. To trigger an autoimmune response, the peptide must be embraced by an HLA class II molecule and presented to uncommitted (naı¨ ve) CD4+ T helper (Th0) cells by professional antigen-presenting cells

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(APC), with the co-stimulation of ligand–ligand (CD28+ on Th0, CD80+ on APC) fostering interaction between the two cells. Th0 cells become activated, differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen, and initiate a cascade of immune reactions determined by the cytokines these activated T cells produce. Th1 cells, arising in the presence of the macrophage-produced interleukin 12 (IL-12), secrete mainly IL-2 and interferon gamma (IFN-g), which activate macrophages, enhance expression of HLA class I antigens (increasing liver cell vulnerability to a CD8+ T cell cytotoxic attack) and induce expression of HLA class II molecules on hepatocytes. Th2 cells, which differentiate from Th0 if the microenvironment is rich in IL-4, produce mainly IL-4, IL-10 and IL-13 which favour autoantibody production by B lymphocytes. Physiologically, Th1 and Th2 antagonize each other. Th17 cells, a recently described population (Weaver et al., 2006; Steinman, 2007), arise in the presence of transforming growth factor beta (TGF-b) and IL-6 and appear to have an important effector role in inﬂammation and autoimmunity. The process of autoantigen recognition is strictly controlled by regulatory mechanisms, such as those exerted by CD4+CD25+ regulatory T cells, which are derived from Th0 in the presence of TGF-b, but in the absence of IL-6. If regulatory mechanisms fail, the autoimmune attack is perpetuated. Over the past three decades, different aspects of the above pathogenic scenario have been investigated.

5.2.1. T regulatory cells Autoimmunity arises on the background of defective immunoregulation and this has been repeatedly reported in AIH. Early studies showed that patients with AIH had low levels of circulating T cells expressing the CD8+ marker, and impaired suppressor cell function which segregates with the possession of the disease-predisposing HLA haplotype B08/DRB103 (formerly B8/DR3) and is correctable by therapeutic doses of corticosteroids (Nouri-Aria et al., 1985; Nouri-Aria et al., 1982). It is possible, though not formally tested, that these early characterized CD8+ T cells with a

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IL-17

NK APC Liver cell

Class II Peptide

IL-1

Class I Class II

Co-stimuli

IL-17

Th0

IL-12

TNF-α

Tc

IFN-γ

Tr Th1 IL-2

IL-4 TGF-β

M

IFN-γ

Th2

P

IL-4 IL-10 IL-13

B Th17

IL-6 Figure 3. Autoimmune attack to the liver cell. A speciﬁc autoantigenic peptide is presented to an uncommitted T helper (Th0) lymphocyte within the HLA class II molecule of an antigen-presenting cell (APC). Th0 cells become activated and, according to the presence in the microenvironment of interleukin (IL)-12 or -IL4 and the nature of the antigen, differentiate into Th1 or Th2 and initiate a series of immune reactions determined by the cytokines they produce: Th2 secrete mainly IL-4, IL-10 and IL-13, and direct autoantibody production by B lymphocytes; Th1 secrete IL-2 and IFN-g, which stimulate T cytotoxic (Tc) lymphocytes, enhance expression of class I and induce expression of class II HLA molecules on hepatocytes and activate macrophages; activated macrophages release IL-1 and TNF-a. If T regulatory cells (T-regs) do not oppose, a variety of effector mechanisms are triggered: Liver cell destruction could derive from the action of Tc lymphocytes; cytokines released by Th1 and recruited macrophages; complement activation or engagement of Fc receptor-bearing cells such as natural killer (NK) lymphocytes by the autoantibody bound to the hepatocyte surface. The role of the recently described Th17 cells, which arise in the presence of transforming growth factor beta (TGF-b) and IL-6 is under investigation.

suppressor function represent the recently deﬁned CD8+CD28 suppressor T cells (Cortesini et al., 2001). Furthermore, patients with AIH were shown to have a defect in a subpopulation of T cells controlling the immune response to liver-speciﬁc membrane antigens (Vento et al., 1984). Novel experimental evidence conﬁrms an impairment of the immunoregulatory function in AIH. Amongst recently deﬁned T cell subsets with potential immunosuppressive function, CD4+ T cells constitutively expressing the IL-2 receptor alpha chain (CD25) [T regulatory cells (T-regs)] have emerged

as the dominant immunoregulatory subset of lymphocytes (Shevach et al., 2001). These cells, which represent some 5% of the total population of peripheral CD4+ T cells in health, control innate and adaptive immune responses by preventing proliferation and effector function of autoreactive T cells. In patients with AIH, T-regs are defective in number and function compared to normal controls, and this impairment relates to the stage of disease, being more evident at diagnosis than during drug-induced remission (Longhi et al., 2004; Longhi et al., 2005; Longhi et al., 2006). The

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percentage of T-regs inversely correlates with markers of disease severity, such as anti-SLA and anti-LKM-1 autoantibody titres, suggesting that a reduction in regulatory T cells favours the serological expressions of autoimmune liver disease. If loss of immunoregulation is central to the pathogenesis of AIH, treatment should concentrate on restoring T-regs’ ability to expand, with consequent increase in their number and function. This is at least partially achieved by standard immunosuppression, since numbers of T-regs increase during remission (Longhi et al., 2004, 2005, 2006).

5.2.2. Autoreactive T cells As mentioned above, to trigger an autoimmune response, a peptide embraced by an HLA class II molecule must be presented to uncommitted T helper (Th0) cells by professional APCs (Fig. 3). Given the impaired regulatory function described above, it is suspected that in AIH an autoantigenic peptide is indeed presented to the helper/inducer T cells, leading to their sustained activation. There is direct, albeit limited, evidence that an autoantigenic peptide is presented and recognized in AIH type 2 (Ma et al., 2006). Activation of T helper cells has been documented in earlier studies on AIH, both in the liver and in the peripheral blood (Senaldi et al., 1992; Lobo-Yeo et al., 1987). These activated cells are mainly of the CD4 phenotype, and their numbers are highest in the most active stages of AIH. Advances in the study of T cells have occurred in AIH type 2, since the knowledge that CYP2D6 is the main autoantigen has enabled the characterization of both CD4 and CD8 T cells targeting this cytochrome. One study has shown that CD4 T cells from patients with type 2 AIH positive for the predisposing HLA allele DRB10701 recognize seven regions of CYP2D6 (Ma et al., 2006), ﬁve of which have later been shown to be also recognized by CD8 T cells (Longhi et al., 2007). High numbers of IFN-g-producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage, suggesting a combined cellular immune attack. What triggers the immune system to react to an autoantigen is unknown. A lesson may be learned by the study of humoral autoimmune responses

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during viral infections. Thus, recent studies aimed at determining the speciﬁcity of the anti-LKM-1, present in both the juvenile form of AIH and in some patients with chronic HCV infection, have shown a high amino acid sequence homology between the HCV polyprotein and CYP2D6, the molecular target of anti-LKM-1, implicating a mechanism of molecular mimicry as a trigger for the production of anti-LKM-1 in HCV infection (Manns et al., 1991; Vento et al., 1997; Kerkar et al., 2003). It is therefore conceivable that an as yet unknown virus infection may be at the origin of the autoimmune attack in AIH. Titres of antibodies to liver-speciﬁc lipoprotein, a macromolecular complex present on the hepatocyte membrane, and to its well-characterized component asialoglycoprotein receptor, correlate with the biochemical and histological severity of AIH (Jensen et al., 1978; McFarlane et al., 1986). Antibodies to alcohol dehydrogenase, a second well-deﬁned component of liver-speciﬁc lipoprotein, have been described in patients with AIH (Ma et al., 1997). Immunoﬂuorescence studies on monodispersed suspensions of liver cells obtained from patients with AIH showed that these cells are coated with antibodies in vivo (Vergani et al., 1987). A pathogenic role for these autoantibodies has been indicated by cytotoxicity assays showing that autoantibody-coated hepatocytes from patients with AIH are killed when incubated with autologous (Mieli-Vergani et al., 1979) lymphocytes. The effector cell was identiﬁed as an Fc receptor–positive mononuclear cell (Mieli-Vergani et al., 1979). T cell clones obtained from liver biopsies of patients with AIH and expressing the gamma/delta T cell receptor have been shown to be cytotoxic to a variety of targets but to preferentially kill liver-derived cells as opposed to cell lines derived from other organs (Wen et al., 2001). The establishment of cell lines and clones has enabled Wen and colleagues (Wen et al., 1990, 2001), and Lohr and colleagues (Lohr et al., 1991; Lohr et al., 1992) to show that the majority of T cell clones obtained from the peripheral blood and a proportion of those from the liver of patients with AIH are CD4 positive and use the conventional alpha/beta T cell receptor. Some of these CD4 positive clones were further characterized and

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were found to react with partially puriﬁed antigens, such as crude preparations of liver cell membrane or liver-speciﬁc lipoprotein (Wen et al., 1990), and with puriﬁed asialoglycoprotein receptor (Wen et al., 1990; Lohr et al., 1992) or recombinant CYP2D6 (Lohr et al., 1991) and to be restricted by HLA class II molecules in their response. Because CD4 is the phenotype of Th cells, both Wen and colleagues (1990) and Lohr and colleagues (1992) investigated whether these clones were able to help autologous B lymphocytes in the production of immunoglobulin in vitro and found that their coculture with B lymphocytes resulted in a dramatic increase in autoantibody production. All of the above experimental evidence suggests that cellular immune responses are involved in the liver damage of AIH even though the evidence that the trigger is an autoantigen is still incomplete.

6. Management and prognosis Three small controlled clinical trials in the early 1970s have provided the basis for the current immunosuppressive regimens, collectively suggesting that treatment with prednisolone improves liver function tests, ameliorates symptoms and prolongs survival (Johnson, 1997; Czaja and Freese, 2002). Though azathioprine was not able to induce remission when used on its own, it did allow maintaining remission in association with a signiﬁcantly reduced dose of steroids. In the 1980s and 1990s, a number of studies addressed two important questions: Whether immunosuppression could be safely withdrawn after obtaining remission and whether steroid-free maintenance could be achieved (Johnson, 1997; Czaja and Freese, 2002). It was shown that the great majority of cases relapse rapidly upon immunosuppression withdrawal, but that steroid-free maintenance could be achieved with azathioprine alone provided that its dose is increased to 2 mg/kg/day. There is no doubt that immunosuppressive treatment is beneﬁcial in patients with severe symptomatic disease and it should be started as soon as possible, without waiting for six months as suggested in early studies. Most patients, including those with cirrhosis (Czaja and Freese, 2002), will

achieve remission on 30 mg prednisolone daily for one month, after which azathioprine can be introduced at 1 mg/kg/day and the dose of prednisolone reduced to 5–15 mg/day to maintain the aminotransferase activity within the normal range. Though some authors deﬁne remission as transaminase levels up to twice the upper limit of normal, a better outcome has been reported when normal transaminase levels are attained and maintained (Seela et al., 2005). If the patient develops steroid side effects, the dose of azathioprine can be increased to 2 mg/kg/day and a complete withdrawal of steroids can be considered. The optimal duration of treatment is unknown. It is prudent not to attempt withdrawal of immunosuppression within two years of diagnosis. During withdrawal attempts, it is essential to closely monitor the liver function tests since relapse may be severe and even fatal. Patients who have successfully stopped immunosuppression should be followed up for long term, since relapse may occur even 10 years later. Nonadherence to treatment is common, particularly in adolescents and young adults, and is one of the most important causes of relapse (Kerkar et al., 2006). A question frequently asked is whether treatment can be safely continued during pregnancy. Although the experience is limited, there does not appear to be adverse events for mother and baby (Heneghan et al., 2001). In particular, no teratogenic effects have been described with azathioprine in humans, though for women concerned about its use, treatment with steroids alone can be considered. It is now clear that there are patients with a milder form of the disease who may be asymptomatic or pauci-symptomatic and are detected incidentally, during routine check-ups. For these patients the approach to treatment is less clear. The beneﬁt of therapy is undeﬁned and it may be so low that the risk of corticosteroid side effects is unjustiﬁed. This is particularly relevant to postmenopausal women and elderly patients. The latter, however, frequently have severe disease that needs active management to achieve normal life expectancy (Al-Chalabi et al., 2006). The most common side effect of steroid treatment is cushingoid changes which affect most

Autoimmune Hepatitis

patients after prolonged treatment. Less common, but severe, side effects include osteoporosis, vertebral collapse, diabetes, cataract, hypertension and psychosis. Only 13% of treated patients develop complications that necessitate dose reduction or premature drug withdrawal, the most common reasons for treatment withdrawal being cosmetic changes or obesity, osteopaenia with vertebral collapse, and brittle diabetes (Czaja and Freese, 2002). Side effects of azathioprine are uncommon affecting less than 10% of the patients and include cholestatic hepatitis, veno-occlusive disease, pancreatitis, nausea and vomiting, rash, and bone marrow suppression. Usually these complications subside upon drug withdrawal (Czaja and Freese, 2002). A theoretical long-term complication of continuous immunosuppressive therapy is the development of malignancies. The risk of extra-hepatic cancer in AIH has been reported to be 1.4-fold higher than that of an age- and sex-matched normal population (Wang et al., 1989). Akin to other chronic liver diseases, the risk of primary hepatocellular cancer is related mainly to the presence of cirrhosis and is generally reported to be uncommon. When the standard treatment fails, other drugs that have been tried, which include cyclosporin, ursodeoxycholic acid, budesonide, and mycophenolate mofetil. Though encouraging results are described, these reports are anecdotal. Liver transplantation is the ultimate treatment for most patients who present with fulminant hepatic failure and those who reach end-stage chronic liver disease. Transplantation in AIH has an excellent prognosis, with a ﬁve-year patient and graft survival between 80 and 90%. Before transplantation is considered, however, it is important to remember that even patients presenting with decompensated cirrhosis can respond to immunosuppressive treatment and avoid surgery for a long time (Czaja and Freese, 2002). AIH may recur after transplant.

7. Recurrence of AIH after transplant Recurrence of AIH after liver transplant has been shown in several studies (Vergani and Mieli-Vergani,

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2002). The diagnosis is based on reappearance of clinical symptoms and signs, histological features of periportal hepatitis, elevation of transaminases, circulating autoantibodies and elevated IgG, associated to response to steroids and azathioprine. Possession of the HLA DR3 allele appears to confer predisposition to disease recurrence, as it does to the original AIH, though this has not been universally conﬁrmed. Recurrence has been noted in both adult and paediatric series, and though the rate of this complication increases with the posttransplant interval, it may appear as early as one month post-surgery. Most transplant recipients with recurrent AIH respond to an increase in the dose of corticosteroids and azathioprine, but, in a few, recurrence can lead to graft failure and to the need for re-transplantation. Caution should be taken in weaning immunosuppression in patients who undergo transplantation for AIH since discontinuation of corticosteroid therapy may increase the risk for recurrent disease.

8. De novo AIH after transplant Tissue autoantibodies after liver transplantation, in particular ANA and SMA, are common also in patients transplanted for non-autoimmune liver disease (Vergani and Mieli-Vergani, 2002). AntiLKM-1 is the third most frequently reported antibody, but its ﬂuorescence pattern is at times atypical, staining preferentially the renal tubules and sparing the liver. The described prevalence of post-liver-transplant autoantibodies is variable, probably reﬂecting different techniques used for their detection, the cut-off point above which the autoantibodies are considered positive, the time post-transplant at which they are tested, the nature of the clinical condition leading to transplantation, and the presence or absence of post-transplant complications. In the late 1990s, it was observed that AIH can arise de novo after liver transplantation in patients who had not been transplanted for autoimmune liver disease (Kerkar et al., 1998). After the original report in children, de novo AIH after liver transplant has been conﬁrmed by several studies in both adult and paediatric patients (Vergani and Mieli-Vergani, 2002; Mieli-Vergani

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and Vergani, 2004). More importantly, treatment with prednisolone and azathioprine, using the same schedule for classical AIH, is also effective in de novo AIH leading to excellent graft and patient survival. It is of interest that these patients do not respond satisfactorily to standard anti-rejection treatment, making it essential to reach an early diagnosis to avoid graft loss. Recurrence of AIH post transplant can be readily explained. The recipient’s immune system is sensitized to species-speciﬁc antigens and has a pool of memory cells, which are re-stimulated and re-expanded when the target antigens, ‘auto antigens’, are presented to the recipient’s immune system either by recipient’s APC repopulating the grafted liver or by donor’s APC sharing histocompatibility antigens with the recipient. In contrast, akin to autoimmune liver disease outside transplantation, the pathogenesis of post-transplant de novo AIH remains to be deﬁned. There are several non-mutually-exclusive explanations: In addition to release of autoantigens from damaged tissue, a possible mechanism is molecular mimicry, whereby exposure to viruses sharing amino acid sequences with autoantigens leads to cross-reactive immunity (Vergani et al., 2002). Viral infections, which are frequent post transplant, may lead to autoimmunity also through other mechanisms, including polyclonal stimulation, enhancement and induction of membrane expression of MHC class I and II antigens and/or interference with immunoregulatory cells. Another possible mechanism is suggested by animal experiments showing that the use of calcineurin inhibitors predisposes to autoimmunity and autoimmune disease, possibly by interfering with the maturation of T lymphocytes or with the function of regulatory T cells, with consequent emergence and activation of autoaggressive T cell clones (Mieli-Vergani and Vergani, 2004). Another proposed mechanism stems from observations by Aguilera et al. (2001), who reported that an antibody directed to glutathione-S-transferase T1 (GSTT1) characterized their patients with de novo AIH (Aguilera et al., 2001, 2004, 2005). Since the gene encoding this protein is defective in a ﬁfth of caucasoid subjects and the encoded enzyme was absent in patients experiencing de novo AIH, the authors speculated that graft dysfunction resulted

from recognition as foreign of GSTT1 acquired with the graft. We have been, however, unable to conﬁrm this observation, having investigated sequentially on 60 occasions the reactivity against GSTT1 in 20 patients with post-liver-transplant de novo AIH (Komorowski et al., unpublished data). That allogeneic transplantation of a solid organ can lead to the development of autoimmunity has been unequivocally demonstrated in a murine model of heart allograft (Fedoseyeva et al., 1996, 1999); heart transplant from an allogeneic donor resulted not only in signs of rejection, but also in the production of antibodies and CD4+ T cells directed against cardiac myosin in the recipient. The relative importance of autoantigenic and allogeneic stimuli in the development of de novo AIH post liver transplant remains to be elucidated.

9. Conclusion With immunosuppressive treatment, prognosis of AIH is excellent with symptom-free long-term survival in the majority of patients. Over the past three decades, several pathogenic aspects of AIH have been elucidated, including predisposing genetic factors and disease-speciﬁc humoral and cellular immune responses. Tasks for the future include further elucidation of its pathogenesis and the establishment of novel treatments aimed at arresting speciﬁcally liver autoaggression or, ideally, at reinstating tolerance to liver antigens.

References Aguilera, I., Sousa, J.M., Gavilan, F., Bernardos, A., Wichmann, I., Nunez-Roldan, A. 2004. Glutathione S-transferase T1 mismatch constitutes a risk factor for de novo immune hepatitis after liver transplantation. Liver Transpl. 10 (9), 1166–1172. Aguilera, I., Wichmann, I., Gentil, M.A., Gonzalez-Escribano, F., Nunez-Roldan, A. 2005. Alloimmune response against donor glutathione S-transferase T1 antigen in renal transplant recipients. Am. J. Kidney Dis. 46 (2), 345–350. Aguilera, I., Wichmann, I., Sousa, J.M., Bernardos, A., Franco, E., Garcia-Lozano, J.R., et al. 2001. Antibodies against glutathione S-transferase T1 (GSTT1) in patients with de novo immune hepatitis following liver transplantation. Clin. Exp. Immunol. 126 (3), 535–539.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 14

Primary Sclerosing Cholangitis Roger Chapman Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease caused by a diffuse inﬂammation and ﬁbrosis that can involve the entire biliary tree. The progressive pathological process obliterates intra- and extrahepatic bile ducts in ultimately leading to biliary cirrhosis, portal hypertension and eventually hepatic failure. In addition, cholangiocarcinoma develops in about 10–30% of patients during the course of the disease. The generally accepted diagnostic PSC are as follows: generalized beading and stenosis of the biliary system on cholangiography (Fig. 1) absence of choledocholithiasis (or history of bile duct surgery) exclusion of bile duct cancer, usually by prolonged follow-up The term ‘secondary sclerosing cholangitis’ is used to describe the typical bile duct changes described above when a clear predisposing factor to duct ﬁbrosis can be identiﬁed. The causes of secondary sclerosing cholangitis are shown in Table 1.

1. Aetiology A number of causative agents have been implicated in the pathogenesis of PSC, but no single Corresponding author.

Tel.: 44-1865-228756; Fax: 44-1865-771100 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00014-1

hypothesis has provided a unifying explanation for all the clinical and pathological features of this disease. Any hypothesis has to integrate the close association of PSC with inﬂammatory bowel disease (IBD); the majority (65–86%) of patients with PSC have coexistent ulcerative colitis (UC) whilst a minority of patients have Crohn’s colitis. The prevalence of PSC in UC populations is between 2 and 6% (Schrumpf et al., 1982; Shepherd et al., 1983; Chapman et al., 1983). In a patient with UC, abnormal liver function tests, particularly an elevated serum alkaline phosphatase, may be the ﬁrst indication of this insidious condition. The precise aetiology and pathogenesis of PSC is still not completely understood. Evidence suggests that immune mechanisms play a key role in the development of the disease.

1.1. Autoimmunity The 2:1 male-to-female gender ratio of patients with PSC and the relatively poor response of the disease to immunosuppression suggest that PSC is not a classical autoimmune disease. PSC patients do have an increased frequency of the HLA B8 DR3 DQ2 haplotype, however, in common with a number of organ-speciﬁc autoimmune diseases such as lupoid chronic active hepatitis, type 1 diabetes mellitus, myasthenia gravis and thyrotoxicosis (Schrumpf et al., 1982; Shepherd et al., 1983; Chapman et al., 1983). PSC is also independently associated with a range of autoimmune diseases,

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Figure 1. Endoscopic retrograde cholangiogram showing the characteristic changes of primary sclerosing cholangitis. There is severe stricturing and dilatation of both intra- and extrahepatic bile ducts.

Table 1 Causes of secondary sclerosing cholangitis Previous bile duct surgery with stricturing and cholangitis Bile duct stones causing cholangitis AIDS––probably infective as a result of cytomegalovirus or cryptosporidium Intra-hepatic arterial infusion of 5-ﬂuorodeoxyuridine Insertion of formalin into hepatic hydatid cysts

diabetes mellitus and Graves’ disease being the most common. Saarinen et al. (2000) found that 25% of patients with PSC had one or more autoimmune disease, compared to 9% of patients with IBD alone.

1.2. Autoantibodies A wide range of autoantibodies can be detected in the serum of patients with PSC, clearly indicating

an altered state of immune responsiveness or immune regulation. Although a few studies have demonstrated some correlation between particular clinical parameters and the presence of autoantibodies, there is presently insufﬁcient evidence to make use of any of them in determining prognosis. Most are present at low prevalence rates and at relatively low titres (Table 2). Anti-neutrophil-speciﬁc antibodies are a fairly consistent feature of PSC, occurring in up to 88% of patients. The anti-neutrophil antibodies associated with PSC are distinct from c-ANCA and classical p-ANCA that are commonly used as diagnostic and therapeutic seromarkers for Wegener’s granulomatosis and microscopic polyangiitis, respectively. PSC, UC and autoimmune hepatitis are associated with ‘atypical p-ANCA’ which has a distinct staining pattern on indirect immunoﬂuorescence microscopy. The prevalence of atypical p-ANCA in PSC, UC and autoimmune hepatitis is 33–88%, 40–87% and 50–96%, respectively. Work

Primary Sclerosing Cholangitis Table 2 Prevalence of autoantibodies in primary sclerosing cholangitis Antibody

Prevalence

Anti-nuclear antibody (ANA) Anti-smooth muscle antibody (ASMA) Anti-endothelial cell antibody (AECA) Anti-cardiolipin antibody Thyroperoxidase Thyroglobulin Rheumatoid factor

7–77% 13–20% 35% 4–66% 7–16% 4% 15%

NB Antimitochondrial antibody is only rarely detected in PSC (o10%). This is useful in differentiating PSC from primary biliary cirrhosis (PBC).

by Terjung and Worman (2001) has demonstrated that the target antigen for atypical p-ANCA appears to be localized to the nuclear periphery, and it has been suggested that the anti-neutrophil antibody in PSC therefore be renamed p-ANNA (anti-neutrophil nuclear antibody). The speciﬁc target antigen of this antibody remains to be clariﬁed, but Terjung’s group has demonstrated that about 90% of p-ANNA from individuals with PSC reacted with a neutrophil-speciﬁc nuclear envelope protein with a molecular mass of approximately 50 kDa. The molecular identity of this nuclear envelope protein remains unknown, however. The importance of autoantibodies in the development of PSC remains unclear. To date there is no convincing model of the pathogenesis of PSC, UC or autoimmune hepatitis that implicates antineutrophil antibodies, and it may be that these antibodies are simply a marker for an as yet undetermined immune dysregulation. There is, however, some evidence that a monoclonal antibody to a colonic epithelial protein in patients with UC cross-reacts with epithelial cells lining the extrahepatic bile ducts of PSC patients with UC, suggesting that the pathogenesis of these two conditions might be associated with a common antigen (Mandal et al., 1994). An interesting paper by Xu et al. has demonstrated the presence of autoantibodies to surface antigens expressed on biliary epithelial cells (BECs) in PSC. This study also showed that these autoantibodies induced increased expression of CD44 on the BEC,

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demonstrating that the BEC may be the candidate epithelial cell in PSC (Xu et al., 2002). More work is needed in this area to clarify if this might be mechanism of action of autoantibodies in the development of the clinical disease.

1.3. MHC genes The major histocompatibility complex on the short arm of chromosome 6 encodes the HLA molecules which have a central role in T cell response and are highly polymorphic. The MHC class I and class II regions encode the classical transplantation antigens of the HLA A, B, Cw, and DR, DQ and DP families. The class III region encodes a range of immune response genes, including those encoding tumour necrosis factor-alpha and -beta (TNF-a and -b), the heat shock protein family (HSP-70), complement proteins C2, C4A, C4B and Bf, and the genes encoding the MHC class I chain-related proteins, MICa and b (MICA and MICB). Early studies based on HLA serotyping found an increased frequency of the HLA B8 DR3 haplotype in PSC patients compared to controls. More recently, serotyping has been replaced by the more detailed technique (Donaldson, 2003) (Table 2). The technique of molecular genotyping has elucidated ﬁve key HLA haplotypes associated with PSC (Spurkland et al., 1999). It is not yet clear whether there is a single primary susceptibility allele on each of these haplotypes, although MICA008 (mapping to the HLA class I/class III boundary between B8 and TNFA) occurs on two of the key haplotypes (Table 3). Studies of genes encoding the key proteins in the immune system have contributed towards our understanding of the inﬂuence of the immune system on the development and progression of PSC. PSC appears to be a ‘complex’ disease in that it is not attributable to a single gene locus. Susceptibility to PSC is probably acquired through inheriting one of a number of patterns of genetic polymorphisms which together cause a predisposition to development of the disease.

R. Chapman

172 Table 3 Key HLA haplotypes associated with primary sclerosing cholangitis Haplotype

Signiﬁcance in PSC

B8-TNF2-DRB30101DRB10301-DQA10501DQB10201

Strong association with disease susceptibility

DRB30101-DRB11301DQA10103-DQB10603

Strong association with disease susceptibility

DRB50101-DRB11501DQA10102-DQB10602

Weak association with disease susceptibility

DRB40103-DRB10401DQA103-DQB10302

Strong association with protection against disease

MICA 008

Strong association with disease susceptibility

1.4. Non-MHC immunoregulatory genes in PSC A range of non-MHC immunoregulatory genes has been studied in relation to PSC. Cytotoxic lymphocyte antigen-4 (CTLA-4, CD152) is one of the differentiation antigens exclusively expressed on activated CD4+ and CD8+ T cells. It acts by binding to B7, the same ligand as CD28, thereby disrupting the crucial CD28–B7 interaction, one of the key costimulatory events in the initiation and progression of the T cell immune response. An amino acid changing single-nucleotide polymorphism (snp) in codon 17 of the leader peptide of CTLA-4 has been associated with susceptibility to autoimmune thyroid disease, insulin-dependent diabetes mellitus, AIH and PBC. The role of this polymorphism in PSC, however, is controversial and to date results have been conﬂicting. After antigen presentation, the next step in the adaptive immune response is the release of cytokines and chemokines at the site of inﬂammation. One polymorphism in TNF-a, as discussed above, is associated with PSC but this appears to be related to the extended HLA B8 DR3 DQ2 haplotype rather than being an independent effect (Bernal et al., 1999; Mitchell et al., 2001a, b). Polymorphisms have also been studied in IL-1 and IL-10 and chemokine CCR-5 to assess a relationship to PSC (Donaldson et al., 2000). So far these

studies have been negative or controversial and no clear association has emerged. The end result of inﬂammation in PSC is periductal ﬁbrosis. Genes involved in the regulation of the production and destruction of extracellular matrix are therefore also good candidate genes for study. One such family of genes is that comprising the matrix metalloproteinases. A functional polymorphism of MMP-3 (stromelysin) has been shown to be associated with both susceptibility to PSC and progression to portal hypertension in a British population (Satsangi et al., 2001).

1.5. Cellular immune abnormalities The initiation and maintenance of the immune cascade is determined not only by MHC recognition but also by the presence of accessory cells and molecules to provide costimulatory signals and the production of cytokines to amplify or modify the immune response. Studies of circulating lymphocyte subsets in PSC have produced rather conﬂicting results, although there does seem to be some consensus on the ﬁnding that there is a fall in CD8+ T cells as the disease progresses (Lindor et al., 1987). The fact that this change occurs only in advanced disease, however, means that it is unlikely to be signiﬁcant in the pathogenesis of the disease. The cellular inﬁltrate at the site of tissue injury is probably more relevant than the circulating population. Although it is clear that there is a T cell predominant portal tract inﬁltrate in PSC, there is still some uncertainty regarding the relative importance of CD4+ and CD8+ cells in this inﬁltrate. The hypothesis that these T lymphocytes are involved in the pathogenesis of the disease (rather than simply being markers for its presence) is supported by evidence that these cells are functional. This evidence comes from studies of surface markers expressed on activated and memory T cells.

1.6. T cell receptor Most T cells carry a T cell receptor (TCR) consisting of two disulphide-linked polypeptides, termed

Primary Sclerosing Cholangitis

a and b. A group of T cells carrying an alternative receptor, termed gd, has been identiﬁed over the past 13 years. These cells appear to be involved in autoimmunity, although their exact function is not clear (Hayday and Geng, 1997). An increase in the number of gd T cells has been found in the peripheral blood and portal inﬁltrates of patients with both PSC and AIH compared with controls (Martins et al., 1996). There was no concentration of the gd cells in the areas of bile ducts or interface hepatitis, however, and the predominant cell type was still ab. The signiﬁcance of gd cells in the pathogenesis of PSC is therefore not clear although they might function by modulating ab T cell activation or regulating antibody or autoantibody production from B cells. Although TCR gene rearrangements serve to generate genetic diversity, a particular Vab gene segment can play a dominant role in recognition of certain peptide–MHC complexes. Expanded T cell populations using restricted sets of TCR V gene segments have been identiﬁed in areas of inﬂammation in diseases such as rheumatoid arthritis and Sjo¨gren’s disease. This suggests the presence of a speciﬁc antigen with the capacity of driving the production of T cells with this restricted Vab segment product (Sumida et al., 1992; Imberti et al., 1993). Studies from Broome et al. (1997) indicated that the hepatic, but not peripheral, T cells in PSC preferentially have Vb3 T cell repertoires. An oligoclonal expansion was not demonstrated in this study, but oligoclonal TCR which proliferate in culture with enterocytes and are cytotoxic to enterocyte cell lines in vitro have also been reported in PSC (Probert et al., 1997).

1.7. Cytokines Most studies in the context of PSC have looked at cytokine secretion from peripheral, rather than liver-derived, lymphocytes. This work has not been conclusive. There are some preliminary data (published only in abstract form to date) that show an increased expression of both Th1 and Th2 cytokines within the liver of PSC patients compared with healthy controls (Mitchell et al., 1997a, b). Downregulation of IL-10 mRNA expression in

173

PSC and PBC was also demonstrated. These changes were reversed after treatment with ursodeoxycholic acid (UDCA) (Mitchell et al., 1997a, b). An abnormal cytokine repertoire and the high expression of cytokine mRNA in the early stages of PSC suggest that Th1 and Th2 cytokines may play a role in the pathogenesis of the disease. Cytokines could have an inﬂuence on many aspects of the progression of PSC including the cytotoxic T cell development, aberrant expression of class II MHC molecules on BECs, and matrix metalloproteinase gene expression in ﬁbroblasts (Mitchell and Chapman, 2000). Their true role in the development and progression of PSC has yet to be clearly deﬁned.

1.8. Biliary epithelial cells The BEC is the target of immune attack in PSC, whilst at the same time appearing to be an active participant in the immune response. Aberrant expression of HLA molecules on target cells is important in the pathogenesis of autoimmune diseases. Normal BECs express only HLA class I, and not class II, antigens. However, the HLA class II antigens HLA DR, DQ and DP have all been found to be expressed by the BECs of patients with PSC (Chapman et al., 1988; Broome et al., 1990). These antigens have the potential to initiate an immune response by binding autoantigens or exogenous antigens and presenting the peptides to class II restricted T lymphocytes. ‘Professional’ antigen-presenting cells (APC) also express cell-surface costimulatory molecules such as CD54 (ICAM-1) and members of the B7 family (CD80 and CD84) which are required for T cell activation. These co-stimulatory molecules appear to be lacking on the BECs in PSC, and this observation has cast doubt upon the theory that BECs act as APC (Leon et al., 1996). Aberrant expression of CD54 (ICAM-1), however, has recently been demonstrated as occurring in patients with end-stage PSC. This ﬁnding could not be replicated in patients with earlier stage disease (Adams et al., 1992; Broome et al., 1993). Recently, Cruickshank et al. (1999) have also demonstrated that CD44, the lymphocyte homing

174

R. Chapman

receptor, is highly expressed on BECs in a range of inﬂammatory liver diseases including PSC. This phenomenon may occur as a function of biliary cell response to stress or damage and, through the ability of CD44 to bind chemokines and growth factors, might mediate local inﬂammatory responses. BECs, therefore, may act as APC although they seem to be less active in this role than dendritic cells or macrophages.

1.9. Role of bacteria in the aetiopathogenesis of PSC The coexistence of inﬂammatory colitis in around 75% of Northern European patients with PSC has led to the hypothesis that the initiating step in this disease is the access of intestinal bacteria through an inﬂamed and leaky bowel wall, to the portal circulation. An abnormal immune response to bacterial antigens (possibly acting as molecular mimics for autoantigens) in an immunogenetically susceptible host might be sufﬁcient to precipitate the cascade of immune reactions detailed above. Investigation of bacterial growth from human tissue is confounded by the bacterial contamination caused by intubation of the bile duct at ERCP. Several animal models, however, have been used to investigate this proposal. Wistar and Sprague–Dawley rats develop a pattern of hepatic injury somewhat similar to human PSC after artiﬁcially induced small bowel bacterial overgrowth (Lichtman et al., 1990). Rat models have also demonstrated that bacterial peptides instilled into the rectum of rats with a chemically induced colitis appear very quickly in the bile and will initiate a small duct cholangitis, although no extrahepatic strictures are produced (Yamada et al., 1994).

1.10. Hypotheses for the aetiopathogenesis of PSC A plausible unifying hypothesis for the aetiopathogenesis of PSC has been put forward by Vierling (1998). This suggests that the initial insult is the reaction of an immunogenetically susceptible

host to bacterial cell wall products entering the portal circulation through a permeable gut wall either due to colitis or possibly during episodes of intestinal infection. The resulting Kuppfer cell (hepatic macrophage) activation would result in peribiliary cytokine and chemokine secretion attracting activated neutrophils, monocyte/macrophages, lymphocytes and ﬁbroblasts to the site of infection. The resultant concentric ﬁbrosis around the bile ducts could then lead to ischaemia and then atrophy of the BEC. The bile duct loss would then lead to progressive cholestasis, ﬁbrosis and secondary biliary cirrhosis. This hypothesis does not explain why there is a relative paucity of patients with PSC and underlying Crohn’s colitis, nor the association of PSC with stricturing of the pancreatic duct. More recently, Grant et al. have proposed the existence of an enterohepatic circulation of lymphocytes, whereby some mucosal lymphocytes produced in the gut during active inﬂammation persist as memory cells capable of recirculation through the liver (Grant et al., 2002). Under certain circumstances, these gut-derived lymphocytes might become activated resulting in hepatic inﬂammation. This hypothesis is supported by the ﬁnding that some lymphocyte homing receptors are shared by the liver and gut. This concept of dual homing lymphocytes helps to explain the observation that PSC runs a course independent of inﬂammation in the bowel and indeed can develop even after proctocolectomy. In conclusion, current evidence suggests that PSC is an immune-mediated, rather than a classical, autoimmune disease. The association with inﬂammatory colitis suggests that an abnormal immune response may be initiated in an immunogenetically susceptible host by the access of bacterial antigen, through a permeable gut wall, to the portal circulation. This bacterial antigen might then act as a molecular mimic of an autoantigen precipitating an immune cascade which results in structuring and scarring of the intra- and extrahepatic bile ducts, peribiliary ﬁbrosis and ultimately, cirrhosis. There are difﬁculties in determining which of the wide range of immune abnormalities identiﬁed in these patients are causal and which are the consequences of tissue injury.

Primary Sclerosing Cholangitis

2. Diagnosis Serum biochemical tests usually show a cholestatic pattern, often in asymptomatic patients with IBD. Although ERCP remains the gold standard for the diagnosis of PSC, it is an invasive technique that carries a small but signiﬁcant risk of morbidity and mortality. Magnetic resonance cholangiography (MRC) is a relatively new non-invasive technique, and increasing data exist on its performance relative to ERCP. In one recent study (Angulo et al., 2000), the ERCP and MRC of patients with a suspected diagnosis of PSC were independently evaluated, and MRC was as sensitive and speciﬁc as either ERCP or percutaneous hepatic cholangiography. Current evidence suggests that MRCP should be used in place of ERCP to establish the diagnosis of PSC. Liver biopsy changes are only diagnostic in approximately one-third of patients who show the characteristic changes of concentric ‘onion skin’ ﬁbrosis, although there is usually histological evidence of cholestasis. Therefore, liver biopsy is not normally required to establish the diagnosis in patients with PSC with diagnostic cholangiographic changes.

3. Small duct PSC There are a group of patients with cholestatic liver function tests and diagnostic features of PSC on liver histology who have normal cholangiography; the term ‘small duct PSC’ has been coined to apply to such patients. Approximately 6–16% of the PSC population have small duct PSC. In general, they follow a benign course and have a favourable prognosis. Only 25% of patients will develop large duct disease, and to date no patients with small duct PSC have developed cholangiocarcinoma.

4. Autoimmune pancreatitis (AIP) Patients with the multisystem disease, AIP, have been reported to have biliary strictures similar to

175

PSC. Serum IgG4 levels are increased in approximately 75% of AIP patients, whereas elevated IgG4 levels are found in 9% of PSC patients. Unlike adult PSC, biliary strictures improve with corticosteroid therapy. The relationship between PSC and AIH remains to be determined.

5. Prognosis The clinical course of PSC is quite variable; the disease is indolent in some patients and more rapidly progressive in others. The natural history of PSC is described in a number of retrospective studies with the median survival time from diagnosis to death or orthotopic liver transplantation (OLT) reported between 12 and 21 years (Broome et al., 1996; Wiesner et al., 1989; Farrant et al., 1991; Helzberg et al., 1987). Differences in survival estimations may reﬂect the variation in the deﬁnition of onset and outcome. As there is no reliable marker of early disease in PSC, the onset is difﬁcult to identify clearly. Whether the onset is deﬁned as the occurrence of the ﬁrst symptoms consistent with PSC, as the time of the ﬁrst abnormal liver function test or as the time of diagnosis by ERCP will result in differences in survival estimates. In retrospective studies, details of distant events may be sparse and there is likely to be failure to recognize early signs and symptoms. Patients with late-stage disease may predominate, whilst patients who die from rapidly progressive disease may be missed. The ideal study of prognosis is prospective and follows patients from a deﬁned point in the disease process, usually diagnosis. There have been no studies using such an inception cohort in PSC because the disease is rare and its slow progression makes a prospective study impractical. A large retrospective study published by Broome et al. (1996) did include a high proportion (46%) of patients with early (stage I and II) disease. Fortyfour percent of patients were asymptomatic at diagnosis, and these patients exhibited longer survival than symptomatic patients. The estimated median survival for the whole PSC group was 144

R. Chapman

176

Table 4 Studies of prognosis in primary sclerosing cholangitis: multivariate analysis Study

Number of patients

% asymptomatic

Median survival (year)

Independent prognostic factors

Helzberg et al. (1987)

53

25

a

Wiesner et al. (1989)

174

21

11.9

Age Serum bilirubin Blood hemoglobin conc. Presence of IBD Histological stage

Farrant et al. (1991)

126

16

12.0

Hepatomegaly Splenomegaly Serum alkaline phosphatase Histological stage Age

Broome et al. (1996)

305

44

12.0

Age Serum bilirubin Histological stage

a

Hepatomegaly Serum bilirubin W1.5 mg/day at onset of disease

5% survival=9 years.

months. For patients with symptoms at the time of diagnosis, the estimated median survival was signiﬁcantly less, at 112 months. Over one-ﬁfth of the asymptomatic patients became symptomatic during the median follow-up period of 63 months. From these studies a number of prognostic models have been developed, mainly using parameters deﬁned at diagnosis (Tables 4 and 5). Perhaps the most controversial prognostic factor is HLA DR4. Studies from Oxford (Mehal et al., 1994) and the Mayo Clinic (Aguilar et al., 1994) suggest that HLA DR4 is associated with poor prognosis, whilst studies from London (Maloney et al., 1996) were unable to conﬁrm this association. Although these models successfully predict the natural history of the disease in a cohort of PSC patients, they are less successful when applied to individual patients. The confounding factor is the development of hepatobiliary or colonic cancer. Cholangiocarcinoma is difﬁcult to diagnose (Miros et al., 1991), is associated with poor prognosis (Kornﬁeld et al., 1997) and precludes OLT (Herbener et al., 1988). In Broome et al.’s study (1996) cholangiocarcinoma was found in 8% of patients with PSC but occurred in 30% of

Table 5 Studies of prognosis in primary sclerosing cholangitis: univariate analysis Study

Number of patients

Prognostic indicator

Comments

Craig et al. (1991)

129

Disease assessment by cholangiography

Intrahepatic disease worse than extrahepatic

Mehal et al. (1994)

83

HLA DR4

HLA DR4 associated with poor prognosis

Olsson et al. (1995a, b)

94

Disease assessment by cholangiography

High grade intrahepatic strictures indicate early jaundice and short survival

HLA DR4

HLA DR4 not associated with poor prognosis but confers resistance to developing PSC

Maloney, 1996

120

the 79 patients who died or underwent OLT. In this and other studies, none of the investigated clinical or laboratory parameters could identify those patients who would subsequently develop

Primary Sclerosing Cholangitis

cholangiocarcinoma, although PSC patients with coexistent UC have a three- to fourfold higher risk of developing cholangiocarcinoma. A recent casecontrol study has suggested that long duration of UC and smoking are independent risk factors associated with the development of hepatobiliary malignancy in PSC (Bergquist et al., 1998). Two studies have shown that biliary dysplasia seen on liver biopsy can antedate the development of cholangiocarcinoma by at least two years, and may be an indication for early liver transplantation. Patients with UC and PSC are also considered to be at higher risk of developing colonic dysplasia and carcinoma (D’Haens et al., 1993). Early studies (Loftus et al., 1996; Marchesa et al., 1997) investigating this risk gave conﬂicting results due to the different methodologies employed, small numbers, design ﬂaws and different endpoints (Ahnen, 1996). However, a recent study of a retrospectively deﬁned inception cohort (Lashner et al., 1998) has shown that the risk of developing colonic dysplasia or cancer is signiﬁcantly increased in UC patients with PSC compared with patients with UC alone. A high proportion of right-sided cancers was noted in the PSC patients, consistent with the hypothesis that these cancers arise due to exposure to carcinogenic bile acids (Marchesa et al., 1997). Consensus has emerged that PSC deﬁnitely predisposes to colonic dysplasia and cancer. Recent studies have shown that patients treated with UDCA have a 30% reduction in the incidence of colonic dysplasia or carcinoma (Pardi et al., 2003). PSC patients with UC remain at risk of developing colon cancer or dysplasia even after they have undergone OLT (Bleday et al., 1993). The evidence is that physicians can only provide their PSC patients with a tentative survival estimate using the variables derived from prognostic models. The development of cholangiocarcinoma is often insidious and unpredictable. Although a signiﬁcant impact of screening on mortality is unproven, we recommend that PSC patients with UC should immediately enter a yearly colonoscopic surveillance programme, in contrast to the two yearly surveillance programme after eight years of colitis that is recommended for UC patients without PSC.

177

5.1. Management of complications As PSC slowly progresses to biliary cirrhosis and portal hypertension, complications may arise from chronic cholestasis or chronic liver failure (as in PBC and other liver diseases) or complications speciﬁc to PSC such as biliary strictures and the development of cholangiocarcinoma. The general management of the complications of cholestasis will not be discussed here.

5.1.1. Management of the complications of chronic liver disease The complications of end-stage chronic liver disease, namely oesophageal varices, ascites and porto-systemic encephalopathy, are equally observed in the later stages of PSC. The management of these complications is common to all advanced liver disease and warrants no further discussion here. Special mention should be made of the problem of bleeding from peristomal varices which occur as a consequence of portal hypertension in PSC patients who have undergone proctocolectomy for underlying IBD and have an ileal stoma. Peristomal variceal bleeding can be severe and difﬁcult to treat. Local measures such as injection of sclerosant, venous ligation and ileostomy revision are usually unsuccessful and associated with recurrent bleeding. Porto-systemic shunts, i.e. TIPPS, can control severe bleeding episodes, but such patients may ultimately require hepatic transplantation. Ideally, patients with PSC who require a proctocolectomy for control of their UC should have ileal pouch-anal anastomosis so as to avoid the formation of an ileal stoma and the problem of peristomal varices. With the recognition that PSC patients with UC have a greater risk of developing colonic dysplasia or DNA aneuploidy compared with patients with UC alone (Broome et al., 1995), surveillance of the anastomosis is required. Although there is no direct evidence, there is consensus that patients with UC with an intact colon should undergo annual surveillance colonoscopy with multiple biopsies The incidence of pouchitis is also increased in patients with an ileal

178

R. Chapman

pouch anal anastomosis and coexistent PSC (Penna et al., 1996).

5.1.2. Management of complications specific to PSC PSC is characterized by multiple small annular strictures in the biliary tree seen at ERCP. Tight biliary strictures, particularly in the extrahepatic biliary tree, may interrupt the indolent course of disease and cause deterioration of liver function with more rapid progression to biliary cirrhosis. Such benign dominant biliary strictures cannot be reliably differentiated from cholangiocarcinoma by cholangiographic appearance. In one study of patients awaiting OLT, ultrasound-guided biopsy of a dominant biliary stricture accurately demonstrated cholangiocarcinoma complicating PSC in 75% of cases (Mirza et al., 1994). Exfoliative brush cytology of strictures at ERCP has a high speciﬁcity and positive predictive value for the diagnosis of cholangiocarcinoma but low sensitivity and negative predictive value (Ferrunior et al., 1994). Despite the relatively low sensitivity, endoscopic bile duct brush cytology may be diagnostic for malignancy or reveal high-grade dysplasia (Lee et al., 1995a, b). No single serum marker accurately predicts the development of cholangiocarcinoma, but an index combining two serum markers, CA19-9 and CEA, may be useful to identify PSC patients with occult tumours (Ramage et al., 1995). This ﬁnding has not been conﬁrmed by other investigators (Bjornsson et al., 1999). Dominant strictures may be treated endoscopically or surgically. Endoscopic treatment involves balloon dilatation of the stricture and/or placement of a biliary stent. Surgical procedures aim to bypass the obstruction and drain the biliary system into the gut. Unfortunately, there are no controlled trials which examine the validity of either approach and guide future management. Since biliary manipulation increases the risk of stricturing and bacterial cholangitis and may jeopardize future OLT, endoscopic and surgical intervention in PSC is as a rule best avoided for as long as possible. Selected non-cirrhotic PSC patients with dominant extrahepatic strictures may beneﬁt from a bilioenteric bypass (Hepburgh, 1994). A non-randomized

retrospective study of endoscopic intervention including dilatation or stenting of strictures, placement of nasobiliary drainage and extraction of stones in PSC suggested that 77% of the patients showed improvements of their clinical symptoms, liver function tests or cholangiograms (Lee et al., 1995a, b). A report from Amsterdam described 32 patients with dominant strictures treated with shortterm endoscopic stenting for a mean of 11 days. Primary endpoints were improvements in symptoms and cholestasis which were seen in all patients, and which were maintained for several years. Seven transient procedure-related complications occurred in 45 therapeutic procedures (Ponsioen et al., 1999). Where OLT is precluded, as in biliary obstruction due to cholangiocarcinoma, endoscopic stenting is undoubtedly the best option for more distal lesions.

5.2. Medical therapy: the prevention of disease progression In both PBC and PSC, the primary site of inﬂammation and damage is the biliary epithelium. When severely damaged or destroyed, the bile ducts do not have the capacity to regenerate like hepatocytes which are the primary target for injury in various parenchymal liver diseases. Given the ﬁnite number of bile ducts in the liver, the natural history of PSC, like PBC, is that of progressive loss of functioning intrahepatic bile ducts (ductopenia). This ductopenia leads to a progressive and irreversible failure of hepatic biliary excretion. To delay and reverse this process, physicians have tried a variety of agents, but in PSC, in contrast to PBC, few randomized controlled trials have been performed.

5.2.1. D-penicillamine Increased hepatic copper levels are detected in all patients with prolonged cholestasis including those with PSC. This observation provided the rationale for the controlled trial of the cupruretic, D-pencillamine, performed by the Mayo Clinic (LaRusso et al., 1988). Seventy patients were randomized to either D-pencillamine or placebo for 36 months. No improvement was observed on

Primary Sclerosing Cholangitis

disease progression or overall survival in the treatment group. Major adverse effects including pan-cytopenia and proteinuria led to the permanent discontinuation of penicillamine in 21% of the treated patients.

5.2.2. Corticosteroids It is surprising that there have been no long-term studies of the effect of corticosteroid therapy on histological progression and survival in PSC, especially as the disease may be immune mediated. This may reﬂect concerns about the long-term adverse effect proﬁle of corticosteroids. Systemic and topical corticosteroid therapy has been evaluated in a number of small, often uncontrolled, trials (Sivak et al., 1981; Burgert et al., 1984). In one such study, 10 patients diagnosed by ERCP and liver biopsy with early PSC (elevated serum alkaline phosphatase, but none with biliary cirrhosis) were treated with prednisone without a signiﬁcant response (Sivak et al., 1981). In another uncontrolled pilot study, 10 patients with PSC, selected because they had elevated aminotransferases, were given prednisolone, and the majority responded with improvement in their biochemistry (Burgert et al., 1984). In a subsequent study, Lindor et al. (1991) were unable to conﬁrm these optimistic results. They treated 12 patients with a combination of low-dose prednisone (10 mg daily) and colchicine (0.6 mg twice daily). The clinical course of the treated patients was compared with a control group, but the study was not randomized. After two years, no signiﬁcant differences in the biochemistry and liver histology were detected between the two groups. In this study, treatment did not alter the rate of disease progression or improve survival. The absence of a beneﬁcial response, and the suspicion that corticosteroid therapy enhanced cortical bone loss and hence the risk of developing compression fractures of the spine even in young male patients, led the authors to advise against empirical corticosteroid therapy in these patients. This conclusion was strengthened by the observation that spontaneous fractures in patients who have undergone liver transplantation occur almost exclusively in PSC patients who are already

179

osteopenic at the time of transplantation (Porayko et al., 1991). Topical corticosteroids are usually administered through a nasobiliary drain left in situ following ERCP. Three anecdotal studies (Grijm et al., 1986; Jeffrey et al., 1990; Craig et al., 1990) have reported beneﬁt. The only controlled trial of nasobiliary lavage with corticosteroids from the Royal Free Hospital (Allison et al., 1986) showed no beneﬁt when compared with a placebo group. Although the numbers were small, the bile of all the treated patients became rapidly colonized with enteric bacteria and a higher incidence of bacterial cholangitis was recorded in the treatment group. More recent clinical trials have studied the possible beneﬁt of budesonide, a second-generation corticosteroid with a high ﬁrst-pass metabolism and minimal systemic availability. Unfortunately, preliminary results both alone (Angulo et al., 1999a, b) and in combination with UDCA (van Hoogstraten et al., 2000) have been disappointing. There is no direct evidence to suggest that either oral or topical corticosteroids are beneﬁcial in PSC. Indeed, when PSC patients with coexistent UC are given courses of corticosteroids to treat their UC, this treatment appears to have little inﬂuence on the behaviour of their liver disease. It may be difﬁcult to justify a trial using corticosteroids as monotherapy, but a large controlled trial could clarify their role in combination with a choleretic agent. Potentially serious adverse effects may be reduced by new agents such as biphosphonates which prevent cortical bone loss.

5.2.3. Methotrexate After demonstrating a promising response to lowdose oral pulse methotrexate in an open study (Knox and Kaplan, 1991) involving 10 PSC patients without evidence of portal hypertension, Knox and Kaplan (1994) performed a doubleblind, randomized placebo controlled trial of oral pulse methotrexate at a dose of 15 mg/wk. Twelve patients with PSC were entered into each group. Although each patient was monitored with both liver biopsy and ERCP (at baseline and yearly) and biochemical tests, the only signiﬁcant change

180

R. Chapman

was a fall in the serum alkaline phosphatase by 31% in those receiving methotrexate. There were no signiﬁcant improvements in liver histology, treatment failure or mortality rates. The only toxicity attributed to methotrexate during the study was a transient decrease in the white cell count related to a bout of bacterial cholangitis and Campylobacter enterocolitis in a single patient. The study was too small in terms of numbers of patients and of too short duration to have adequate power to detect a signiﬁcant beneﬁt in patients with early disease, should such a beneﬁt exist. Nevertheless, with the negative results of this controlled trial and more recent reports of the toxicity of pulse methotrexate in patients with PBC (interstitial pneumonitis, severe lung damage, hepatotoxicity), it would be difﬁcult to justify a larger controlled trial of methotrexate therapy at present. In a pilot study, Lindor et al. (1996) found that methotrexate given in combination with ursodeoxycholic acid (UDCA) to 19 PSC patients was associated with toxicity (alopecia, pulmonary complications) but showed no additional improvement in liver biochemistries compared to a control group of nine patients treated with UDCA alone.

5.2.4. Other immunosuppressants Despite the evidence that PSC may be an immunemediated disease, there have been few randomized controlled trials of immunosuppressive agents containing sufﬁcient numbers of patients with early disease. Immunosuppression is unlikely to be effective in patients with advanced liver disease and irreversible bile duct loss, and this may account for the disappointing results so far seen in PSC with these agents. No controlled trials of azathioprine in PSC have been reported. In one case report (Javett, 1971), two patients improved clinically on azathioprine, but in another the patient deteriorated (Wagner, 1971). The use of cyclosporin in PSC has been evaluated in a randomized controlled trial from the Mayo Clinic (Kyokane et al., 1994) involving 34 patients with PSC and, in the majority, coexistent UC. Treatment with cyclosporin reduced the symptoms of UC (Sandborn et al., 1993) but had no effect on the course or prognosis of PSC. Follow-up liver

histology after two years of treatment revealed progression in 9/10 of the placebo group, but only 11/20 of the cyclosporin-treated group. This was not reﬂected by any beneﬁcial effect on the biochemical tests. The prevalence of adverse effects was low; serious renal complications were not reported. A combination of cyclosporin and prednisolone elicited a beneﬁcial response in a 65-year-old man with PSC accompanied by pancreatic duct abnormalities (Kyokane et al., 1994). Tacrolimus (FK 506), an immunosuppressive macrolide antibiotic, has been used to treat 10 patients with PSC in an open study (Van Thiel et al., 1995). After one year of treatment with a twice daily oral regimen, all patients experienced an improvement in their liver biochemical tests. For example, the median serum bilirubin level was reduced by 75% and the serum alkaline phosphatase was reduced by 70%. No major adverse events were reported in this initial study in PSC. A randomized controlled trial is required to conﬁrm these encouraging preliminary results. Cladribine, a nucleoside analogue with speciﬁc antilymphocyte properties, has been used to treat a variety of autoimmune disorders. In a recent pilot study on PSC, six patients with early disease were treated for six months and followed for two years. Whilst signiﬁcant decreases were seen in peripheral and hepatic lymphocyte counts, no signiﬁcant changes were observed in symptom scores, liver function tests or cholangiograms (Duchini et al., 2000). The hepatobiliary injury which occurs in rats with experimental bacterial overgrowth is said to result from peptidoglycan-polysaccharide-mediated activation of Kupffer cells which in turn release cytokines such as tumour necrosis factor-alpha (TNF-a). In rats the liver injury can be prevented by pentoxifylline. In an open pilot study, 20 patients with PSC were treated with pentoxifylline 400 mg qid for one year. In this dose, pentoxifylline did not improve symptoms or liver tests (Bharucha et al., 2000).

5.2.5. Anti-fibrogenic agents In the light of initial reports which suggested a positive trend of the anti-ﬁbrogenic agent

Primary Sclerosing Cholangitis

colchicine on survival in PBC and other types of cirrhosis, a randomized trial from Sweden (Olsson et al., 1995a, b) compared colchicine in a dose of 1 mg daily by mouth in 44 patients with PSC with a matched placebo group of 40 patients. At threeyear follow-up, there were no differences in clinical symptoms, serum biochemistry, liver histology or survival between the two groups. The only recorded adverse effect attributable to colchicine was diarrhoea in a single patient. The absence in this study of any proven effect of colchicine on disease progression, outcome or survival is in keeping with more recent long-term studies of colchicine in PBC and other chronic liver diseases which have failed to conﬁrm the initial reported survival beneﬁts.

5.2.6. Ursodeoxycholic acid This hydrophilic bile acid has become widely used in the treatment of cholestatic liver of all causes. UDCA appears to exert a number of effects all of which may be beneﬁcial in chronic cholestasis: a choleretic effect by increasing bile ﬂow, a direct cytoprotective effect, an indirect cytoprotective effect by displacement of the more hepatotoxic endogenous hydrophobic bile acids from the bile acid pool, an immunomodulatory effect and ﬁnally an inhibitory effect on apoptosis. Using a labelled bile acid analogue, Jazrawi et al. (1994) demonstrated a defect in hepatic bile acid excretion but not in uptake in patients with PBC and PSC, resulting in bile acid retention. They observed an improvement of hepatic excretory function with UDCA in patients with PBC but only a trend towards improvement in the small number of patients with PSC. Not only is hepatic bile acid excretion affected by UDCA but so is ileal reabsorption of endogenous bile acids. The net result is enrichment of the bile acid pool with UDCA. Hydrophobic bile acids are more toxic than UDCA which can protect and stabilize membranes. Studies have demonstrated that long-term treatment with UDCA decreases aberrant expression of HLA class I on hepatocytes and reduces levels of soluble cell adhesion molecules (sICAM) in PBC patients. In vitro studies have shown that UDCA

181

may alter cytokine production by human peripheral mononuclear cells. In PSC, one study has shown that UDCA has been shown to decrease aberrant HLA DR expression on bile ducts (Lo et al., 1992). However, a more recent study could not demonstrate any alteration in expression of either HLA class I and II or ICAM-1 on either BECs or hepatocytes (van Milligen de Wit et al., 1999). The body of evidence suggests that UDCA does have some modulatory effects on immune function, but how important these are remains unclear. Numerous studies have attempted to address the clinical efﬁcacy of UDCA treatment in PSC. The majority have been uncontrolled studies in small numbers of patients. In a pilot study, O’Brien et al. (1991) treated 12 patients with UDCA on an open basis over 30 months. They documented improvement in fatigue, pruritis and diarrhoea and signiﬁcant improvement of all liver biochemical tests, particularly alkaline phosphatase during the two UDCA treatment periods. Symptoms and liver biochemistry relapsed during a six-month withdrawal period between treatment phases. During UDCA treatment, the amount of cholic acid declined slightly but the levels of other relatively hydrophobic bile acids did not change signiﬁcantly. In the ﬁrst randomized double-blind controlled trial of UDCA in PSC, Beuers et al. (1992) compared over a 12-month period six patients who received UDCA 13–15 mg/kg body weight with eight patients who received placebo (Table 6). The majority of patients had early disease (Ludwig classiﬁcation stages I and II). After six months, a signiﬁcant reduction in alkaline phosphatase and aminotransferases was achieved in the treatment group. A signiﬁcant fall in bilirubin was only noted after 12 months. Using a multiparametric score, the UDCA-treated group showed signiﬁcant improvement in their liver histology, mainly attributed to decreased portal and parenchymal inﬂammation. Unfortunately, treatment did not ameliorate their symptoms. UDCA-induced diarrhoea was the only important side effect requiring a patient to withdraw. Similar results were obtained by Stiehl et al. (1994) who randomized 20 patients to either 750 mg

182

Table 6 Controlled trials of ursodeoxycholic acid in PSC Author

Patient numbers

Study type

Dose

Study duration

LFTs improved Alk P

GGT

Bili

AT

Symptoms improved

Liver histology improved

Proportion with early diseasea

14

DBPC

13–15 mg/kg daily

12 months

Yes

Yes

Yes

Yes

No

Yes

57%

Lo et al. (1992)

23

DBPC

10 mg/kg daily

24 months

Trend

Trend

No

Trend

No

No

74%

Stiehl et al. (1994)

20

DBPC, Unc

750 mg daily

Controlled for three months, uncontrolled up to four years

Yes

Yes

No

Yes

No

Yes

35%

Mitchell et al. (2001a, b)

26

DBPC

20–25 mg/kg daily

12 months

Yes

Yes

No

No

No

Yes

30%

van Hoogstraten et al. (1998)

48

DB

10 mg/kg daily in single (Group1) or three (Group 2) doses

24 months

Yes

Yes

No

Yes

No

NA

NA

DBPC

13–15 mg/kg daily

Mean 2.9 years

Yes

Yes

Yes

Yes

No

No

NA

Lindor (1997)

105

Key: Unc=uncontrolled, DB=Double blinded trial, PC=Placebo-controlled trial; Alk P=alkaline phosphatase, GGT=gglutamyltranspeptidase, Bili=Bilirubin; NA=Data not available. a Proportion with early disease, i.e. stages I and II.

R. Chapman

Beuers et al. (1992)

Primary Sclerosing Cholangitis

daily of UDCA or placebo (Table 6). However, in a larger randomized placebo-controlled trial of UDCA in PSC by Lindor (1997). No beneﬁt was demonstrated. In this trial, 105 patients were randomized to treatment with UDCA in conventional doses, viz. 13–15 mg/kg body weight daily, or placebo and followed up for up to six years (mean 2.9 years). Treatment with UDCA had no effect upon the time until treatment failure deﬁned as death, liver transplantation, the development of cirrhosis, quadrupling of bilirubin, marked relapse of symptoms or the development of signs of chronic liver disease. Furthermore, the signiﬁcant improvement in liver biochemical tests seen in the treated group was not reﬂected by any beneﬁcial changes in liver histology. On the contrary, there was a suggestion that the liver histology of patients on UDCA showed a greater tendency to progress towards ﬁbrosis. However, this could also be explained by sampling variability between serial liver biopsies (Olsson et al., 1995a, b). The failure of standard doses of UDCA to provide clinical beneﬁt led our group to consider the use of higher doses. Our rationale is that with increasing cholestasis, there is decreasing enrichment of the bile acid pool with UDCA and higher doses are required to achieve the same level of enrichment (Stiehl et al., 1995). Furthermore the in vitro immunomodulatory effects of UDCA are enhanced with increasing UDCA concentrations (Hirano et al., 1996). In a pilot study we evaluated 26 patients with PSC who were randomized to either high-dose (20–25 mg/kg) UDCA or placebo (Mitchell et al., 2001a, b) for two years. High-dose UDCA had no effect on symptoms, but as expected, there was a signiﬁcant improvement in liver biochemistry. More importantly, we found a signiﬁcant reduction in cholangiographic appearances and liver ﬁbrosis. In the treatment group, bile acid saturation with UDCA W70% conﬁrmed patient compliance. No signiﬁcant adverse effects were reported, in particular no worsening of colitis was seen. Similar encouraging results were obtained in an open study on 30 patients with PSC treated for one year (Harnois et al., 2001). When compared to historical controls, a signiﬁcant improvement in projected survival using the Mayo risk score was observed with high dose but

183

not with the conventional dose (13–15 mg/kg/day) of UDCA. In the light of these promising results, a large controlled trial of high-dose UDCA has been completed in Scandanavia. The results have shown no signiﬁcant differences between the two groups, although there was a strong trend in favour of improved survival in the UDCA group. Moreover, the study was probably underpowered to show a positive result, as the endpoints of death or transplant were lower than expected in both groups (Ollson et al., 2006). Whilst it is established that hydrophilic bile acid UDCA inhibits injury by hydrophobic bile acids, hepatocyte cell death from bile acid induced toxicity occurs more frequently from apoptosis than from necrosis. It has been demonstrated that UDCA inhibits deoxycholic acid induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production (Rodrigues et al., 1998). Moreover, UDCA inhibited in vitro deoxycholic acid stimulated growth in several tumour cell lines including colon cancer (Martinez et al., 1998). This has led to the suggestion that UDCA may reduce the risk of dysplasia and cancer in the biliary tree and/or the colon. Tung et al. (2001) studied 59 patients with PSC and UC followed with three yearly surveillance colonoscopy. Colonic dysplasia was signiﬁcantly less common in those patients treated with UDCA. However, these results were not conﬁrmed in a study of 120 patients followed with two yearly colonoscopic surveillance (Wolf et al., 2001). The recent study of Pardi et al. (2003) has conﬁrmed the chemopreventive effect of UDCA. To date, there is only anecdotal evidence that the high rate of bile duct cancer is reduced by UDCA therapy.

5.2.7. Miscellaneous treatments In keeping with UC, there is a strong inverse relationship between PSC and cigarette smoking. This led Angulo et al. (1999a, b) to test the hypothesis that oral nicotine might have a beneﬁcial effect in PSC. Eight non-smoking patients with PSC were treated with nicotine 6 mg qid for up to one year. Adverse effects were frequent requiring

184

R. Chapman

cessation in three patients and no beneﬁcial effects were seen.

5.2.8. Combined therapy In an important pilot study, the potential of combination therapy was explored by Schramm et al. (1999), who treated 15 patients with PSC. All patients received low-dose UDCA (500–750 mg daily), prednisolone 1 mg/kg daily and azathioprine 1–1.5 mg/kg daily. After a median follow-up period of 41 months, all patients had a signiﬁcant improvement in liver function tests. Seven patients had been previously treated with UDCA, but liver enzymes improved only after immunosuppressive therapy was added. More importantly, 6 of 10 with follow-up biopsies showed histological improvement, and signiﬁcant radiological deterioration was only seen in 1 of 10 patients who had endoscopic retrograde cholangiography. In a 13-year prospective study, Stiehl et al. (1997, 2002) studied the survival of 106 patients with PSC treated with 750 mg UDCA daily and by endoscopic balloon dilatation of major dominant stenoses whenever necessary. Ten patients had a dominant stricture at entry, and over a median follow-up of ﬁve years another 43 developed a dominant stenosis. This was not prevented by lowdose UDCA treatment but was successfully treated by balloon dilatation in the majority, only ﬁve requiring temporary stenting. This combined approach of UDCA and endoscopic intervention signiﬁcantly improved the survival compared with predicted survival rates. This was an uncontrolled study which provides only relatively weak evidence that UDCA and/or endoscopic therapy prolonged survival, although the results are promising.

5.2.9. Orthotopic liver transplantation For patients with advanced PSC, orthotopic liver transplantation (OLT) is the only therapeutic option. A number of centres report a ﬁve-year survival rate in excess of 75% (Gow and Chapman, 2000). Farges et al. (1995) advocate assessment for OLT earlier in the course of the disease to reduce the operative risk and to prevent the development

of hepatobiliary malignancy. Against this approach is the recognition that PSC may recur in the graft (Graziadei et al., 1999) and that colon cancer is the most frequent cause of death in PSC patients after OLT (Vera et al., 2003). A recent study has shown that PSC recurrence is commoner in male IBD patients who have an intact colon. Five-year survival rates are also improved in colectomized patients. In absence of prognostic models capable of predicting the course of disease or the onset of complications in individual patients, the timing of OLT continues to be controversial (Brandsaeter et al., 2003). A recent report suggests that prior treatment with UDCA is associated with a better outcome after transplantation (van Hoogstraten et al., 1998).

6. Conclusion There is no established effective medical treatment for PSC. Recent studies suggest that high-dose UDCA may have a role in at least slowing disease progression, although the results of larger longterm randomized trials are awaited. Randomized controlled trials of immunosuppressive agents in early PSC are needed, possibly in combination with high-dose UDCA. With the identiﬁcation of T cell subsets involved in PSC and the cytokines they produce, it may be possible to use particular recombinant cytokines or antibodies to speciﬁc cytokines such as anti-TNF antibody (inﬂiximab) to manipulate the immune response in PSC and alter disease progression. Greater insight into the pathogenetic mechanisms involved in PSC would enable therapy to be targeted more speciﬁcally at the area of initial damage, namely the biliary epithelium. Liver transplantation remains the mainstay of treatment for patients with end-stage disease but the disease will recur in at least 30% of patients.

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Schramm, C., Schirmacher, P., Helmreich-Becker, I., Gerken, G., zum Bu¨schenfelde, K.H., Lohse, A.W. 1999. Combined therapy with azathioprine prednisolone and ursodiol in patients with primary sclerosing cholangitis. A case series. Ann. Intern. Med. 131, 943–946. Schrumpf, E., Fausa, O., Forre, O., Dobloug, J.H., Ritland, S., Thorsby, E. 1982. HLA antigens and immunoregulatory T cells in ulcerative colitis associated with hepatobiliary disease. Scand. J. Gastroenterol. 17, 187–191. Shepherd, H.A., Selby, W.S., Chapman, R.W., Nolan, D., Barbatis, C., McGee, J.O., Jewell, D.P. 1983. Ulcerative colitis and persistent liver dysfunction. Q. J. Med. 52, 503–513. Sivak, M., Jr., Farmer, R.G., Lalli, A.F. 1981. Sclerosing cholangitis: its increasing frequency of recognition and association with inﬂammatory bowel disease. J. Clin. Gastroenterol. 3, 261–266. Spurkland, A., Saarinen, S., Boberg, K.M., Mitchell, S., Broome, U., Caballeria, L., Ciusani, E., Chapman, R., Ercilla, G., Fausa, O., Knutsen, I., Pares, A., Rosina, F., Olerup, O., Thorsby, E., Schrumpf, E. 1999. HLA class II haplotypes in primary sclerosing cholangitis patients from ﬁve European populations. Tissue Antigens 53, 459–469. Stiehl, A., Rudolph, G., Kloteis-Plodsky, P., Samuel, P., Walker, S. 2002. Development of dominant bile duct stenoses in patients treated with ursodeoxycholic acid, outcome after endoscopic treatment. J. Hepatol. 36, 151–156. Stiehl, A., Rudolph, G., Sauer, P., Benz, C., Stremmel, W., Walker, S., Theilmann, L. 1997. Efﬁcacy of ursodeoxycholic acid treatment and endoscopic dilatation of major duct stenoses in primary sclerosing cholangitis. A 8 years prospective study. J. Hepatol. 26, 56–61. Stiehl, A., Rudolph, G., Sauer, P., Theilmann, L. 1995. Biliary secretion of bile acids and lipids in primary sclerosing cholangitis. Inﬂuence of cholestasis and effect of ursodeoxycholic acid treatment. J. Hepatol. 23, 283–289. Stiehl, A., Walker, S., Stiehl, L., Rudolph, G., Hofmann, W.J., Theilmann, L. 1994. Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3-year pilot study with a placebo-controlled study period. J. Hepatol. 20, 57–64. Sumida, T., Yonaha, F., Maeda, T., Tanabe, E., Koike, T., Tomioka, H., Yoshida, S. 1992. T cell receptor repertoire of inﬁltrating T cells in lips of Sjogren’s syndrome patients. J. Clin. Invest. 89, 681–685. Terjung, B., Worman, H.J. 2001. Anti-neutrophil antibodies in primary sclerosing cholangitis. Best Pract. Res. Clin. Gastroenterol. 15, 629–642. Tung, B.Y., Edmond, M.J., Haggitt, R.C., Bronner, M.P., Kimmey, M.B., Kowdley, K.V., Brentnall, T.A. 2001. Ursodiol use is associated with a lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann. Intern. Med. 134, 89–95.

van Hoogstraten, H.J., Vleggaar, F.P., Boland, G.J., van Steenbergen, W., Grifﬁoen, P., Hop, W.C., van Hattum, J., van Berge Henegouwen, G.P., Schalm, S.W., van Buuren, H.R. 2000. Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis. A randomized double-blind pilot study. Am. J. Gastroenterol. 95, 2015–2022. van Hoogstraten, H.J., Wolfhagen, F.J., van de Meeberg, P.C., van Buren, H.R., Schaerm, S. 1998. Ursodeoxycholic acid therapy for primary sclerosing cholangitis; single versus multiple doses. J. Hepatol. 29, 215–222. van Milligen de Wit, A.W., Kuiper, H., Camoglio, L., van Bracht, J., Jones, E.A., Tytgat, G.N., van Deventer, S.J. 1999. Does ursodeoxycholic acid mediate immunomodulatory and anti-inﬂammatory effects in patients with primary sclerosing cholangitis? Eur. J. Gastroenterol. Hepatol. 11, 129–136. Van Thiel, D.H., Wright, H., Carroll, P., Abu-Elmagd, K., Rodriguez-Rilo, H., McMichael, J., Irish, W., Starzl, T.E. 1995. Tacrolimus (FK 506), a treatment for primary sclerosing cholangitis: results of an open-label preliminary trial. Am. J. Gastroenterol. 90, 455–459. Vera, A., Gunson, B.K., Ussatoff, V., Nightingale, P., Candinas, D., Radley, S., Mayer, A.D., Buckels, J.A., McMaster, P., Neuberger, J., Mirza, D.F. 2003. Colorectal cancer in patients with inﬂammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Transplantation 75, 1983–1988. Vierling, 1998. Aetiopathogenesis of primary sclerosing cholangitis. In: P.C.R. Manns, A. Stieihl, R. Wiesner (Eds.), Primary Sclerosing Cholangitis. Kluwer Academic Publishers, London, p. 9. Wagner, A. 1971. Azathioprine treatment in primary sclerosing cholangitis. Lancet 2, 663–664. Wiesner, R.H., Grambsch, P.M., Dickson, E.R., Ludwig, J., MacCarty, R.L., Hunter, E.B., Fleming, T.R., Fisher, L.D., Beaver, S.J., LaRusso, N.F. 1989. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 10, 430–436. Wolf, J.M., Rybicki, L., Lashner, B.A. 2001. Ursodeoxycholic acid is not chemoprotective for colorectal cancer in ulcerative colitis patients with primary sclerosing cholangitis [Abstract]. Gastroenterology 121, 2276. Xu, B., Broome, U., Ericzon, B.G., Sumitran-Holgersson, S. 2002. High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind biliary epithelial cells and induce expression of CD44 and production of interleukin 6. Gut 51, 120–127. Yamada, S., Ishii, M., Liang, L.S., Yamamoto, T., Toyota, T. 1994. Small duct cholangitis induced by N-formyl L-methionine L-leucine L-tyrosine in rats. J. Gastroenterol. 29, 631–636.

PART IV:

Autoimmunity and Viral Hepatitis

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 15

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection Christian Pagnoux, Loı¨ c Guillevin Department of Internal Medicine, National Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Hoˆpital Cochin, Universite´ Paris 5 – Rene´ Descartes, 27 rue du faubourg Saint-Jacques, 75679 Paris cedex 14, France

1. Introduction Effective vaccination campaigns, more stringent blood donor selection, and effective viral inactivation procedures have greatly decreased the incidence of hepatitis B virus (HBV) infection in industrialized countries, yet it remains a major public health problem, especially in developing countries. In endemic countries, more than 10% of the population may have chronic infection, with HBV remaining among the leading causes of cirrhosis and liver cancer. Indeed, an estimated 350–400 million people worldwide are chronically infected with HBV and up to 1 million die annually because of HBV-related complications (Lavanchy, 2004; Van Damme and Van Herck, 2007). In non-vaccinated people, acute HBV infection often remains clinically undetectable or is responsible for only transient icterus in 10–30% of cases. Conversely, in approximately 1% of newly infected adult patients, acute and fulminant hepatitis can develop, and in another 5–10%, the virus remains. Indeed, chronic infection is deﬁned as the persistence of HBV surface antigens (HBs Ag) 6 months after acute hepatitis. One-third of

Corresponding author.

Tel.: +33-1-58-41-14-61; Fax: +33-1-58-41-29-68 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00015-3

these chronically infected patients are asymptomatic chronic carriers, whereas chronic hepatitis develops in the remaining two-thirds, then hepatic cirrhosis in 20%, and eventually hepatocellular carcinoma in 20% of the latter group of patients with cirrhosis (Krastev, 2006; Yim and Lok, 2006). Besides all these potential hepatic manifestations of HBV infection, some extra-hepatic systemic and/or autoimmune manifestations may occur with both acute and chronic viral infections, usually independently of hepatic involvement. The most common extra-hepatic manifestation is the prodromal pre-icteric ﬂu-like syndrome with arthralgias and sometimes urticarian cutaneous rash, observed in some patients with acute infection. Other extra-hepatic manifestations, such as HBV-related glomerulonephritis or polyarteritis nodosa (HBV-PAN), have become very rare in parallel with the decreased incidence of HBV infection. However, the extra-hepatic HBV-related manifestations we review here, such as those associated with chronic hepatitis C virus (HCV) infection receiving much attention in recent years, are still in evidence and must be acknowledged by physicians. In addition, such manifestations were the ﬁrst to illustrate that some infectious agent may be responsible for, or at least trigger, systemic diseases, with clear epidemiological and physiopathological evidence.

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2. Hepatitis B virus infection 2.1. Virus characteristics HBV, a member of the hepadnavirus family, is a circular and partially double-stranded DNA virus of 3200 base pairs. The HBV particle consists of an envelope with three related surface proteins—the S (small), M (medium), and L (large) HBs Ag sharing some common epitopes, primarily the ‘a’ dominant epitope, a main target of anti-HBs antibodies (Ab)—enclosing an icosahedral nucleocapsid of approximately 30 nm in diameter containing core protein C, and, ﬁnally, the viral DNA genome and DNA polymerase-reverse transcriptase. The eight different HBV genotypes (A–H) identiﬁed at present differ by more than 8% in sequence and show differences in their worldwide geographical distribution and clinical outcome (Kidd-Ljunggren et al., 2004; Schaefer, 2007). In Europe, genotypes A and D are predominant, whereas in Asia, genotypes B and C are more frequent, and in the Middle East, genotype D. Genotype E seems restricted to Africa. Genotype F is found largely in Central and South America and Alaska. All eight HBV genotypes are found in the United States, genotypes A and C being the most common (Chu et al., 2003; Kramvis and Kew, 2005). Indeed, these genotypes can now be divided into at least 24 subgenotypes, differing by at least 4% in sequence and with distinctive epidemiological properties. Notably, because of the high replication capacity of HBV—with a release of up to 1000 viral particles per day via reverse transcription of RNA intermediates— mutations and additional recombinations continuously occur in chronic infection. Furthermore, superinfection with a different genotype that may also favor recombinations has been reported to occur in up to 17.5% of patients (Schaefer, 2007). The HBV genome has four open-reading frames encoding for the pre-S/S gene, which codes for the envelope proteins, the C gene for the core proteins, the P gene for the DNA polymerase-reverse transcriptase, and the X gene for the X protein. The C gene includes a core and a pre-core region and codes for two mRNAs with slightly different starts, ends, and lengths. The shorter of the

mRNAs encodes for a protein that assembles to form structural nucleocapsid particles, named HBc Ag. The longer mRNA encodes for the so-called pre-core protein, which is consequently cleaved of its C-terminal region into HBe Ag, a secretory, non-structural, and non-particulated viral product, used as a seromarker for high viral replication. Notably, disruption of the conformational particles deﬁning HBc Ag results in a loss of HBc antigenicity and the appearance of HBe antigenicity (Schlicht and Wasenauer, 1991; Schodel et al., 1993). Pre-core mutants are the most common mutant viruses, with pre-core mutations responsible for the decrease or non-production of HBe Ag. Moreover, such mutations often occur at the time of seroconversion from HBe Ag to anti-HBe Ab (Bozkaya et al., 1996; Miyakawa et al., 1997). Because the selective advantage of the wild-type virus decreases during chronic infection in patients with both the wild-type and pre-core mutant virus, HBe Agnegative chronic hepatitis now predominates. Some studies have found patients negative for HBe Ag tending to be older, male, have lower HBV-DNA and transaminase levels, with disease that more frequently progresses to cirrhosis (Zarski et al., 1994, 2006). Finally, the X protein is a non-structural regulatory protein whose precise functions are not yet fully elucidated, but is required for efﬁcient viral replication. It acts as a positive transcriptional coregulator and was recently shown to increase the activity of androgen-receptor-mediated transcriptional activity (Chiu et al., 2007; Miyakawa et al., 1997), and the gene expression and transcriptional activity of sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferatoractivated receptor-gamma (PPAR-g), implicated in hepatic lipid accumulation (Kim et al., 2007).

2.2. Natural history of infection HBV is transmitted only on a human-to-human basis, even though a virus reservoir in certain apes may exist. Although HBs Ag does not reveal the whole infective HBV particle, it can be detected in all kinds of human secretions, including blood,

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection

serum, saliva, tears, sweat, urine, stool, semen, vaginal secretions, and maternal milk. HBV is very resistant and can persist on surfaces out of the body for up to 7 days. It can be transmitted by tight and repeated contact with chronic-infected subjects (horizontal transmission, probably prevalent in Africa), especially in families or institutions, but the three main and clearly identiﬁable routes are parenteral (blood transfusion, needle sharing among injection drug users, needlestick injury, tattooing and piercing, acupuncture), sexual, and perinatal, mainly during delivery, particularly in Mediterranean, Asian, and developing countries (Abdool Karim et al., 1991; Botha et al., 1984). Transplacental transmission accounts for less than 2% of all the perinatal transmissions (Shepard et al., 2005). However, the source and/or route of infection remains unidentiﬁable in nearly one-third of patients (Custer et al., 2004; Guillevin et al., 2005; McMahon, 2005; Tre´po and Guillevin, 2001). The mean time of incubation of HBV is 60–90 days and the range 45–180 days. Icterus occurs in approximately one-third of adult patients but in less than 10% of children younger than 5 years. Fulminant hepatitis and death occur in less than 1% of patients. Chronic infections develop in 2–10% of adult patients but in 30–90% of children, especially those infected as newborns. HBV has a dynamic natural history, since disease can ﬂuctuate between periods of active replication and/or liver inﬂammation and periods of inactivity, with less or transiently no viral replication, sometimes with delayed spontaneous seroconversion. Disease progression is inﬂuenced by various factors, including viral genotype, speciﬁc mutations, demographic features, duration of disease, concurrent viral infections, and/or social and environmental factors (McMahon, 2005). Although the clinical relevance is not absolute, genotype A seems to have better outcome in Europe, whereas in Asia, genotype B, especially Bj, is associated with a lower risk of cirrhosis and hepatocellular carcinoma (Kramvis and Kew, 2005). In up to 25% of children and older children with chronic HBV infection, HBV-related cirrhosis or hepatocellular carcinoma eventually develops, at a rate of 5% per decade of adulthood for the latter complication (Shepard et al., 2005).

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The clinical signiﬁcance and impact of coinfection with hepatitis D virus (HDV), especially genotype I HDV (Su et al., 2006), HCV, and/or human immunodeﬁciency virus (HIV) among patients with HBV chronic hepatitis, has emerged as a major issue (Shukla and Poles, 2004). Approximately 5% of the global HBV carriers are coinfected with HDV (Hsieh et al., 2006). The prevalence of chronic HBV infection among HIVinfected individuals has been reported to be 6–10% in Western countries and up to 20% in Asia (Sheng et al., 2004); a recent cross-sectional study of HBVinfected patients in French departments of internal medicine found 53% coinfected with HIV (Sene et al., 2007). Occult HBV infection, deﬁned by the presence of HBV DNA in the serum or liver in the absence of HBs Ag, was found in 45% of HCVinfected injection-drug users in the United States (Torbenson et al., 2004).

2.3. Immunopathophysiology and biological diagnosis HBV has a tropism for hepatic cells, but does not have cytopathogenic effects per se. Indeed, hepatic cell necrosis is caused by physiological immune responses to viral antigens, mainly involving cytotoxic CD8+ T lymphocytes, which may be excessive in symptomatic infection and/or persistent in chronic infection. Notably, HBV DNA sequences have been found in circulating leukocytes (Hadchouel et al., 1988), predominantly lymphocytes and especially CD4+ but also CD8+ T lymphocytes (Calmus et al., 1994), as well as in lymph nodes, but without evidence of replicative forms of HBV (Umeda et al., 2005). Such sequences have been found to a lesser degree in endothelial cells or stromal ﬁbroblasts, in spleen, small bowel, gonads, thyroid gland, kidneys, pancreas, and adrenal glands, during both acute and chronic infection (Mason et al., 2005; Yoffe et al., 1990). Diagnosis and management of HBV infection now relies on both the standard serologic markers but also, largely for chronic infection, on tests to quantify HBV load and study the virus genotype and possible mutations. In acute infection, viral

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replication can ﬁrst be evidenced by the detection of HBV-DNA and HBs Ag in sera. Next appears anti-HBc Ab, of IgM then Ig G isotypes, then antiHBs Ab, which testify to the effective clearance of the virus and are protective. In chronic infection, anti-HBc Ab is adequately produced, but the nonclearance of the virus leads to persistent detection of HBV-DNA, at least during the initial and replicative phases, and HBs Ag without anti-HBs Ab. HBe Ag is associated with viral replication and therefore detectable early during acute infection and during the initial and reactivation phases in chronic infection. With the wild-type virus, the seroconversion to anti-HBe Ab theoretically occurs concomitantly toward the end of virus replication, but in up to 5% of chronic infection cases (Yim and Lok, 2006; McMahon et al., 2001; Lok et al., 1987), reversion may still occur in the year following seroconversion. Most importantly, HBV replication can continue in HBe Ag-negative patients, because of the frequent pre-core mutations that can occur during chronic infection, as described above, especially during seroconversion of HBe Ag to anti-HBe Ab itself, occurring spontaneously and/or under antiviral therapy (Yim and Lok, 2006).

3. Extra-hepatic manifestations of HBV infection Most of the described and clinically overt extrahepatic manifestations of HBV infection occur with acute infection or within the months following initial infection. In some cases, especially for patients with the most severe and sometimes lifethreatening manifestations, that is, those with HBV-related PAN, antiviral therapy is required. Such a situation is highly unique, because antiviral agents were developed and are approved ofﬁcially for HBV infection to treat only chronic hepatitis. With the exception of glomerulonephritis, extrahepatic manifestations during chronic infection are generally less pronounced, and therefore have rarely been emphasized in hepatology trials or textbooks on HBV infection, as compared with HCV infection (Amarapurkar and Amarapurkar,

2002; Han, 2004). Nonetheless, extra-hepatic clinical or biological manifestations have been reported to occur in up to 16% of patients with chronic infection (Cacoub et al., 2005). Case reports and the few studies available show that in both acute and chronic settings, extrahepatic manifestations do not seem to be linked to a speciﬁc HBV genotype. However, such manifestations differ in geographical distribution, and extrahepatic biological manifestations might be more frequent in patients infected with pre-core mutant virus (Cacoub et al., 2005). Indeed, HBV-PAN was more frequently reported among European, Mediterranean, and North American adult patients, whereas glomerulonephritis is more frequent in children in endemic regions of the world, such as Asia or South America, where HBV transmission is chieﬂy perinatal or horizontal and leads more commonly to chronic infection (Han, 2004). These manifestations are suggested to result from the formation and deposition of HBV Ag and anti-HBV Ab immune complexes, then their inappropriate persistence leading to excessive activation of the complement cascade. The precise identiﬁcation of causative HBV Ag remains controversial. Notably, a direct role of HBV virus through its continuous replication in some extrahepatic tissues is not totally excluded, even though no overt cytopathogenic effects have been unveiled in these tissue cells (Mason et al., 2005).

3.1. Prodromal pre-icteric syndrome In up to 30% of adult patients and fewer children, symptoms of acute HBV infection develop. After the incubation period, a prodromal pre-icteric syndrome may occur, with non-speciﬁc symptoms such as nausea, asthenia, and anorexia but also fever, arthralgias mainly involving the neck and spine, and/or arthritis, myalgias, and sometimes urticarian skin rash. Glomerulonephritis, especially in children, and/or central and/or peripheral nervous-system involvement may also occur. This syndrome is usually transient, and symptoms spontaneously resolve after 3–7 days, whereas icterus appears 1–3 wk later. The symptoms are

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection

likely to correspond to a serum-sickness disease in the context of high viral replication and immune response with formation of immune complexes. At this stage, HBs Ag and HBV-DNA are already detectable, whereas anti-HBc Ag IgM appears at the beginning of symptoms, then anti-HBc Ag IgG and HBe Ag a few days before icterus onset. Prodromic syndrome is not predictive of fulminant hepatitis or chronic infection (Krugman et al., 1979). However, arthralgias and/or arthritis may occasionally persist for longer, without joint destruction (Han, 2004; Tre´po and Guillevin, 2001), possibly, but not always, reﬂecting the transition to chronic infection.

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of the recent HBV-PAN patients we have seen came from countries with no vaccination policy, were intravenous drug addicts, or were at risk for sexually transmitted diseases. Strikingly, since 2002, the overall incidence of PAN, related to HBV or not, has decreased, which further supports, albeit indirectly, the hypothesis of a potential exogenous and/or infectious cause of PAN (HBV and/or another yet unidentiﬁed agent(s)). Conversely, the incidence of some other systemic vasculitides, such as microscopic polyangiitis, Wegener’s granulomatosis, and Churg–Strauss syndrome, is increasing (Mahr et al., 2004, 2006).

3.2.2. Pathogenesis 3.2. HBV-related polyarteritis nodosa 3.2.1. Epidemiology Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis predominantly involving mediumsized arteries that can affect most of the body’s organs. First described by Kussmaul and Maier (1866), PAN is rare. It can affect all racial groups. Estimates of the annual incidence of PAN in the general population range from 4.6 per 1,000,000 inhabitants in England (Scott et al., 1982) to 77 per 1,000,000 in Alaska, an HBV-hyperendemic region (McMahon et al., 1989). During the 1970s, about half of the patients with PAN were indeed infected with HBV, which therefore appeared to be the leading identiﬁable cause of PAN (Prince and Tre´po, 1971; Tre´po and Thivolet, 1970). However, the frequency of HBV-PAN among all the cases of PAN has declined from 38.5% during 1972–1976 to 17.4% during 1997–2002, with a peak of 48.8% between 1982 and 1986 (Guillevin et al., 2005; Mahr et al., 2004). The main reduction is explained by donor selections reinforced, with systematic blood testing for Hbs Ag, anti-HBc Ab and transaminase (GPT) level, and widespread vaccination campaigns organized for teenagers and people at risk. Similarly, in the United States, the incidence of acute HBV infection in children and adolescents has decreased by 89% (CDC, 2004), and with the possible exception of China, many Asian countries have now become intermediateprevalence areas (Custer et al., 2004). Indeed, most

The immunopathogenic mechanisms leading to vascular injury in PAN and HBV-PAN are probably comparable but heterogeneous. The mechanism of vascular inﬂammation implicated most often is an immune-complex–induced lesion (Guillevin et al., 1990; Lambert et al., 1980; Tre´po and Thivolet, 1970), like for the prodromal preicteric syndrome, but with more severe and longer lasting clinical presentation because of more persistent infection and viral replication. Indeed, almost all cases of HBV-PAN are associated with wild-type HBV and high virus replication with HBe antigenemia, which suggest that lesions could result from the deposition of soluble viral Ag–Ab complexes in Ag excess. However, the precise identiﬁcation of this latter Ag remains controversial, since all the three HBs, HBc, and HBe Ag have been suspected. Notably, cases of PAN occurring after anti-HBV vaccination—a controversial topic, especially in Europe, and out of the scope of this chapter—are extremely infrequent and lack epidemiological conﬁrmation and/or strong imputability proof (Degos, 2006). These circulating immune complexes would deposit in the vessel walls, although only rarely histologically proven (Gower et al., 1978; Prince and Tre´po, 1971; Tre´po and Thivolet, 1970), and, in turn, would activate the complement cascade, then neutrophils, resulting in endothelial injury. Although theoretically possible, HBV-PAN occurring during chronic infection as a viral recombination or superinfection with a different HBV genotype has not been reported,

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and published cases of HBV-PAN with mutant pre-core virus are extremely rare to date (Miguelez et al., 1998). However, no published results of PAN-HBV patients have described a systematic analysis of the HBV genotype. Notably, some other viruses have been reported to engender PAN features, although more rarely than HBV; examples include HCV, GB virus-C (Servant et al., 1998), parvovirus B19 (Corman and Dolson, 1992), some members of the Herpes viridae family (Rodriguez-Pereira et al., 1997), and HIV (Gisselbrecht et al., 1997; Pagnoux et al., 2006a). Conversely and to date, no case of superinfection with HDV causing PAN has been reported in HBV-infected patients.

3.2.3. Histology Vasculitic lesions have a segmental distribution pattern, with a predilection for arterial bifurcations. Early inﬂammatory inﬁltrates of and/or around the vessel walls contain lymphocytes, plasmocytes, histiocytes, and some neutrophils. Fibrinoid necrosis predominates in the internal layer of the arterial media, thereby supporting thrombosis development (Fig. 1). Segmental necrosis of medium-sized

vessel walls may actually give rise to microaneurisms, detectable on angiography (Fig. 2), mainly on renal and celio-mesenteric arteries, which usually regress or disappear with effective treatment (Darras-Joly et al., 1995).

3.2.4. Clinical manifestations and diagnosis In HBV-PAN, symptoms of most cases developed less than 6 months (range, 30–1695 days) following infection (Guillevin et al., 2005). Symptoms are listed in Table 1 (Guillevin et al., 2005). HBV-PAN patients are usually younger than 40 years. Main manifestations are those described for PAN not related to HBV: weight loss, fever, myalgias, arthralgias, asthenia, cutaneous lesions (livedo, cutaneous nodules, and/or necrosis), peripheral neuropathy, especially mononeuritis multiplex (Moore, 1995), gastrointestinal tract involvement, and/or cardiac failure. Abdominal manifestations (53%), and especially those requiring emergency surgery, such as gastrointestinal tract infarctions, perforations, and/or necrotizing pancreatitis, are frequent, and represent the leading cause of death (Guillevin et al., 2005; McMahon et al., 1989; Pagnoux et al., 2005; Sergent et al., 1976).

Figure 1. Muscle biopsy of a patient with polyarteritis nodosa showing leukocyte inﬁltrates in the wall of a medium-sized artery (blank arrow), with ﬁbrinoid necrosis (plain arrow), and thrombosis in the vessel lumen (asterisk). (See Colour Plate Section.)

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection

Figure 2. Renal angiogram showing artery stenoses (arrowheads) and microaneurisms (arrows) in a female patient with polyarteritis nodosa. (See Colour Plate Section.)

Hypertension and/or renal impairment are also among the most frequent symptoms and are included in the classiﬁcation criteria established in 1990 by the American College of Rheumatology (Table 2—Lightfoot et al., 1990); they result from renal artery involvement with consecutive renal ischemia and some infarction, but not from glomerulonephritis, which is more characteristic of small-sized vessel vasculitides such as microscopic polyangiitis or Wegener’s granulomatosis. Only very rare cases of glomerulonephritis occurring in PAN or HBV-PAN patients have been reported. Hence, kidney biopsy is not part of the usual diagnostic and/or initial investigations in patients with suspected or established PAN. When it is performed, if there are no renal microaneurisms seen on angiography that would

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contra-indicate the biopsy, the presence of glomerulonephritis should primarily lead to reconsider the diagnosis. Notably, HBV-PAN patients less frequently tend to have malignant hypertension (5%), renal infarction, and/or orchiepididymitis (25%) than those with PAN not linked to HBV infection. Hepatitis habitually remains silent before the onset of PAN symptoms, which can be the ﬁrst manifestations of HBV infection. Transamine (GPT and GOT) levels are usually only moderately elevated and even remain at normal levels in onethird of patients (Guillevin et al., 2005), whereas cholestasis is usually absent or minor. Liver biopsy, when performed, frequently reveals signs of chronic hepatitis, even when taken just a few months after HBV infection, which further suggests that pathogenic mechanisms differ between liver disease in HBV-PAN and that in acute hepatitis. Notably, hepatic biopsy must not be performed for diagnosis of HBV-PAN because vasculitis is rarely seen on histology and the biopsy itself can be hazardous because of the possible traumatic injury of microaneurisms with subsequent and potentially life-threatening bleeding. The diagnosis of HBV-PAN ideally relies on the combination of clinical symptoms; radiological investigations, especially angiography, when patients have abdominal pain resembling mesenteric ischemia; biopsy of an affected tissue, especially nerve and muscle in case of neuropathy, but also sometimes of skin lesions; and, of course, the detection of replicative HBV infection. Patients must of course be tested for other possible coinfections, such as HCV or HIV. As already emphasized, kidney and/or liver biopsies should theoretically not be performed in patients with PAN, regardless of relation to HBV or not, because they may be dangerous and because PAN is a medium-sized vessel vasculitides, usually without evidence of vasculitis in the liver parenchyma or glomerular involvement. Moreover, angiography is mandatory before any kidney or liver biopsy in the rare HBV-PAN patient for whom it is indicated, that is, with suspected glomerulonephritis, usually infrequent, or possible liver dysfunction resulting from another associated liver disease, such as autoimmune hepatitis or cancer.

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Table 1 Characteristics of the 115 HBV-PAN patients reported by the French vasculitis study group (adapted from Guillevin et al., 2005) Patient characteristics Age (years, mean7SD) Sex ratio M:F Interval between HBV infection and the ﬁrst manifestation(s) of PAN [available for 12 patients] (days, mean7SD(range)) Delay between ﬁrst symptom(s) and diagnosis (days, mean7SD) Clinical manifestations at diagnosis (%) General symptoms Fever Weight loss >5 kg Myalgia Arthralgia Neurological involvement Mononeuritis multiplex Superﬁcial peroneal nerve involvement Deep peroneal nerve involvement Radial involvement Ulnar involvement Bilateral neuropathy Central nervous system involvement

51.1717 1.8 5967628 (30–1695)

Table 1 (continued ) Myocardial infarction Pericarditis Retinal vasculitis

1.7

Disease scoring BVAS (mean7SD)

17.878.2

FFS (% of patients) >1 >2 84784

96.5 68.7 87 47.5 55.7 83.5 71.3 40 10.4 21.7 72.5 9.6

Renal and urological involvement Proteinuria/he´maturia Renal vasculitis Dialysis/anuria at diagnosis Orchitis Recent hypertension Malignant hypertension

38.3 18.3 29.6 3.5 25.3 31.3 5.2

Skin manifestations (except edema) Nodules Purpura Livedo reticularis Ankle edema

31.3 8.7 16.5 10.4 15.7

Gastrointestinal manifestations Abdominal pain Bleeding Small intestine perforation/ ischemia Cholecystitis Appendicitis Pancreatitis

53.0 51.3 2.6 2.6

Cardio-vascular signs Raynaud phenomenon Cardiac insufﬁciency

30.7 2.6 12.2

5.2 1.7 6.1

0.9 5.2

Radiology (%) Microaneurisms on angiography (performed in 67 patients) Renal infarcts Outcome Follow-up (months, mean7SD) Remission (%) HBe Ag to anti-HBe Ab seroconversion Relapses Deaths (including those who died after achieving complete remission)

61.7 31.3 68.6 28.3 697135.8 80.9 36.0 9.7 35.7

3.2.5. Treatment For HBV-related PAN, conventional treatment with corticosteroids and cyclophosphamide is not recommended because it favors virus replication and, hence, facilitates evolution to chronic infection. Therefore, a combination strategy has been devised (Guillevin et al., 2005; Gupta et al., 2001): to rapidly control the most severe and potentially life-threatening manifestations, initial and short treatment with corticosteroids (1–2 wk at a 1 mg/kg/day equivalent dosage of prednisone), then their abrupt discontinuation to enhance immunological clearance of the HBV-infected hepatocytes and favor seroconversion of HBe Ag to anti-HBe Ab; to clear circulating immune complexes and control the course of the disease, plasma exchange (60 ml/kg 3–4 times/wk for 3 wk, then 2–3 times/wk for 2 wk, progressively tapered and discontinued when anti-HBe Ab is detected to avoid the clearance of the newly synthesized immunoglobulins); antiviral agents for several months, at least until virologic response with seroconversion and complete remission are achieved.

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection Table 2 1990 ACR criteria for the classiﬁcation of polyarteritis nodosa (adapted from Lightfoot et al., 1990) Criterion

Deﬁnition

1.

Weight loss >4 kg

2.

Livedo reticularis

3.

Testicular pain or tenderness

4.

Myalgias, weakness, or polyneuropathy

5.

Mononeuropathy or polyneuropathy

6.

Diastolic blood pressure >90 mmHg Elevated blood urea nitrogen or creatinine

7.

8.

Hepatitis B virus

9.

Arteriographic abnormality

10.

Biopsy of small- or medium-sized artery containing polymorphonuclear neutrophils

Loss of 4 kg or more of body weight since illness began, not due to dieting or other factors Mottled reticular pattern over the skin of portions of the extremities or torso Pain or tenderness of the testicles, not due to infection, trauma, or other causes Diffuse myalgias (excluding shoulder and hip girdle) or weakness of muscles or tenderness of leg muscles Development of mononeuropathy, multiple mononeuropathies, or polyneuropathy Development of hypertension with the diastolic blood pressure higher than 90 mmHg Elevation of blood urea nitrogen >40 mg/dl (14.3 mmol/L) or creatinine >1.5 mg/dl (132 mmol/L), not due to deshydratation or obstruction Presence of HBs Ag or antiHBs Ab in serum Arteriogram showing aneurysms or occlusions of the visceral arteries, not due to arteriosclerosis, ﬁbromuscular dysplasia, or noninﬂammatory causes Histologic changes showing the presence of granulocytes or mixed leukocytes inﬁltrate in the artery wall

A patient with vasculitis can be classiﬁed as having polyarteritis nodosa if at least 3 of these 10 criteria are present. The presence of any three or more criteria yields a sensitivity of 82.2% and a speciﬁcity of 86.6%.

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remission, 4 (5%) relapse and 24 (30%) died as compared with 20 (57%) remissions, 5 (14%) relapses, and 17 (49%) deaths (not signiﬁcant) among the remaining 35 who received corticosteroids alone or in combination with cyclophosphamide and/or plasma exchange but no antiviral agents. Moreover, seroconversion rates for HBe Ag to anti-HBe Ab for the two groups were 49% and 15%, respectively (po0.001). The antiviral agents and their dosages for these patients are similar to those prescribed for chronic HBV hepatitis, and included vidarabine for the ﬁrst patients, then interferon (IFN)-alpha or lamivudine. Indeed, vidarabine is no longer used because of its high and frequent occurrence of neurological and hematological toxicity. Lamivudine has been shown to increase seroconversion rate in up to 60% of patients (Guillevin et al., 2005), but was not able to improve survival rate at 18 months as compared with conventional treatment without antiviral drugs (mortality rate at 18 months was 28% with conventional immunosuppressive therapy vs. 18% with combined antiviral therapy, p=0.46). Other combination strategies, including Pegylated IFNalpha-2 and/or lamivudine and/or newer agents, such as entecavir, emtricitabine, or adefovir dipivoxil, are probably at least as effective as IFNalpha-2 or lamivudine alone and may be preferentially prescribed in the future. They might be more effective in controlling HBV replication in those patients in whom vasculitis resolved but HBV infection persisted (Krastev, 2006). Because of the rarity of HBV-PAN at present, a trial investigating this therapeutic issue is unlikely, but advances in the treatment of chronic HBV hepatitis must be considered for the antiviral treatment of HBVPAN, in combination with plasma exchange and the short initial corticosteroid course.

3.2.6. Outcome Immunosuppressants should only be given to patients with worsening PAN manifestations despite well-conducted therapy as recommended above. The efﬁcacy of this antiviral strategy was conﬁrmed in a series of 115 HBV-PAN patients (Guillevin et al., 2005): among the 80 who were treated with the antiviral strategy, 73 (91%) exhibited

HBV-PAN is an acute disease that can be severe initially, but the outcome is excellent in most cases with the timely application of adequate treatment. Localized forms, such as those limited to cutaneous manifestations or muscle involvement described for PAN not related to HBV, are exceptional in HBV-PAN. With the application of the effective,

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precise combined antiviral strategy deﬁned above, the prognosis of HBV-PAN has improved and the overall survival rate increased to between 64 and 70% (Guillevin et al., 2005). Seroconversion usually parallels recovery. Once remission has been obtained, PAN tends not to recur, unlike other systemic vasculitides such as Wegener’s granulomatosis or microscopic polyangiitis. Indeed, only 8–12% of HBV-related PAN and 19–32% of non– HBV-related PAN tend to relapse, with a mean time to ﬁrst relapse of 37 and 29 months, respectively (Gayraud et al., 2001; Pagnoux et al., 2006b). Notably, HBV-PAN relapses occur almost exclusively in patients with continued active virus replication despite treatment. In these rare cases, the clinical pattern of relapse does not necessarily repeat the original presentation. However, even after disease cure, sequelae such as vascular nephropathy or peripheral neuropathy may persist for years or sometimes indeﬁnitely.

3.3. HBV-related glomerulonephritis Besides ischemic renal vasculopathy seen in HBVPAN, different forms of renal disease have been described with HBV infection: membranous nephropathy, membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, and, more rarely, minimal change disease, IgA nephropathy, or focal segmental glomerulosclerosis (Bhimma and Coovadia, 2004). Although rare in North America and the other Asian countries, HBV-related or, more cautiously, HBV-associated glomerulonephritis remains among the most common causes of glomerulonephritis in children in endemic countries such as China (Bhimma and Coovadia, 2004). Indeed, glomerulopathy was diagnosed in 5% of adult patients with chronic HBV infection in a French cross-sectional study (Cacoub et al., 2005), but it has also been reported during acute HBV infection. The potential causative role of HBV in these renal diseases is supported by their decreased incidence following vaccination campaigns (Sun et al., 2003) and by the results of a Chinese study revealing that HBV-infected people with diabetes were signiﬁcantly more prone to develop end-stage renal disease than their

HBV-negative counterparts (8.7% vs. 6.4%), after controlling for potential confounding factors such as age or glycemic control (Cheng et al., 2006). Biologically, HBV Ag was found expressed in kidney tissue in some studies, as was HBV-DNA in the nucleus and cytoplasm of epithelial cells of renal tubules, which correlates with the duration of proteinuria (Xin et al., 1998). In some patients with chronic HBV infection, especially those positive for HBV-DNA, serum showed the in vitro ability to promote apoptosis in renal tubular cells through a Fas/Fas-ligand pathway (Deng et al., 2006). A direct cytopathogenic role of HBV in the kidney cannot be excluded. However, the more frequently invoked mechanism for glomerular injury in HBV infection is, once again, the formation of immune complexes of viral Ag and anti-HBV Ab, with their subsequent subendothelial and/or mesangial deposition in the kidneys. Indeed, the expression of HBV-DNA could persist in renal tissues, leading to the continuous expression of viral Ag. Earlier studies suggested that HBe Ag was the most likely HBV Ag responsible, but controversies further emerged concerning this point, because all types of glomerular depositions, with HBs Ag, HBc Ag, and/or HBe Ag, have been reported (Lin, 1990). Finally, why nephropathy develops only in some individuals with chronic HBV infection remains unknown, and underlying genetic and/or socio-environmental factors and/or a predisposing host immunological abnormality, especially concerning HBV-speciﬁc cellular immune response, may therefore also play a role (Bhimma and Coovadia, 2004). The main symptoms of these HBV-related glomerulopathies are proteinuria and nephrotic syndrome, occurring predominantly in males, especially children. As for HBV-PAN, liver functions are generally spared, and most patients with renal involvement are chronic ‘asymptomatic’ carriers and do not have chronic hepatitis. HBVrelated membranous nephropathy is the most frequent form and resolves spontaneously in most children, usually in parallel with HBe Ag clearance, whereas progression to renal failure may occur in up to one-third of adults (Lai et al., 1991). Corticosteroids do not have any beneﬁcial effect and can induce virus replication. Antiviral

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection

treatment, with IFN-alpha and/or other, newer antiviral drugs and/or combinations, can be more efﬁciently used. In the study by Lin (1995), complete resolution of proteinuria was obtained in all 40 patients treated with IFN-alpha, and seroconversion of HBe Ag to anti-HBe Ab was achieved in 16 as compared with none of the 20 patients receiving only supportive treatment, for both parameters.

3.4. Gianotti–Crosti syndrome Gianotti–Crosti syndrome, also named infantile papular acrodermatitis, is characterized by an acral, self-limiting, symmetrical, papular skin rash in children. It is preferentially located on the dorsal faces of hands and feet (Fig. 3—Brandt et al., 2006; Gianotti, 1973), but it can also affect, although rarely, the face and/or buttocks. Diagnostic criteria include three positive clinical features (at least a 10-day duration of symmetrical papules or

201

papulovesicles; 1–10 mm in diameter; on at least three of the following four sites—cheeks, buttocks, extensor surfaces of the forearms, and extensor surfaces of legs) and two negative features (extensive truncal lesions and scaly lesions) (Chuh, 2001). The syndrome can occur during acute HBV infection and was reported in a non-negligible number of cases in conjunction with superinfection with measles or after a concomitant vaccination against both these latter viruses (Andiran et al., 2002). It has also been observed after vaccination against HBV (Karakas et al., 2007). The cutaneous lesions spontaneously resolve within a few weeks, usually in parallel to the clearance of HBs Ag, and hence do not warrant any speciﬁc therapy. The underlying mechanisms remain elusive, even though the syndrome might also be related to the formation of immune complexes during the acute phase of the infection, in a particular genetic and environmental setting. In earlier papers, HBV serotypes ayw, adr and adw were preferentially

Figure 3. Gianotti–Crosti syndrome (infantile papular acrodermatitis). Pseudo-urticarian rash on the dorsum of the hands and on the calves. (See Colour Plate Section.)

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associated with this syndrome. No HBV genotype study has been performed since, largely because of the rarity of the syndrome. Some single case-report descriptions have suggested that HBV genotype D might be more frequently associated with the syndrome (Michitaka et al., 2004). Of note, the syndrome is not speciﬁc to HBV, because it was also reported with Epstein Barr Virus, Respiratory Syncytial Virus, enterovirus or Human Herpes Virus 6 (Caputo et al., 1992; Draelos et al., 1986), and some bacterial infections (Khan et al., 2007) or after vaccination against hepatitis A virus (Monastirli et al., 2007). However, the syndrome is a very rare HBV-associated manifestation, whose frequency has decreased during the past decades, for some not completely explainable reasons.

in another study of 66 patients, the frequency of HBV or HCV infection was somewhat lower, 21% for each, and one-third of infected patients had both infections (Stransky et al., 2000). The truth probably lies somewhere between these values, with chronic HCV infection probably more frequent than chronic HBV infection (Gisbert et al., 2003). No speciﬁc treatment is recommended, except for usual skin care and avoidance of sunlight, alcohol and, possibly, estrogen therapy (Thadani et al., 2000). Antiviral treatment is indicated only for chronic HBV hepatitis, when necessary, with insufﬁcient data to predict its effect, if any, on this particular cutaneous manifestation.

3.6. Diabetes mellitus 3.5. Porphyria cutanea tarda Porphyria cutanea tarda is a relatively rare disease, with an estimated overall prevalence of approximately 1/25,000 inhabitants in the United Kingdom. Two forms exist: the familial form and the sporadic form, which accounts for 80–90% of cases. The disorder is characterized by skin lesions and liver damage in most cases, especially in the familial form, in relation to a metabolic disorder caused by reduced hepatic uroporphyrinogen decarboxylase activity (Roux et al., 1996). Skin lesions include fragile skin, subepidermal bullae, pigmentation in sun-exposed areas such as the dorsal faces of the hands, and hypertrichosis, particularly on the forehead and upper cheeks. Patients do not have increased risk of acute neurological manifestations as compared with those affected by variegate porphyria or hereditary coproporphyria, who might have similar skin lesions. In the sporadic form, etiological and/or associated factors include alcohol and estrogen use, iron overload, and toxins such as hexachlorobenzene but also HCV and/or HBV infection(s) (Valls et al., 1986). Indeed, serologic markers of chronic infection with HCV or HBV were detected in 91 and 41%, respectively, of 34 patients in one study, with viral genomes of HCV or HBV detected in 65 and 40%, respectively (Navas et al., 1995). However, available data are not all in concordance, and

An association of diabetes mellitus and both HBV and/or HCV infection(s) has been suggested by some study results, especially those conducted in regions with high HBV and HCV prevalence. Indeed, diabetes mellitus was signiﬁcantly more frequent in a study of Asian Americans with HBV infection (65% vs. 27.5% for HBV-negative controls), as well as in patients infected with HCV or both HBV and HCV (Li-Ng et al., 2007). In a study in Niger, 9% of patients with diabetes showed HBs Ag in sera as compared with 2.9% of non-diabetic controls (Oli and Okafor, 1980). Patients with diabetes may have greater exposure to the virus through poor hygiene practice in insulin injections and/or the use of ﬁnger sticks (Khan et al., 2002). Indeed, in a European study, HBV markers were more frequently detected in diabetic patients treated with insulin than in those treated orally (Hasslacher et al., 1977). As well, a subsequent series in the same regions showed a decline or even disappearance in frequency of HBV Ab among diabetic patients (Onyekwere et al., 2002), perhaps due to improved hygienic measures. Conversely, a Turkish study revealed a signiﬁcant difference in prevalence of HBV markers between diabetic patients and controls (51% vs. 25%) not related to diabetes duration, patient age, and, more importantly, insulin injections (Khuri et al., 1985), which suggests that other mechanisms may explain the possible link between HBV and

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection

diabetes mellitus. Moreover, gestational diabetes mellitus was diagnosed slightly more frequently in women with chronic HBV infection than in HBV-negative pregnant women (Lao et al., 2003, 2007). Diabetic patients may have impaired ability for HBV removal and/or be highly susceptible to subclinical HBV infection, whereas HBV itself, or some serum constituents of infected patients, may play a causative or participating role in the development of diabetes mellitus. Potential pancreatic damage secondary to extra-hepatic viral replication has been evoked to support this latter theory. However, links between HBV and diabetes mellitus remain controversial, as does the respective inﬂuence of HBV or HCV, particularly because of numerous potential confounding factors. In contrast to HCV, HBV was indeed not identiﬁed as being associated with diabetes mellitus in some Asian studies (Chen et al., 2006; Okan et al., 2002), whereas diabetes mellitus was found in 5.6% of HCV-positive and no HBV-positive Pakistanian patients without liver disease and with comparable frequencies of 24.5 and 19.4% in those with chronic liver disease due to HCV or HBV infection, respectively (Qureshi et al., 2002). Conversely, in an Italian study of type 2 diabetes patients (Sangiorgio et al., 2000), the prevalence of HCV and HBV infection was similar (7.6 and 7.1%, respectively), with an overall prevalence of HBV and/or HCV infection of 11%.

3.7. Autoimmunity 3.7.1. Thyroid manifestations Serum thyroxine level was increased proportional to transaminase levels in 60% of patients with acute HBV infection, presumably because of the release of thyroxin-binding globulin into the circulation from injured hepatocytes (Zafar et al., 1992). The thyroxine level usually returns to normal after HBV recovery (Gardner et al., 1982). Data on serum triiodothyronine levels are conﬂicting; levels were reported to increase in 10% of acute HBV cases in one study (Zafar et al., 1992) but decrease in another (Gardner et al., 1982), with a return to normal levels after HBV

203

recovery in both. Some HBV-infected children were reportedly positive for anti-thyroid Ab. Thyroid hormones were within the normal range in those latter patients positive for anti-thyroid Ab, but thyrotropin-releasing hormone-stimulation test revealed subclinical hypothyroidism (Kansu et al., 2004). Indeed, thyroid gland dysfunction is a known complication of INF-alpha therapy in patients with chronic viral hepatitis (Wong et al., 2002), especially HCV hepatitis. However, antithyroid peroxidase Ab and anti-thyroglobulin Ab can be detected in up to 5 and 3% of HBV-infected patients, respectively, before any antiviral treatment (Fernandez-Soto et al., 1998) and do not appear to be inﬂuenced by subsequent IFN-alpha therapy (Gregorio et al., 1996), except in one study in which 45% of the patients developed anti-thyroid auto-Ab 4–8 months after beginning IFN-alpha therapy (Mayet et al., 1989). Intriguingly, still unknown is the pathophysiological meaning of thyroxine and triiodothyronine binding sites present on the spherical particles associated with HBs Ag (Neurath et al., 1975).

3.7.2. Anticardiolipin autoantibodies Anticardiolipin Ab of IgG, IgM, and/or IgA isotype(s) have been found in 14–21.5% of patients with HBV infection, especially chronic infection (Elefsiniotis et al., 2003; Mangia et al., 1999; Zachou et al., 2003), but anti-beta2-glycoprotein I (GPI) Ab in only 2% (Zachou et al., 2003), thus arguing for cofactor beta2-GPI independency in most cases (Guglielmone et al., 2001). Indeed, Ab titers were relatively low and the levels and distribution of isotypes did not differ much between patients with acute or chronic HBV infection (Guglielmone et al., 2001). Notably, high anticardiolipin Ab level might be more frequent among patients coinfected with HDV (42.8%) (Zachou et al., 2003). Importantly, the detection of anticardiolipin Ab is not associated with clinical features of anti-phospholipid syndrome, but perhaps with some extra-hepatic manifestations such as leucocytoclastic angiitis or membranoproliferative glomerulonephritis, and, among patients with HBV-related hepatocellular carcinoma, a high risk of venous portal thrombosis (Elefsiniotis et al., 2003).

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3.7.3. Other autoantibodies Diverse other auto-Ab have been reported with chronic viral hepatitis, including HBV infection, and usually occur as an epiphenomenon and at relatively low titers. About 15% of the HBVinfected patients have at least one detectable auto-Ab, particularly anti-smooth muscle cell Ab (7%), antinuclear Ab (3%), antinucleosome Ab, cryoglobulin, rheumatoid factor, and/or antiliver–kidney–microsome (anti-LKM) Ab (2% for each) (Cacoub et al., 2005; Lohse et al., 1995; Mangia et al., 1999). In children, the prevalence of an auto-Ab, especially anti-smooth muscle cell and antinuclear Ab, can be as high as 34% (Gregorio et al., 1996). Mutant pre-core virus seems to be more frequently associated with such auto-Ab but only by univariate analysis; no correlation with any HBV genotype has been identiﬁed (Cacoub et al., 2005). Moreover, as for antithyroid Ab, these other auto-Ab do not seem to be induced or modiﬁed by IFN-alpha therapy (Gregorio et al., 1996). In contrast to mixed cryoglobulinemia in HCV infection, clinical expression of these Ab is rare in HBV-infected patients (Czaja, 1997).

3.8. Miscellaneous During acute HBV infection, other manifestations have been reported, such as isolated arthralgias, myalgias, or, more rarely, neuropathy, Guillain– Barre´-like syndrome (Han, 2004; Tre´po and Guillevin, 2001), or epididymitis (Tasar et al., 2005); such manifestations might correspond to a minor prodromal pre-icteric phase or to limited forms of systemic HBV-PAN. Similar concerns relate to other extra-hepatic manifestations infrequently reported for patients with chronic HBV infection; examples include psoriasis skin lesions (1% of patients), skin vasculitis (1%), pruritus (1%), Raynaud phenomenon (2%), uveitis (2%), myalgias (3%), arthralgias (3%), sicca syndrome (3%), and/or sensory-motor neuropathy (5%) (Cacoub et al., 2005). These manifestations most often occur in the early years following infection and possibly correspond to mild and/or localized forms of HBV-PAN or during an acute increase of HBV replication. However, the

precise relation of these manifestations with HBV infection remains elusive and they might indeed occur coincidentally. Isolated acute pancreatitis, a possible feature of severe HBV-PAN, has been documented in acute HBV infection but also in acute exacerbation of chronic HBV infection (Fournier et al., 1991), sometimes following liver transplantation. Patients with possible HBV-PAN-related isolated pancreatitis seem to have a higher mortality rate (80%) than patients with pancreatitis from other causes (12%) or with acute exacerbation of chronic HBV infection without pancreatitis (2%) (Yuen et al., 2001). In some patients with fatal acute necrotizing pancreatitis, damage of both exocrine and endocrine epithelial cells with inﬂammatory responses was observed on autopsy, whereas immunohistochemistry and in situ hybridization of the pancreas revealed the presence of HBs Ag and HBV-DNA in the cytoplasm of acinar cells, and electron-microscopically showed core-like particles in the nucleus and cytoplasm (Cavallari et al., 1995; Yoshimura et al., 1981). HBV-related ophthalmological manifestations, mainly vasculitic retinal ischemia (Akova et al., 1993; Lortholary et al., 1989), are rare but can occur during HBV-PAN, as in PAN not due to HBV, but also during chronic HBV infection, with conjunctival and perilimbic microcirculation abnormalities, possibly resulting in scleritis, peripheral ulcerative keratitis, non-granulomatous uveitis, and/or central retinal artery occlusion and/or optic nerve dysfunctions (Cusnir et al., 1997; Morgan et al., 1986). Myalgias are frequent during acute prodromal pre-icteric syndrome and in HBV-PAN, as mentioned previously. HBV serology is therefore often included in the initial diagnostic investigations for patients with suspected myositis. However, less than 10 cases of polymyositis or dermatomyositis supposedly related to HBV infection have been reported. However, this association could be just coincidental because evidence are lacking. The reportedly simultaneous occurrence of hepatitis and myositis or the worsening of myositis following exacerbation of hepatitis in those latter 10 chronically infected patients are indeed clearly not sufﬁcient as an argument to support this assoiation

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection

(Nojima et al., 2000). Immunoﬂuorescence of both muscle and liver revealed HBs Ag/anti-HBs Ab immune complexes and complement deposits in only a few patients (Mihas et al., 1978; Pittsley et al., 1978), and in almost all patients, corticosteroid therapy alone was effective.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 16

Extrahepatic Manifestations in Patients with Chronic Hepatitis C Virus Infection Manuel Ramos-Casalsa,, Xavier Fornsb, Jose-Maria Sanchez-Tapiasb, Juan Rode´sb a

Laboratory of Autoimmune Diseases ‘‘Josep Font’’, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain b Liver Unit, ICMD, Ciberehd, ‘‘Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

1. Introduction Autoimmunity and viral infections are closely related ﬁelds, and viruses have been proposed as possible etiologic or triggering agents of systemic autoimmune diseases (SAD). The hepatitis C virus (HCV), a linear, single-stranded RNA virus identiﬁed in 1989 (Choo et al., 1989), is recognized as one of the viruses most often associated with autoimmune features. A decade ago, various authors described the association of HCV infection with a heterogeneous group of extrahepatic conditions, such as pulmonary ﬁbrosis, cutaneous vasculitis, glomerulonephritis, Mooren ulcers, porphyria cutanea tarda, or lichen planus (Gumber and Chopra, 1995), although it is currently accepted that a weak degree of association exists in some of them (Campisi et al., 2004). More recently, there has been growing interest in the relationship between HCV and SAD (Ramos-Casals et al., 2001a). The clinical association of the different SAD with chronic HCV infection may be analyzed from two different, but complementary, points of view. Firstly, a review of the literature found nearly 500 patients with coexisting SAD and chronic HCV infection

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Tel.: +34-93-2275774; Fax: +34-93-2275774 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00016-5

(Ramos-Casals et al., 2005d), with Sjo¨gren’s syndrome (SS; 182 cases), rheumatoid arthritis (RA; 94 cases), systemic lupus erythematosus (SLE; 67 cases), and polyarteritis nodosa (PAN; 41 cases) being the most frequent SAD described. Secondly, analysis of all references to series of patients with SAD tested for HCV shows the highest prevalences of HCV infection in patients with SS (17.6%), PAN (14.4%), SLE (9.6%), and RA (5.9%) (Ramos-Casals et al., 2005d). Other recent studies have focused on the association between chronic HCV infection and circulating autoantibodies, organ-speciﬁc autoimmune diseases, and lymphoproliferative processes.

2. Autoantibodies and HCV Circulating autoantibodies are often detected in patients with chronic HCV infection. Anti-nuclear antibodies, rheumatoid factor, and anti-smooth muscle antibodies are the most frequently found, while other autoantibodies (such as anti-dsDNA, anti-ENA, AMA, or anti-LKM-1) are infrequent (Fried et al., 1993; Abuaf et al., 1993; Rolachon et al., 1994; Pawlotsky et al., 1994; McFarlane et al., 1994; Richardet et al., 1994; Borotto et al., 1994; Clifford et al., 1995; Czaja et al., 1995; Cassani et al., 1997; Buskila et al., 1998; Rivera

M. Ramos-Casals et al.

210

Table 1 Meta-analysis of the main studies analysing prevalence of autoantibodies in unselected series of patients with chronic HCV infection Autoantibodies

Cryoglobulins Rheumatoid factor Anti-SMA Antinuclear antibodies Anti-LKM Anti-dsDNA Anti-ENA AMA

HCV patients tested

Positive markers

Percentage (%)

514 738

204 281

39.7 38.1

2203 3169

481 589

21.8 18.6

2193 606 444 1210

75 16 11 4

3.4 2.6 2.5 0.3

Abbreviations: HCV, hepatitis C virus; SMA, anti-smooth muscle antibodies; LKM, anti-liver-kidney microsomes antibodies; ENA, anti-extractable nuclear antigens (anti-Ro/SS-A, anti-La/SS-B, anti-RNP, anti-Sm); AMA, anti-mitochondrial antibodies.

et al., 1999b; Cacoub et al., 2000; Drygiannakis et al., 2001; Stroffolini et al., 2004; Yee et al., 2004) (Table 1). ANA have been detected in 589 (18.6%) out of 3169 unselected HCV patients included in 16 studies (Table 1), although the geographic prevalence varied signiﬁcantly (Yee et al., 2004). Yee et al. (2004) reported a threefold higher prevalence of ANA in HCV females compared with males, with no correlation between ANA and the response to antiviral therapy, while Stroffolini et al. (2004) found no correlation between non-organ-speciﬁc autoantibodies (NOSA) and the main HCV-related epidemiological, biochemical, and histological features, or the response to anti-viral treatment. This suggests that the presence of ANA or NOSA in HCV patients should not be considered a contraindication for anti-viral treatment. In addition a recent study has shown that combined anti-viral treatment (IFNribavirin) is safe and effective in NOSA-positive HCV patients, with a similar prevalence of long-term response between NOSA-positive and NOSAnegative patients (49 vs. 57%) (Muratori et al., 2005). With respect to other immunological markers, Watt et al. (2004) found a correlation between serum immunoglobulin levels in HCV patients (IgA, IgG, and total Ig) and histological progression to liver ﬁbrosis. These results are consistent with our ﬁndings in 321 patients with HCV-related

cryoglobulinemia, in whom hypergammaglobulinemia was observed more frequently in cirrhotic than in non-cirrhotic patients (Font et al., 2004).

3. Organ-speciﬁc autoimmune diseases and HCV Recent studies have analyzed the association of HCV with some organ-speciﬁc autoimmune diseases such as thyroiditis or diabetes mellitus (DM).

3.1. Thyroiditis The role of HCV in inducing thyroid autoimmunity is still unclear. Bini and Mehandru (2004) described the development of thyroid disease (overt or subclinical) in the 11% of 225 male HCVinfected patients treated with combined anti-viral therapy, although the thyroid disease responded well to speciﬁc treatment and was reversible in most cases. Antonelli et al. (2004c) reported a higher frequency of hypothyroidism (13%) and anti-thyroid antibodies (21%) in 630 treatmentnaı¨ ve HCV patients compared with normal controls, and also found similar results in a subset of these HCV patients with associated mixed cryoglobulinemia (MC) (Antonelli et al., 2004a). However, other studies, performed in the same geographical area, did not ﬁnd this close association (Tomer and Villanueva, 2004). Floreani et al. (2006) tested 697 Italian subjects for thyroid autoantibodies and anti-HCV antibodies. Of the 71 HCV-positive patients, 4 (6%) were positive for at least one thyroid autoantibody, compared with 7 (5%) of the HCV-negative sex- and age-matched controls.

3.2. Diabetes mellitus and steatosis Several clinical studies have suggested a possible link between chronic hepatitis caused by HCV and the development of DM. Antonelli et al. (2004b) have also reported that the prevalence of type 2 diabetes is higher in patients with MC-HCV than in controls, with diabetic MC-HCV patients having a more pronounced autoimmune reactivity than

Extrahepatic Manifestations in Patients with Chronic HCV Infection

non-HCV patients with type 2 diabetes. In addition, recent ﬁndings suggest that the development of liver ﬁbrosis is associated with insulin resistance in HCV-infected patients (Taura et al., 2006) and that DM may contribute to the presence and severity of hepatic encephalopathy independent of the severity of liver disease. Metabolic disorders in HCV patients may be related to the development of steatosis, whose clinical signiﬁcance in HCV patients has been recently emphasized (Lonardo et al., 2004). Various factors are associated with hepatic steatosis, including obesity, high alcohol consumption, type II DM, and hyperlipidaemia. These factors may contribute to steatosis in HCV patients. Indeed, after anti-viral treatment, HCV-related steatosis disappears (Asselah et al., 2006). Hepatic inﬂammation may mediate ﬁbrogenesis in patients with liver steatosis. Leandro et al. (2006) conducted a meta-analysis from 3068 patients with histologically conﬁrmed chronic hepatitis C. Steatosis was present in 1561 patients (51%) and ﬁbrosis in 2688 (88%). Steatosis was independently associated with genotype 3, ﬁbrosis, diabetes, hepatic inﬂammation, ongoing alcohol abuse, higher body mass index, and older age. The association between steatosis and ﬁbrosis was invariably dependent on a simultaneous association between steatosis and hepatic inﬂammation. Control of metabolic factors such as overweight by lifestyle adjustments appears important in the management of chronic hepatitis C.

4. Systemic autoimmune diseases and HCV The association between HCV and SAD has generated growing interest in recent years. The extrahepatic manifestations often observed in patients with chronic HCV infection (both clinical and immunological) may lead to the fulﬁllment of the current classiﬁcation criteria for some SAD (Table 2).

4.1. Sjogren’s syndrome Recent experimental (De Vita et al., 1995; Koike et al., 1997), virological (Arrieta et al., 2001; Toussirot et al., 2002), and clinical evidence (Jorgensen et al.,

211

Table 2 Different degrees of association between HCV and systemic autoimmune diseases Degree of association

High Sjo¨gren’s syndrome

Rheumatoid arthritis Systemic lupus erythematosus

Extrahepatic HCV features overlapping with the classiﬁcation criteria

Xerostomia, xerophthalmia, ocular tests (+), salivary biopsy (+), ANA, RF Arthritis of 3 or more joint areas, arthritis of hand joints, symmetric arthritis, RF Articular involvement, renal involvement, ANA, aPL, cytopenias

Intermediate Polyarteritis nodosa Weakness, peripheral neuropathy, elevated creatinine, positive HBV markers Anti-phospholipid Positive aPL, atypical thrombotic syndrome events Sarcoidosis Pulmonary ﬁbrosis Inﬂammatory Weakness, elevated GOT, GPT myopathies Low Systemic sclerosis Wegener granulomatosis Giant cell arteritis Polymyalgia rheumatica Ankylosing spondylitis

Pulmonary ﬁbrosis Renal involvement Age W50 years – –

1996; Ramos-Casals et al., 2001c; De Vita et al., 2002) has revealed a close association between HCV and SS. In 2002, we formed the SS-HCV Study Group, a multicenter international collaboration that has, so far, recruited 137 SS-HCV patients (Ramos-Casals et al., 2005). We found that HCV-associated SS is indistinguishable in most cases from the primary form using the most recent set of classiﬁcation criteria, and we have proposed the term ‘SS secondary to HCV’ in those HCV patients who fulﬁll the 2002 Classiﬁcation Criteria (Vitali et al., 2002). Chronic HCV infection should be considered an exclusion criterion for the classiﬁcation of primary SS, not because it mimics primary SS, but because the virus may be implicated in the development of SS in a speciﬁc subset of patients (Ramos-Casals et al., 2001b).

M. Ramos-Casals et al.

212

Table 3 Prevalence of the 1993 European criteria for SS diagnosis in large series of patients with chronic HCV infection 1993 European criteria

Present feature/ HCV patients

Prevalence (%)

Xerostomia Xerophthalmia Positivite ocular tests Parotid scintigraphy Salivary gland biopsy Immunological tests Anti-nuclear antibodies Rheumatoid factor Ro/SS-A La/SS-B

158/859 129/769 83/216 No data 64/251

18 17 38 No data 25

481/2641 357/1117 30/765 27/765

18 40 4 3

There is a considerable overlap between European diagnostic criteria for SS and some extrahepatic features of HCV infection (Table 3). Extrapolating from the main studies with large series of HCV patients, xerostomia was observed in 158 (18%) of 859 patients, xerophtalmia in 129 (17%) of 769, positive ocular tests in 83 (38%) of 216, positive salivary gland biopsy (grades 3–4 of Chisholm-Mason classiﬁcation) in 64 (25%) of 251, positive ANA in 481 (18%) of 2641, and positive RF in 357 (40%) of 1117 HCV patients. In contrast, positive anti-Ro/SS-A antibodies were described in only 30 (4%) of 765 HCV patients and anti-La/SS-B in 27 (3%) of 765. These percentages suggest that a diagnosis of SS could be easily made in HCV patients presenting sicca syndrome, positive ANA, and/or RF. The SS diagnosed in these HCV patients may be considered as one of the extrahepatic manifestations of chronic HCV infection. The main differential aspect between primary and HCV-related SS is the immunological pattern, with a predominance of cryoglobulinemic-related markers (mixed cryoglobulins, RF, hypocomplementemia) over SS-related markers (anti-Ro/SS-A and anti-La/SS-B autoantibodies) in HCV-related SS (Ramos-Casals et al., 2005c). We found a threefold higher prevalence of hypocomplementemia in SS-HCV patients compared with patients with primary SS (Ramos-Casals et al., 2005a). Cryoglobulinemia seems to be the key immunological marker of SS associated with HCV, having a

close association with RF activity and complement activation. A recent study (Ramos-Casals et al., 2007) has ﬁrstly described the disease characteristics of B-cell lymphoma in SS-HCV patients, its treatment, outcome, and survival prognosis. These patients are clinically characterized by a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of RF and mixed type II cryoglobulins, the predominance of MALT lymphomas and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (exocrine glands, liver and stomach). The triple association between SS, HCV and B-cell lymphoma suggests an important role for associated autoimmune and chronic viral diseases in the pathogenesis of B-cell lymphoproliferative disorders and reinforces the idea that autoimmunity, infection and cancer may be closely related. A careful evaluation and followup of HCV patients with associated SS to aid early diagnosis and treatment of possible B-cell lymphoma should be recommended.

4.2. Rheumatoid arthritis It is understandable that HCV patients with polyarthritis and positive RF may be clinically classiﬁed as having RA. Of the 1988 revised ACR criteria, there are 4 (arthritis of 3 or more joint areas, arthritis of hand joints, symmetric arthritis and RF) that some HCV patients may present. Rosner et al. (Rosner et al., 2004) reviewed the prevalence and clinical characteristics of the HCVrelated arthritis exhaustively, and also analysed the signiﬁcant overlap with RA. The most frequent clinical presentation of HCV-related arthritis is chronic inﬂammatory polyarthrtis, which may lead to the fulﬁllment of the ACR classiﬁcation criteria for RA in more than 50% of cases. The existence of morning stiffness, rheumatoid nodules and erosive arthritis (rarely described in the setting of HCV infection) (Rivera et al., 1999a; Zuckerman et al., 2000a) may be useful to diagnose a true coexistence of RA and HCV. Recent studies have focused on the prevalence and clinical signiﬁcance of antibodies to cyclic

Extrahepatic Manifestations in Patients with Chronic HCV Infection

citrullinated peptide (CCP) in patients with chronic HCV infection. Wener et al. (2004) found no anti-CCP antibodies in HCV patients, although some false-positive results were observed in patients with MC, while Bombardieri et al. (2004) found anti-CCP antibodies in 76% of patients with RA and in 60% of those with coexisting RA and HCV, but not in HCV patients, irrespective of their articular involvement. Lienesch et al. (2005) found anti-CCP antibodies in 1/50 HCV patients without arthritis. Sene et al. (2006) investigated the diagnostic reliability of anti-CCP antibodies in distinguishing HCV-associated rheumatological manifestations from RA. Anti-CCP antibodies were detected in only two HCV infected patients with articular involvement (6%), in none without arthralgia and in 78% of patients with RA. With a speciﬁcity of 93% and a positive predictive value of 96%, anti-CCP antibodies were the most speciﬁc biological marker for RA. These studies suggest that anti-CCP antibodies may be useful in discriminating HCV patients with a true RA from those with HCV-associated arthropathy.

4.3. Systemic lupus erythematosus Viruses have been postulated as potential etiologic or triggering agents in the pathogenesis of SLE. Chronic HCV infection can induce clinical and serologic features (arthritis, nephropathy, haemocytopenias and low titers of ANA or anti-dsDNA) which, in combination, may meet the ACR 1982 criteria for SLE. In this context of autoimmunity related to HCV, some reports have suggested that HCV infection may mimic SLE. Some authors have analysed the prevalence of HCV infection in SLE patients (Cacoub et al., 1992; Kowdley et al., 1997; Marchesoni et al., 1995), and case reports of their association have also been published (Marvisi, 1998; Nepveu and Libman, 1996). Cacoub et al. (1992) found anti-HCV antibodies (ELISA-2) in 7 (11%) of 62 patients, although RIBA-2 was positive in only one (2%). Kowdley et al. (1997) found anti-HCV antibodies (ELISA-2) in 5 (12%) of 42 SLE patients, but only 3 (7%) patients were positive in the immunoblot analysis and 2 (5%)

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were PCR positive. None of these patients had chronic liver disease symptoms, and only one had abnormal liver test results. We analysed a large series of SLE patients and found that HCV infection was present in 11% of an unselected SLE population (Ramos-Casals et al., 2000). This prevalence is signiﬁcantly higher than the prevalence of HCV infection found in the control group (1%) and in the general population in Catalonia (1.2%), and suggests a possible link between HCV infection and SLE. Similar results have been obtained by Ahmed et al. (2006) in the United States (10% in SLE patients compared with 1.3% in the general population). In comparison with patients with idiopathic SLE, SLE-HCV patients have a different pattern of clinical and immunologic manifestations, mainly characterized by a lower frequency of cutaneous SLE features, a higher prevalence of liver involvement, a lower frequency of anti-dsDNA antibodies and a higher prevalence of hypocomplementemia and cryoglobulinemia. Thus, it appears that several SLE criteria are very speciﬁc to SLE and are rarely present in HCV infection (malar rash, discoid lesions, subacute cutaneous lesions, photosensitivity, neurological manifestations, high titers of ANA or anti-dsDNA and presence of anti-Sm antibodies). Two differentiated subsets of SLEHCV patients may be deﬁned: patients with HCV infection and a ‘true’ SLE, in which HCV might be a concomitant process or, perhaps, might act as a triggering factor, and patients with a ‘lupus-like syndrome’ possibly caused by HCV infection. The ﬁrst group of patients have at least two of the following speciﬁc SLE features: malar rash, discoid lesions, subacute cutaneous lesions, photosensitivity, neurological criteria, ANA Z1/160, anti-dsDNA W15 U/mL or anti-Sm antibodies. We believe that this subset of SLE-HCV patients should be considered as having a ‘true’ SLE with an associated HCV infection. Although the pathogenic role of HCV infection in these patients is unclear, it is possible that HCV acts, in our geographical area, as a triggering factor in some patients with a deﬁnite genetic background. The second subset present a ‘mild’ SLE, mainly characterized by articular involvement, hematologic features, lower titers of ANA and anti-dsDNA and positive

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cryoglobulins in the majority of cases. It is known that patients with cryoglobulinemia can show several features commonly observed in SLE, such as arthritis, nephropathy or hypocomplementemia (Perlemuter et al., 2003). In this subset of patients, it is possible that chronic HCV infection (associated with cryoglobulinemia in some cases) may produce a ‘lupus-like syndrome’, mimicking a ‘true’ SLE according to the 1982 revised criteria for SLE classiﬁcation. These studies suggest that HCV testing should be considered in the diagnosis of SLE, especially in patients without typical SLE cutaneous features and with low titers of autoantibodies (ANA and anti-dsDNA), liver involvement or cryoglobulinemia (61). Conversely, patients with chronic HCV infection and extrahepatic features mimicking SLE should be tested for the presence of ANA and anti-dsDNA.

4.4. Anti-phospholipid syndrome Recently, the possible association of anti-phospholipid syndrome (APS) with viruses has generated growing interest. Historically, aPL have always being closely associated with infectious agents, ever since they were ﬁrst detected in sera from syphilis patients (Cervera and Asherson, 2003). In a recent review, Uthman and Gharavi (2002) have analysed the etiopathogenic role of viruses in APS and described isolated cases associated with viruses such as cytomegalovirus, varicella zoster, Epstein–Barr virus and HCV. We have recently analysed a total of 45 HCV patients with clinical features related to APS (Ramos-Casals et al., 2004a). In comparison with general APS series, APS-HCV patients had a higher mean age and a differentiated clinical spectrum of thrombotic involvement, with a lower frequency of the more typical APS features such as peripheral thrombosis or neurological features and, in contrast, a higher prevalence of atypical or infrequent APS features, such as myocardial infarction or intra-abdominal thrombotic events. In addition, a higher frequency of positive immunological markers that are often detected in chronic HCV infection, such as ANA, cryoglobulins, hypocomplementemia, and rheumatoid factor, was observed

in patients with APS-HCV. In addition, the higher presence of LA (80%) in APS-HCV patients may well explain the occurrence of thrombotic events in this subset of HCV patients, since its prevalence in unselected series of HCV patients is extremely low (less than 1%). Infectious agents may play a diverse etiopathogenic role in the clinical expression of APS, with bacterial infections probably acting as acute triggering agents of a devastating, multiorganic form of APS (catastrophic APS), while chronic viral infections (such as HCV and HIV) may trigger a heterogeneous, atypical presentation of APS.

4.5. Cryoglobulinemic vasculitis Patients with cryoglobulinemia present a very broad spectrum of clinical features. Although more than 50% of patients present a relatively benign clinical course with a good prognosis and survival (Ferri et al., 2004), some patients may present severe, life-threatening internal organ involvement. Why some cryoglobulinemic patients present this severe cryoglobulinemic vasculitis remains unclear. Ferri et al. (2004) recently found that 35% of their patients with cryoglobulinemic vasculitis had a moderate-severe clinical course, with the prognosis being severely affected not only by cryoglobulinemic involvement but also by associated conditions such as HCV-related liver failure. Two recent studies have analysed the clinical characteristics of HCV-related cryoglobulinemia in large series of patients. Sene et al. (2004) studied 125 patients with MC retrospectively and found that cryoglobulinemic vasculitis was associated with advanced age, longer duration of HCV infection, type II MC, and a higher MC serum level. Ferri et al. (2004) analysed demographic, clinical and serologic features and survival in 231 patients with MC. One hundred sixty eight patients were tested for HCV infection, with 155 (92%) being positive. Malignancies were observed in 15% of patients, mainly non-Hodgkin lymphoma (NHL) and hepatocellular carcinoma, and the main causes of death were related to MC (64%), NHL (13%), and liver involvement (13%).

Extrahepatic Manifestations in Patients with Chronic HCV Infection

Life-threatening cryoglobulinemia is found in 10–15% of patients with cryoglobulinemic syndrome. The most frequent type of life-threatening involvement is renal failure due to cryoglobulinemic glomerulonephritis. Recent data suggest that cryoglobulinemic glomerulonephritis signiﬁcantly affects the prognosis and survival. Ferri et al. (2004) described renal failure secondary to cryoglobulinemic glomerulonephritis as the main cause of death in their patients with cryoglobulinemia, with a survival rate of 33% after a mean follow-up of 10 years, while Tarantino et al. (1995) described a survival rate of 49% at 10 years after renal biopsy in 105 patients with cryoglobulinemic glomerulonephritis. We found a survival rate of 39%, with cryoglobulinemic involvement contributing directly to death in only one third of cases, with infection and liver disease being the most frequent causes of death (Ramos-Casals et al., 2006). Likewise, Tarantino et al. (1995) found that the main causes of death were cardiovascular disease, hepatopathy, and infection. Cryoglobulinemic glomerulonephritis seems to have a poor prognosis in patients with HCV-related cryoglobulinemia. Most of our patients with severe renal involvement had chronic HCV infection, while Beddhu et al. (2002) reported that all their patients whose serum creatinine doubled or who progressed to end-stage renal disease were HCV positive. Impaired renal function at diagnosis has also been related to poor prognosis. Tarantino et al. (1995) found that patients with an initial serum creatinine level higher than 1.5 mg/dL had a higher risk of end-stage renal disease or death. In addition, chronic renal failure may enhance immunosuppression and the risk of infectious processes. In fact, four out of the ﬁve patients who died in our series due to infectious processes had chronic renal failure due to cryoglobulinemic glomerulonephritis (2006). Gastrointestinal vasculitis and pulmonary hemorrhage are very rare and had a very poor prognosis in patients with cryoglobulinemia. Of the 33 well-reported cases, 26 (80%) died (Ramos-Casals et al., 2006). This illustrates the extremely poor prognosis of cryoglobulinemic pulmonary and intestinal involvement, with a high mortality at presentation and a poor prognosis in survivors presenting a further

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episode. The lack of a therapeutic protocol (due to the rarity of this type of involvement) together with the high mortality in patients with other types of vasculitis means that both clinical presentation are one of the main challenges in dealing with patients with cryoglobulinemia.

4.6. Sarcoidosis The ﬁrst association between sarcoidosis and HCV was reported in 1993 by Blum et al. (1993), and was directly related to the onset of a-interferon therapy. A recent study have analysed the clinical characteristics and outcome of 68 cases of coexisting sarcoidosis and chronic HCV infection, in nearly 75% of whom sarcoidosis was triggered by anti-viral therapy (Ramos-Casals et al., 2005). Two other patterns of association between sarcoidosis and HCV have been described: the coexistence of both diseases in treatment-naı¨ ve HCV patients, and the reactivation of a pre-existing sarcoidosis in HCV patients subsequently treated with anti-HCV therapies.

4.6.1. Sarcoidosis triggered by anti-viral therapy Sarcoidosis may be precipitated or exacerbated in some HCV patients receiving anti-viral therapy. Nevertheless, this phenomenon remains uncommon. We recorded ﬁve cases of sarcoidosis triggered by anti-viral therapy from nearly 2000 HCV patients treated in our Liver Unit (Ramos-Casals et al., 2005e), a prevalence of 0.2%, which is very similar to that observed by Leclerc et al. (2003), who described one case out of 1159 HCV patients treated with a-interferon (0.1%). Thus, a prevalence of 1–2 cases of sarcoidosis per 1000 HCV patients treated with anti-viral agents should be postulated. As the estimated prevalence of sarcoidosis ranges from 1 to 40 cases per 100,000 population, the frequency of sarcoidosis seems to be higher in HCV patients receiving anti-viral therapy than in the general population. Analysis of 50 cases of sarcoidosis triggered by anti-viral therapy for HCV infection (Ramos-Casals et al., 2005e) has permitted a better deﬁnition of the

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main clinical manifestations and outcome of this induced form of sarcoidosis. It appears predominantly in middle-aged women, of whom a round a quarter had received previous anti-viral courses, with no response in most cases. In two thirds of the 50 cases, sarcoidosis was triggered in the ﬁrst 6 months of anti-viral therapy. Although less frequent, sarcoidosis may also appear after completion of anti-viral therapy, but in all these cases the disease emerged in the ﬁrst 3 months after completion. The cause–effect relationship between interferon administration and the development of sarcoidosis seems to be clear in nearly all cases. However, a possible additional role for ribavirin should be considered. In 10 out of 12 patients who had received a-interferon monotherapy before the development of sarcoidosis, the granulomatous lesion appeared during a second course of treatment with interferon and ribavirin and not earlier with interferon alone. Ribavirin may enhance the Th1 response by increasing production and expression of IL-12 mRNA, by increasing production of IFN-g and tumor necrosis factor-a, and by lowering the Th2 response. Consequently, the enhancement of a Th1-type immune reaction induced by the combined therapy might trigger granulomatous reactions more frequently than a-interferon monotherapy. This might explain the progressively higher number of cases published in recent years: only 10 cases published between 1993 and 1999, while in the last 4 years, coinciding with the generalized use of combined therapy, the number of cases reported has increased fourfold. A speciﬁc clinical pattern was observed in HCV patients with sarcoidosis triggered by the anti-viral therapy, with a higher prevalence of cutaneous and articular involvement and a lower frequency of hilar and extrapulmonary adenopathies in comparison with unselected HCV-negative patients with sarcoidosis. The lungs are affected in more than 90% of all patients with sarcoidosis, while in the HCV patients with sarcoidosis the observed percentage is 76%. In contrast, while cutaneous involvement usually occurs in about 25% of all sarcoidosis patients, the percentage in sarcoidosis triggered by anti-viral therapy is 60%. In addition, cutaneous sarcoidosis was the only clinical feature in six patients (Ramos-Casals et al., 2005e), a

clinical presentation rarely observed in non-HCV patients. The reasons for this speciﬁc predilection for cutaneous involvement are not known. Although cutaneous sarcoidosis may occur in isolation, it is more commonly seen as a manifestation of systemic disease. Severe sarcoid involvement (e.g., progressive pulmonary ﬁbrosis, cardiac, and central nervous system) was observed in less than 5% of HCV patients with sarcoidosis triggered by anti-viral therapy (Ramos-Casals et al., 2005e), a similar ﬁgure to those reported in general series of sarcoidosis patients (Hunninghake et al., 1999). Although the natural history of sarcoidosis is highly variable, spontaneous remission occurs in nearly two-thirds of patients, while the course is chronic and progressive in 10–30% (Hunninghake et al., 1999). Nearly 85% of cases of sarcoidosis triggered by anti-HCV therapy improved or remitted spontaneously (Ramos-Casals et al., 2005e), with less than 10% of cases having a chronic and stable course. Improvement or remission was clearly related to discontinuation of anti-viral therapy, with only 35% of patients requiring systemic corticosteroids. In most large published series, 30–50% of unselected patients with sarcoidosis were treated with corticosteroids (Hunninghake et al., 1999), although the symptoms requiring corticosteroid therapy remain controversial. In patients with mild disease (mainly skin), topical steroids may be all that is necessary, while in those with systemic, symptomatic disease, oral corticosteroids are often employed. Few data are available about the response to anti-viral therapy in HCV-sarcoidosis patients. Near to 50% of our patients treated with IFN/ RBV presented a viral response at the end of the therapy, a similar prevalence to that observed in unselected HCV patients. We have also reviewed the response to anti-HCV patients in the cases published in the literature (Ramos-Casals et al., 2005e). The response was detailed in only 23 cases, with a rate of viral response of 48%. According to these ﬁgures, a similar viral response to anti-HCV therapy seems to be observed in HCV patients with sarcoidosis compared with the most recent series of unselected HCV patients. Some recommendations for the management of HCV patients with triggered sarcoidosis should be

Extrahepatic Manifestations in Patients with Chronic HCV Infection Table 4 Recommendations for the management of sarcoidosis in patients with chronic hepatitis C virus infection Perform baseline chest X-ray upon starting anti-viral therapy Evaluate IFN-related adverse effects accurately, discarding the existence of an undiagnosed sarcoidosis in patients with unexpectedly severe or prolonged IFN-related side effects Speciﬁc follow-up centered on the possible development of cutaneous or respiratory symptoms suggestive of sarcoidosis Discontinue anti-viral therapy in patients with mild sarcoidosis (cutaneous involvement, lymphadenopathy), although continuation might be considered under close follow-up In patients with severe sarcoidosis (diffuse pulmonary involvement, systemic involvement), cessation of anti-viral therapy is mandatory When the severity of sarcoid involvement requires treatment with corticosteroids and/or immunosuppressive agents, a close monitoring of liver function, HCV-RNA levels, and cell counts is mandatory In HCV patients with previous sarcoidosis, anti-viral therapy should only be indicated with extreme caution and strict individualized assessment

suggested for the daily clinical practice (Table 4). Firstly, an accurate evaluation of the interferonrelated adverse effects (such as arthralgias, fever, myalgyas, or fatigue) should be made, in order to clearly separate these effects from the symptomatology originated by the triggered sarcoidosis, discarding the existence of an underlying triggered sarcoidosis in patients with more severe side effects. Secondly, we suggest a baseline chest X-ray upon starting anti-viral therapy, with a speciﬁc follow-up centered on the possible development of cutaneous or respiratory symptoms. Thirdly, a different therapeutic approach should be considered according to the severity of the triggered sarcoidosis. In patients with mild disease (cutaneous involvement, lymphadenopathy) cessation of anti-viral therapy will probably be sufﬁcient, although continuation might be considered under close follow-up (especially in patients with isolated cutaneous lesions). In patients with severe disease (diffuse pulmonary involvement, systemic disease) cessation of antiviral therapy is mandatory, probably together with initiation of oral corticosteroids (adding immunosuppressive agents according to the clinical

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evolution). In these cases, a close monitoring of liver function, HCV-RNA levels and cell counts is mandatory. Finally, with respect to the use of antiviral therapy in HCV patients with previous sarcoidosis, anti-viral therapy in these patients should only be indicated with extreme caution and strict individualized assessment, especially in patients who received previous anti-viral courses.

4.6.2. Sarcoidosis in treatment-naı¨ve patients The ﬁrst case of sarcoidosis in treatment-naı¨ ve HCV patient was reported by Belgodere et al. (1999) in 1999, and the association of the two diseases was considered casual. Eighteen additional cases have been published over the last 4 years, suggesting that this situation may be more frequent than previously supposed. However, this association should be considered as less frequent than that associated with anti-HCV treatment. No differences in clinical features or prognosis being found between treatment-naı¨ ve HCV patients and sarcoidosis triggered by anti-HCV therapy. In fact, no study has analysed the prevalence of HCV infection in large series of unselected patients with sarcoidosis, although Bonnet et al. (2002) have reported a higher prevalence in a small series of patients with sarcoidosis, detecting HCV infection in 5 out of 32 patients with sarcoidosis. Although a casual coexistence of two independent diseases can occur in some of these patients, the role of HCV as an etiopathogenic agent for sarcoidosis should be investigated in future large matched case–control studies.

4.7. Systemic vasculitis PAN is considered the most-frequent systemic vasculitis associated with chronic HCV infection. More than 60 HCV patients have been reported, in some cases in association with HBV coinfection (Ramos-Casals et al., 2005d). In addition, the prevalence of HCV markers in patients with PAN is high, with positive HCV antibodies being detected in 25 (14%) of the 173 patients analysed. Several of the 1990 criteria for the classiﬁcation of PAN, such as weight loss, myalgias or weakness, peripheral neuropathy, elevated BUN/creatinine,

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and positive HBV markers, are often observed in HCV patients. Although cryoglobulinemic vasculitis could histologically mimic cutaneous or renal involvement observed in microscopic polyarteritis, classic PAN shows necrotizing inﬂammation of small or medium-sized arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Thus, the main difference between the two types of systemic vasculitis most frequently associated with HCV (PAN and cryoglobulinemia) is the different size of the vasa involved. The high speciﬁcity of this histologic criterium may be useful in the differential diagnosis of PAN or HCV-cryoglobulinemic vasculitis. Other systemic vasculitides are rarely associated with chronic HCV infection, such as giant cell arteritis, Takayasu’s arteritis, Wegener granulomatosis, Churg–Strauss vasculitis, and Henoch– Scho¨nlein purpura (Ramos-Casals et al., 2005b). The 1990 criteria for these vasculitis showed a small overlap with the most common extrahepatic features observed in HCV infection, and the coexistence of these vasculitis with HCV infection may be considered a chance phenomenon.

4.8. Inflammatory myopathies The association of HCV with inﬂammatory myopathies is mainly found in isolated case reports, with a total of 36 cases published, of which 21 were polymyositis (Ramos-Casals et al., 2005b). In contrast, only three studies have analyzed the prevalence of HCV in series of patients with inﬂammatory myopathies and found HCV infection in 12 of 126 (9.5%) patients (Ramos-Casals et al., 2005b). The criteria of Bohan and Peter show a small degree of overlap with HCV infection, since HCV patients infrequently present muscle weakness with elevation of muscle enzyme levels or electromyographic evidence of a generalized myopathy. Thus, at present, inﬂammatory myopathies are tenuously associated with HCV infection.

association should be considered as very infrequent. The criteria for the diagnosis of systemic sclerosis are highly speciﬁc, since the existence of cutaneous sclerosis and positive anti-Scl70/anticentromere antibodies are infrequently described in HCV patients. Other SAD associated with HCV have been reported, including Behc- et disease (seven cases), Still disease (one case), ankylosing spondylitis (one case), and mixed connective tissue disease (one case) (Ramos-Casals et al., 2005d). Herrera et al. (2004) reported a patient with relapsing polychondritis (RP), HCV, and MC, in whom treatment with anti-HCV therapy improved the symptoms of RP.

5. Hematological diseases and HCV The speciﬁc tropism of HCV for many extrahepatic cell types (Table 5), especially for circulating blood cells, has recently been suggested by several studies (Arrieta et al., 2001; Toussirot et al., 2002; Crovatto et al., 2000; De Almeida et al., 2004; De Vita et al., 2000; Authier et al., 2003; Di Muzio et al., 2003; Bonetti et al., 1999; Radkowski et al., 2002; Okabe et al., 1997; Agnello and Abel, 1997; Table 5 Extrahepatic localizations of the hepatitis C virus infection References Circulating blood cells B-lymphocytes T-lymphocytes Monocytes Neutrophils Platelets Extrahepatic tissues Salivary glands Gastric mucous Striate muscle Peripheral nerve

4.9. Other systemic autoimmune diseases Although we have described seven patients with systemic sclerosis and HCV infection (76), this

Central nervous sytem Myocardium Cutaneous lesions

Crovatto et al. (2000), Ducoulombier et al. (2004) Crovatto et al. (2000) Crovatto et al. (2000) Crovatto et al. (2000) Crovatto et al. (2000) Arrieta et al. (2001), Toussirot et al. (2002) De Vita et al. (2000) Authier et al. (2003), Di Muzio et al. (2003) Authier et al. (2003), Bonetti et al. (1999) Radkowski et al. (2002) Okabe et al. (1997) Agnello and Abel (1997)

Extrahepatic Manifestations in Patients with Chronic HCV Infection

Ducoulombier et al., 2004), providing a clear link between HCV and the development of autoimmune and neoplasic hematological processes. The susceptibility of blood cells to HCV infection might be enhanced by coexisting additional chronic viral infections. Laskus et al. (2004) reported that HIV facilitates the infection and replication of HCV in circulating blood cells, a fact that might be related to the development of severe cytopenias in some HCV-HIV patients (Ramos-Casals et al., 2003).

5.1. Autoimmune cytopenias Although HCV-related cytopenias are not uncommon, they are usually considered as mild laboratory abnormalities with no clinical signiﬁcance, especially in patients with hypersplenism. The most frequent is thrombocytopenia, which has a chronic clinical course with severe bleeding being uncommon. De Almeida et al. (2004) found no association between HCV genotypes and thrombocytopenia, although HCV-RNA was detected more frequently in the platelets of thrombocytopenic patients than in those with a normal platelet count. Wang et al. (2004) described a 10-fold higher frequency of thrombocytopenia in HCV patients compared with HCV-negative controls, and thrombocytopenia correlated with the severity of HCV-related liver disease. Severe cytopenias are observed in some HCV patients, related or not to anti-viral therapy. Thrombocytopenia may be severe (o30 109/L) in treatment-naı¨ ve HCV patients, and in some is associated with concomitant autoimmune diseases, cryoglobulinemia, and HIV coinfection (RamosCasals et al., 2003a). Two cases of severe Coombspositive autoimmune hemolytic anemia (AHA) have recently been reported in patients not treated with IFN (Elhajj et al., 2004; Etienne, 2004). Previously, 17 cases of HCV-related AHA had been reported (Ramos-Casals et al., 2003), frequently associated with autoimmune diseases, with cryoglobulinemia being the most frequent immunologic marker. Finally, isolated cases of pure red-cell aplasia have also been described in HCV patients (Ramos-Casals et al., 2003a; Tanaka et al., 2004).

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5.2. Lymphoproliferative diseases Recent studies have found a higher prevalence of lymphoproliferative disorders in HCV patients (Bianco et al., 2004; Morton et al., 2004; Iwata et al., 2004). Matsuo et al. 2004; Iwata et al., 2004) performed an elegant meta-analysis of 23 epidemiological studies on the association between HCV and NHL, including 4049 NHL patients. The summary odds ratio (OR) for NHL in HCV patients was 5.70, being 5.04 for B-cell, and 2.51 for T-cell NHL (Matsuo et al., 2004). A similar meta-analysis was conducted by Dal Maso and Franceschi (2006) to evaluate the strength and the consistency of the association between HCV and NHL, including only studies with Z100 cases which were also adjusted for sex and age. The pooled RR of all NHL in HCV-positive individuals was 2.5. Nieters et al. (2006) tested for HCV infection serum samples of 1807 lymphoma cases and 1788 controls, and found HCV infection in 53 (2.9%) lymphoma cases and in 41 (2.3%) control subjects (OR, 1.42). When restricted to individuals who tested positive for HCV-RNA, the OR raised to 1.82. The prevalence of HCV infection in NHL patients may be higher, since Paydas et al. (2004) have described false negative results in the ELISA detection of anti-HCV antibodies in 8 (72%) out of 11 patients with NHL, in whom the presence of HCV-RNA was conﬁrmed in parafﬁn-embedded lymphomatous tissues. This occult HCV infection has also been described in some patients with an altered liver proﬁle of unknown origin (Castillo et al., 2004), in whom the virus was isolated from liver tissue and circulating mononuclear cells, and was not detectable by ELISA and PCR techniques in serum. Lymphomagenesis in HCV patients might be initiated by the chronic stimulation of polyclonal B cells by the virus (Starkebaum and Sasso, 2004) and the compartmentalization of HCV quasispecies in blood mononuclear cells (Di Liberto et al., 2006), with the posterior development of speciﬁc B-cell clonal expansions (Sansonno et al., 2004; Vallat et al., 2004) and pro-carcinogenic mutations (Machida et al., 2004; Libra et al., 2004). Vallat et al. (2004) suggested that B-cell clonality in the blood and liver may be a marker of lymphoma development in some HCV patients. Machida et al.

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(2004) reported that both acute and chronic HCV infection caused a 5- to 10-fold increase in mutation frequency in the Ig heavy chain, BCL-6, p53, and beta-catenin genes, while Libra et al. (2004) detected bcl-2 rearrangement in mucosaassociated lymphoid tissue (MALT) lymphomas from HCV patients. Rosa et al. (2005) have recently proposed that CD81-mediated activation of B cells in vitro mimics the effects of HCV binding to B cell CD81 in vivo and that polyclonal proliferation of naive B lymphocytes is a key initiating factor for the development of HCV-associated B lymphocyte disorders. The close relationship between autoimmunity, viruses, and cancer is demonstrated by the description of patients with HCV infection, SAD, and B-cell lymphoma, who had a high prevalence of cryoglobulinemia, a high frequency of primary extranodal NHL involvement, and a poor prognosis (Ramos-Casals et al., 2004c). The clearest example is the development of NHL in patients with SS-HCV (Ramos-Casals et al., 2002) (Fig. 1). Recently, Ambrosetti et al. (2004) have reported that most cases of primary salivary MALT

lymphoma are associated either with SS or HCV infection. In addition, Arcaini et al. (2007) retrospectively studied 172 patients with a histological diagnosis of marginal zone B-cell MALT lymphoma, in whom HCV infection was found in 60 patients (35%). HCV-positive patients showed more frequent skin (35%), salivary glands (25%), and orbit (15%) lymphomatous involvement. The close relationship between HCV and NHL might have therapeutic implications (Emens and Sulkowski, 2002; Levine et al., 2003), since Tursi et al. (2004) have reported the disappearance of gastric MALT lymphoma in 13 out of 18 HCV patients after 6 months of anti-viral therapy. We recommend a careful evaluation of patients with B-cell NHL in order to detect silent autoimmune or chronic viral diseases.

6. Therapeutic management of extrahepatic features The therapeutic management of HCV-related autoimmune features has become a clinical

Figure 1. The triple association between Sjo¨gren’s syndrome, hepatitis C virus, and B-cell lymphoma: etiopathogenic links. (See Colour Plate Section.)

Extrahepatic Manifestations in Patients with Chronic HCV Infection Table 6 Use of the new immunosuppressive and biological agents in patients with autoimmune or lymphoproliferative diseases associated with chronic HCV infection Agent

Autoimmune disease

Rituximab

HCV-related cryoglobulinemia Coombs+ haemolytic anemia B-cell lymphoma, SS, and HCV

Anti-TNF

RA and HCV HCV-related cryoglobulinemia Psoriatic arthritis+HCV

MMF

HCV-related cryoglobulinemia Myasthenia gravis+HCV HCV-related thrombocytopenia Coombs+ haemolytic anemia

Abbreviations: MMF, mycophenolate mofetil; anti-TNF, anti-tumor necrosis factor agents.

challenge in HCV patients, in whom chronic liver disease associated with severe autoimmune features contributes to a very poor prognosis (Ramos-Casals et al., 2003b). Both anti-viral and immunosuppressive therapies, either alone or in combination, seem likely to have an important role, although these treatments should be individualized according to cost, follow-up, relapses, organ involvement, risk of exacerbation of autoimmune disease, and the possible consequences of immunosuppression in the setting of chronic HCV infection (Vassilopoulos and Calabrese, 2002). In spite of the small number of patients included in the available reported studies, combined anti-viral therapy plus corticosteroids, and/or immunosuppressive agents may achieve symptomatic relief and even long-term remission of the cryoglobulinemic syndrome. In severe, symptomatic cryoglobulinemic vasculitis, plasmapheresis should also be considered. The optimum length of treatment remains to be established, and severe cases may need long-term or even lifelong therapy. Recent data are available for the use of immunosuppressive and biological agents in HCV patients with autoimmune or lymphoproliferative manifestations (Table 6).

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combined therapy with pegylated interferon alpha and ribavirin. This treatment has provided much better short and long-term results in patients with HCV-related vasculitis than historically reported with monotherapy with IFNa. In three uncontrolled studies (Zuckerman et al., 2000b; Naarendorp et al., 2001; Cacoub et al., 2002), combination therapy with standard IFNa and ribavirin demonstrated signiﬁcant efﬁcacy on the main HCV-related vasculitic manifestations. Two studies reported reduced proteinuria in sustained viral responders treated with IFNa plus ribavirin (Bruchfeld et al., 2003; Alric et al., 2004). Saadoun et al. (2006) recently studied 72 consecutive HCV-MC patients and found that Peg-IFNa plus ribavirin achieved a higher rate of complete clinical response (67 vs. 56%) and virological response (62 vs. 53%) compared with standard IFNa plus ribavirin, regardless of HCV genotype and viral load. Early virologic response was independently associated with a complete clinical response of MC.

6.2. Mycophenolate mofetil Recent reports have suggested a promising role for mycophenolate mofetil (MMF) in the treatment of HCV-related autoimmune processes, especially severe cytopenias (Ierardi et al., 2003) and cryoglobulinemic vasculitis (Reed et al., 2001; Caponnetto et al., 2001). In addition, Medina et al. (2004) have reported preliminary results on the successful use of MMF to treat diffuse proliferative glomerulonephritis in ﬁve patients with HCV-related SLE. The favorable response to MMF in these patients, with no major side effects and no signs of worsening of HCV infection, suggests that MMF may be used as monotherapy or in association with other drugs in patients with SAD associated with chronic HCV infection.

6.3. Rituximab 6.1. Anti-viral therapy The treatment of HCV infection has progressed signiﬁcantly with the recent introduction of

In 2003, some studies demonstrated the efﬁcacy of using rituximab in cryoglobulinemic vasculitis (Lamprecht et al., 2003; Zaja et al., 2003; Sansonno

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et al., 2003). Recent reports have described the successful use of rituximab in HCV patients with cryoglobulinemic glomerulonephritis, although the nephritis relapsed and required a second course of rituximab in some patients (Roccatello et al., 2004). A recent study by Quartuccio et al. (2006) described a rapid, sustained renal response in 5 HCV patients with active, biopsy-proven, cryoglobulinemic glomerulonephritis. Rituximab also proved effective against other active cryoglobulinemic manifestations, no major side-effects occurred and steroids were not required in the follow-up. The successful use of rituximab to treat hematological processes associated with HCV, such as severe cytopenias or NHL, has also been reported. Etienne et al. (2004) have successfully treated an HCV patient with severe AHA, and we have used rituximab to treat indolent B-cell lymphoma in patients with SS and HCV (Ramos-Casals et al., 2004b). In comparison with standard chemotherapy regimens, monotherapy with rituximab is generally well tolerated and serious adverse effects are uncommon.

6.4. Anti-TNF agents Finally, anti-tumor necrosis factor (TNF) agents have recently been used in some HCV patients with coexisting systemic and rheumatic diseases. AntiTNF agents (inﬂiximab or etanercept) have been used in patients with coexisting RA and HCV infection (Parke and Reveille, 2004; Peterson et al., 2003; Oniankitan et al., 2004), although few details on the clinical response of the articular involvement were included. Other authors have described the use of inﬂiximab in isolated cases of refractory cryoglobulinemic vasculitis (Chandesris et al., 2004) and the use of etanercept in HCV patients with psoriatic arthritis (Magliocco and Gottlieb, 2004). A recent study by Marotte et al. (2007) reports nine patients with HCV-related rheumatological manifestations treated with etanercept. Although etanercept appeared to be safe in these patients, the effect on the extrahepatic manifestations was heterogeneous and lower than that observed in RA. Although these agents seem to

have a reasonable safety proﬁle in the setting of HCV infection (Calabrese et al., 2004), the available data are still insufﬁcient to evaluate their clinical efﬁcacy and possible long-term side effects in patients with chronic HCV infection and autoimmune features.

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PART V:

Other Conditions

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 17

Autoantibodies in Gastrointestinal Autoimmune Diseases Neophytos P. Papageorgiou, Yehuda Shoenfeld Center for Autoimmune Diseases, Department of Medicine B, Chaim Sheba Medical Center (Affiliated to Tel-Aviv University), Tel-Hashomer 52621, Israel

1. Antibodies in inﬂammatory bowel diseases

1.2. The antibodies

1.1. Introduction Crohn’s disease (CD) and ulcerative colitis (UC), also known as inﬂammatory bowel diseases (IBD), are chronic diseases affecting the intestinal tract. Although the etiology is still unknown, it is believed that a combination of environmental factors, genetic predisposition and a dysregulated immune response to endogenous bacteria in the gastrointestinal tract play signiﬁcant role in the development of these diseases (Nakamura et al., 2003). Several antibodies have been described in the past that are associated with IBD and have been found to be useful for diagnosing and differentiating CD from UC (Nakamura et al., 2003). The most important and frequently studied are as follows: (a) anti-Saccharomyces cerevisiae antibodies (ASCA), (b) atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA), (c) anti-OmpC (outer membrane porin from Escherichia coli) and most recently described (d) the antibody to CBir1 (anti-CBir1 ﬂagellin) (Nakamura et al., 2003; Israeli et al., 2005; Reumaux et al., 2003; Targan et al., 2005).

Atypical pANCA are IgG class autoantibodies directed against antigens of the inner side of the nuclear membrane of the neutrophil (Nakamura et al., 2003; Jaskowski et al., 2006). Some studies showed that pANCA are produced locally in the colonic mucosa, suggesting that antigens of microbial agents may be involved in the development of IBD (Nakamura et al., 2003). ASCA are antibodies of the IgG and IgA class directed against mannose sequences of S. cerevisiae cell wall (Nakamura et al., 2003; Reumaux et al., 2003; Jaskowski et al., 2006). ASCA is a highly speciﬁc serological marker of CD (Nakamura et al., 2003). Anti-OmpC are antibodies directed against the outer membrane porin C of E. coli. These antibodies are of IgA and IgG class found to be associated with both CD and UC (Nakamura et al., 2003; Reumaux et al., 2003; Jaskowski et al., 2006). Anti-CBir1 ﬂagellin is an IgG class antibody against the ﬂagellin CBir1, a bacterial antigen ﬁrst identiﬁed in a murine model, which is associated with IBD, speciﬁcally with a subset of CD patients (Targan et al., 2005; Lodes et al., 2004).

Corresponding author.

1.2.2. Methods of detection

Tel.: 972-3-5302652; Fax: 972-3-5352855 E-mail address: [email protected] r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00017-7

1.2.1. Definitions

Detection of atypical pANCA IgG is performed usually by indirect immunoﬂuorescence (IIF)

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technique on ethanol and formalin-ﬁxed neutrophils. Sera that show a perinuclear pattern on ethanol-ﬁxed neutrophils but that are negative on formalin-ﬁxed neutrophils are considered to be positive for atypical pANCA (Jaskowski et al., 2006). In addition, positive samples marked as atypical pANCA can be further analyzed by enzyme-linked immunosorbent assay (ELISA) for the exclusion of antiproteinase 3 (PR3), antimyeloperoxidase (MPO) and other known autoantibodies (Israeli et al., 2005; Reumaux et al., 2003; Jaskowski et al., 2006). ASCA IgG and IgA are detected using an ELISA assay. A variety of ASCA tests are available today showing several sensitivities and speciﬁcities possibly due to different cut-off values (Reumaux et al., 2003). An ELISA assay is also used for the detection of IgG and IgA anti-OmpC. Puriﬁed antigens isolated from E. coli are used to bind the antibodies (Zholudev et al., 2004). In the same way, anti-CBir1 IgG detection is performed by ELISA analysis using the NH2terminal fragment of CBir1 (147 AA) (Targan et al., 2005).

1.2.3. Genetics It has always been questioned if the antibodies associated with IBD are genetically determined. Data from several family studies showed an increased positivity of pANCA in 16–30% of healthy ﬁrst-degree relatives of UC patients (Reumaux et al., 2003; Seibold, 2005). Another study showed an increased HLA-DR2 expression in ANCA-positive UC patients (Reumaux et al., 2003). Nevertheless, more studies are needed to be done to conﬁrm these results. Concerning ASCA, they have also been demonstrated to be positive in 20–25% of unaffected ﬁrst-degree relatives of patients with CD (Israeli et al., 2005; Reumaux et al., 2003; Seibold, 2005). This indicates that ASCA may represent a genetic marker speciﬁc for susceptibility to CD. Data from a recent study showed an increased frequency of anti-OmpC in unaffected family members of CD patients, raising again the possibility of a genetic susceptibility to CD (Mei et al., 2006).

In conclusion, a reasonable question is raised, whether these positive asymptomatic family members will eventually develop the disease and need to be monitored. Deﬁnitely, larger studies need to be performed with long time period follow-up in order to obtain more conclusive data.

1.2.4. Pathogenic role The mechanisms triggering the development of IBD still remain unknown. However, several theories are proposed trying to illuminate the exact pathophysiologic concepts of these diseases and the pathogenetic role of the associated antibodies. A loss of immune tolerance to endogenous bacteria of the gastrointestinal tract results in dysregulation of the immune response and the production of antibodies to certain bacterial antigens (Nakamura et al., 2003; Seibold, 2005). Possibly the development of the pANCA is due to cross-reactivity to bacterial antigens (Reumaux et al., 2003; Seibold, 2005). However, none of the ASCA, pANCA or anti-OmpC have been shown to play a direct pathogenic role. On the contrary, CBir1 ﬂagellin has proven to induce the production of anti-CBir1 antibodies and T helper-1 cell responses to ﬂagellin leading to the development of colitis in mice. CBir1 ﬂagellin possibly shows a similar immune response in patients with CD (Targan et al., 2005; Lodes et al., 2004).

1.2.5. Sensitivity and specificity It is well known that one of the main characteristics of autoimmune diseases is the presence of autoantibodies in the sera of patients. Based on this fact, several serological markers have been studied in the recent years and found to be helpful not only in diagnosing IBD but even in predicting the development of the disease (Harel and Shoenfeld, 2006). Antibody evaluation is also very signiﬁcant in cases of indeterminate colitis (Seibold, 2005). Many studies in the literature demonstrate a large range in sensitivity and speciﬁcity of serological markers used in diagnosing CD and UC (Reumaux et al., 2003; Targan et al., 2005) (Table 1).

Autoantibodies in Gastrointestinal Autoimmune Diseases Table 1 Sensitivity and speciﬁcity of several autoantibodies in IBD and celiac disease Autoantibodies

Sensitivity (%)

Speciﬁcity (%)

pANCA in UC ASCA in CD AGA IgG in celiac disease

45–82 48–69 83–100a 57–78b 52–100a 55–100b 88–100a 86–100b 94–100a 77–100b

65–94 86–95 47–94a 71–87b 71–100a 82–100b 90–100a 99–100b 90–100a 91–100b

AGA IgA in celiac disease EMA IgA in celiac disease tTG2 IgA in celiac disease

CD=Crohn’s disease, UC=Ulcerative colitis a Children population. b Adult population.

The prevalence of pANCA is reported to be 45–82% in patients with UC and from 2 to 28% in CD patients. The speciﬁcity of pANCA-positive test for UC can reach 94% (Reumaux et al., 2003). ASCA levels were found to be remarkably higher in CD patients. Sensitivity ranges from 48 to 69% in CD and from 5 to 15% in UC (Reumaux et al., 2003). IgG ASCA is more sensitive than IgA ASCA for diagnosing CD (Buckland et al., 2005). Speciﬁcity of ASCA is also high, reaching 95%. Combining ASCA and pANCA increases the speciﬁcity and positive predictive value both for CD and UC (Reumaux et al., 2003; Buckland et al., 2005; Reese et al., 2006). Deﬁnitely, these markers are disease speciﬁc, but their low sensitivity and the fact that both antibodies are found also in other autoimmune gastrointestinal diseases make them unsuitable for routine screening (Reumaux et al., 2003; Seibold, 2005; Buckland et al., 2005). However, a currently available panel that includes ASCA (IgG and IgA), pANCA and anti-OmpC together has been shown to exhibit good sensitivity and very high speciﬁcity for identifying patients with CD and UC. Anti-OmpC used in this panel, despite its low sensitivity, can be useful because it recognizes a small group of IBD patients not detectable by the other assays (Zholudev et al., 2004).

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Anti-CBir1 ﬂagellin is present in 50–55% of patients with CD and in only 6% of patients with UC, making this marker speciﬁc for CD. Also, this marker identiﬁes a unique subgroup of CD patients who are negative to other serological markers (Targan et al., 2005). In cases of patients with indeterminate colitis and positive serological response, positive ASCA/ negative pANCA predicts CD in 80% of patients and negative ASCA/positive pANCA predicts UC in 63.3% (Seibold, 2005). In addition, the fact that anti-CBir1 is present in 40–44% of positive pANCA CD patients and in only 4% of positive pANCA UC patients makes this marker an additional tool in assessment of indeterminate colitis (Targan et al., 2005).

1.3. Discussion and conclusions IBD are chronic idiopathic inﬂammatory disorders characterized by excessive inﬂammatory response of the gastrointestinal tract that results in tissue damaging and often in the production of several antibodies (Israeli et al., 2005). Strong evidence suggests the etiology to be multifactorial involving genetic factors and dysregulated immune reactivity to the microbiota of the gastrointestinal tract (Nakamura et al., 2003). The presence of speciﬁc antibodies in the sera of IBD patients have always been the focus of intense studies. Such antibodies that have been shown to be related with the presence of IBD are the atypical pANCA, ASCA, anti-OmpC and lately the anti-CBir1 ﬂagellin. These serological markers are highly speciﬁc for IBD and when combined together they increase the diagnostic ability. However, because of their low sensitivity, serological testing is not used as a single test in evaluation of suspected patients. Some studies suggest that there is a correlation of serological markers with disease phenotype and that these serological markers can be used to predict not only the course of the disease but also the disease itself (Israeli et al., 2005; Zholudev et al., 2004; Harel and Shoenfeld, 2006; Amre et al., 2006; Dubinsky et al., 2006).

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ASCA positivity and high titers are associated with the development of early complications, such as ﬁstulae and abscesses (Zholudev et al., 2004; Amre et al., 2006; Dubinsky et al., 2006). The risk of progressing to a more aggressive phenotype is increased in those individuals with immune reactivity to more than one microbial antigen (Targan et al., 2005; Dubinsky et al., 2006). Recently, a study demonstrated the presence of ASCA and atypical pANCA in the sera of CD patients long before the clinical diagnosis, suggesting that antibody positivity may precede or even predict the development of the disease (Israeli et al., 2005). This evidence is of great importance because it allows the identiﬁcation of asymptomatic individuals who are at risk of developing IBD, and therefore, it might allow several preventive modiﬁcations (Harel and Shoenfeld, 2006). Search for the ideal serological test that could lead to an accurate diagnosis of IBD or even to distinguish CD from UC is the challenge of the near future.

2.2. The antibodies 2.2.1. Definitions Anti-gliadin antibodies (AGA) are antibodies of the IgA and IgG classes found in the sera of CD patients. These antibodies mainly target gliadinderived peptides, which are the main proteins of gluten. AGA are not speciﬁc for CD as they are also found in patients with other gastrointestinal diseases such as gastritis, gastroenteritis and IBD (Basso et al., 2006; Bizzaro and Tonutti, 2007). Anti-endomysial antibodies (EMA) are IgA class autoantibodies directed against endomysium, the collagen matrix of human and monkey tissues (Akbari et al., 2006). The antigen of the endomysium is considered to be the enzyme tTG2 (van Heel and West, 2006). Anti-tTG2 are autoantibodies of class IgA and IgG produced by tTG2-speciﬁc B cells (Esposito et al., 2002). Speciﬁcally, IgA autoantibodies recognize the enzyme tTG2, making them speciﬁc markers for CD (Tonutti and Bizzaro, 2007). tTG2 is a calcium-dependent cytosolic protein possessing both intracellular and extracellular functions, and it appears to play a critical role in controlling cell and tissue homeostasis (Caputo et al., 2004).

2. Antibodies in celiac disease 2.2.2. Methods of detection 2.1. Introduction Celiac disease (CD) is an autoimmune disease triggered by exposure to gluten, a wheat protein, and is characterized by an inﬁltration of the mucosal epithelium by lymphocytes, villous atrophy and hyperplastic crypts (Basso et al., 2006; Akbari et al., 2006). The ingestion of gluten in genetically predisposed patients leads to the occurrence of disease-speciﬁc reactive antibodies against the enzyme tissue transglutaminase type 2 (tTG2), against endomysium and against gliadin (Basso et al., 2006; Collin et al., 2005; Hill, 2005). Measurement of such antibodies in serum can help establish the diagnosis, but despite their high speciﬁcity and sensitivity, a small bowel biopsy should be performed to evaluate the histological ﬁndings and to conﬁrm the diagnosis (Basso et al., 2006).

IgA endomysial antibodies can be determined by an immunoﬂuorescence test, using either the human umbilical cord as antigen or the monkey esophageal antigen. The test is based on the immunoﬂuorescence ﬁndings of a reticular staining pattern when the antibody binds to the endomysium (Akbari et al., 2006; Collin et al., 2005). IgA tTG2 can be determined by an indirect noncompetitive ELISA assay using either human recombinant antigen or guinea pig protein as the source of tTG2 antigen (Akbari et al., 2006). The source of tTG2 used in ELISA has a signiﬁcant role as it was shown that the human recombinant based tTG2 is more sensitive and speciﬁc when compared to the guinea pig protein (Hill, 2005). Another method of measurement of anti-tTG2 is the immunochemiluminescent assay using human recombinant antigen that shows even better sensitivity when compared to the second-generation

Autoantibodies in Gastrointestinal Autoimmune Diseases

ELISA (human recombinant antigen) (Basso et al., 2006). The determination of AGA of the IgA and IgG classes can be established by immunoﬂuorescence and ELISA. Because of their low diagnostic accuracy and the introduction of newer, more accurate serological tests, AGA testing is not commonly used today in the investigation of celiac disease. However, recent ELISA tests using synthetic gliadin peptides show diagnostic accuracy similar to that of anti-tTG tests (Bizzaro and Tonutti, 2007).

2.2.3. Pathogenic role Although it is still unclear whether antibodies play a role in the pathogenesis of celiac disease, several studies showed that anti-tTG2 autoantibodies can inhibit the catalytic activity of human tTG2 both in vitro and in situ (Esposito et al., 2002; Sollid and Jabri, 2005). In addition to this, it was shown that differentiation of intestinal crypt epithelial cells dependent on transforming growth factor B (TGF-b) can be inhibited by tTG2 autoantibodies (Esposito et al., 2002; Sollid and Jabri, 2005; Guandalini and Gokhale, 2002). It is also proposed that the presence of autoantibodies to tTG2 is involved in the extraintestinal manifestations of CD (Sollid and Jabri, 2005). Recently, a study showed that a subset of anti-tTG2 autoantibodies have the ability to increase intestinal permeability and activate monocytes through binding with tolllike receptor 4 (TLR4). These antibodies recognize rotavirus protein VP-7, suggesting that molecular mimicry may be a possible mechanism of viral involvement in the pathogenesis of the disease (Zanoni et al., 2006).

2.2.4. Genetics A very high percentage of patients with CD possess either the HLA-DQ2 heterodimer or the HLA-DQ8 demonstrating the strong genetic relation that is involved in the development of the disease. More than 97% of CD patients have the DQ2 and/or DQ8 heterodimer encoded by the DQA1*0501 and DQB1*0201 genes compared to one-third of the general population (Basso et al.,

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2006; Periolo and Chernavsky, 2006). Also the concordance rate in the monozygotic twins is 86%, whereas in dizygotic twins it reaches only 20% (Stepniak and Koning, 2006). The observation that HLA-DQ2 homozygous individuals have at least ﬁvefold higher risk of developing the disease than HLA-DQ2 heterozygous individuals shows clearly the strong HLA-DQ2 gene dose effect (Tonutti and Bizzaro, 2007; Stepniak and Koning, 2006). Modiﬁcation of wheat gluten proteins by tissue transglutaminase into peptides with negatively charged amino acids leads to more efﬁcient binding to the speciﬁc and positively charged HLA-DQ2 or DQ8 receptors (van Heel and West, 2006; Periolo and Chernavsky, 2006; Stepniak and Koning, 2006). T-cell activation by gliadin–tTG2 complexes presented by HLA-DQ molecules provides the necessary help for production of antigliadin and anti-tTG2 antibodies (Sollid and Jabri, 2005; Stepniak and Koning, 2006; Hourigan, 2006).

2.2.5. Sensitivity and specificity A number of studies have been conducted to report the sensitivity and speciﬁcity of several serological tests used commercially for diagnosing CD. A review of these studies report interesting results. AGA IgG, AGA IgA, EMA IgA and tTG2 IgA were evaluated (Hill, 2005) (Table 1). AGA IgA and AGA IgG are characterized by low speciﬁcity and sensitivity when compared with the newer serological tests. AGAs should not be used in the evaluation of suspected individuals having CD (Basso et al., 2006). EMA IgA antibodies have shown good sensitivity and speciﬁcity in both adult and children population. The overall sensitivities ranged from 86 to 100% and speciﬁcities ranged from 90 to 100%. A ﬁrst look on results for tTG2 IgA can be misleading, suggesting lower overall sensitivity and speciﬁcity compared with EMA –IgA; however, these studies used either guinea pig protein or human recombinant protein for anti-tTG2 determination. Today it is well established that anti-guinea–pig tTG2 has lower sensitivity and speciﬁcity than recombinant anti-human tTG2 (Basso et al., 2006; Lefﬂer and Kelly, 2006). Although EMA IgA and human recombinant tTG2 IgA have no signiﬁcant

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differences in recognizing individuals suspected for CD, EMA IgA testing is time and money consuming and operator dependent. This fact leads to the conclusion that the use of anti-tTG2 IgA using human recombinant antigen is the test of choice today for the detection of people with CD (Basso et al., 2006; van Heel and West, 2006; Tonutti and Bizzaro, 2007). In persons with IgA deﬁciency and suspicion of CD, anti-tTG2 IgG is recommended as the most appropriate test for evaluating these cases (Basso et al., 2006).

2.3. Discussion and conclusion CD is a multifactorial disease involving both environmental and genetic factors. Gliadin plays a key role in the pathogenesis of CD. Gliadin peptides, after ingestion and modiﬁcation by the enzyme tTG2, are more easily recognized by the mucosal antigen-presenting cells that express HLADQ2 and HLA-DQ8 molecules leading to T-cell activation and ﬁnally to the production of highly disease speciﬁc autoantibodies to tTG2. Tests using human recombinant or human puriﬁed tTG2 are considered to be highly speciﬁc and sensitive and are recommended as the initial test of choice in the diagnostic evaluation of CD. Also anti-tTG2 antibody determination can be used for monitoring patients diagnosed with CD (Basso et al., 2006). However endoscopy, accompanied by multiple duodenal biopsies, still remains the necessary diagnostic tool for conﬁrming the diagnosis of CD (Basso et al., 2006; Caputo et al., 2004). It is too early to recommend a mass screening for CD in asymptomatic individuals using serological tests (Moritoki et al., 2006).

whereas others are disease speciﬁc (Moritoki et al., 2006). The three most important autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). AIH is a chronic, progressive hepatitis of unknown etiology occurring in individuals of all ages (Krawitt, 2006). Based on the autoantibody proﬁle, AIH may be divided into three subtypes (Moritoki et al., 2006; Czaja and Norman, 2003). PBC is a chronic cholostatic liver disease of unknown cause characterized by female predominance and by the destruction of small intrahepatic bile ducts that leads eventually to cirrhosis and liver failure (Kaplan, 1996). PSC is a ﬁbrosing disease affecting the large bile ducts that are frequently associated with inﬂammatory bowel disease (Cullen and Chapman, 2003). The presence of autoantibodies in autoimmune liver diseases reﬂects immune reactivity and many times is helpful in establishing the diagnosis. Their presence may have a role in the pathogenesis of these diseases, but on the other hand, their existence may simply represent the result of liver injury. The basic autoantibodies used in diagnosing autoimmune liver diseases are antinuclear antibodies (ANA), smooth muscle antibodies (SMA), antibodies to liver–kidney microsome type 1 (antiLKM1), antimitochondrial antibodies (AMA) and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA). Today more serological markers are emerging, expanding the diagnostic capability in diagnosing autoimmune liver diseases (Table 2) (Czaja and Norman, 2003).

3.2. The antibodies 3.2.1. Antinuclear antibodies

3. Antibodies in autoimmune liver diseases 3.1. Introduction Autoimmune liver diseases are chronic diseases affecting the liver and are characterized by the presence of several autoantibodies, some of which are present in more than one autoimmune disease

ANA are autoantibodies directed against nuclear antigens such as ribonucleoproteins, ribonucleoprotein complexes and centromeres. Usually they are used as serological markers of AIH but are also present in PBC, PSC and other autoimmune diseases. In addition, the fact that a percentage of healthy individuals are ANA positive makes these markers least speciﬁc in AIH (Czaja and Norman,

Autoantibodies in Gastrointestinal Autoimmune Diseases Table 2 Autoantibodies in autoimmune liver diseases AIH Characteristic ANA autoantibodies SMA Anti-LKM1 Anti-LKM3 Anti-LC1

PBC

PSC

AMA ANA Anti-gp210 Anti-p62 Anti-lamin B receptor

Atypical pANCA ANA

Anti-SLA/LP Anti-ASGPR Atypical pANCA

2003). ANA are detected by indirect immunoﬂuorescence (IIF) assay using human epithelial cells (HEp-2) or by enzyme-linked immunosorbent assay (ELISA) (Czaja and Norman, 2003; Nishioka and Morshed, 1999). The patterns of nuclear ﬂuorescence are the homogenous, the speckled, the peripheral or the rim pattern and the centromeric pattern. Homogenous and speckled pattern appear more frequently in AIH. Immune reactivity to several nuclear antigens is associated with different patterns of immunoﬂuorescence, but it may also be associated with different clinical features of the autoimmune liver diseases (Nishioka and Morshed, 1999). ANA are commonly found in PBC in up to 70% of the cases, and in PSC the prevalence ranges from 7 to 77% (Cullen and Chapman, 2003; Nishioka and Morshed, 1999).

3.2.2. Smooth muscle antibodies SMA are autoantibodies directed against actin and non-actin cytoskeleton components such as vimentin, tubulin and desmin, and they are commonly used for the diagnosis of AIH (Moritoki et al., 2006; Czaja and Norman, 2003). Detection of these antibodies is done by IIF using as substrates murine stomach, liver and kidney, demonstrating a variety of staining patterns. In type 1 AIH, the most speciﬁc SMA pattern is the SMA-T. SMA can also be found in other autoimmune liver diseases like celiac disease and viral diseases like chronic hepatitis C. Although the prevalence of SMA in type 1 AIH

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reaches 80%, they are characterized by lack of disease speciﬁcity (Selmi et al., 2007). A subset of SMA, autoantibodies against F-actin, showed even better speciﬁcity than the typical SMA as it was demonstrated to be common in AIH and absent in other liver diseases. Also the presence of anti-actin autoantibodies are associated with early age onset of the disease and worse prognosis (Moritoki et al., 2006; Czaja and Norman, 2003).

3.2.3. Antibodies to liver–kidney microsome Anti–LKM1 are autoantibodies directed against the cytochrome monooxygenase P450 IID6 (CYP2D6), a signiﬁcant enzyme system located in the cytosol of the liver. The presence of these antibodies is highly associated with type 2 AIH. In 10% of patients with hepatitis C, anti-LKM1 are found to be positive possibly due to crossreactivity between CYP2D6 and hepatitis C virus (Moritoki et al., 2006; Czaja and Norman, 2003). The sensitivity of anti-LKM1 is very low (4–20%) and varies among different geographic regions (Czaja and Norman, 2003). Anti-LKM3 are autoantibodies, ﬁrst described in chronic hepatitis D, that target a 55 kDa molecular weight molecule found to be the uridine diphosphate glucuronosyltransferase (UGT). UGTs are enzymes that catalyze the glucuronidation of many endogenous and exogenous compounds and are located in the endoplasmic reticulum. These serological markers ﬁnd use in the diagnosis of type 2 AIH. Anti-LKM3 are present in 8–19% of patients with type 2 AIH, and also in 6–13% of patients with chronic hepatitis D. They are highly speciﬁc for type 2 AIH as they were not detected in the sera of patients with other autoimmune liver diseases. Anti-LKMs are detected by IIF on murine liver and kidney tissue and subclassiﬁcation is achieved by Western blotting and ELISA (Fabien et al., 2004). Although LKM3 antibodies recognize many isoforms of UGT, they exhibit a higher reactivity with UGT1A1, the isoform that is involved in bilirubin glucuronidation (Moritoki et al., 2006; Fabien et al., 2004).

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3.2.4. Antimitochondrial antibodies AMA are autoantibodies directed against inner mitochondrial membrane proteins which are the E2 subunits of pyruvate dehydrogenase complex (PDC-E2), the branched chain 2-oxo acid dehydrogenase complex (BCOADC-E2), the 2-oxoglutarate dehydrogenase complex (OGDC-E2), the E1a and E1b subunits of PDC and the dehydrogenasebinding protein of the PDC (PDC-E3 BP) (Medina et al., 2001; Jones, 2000; Invernizzi et al., 2007). These enzymes participate in oxidative phosphorylation and have an important role in the glycolytic pathway, tricarboxylic acid cycle and the pathway of branched-chain amino acids metabolism (Invernizzi et al., 2007). The detection of AMA is signiﬁcant for the diagnosis of PBC (Jones, 2000). The prevalence of AMA in PBC reaches 95% with a speciﬁcity of 98% for the disease (Kaplan, 1996). AMA show the highest speciﬁcity for an autoimmune liver disease among the rest of the serological markers. AMA are detected by IIF on murine kidney and stomach tissues but immunoblotting and ELISA may also be used, leading to an increase in sensitivity and speciﬁcity of the test (Czaja and Norman, 2003; Invernizzi et al., 2007).

3.2.5. Atypical perinuclear antineutrophil cytoplasmic antibodies Atypical pANCA are autoantibodies against a variety of neutrophil antigens. Although the autoantigen is not clearly deﬁned, it is proposed that pANCA are directed against several antigens such as catalase, enolase, cathepsin G and bacterial permeability increasing protein (BPI) (Czaja and Norman, 2003; Aoki et al., 2005). Some other studies demonstrate that the autoantigen is considered to be a neutrophil-speciﬁc 50 kDa nuclear envelope protein (Moritoki et al., 2006; Czaja and Norman, 2003). Atypical pANCA are found in 33–88% of patients with PSC and in 50–96% of patients with AIH (Cullen and Chapman, 2003). These autoantibodies are not disease speciﬁc as they are also present in patients with ulcerative colitis (UC).

3.2.6. Antibodies to liver cytosol type 1 (anti-LC1) Anti-LC1 are autoantibodies that recognize the antigen formiminotransferase cyclodeaminase (FTCD), which is a liver-speciﬁc enzyme having a role in converting histidine to glutamic acid (Strassburg and Manns, 2007). These antibodies are speciﬁc for AIH, and frequently express in patients also positive for anti-LKM1. They are found in 30–50% of patients with type 2 AIH and have been shown to be present in 10% of AIH patients negative to other serological markers (Moritoki et al., 2006; Strassburg and Manns, 2007). In addition, it was demonstrated that antiLC1 are associated with disease activity and may represent markers of residual liver inﬂammation. IIF and immunodiffusion are the preferable methods of detection of these autoantibodies (Czaja and Norman, 2003; Strassburg and Manns, 2007).

3.2.7. Antibodies to soluble liver antigen/ liver pancreas antigen (anti-SLA/LP) Anti-SLA are autoantibodies found to be reactive with a 50 kDa cytosolic transfer ribonucleoprotein complex (tRNP), the same autoantigen recognized by antibodies to the liver/pancreas. Anti-SLA/LP were shown to be highly speciﬁc markers for AIH occurring in 10–30% of the cases with the speciﬁcity reaching 99%. They are helpful markers in identifying a small group of patients with cryptogenic hepatitis (Czaja and Norman, 2003; Manns, 2000). These autoantibodies are detected by an ELISA based on recombinant antigen from prokaryotic and eukaryotic systems (Czaja and Norman, 2003).

3.2.8. Antibodies to asialoglycoprotein receptor (anti-ASGPR) Anti-ASGPR are autoantibodies directed against a liver-speciﬁc lipoprotein located on hepatocyte membranes that have a role in recognition and transportation of potential antigens (Czaja and Norman, 2003). Anti-ASGPR are expressed in

Autoantibodies in Gastrointestinal Autoimmune Diseases

up to 88% of patients with AIH but are also present in other liver diseases such as PBC, alcoholic liver disease and viral hepatitis (Moritoki et al., 2006; Czaja and Norman, 2003). Also these antibodies showed a correlation with disease activity and treatment response. Assays used to detect anti-ASGPR are ELISA using human, rabbit or rat ASGPR and radioimmunoﬁltration (RIFA) using rabbit ASGPR (Czaja and Norman, 2003).

3.2.9. Antibodies to nuclear pore complex antigens Antibodies to nuclear pore complex antigens were shown to be highly associated with the presence of PBC. Particularly, antibodies to glycoprotein gp210 are present in 10–41% of PBC patients with the speciﬁcity reaching over 99%. Also anti-gp210 are found in 20–41% of cases with negative AMA, making these antibodies helpful serological markers for establishing a diagnosis in this group of patients. The prevalence of anti-p62 antibodies in PBC patients is lower (23–32%) but with high speciﬁcity, similar to anti-gp210. Anti-lamin B receptor antibodies are also highly speciﬁc for PBC, but they are characterized by very low sensitivity (1–3%). Antibodies to nuclear pore complex antigens are best identiﬁed by IIF using HEp-2 cells giving a membrane-like pattern of staining. The high speciﬁcity of these antibodies for PBC deﬁnitely points out their signiﬁcance as serological markers for diagnosing patients with PBC (Jones, 2000; Nesher et al., 2001).

3.3. Genetics Several studies in the literature suggest a genetic susceptibility to autoimmune liver diseases with speciﬁc genes identiﬁed to be associated with AIH, PBC and PSC. HLA-DRBI*0301DRB3*0101DQA1*0501DQB1 *0201 and HLA-DRB1*0401 are commonly associated with AIH. In addition, different populations have found to be related with speciﬁc alleles. Thus,

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in South American populations, the most frequently related haplotype is HLA-DRB1*1301 and in Japan it is the HLA-DRB1*0405DQB1*0401. Also, HLADRB1*03 and HLA-DRB1*13 alleles are more common in children populations (Krawitt, 2006). Some studies reported PBC to be more frequent in patients with an affected family member, suggesting a genetic predisposition to the disease (Selmi et al., 2004). A weak association of PBC with haplotype HLA-DR8 and DPB1 gene is also reported in the literature (Kaplan, 1996). In PSC, a strong association was demonstrated with DRB1*03-DQA1 *0501-DQB1*02 haplotype, whereas the HLADRB1*04-DQA1*03-DQB1*0302 haplotype is negatively associated with the disease (Aoki et al., 2005).

3.4. Pathogenic role As in many autoimmune diseases that are characterized by the presence of autoantibodies, a question is raised whether this presence reﬂects the outcome of the disease itself or has a direct pathogenic role in the development of the disease. The role of autoantibodies in autoimmune liver diseases still remains unclear. Nevertheless, several studies imply involvement of autoantibodies in the pathogenesis of the disease. It is proposed that destruction of biliary epithelial cells may be possible after binding of circulating AMA with the speciﬁc autoantigens expressed on cell surface membranes in PBC patients (Medina et al., 2001; Selmi et al., 2004). Also AMA interference with cellular functions after penetration of biliary epithelial cells could be a possible mechanism (Medina et al., 2001; Jones, 2000). However, these theories need to be conﬁrmed. It is well known that catalase is an antioxidant enzyme found in the cytosole of hepatocytes and biliary epithelial cells and its role is to protect cells from damage by oxygen-derived radicals. In PSC patients, impairment of catalase antioxidant functions by the presence of catalase speciﬁc pANCA may lead to oxidative stress and biliary epithelial cells destruction (Medina et al., 2001; Aoki et al., 2005). In addition, neutrophil binding to bacterial

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lipopolysaccharide (LPS) of Gram-negative organism or endotoxins may be inhibited by pANCA autoantibodies targeting BPI (Aoki et al., 2005). Anti-LKM1 autoantibodies were found to inhibit CYP2D6 in vitro and induce liver-inﬁltrating T-lymphocytes activation, thus suggesting a role in the development of AIH (Strassburg and Manns, 2007).

3.5. Discussion and conclusions The existence of autoantibodies and their importance in diagnosing autoimmune liver diseases is unquestionable. Their role in the pathogenesis of autoimmune liver diseases and their diagnostic speciﬁcity is well-studied. The possibility that autoantibodies contribute to the development and progression of AIH, PBC and PSC is supported by several studies, but more evidence need to come forward. In addition, some autoantibodies such as anti-LC1 and anti-ASGPR may correlate with disease activity and treatment response. On the other hand, autoantibody production may be just the result and not the cause of liver injury, suggesting their non-pathogenic nature (Czaja and Norman, 2003). The ongoing effort of new autoantibody identiﬁcation that will help to reveal new autoantigens and new immunopathogenic mechanisms and to improve the current diagnostic tools is of major signiﬁcance.

References Akbari, M.R., Mohammadkhani, A., Fakheri, H., Javad Zahedi, M., Shahbazkhani, B., Nouraie, M., Sotoudeh, M., Shakeri, R., Malekzadeh, R. 2006. Screening of the adult population in Iran for coeliac disease: comparison of the tissue-transglutaminase antibody and anti-endomysial antibody tests. Eur. J. Gastroenterol. Hepatol. 18, 1181–1186. Amre, D.K., Lu, S.E., Costea, F., Seidman, E.G. 2006. Utility of serological markers in predicting the early occurrence of complications and surgery in pediatric Crohn’s disease patients. Am. J. Gastroenterol. 101, 645–652. Aoki, C.A., Bowlus, C.L., Gershwin, M.E. 2005. The immunobiology of primary sclerosing cholangitis. Autoimmun. Rev. 4, 137–143.

Basso, D., Guariso, G., Fogar, P., Navaglia, F., Zambon, C.F., Plebani, M. 2006. Insights in the laboratory diagnosis of celiac disease. Lupus 15, 462–465. Bizzaro, N., Tonutti, E. 2007. Anti-gliadin antibodies. In: Y. Shoenfeld, M.E. Gershwin, P.L. Meroni (Eds.), Autoantibodies. Elsevier, Amsterdam, pp. 451–456. Buckland, M.S., Mylonaki, M., Rampton, D., Longhurst, H.J. 2005. Serological markers (anti-Saccharomyces cerevisiae mannan antibodies and antineutrophil cytoplasmic antibodies) in inﬂammatory bowel disease: diagnostic utility and phenotypic correlation. Clin. Diagn. Lab. Immunol. 12, 1328–1330. Caputo, I., D’Amato, A., Troncone, R., Auricchio, S., Esposito, C. 2004. Transglutaminase 2 in celiac disease: minireview article. Amino Acids 26, 381–386. Collin, P., Kaukinen, K., Vogelsang, H., Korponay-Szabo, I., Sommer, R., Schreier, E., Volta, U., Granito, A., Veronesi, L., Mascart, F., Ocmant, A., Ivarsson, A., Lagerqvist, C., Burgin-Wolff, A., Hadziselimovic, F., Furlano, R.I., Sidler, M.A., Mulder, C.J., Goerres, M.S., Mearin, M.L., Ninaber, M.K., Gudmand-Hoyer, E., Fabiani, E., Catassi, C., Tidlund, H., Alainentalo, L., Maki, M. 2005. Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsyproven European multicentre study. Eur. J. Gastroenterol. Hepatol. 17, 85–91. Cullen, S., Chapman, R. 2003. Primary sclerosing cholangitis. Autoimmun. Rev. 2, 305–312. Czaja, A.J., Norman, G.L. 2003. Autoantibodies in the diagnosis and management of liver disease. J. Clin. Gastroenterol. 37, 315–329. Dubinsky, M.C., Lin, Y.C., Dutridge, D., Picornell, Y., Landers, C.J., Farrior, S., Wrobel, I., Quiros, A., Vasiliauskas, E.A., Grill, B., Israel, D., Bahar, R., Christie, D., Wahbeh, G., Silber, G., Dallazadeh, S., Shah, P., Thomas, D., Kelts, D., Hershberg, R.M., Elson, C.O., Targan, S.R., Taylor, K.D., Rotter, J.I., Yang, H. 2006. Serum immune responses predict rapid disease progression among children with Crohn’s disease: immune responses predict disease progression. Am. J. Gastroenterol. 101, 360–367. Esposito, C., Paparo, F., Caputo, I., Rossi, M., Maglio, M., Sblattero, D., Not, T., Porta, R., Auricchio, S., Marzari, R., Troncone, R. 2002. Anti-tissue transglutaminase antibodies from coeliac patients inhibit transglutaminase activity both in vitro and in situ. Gut 51, 177–181. Fabien, N., Desbos, A., Bienvenu, J., Magdalou, J. 2004. Autoantibodies directed against the UDP-glucuronosyltransferases in human autoimmune hepatitis. Autoimmun. Rev. 3, 1–9. Guandalini, S., Gokhale, R. 2002. Update on immunologic basis of celiac disease. Curr. Opin. Gastroenterol. 18, 95–100. Harel, M., Shoenfeld, Y. 2006. Predicting and preventing autoimmunity, myth or reality? Ann. N.Y. Acad. Sci. 1069, 322–345. Hill, ID. 2005. What are the sensitivity and speciﬁcity of serologic tests for celiac disease? Do sensitivity and speciﬁcity vary in different populations? Gastroenterology 128, S25–S32.

Autoantibodies in Gastrointestinal Autoimmune Diseases Hourigan, C.S. 2006. The molecular basis of coeliac disease. Clin. Exp. Med. 6, 53–59. Invernizzi, P., Selmi, C., Gershwin, M.E. 2007. Antimitochondrial antibodies. In: Y. Shoenfeld, M.E. Gershwin, P.L. Meroni (Eds.), Autoantibodies. Elsevier, Amsterdam, pp. 473–477. Israeli, E., Grotto, I., Gilburd, B., Balicer, R.D., Goldin, E., Wiik, A., Shoenfeld, Y. 2005. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inﬂammatory bowel disease. Gut 54, 1232–1236. Jaskowski, T.D., Litwin, C.M., Hill, H.R. 2006. Analysis of serum antibodies in patients suspected of having inﬂammatory bowel disease. Clin. Vaccine Immunol. 13, 655–660. Jones, D.E. 2000. Autoantigens in primary biliary cirrhosis. J. Clin. Pathol. 53, 813–821. Kaplan, M.M. 1996. Primary biliary cirrhosis. N. Engl. J. Med. 335, 1570–1580. Krawitt, E.L. 2006. Autoimmune hepatitis. N. Engl. J. Med. 354, 54–66. Lefﬂer, D.A., Kelly, C.P. 2006. Update on the evaluation and diagnosis of celiac disease. Curr. Opin. Allergy Clin. Immunol. 6, 191–196. Lodes, M.J., Cong, Y., Elson, C.O., Mohamath, R., Landers, C.J., Targan, S.R., Fort, M., Hershberg, R.M. 2004. Bacterial ﬂagellin is a dominant antigen in Crohn disease. J. Clin. Invest. 113, 1296–1306. Manns, M.P. 2000. Antibodies to soluble liver antigen: speciﬁc marker of autoimmune hepatitis. J. Hepatol. 33, 326–328. Medina, J., Jones, E.A., Garcia-Monzon, C., Moreno-Otero, R. 2001. Immunopathogenesis of cholestatic autoimmune liver diseases. Eur. J. Clin. Invest. 31, 64–71. Mei, L., Targan, S.R., Landers, C.J., Dutridge, D., Ippoliti, A., Vasiliauskas, E.A., Papadakis, K.A., Fleshner, P.R., Rotter, J.I., Yang, H. 2006. Familial expression of anti-Escherichia coli outer membrane porin C in relatives of patients with Crohn’s disease. Gastroenterology 130, 1078–1085. Moritoki, Y., Lian, Z.X., Ohsugi, Y., Ueno, Y., Gershwin, M.E. 2006. B cells and autoimmune liver diseases. Autoimmun. Rev. 5, 449–457. Nakamura, R.M., Matsutani, M., Barry, M. 2003. Advances in clinical laboratory tests for inﬂammatory bowel disease. Clin. Chim. Acta 335, 9–20. Nesher, G., Margalit, R., Ashkenazi, Y.J. 2001. Anti-nuclear envelope antibodies: clinical associations. Semin. Arthritis Rheum. 30, 313–320. Nishioka, M., Morshed, S.A. 1999. Heterogeneity of antinuclear antibodies in autoimmune liver diseases. Biomed. Pharmacother. 53, 293–300. Periolo, N., Chernavsky, A.C. 2006. Coeliac disease. Autoimmun. Rev. 5, 202–208.

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Reese, G.E., Constantinides, V.A., Simillis, C., Darzi, A.W., Orchard, T.R., Fazio, V.W., Tekkis, P.P. 2006. Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inﬂammatory bowel disease. Am. J. Gastroenterol. 101, 2410–2422. Reumaux, D., Sendid, B., Poulain, D., Duthilleul, P., Dewit, O., Colombel, J.F. 2003. Serological markers in inﬂammatory bowel diseases. Best Pract. Res. Clin. Gastroenterol. 17, 19–35. Seibold, F. 2005. ASCA: genetic marker, predictor of disease, or marker of a response to an environmental antigen? Gut 54, 1212–1213. Selmi, C., Invernizzi, P., Keeffe, E.B., Coppel, R.L., Podda, M., Rossaro, L., Ansari, A.A., Gershwin, M.E. 2004. Epidemiology and pathogenesis of primary biliary cirrhosis. J. Clin. Gastroenterol. 38, 264–271. Selmi, C., Muratori, P., Podda, M., Bianchi, B.F. 2007. Smooth muscle antibodies. In: Y. Shoenfeld, M.E. Gershwin, P.L. Meroni (Eds.), Autoantibodies. Elsevier, Amsterdam, pp. 487–491. Sollid, L.M., Jabri, B. 2005. Is celiac disease an autoimmune disorder? Curr. Opin. Immunol. 17, 595–600. Stepniak, D., Koning, F. 2006. Celiac disease–sandwiched between innate and adaptive immunity. Hum. Immunol. 67, 460–468. Strassburg, C.P., Manns, M.P. 2007. Liver cytosol antigen type 1 autoantibodies, liver kidney microsomal autoantibodies, and liver microsomal autoantibodies. In: Y. Shoenfeld, M.E. Gershwin, P.L. Meroni (Eds.), Autoantibodies. Elsevier, Amsterdam, pp. 463–470. Targan, S.R., Landers, C.J., Yang, H., Lodes, M.J., Cong, Y., Papadakis, K.A., Vasiliauskas, E., Elson, C.O., Hershberg, R.M. 2005. Antibodies to CBir1 ﬂagellin deﬁne a unique response that is associated independently with complicated Crohn’s disease. Gastroenterology 128, 2020–2028. Tonutti, E., Bizzaro, N. 2007. Anti-tissue transglutaminase and anti-endomysial antibodies. In: Y. Shoenfeld, M.E. Gershwin, P.L. Meroni (Eds.), Autoantibodies. Elsevier, Amsterdam, pp. 443–450. van Heel, D.A., West, J. 2006. Recent advances in coeliac disease. Gut 55, 1037–1046. Zanoni, G., Navone, R., Lunardi, C., Tridente, G., Bason, C., Sivori, S., Beri, R., Dolcino, M., Valletta, E., Corrocher, R., Puccetti, A. 2006. In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes. PLoS Med. 3, e358. Zholudev, A., Zurakowski, D., Young, W., Leichtner, A., Bousvaros, A. 2004. Serologic testing with ANCA, ASCA, and anti-OmpC in children and young adults with Crohn’s disease and ulcerative colitis: diagnostic value and correlation with disease phenotype. Am. J. Gastroenterol. 99, 2235–2241.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rode´s, editors

CHAPTER 18

Gastrointestinal Complications of Anti-Rheumatic Drugs K.D. Rainsforda, Iain R.L. Keana, Walter F. Keanb, a

Biomedical Research Centre, Sheffield Hallam University, Sheffield S1 1WB, England, UK Department of Medicine, McMaster University Faculty of Health Sciences, Suite #401, 1 Young Street, Hamilton, Ont., Canada L8N 1T8

b

1. Introduction In this chapter we review (a) the current status for treating pain and inﬂammation in chronic arthritic conditions; (b) the occurrence of gastrointestinal (GI)1 adverse reactions during arthritis therapy with non-steroidal anti-inﬂammatory drugs (NSAIDs)2 Corresponding author. Tel.: +1-9055210514; Fax: +1-9055282385 E-mail address: [email protected] 1 The term GI reactions used here is meant to embrace the whole range of the entire GI tract. They include ulceration, haemorrhage, inﬂammatory bowel diseases (IBD), bowel perforation and peritonitis, diaphragmatic strictures, ‘water melon stomach’ (Dulai and Jensen, 2004), digestive malfunction (‘disorders’), painful symptoms notably associated with indigestion or use of drugs and other symptomologies. This list is by no means complete. Peptic ulcer disease (PUD) is a clinically deﬁned condition in which there are ulcers present in the stomach and/or duodenum (upper GI ulcers) with or without accompanying haemorrhage. 2 In this chapter, the terms traditional NSAID (or tNSAID) and NS-NSAID (non-speciﬁc NSAID) are used interchangeably. The tNSAIDs denote those NSAIDs that were introduced in the period of the 1950s–1980s and include aspirin and other salicylates many of which were discovered prior to this period. They are separated from the highly cyclo-oxygenase-2 (COX-2) selective drugs, known as the coxibs that were initially discovered during the 1990s. Because of their high COX-2 selectivity they are distinguished from less COX-2-speciﬁc drugs (e.g. diclofenac, ibuprofen, and naproxen) which are by convention termed non-selective NSAIDs (or NS-NSAIDs) and preferentially selective COX-2 inhibitors (e.g. etodoloac and nimesulide), which have COX-2 selective with COX-2 activity intermediate between NS-NSAIDs and coxibs.

r 2008 Elsevier B.V. All rights reserved. DOI: 10.1016/S1571-5078(07)00018-9

and other drug combinations; (c) the GI reactions that occur in patients with autoimmune arthropathies; (d) the GI reactions and other adverse events that occur with newer supposedly GI safe NSAIDs, especially the coxibs, with a critical evaluation of the evidence for their claims to have reduced occurrence of serious and symptomatic GI adverse events; (e) approaches for reducing the development of GI ulceration and other adverse reactions; and (f) considerations of prescribing practice for the patient with rheumatoid arthritis (RA) and related autoimmune arthropathies.

2. The clinical setting 2.1. Populations with musculoskeletal pain World Health Organisation (WHO) statistics and International population studies have demonstrated that 10–50% of people around the world suffer from musculoskeletal disorders requiring treatment, including 25% of adults over 65 years (WHO, 2003). In Canada, studies by The Arthritis Society demonstrate that the number of people with musculoskeletal disorders will rise from 2.9 million in 1991 to 6.5 million by 2031 (Badley and Wang, 1998), and that this acceleration in new cases, equivalent to 300 new patients per day, will parallel the increase in prevalence of disability due to arthritis from 2.3% in 1991 to 3.3% by 2031 (Badley, 1995). Arthritis with the associated chronic pain process is the main cause of work-related

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disability, and its outcome affects all socioeconomic classes and all age groups (Badley, 1995). In the age group 20–89 years, back pain and sciatica have been documented to be present in up to 27% of cases (Lyons et al., 1994), and the majority of these people with musculoskeletal disease will suffer from pain. Up to 65% of rheumatoid patients rank pain as the most important symptom which requires treatment (Anderson et al., 1994), and 55% of osteoarthritis (OA) patients report pain as the worst aspect of their disease (Ofﬁce of National Statistics, 2002). In a 1993 Welsh community survey on health status, on 1201 randomly selected adults (827 respondents) aged 20–89, it was found that 39.3% of people treated by their doctor in the previous 12 months had chronic musculoskeletal pain due to arthritis (19.1%) or back pain (20.2%) or sciatica (6.3%) compared to much lower numbers for other signiﬁcant disorders such as hypertension (13.1%), insomnia (10.3%), anxiety (8.8%), depression (6.6%), angina (7.4%), asthma (6.6%), and diabetes (2.8%). The SF 36 health status instrument, especially in the physical functioning role—physical, and bodily pain domains, demonstrated the substantial health burden of musculoskeletal disorders (Lyons et al., 1994). Elliott and colleagues (1999) performed a chronic pain study in Scotland with 5000 questionnaires (80% replied). Chronic pain was deﬁned as ‘pain or discomfort that persisted continuously or intermittently for longer than 3 months’. Approximately 50% of the respondents reported to have chronic pain, and this increased from 33% in those of 25–34 years age to 66% of those greater than 65 years. Fox and colleagues (1999) from McMaster University identiﬁed that the pain prevalence of nursing home residents was 49–83%, and that the prevalence of this pain was almost entirely due to OA or related disorders. There is a wide range of disorders that constitute the problem of musculoskeletal pain in the young and elderly, with OA, back pain, and sciatica as the most common. The prevalence of RA is 1–2% (Kean et al., 1982, 1983; Gabriel, 2000). Crystal diseases such as gout and pseudogout are present in 0.5–2.8% of males over 40 years, and the prevalence of all types of reactive arthritis including Reiter’s syndrome, ankylosing spondylitis, psoriatic arthritis, and inﬂammatory bowel disease is 1–6%

(Felson, 1996). In addition, a small number of patients suffer from immune disorders such as systemic lupus and polymyalgia rheumatica, and from myofascial disorders such as ﬁbromyalgia. Notwithstanding that the overall management of musculoskeletal disease is a multidisciplinary problem, and involves collaboration of all the health and social disciplines, the majority of patients with musculsoskeletal disorders require analgesic and anti-inﬂammatory medications for pain relief. Many of these patients especially in the over 50 years age group also require aspirin for cardiovascular (CV) prophylaxis. NSAIDs are among the most commonly used pharmacologic agents worldwide. They have been calculated to annually comprise 70 million prescriptions dispensed in the United States (Gabriel et al., 1993), 10 million in Canada (IMS Canada, 1999), and 25 million in the United Kingdom (Hawkey, 1990). Estimates show that a UK general practitioner with an average list of 2000 registered patients has 374 patients with connective tissue disorder of whom 63 have formally been diagnosed with OA (Eccles et al., 1998). On this basis, although 1.6 million people in the United Kingdom have formally been diagnosed with OA, the total number of dispensed NSAID prescriptions suggests their much wider use. In the United Kingdom, the cost of dispensed prescriptions has been reported as d150 million (US$213 million), represented by volume, with ibuprofen (26%) and diclofenac (37%) (Eccles et al., 1998). In the United States, it has been estimated that 70% of patients over 65 years or greater take NSAIDs once per week with an estimated 111,400,000 prescriptions annually from September 1999 to August 2000 resulting in $4.8 billion of annual drug costs and $3 billion additional costs on over the counter (OTC) analgesics including acetaminophen (Laine, 2001). The potential for GI side effects of analgesic and anti-inﬂammatory medications is the major limitation to safe management of musculoskeletal and related pain disorders.

2.2. Burdens of analgesic and anti-inflammatory medication use Almost all patients with musculoskeletal disorders will need treatment with analgesic agents, NSAIDs,

Gastrointestinal Complications of Anti-Rheumatic Drugs

or steroids (Buchanan and Kean, 2002; Kean and Buchanan, 2005). The incidence of musculoskeletal disorders increases with age (Elliott et al., 1999), in parallel to the increased risk of adverse effects to the NSAIDs (Laine, 2003). The major therapeutic limitations to the successful management of musculoskeletal disease and disability are the side effects from the medications, especially the NSAIDs including aspirin (Buchanan and Kean, 2002). The oral and sometimes systemic versions of these medications can cause injury or other complications to the GI tract (Wolfe et al., 1999), the kidney (Whelton, 1999), the CV homeostatic mechanisms (Pope et al., 1993; Kean and Buchanan, 2005), the liver, and the skin (Buchanan and Kean, 2002). While concomitant physiological failure results in an increase in renal, CV, and other NSAID adverse responses especially with age, the most serious side effects are due to GI toxicity (Hirschowitz, 1994; Singh and Ramey, 1998; Langman et al., 1999; Buttgereit et al., 2001; Kean and Buchanan, 2005). The majority of GI effects are symptomatic responses such as bloating, cramping, pain, diarrhoea, constipation, and acid reﬂux, but the most dangerous are erosions, gastric and duodenal ulcers, perforations, and bleeds (Hirschowitz, 1994; Hawkey et al., 2005, 2007a, b). When used for primary CV protection, aspirin has been shown to increase bleeding complications by 69% (Sanmuganathan et al., 2001). Yeomans and colleagues (2005) reported in a study of users of low dose (75–325 mg od) of aspirin that the ulcer prevalence was 11% (lesion >3 mm with depth) with age and Helicobacter pylori being predictive factors but warned that symptoms were infrequent and indeed symptoms were more common in the non-ulcer group in their study. It has been shown that low and greater doses of aspirin over long term were associated with a bleeding rate of 2.3 and 2.5% respectively compared to 1.4% in placebo controls in a meta-analysis of 24 randomised controlled trials which included more than 66,000 subjects. In a case-controlled study of patients hospitalised with ulcer bleeding, 25.1% of patients were taking low-dose aspirin (>300 mg od) compared to only 7.4% of controls. However, it has been identiﬁed that the risk of serious GI bleeding is reduced in low-dose aspirin users if anti-secretory

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therapy is co-administered (Serrano et al., 2002), and recurrence can be reduced by co-administration of the proton-pump inhibitor (PPI), lansoprazole, to patients who have had a previous complicated ulcer on low-dose aspirin (Lai et al., 2002). GI side effects to NSAIDs have been estimated to occur in approximately 25–40% of patients: 15–20% with gastric ulcers; 5–8% with duodenal ulcers; and 1–3% of users are thought to develop GI bleeding as a consequence, especially when exposed to the traditional NSAIDs (tNSAIDs*) (Hirschowitz, 1994; Tannenbaum et al., 1996; Singh and Ramey, 1998; Langman et al., 1999; Buttgereit et al., 2001). Each year, as many as 2000 estimated deaths in the United Kingdom (Trame`r et al., 2000), 7600 deaths and 76,000 hospitalisations in the United States, and 365 deaths and 3900 hospitalisations in Canada (Tamblyn et al., 1997; Tannenbaum et al., 1996) may be attributable to NSAIDs. However, in a review of 74,666 patients in 12 trials, only 138 deaths and 248 serious GI events were identiﬁed. (Hooper et al., 2004). Thus, reﬂecting that the exact estimates of GI complications and even estimates of death rate may be very difﬁcult to assess due to factors such as under reporting, drop-outs not evaluated, and assignment of the event to other causes. The gastointestinal adverse effects, whether only symptomatic or clinically serious, can signiﬁcantly affect quality of life (QoL) (Hawkey et al., 2005), and can result in discontinuation of treatment for musculoskeletal pain in up to 10% of patients (Hirschowitz, 1994; Singh and Ramey, 1998; Langman et al., 1999; Buttgereit et al., 2001). Initial studies on the effect of steroids on the GI tract did not identify a clear relationship between oral steroids and GI complications (Green, 1976; Conn and Poynard, 1994), but Messer and colleagues (1983) did identify a small risk for peptic ulcer disease (PUD) and steroid use. However, it is now well established the steroids alone convey an increased risk of upper GI complications and that risk markedly increases when the steroids are taken concomitantly with NSAIDs. Piper and colleaques (1991) identiﬁed an odds ratio (OR) of 1.1 (95% conﬁdence interval (CI): 0.5–2.12) for steroid use only, but 14.6 (95% CI: 6.7–32.0) for steroids plus NSAIDs versus patients on no drugs.

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Herna´ndez-Dı´ az and Rodrı´ guez (2001) estimated the risk of upper GI complications associated with use of steroids alone and in combination, using a nested case-control analysis which was conducted on the General Practice Research Database from the United Kingdom. The authors identiﬁed 2105 cases of upper GI complications and 11,500 controls between 1993 and 1998. The adjusted ORs associated with current use of oral steroids were 1.8 (95% CI: 1.3, 2.4) for upper GI complications overall, 2.4 (95% CI: 1.7, 3.4) for gastric, and 1.2 (95% CI: 0.8, 1.9) for duodenal damage. Steroids were similarly associated with bleeding (OR 1.8; 95% CI: 1.3, 2.4) and perforations (OR 1.6; 95% CI: 0.9, 3.1). Simultaneous use of steroids with low-, medium-, and high-NSAID doses, respectively, produced ORs of 4.0 (95% CI: 1.3, 12.0) and 12.7 (95% CI: 6.2, 26.1), compared with users of none. This marked increase in risk for concomitant NSAID and steroid use may be related to impaired ulcer healing induced by the steroids (Luo et al., 2004).

carbonate (Rainsford, 1988a, b, 2001); (d) enhanced oxyradicals and in combination with nitric oxide formation of tissue destructive peroxynitrite (Rainsford, 2001); (e) activation of NFkB signalling pathways with consequent production of TNFa, other cytokines and metalloproteinases (Rainsford, 2001); (f) reduced ATP and mitochondrial effects leading to enhanced caspases activation and apoptosis (Rainsford, 2001); and (g) altered cyclic nucleotide production affecting control of acid, pepsin and other physiological functions (Rainsford, 2001). The NSAIDs are a necessary choice in pain management because of the integrated role of the cyclo-oxygenase (COX) pathway in the generation of inﬂammation and in the biochemical recognition of pain (Bevilacqua, 2002; Dallegri and Ottonello, 2002). The inﬂammatory reaction and tissue injury result in cellular release of interleukin-1 (IL-1) and tumour necrosis factor a (TNF-a), which then stimulate macrophage nuclear factor kappa B to produce cyclo-oxygenase 2 (COX-2) and hence the production of large quantities of prostaglandin E2 (PGE2) which facilitates nociceptor recognition and hence the perception of joint pain.

2.3. Mechanisms of action of the NSAIDs Almost all of the original or tNSAIDs are weak acids with a pKa of 3.5–5.0 and thus demonstrate either hydrophilic (in the ionised state) or lipophilic properties (non-ionised state) dependent on the pH of the surrounding milieu. The mechanisms of the serious adverse effects are well established, and are related to a series of actions including local solute effects (Kean and Buchanan, 1987), back diffusion of hydrogen ions (Davenport, 1967; Somasundaram et al., 1995; Sigthorsson et al., 2000), and systemic effects on cell migration and prostaglandin (PG) synthesis (Schoen and Vender, 1989; Wolfe, 1996; Cryer and Feldman, 1998). Other biochemical effects of importance in the development of mucosal injury by NSAIDs include (a) enhanced production of vasoconstrictor peptide-leukotrienes and leucoattractant leukotriene B4 as a consequence of cyclooxygenase inhibition (Rainsford, 1986, 1992, 1997d, 1999a, b) which can also lead to increased acid-pepsin production; (b) delayed ulcer healing (Halter et al., 1997a, b), (c) reduced production of protective mucus and bio-

3. Gastrointestinal reactions in autoimmune arthropathies GI reactions are among the most frequently seen in patients with auto-immune arthropathies (Schneider et al., 2006). These events are more frequent in women than in men (Schneider et al., 2006) and the classical picture of the ‘elderly frail female rheumatic patient that is under weight’ is probably the likely candidate for severe GI disorders, most especially with ulcers in the upper and lower GI regions and haemorrhage. Long-term use of NSAIDs while essential for relief of symptoms of joint pain in patients with auto-immune arthropathies is also accompanied by increased risks of GI reactions (Schaffer et al., 2006). Anaemia and subnormal functional GI physiology leading to subnormal digestive processes and, in the extreme, protein-loosing enteropathy comprise the consequences of GI disorders in these elderly patients (Bjarnason et al., 1991; Hogan et al.,

Gastrointestinal Complications of Anti-Rheumatic Drugs

1994a, b). Modern medical management should, but not always, involve GI evaluation and treatment (Schneider et al., 2006) where there are suspicions of GI disorders such as reduced/ subnormal body mass, anaemia, gastric distress, or other GI symptoms. Of course, the elderly frail female is not the only ‘category’ of arthritic patient who suffers GI symptoms, but may present with life-threatening symptoms. Moreover, the consequences of subnormal digestive processes leading to impaired nutrition may have profound consequences, e.g. cognitive impairment, decline in the status of the arthritic disease, and reduced sociality and independence as part of the deterioration in QoL (Taha et al., 1993).

3.1. Multiple origins of GI reactions The origins of these GI reactions are manifold (Table 1), among them are: a. Use of drugs that are known to cause GI ulceration, haemorrhage, or gastric upsets. These include agents that are well known to cause these effects such as aspirin (Rainsford, 1999b, 2004), non-selective COX inhibitory NSAIDs (Hernandez-Diaz and Garcia-Rodriguez, 2000), Table 1 Risk factors for the development of NSAID-associated gastroduodenal ulcers Established risk factor

Possible risk factor

Advancing age High-dose NSAID or paracetamol Use of more than two NSAIDs Concurrent paracetamol Concurrent anti-coagulants Concurrent aspirin (even low dose) Concurrent corticosteroids (dose-dependent) Helicobacter pylori infection Prior history of peptic ulcer disease Rheumatoid arthritis

High alcohol consumption Cigarette smoking Diuretics Anti-hypertensive agents

Note: Modiﬁed and with additional information from Wolfe et al. (1999), Garcia Rodriguez and Hernandez-Diaz (2001a, b), Laine (2001), and Rainsford (2004).

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the coxib class of NSAIDs (Peng and Duggan, 2005), and notably paracetamol (acetaminophen) (Rainsford and Whitehouse, 2006) given at high dosages (2–4 g/day) (Table 2) (GarciaRodriguez and Hernandez-Diaz, 2001a, b). Low doses of NSAIDs such as in OTC preparations lead to much lower incidence of GI effects (Rainsford, 1997c; Rainsford & Powanda, 1997) conﬁrming that there are pronounced dose-response effects in NSAID associated GI ulcers and bleeding. It should also be noted that GI reactions are sometimes associated with the use of disease-modifying anti-rheumatic drugs (DMARDs), e.g. gold complexes, methotrexate (Kelly and Hamilton, 2007). Thus, the usual culprits, the NSAIDs, are implicated in gastroduodenal-opathies in auto-immune arthritic conditions and may not alone be the cause of severe GI disorders (ulceration, haemorrhage) or of painful symptoms (Talley et al., 1995). b. H. pylori infection of the gastroduodenal region (Hunt and Tytgat, 1993, 1996) and, although less well-known, pathogenic enterobacteria strains including Escherichia coli, Clostridium difficile, Campylobacter jejunii, Gastrospirillium spp., and other indigenous enteric ﬂora (Neu, 1985; Sjo¨stedt, 1989). H. pylori infection like that of many other enteric bacteria is commensual and the conditions for the development of pathogenic strains are not clear, although generalised host population characteristics such as increasing population density, use of antibiotics, and other agents that create selection pressure leading to selection of certain strains are likely factors. From a clinical standpoint the identiﬁcation of the known pathogenic strains of H. pylori, comprising CagA+ and VagA+ combinations, is rarely undertaken in patients with H. pylori associated PUD. Thus, the conclusion that H. pylori infection is responsible for PUD in a particular patient or group of patients may not be adequately justiﬁed. Likewise, the inference that H. pylori infection may contribute to PUD in patients receiving NSAIDs or as popularised by Hawkey (2000) that NSAIDs may inhibit or prevent the mucosal inﬂammation attributed to

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Table 2 Epidemiological data from General Practice Database (UK) on peptic ulcer bleeding risks from aspirin and other NSAIDs and paracetamol and other sources Drug

Usage/factor

Aspirin

Overall use

Dose

Period of use

Concurrent NSAIDs Formulation

Users cf Non-users Recent users Past users 75–300 mg/day >400 mg/day o50 mg/day 1–60 days 61–180 days 181–730 days >730 days Low-medium dose High dose Plain versus coated, both for GU and DU o1 g/day 1–2 g/day 2–4 g/day >4 g/day 2 g with NSAID >2 g with NSAID cf NSAID alone

Paracetamol

NSAIDs Duration Indication

Formulation

Ibuprofen

Relative risk

Low dose High dose 1–30 days >730 days OA Adjusted Crude RA Adjusted Crude Pain Adjusted Plasma t1/2 o12 h (high dose) Z12 h Slow release o12 h (low dose) Z12 h Overall slow release Lowest risk (dose dependent)

2.0 1.0 1.5 1.1 2.1 3.1 0.7 4.5 2.7 1.0 1.6 2.4 4.3 B2.0

1.0 0.9 3.4 6.5 4.2 13.5 3.5 2.5 5.0 4.3 3.5 4.3 3.7 4.7 5.3 4.2 4.2 5.4 6.2 2.4 2.8 3.9

B1.0–2.0

Note: From Garcia-Rodriguez and Hernandez-Diaz (2001a, b) and modiﬁed by Rainsford (2004).

H. pylori infection may be suspected unless the pathogenicity of the infecting strain is clearly established (Wilcox, 1997). Nonetheless CagA+/VagA+ strains of H. pylori are frequently found in patient isolates, so that the infection with this organism must at least be considered suspect in many patients with PUD where there has been a positive increase or immuno- (histochemical-) assays employed to identify the infection. For the other enteric ﬂora discussed above, there is little if any clinical evidence to identify their involvement in GI reactions in patients with autoimmune arthropathies. Some in vivo studies in rats have shown that repeated oral administration of indomethacin (10 mg/kg/day) or the same dose given subcutaneously resulted in a marked increase in faecal anaerobic and aerobic bacteria coincident with the development of ileo-caecal ulceration (Benoni et al., 1984; Konaka et al., 1999). Intestinal lesions from indomethacin do not develop in germ-free animals (Robert and Asano, 1997) or in those given antibiotics (Rainsford, 1988c), highlighting the role of enteric bacteria in the development of intestinal lesions in rats. Indeed it has been suggested that use of poorly absorbed antibiotics such as rifaxamin may be useful in preventing intestinal injury in patients taking NSAIDs (Lanas and Scarpignato, 2006). An increase in the number of gram-negative intestinal bacteria has been observed with NSAIDs, with bacterial lipopolysaccharide contributing to the development of intestinal lesions in rats (Hagiwara et al., 2004). Similar implications of intestinal ﬂora in the pathogenesis of intestinal pathology involving alterations in faecal ﬂora by NSAIDs (Rainsford, 1988c; Uejima et al., 1996). Colonisation of gastric ulcers by enteric bacteria has been found to impair ulcer healing in rats (Elliott et al., 1998). Faecal Clostridium perfringens have been found to be increased by NSAIDs in RA, but not in patients with OA; in the RA patients this was paralled by an increase in serum IgA antibody to the a-toxin of C. perfringens (Dearlove et al., 1992). These results suggest that there may be marked

Gastrointestinal Complications of Anti-Rheumatic Drugs

changes in faecal ﬂora by NSAIDs especially in patients with RA and this may contribute to the intestinal pathology seen in this patient group. Recent studies show that following H. pylori eradication therapy in patients with gastric or duodenal ulcers, there is an increase in Klebsiella and Enterobacter species (Shimbo et al., 2005) suggesting that there may be important consequences of eradication therapy on the levels and status of GI ﬂora. The clinical signiﬁcance of these observations in relation to ulcer development has not, to our knowledge, been established in arthritic patients, though it is clearly important to establish if this is the case. c. HLA-B27-associated immuno-inﬂammatory reactions in the intestinal mucosa, including the development of ulcerative colitis (UC), are well established to occur frequently in patients with ankylosing spondilitis (AS). Moreover, use of NSAIDs in these patients has been shown to exacerbate symptoms of UC (Hawkey, 2006). Whether upper symptoms, e.g. PUD, develop or are exacerbated in patients with AS is not known, although they may be suspected. Exacerbation of GI symptoms has also been reported in patients with systemic lupus erythematosis (Khoury, 1989). d. The systemic consequences of rheumatoid and other seropositive or seronegative arthropathies in promoting or potentiating upper GI ulcer disease from intake of NSAIDs and other drugs have long been suspected with evidence in support of this disease–drug interaction being derived from extensive studies in laboratory animal models (e.g. adjuvant-induced chronic polyarthritis, acute inﬂammatory states, physical stress conditions) (Rainsford, 1975, 1977a, b, 1978, 1981, 1989b, 1992; Whitehouse and Rainsford, 1977). These studies have shown that there is marked increase in the development of mucosal lesions and ulcers in animals with these inﬂammatory or stressful states given NSAIDs. It is known that patients with rheumatic disorders experience profound socio-psychologic stress (Eich, 2004) so these studies in laboratory animal models of

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rheumatic disease have particular relevance in highlighting the potential of stress factors to exacerbate development of GI ulcers in these patients. Conﬁrmation of these observations has been difﬁcult to establish in rheumatic patients taking NSAIDs. Comparisons have been made of the incidence of ulcers, endoscopically observed lesions of the upper GI tract and bleeding episodes or micro-bleeding in subjects receiving different NSAIDs who have RA compared with OA. Some studies have shown that the incidence of these upper GI pathologies following intake of NSAIDs is greater in patients with RA compared with OA, but in other studies the results have been equivocal. If it is accepted that NSAIDs cause more injury to the GI tract in patients with RA than with OA, it would suggest that the systemic manifestations in RA that lead to mucosal susceptibility to these drugs might involve: (a) altered liver metabolism of the drugs such as to enhance their toxicity, (b) reduced production of albumin or other plasma proteins that bind the drugs in the circulation, (c) enhanced production of pro-inﬂammatory cytokines with consequent inﬂammation in mucosal cells and reduction in mucosal protective mechanisms, impaired digestive functions, and in the extreme TNF-a-related cachexia. Attractive as these mechanisms may seem it is equally possible that the debilitating effects of sustained joint pain and disability that is evident in OA, with consequent psychological stress, may also promote mucosal susceptibility to NSAIDs and other ulcerogenic drugs. Thus, comparisons of the occurrence and severity of ulcers or mucosal injury in RA with OA patients may not provide convincing evidence for systemic manifestations contributing to susceptibility to these dugs in patients with RA. The discussion about the role of systemic, sociopsychological and disease-manifestation that are evident in autoimmune and osteo-arthropathies serves to illustrate the potential importance of these states in predisposing the GI tract to the ulcerogenic effects of NSAIDs and other ulcerogens. e. Many middle-aged and elderly patients with autoimmune arthropathies may have other

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chronic debilitating conditions (e.g. diabetes mellitus, atherosclerosis, coronary vascular disease, subnormal, or impaired hepato-renal functions) that can have profound consequences for vascular functions and drug toxicities that affect mucosal functions and integrity. Indeed studies in streptozotoicin diabetic rats (Tashima et al., 2000) or rats with spontaneous hypertension have shown that these have markedly enhanced susceptibility to the ulcerogenic effects of NSAIDs or other gastric irritants (Rainsford, unpublished studies; Shichijo et al., 1991). Even subtle alterations of blood glucose inﬂuence the ulcerogenic effects of NSAIDs (MacDonald, 1997).

Another consequence of these concomitant chronic illnesses is that the drugs taken by patients with these conditions sometimes promote or enhance the development of ulceration or haemorrhage attributed to NSAIDs. The list of these drugs includes diuretics, calcium channel blockers, anti-hypertensive agents, and corticosteroids (Gabriel et al., 1991; Garcia-Rodriguez and Hernandez-Diaz, 2001a, b; Peura, 2002; Rainsford, 1997b). With some of these drugs, NSAIDs may affect their pharmacokinetics or pharmacodynamics, thus contributing to the GI toxicity of NSAIDs.

3.2. Variation in ulcerogenicity of NSAIDs It is now well established that individual NSAIDs vary considerably in their propensity to cause ulceration and haemorrhage (Carson and Strom, 1992; Taha et al., 1994; Cheatham et al., 1999; Lanza et al., 1999; Hunt et al., 2000; Uemura et al., 2003; Lungardon et al., 2004). Evidence in support of this variability has come from (a) pharmacoepidemiological studies, (b) case-controlled studies and clinical trials, (c) endoscopic investigations in volunteers, and (d) radiochromium (51Cr)-labelled red cell or other blood-loss investigations in volunteers. Data in laboratory animal models have also contributed valuable information (Rainsford, 1981, 1989a, b, 1992, 1997a, b). Often because this is at variance with the data from human studies, the data from animal studies have been dismissed or downgraded as being unreliable or not of human relevance (Rainsford, 1991)! This is a patently ﬂawed reasoning particularly as the speciﬁc experimental conditions in which the studies in animals and humans as well as important pharmacokinetic considerations have failed to be considered in the translation of animal to human situations and vice versa. These aspects have been reviewed elsewhere in extenso (Rainsford, 1988a, b, 1989a, b, 1992, 1997a, b, 2006) and the reader should consult this literature for further detailed considerations. Data from epidemiological studies (e.g. as shown in Fig. 1; Henry et al., 1998) typically show that

Figure 1. Estimated relative risk of major gastrointestinal complications with individual drug. (Reproduced with permission from Henry et al., 1998.)

Gastrointestinal Complications of Anti-Rheumatic Drugs

ibuprofen is among the least ulcerogenic NSAIDs, a feature which is evident in most record-linkage, case-controlled or other epidemiological studies as well as in endoscopy investigations (Henry et al., 1998). For consideration of data on the association for different NSAIDs to cause serious GI conditions in patients with auto-immune diseases, it is necessary to consult speciﬁc pharmaco-epidemiological databases, case-controlled studies, or GI investigations in patients with rheumatic diseases (Singh et al., 1994; Singh and Ramey, 1998).

4. Coxibs versus non-selective NSAIDs 4.1. Pharmacological rationale for development of coxibs By the early 1990s, two forms of the COX enzyme were ‘identiﬁed’ using molecular biological techniques. Needleman and Isakson were among several investigators who reported that a constitutive isoform, COX-1, was present in most cell types and maintained a homeostatic function. However, the COX-2 isoform, normally undetectable in most tissues, was shown to be induced in response to inﬂammatory mediators, tumour promoters, and growth factors (Fro¨lich, 1995; Needleman and Isakson, 1997; Crofford, 1997; Brooks et al., 1999; Hawkey, 1999; Silas and Clegg, 1999). The present terminology used to describe the cyclo-oxygenases is to call COX-1 the constitutive isoform and COX-2 the inducible isoform (Hla and Neilson, 1992; Jones et al., 1993; Smith et al., 1996). However, these deﬁnitions may be an over simpliﬁcation since the enzymes are the expression of complex regulatory mechanisms that govern their production. COX-2 is located in brain and kidney in the absence of inﬂammation, and growth factor induction and developmental regulation of the COX-1 gene have been reported (Harris et al., 1994; Guan et al., 1997; Komhoff et al., 1997; Yang et al., 1997). The original NSAIDs inhibit both COX-1 and COX-2 activity, whereas the glucocorticoids inhibit COX-2 expression (Masferrer et al., 1990; Crofford et al., 1994). Experiments by Crofford (1997) and Siegle et al.

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(1998) have shown that COX-2 is not expressed in normal joint synovium, but is present in various degrees in the synovial ﬁbroblasts, endothelial cells, and macrophages of patients with RA, OA, and other inﬂammatory joint diseases. Further induction of COX-2 can take place in vitro by addition of inﬂammatory cytokines (Crofford, 1997; Siegle et al., 1998). The much heralded introduction slightly less than a decade ago of highly selective COX-2 inhibitors classed as ‘coxibs’ with claims of being GI safer than conventional NSAIDs (Bensen et al., 1999; Hawkey, 1999; Langman et al., 1999; Simon et al., 1999, 2001; Bombardier et al., 2000; Goldstein et al., 2001) has proved to have had mixed outcomes. In essence most if not all the controlled investigative studies performed in volunteers (e.g. radiochromium blood loss or endoscopy observational studies), observational, and/or endoscopic investigations in patients with rheumatoid or OA (Feldman and McMahon, 2000) comparing individual coxibs with NSAIDs have shown that there are fewer upper GI ulcers or bleeds in those subjects that have received coxibs. In some patient groups, these controlled studies extended for up to 6–12 months. Often the rates of peptic ulcer bleeds (PUBs) or other indices of serious GI complications (ulceration) have been similar to or slightly above those from placebo or paracetamol and statistically signiﬁcant and lower than the values observed with the NS-NSAIDs grouped together instead of individually (Langman et al., 1999; Silverstein et al., 2000; Watson et al., 2001; Hochberg, 2003; VIGOR Study Mamdani et al., 2002; Singh et al., 2006). The grouping together of all NS-NSAIDs is both pharmacologically and statistically unjustified. On the pharmacological side, drugs such as diclofenac, ibuprofen, and naproxen (which have frequently been used as comparators) have widely differing incidences of upper GI ulceration and haemorrhage and each has marked differences in pharmacokinetics and potency as PG synthesis inhibitors and other anti-inﬂammatory activities. On the statistical side grouping of data with data on individual drugs each with their relative means variance or errors that often differ can give an artiﬁcial impression of homogeneity and disguise

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underlying statistical differences between the NS-NSAIDs and may lead to disguising of what could be potential differences between individual NS-NSAIDs and coxib(s). There is an impression that the grouping of NS-NSAIDs for comparison with coxibs may have been driven by the commercial interests that dominate the support of many of the clinical studies published on the new coxibs. Another comparison which has found favour in recent years is the comparison of coxibs with NS-NSAIDs in combination with PPIs (Chan et al., 2002; Lai et al., 2005). Some of the patients in these studies were receiving low-dose aspirin for cardioprotection and since this treatment has been associated with increased risk of ulcers or bleeding, use of a PPI blocker is justiﬁed on the grounds of preventing aspirin as well as NSAID injury (Laheij et al., 2003; Laine, 2003; Kimmey and Lanas, 2004). The results from these studies show that PPI inhibitors taken with an NSAID in H. pylori negative patients for up to 24 months have lowered risk of developing GI ulcers and complications and that this is comparable with that observed in patients that received celecoxib (Lai et al., 2005). Other studies (Chan et al., see also review by Laine, 2004) show that PPI inhibitors given with NS-NSAIDs reduce the occurrence of serious GI events to that which may be comparable with coxibs. Despite evidence from controlled clinical trials that coxibs may reduce the risks of developing serious upper GI events compared with that from NS-NSAIDs, careful re-evaluation of some of the published data (Schoenfeld, 2001; Ju¨ni et al., 2002), including that from two large-scale studies that evaluated ulcer complications from celecoxib with those from diclofenac and ibuprofen in a trial known as Celecoxib Long-term Arthritis Safety Study (CLASS) (Table 3; Silverstein et al., 2000) and the other known as Vioxx Gastrointestinal Outcomes Study (VIGOR), has questioned the ‘reduced GI risk from coxibs’ (Table 4; Bombardier et al., 2000). It should be noted that both these studies were probably the largest GI investigations that had been performed up to the early 2000s and undoubtedly set the standard for future studies with new NSAIDs. Unfortunately, the outcomes from these studies were not all that clear and

Table 3 Summary of adverse events in the CLASS study Event %

Celecoxib

Diclofenac

Ibuprofen

GI Withdrawal Renal Withdrawal CV non-ASA Hepatic Withdrawal

45.6 12.2 6.8 1.0 1.6 1.8 0.3

55.0 16.6a 6.7 0.6 1.2 6.9a 3.5a

46.2 13.4 10.3a 1.3 0.4 1.9 0.3

Note: Based on data published by Silverstein et al. (2000). a Signiﬁcantly different compared with celecoxib. Table 4 Summary of the adverse events in the VIGOR study Event %

Rofecoxib

Naproxen

GI abdominal pain CV Renal Hepatic

9.3a 1.8 0.2 0.25

7.8 0.7 0.002 0.007

Note: Based on data published by Bombardier et al. (2000). a Signiﬁcant increase compared with naproxen.

reﬂected problems in trying to relate studies from controlled clinical trails in selected patient groups and translating these results to large patient groups nearer to the real-world situation. Thus, it has become clear from a number of critical data (re)evaluations that the relative advantages of these two coxibs in comparison with NSAIDs in relation to serious GI complications, ulcers, or bleeding are much lower than originally apparent from the published reports. Indeed there have been some highly critical analyses and commentaries (Bjarnason and Rainsford, 2001a, b; Ostor and Hazleman, 2005; Bjarnason and Thjodleifsson, 2005; Khanna et al., 2005; Halpern, 2005; Rainsford, 2005). The most critical issue concerns the analysis of relative or absolute risk reduction (ARR), number needed to treat, and the clinical beneﬁts. Tables 3 and 4 summarise these assessments in CLASS and VIGOR studies, which were reported by Schoenfeld (2001). These calculations (Table 5) show that although the percentage of relative risk reduction (RRR) for celecoxib cf NSAIDs (ibuprofen, diclofenac) is 61% and for rofecoxib cf naproxen is 60%, the values for ARR are relatively small being 0.7 and 0.8% respectively for the two trials. The latter

Gastrointestinal Complications of Anti-Rheumatic Drugs Table 5 Estimation of serious gastrointestinal reactions from rofecoxib (VIGOR) and celecoxib (CLASS) trials compared with NSAIDs In the VIGOR trial: percentage of patients with serious NSAID-associated gastrointestinal complications Rofecoxib=0.6%, naproxen=1.4% ARR=1.4–0.6=0.8%, NNT=1/0.8%=1/0.008=125 RRR=1.4–0.6/1.4=60% In the CLASS trial (non-aspirin-using patients only): percentage of patients with serious NSAID-associated gastrointestinal complications Celecoxib=0.44%, diclofenac=0.48% (no statistically signiﬁcant difference between diclofenac and celecoxib) Celecoxib=0.44%, ibuprofen=1.14% ARR=1.14–0.44=0.7%, NNT=1/0.7%=1/0.007=143 RRR=1.14 0.44/1.14=61% Note: From Schoenfeld (2001). ARR, absolute risk reduction; RRR, relative risk reduction; NNT, number needed to treat. Results are reported as serious NSAID-associated gastrointestinal complications (i.e. gastrointestinal bleeds, perforations, and obstructions) per 100 patients per year.

values represent the fact that the percentage incidence of GI complications for the NS-NSAID as well as for the two coxibs is in the low end range of 0.4–1.14% which are very low percentages. Thus, with such small differences calculations of RRR are meaningless and give a false impression of improved beneﬁt to the GI tract of the coxibs. This approach of using RRR percentage beneﬁts has been extensively exploited in published data on coxib trials and must, therefore, be regarded as suspect statistical treatment of data which has little relevance clinically. Indeed clinical significance in many coxib trials has rarely been considered in contrast to statistical significance. Three other major groups of adverse reactions have emerged with the coxibs—CV, hepatic, and renal, and to some extent they may be inter-related (Khanna et al., 2005; Ostor and Hazleman, 2005; Rainsford, 2005). Thus, any consideration of relative safety of coxibs compared with NS-NSAIDs has to involve CV and hepato-renal ADRs. As shown in Tables 4 and 5 these serious ADRs were frequently reported in the CLASS and VIGOR studies respectively. The CV events amounted to myocardial infarction and hypertension and were noted particularly with rofecoxib. They were of

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Table 6 Issues concerning safety and efﬁcacy of coxibs and preferential COX-2 inhibitors Cardiovascular (CV) reactions rofecoxiv, valdecoxib, and celecoxib (twofold increased risk); withdrawal of refecoxib (VIOXX) 30 September 2004 (marketing and PR disaster!) FDA, EMEA, and other national agencies instigate review of coxibs and NSAIDs Evidence for lack of highly favourable GI safety of celecoxib cf NSAIDs (Ju¨ni et al., 2002, BMJ 324:1287), extensive hepatic metabolism, drug interactions, and liver reactions with celecoxib Delayed gastric ulcer healing—clinically unproven Skin reactions with valdecoxib Renal toxicity with rofecoxib, possibly less with celecoxib Symptomatic ADRs (nausea, abdominal pain, dyspepsia, etc.) same with coxibs as conventional NSAIDs Perception that rofecoxib is not a good analgesic Possibility that rofecoxib may be safe(r) in aspirin-sensitive asthma compared with other NSAIDs Cost/beneﬁt cf conventional NSAIDs with low upper GI effects—ibuprofen, diclofenac but maybe with naproxen

sufﬁcient concern for the company producing this drug, Merck Sharp and Dohme, to withdraw it from the market. The FDA and other agencies worldwide were alerted and alarmed about the CV ADRs with rofecoxib such that extensive reviews were undertaken by these agencies worldwide of both coxibs and NSAIDs (Kean and Buchanan, 2005). From the point of view of GI safety, there may have been pathological consequences of hepato-renal ADRs and hypertension that contributed to the vascular aetiology of upper GI ulcer disease as well as the consequences of the diuretics and antihypertensive drugs (which as noted earlier increase the risk for developing ulcers) as well as NSAID– drug interactions that patients with hepato-renal conditions and hypertension received for treatment of these conditions. In the end what has emerged in the overall safety analysis of the coxibs is summarised in Table 6, it is clear that the beneﬁts of what now are classed as ‘ﬁrst generation’ coxibs (celecoxib, rofecoxib, valdecoxib) may have been marginal compared with some conventional NSAIDs, among which etodolac, ibuprofen, nabumetone, and

K.D. Rainsford et al.

254

Table 7 Adverse drug reaction reporting odds ratio (OR) (with their 95% conﬁdence interval) according to main classes of non-steroidal anti-inﬂammatory drugs (NSAIDs) from the French Pharmacovigilance Database (Lungardon et al., 2004) Drugs

Adjusted ORa (95% CI)

Adjusted ORb (95% CI)

Coxibs Rofecoxib Celecoxib Oxicams

4.6 5.2 3.7 12.2

(3.3–6.5) (3.1–8.7) (2.4–5.8) (6.7–22.2)

14.9 21.0 11.7 25.3

(9.3–23.7) (10.6–41.6) (6.6–20.9) (11.9–53.6)

Heteroaryl acetic Ibuprofen Diclofenac Naproxen Ketoprofen

acids 4.5 (3.2–8.8) 3.9 (2.1–7.2) 10.6 (4.7–23.7) 8.6 (5.3–13.9)

7.3 9.2 17.9 19.9

(3.2–16.6) (3.8–22.2) (6.7–47.6) (10.7–37.0)

po0.0001. a Adjustment for matching factors (age, gender, period of occurrence). b Adjustment for matching factors (age, gender, period of occurrence) and confounding factors (regional pharmacovigilance centre, work place of health professional, and drug exposure: anti-coagulants, anti-platelet drugs, aspirin, gastroprotective, and other NSAIDs).

possibly diclofenac (although the intestinal ulceration and hepatotoxicity from this drug limit it being considered to have a favourable safety proﬁle). The limited value of coxibs compared with NS-NSAIDs is highlighted in data on the adverse events reported in the French Pharmacovigilance Study (Lugardon et al., 2004), a summary of which is shown in Table 7.

5. Potential for impact of arthritic disease An interesting and possibly important point which should be considered is the arthritic condition in the CLASS and VIGOR as well as other studies with the coxibs. Patients in the VIGOR only had RA whereas those in the CLASS Study had both RA and OA. It has been claimed that there were no differences in ulcer complications in patients with OA cf RA. This is in one sense surprising since as noted earlier it has been speculated that patients with RA may be more susceptible to NSAIDs than those with OA. It could be that the selection criteria for patients entered in the CLASS Study were such that RA as well as OA patients were relatively ‘ﬁt’ and without complicating

chronic conditions that inevitably occur in older more inﬁrmed patients, especially those with RA. Indeed the ulcer incidence in the CLASS Study as well as in the meta-analysis of celecoxib trials by Moore et al. (2005) reveals a remarkably low incidence in placebo and NSAID groups. This gives support to the view that patients selected for inclusion in these studies may have been of relatively favourable health. Another issue is that if there were any real differences in data of ulcer complications in say a proportion of patients with RA cf those with OA these may have been disguised in the grouping of data together such as in the CLASS results. The data on ulcer complications in the CLASS Study observed at 6 months showed there were differences between celecoxib and NSAIDs. However, as pointed out by Ju¨ni et al. (2002) these differences were not apparent at 12 months, suggesting there are time-dependent factors that are signiﬁcant in considering ulcer incidence of both coxibs and NS-NSAIDs. The clinical signiﬁcance of these data like that from other long-term studies is that when coxibs are taken for relatively short periods of time (2–4 wk) they are likely to cause less ulcer complications than NS-NSAIDs such as naproxen and diclofenac than if they are taken for several months or longer. There is also the issue of what has been described as ‘channelling’ where patients with a history of GI complaints or GI ulcer disease may be prescribed coxibs in the belief they will be ‘gastricsafe’, this may be such that beneﬁts for using these dugs may be less apparent and the patients may require anti-ulcer co-therapy [e.g. with H2-receptor antagonists (H2RAs) or PPIs]. The cost-beneﬁts of coxibs therapy may prove less favourable as not only are these drugs notably more expensive than conventional NSAIDs, but also if PPIs or other anti-ulcer therapies have to be employed they may as well be given with cheaper NSAIDs, especially those with a lower propensity to cause CV complications (e.g. naproxen) or combinations with aspirin for cardioprotection. As an example of how their cost-beneﬁt analyses can impact decisions on the choice of coxib therapy, the UK National Institute for Clinical Excellence (NICE; which advises the UK National Health Service on approved choices for therapies)

Gastrointestinal Complications of Anti-Rheumatic Drugs

has recommended that celecoxib only be prescribed for elderly patients at risk of upper GI complications. The question of co-therapy with anti-ulcer drugs is another issue which has not been satisfactorily resolved at the time of writing this chapter. Elsewhere in this chapter we consider the confounding factors in relation to beneﬁts of using anti-secretory agents in the elderly for protection against NSAID ulcer complications. In the VIGOR Study performed in RA patients it is possible that the CV ADRs developed in these patients because they had rheumatoid disease. It is known that patients with RA are more prone to CV diseases and it is possible that rofecoxib ‘triggered’ development of myocardial infarction or hypertension in these patients as a result of the actions of the oxidised metabolite of the drug reacting with LDL and elastin molecules in vascular tissues so precipitating or exacerbating atherosclerotic changes in arteriolar vessels that were prone to weakness or obstruction. The renal effects of rofecoxib may also have contributed to the hypertension so contributing to further explosive weakness in vessels at risk. Since CV and hypertensive effects of NSAIDs may play a role in the development of GI mucosal lesions, these CV and renal effects may have contributed to the ulcer complications that were observed in RA patients on rofecoxib.

6. GI symptomatic adverse drug reactions Meta-analysis of the tolerability and adverse events from a range of trials of celecoxib compared with NS-NSAIDs, paracetamol, and placebo (using data from the published and unpublished trials from Pﬁzer) (Moore et al., 2005) revealed some interesting features and trends concerning the occurrence of GI symptoms notably nausea, dyspepsia, diarrhoea, abdominal pain, vomiting. These constitute main reasons (other than ulcer/bleeds or other serious ADRs) for withdrawal from therapy, and indeed the data by Moore et al. conﬁrmed this pattern. Data in Table 8 show the principal dyspeptic symptoms summarised in the report by Moore et al. (2005). They highlight: (1) the occurrence and relative risks (RR) of most GI symptoms in patients

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Table 8 Meta-analysis of dyspepsia events (%) in patients OA (25,903) or RA and OA (10,470) Treatments

Celecoxib

Comparator

Cele Cele Cele Cele Cele

6.9 2.9 4.4 5.7 8.1

4.8 2.2 4.9 7.3 10.7

versus placebo versus paracetamol (4 g/day) versus rofecoxib (50 mg/day) (200–400 mg/day) versus NSAIDs versus NSAIDs (all dosages)

Note: Cele, celecoxib. From Moore et al. (2005).

receiving celecoxib, rofecoxib, or paracetamol being greater than that of placebo, (2) while there are trends for a lower incidence of some symptoms with low-dose celecoxib the differences are less distinct with higher dose celecoxib, and (3) the data on CIs in RRs with most comparisons often overlap to the extent that it is doubtful if any differences, especially those favouring celecoxib, have any meaning.

6.1. Individual symptoms The authors of this study noted that the proportion of patients having dyspepsia was about 7% and that there were no differences in comparison with placebo, paracetamol, or rofecoxib, but there were more patients on NSAIDs. Celecoxib was responsible for abdominal pain in about 5% patients there being no difference cf placebo or paracetamol but more patients on NSAIDs and rofecoxib experienced this adverse effect. In these and other GI symptomatic effects as well as overall GI tolerability there were trends in favour of celecoxib in comparison with the other treatments but the 95% CIs for RR often overlapped those of comparator drugs. Making much of what are relatively small values for incidence and percentage differences of symptomatic GI ADRs like that of clinical ulcers and bleeds in this meta-analysis (Moore et al., 2005), is probably of limited value and meaning.

7. Enter the second-generation coxibs Merck, Pﬁzer, and Novartis all had follow-up coxibs in development around the time that

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rofecoxib and celecoxib were introduced at the turn of this decade. Clearly, with events surrounding the withdrawal of rofecoxib and the knock-on effects with other drugs that followed the investigations of this and other coxibs and the NSAIDs in general, development of a second generation of coxibs has proceeded apace. These developments have been guided by experience from the ‘coxib disaster’. In the wake of the issues surrounding withdrawal of rofecoxib the FDA determined that valdecoxib (Pﬁzer) had similar CV risks as well as the skin reactions that emerged with this drug, led to its withdrawal in 2005. Etoricoxib (Arcoxias) developed by Merck Sharp and Dohme is probably the most selective inhibitor of COX-2 of those drugs that have been developed to date. While long-term investigations are awaited there are indications that GI and CV events from etoricoxib may be lower than with tNSAIDs and celexocib (Laine et al., 2007). Lumiracoxib (Novartis) (now withdrawn in Australia, Canada and not approved in USA) is not chemically like that of other coxibs being a derivative of diclofenac. It does not have the high COX-2 selectivity of etoricoxib or rofecoxib. In a large-scale multicentre trial of lumiracoxib versus naproxen and ibuprofen in some 14,000 patients both GI and CV complications were lower than from ibuprofen and naproxen. A summary of the combined GI and CV events is shown in Table 9 (Schnitzer et al., 2004). These data show that the hazard ratio is signiﬁcantly lower for lumiracoxib

than the two NS-NSAIDs although there is considerable overlap of the values of the 95% CIs. The same arguments about the clinical beneﬁts in relation to GI adverse events from the newer second-generation coxibs, as considered earlier in relation to VIGOR and CLASS studies, need to be considered (Laine et al., 2007). To quote the oftused phrase ‘the jury is undoubtedly out’ in assessment of the GI beneﬁts of these new drugs.

8. Strategies to minimise or eliminate gastrointestinal complications Over the years, numerous strategies have been devised to prevent, minimise, and treat GI complications of analgesics, NSAIDs, and steroids. There have been many attempts at altering the GI absorption rate and site of drugs by creating alterations in route of drug dispensed (e.g. suppositories, injections): changes in formulation with the use of suspensions and mixtures; and various types of enteric coating (Kean and Buchanan, 1987). There has been very little success gained by these methods in preventing GI complications related to the drug use. In addition, attempts at prevention and/or management of analgesic, NSAID, and steroid GI-induced side effects have included the use of antacids, H2RAs, PG analogues, and PPIs.

Table 9 Combined incidence of gastrointestinal and cardiovascular events from lumiracoxib, compared with ibuprofen and naproxen, by substudy (safety population Schnitzer et al., 2004)

Both substudiesw Lumiracoxib Non-steroidal anti-inﬂammatory drugs Lumiracoxib versus ibuprofen substudy= Lumiracoxib Ibuprofen Lumiracoxib versus naproxen substudy= Lumiracoxib Naproxen

Number of patients with events/number at risk (%)

Hazard ratio (95% CI)

p

89/9117 (98%) 133/9127 (1.46%)

0.65 (0.49–0.84)

0.0014

30/4376 (0.69%) 56/4397 (1.27%)

0.50 (0.32–0.79)

0.0025

59/4741 (1.24%) 77/4730 (1.63%)

0.75 (0.53–1.05)

0.0961

Based on Wald w2 statistic for treatment group comparison. Cox proportional-hazards models include, in addition to treatment group, the factors wsubstudy, low-dose aspirin, and age; and =low-dose aspirin and age.

Gastrointestinal Complications of Anti-Rheumatic Drugs

For over 80 years, the management of musculoskeletal pain was hampered by NSAID toxicity problems related to these original or so-called tNSAIDs, and many clinicians have been reluctant to use the tNSAIDs for pain management because of this issue. A 1999 report by IMS health on the COX-2 inhibitor market indicated that 20% of celecoxib use in the United States was in new or incremental patients (IMS Health, 1999), and similar increases were identiﬁed in Canada (IMS Health, Canada, 1999). These ﬁndings are indirect indicators that a proportion of patients have been denied the beneﬁts of NSAIDs for management of their musculoskeletal pain. This is discussed later and has been described in detail elsewhere (Won et al., 2004; Kean and Buchanan, 2005).

8.1. Effects of NSAIDs and H. pylori on acid secretion The concept that acid secretory status plays a major role in the aetiopathogenesis of NSAID- and H. pylori associated PUD has received wide acceptance (Soll, 1990; Rainsford, 1992; Hunt and Tytgat, 1993, 1996). Likewise, the application of potent acid anti-secretory agents to control and treat this condition has undoubtedly been of major therapeutic beneﬁt (Hunt and Tytgat, 1996). The rationale for the use of acid-secretory inhibitors (histamine H2RAs and H-pump blockers) for the prevention of NSAID-induced gastroduodenal mucosal injury, especially in patients at risk (e.g. the elderly or frail rheumatic patients), has been based on evidence that (a) NSAID-induced inhibition of PG production, especially that of PGE2, blocks or prevents the auto-regulation of gastrin secretion (Befrits et al., 1984) which controls acid secretion (Levine and Schwartzel, 1984); (b) E-type PGs have been found to inhibit gastric acid secretion in isolated parietal cells in vitro (Choquet et al., 1993) and in human volunteers (Karim et al., 1973; Konturek et al., 1976); (c) the deﬁciency in mucosal concentrations of PGs in gastroduodenal ulcers (Wright et al., 1982; Ahlquist et al., 1983; Konturek et al., 1982) may contribute to the pathogenesis of these conditions by

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dysregulation of acid secretion as well as affecting other mucosal functions including mucosal protection (Hawkey and Walt, 1986); and (d) the effects of E-PGs and their analogues in the treatment of gastroduodenal ulcers in humans are apparent at doses which exhibit anti(acid)-secretory activity (Hawkey and Walt, 1986). However, the central issue of whether NSAIDs given to humans do, in fact, stimulate acid secretion as a consequence of reduced PGs has been debatable (Rademaker et al.,1995). In many of the earlier studies the possibility of controlling H. pylori infection, which causes stimulation of acid secretion, via enhanced levels of gastrin and pepsinogen (Chittajallu et al., 1991, 1992; Levy et al., 1989) was not considered or feasible to be eliminated or in earlier studies (Rademaker et al., 1995). The growth of H. pylori adjacent to the stomach mucosa is known to depend upon local acid secretion (Lee et al., 1995). The evolution of different forms of gastritis that is associated with H. pylori infection depends on the state of acid secretion (Sipponen et al., 1996a, b). Thus, peak acid output stimulated by pentagastrin is greater in subjects with mild or no gastritis than those with severe chronic gastritis (Sipponen et al., 1996a). There are complex inter-relationships between acute effects of H. pylori in stimulating cytokine production (Bodger and Crabtree, 1988) that leads to hypergastrinaemia and stimulation of acid production (Chittajallu et al., 1991, 1992; Levy et al., 1989; Beales et al., 1996). Environmental pH clearly inﬂuences the growth of H. pylori (Meyer-Rosberg et al., 1996), so there is a cyclic inter-relationship between inﬂuences of the microorganism on inﬂammatory reactions and the consequent effects on acid secretion leading to acidic pH conditions that favour growth of H. pylori. The persistent inﬂammatory response driven by chemokines and pro-inﬂammatory cytokines presumably leads to gastritis, which under chronic conditions results, paradoxically, in reduced acid secretion or achlorhydria. The signiﬁcance of previous studies on the effects of NSAIDs on acid secretion and gastrin production (Konturek et al., 1982; Caldara et al., 1978; Stern et al., 1984) should be considered against the possibility that some of the patients or volunteers may

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have been infected with H. pylori. It does not appear that the acute response to indomethacin (i.e. over about 1–3 days) in subjects with unknown H. pylori status resulted in increased production of basal-, sham-fed-, and histamine-induced acid secretion in normal volunteers. However, the majority of studies in normal volunteers indicates that basal acid secretion is unaffected after one or more weeks of treatment; the effects of histamine on the acid secretion in normal or arthritic subjects receiving indomethacin for these periods are clearly more variable. Since healthy elderly subjects have increased capacity to produce acid (Goldschmiedt et al., 1991), it is possible that the variable response in arthritic patients could be related to differences in effects of gastritis and other health parameters as well as age in the latter group of patients (Feldman et al., 1996). To eliminate the possibility of confounding inﬂuences of H. pylori infection, studies were performed in proven H. pylori-negative individuals who received indomethacin 50 mg t.i.d. for 7 days. It was found that this treatment did not affect 24 h integrated pH or 2 h meal-stimulated acid secretion (Rademaker et al., 1995) under conditions which in the early period up to 4 h would have inhibited mucosal PGs by this drug (Rainsford et al., 1993). Hamlet et al. (1998) showed that antral distentioninduced stimulation of acid secretion in H. pylori negative subjects was reduced by 3 days treatment with aspirin 2 g/day, but there was no effect on gastrin secretion. These authors also showed that the aspirin treatment increased the production of IL-1b, IL-6, and IL-8 but not of TNF-a or interferon (IFN)-a, coincident with the development of an apparent gastritis. It appears therefore, that NSAIDs vary in their effects on acid secretion in H. pylori negative normal subjects depending on the drug, duration of treatment, and nature of the stimulus for acid secretion. The drug-associated changes in patterns of pro-inﬂammatory cytokine production may inﬂuence acid secretory responses in part from the effects of IL-1 and possibly other pro-inﬂammatory cytokines stimulating production of PGE2. This would be expected to have a negative effect on acid secretion (Hawkey and Walt, 1986; Bennet et al.,

1973). There may also be inﬂuences of stimulated PGE2 production enhancing bicarbonate secretion (Hogan et al., 1994a, b).

8.2. Acid secretion and gastrin production in rheumatic patients When considering the issue of acid secretion in patients with rheumatic diseases receiving NSAIDs for long periods of time more complex factors may prevail. It is, for instance, well known that mucosal adaptation occurs to long-term (3–4 wk) after intake of several NSAIDs manifest by a reduction in lesions or ulcers observed by endoscopy (Graham et al., 1988a; Shorrock and Rees, 1989, 1992; Shorrock et al., 1990; Shorrock, 1993, Konturek et al., 1994). The clinical relevance of the adaptive response is controversial (Shorrock, 1993) but may be related to acid secretion being somehow inhibited. It is also possible that mucosal regenerative responses may also be affected by continuous intake of NSAIDs. There have been a number of reports that acid secretion is subnormal in certain patients with arthritic diseases (Edstrom, 1939; Henriksson et al., 1986; DeWitte et al., 1979; DiMario et al., 1989; Kanerud et al., 1991) and some patients, especially the elderly, are achlorhydric. This situation is, however, complicated by the observation that plasma gastrin levels are increased in patients with RA and Sjoegren’s disease (DeWitte et al., 1979; DiMario et al., 1989; Kanerud et al., 1991; Buchanan et al., 1996; Maury et al., 1985; Rooney et al., 1973, 1976a, b). The question to be considered, therefore, is that the gastrin receptor-mediated control of acid secretion is somehow affected in the patients perhaps as a result of downregulation of gastrin receptors, post-receptor events from the inﬂuence of the disease process. Rowden et al. (1978) postulated that hypergastrinaemia may be associated with RA, so it is possible this state could be intrinsic to RA. Alternatively, it may be a property of the drugs used to treat RA, as the long-term use of anti-rheumatic agents such as auranoﬁn may differentially stimulate COX-1-derived mucosal protective PGs (Yamada et al., 1997), so directly

Gastrointestinal Complications of Anti-Rheumatic Drugs

inhibiting acid secretion via PGE2 receptor activation on parietal cells.

8.3. Why give anti-secretory agents to rheumatic patients? Irrespective of the responses to gastrin in rheumatic patients it is clear that there is reduced acid secretion in certain patients. This raises the issue whether anti-ulcer agents that exert their actions by inhibition of acid secretion should be employed in the prophylaxis of NSAID-associated upper GI ulceration and haemorrhage in ‘at risk’ individuals, especially the elderly who often may have subnormal acid secretion or be achlorhydric? There are important consequences from the use of anti-secretory agents in the elderly rheumatic patient. Thus, there may be risks from persistent achlorhydria or subnormal secretion in the elderly rheumatic patient combined with the effect of an anti-secretory drug that may create conditions for bacterial overgrowth in the stomach, a factor that is known to promote the development of gastric cancers (Stockbruegger, 1985; Bartsch et al., 1992; Houben and Stockbruegger, 1995). The lack of acid in the stomach may result in suboptimal or subnormal pepsin activity and this may lower the protein nutritional status in the elderly. Finally, it is known that achlorhydria or suppressed acid production does not result in reduced propensity for aspirin-induced GI ulcers (Jazewsky et al., 1989; Janssen et al., 1994), so the beneﬁts of creating an anacidic state to reduce the risk of ulcer development would appear to be very limited. Of course, it is possible that PPIs such as omeprazole could have effects in controlling the growth of H. pylori (Hunt and Tytgat, 1996). In those elderly rheumatic patients given this drug to prevent ulcers from the NSAIDs, this may be considered a beneﬁcial effect. However, the ready availability of non-invasive tests for H. pylori enables the presence of an infection from these bacteria to be established in the ﬁrst instance. Thus, good practice would indicate that H. pylori infection should be ruled out or treated as the case may be. Likewise, in those patients with hypersecretion the use of anti-secretory agents would, of course, be

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justiﬁed. Prior investigation is, therefore, important to establish if the patient with musculoskeletal disease has H. pylori infection or abnormal acid secretion before being continued on NSAIDs.

8.4. Risk factors Several international experts over the years have attempted to identify the RR of toxicity to the GI tract by analgesics and NSAIDs, in case control and cohort studies (Henry et al., 1996; Garcia-Rodriguez and Hernandez-Diaz, 2001a, b). Unfortunately even the best of these studies still suffer from problems of population inclusion bias, and case interpretation and selection bias (Henry et al., 1996). The risks for a serious GI event are most common in the ﬁrst 3 months and the majority of patients who have a serious GI event are asymptomatic prior to the event. The risk factors for NSAID-associated ulcer complications are well documented and include: past complicated ulcer, OR 13.5; multiple NSAIDs including ASA, OR 9.0; high-dose NSAID, OR 7.0; anti-coagulant use, OR 6.4; past uncomplicated ulcer, OR 6.1; age >70 years, OR 5.8; and steroid use, OR 2.2 (Gabriel et al., 1991; Garcia Rodrguez and Jick, 1994; Silverstein et al., 1995). Thomas et al. (2002) showed that OTC NSAIDs were a signiﬁcant cause of GI side effects with up to 30% of people having a GI problem in the previous 30 days and individual events resulting in GI bleed or ulcer 1%: nausea and vomiting, bloating, heartburn, cramping pain in 2–5%, and constipation and/or diarrhoea in up to 10%. The consumption of alcohol while taking NSAIDs can double the risk of GI bleeding, and this increases to a ﬁvefold increase for people taking OTC drugs (Peura et al., 1997).

8.5. Agents used to control acid 8.5.1. Antacids Antacids such as calcium carbonate, aluminium, and magnesium hydroxides and combinations thereof provide a degree of symptomatic relief for

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mild dyspepsia and acid reﬂux by elevating the gastric pH, but are not of value in the prevention or cure of signiﬁcant GI adverse events.

8.5.2. H2-receptor antagonists The H2RAs are competitive inhibitors of histamine at the parietal cell H2 receptor. They block the action of histamine released from enterochromafﬁn cells, with resultant reduction in acid secretion, and in addition they reduce the promotion of acid secretion by gastrin and acetylcholine. Over the last 30 years, H2-receptor anatagonists have been traditionally used for the treatment of dyspepsia, acid reﬂux, and PUD. The most commonly used are cimetidine, ranitidine, famotidine, and nizatidine. All are relatively well tolerated but cimetidine which has a signiﬁcant inhibition of the cytochrome P450 enzymes can result in increase in plasma and tissue levels of concomitantly used drugs such as warfarin, Beta blockers, tricyclic anti-depressants, calcium channel blockers, sulphonylureas, metronidazole, and alcohol. Cimetidine use is associated with headache, constipation, diarrhoea, hypotension, dizziness, and is also associated with gynaecomastia, loss of libido, and impotence in males. Rostom et al. (2002) showed that in a pooled analysis of ﬁve randomised controlled trials of H2RAs that standard doses reduced the risk of duodenal ulcers, but not gastric ulcers. In three randomised trials it was shown that double the dose of H2RAs were effective against NSAID-related gastric and duodenal ulcers with the greatest beneﬁt or effect in patients with prior history of ulcers (Hudson et al., 1997; ten Wolde et al., 1996; Taha et al., 1996). Analysis of the study by Hudson et al. (1997) showed that the major effect was in patients with H. pylori infection. Leonard et al. (2007) in an analysis of 12 studies evaluating 2948 patients with C. difficile identiﬁed an increased risk of taking anti-secretory therapy in those infected with C. difficile. In six studies on Salmonella, Campylobacter, and other enteric infections were identiﬁed in 11,280 patients, again identiﬁed that there was an increased risk of taking acid suppression in those with enteric infections (OR 2.55; 95% CI: 1.53–4.26).

8.5.3. Misoprostol Misoprostol is a synthetic PGE1 analogue which has been shown to be of beneﬁt in the prevention of NSAID-induced gastric ulceration (Silverstein et al., 1995; Graham et al., 1988b) at a dose of 200 mg qid. It has also been manufactured as a combined product with the NSAID Diclofenac. While it has been shown to be useful in the prevention of gastric ulceration (Silverstein et al., 1995; Hooper et al., 2004; Elliott et al., 2006), its use has been greatly limited by patient intolerance to the proven effective anti-gastric ulcer dosage of 800 mg/day (Silverstein et al., 1995). Up to 13% of patients can develop diarrhoea often in conjunction with bloating, cramping, and ﬂatulence. This adverse effect can last for up to 8 days with 2% or greater of patients discontinuing the drug. It has been established in a meta-analysis of 33 randomised controlled trials that misoprostol, H2RAs, and PPIs reduce the incidence of NSAID-related gastrodudenal ulcers (Rostom et al., 2002). However, only misoprostol at 200 mg qid dosage has been shown to reduce the NSAID-related ulcer complications with a 40% reduction (Silverstein et al., 1995). However, the median dose tolerated was only 600 mg/day. Although misoprostol 200 mg qid has been shown to be superior to lansoprazole 15 and 30 mg/day, for the prevention of gastroduodenal ulcer at 12 wk, with ulcer rates of 15, 43, 47 per 100 patients for misoprostol, lansoprazole 15 and 30 mg respectively, the patients on misoprostol had a much higher withdrawal rate (Graham et al., 2002). A theoretical point of concern for long-term use of PG analogues is the potential for local and metastatic spread of cancer cells and recent work has shown that PGE2 promotes tumour progression by inducing myeloid-derived suppressor cells (Sinha et al., 2007).

8.5.4. Proton-pump inhibitors PPIs act by irreversibly blocking the hydrogen/ potassium adenosine triphosphatase enzyme system (H+/K+ ATP-ase) known as the protonpump in the gastric parietal cell. The PPIs are much more effective than the H2RAs and reduce

Gastrointestinal Complications of Anti-Rheumatic Drugs

acid secretion in the gastric lumen by 99%, with resultant promotion of ulcer healing and reduction in acid-related symptoms. The commonly used PPIs are omeprazole, lansoprazole, esomeprazole (the active enanatyiomer of omeprazole), pantoprazole, and rabeprazole (Peura et al., 2007). The PPIs are generally well absorbed with a slight reduction in absorption rate with food. The plasma half life is approximately 0.5–2 h, but the acid secretion inhibition can be up to 2–3 days because of the irreversible nature of the drug binding to the proton-pump. The PPIs are generally well tolerated with few side effects. These include headache, nausea, diarrhoea, abdominal pain, constipation, and bloating. Prolonged use can result in decrease in vitamin B12 absorption and elemental calcium absorption with concerns regarding the development of osteoporosis and risk of hip fracture (Yang et al., 2006). The PPIs are effective and recommended for the relief of upper GI symptoms (Peura et al., 2007) which are common in patients using NSAIDs including selective COX-2 inhibitors and may be acid related. The use of the PPI esomeprazole has been assessed for the treatment of upper GI symptoms in a total of 794 and 848 continuous NSAID users, free of gastroduodenal ulcers, erosive esophagitis, and H. pylori, enrolled into two identical, 4 wk, multinational, multicenter double-blind studies [Nexium Anti-inﬂammatory Symptom Amelioration (NASA1), Symptom Prevention by Acid Control with Esomeprazole (SPACE1)] (Hawkey et al., 2005). The 608 and 556 patients were randomised to receive 4 wk of esomeprazole 20 mg, or 40 mg, or placebo once daily. The primary variable was the patientreported change in the upper GI symptom (pain, discomfort, or burning in the upper abdomen) score on a 7-graded severity scale (0–6) from the 7 days prior to treatment to the last 7 days in the study. The results showed that esomeprazole was associated with highly signiﬁcant symptom improvement compared to placebo. Symptom improvements were 2.30 mean (SD 1.63) on esomeprazole 20 mg and 2.03 (1.56) on esomeprazole 40 mg versus 1.64 (1.57) on placebo in NASA1 and 2.17 (1.34) and 2.12 (1.48) versus 1.56 (1.26),

261

respectively, in SPACE1 (all placebo comparisons at least po0.001). Esomeprazole-improved symptoms in patients taking selective COX-2 inhibitors, with changes of 2.21 (1.46) and 1.92 (1.38) versus 1.64 (1.46) in NASA1 and 2.20 (1.26) and 2.24 (1.62) versus 1.58 (1.37) in SPACE1 (all placebo comparisons at least po0.05), as well as those on non-selective NSAIDs. Esomeprazole was well tolerated and associated with signiﬁcant improvements in QoL assessments. Thus, it was concluded that the PPI esomeprazole 20 and 40 mg improved upper GI symptoms associated with continuous, daily NSAID therapy, including selective COX-2 inhibitors. In an extension of the above 4 wk studies, Hawkey et al. (2007a, b) assessed the effects of esomeprazole for maintenance of long-term relief from NSAIDs and selective COX-2 inhibitors, induced upper GI symptoms. Six hundred and ten patients with a chronic musculoskeletal disorder who required NSAIDs and who had achieved relief of NSAID-associated symptoms of pain, discomfort, or burning in the upper abdomen during the two previous studies (Hawkey et al., 2005) were enrolled and randomly assigned into two identical, multicentre, parallel-group, placebo-controlled studies of esomeprazole 20 or 40 mg treatment (NASA2 and SPACE2 studies; ClinicalTrials.gov identiﬁers NCT00241514 and NCT00241553, respectively) performed at various rheumatology, gastroenterology, and primary care clinics. Four hundred and twenty-six patients completed the 6-month treatment period. The primary measure was the proportion of patients with relapse of upper GI symptoms, recorded in daily diary cards, after 6 months. Relapse was deﬁned as moderate-to-severe upper GI symptoms (a score of more than or equal to 3 on a 7-grade scale) for 3 days or more in any 7-day period. Esomeprazole was signiﬁcantly more effective than placebo in maintaining relief of upper GI symptoms throughout 6 months of treatment. Life-table estimates (95% CIs) of the proportion of patients with relapse at 6 months (pooled population) were placebo, 39.1% (32.2–46.0%); esomeprazole 20 mg, 29.3% (22.3–36.2%) (p=0.006 versus placebo); and esomeprazole 40 mg, 26.1% (19.4–32.9%) (p=0.001 versus placebo). Patients

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on either NSAIDs or selective COX-2 inhibitors appeared to beneﬁt. The frequency of adverse events was similar in the three groups. Thus, it was concluded that the PPI, esomeprazole maintains relief of NSAID-associated upper GI symptoms in patients taking continuous tNSAIDs or selective COX-2 inhibitors. The same group of investigators (Hawkey et al., 2007a, b) assessed the efﬁcacy of esomeprazole 20 and 40 mg for resolution of heartburn and acid regurgitation in patients receiving continuous NSAIDs. They studied a post hoc analysis of ﬁve clinical trials. Two identically designed, placebo-controlled, 4 wk studies (NASA1, SPACE1) enrolled non-ulcer, NSAIDstreated patients with upper abdominal pain, discomfort or burning. PLUTO and VENUS were identically designed, placebo-controlled, 6-month studies that enrolled patients at risk of NSAIDsinduced ulcers. Study 285 was an 8 wk comparative study with ranitidine (300 mg/day) in patients with NSAIDs-induced gastric ulcers. Resolution of investigator-assessed heartburn and acid regurgitation was deﬁned as symptom severity of ‘none’ in the last 7 days. The results showed that in the NASA1/SPACE1 trials, heartburn resolved in 61 and 62% of patients taking esomeprazole 20 and 40 mg, respectively (versus 36% on placebo, po0.001), and acid regurgitation resolved in 65 and 67% (versus 48%, po0.001). Resolution of both symptoms was greater with esomeprazole than with placebo in the PLUTO/VENUS studies (pr0.001). Resolution of both symptoms was greater for esomeprazole 20 mg versus ranitidine 300 mg (po0.05), study 285. It was concluded that while heartburn and regurgitation are common in patients taking NSAIDs, the PPI esomeprazole is effective in control of these symptoms. Scheiman et al. (2006) assessed the PPI esomeprazole for ulcer prevention in at-risk patients (Z60 years and/or ulcer history) taking NSAIDs, including COX-2 inhibitors in two similar double-blind, placebo-controlled, randomised, multicenter studies; VENUS (United States) and PLUTO (multinational). A total of 844 and 585 patients requiring daily NSAIDs, including COX-2 inhibitors, were randomised to receive esomeprazole (20 or 40 mg) or placebo, daily for 6 months. It was identiﬁed

that in the VENUS Study, the life-table estimated proportion of patients who developed ulcers over 6 months (primary variable, intent-to-treat population) was 20.4% on placebo, 5.3% on esomeprazole 20 mg (po0.001), and 4.7% on esomeprazole 40 mg (po0.0001). In the PLUTO Study, the values were 12.3% on placebo, 5.2% with esomeprazole 20 mg (p=0.018), and 4.4% with esomeprazole 40 mg (p=0.007). These signiﬁcant reductions were observed for users of both non-selective NSAIDs and COX-2 inhibitors. Pooled ulcer rates for patients using COX-2 inhibitors (n=400) were 16.5% on placebo, 0.9% on esomeprazole 20 mg (po0.001), and 4.1% on esomeprazole 40 mg (p=0.002). Esomeprazole was well tolerated and associated with better symptom control than placebo. They concluded that in at-risk patients, esomeprazole was effective in preventing ulcers in long-term users of NSAIDs including selective COX-2 inhibitors. Laheij et al. (2004) reported on the increased incidence of community-acquired pneumonia thought to be associated with impaired elimination of pathogenic organisms due to the relative achlorhydria, and recommeded that high-risk pneumonia patients only receive short courses of low-dose PPIs. Leonard et al. (2007) in an analysis of 12 studies evaluating 2948 patients with C. difficile identiﬁed an increased risk of taking anti-secretory therapy in those infected with C. difficile (pooled OR 1.94; 95% CI: 1.37–2.75). This association was greater for PPI use (OR 1.96; 95% CI: 1.28–3.00) compared with H2RAs use (OR 1.40; 95% CI: 0.85–2.29). A total of six studies evaluated Salmonella, Campylobacter, and other enteric infections in 11,280 patients. Again, it was identiﬁed that there was an increased risk of taking acid suppression in those with enteric infections (OR 2.55; 95% CI: 1.53–4.26). The association was greater for PPI use (OR 3.33; 95% CI: 1.84–6.02) compared with H2RAs use (OR 2.03; 95% CI: 1.05–3.92). It was therefore concluded that there is an association between acid suppression and an increased risk of enteric infection. Further studies on patients taking long-term acid suppression are needed to establish whether this association is causal.

Gastrointestinal Complications of Anti-Rheumatic Drugs

8.6. Evaluation of relative benefits of anti-secretory therapies Hooper and associates (2004) have attempted to determine if there is an effective measure to protect the GI tract in patients who require NSAIDs. They assessed the effectiveness of ﬁve gastroprotective strategies for people taking NSAIDs: H2RAs plus tNSAIDs; PPIs plus tNSAIDs; misoprostol plus tNSAIDs; COX-2 selective NSAIDs (etodolac, meloxicam, nabumetone, and nimesulide); or COX2-speciﬁc NSAIDs in reducing serious GI complications, symptomatic ulcers, serious CV or renal disease, and deaths, and improving QoL. They reviewed 112 randomised controlled trials (74,666 participants), and identiﬁed 138 deaths and 248 serious GI events overall. On comparing gastroprotective strategies versus placebo, they found no evidence of effectiveness of H2RAs for any primary outcomes. They stated that PPIs might reduce the risk of symptomatic ulcers (RR 0.09; 95% CI: 0.02–0.47) and that misoprostol reduced the risk of serious GI complications (0.57, 0.36–0.91) and symptomatic ulcers (0.36, 0.20–0.67). For the COX-2-selective NSAIDs there was a reduced risk of symptomatic ulcers (0.41, 0.26–0.65) and similarly the COX-2-speciﬁc NSAIDs reduced the risk of symptomatic ulcers (0.49, 0.38–0.62) and possibly serious GI complications (0.55, 0.38–0.80). All strategies except COX-2 selectives reduced the risk of endoscopic ulcers (at least 3 mm in diameter). The authors concluded that misoprostol, COX2-speciﬁc and -selective NSAIDs, and probably PPIs signiﬁcantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 speciﬁcs signiﬁcantly reduce the risk of serious GI complications, but warned that data quality was low. It was felt that more data on H2RAs and PPIs were needed, in addition to better reporting of rare but important outcomes. Effective misoprostol use is limited by diarrhoea, cramping, and bloating intolerance to the recommended dosage of 800 mg od. Subsequent studies have shown that PPIs are effective at signiﬁcantly reducing the GI complications of tNSAIDs and COX-2-selective NSAIDs for symptomatic relief and prevention of symptoms and prevention of gastric ulceration (Hawkey et al.,

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2005, 2007a, b; Scheiman et al., 2006). Cost of therapy is of great importance to ﬁnancial governing bodies and numerous detailed reports address this point. Elliott and colleagues (2006) in their cost utility analysis suggest that a tNSAID plus an H2RA was more cost effective than a tNSAID alone and equally effective and less costly than selective COX-2 inhibitors and Scheiman and Fendrick (2007) stated that it may not be feasible to recommend the ‘safest’ regime in every circumstance, but cautioned that cost is ultimately assessed based on the patient’s underlying risk. The question of CV risk remains as to whether COX2-selective drugs should be used (Kean and Buchanan, 2005), and notwithstanding the debate that there may or may not be a CV risk from tNSAIDs (McGettigan and Henry, 2006), the ﬁndings are that the risk from tNSAIDs is less. Thus, on the balance as to whether to risk major organ damage to the stomach or the CV and cerebral system, it is our opinion that use of a PPI with a tNSAID is the most reasonable strategy to adopt in the prevention of GI symptoms and ulceration in patients who require NSAID therapy.

8.7. Modification of analgesics to prevent gastric complications Changes of anti-rheumatic drug formulations such as the use of topicals, injections, oral suspensions, suppositories and various forms of enteric coating, and attempts at slow-release formulations, all have had some degree of merit but problems of effectiveness, ease of patient use, and ultimate reduction in GI toxicity result in a need to continue to seek alternative strategies to effectively treat the pain in patients with musculoskeletal disease while avoiding or minimising gastric and other major organ toxicity. Some of the issues concerning the development of newer NSAIDs and anti-rheumatic drugs have been explored elsewhere (Rainsford, 2006, 2007). Many of the newer developments are focussed on achieving disease modiﬁcation as well as pain relief in RA (Rainsford, 2007). With increasing focus on drugs directed at disease modiﬁcation there may be

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coincidently sparing of the GI protective mechanisms from the actions of these drugs so leading to reduced risk of GI events. We await detailed studies in rheumatic patients with these newer agents and especially long-term clinico-epidemiological investigations directed at establishing their relative safety compared with existing NSAIDs and anti-rheumatic drugs.

Current alternatives to NSAIDs for pain relief include non-narcotic analgesics, acetaminophen (paracetamol), dipyrone or the narcotics (codeine, dextropropoxyphene, fentanyl). The use of acetaminophen for pain relief in osteoarthritis A has been stated in some studies to be equivalent to that of NSAIDs (Brandt, 1993a, b; Brandt and Bradley, 1993) while in others the results are equivocal and the issue is highly debatable (Buchanan and Kean, 2002; Kean and Buchanan, 2005). However, for episodes of local inﬂammatory ‘‘ﬂare’’, acetaminophen would probably have limited effects (Dieppe et al., 1993a, b, c; Williams et al., 1993). More recently the weak narcotics (e.g. tramadol, dextropropoxyphene, fentanyl) have been shown to be effective in controlling rheumatic and other chronic non-cancer pain states (Buchanan and Kean, 2002; Ackerman et al., 2003; Schnitzer et al., 2000). These therapeutic alternatives to NSAIDs may be usefully employed in rheumatic patients although appropriate caution must be taken in the elderly and in patients with concomitant disease.

The popular use of natural products with claimed beneﬁts for relieving symptoms of pain and inﬂammation but with possibly low GI adverse effects is much debated. Some of these preparations (e.g. St. John’s Wort) have attracted much attention for their potential to cause interactions with drug metabolising systems and thus affect the safety of some conventional drugs that may necessarily be taken by rheumatic patients. Other natural

products may be safer but they need investigation to establish their relative safety. In an attempt to facilitate a uniform approach to the clinical management of arthritis, academic advisory bodies, such as the British Society for Rheumatology with the Royal College of Physicians (UK) and the American College of Rheumatology (ACR), developed treatment guidelines aimed at reducing toxicity while maintaining effectiveness. One such strategy was used for the management of OA (Guidelines, 1993; Hochberg et al., 1995a, b). While the UK and the ACR guidelines had good attributes, both advocated the use of paracetamol as the drug of ﬁrst choice in the treatment of OA based on a study by Bradley et al. (1991) which had signiﬁcant methodological and reporting bias. It was assumed that paracetamol would be less toxic on the GI tract but would provide good analgesia based on the results of the Bradley Study. However, it should be noted that OA is often a painful inﬂammatory condition, and should therefore respond better to a NSAID (Hungin and Kean, 2001). Although the UK and ACR guidelines for the management of OA were well intentioned, the literature evidence for paracetamol as a ﬁrst drug of choice is weak (Hungin and Kean, 2001; Kean and Buchanan, 2005) especially since Bradley et al. (1992b) subsequently showed that it was the anti-inﬂammatory activity of the S enantiomer of ibuprofen that was the active compound responsible for the clinical beneﬁt in OA of the hip and knee. Nevertheless literature citations and guidelines (Bradley et al., 1992a; Brandt, 1993a, b; Dieppe, 1993; Dieppe et al., 1993a, b, c; Williams et al., 1993; Creamer, 2000; Tannenbaum et al., 1996) with respect to the ﬁrst line treatment beneﬁts of paracetamol in OA appear to have inﬂuenced a large number of clinicians around the world into withholding or modifying the use of NSAIDs in the management of OA (Won et al., 2004), Won and colleagues studied the use of analgesics in 21,380 residents over age 65 years, in US nursing homes and persistent pain was identiﬁed in 49% of residents. The persistent pain was prevalent in 63% who had a history of fracture and 64% who had a history of surgery in the last 6 months. One quarter received no analgesics. It must be argued that ACR

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guidelines of 1995 inﬂuenced this practice? It is of interest that the most common analgesic administered to these nursing home patients was paracetamol (37.2%), followed by propoxyphene (18.2%), hydrocodone (6.8%), and tramadol (5.4%) (Won et al., 2004; Kean and Buchanan, 2005). In addition, the ACR guidelines also advocated the use of short half life NSAIDs in preference to long half life NSAIDs despite the fact that there is no evidence that the phamacokinetic short half life property correlates with less toxicity (Hungin and Kean, 2001). It is most likely that the ACR committee (not properly informed) (Hochberg et al., 1995a, b) probably intended there comments to more correctly refer to rate of plasma or tissue clearance of the drugs, but this also does not correlate with reduction in toxicity. The ARAMIS data on toxicity in rheumatoid disease indicated that the short half life, rapid clearance drug ketoprofen ranked highly for GI toxicity (Fries et al., 1991), and the study by Cryer and Feldman (1998) on gastric mucosal PG inhibition indicated that the short half life, rapid clearance drug ibuprofen was a potent inhibitor of gastric PGs. Subsequent studies have shown that paracetamol greater than 2000 mg od has a signiﬁcant GI toxicity proﬁle. Garcia-Rodriguez and Hernandez studied the association between paracetamol and NSAIDs and the risk of upper GI bleed/perforation in a population-based cohort of 958,397 persons in the United Kingdom between 1993 and 1998. The case-control analysis included 2105 cases and 11,500 controls. RR estimates were adjusted for several factors known to be associated with upper GI bleed/perforation. Compared with nonusers, the users of paracetamol at doses less than 2000 mg did not have an increased risk of upper GI complications. However, the adjusted RR for paracetamol at doses greater than 2000 mg that were advocated by the ACR Guidelines committee (Hochberg et al., 1995a, b) was 3.6 (95% CI: 2.6–5.1). The corresponding RRs for low/ medium and high doses of NSAIDs were 2.4 (95% CI: 1.9–3.1) and 4.9 (95% CI: 4.1–5.8). The RR was 3.1 (95% CI: 2.5, 3.8) for short plasma halflife, NSAIDs, 4.5 (95% CI: 3.5–5.9) for long half-life, NSAIDs, and 5.4 (95% CI: 4.0–7.1) for slow-release formulations of NSAIDs. Thus, not

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only does paracetamol at greater than 2000 mg od have a signiﬁcant GI toxicity proﬁle, but also have lower analgesic efﬁcacy than NSAIDs, and is thus not an effective alternative to NSAIDs in any of the inﬂammatory arthritides (Hungin and Kean, 2001). Thus, recommendations on the use of paracetamol at 200 mg od or more as an alternative to NSAIDs was an incorrectly conceived concept (Hochberg et al., 1995a, b) and would not theoretically result in reduced toxicity to the GI tract (Kean and Buchanan, 2005).

8.7.1. COXIBs The rationale for the use of coxibs has been discussed in detail above (see Section 4) and is brieﬂy summarised in this section on Strategies. The COX-2 selective inhibitors arrived on the clinical scene with great promise but riding a shallow ‘evidence-based’ wave of clinical abstracts that ultimately would swallow its advocates. Although there has been a trend to increase usage of COX-2 selective inhibitors based on their presumed low GI toxicity, the potential for CV side effects, and the concern that they may not have less GI toxicity (Simon et al., 2002; Strand and Hochberg, 2003; Ju¨ni et al., 2002), makes the re-evaluation of the use of the tNSAIDs a reasonable consideration. Laine et al. (2007) reported that the selective COX-2 inhibitor etoricoxib (60 or 90 mg od) use was associated with less upper GI clinical events than patients who received diclofenac (150 mg od) but that this decrease was related to uncomplicated events while the risk of complicated events was the same in the two groups (Laine et al., 2007). Ju¨ni et al. (2002), in an article in the British Medical Journal, reviewed reports published for the so-called CLASS Study which compared celecoxib 800 mg/day with ibuprofen 2400 mg/day and diclofenac 150 mg/day in OA or RA. These authors criticised that only the ﬁrst 6 months of the trial was published, despite the fact that some patients received treatment for up to 12–15 months. While the results of the ﬁrst 6 months data showed that celecoxib may have less GI adverse reactions than the ibuprofen and the diclofenac, the authors concluded that information

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obtained after the 6 months showed that there was no difference in the incidence of adverse effects amongst the three drugs, celecoxib, ibuprofen, and diclofenac. They concluded that there may not be an increased beneﬁt to the use of this COX-2-selective NSAID over tNSAIDs, if it has no advantage in GI protection. COX-2 inhibitors while having shown some reduction in incidence of upper GI ulcers and bleeding (Hooper et al., 2004) this has not been the ﬁndings of all studies and Laporte et al. (2004) in a study of upper GI bleeding from a gastric or duodenal ulcer (2813 cases versus 7193 matched controls) showed that greater COX-2 selective inhibition did not confer less risk of upper GI bleeding. COX-2 selective inhibitors were not originally claimed to reduce symptomatic side effects frequently seen with NSAIDs, e.g. dyspepsia, epigastric pain, nausea. These adverse reactions are the most frequent reasons for cessation of NSAID therapy. The question whether or not the highly selective COX-2 inhibitors (coxibs) have reduced incidence of dyspepsia have yielded mixed results. In general, dyspepsia is still a frequent occurrence in patients taking COX-2-selective inhibitors and there is evidence that patients still need therapy with PPIs or other anti-secretory agents (Hawkey et al., 2005, 2007a, b).

9. Discussion and conclusions Clearly, there is a large population worldwide with musculoskeletal conditions, which requires analgesic, NSAIDs, and/or steroid treatment for musculoskeletal disorders, but a serious impairment in QoL and potential for serious GI adverse effects results in a signiﬁcant limitation in the effective management of these patients. Basic science and clinical studies have attempted to establish cause and effect of the analgesics, NSAIDs, and steroids in their action on the GI tract. Numerous strategies have been attempted to counter the adverse effects of the analgesics, NSAIDs, and steroids. These strategies have included changes in drug formulations and route of administration, and the use of pharmacological agents to protect or heal the GI tract. Some

of these interventions may prove to result in fewer adverse consequences for the GI tract in patients with RA and the other arthritides. It is clear that the ﬁrst-generation coxibs, when taken long-term, have proven to have had limited beneﬁts in signiﬁcantly reducing the serious GI complications normally seen with tNSAIDs in patients with musculoskeletal disorders. Whether the newer second-generation coxibs (etoricoxib, lumiracoxib) will have any signiﬁcant beneﬁts in the long-term, is an open question until more experience has been gained from extensive use of these drugs. There are clearly cost issues and problems with increased risks of GI events that have to be faced when using the coxibs with other drugs, especially when low-dose aspirin is required. There may be small beneﬁts to the GI tract from use of coxibs in the short-term, but for the patient with RA or other chronic musculoskeletal disorders, because of their requirement for long-term pain relief, a sustained GI beneﬁt may not be achieved by the coxibs over the use of tNSAIDs. As stated above, the issue of CV risk remains as to whether coxibs should be used at all (Kean and Buchanan, 2005), and notwithstanding the debate that there may or may not be a CV risk from tNSAIDs (McGettigan and Henry, 2006), the ﬁndings are that the overall risk to general well being from tNSAIDs is less. Thus on balance, with respect to the question whether one should risk major organ damage to the GI tract, or the CV and cerebral system, it is our opinion that use of a PPI with a tNSAID is the most reasonable strategy to adopt in patients with musculoskeletal disorders who require NSAID therapy (Kean and Buchanan, 2005).

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Index

A A77-1726 112 Abdomen arteriography 92 Abdominal ﬁlms. See Plain abdominal ﬁlms Abdominal pain 32–34 treatment 32 A1-B8-DRB1*03 126 A4b1 integrin 4 A4b7 integrin 4 Absolute risk reduction (ARR) 252 Acetaminophen 244, 264 Acid secretion effects of NSAIDs and H. pylori 257–258 in rheumatic patients 258–259 stimulation of 257 Acid-secretory inhibitors, use of 257 Adaptive immune responses 6 Adrenocortical failure, primary 158 Adventitia aortic 88 dendritic cells in 86 mononuclear inﬁltration of 85 and vasa vasorum 85 Adverse drug reactions (ADRs) 253 GI symptomatic 255 Ag receptors 86 AIRE1 gene 158 Air esophagogram 103 Alanine 130–131 effect of CTLA-4 gene on 125 Alcohol dehydrogenase, antibodies to 161 Alemtuzumab (CAMPATH 1-H) 92 Allogeneic transplantation 164 Alopecia universalis 67 Alpha/beta T cell receptors 159, 161 Amaurosis fugax 39 American College of Gastroenterology 52, 55 American College of Rheumatology (ACR) 86, 112, 264 Amino acid sequences 130 homologous 123 Amyloidosis 84, 110 Anaemia 246 Analgesia 111 Analgesic agents 244–245

Analgesic and anti-inﬂammatory medication use 244–246 Analgesics, modiﬁcation of 263–265 Anal sphincter 59 ANCA. See Anti-neutrophil cytoplasm antibody (ANCA) Anchylosing spondylitis. See Autoimmune diseases Aneurysms 85 abdominal 87 angiographic ﬁnding of 89 necrotizing inﬂammation effect on 89 thoracic 87 Angiography 83 CT 87 Angioplasty, mesenteric 34 Animal experiments 164 Ankylosing spondilitis (AS) 218, 249 Antacids 105, 259–260 Anti-actin reactivity 157 Antiaorta antibodies 85 Antiapoptotic protein bcl-2 144 Anti-b2-glycoprotein-I antibodies 39 Antibiotic therapy 92, 95 Antibodies 9, 132, 123 to asialoglycoprotein receptor (anti-ASGPR) 238–239 in autoimmune liver diseases 236–240 to CBir1 (anti-CBir1 ﬂagellin) 231 in celiac disease 234–236 to glycoprotein (gp210) 239 in inﬂammatory bowel diseases 231–233 to liver cytosol type 1 (anti-LC1) 238 to liver–kidney microsome (Anti–LKM1) 237 to nuclear pore complex antigens 239 to soluble liver antigen/liver pancreas antigen (anti-SLA/LP) 238 Anticardiolipin Ab. See Anticardiolipin autoantibodies Anticardiolipin antibodies (aCL) 39, 42, 44–45 Anticardiolipin autoantibodies 203 Anti-CCP antibodies 213 Anti-CD20 therapy (rituximab) 92 Anticoagulants 40 Anticoagulation 34 Anti-dsDNA 213–214 Anti-ENA 209

278

Anti-endomysial antibodies (EMA) 234 Antiendothelial cell antibodies 85 Anti-ﬁbrogenic agents 180–181 Antigen binding groove 124, 132 of the class II MHC 130, 131 individual’s response to 121 presenting class II MHC 124, 125 presenting molecules 130, 131, 133 recognition sites 121 activation of multiple 132 disturbances in 122–124 Antigen formiminotransferase cyclodeaminase (FTCD) 238 Antigenic peptides 124 Antigenic stimulation 95 Antigen-presenting cells (APC) 124–125, 159, 164, 173 Antigens of HLA 171 Antigen 4 (VLA4) 4 Anti-gliadin antibodies (AGA) 234, 235 Anti-HBs antibodies (Ab) 192 Anti-HBV Ab immune complexes 194 vaccination 195 Anti-HCV antibodies 210, 213 Anti-inﬂammatory drugs (NSAIDs) GI toxicity of 250 global usage of 247 half life, short and long 265 long-term use of 246 pain management of 257 risk factors of 259 ulcerogenicity of 250–251 Anti-lamin B receptor antibodies 239 Anti-LC-1 157 Anti-liver cytosol type 1 (anti-LC-1) 156 Anti-liver/kidney microsomal type 1 antibody (anti-LKM-1). See Anti-LKM-1 Anti- LKM-1 153, 157, 161, 209 charatcterization of 155 molecular target of 154 stains 157 vs. AMA 157 Anti-malarials 32 Antimitochondrial antibody (AMA) 67, 141, 156, 157, 209, 210, 236, 238 and mouse models 144 negative PBC vs. positive PBC 146 role in diagnosis of PBC 146 testing for 142 Antimyeloperoxidase (MPO) 232 Anti-myenteric neuronal antibodies 51

Index

Anti-neutrophil cytoplasm antibody (ANCA) 91, 157 Antineutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitides (ASV) 91–92 Anti-neutrophil-speciﬁc antibodies 170 Antinuclear 204 Anti-nuclear antibody (ANA) 143, 209, 210, 214, 236–237 autoantibodies to 155 detection of 156 seropositivity for 153 target antigens 157 Anti-OmpC (outer membrane porin from Escherichia coli) 231 Anti-p62 antibodies 239 Antiphospholipid antibodies (aPL) 34, 35, 39–46 thrombosis due to 36–37 Anti-phospholipid syndrome (APS) 39–46 as autoantibody-mediated disease 39 catastrophic 214 classic vs. catastrophic 40 digestive involvement in 40 features 214 gastrointestinal involvement in 40–41 immunological markers in 214 infectious agents in 214 Anti-PM-Scl antibodies 64 Antiproteinase 3 (PR3) 232 Antirheumatic drug (DMARD) 111–112 Anti-RNP antibodies 64 autoantibodies, positive 103 Anti-saccharomyces cerevisiae antibodies (ASCA) 231 Anti-secretory therapies 263 Anti-smooth muscle antibody (SMA) 154, 209 detection of 156, 157 titres of 156, 157 Anti-smooth muscle cell Ab 204 Anti-SSA/Ro antibodies, in MCTD 102 Anti-thymocyte globulin 92 Anti-thyroid Ab 203, 204 antibodies 210 Anti-tTG2 234, 235–236 Anti-tumor necrosis factor (TNF) agents 222 Anti-ulcer co-therapy 254 Anti-viral therapy 194, 215–217 Antrectomy 32, 56 Aorta abdominal tract 87, 88

Index

APECED. See Autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED) Aperistalsis 104 APL 214 Apoptosis 6, 124, 127, 128 apoptotic cells 9 cellular 144 extrinsic pathway of 127 of liver cells 129 markers of ongoing 144 Apoptosisinducing factor (AIF) 127 Apoptotic pathways, perturbations in 127–128 ARAMIS data, on toxicity 265 Arginine (R) 130 Argon laser 55, 56 Argon plasma coagulation 56 Arterial nodules 89 wall 86 Arteriosclerosis 83 Arteritic lesion giant cell arteritis (GCA) 86 Takayasu’s 84 Arthritic disease, impact of 254–255 Arthritis Society 243 Ascending aorta 84, 85 Ascites 31, 35 Asherson’s syndrome 40 Asialoglycoprotein 161, 162 Aspartic acid (D) 131 Aspirin 34, 90, 245, 247 Aspirin therapy’s role in GI protective effects 111 Atherosclerosis 33, 34 accelerated 109 Atherosclerotic stenosis 19 Atrophy of villi 104 Atypical perinuclear antineutrophil cytoplasmic antibodies (Atypical pANCA) 170–171, 238 Autoantibodies 7–9, 64, 155–157, 203–204, 209–210 anticardiolipin Ab of, IgG, IgM, and IgA 203 anti-gluten 66 antiliver– kidney–microsome (anti-LKM) Ab 204 antinuclear 204 antinucleosome Ab 204 anti-smooth muscle cell Ab 204 antithyroid Ab 204 cryoglobulin 204 detection 155–156 immunoﬂuorescence of 155, 156 low titers of 213, 214 myositis-associated 64 myositis-speciﬁc 64

279

in PSC 170–171 rheumatoid factor 204 Autoantigen recognition 159 Autoimmune arthropathies 246–247 cytopenias 219 diseases 84 hemolytic anemia (AHA) 219 injury 144 liver diseases 236–240 pancreatitis (AIP) 175 polyendocrine syndrome 1 158 polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) 154, 158, 159 regulator (AIRE) gene 126 Autoimmune hepatitis (AIH) and alleles encoding for lysine postion 132 cell-mediated cytotoxic response in 128 clinical features of 154 as a complexes trait disease 158 cytosolic enzymes role in 125 deﬁciencies in 128 development of 131 diagnosis of 154–157 effect of molecular mimicry 123 female predisposition for 129, 133 genetic risk factors for 121 genetics pathophysiology of 158–159 and HLA DRB1*04 133 and HLA DRB1*13 131 IAIHG scoring system for the diagnosis of 156 immune mechanisms of pathophysiology of 159–162 murine model of 123, 125 occurence of 125 persistence of activated lymphocytes expressing CD95, 127 as polymorphism of the CTLA-4 gene 125 principal susceptibility alleles for 129, 130, 131 recurrence of 163 seronegative 157 treatment of 162–163 type 1 157 type 2 132, 157 Autoimmunity adaptive immune responses 6 graft-versus-host disease 7 gut-associated 3–6 preventing 9 in PSC 169–170 and self-tolerance 6 Wiskott–Aldrich syndrome 8 Autologous DNA 9

280

Autoreactive response 123 effect of counter-regulatory cells on 128 effect of signal pathways on 127 role of molecular mimicry in 123 Autoreactive T cells 161–162 Azathioprine 31, 32, 67, 162, 180. See also Immunosuppressive agents and corticosteroids 37 and prednisolone 36 side effects of 163

B Bacterial antigens 174, 232 cholangitis 178, 179 growth 174 overgrowth 174, 180 permeability increasing protein (BPI) 238 Bacterial overgrowth syndrome diagnosis of 56–57 prothrombin time, in 57 serum carotene, in 56 symptoms 56 treatment 56 Balloon dilatation 178, 184 Barium studies 15 swallow 52, 55 Barrett’s esophagus and adenocarcinoma 52 guidelines, for management of 55 treatment 55 Bayesian approach 147 B-cells 4, 6 auto-reactive 7 B-cell-activating factor (BAFF) receptors 6 clonality 219 depletion treatment 91 early 93 expansion 93, 95 late 93 lymphoma 92, 93, 94, 95, 212, 220 lymphoproliferation, gastric 95 lymphoproliferation, non-neoplastic 92 self-reactive 6 tolerance mechanism for auto-reactive 6–7 Bcl-2 127 BCL-2-interacting mediator (BIM) 6–7 BCL-2 proteins 6–7 B7 expression 7

Index

B2–glycoprotein-I (b2GPI) 39 Bile acid, excretion 181 Bile duct 142–144 cancer 183 loss 174, 180 Biliary epithelial cells (BECs) 141, 143, 171, 173–174, 239 epithelium 178 strictures 175, 178 tract 34, 35 Biliary tree anatomy of 23 bowel opaciﬁcation 16 MRC, to depict 23 pathology 16 Biochemical tests 180, 181 tuning 7–8 Biofeedback therapy 59 Biphosphonates 179 B7 ligands 125 Bloodstream 4 B lymphocytes 159 autologous 162 self-reactive 109 Bone density measurement 57 Botulinum toxin A 66 Bowel angina 90 biopsies 36–37, 234 diseases, inﬂammatory 66 ischemia 19, 20, 34 manifestations, in MCTD 104 Bradley Study 264 Branched-chain 2 oxo-acid dehydrogenase complex (BCOADC) 143 British Medical Journal 265 British Society for Rheumatology 264 Broad-spectrum antibiotic treatment, cyclic 105 Bruits, abdominal 83–84 Budd-Chiari syndrome 19 Bystander activation 9

C C. difficile infection 260, 262 Calcineurin antagonists 32 Campylobacter 260, 262 Campylobacter enterocolitis 180 Campylobacter pylori 9 Cancer, hepato-cellular 163

Index

Cardiovascular (CV) prophylaxis 244 Caspases 127 Catalase 239 Catastrophic APS digestive involvement in 40 gastrointestinal involvement in 40–41 hepatic infarction, in patients with 43 mortality rate, in patients with 41 pancreatic involvement, in patients with 46 rate of microthrombosis, in patients with 41 splenic infarction, in patients with 45 vs. classic APS 40, 41 CD4 T helper cells activation of 124 effect of CTLA-4 on 125 multiple antigen recognition sites within 132 CD4+ T-helper lymphocyte subset 1 (TH1)- type, immune response 109 CD4+ T helper (Th0) cells 159 CD4 T lymphocytes 120 antigen recognition sites 122 liver-inﬁltrating in 127 CD8 T lymphocytes 121 antigen recognition sites in 122 cell proliferation in 128 CD8+ T lymphocytes, cytotoxic 193 Celecoxib 252 cost-befeﬁt analyses of 254 ﬁrst generation 253 meta-analysis of 254 safety analysis of 253 second generation 255–256 vs. NSAIDs 253–254 Celecoxib Long-term Arthritis Safety Study (CLASS) 252–253, 254 Celiac disease 64 Cell lines, T cell 161 Cellular immune abnormalities 172 Cellular inﬁltrate 172 Central lymphoid organs 6 Cerebral infarction 85 Cerebrovascular accidents 39 Chapel Hill Consensus Conference (CHCC) 89 Chelates of gadolinium 23 Chemokine receptors 4 Chemokines 86 Chest roentgenogram 103–104 Chlamydia pneumoniae 144 Chlamydophila spp. 112 Chloroquine 32 Cholangiocarcinoma 176–177, 178

281

Cholangiocytes, immature 143 Choledocholithiasis 37 Choleretic agent 179 Cholestasis 67, 197 Chromosome 10q24.1 127 Chronic active hepatitis 105, 106, 153 hepatitis 191, 192, 197, 200 inﬂammation 95–96, 142–143 interstitial cystitis 35 intestinal pseudo-obstruction (CIPO). See Intestinal pseudo-obstruction intestinal vasculitides 84 liver diseases 154, 163, 177–178 mucocutaneous candidiasis 158 non-suppurative destructive cholangitis 141 pain 244 periaortitis 87–89 Churg-Strauss syndrome (CSS) 89 Cimetidine 260 Cirrhosis 127, 162, 163 Cladribine 180 Clonal anergy 7 Clones, T cell 161 Clopidogre 34 Clostridium perfringens, faecal 248 Coeliac disease 93 Cognitive impairment 246–247 Colchicine 181 Colic mucosa biopsy 92 Colitis pseudomembranosa 92 Colon cancer 177, 183, 184 Colonoscopy 84 Color dopplers 16, 17 Combined therapy 184 Complementarity-determining regions (CDR) 124 Computed tomography (CT) 16–20 angiogram 18, 19 contrast media, iodinated 19–20 imaging protocols in 16–17 multidetector computed tomography (MDCT) 16–20 multiple X-ray transmission 16 scanners 16 Con-A-induced liver injury 128 Conjunctivitis 90 Constipation 57 Contrast agents MR 23–24 US 16 Contrast media, iodinated 19–20 vs. contrast agents in MR 23

282

Coronary arteries 90 Corticosteroid and cyclophosphamide 92 role in chronic periaortitis’s treatment 88 role in giant cell arteritis (GCA) treatment 86–87 role in henoch-scho¨nlein purpura (HSP) treatment 90, 91 role in kawasaki’s disease treatment 90 role in takayasu’s arteritis treatment 85 Corticosteroids 32, 179, 198, 199 and azathioprine 37 Corticosteroid therapy 205 Cortisone 67 Costimulatory molecules 7 Costimuli, limitation of 8–9 COX 111, 243, 251, 253, 256, 261–262 Creatine kinase 63, 66 Crohn’s disease (CD) 66, 67, 231 Cross-reactivity 123 cellular 123 humoral 123 Cryoglobulinemia 210, 214, 215, 219 glomerulonephritis 215 vasculitis 214–215 Crypt hyperplasia 66 Cryptidins 3 Crystal diseases 244 CT. See Computed tomography (CT) CTLA-4. See Cytotoxic T lymphocyte antigen-4 (CTLA-4) CTLA-4 gene 125 Cushingoid changes 162–163 CV ADRs 253, 255 Cyclic citrullinated peptide (CCP) 212–213 Cyclo-oxygenase. See COX Cyclophosphamide 92, 93 clinical trials of 89 and corticosteroid 92 role in chronic periaortitis’s treatment 89 Cyclophosphamide 31, 35–36, 40, 43, 64, 67, 198, 199 Cyclosporin 180 Cyclosporine A 31, 32, 35 CYP2D6 123, 132 Cytochrome c 127 Cytochrome monooxygenase P450 IID6 (CYP2D6) 237 P4502D6 (CYP2D6) 154, 157, 161 P450 enzymes 260 Cytokines 4– 5, 8, 126, 127, 128, 133, 173, 109, 143, 257 IFN-g 109 IL-1 109 local networks of 95 proinﬂammatory 86, 111 TNF-a 109

Index

Cytomegalovirus, infection 32 Cytopenias. See Autoimmune cytopenias Cytoplasm, of grandular cell 93, 95 Cytoskeleton components 237 Cytosolic enzymes 123 phospholipase A2 (cPlA2) 111 Cytosol type 1 (anti-LC1) 132 Cytostatic therapies 31 Cytotoxicity assays 161 Cytotoxic T lymphocyte antigen-4 (CTLA-4) 125, 172 T lymphocyte (CTL) 4

D Defensins 3 Dendritic cells 5, 6, 86 De novo AIH 163–164 Dermatomyositis 63, 67 Desquamation 90 Diabetes mellitus 202–203, 210–211 Diarrhoea 58–59, 90 Dihydrofolate reductase (DHFR), irreversible inhibition of 112 Dihydrolipoamide dehydrogenase binding protein 143 Disease-modifying anti-rheumatic drugs (DMARDs) 248 DNA aneuploidy 177 chromosomal 127 fragmentation of 127 immunization 123 Dominant strictures 178 Dopplers 16, 17 D-penicillamine 66, 178–179 DR molecules 131 Drug withdrawal 163 Dry mouth 31–32, 64 Ductopenia 178 Dysentery 112 Dysmotility 51 of esophagus 110–111 Dysphagia 32, 65–66, 103, 105 Dysplasia biliary 177 colonic 177, 183

E Edema, of submucosa 104 Effector cell 161

Index

Eicosanoid, precursors 111 Elastic lamina 86 Elderly frail female 246 Electrogastrography 55 Electromyography 63 ELISA 157 detection 219 ELISA-2 213 EMG 65 Encoding, gene and enzyme 164 Endocytosis 7 Endomysium 234 Endoplasmic stress 63 Endoscopic ablation 55 dilatations 105 retrograde cholangiography (ERC) 24 treatment, of PSC 178 Endothelial cells 39, 84, 86, 193 Enteric bacteria 179, 248 Enteric ﬂora 248 Enterobacter 248 Enterobacteria strains 248 Enterocytes 3 Enterovirus or human herpes virus 6 202 Enzyme-linked immunosorbent assay (ELISA) 232, 237 Eosinophils 86 Epididymitis 204 Epilepsy 39 Epistasis 124, 126 Epithelial cells 142, 143 Epithelial–mesenchymal ‘cross-talk’ 143 Epithelium cortical epithelium 7 follicle-associated epithelium 3, 5 intestinal epithelium 5 Epstein Barr Virus 202 ERCP 175, 178, 179 Erythema, oropharyngeal 90 Erythrocyte sedimentation rate (ESR) 86 Erythromycin 55, 57 Escherichia coli 144 Esomeprazole 261–262 Esophageal disease 110–111 dysfunction 103–104 dysmotility, radiological evidence of 101–102 manometry (EM) 52, 103, 105 motility 103–104 necrosis 40 peristalsis 105 pH monitoring 105

283

Esophagitis 52 Esophagogram. See Air esophagogram Esophagus 103–104 Estrogen 133 therapy 202 E2 subunit of pyruvate dehydrogenase complex (PDC-E2) 143, 144 Etanercept 85, 92, 222 Etoricoxib 256 European Union Medicines Control Agency (EUMCA) 112 External sphincter myositis 66 Extractable nuclear antigen (ENA) 101 Extrahepatic cell types, for HCV 218 Extra-hepatic manifestations 194–205

F F actin 157 Faecal ﬂora, by NSAIDs 248 Fas gene [tumor necrosis factor receptor super family (TNFRSF)] 126, 127 FasL 127 mediated cytotoxicity 128 Fatigue 145 Fc receptor–positive mononuclear cell 161 FDA 253, 256 Fecal incontinence 58–59 Felty’s syndrome 110 Ferromagnetic implants 24 Fetal cells, persistence of 144 18 F-ﬂuorodeoxyglucose ([18F]FDG) 26 Fibrinoid necrosis 89, 90, 91, 196 Fibroblasts 86 Fibrosis 169, 174, 210, 211 bowel wall 35 muscle 64, 65 Fibrous tissue replacement 65 Fine-needle biopsy 19, 20 Fissuring (redness), of the lips 90 Fluoroscopy 19 Focal liver lesions 16, 23 Focal nodular hyperplasia 23–24 Food and Drug Administration 112, 147 Foreign antigens 121, 123 Formiminotransferase cyclodeaminase (FTCD) , 123, 157 French Pharmacovigilance Study 254 French Vasculitis Study Group 89 Fulminant hepatitis 193, 195

284

G Gadolinium, chelates of 23 Gallbladder 16 Gastric antral vascular ectasia (GAVE) 32, 56 disease 32 electric stimulation 55–56 lymphomas 94 ulceration 40 Gastrin production 258–259 Gastritis 111, 257, 258 Gastroesophageal reﬂux disease (GERD) 52 Gastrointestinal (GI) diseases 112–114, 233, 234 involvement’s in systemic vasculitis 83 ischemia 40–41 manifestations 31 pathology 15 syndromes 32–37 system in rheumatoid arthritis 110 tract 63–67 Gastrointestinal (GI) reactions in autoimmune arthropathies 246–251 death rate, estimates of 245 multiple origins of 247–250 steroid, effect of 245–246 Gastrointestinal tract (GIT) 5, 59 Gastroparesis 55 Gastroprotective strategies 263 Gastroscopy 84 GB virus-C 196 Gender effects 133–134 Gene dose effects 132–133 expression 5–7 microarray technology 124 mutations 158 General Practice Research Database 246 Genes encoding 171 Gene sequence, analyses 95 Genetic polymorphisms effect on cytokine response 126 interactive 124 Genetic predisposition 121, 129 and HLA DRB1*03 126 Genetic risk factors principal 129–131 region-speciﬁc 131–132 Genetic susceptibility hypothesis of 145 in PBC 143

Index

Genome 6 Germline polymorphisms 124 Gianotti–Crosti syndrome 201–202 Giant cell arteritis (GCA) 85–87 Giant cells 85, 86 GI bleeding 90, 93 due to peptic ulcer 93 GI bleeding and perforation 245–246 GI complications and steroid 245–246 strategies to minimise 256–266 GI haemorrhage 90 GI side effects, due to NSAIDs 244, 245, 259 GI symptoms 84, 91 GI toxicity 245, 250, 265 Gliadin peptides 235, 236 Glomerulonephritis 89, 90, 91 symptoms 200 treatment 200–201 Glucocorticoid-induced myopathy 66, 67 Glucocorticoids 35, 64, 111, 251 Glucose metabolism 26 Glutamic acid (E) 131 Glutathione 144 Glutathione-S-transferase T1 (GSTT1) 123, 164 Glutathionylation 144 Gluten 234 Gottron’s papulae 63 Graft dysfunction 164 Granulomas 86, 88 Granulomatous colitis 92 Granzyme B 127 Gray scale equipment, high-resolution 15 Growth factor B (TGF-b) 235 Growth hormone 133 Guillain– Barre´-like syndrome 9, 204 Gut-associated immunity 3–6

H H. pylori infection. See Helicobacter pylori infection Haemophilus influenza 144 Haemorrhagic duodenitis 90 Harmonic imaging 16 Hazard ratio 256 HBc Ag 192 HBe Ag 192, 194 HBV Ag 194, 200 infection vs. HCV infection 194 related cirrhosis 193 surface antigens (HBs Ag) 192–193

Index

Heartburn 32, 52 Heart valve lesions 39 Heat shock protein 65 (HSP-65) 84 Hedgehog ligands 143 Hedgehog pathway 143 Helicobacter pylori 32, 144, 245 eradication therapy 248 growth of 257, 259 infection 93, 95, 248, 257–258 pathogenic strains of 248 Heliotrope rash, of eyelids 63 Hematological diseases 218–219 Hematopoietic abnormalities 112 Hemolytic anemia 39 Hemorrhage 67 Hemostasis activation 43 Henoch-Scho¨nlein purpura (HSP) 90–91 Hepatic cell 193 cirrhosis 191 ﬁbrotic disease 110 inﬂammation 211 tumors 23, 24 Hepatitis autoimmune 64, 67 A virus 131, 202 B virus (HBV) 89, 192–194 C, chronic 132 Hepatitis C virus (HCV) 202–203, 237 anti, antibodies 95 infection 92–96 lupus-like syndrome, due to 213, 214 metabolic disorders in 211 negative 92, 93, 95 positive 94, 95 RNA 93 and Sjogren’s syndrome (SS) 211 vs. HBV 194 Hepatitis D, chronic 237 Hepatitis D virus (HDV) 196 genotype I HDV 193 Hepatobiliary contrast agents 23 injury 180 Hepatocellular carcinoma 193, 214 Hepatocytes 23, 127, 128, 161, 183 Hepato-renal ADRs 253 Hepatosplenomegaly 146 Hepatotoxicity 111–112 HEp2 cells 156 Herpes viridae 196 High endothelial venules (HEV) 5

285

Histamine 257, 258 Histiocytes 85, 86 Histocompatibility lymphocyte antigen (HLA) 158 class I antigens 159 class II molecules 159, 162 haplotypes 171, 172 molecules 171, 173 polymorphisms in 158 possession of 163 predisposing, allele 161 predisposing, haplotype 159 serotyping 171 HLA class I and II antigens 84 Homeostasis homeostatic proliferation 8 intestinal immune homeostasis 5 Homeostatic proliferation 8 Homing receptors 6, 7 Homologous epitopes 121, 123 Hormone replacement therapy 145 H2-receptor antagonists (H2RAs) 105, 254, 260 Human epithelial cells (HEp-2) 237 genome project 124 immunodeﬁciency virus (HIV) 193 Humoral cross-reactivity 123 immunity 85 Hydroxychloroquine 32 Hyperlipidemia 34 Hyperplasia, nodular regenerative 110 Hyper-reﬂexity 65 Hypersensitivity vasculitis 84 Hypoalbuminemia 31, 36, 104 Hypoparathyroidism 158 Hypoperistalsis 32 Hypopharyngeal intrabolus pressure 65 Hyporeﬂexity 65 Hypothyroidism 210

I IAIHG 155, 156 IBM. See Inclusion body myositis (IBM) Ibuprofen 261 ICOS 9 Icterus 193 Idiopathic gastrointestinal dysmotility 51 IFN-alpha therapy 203, 204 IFN-g 109 IFN-ribavirin 210

286

IgA 4 autoantibodies 234 endomysial antibodies 234 IgA-class anti-gliadin (AGA) 66 IgA-dominant immune complexes 90 IgG. See Immunoglobulin G (IgG) IgM 4 IkB kinase-b(IKK-b) 5 IkB-NF-kB 111 IL-1 109 Ileal pouch-anal anastomosis 177 Ileus 83 paralytic 90 IL-10 mRNA, downregulation of 173 IL-2 receptor alpha chain (CD25) [T regulatory cells (T-regs)] 160 Imaging techniques barium studies. See Barium studies computed tomography. See Computed tomography magnetic resonance. See Magnetic resonance (MR) plain abdominal ﬁlms. See Plain abdominal ﬁlms positron emission tomography. See Positron emission tomography technological development of 26 ultrasound. See Ultrasound Immune attack 121, 123 Immune cells 133 Immune disorders 244 Immunoblotting 238 Immunochemiluminescent 234–235 Immunocytes activated 121, 122, 124, 129 differentiation and proliferation of 126 elimination of autoreactive 127 liver-inﬁltrating 126 sensitized 125 Immunodiffusion 238 Immunoﬂuorescence of muscle and liver 205 Immunoﬂuorescence test 234 Immunoglobulins 4, 65, 210 G and M 85 IgA 4 IgM 4 sequence analyses of, rearranged genes 95 Immunoglobulin G (IgG) 51, 151 elevated 163 levels of 154 Immunohistochemistry 143 Immunologic ignorance 6 Immunoreactivity 144 Immunoregulation 159, 161

Index

Immunosuppressants 85, 180, 199 use of 92 Immunosuppression 153, 157, 161, 162, 215, 221 Immunosuppressive agents 85. See also Immunosuppressive drugs Immunosuppressive drugs 31, 32, 35, 64 Immunosuppressive therapy 163 IMS health 257 Inclusion body myositis (IBM) 64 dysphagia in 65–66 Indirect immunoﬂuorescence (IIF) 231–232 assay 237 Indomethacin 248, 258 Infarction 114 cerebral 85 gallbladder 89 prevalence of myocardial 85 stomach 89 Infectious agents 112 Inﬁltration inﬂammatory 67 perivascular 63, 64 Inﬂammation 64, 65, 172, 174, 178 Inﬂammatory bowel diseases (IBD) 231–234, 243 cells, mononuclear 63 colitis 174 inﬁltrates 63 reactions 249, 257 response 257 Inﬂammatory myopathies 218 bowel involvement in 66 dysphagia in 65–66 liver involvement in 66–67 oral cavity in 64–65 Inﬂiximab 85, 222 Intercellular adhesion molecule-1 (ICAM-1) 84 Interface hepatitis 153, 154, 155, 159 Interferon 93 a-interferon 215, 216 Interferon gamma (IFN-g) 159 Interferon (IFN)-alpha 199 Interleukin, polymorphism of 126 Interleukin-1 (IL-1) 258 Interleukin 12 (IL-12) 159 International Autoimmune Hepatitis Group (IAIHG). See IAIHG International population studies 243 Intestinal angina 33 epithelial cells (IEC) 5

Index

inﬂammation 5 ischemia. See Gastrointestinal ischemia lesions 248 pneumatosis 21 pseudo-obstruction 35–36, 56–59, 84 Intestinal vasculitis acute 83 isolated 92 MC-related 93 Intima 85, 86 Intramural haemorrhage 90 Iron deﬁciency anemia 56 Ischaemic necrotic lesions 86 Ischemic bowel disease. See Bowel ischemia Ischemic bowel disease 35 Isolated acute pancreatitis 204 Isolated arthralgias 204 Isoleucine (I) 130

J Jejunal tube 55 Joint destruction 110 Juvenile dermatomyositis 67

K Kawasaki’s disease (KD) 90 Keratoconjunctivitis sicca 102 Keto-acid substrates, metabolism of 143 Keto-glutaric acid dehydrogenase complex 143 Klebsiella 248 Komeda diabetes prone (KDP) rat strain 8 Kupffer cells 6, 23–24, 180

L Lamivudine 199 Langerhans cells 85 Lansoprazole 245, 260 Laxative stimulants 59 Leﬂunomide 112 Leg ulcers 39 Leucopenia 110 Leucoplakia 31, 32 Leukocytes. See also Polymorphonuclear (PMN) leukocytes in HBV DNA 193 Leukocytoclastic angiitis 90 vasculitis 90–91 Lichen planus 32

287

Lipoprotein 161, 162 liver-speciﬁc 238 Livedo reticularis 39 Liver biopsy 146, 154–155, 175 biliary dysplasia in 177 Liver cells 161 cytoplasm 157 immunoﬂuorescence studies on 161 Liver disease drug-induced 154 severity of 145 Liver function tests 162, 175, 178 Liver-inﬁltrating immunocytes 124 Liver/kidney microsome type 1 (anti-LKM1) 132 Liver MR 24 Liver parenchyma 154 Liver transplantation 123, 145, 147, 163 LLEQKR 130 Lower esophageal sphincter (LES) 52, 103, 110–111 Lumiracoxib 256 Lupoid hepatitis 153 Lupus anticoagulants (LA) 42, 43 test 39 Lupus enteritis (gastrointestinal vasculitis) 34–35 Lymphadenopath, nonsuppurative 90 Lymph nodes 193 external iliac 25 left iliac 20 Lymphocytes 193 activated 122, 123, 127 autologous 161 of B cells 159, 162 CD4+ 193 CD4 helper T 127 CD4 T 121, 122 CD4+ T 159 CD8 T 121, 122 CD8+ T 193 circulation 174 collections of 86 cytotoxic T 123 clonal expansion of 126 induction of 127 proliferation of 128 differentiation and activation 4 clonal anergy and tuning 4, 7–8 clonal deletion 4, 6 extrinsic regulation 4, 8 receptor editing 4, 6 homing receptors 174 immunoregulatory subset of 160

288

inﬁltrates of 85 liver-inﬁltrating 127 lymph nodes 193 of non–T-cell lineage 159 persistence of activated 127 portal and periportal 153 self-reactive 6 somatic genome modiﬁcation 6 of T cells 164 TCR characteristic of 128 V(D)J recombination 6 Lymphoid inﬁltration, chronic gastritis 93 Lymphoma 19, 25 B-cell 92, 93, 94, 95 gastric 94, 95 HCV-negative cells 95 HCV-positive cases of 95 MALT 93, 95 Lymphomagenesis 95 in HCV 219 Lymphomatous lesion 95 Lymphopenia 8 Lymphoproliferation 93, 95 MALT 94 Lymphoproliferative intestinal diseases 93 Lymphotoxins lymphotoxin-a1b2 3 lymphotoxin-a-deﬁcient 4 Lysine-71 158 Lysine (K) 130

M Macroglossia 64–65 Macrophage inﬂammatory protein 3 (MIP3) 5 Macrophages 63, 86, 88, 89, 159 Magnetic resonance cholangiography (MRC) 175 Magnetic resonance cholangiopancreatography (MRC) 21 Magnetic resonance (MR) 20–26 abdominal 21 angiography 21, 23, 26 applications 20–21 cholangiopancreatography 21, 24 contrast agents 23–24 endoscopic retrograde cholangiography (ERC) 24 enteroclysis 24 hydrogen atoms, relaxation properties of 20 implants and devices 24 liver 24 scanners 20 technique 20–23 vs. CT 23

Index

Major histocompatibility complex (MHC) 124 alleles of 131 class II 124 antigen-binding groove of 130, 131, 132 antigen-presenting 124 diversity of 130 effect of arginine 130 peptide-binding afﬁnity 132 genes, in PSC 171–172 molecules and complexes 7 Major histocompatibility complex (MHC), Class II antigen presentation of 158 molecules 158 Malabsorption 67, 104, 105 Malnutrition 65 MALT. See Mucosaassociated lymphoid tissue (MALT) Manometry. See Esophageal manometry Masticatory muscle weakness 64 system 103 Matrix metalloproteinases 172 Maximum intensity projection (MIP) 19, 20, 25 M cells 3, 5 MCTD. See Mixed connective tissue disease (MCTD) MDCT. See Multidetector computed tomography (MDCT) MDCT protocols 17 Medium-sized vessel vasculitis (MVV) kawasaki’s disease (KD) 90 polyarteritis nodosa (PAN) 89 vs. small-sized vessel vasculitis (SVV) 89 Megacolon 104 Merck Sharp and Dohme 253, 256 Mesenchymal cells 143 Mesenteric insufﬁciency 32–33 ischemia 19, 20, 83 vasculitis 36 vessels 20 Metabolic myopathy 63 Metastases 16 Methacronous gastric biopsies 95 Methotrexate 62, 111–112, 179–180. See also Immunosuppressive agents Metoclopramide 55, 57 MF pattern 157 MHC. See Major histocompatibility complex (MHC) Microaneurisms 196, 197 Microbubbles 16 Microchimerism 133 Microﬁlaments (MFs), of smooth muscle 154

Index

Micropolyangiitis 90 Microscopic angiitis 91 Microthrombosis 41 Microvascular lesions 109 Misoprostol 260, 263 Mitochondria 127 Mitochondrial dysfunction 67, 127 matrix 143 membrane proteins, inner 238 proteins 143–144 Mixed connective tissue disease (MCTD) 64, 218 bowel manifestations in 104 esophageal dysfunction in 103–104 gastrointestinal tract involvement in 101–102 oral manifestations in 102–103 Sjo¨gren’s syndrome, in MCTD 102 therapeutic considerations for 105 Mixed cryoglobulinemia (MC) 92–96, 210 MMP-3 (stromelysin), polymorphism of 172 Molecular footprint hypothesis 131 genotyping 171 mimicry 122–123, 144, 164 Monoclonal antibody 171 Monooxygenase 123 Mouse mammarytumor virus (MMTC) 144 MR. See Magnetic resonance MR angiography. See Magnetic resonance cholangiopancreatography (MRC) MRC. See Magnetic resonance cholangiopancreatography (MRC) MR contrast agents 23–24 mRNAs encodes, in HBV 192 MR scanners 20 Mucocutaneous lymph node syndrome 90 Mucosaassociated lymphoid tissue (MALT) 93, 95 lymphomas 212, 220 Mucosal lesion 103 membrane 64 Multidetector computed tomography (MDCT) 16–20 Multiplanar capacity 21–22 reformations (MPR) 16–18, 20, 22 Multiple X-ray transmission 16 Muscle atrophy 63, 64 biopsy 63–64 disorders, inﬂammatory 66 impairment 63, 64

289

Muscle weakness cytokine-mediated 63 pharyngeal 63 proximal 67 skeletal 66 thoracic 63 Musculoskeletal pain 243–244 management of 244, 256 in young and elderly 244 Mutant pre-core virus 204 Myalgias 204 Mycobacterial infection 84 Mycophenolate mofetil. See Immunosuppressive agents Mycophenolate mofetil 31, 32 Mycophenolate mofetil (MMF) 221 Myeloperoxidase (MPO) 91 Myocardial infarction 39 Myoﬁbroblastic cells 143 Myonecrosis 63, 65 Myopathy glucocorticoid-induced 64 metabolic 63 steroid 66 Myositis 63 autoantibodies associated with 64 in bowel 66 dysphagia in 67–68 external sphincter 66 in liver 66 oral cavity in 64–65

N Narcotics 264 Nasal regurgitations 65 National Institute for Clinical Excellence (NICE) 254 Natural killer (NK) cells 126, 159 Natural killer T (NKT) cells 128 Nd:YAG laser 56 Necrosis of arterial wall 86 of elastic ﬁbres effect on granulomatous changes 85 full-thickness 90 transmural ﬁbrinoid 89 Necrotizing angiitis 89 arteritis 89 Negative selection, of T cells 7, 8 Neoplastic diseases 19 Nephrotic syndrome 200 Nephrotoxicity, of contrast agents 23 Neurological diseases 65

290

Neuropathy 196, 197, 207 membranous 200 Neutrophil antigens 238 binding 239–240 Nexium Anti-inﬂammatory Symptom Amelioration (NASA1) 261 NF-kB 111 NF-kB (RANK) 5 NF-kB1 activation 7 NF-kB2 activity 8 Nicotine 183 Nicotinic acetylcholine receptor a7 5 NK. See Natural killer (NK) cells NKT. See Natural killer T (NKT) cells Nodosa. See Arterial nodules Non-Hodgkin lymphoma (NHL) 214 odds ratio (OR) for 219 Non-MHC immunoregulatory genes, in PSC 172 Non-organ-speciﬁc autoantibodies (NOSA) 210 Non-steroidal antiinﬂammatory drugs (NSAID) 32, 111 Noradrenergic ﬁbers 5 Novosphingobium aromaticivorans 144 NSAIDs. See Anti-inﬂammatory drugs; Non-steroidal antiinﬂammatory drugs Nuclear body protein 143 pore proteins 143 Nutritional support, parenteral and enteral 105

O Occlusion 19 Octreotide 57 Ocular tests, positive 212 Odds ratio (OR), for NHL 219 Oedema 90 Oesophageal symptoms 32 Oral anticoagulation 41 Oral cavity 64–65 ulcers 31–32 Oropharyngeal dysphagia 65 Oropharyngeal muscles 65 Orthotopic liver transplantation (OLT) 184 Osteoarthritis (OA) 244 Over the counter (OTC) analgesics 244 Oxidative stress 239 OX40L 9 2-oxoglutarate dehydrogenase complex (OGDC) 143

Index

P PAN. See Polyarteritis nodosa (PAN) Panarteritis 85, 92 Pancreatic ducts 24, 34 exocrine deﬁciency 110 Pancreatitis 37, 67, 105 Pan-cytopenia 179 P-ANNA (anti-neutrophil nuclear antibody) 171 Paracetamol 87, 247, 255 and NSAIDs 264, 265 use of 265 Paralytic ileus 90 Paraneoplastic phenomenon 64 Parvovirus B19 196 PBC. See Primary biliary cirrhosis (PBC) PCR, detection 219 PDC-E2. See E2 subunit of pyruvate dehydrogenase complex (PDC-E2) PD1 proteins 7 Pentagastrin 257 Pentoxifylline 180 Peptic ulcer bleeds (PUBs) 251 disease (PUD) 111, 243, 245 Percutaneous transluminal angioplasty 20 Perforation 32, 40, 67, 110, 111 Perforation, spontaneous. See Spontaneous perforation Perforin 127 Periaortal ﬁbrosis 88 Periaortic tissue mass 88 Peritonitis 83 Peroxisome proliferatoractivated receptor-gamma (PPAR-g) 192 Persistent reﬂux 105 Perturbations in activation signals 124–126 apoptotic pathways 127–128 in the cytokine network 126–127 PET. See Positron emission tomography Peyer’s patches 3, 5 Phagocytes 6 Phosphatase 7–8 Phospholipids 39 PI. See Pneumatosis intestinalis (PI) PIM2 8 Pituitary hormones 133 Plain abdominal ﬁlms 15

Index

Plasma cell inﬁltrate 153 cells 85, 86, 88 exchange 198, 199 Plasmapheresis 67, 93 Platelet antiaggregants 34 PLUTO and VENUS studies 262 PMN. See Polymorphonuclear (PMN) leukocytes Pneumatosis cystoides intestinalis 36–37, 58 intestinalis (PI) 104 Pneumoperitoneum. See Pneumatosis cystoides intestinalis Polyarteritis nodosa (PAN) 89, 195–204, 217 vs. cryoglobulinemia 218 Polyarthrtis, chronic inﬂammatory 212 Polymorphonuclear inﬁltrate 104 Polymorphonuclear (PMN) leukocytes 86 Polymyositis 63–67, 103, 105 Porphyria cutanea tarda 202 Portal hypertension 110, 145, 146, 177 Portal inﬂammation 146 Porto-systemic shunts 177 Positive selection, of T cells 7 Positron emission tomography (PET) 25–26 Power dopplers 16 PPI. See Proton pump inhibitors Predilection of female 133–134 Prednisolone 162 Prednisone 32, 35, 85, 86, 87 Pretransplant chemo-radiation 43 Primary biliary cirrhosis (PBC) 66, 121, 133. See also Autoimmune liver diseases AMA-negative vs. positive 146 autoimmune hepatitis 125 bacterial pathogens 144 cohort studies of 147 colchicine in 181 diagnosis of 143, 145–146 and DRB1*0801 130 effect of genetic factors 129 fatigue of 145 genetic associations in 130 and HLA 142 methotrexate toxicity in 180 mouse model for 144 and oral contraceptive use 145 population studies on 141–142 pregnancy as a risk factor for 144 pruritus of 145 rheumatoid arthritis and thyroid disease in 145

291

stages 146 treatment of 147–148 T-reg cell function in patients of 126 ursodeoxycholic acid (UDCA) treatment in 181 Primary sclerosing cholangitis (PSC) 129, 131. See also Autoimmune liver diseases cellular immune abnormalities in 172 and cigarette smoking 183 complications management of 178 diagnosis 175 and inﬂammatory colitis 174 tissue injury in 172, 175 Probiotic therapy 57 Proctocolectomy 174, 177 Prodromal pre-icteric syndrome 194–195 Professional rheumatologic societies 112 Progesterone 133 Programmed cell death. See Apoptosis Prokinetic agents 51, 54 Prolactin 133 Promiscuous immunocyte activity 123–124 Properdin 85 Prostaglandin E2 (PGE2) 257, 258 Prostaglandin (PG) analogues 256, 260 production 257 synthesis 246, 251 Prostanoids 111 Proteinase 3 (PR3) 91 Protein-loosing enteropathy 93, 104, 246 Protein-losing gastroenteropathy (PLGE) 36 Proteinuria 179, 200–201 Protocols abdominal 21 MDCT 17 Proton-pump inhibitor (PPI) 245, 254, 260–261, 262 and NSAID 252 as treatment of upper GI symptoms 261 Proton pump inhibitors 32, 54, 105 Proximal muscle weakness 67 Pruritus 145 PSC. See Primary sclerosing cholangitis (PSC) Pseudomonas aeruginosa 144 Pseudo-obstruction 105 PSS, patients 103 Pulmonary embolism 39 ﬁbrosis 112 infection 67 Pulsed dopplers 16

292

Pulseless disease 84, 85 Pulselessness. See Pulseless disease Pyrimidines 112

R RA. See Rheumatoid arthritis (RA) Radioimmunoﬁltration (RIFA) 239 Radiologist 16 RAVE 92 Raynaud’s phenomenon (RP) 104, 145 Recombination-activating gene (RAG) 6, 7 Rectal incontinence 66 prolapse 59 Regulatory cells with suppressor functions, deﬁciencies in 128 Regulatory networks, deﬁciencies in 124–128 Relapsing polychondritis (RP) 218 Relative risk reduction (RRR) 252 Renal ADRs 253 disease 91 failure 215 transplantation 32 vessel occlusion 67 Resistive indices 16 Respiratory syncytial virus 202 Reticuloendothelial contrast agents 23–24 Revascularization, surgical 34 Rheumatic diseases 67, 103 Rheumatoid arthritis (RA) 145, 212–213 associated esophageal disease 110–111 complications of 110 gastrointestinal system in 110 GI manifestations in 107–109 hepatotoxicity 111 hipple’s disease for 114 mechanism and side-effects of therapeutics modalities of 113–114 NSAIDs treatment for 111 predominance of the CD4+ T-helper lymphocyte subset 1 109 secondary amyloidosis in context of 110 secondary GI syndromes in 110 systemic manifestations of 109 therapy 109, 112 use of methotrexate in 111 whipple’s disease for 114 Rheumatoid factor (RF) 95, 209, 212 Rheumatoid vasculitis 109, 110 RIBA-2 213

Index

Ribavirin 93, 216 Ribonuclease sensitive component (RNP-ribonucleoprotein) 101 Ribonucleoprotein complex 123 Rituximab 221–222 Rockefeller Institute 141 Rofecoxib 253, 255–256 Rotavirus protein VP-7, 235 Royal College of Physicians (UK) 264 Royal Free Hospital 179

S Sacral nerve stimulation 59 Saliva ﬂow rate 64 Salivary gland biopsy 102, 103 positive 212 Salivary secretion, in MCTD 102–103 Salmonella 260 Sarcoidosis 215 by anti-viral therapy 215–217 cutaneous 217 treatment-naı´ ve patients 217 Scanners 16, 20 Scleroderma 103, 104 esophageal dismotility 101 Scleroderma Gastrointestinal Tract 1.0 (SSC-GIT 1.0) 59 Sclerosing cholangitis 67 Self-antigens 121, 123 Self-reactive lymphocytes 6, 8 extrinsic controls of 8 regulation of 9 self-tolerance 6, see also tolerance Self-reactive receptors 6–7 Self-tolerance 6 effect of antigens on 123 effect of host-dependent factors on 121 effect of microchimerism on 133 effect of multiple exposure to viruses on 123 loss of 121 Sepsis 35 Seroconversion 198–199, 200 Serological markers 232–233 of AIH 236 Serological tests 233, 234, 235 Serositis 31, 33, 35 Serotypes, HBV 201 Serum biochemical tests 175 carotene 57 creatinine level 91

Index

determinations 126 IgG4 levels 175 marker 178 muscle enzymes 63 thyroxine, level 203 Serum aminotranferases level 145 Serum amyloid A (SAA) 110 Serum bilirubin 180 levels 147–148 Sex hormones 133 immune-modulating effects of 129 Shared motif hypothesis 131 Sialoadenitis, focal 102 Sialopenia 103 Sicca manifestations 110 Sicca symptoms, in MCTD 102 Single-nucleotide polymorphism (snp) 172 Sjogren’s syndrome (SS) 32, 145, 211–212 associated esophageal disease 110–111 vs. chronic HCV infection 95 in MCTD 102 secondary 62, 64, 65, 67 Skin biopsy 90 lesions 197, 202 rash 63, 201 polymorphous erythematous 90 SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) 32–33 Small bowel anatomy of 24 diseases 24 loops 19, 21 Small-sized vessels vasculitis (SVV) 90–92 Smoking, toxic compounds 145 Smooth muscle antibodies (SMA) 236, 237 Soluble cell adhesion molecules (sICAM) 181 liver antigen (SLA) 157 Somatic hypermutation 6, 9 Somatostatin analogue 57 Spasmolytic drugs 87 Spectral dopplers 16, 17 Splenomegaly 110 Spontaneous perforation 104 SS-HCV Study Group 211 Steatosis 111, 112, 211 Stem cell transplantation, autologous 92 Stenosis of aortic branches, signs and symptoms of 84 Stenotic lesions 85 Stent placement 20

293

Steroids 66, 85, 87 and NSAID 245, 246 oral 245, 246 side effects 162–163 tapering 92 treatment 88, 89, 92 use of 246 Sterol regulatory element binding protein 1 (SREBP1) 192 Still disease 218 Stimuli, autoantigenic and allogeneic 164 Striated muscle, inﬂammation of 64, 65 Stromal ﬁbroblasts 193 Subepithelial dome 3 Submucosal hemorrhage 19 Superior mesenteric artery (SMA) 21–22 Surgical procedures 178 Surveillance colonoscopy 177, 183 Surveillance endoscopy 55 Symptom Prevention by Acid Control with Esomeprazole (SPACE1) 261 Synergy. See Epistasis Synovitis 111 Synovium, inﬂammation of 109 Systemic autoimmune diseases (SAD) 209, 211, 218 Systemic immunity 5–6 Systemic lupus erythematosus (SLE) 9, 39, 44, 45, 89, 103, 145, 213–214. See also Autoimmune diseases diagnostic criterion 31 general symptoms 31 mild 213 patients with 104 true 213 Systemic sclerosis (SSc) 64, 67, 103, 104, 105 anorectal involvement in 58–59 colonic involvement in 58 esophageal involvement in 52–55 Systemic Churg–Strauss vasculitis 218 cryoglobulinemic vasculitis or syndrome 92 disappearance of, features 93 gastrointestinal (GI) involvement in 83 giant cell arteritis (GCA) 85–87, 218 Henoch–Scho¨nlein purpura 218 polyarteritis nodosa (PAN) 89 steroids 32 Takayasu’s arteritis 218 vasculitides 195, 197, 200 vasculitis 217–218

294

T TA. See Takayasu’s arteritis (TA) Tacrolimus (FK 506) 32, 180 Takayasu’s arteritis (TA) 84–86 T cells 158 ab 84 activation 235 auto-reactive 158 and B cells, autoreactive 143 CD4 + 86 cytotoxic 124 gd, role in takayasu’s arteritis 84 immune response 172 self-reactive 158 T cells, autoreactive 7, 9 T cell antigen receptor (TCR) 123 a- and b-chains 124 of activated immunocytes 129 characteristic of lymphocytes ,co-expression of 128 degree of diversity within 124 effect of germline polymorphisms 124 of effector cells 124 ligand 124 of liver-inﬁltrating immunocytes 124 polymorphisms 124 T cell receptor (TCR) 172–173 gene rearrangements 173 polypeptides 173 V gene segments 173 T cells bearing a speciﬁc beta chain variable region (TCRBV3) 145 TCR. See T cell antigen receptor (TCR) Temporomandibular joints 103 Teslas (T) 20 Testosterone 133 Th1 cells 159 Therapeutic protocol 215 Thrombocytopenia 39, 41, 219 Thromboembolic disease, in IBD patients 41 Thromboembolism 46 Thrombosis 19, 67, 86, 196 arterial 39 splenic arteries thrombosis 43 microthrombosis 41 thromboembolism 46 thromboses, arterial and venous 39, 40 venous deep venous 39, 41 hepatic vein 42 portal vein 44, 45 Thymic cortical epithelium 7

Index

Thyroid gland dysfunction, in HCV 203 hormones 203 Thyroiditis 210 Thyrotropin-releasing hormone-stimulation test 203 Thyroxine and triiodothyronine binding 203 Tissue autoantibodies 163 harmonic imaging 16 transglutaminase type 2 (tTG2) 234 T lymphocytes 63, 159, 172 activation 240 self-reactive 109 TNF alpha blocking agents 92 etanercept, as receptor of 85, 92 inhibition 85 TNF-a 109 TNF-a receptor-1(TNF-R1) 127 TNFRSF. See Fas gene [tumor necrosis factor receptor super family (TNFRSF)] Tolerance mechanisms 6–7. See also Self-tolerance Toll-like receptors (TLR) microbial TLR agonist 9 TLR9-induced differentiation 7 TLR ligands 4, 7, 9 Toll-like receptor 4 (TLR4) 235 Tonsillectomy 91 Traditional NSAIDs (tNSAIDs) 245, 256, 263 Transaminases elevation 154, 155, 163 levels of 154, 162 Transamine (GPT and GOT) levels 197 Transducers 15–16 Transfer ribonucleoprotein complex (tRNP) 238 Transforming growth factor-b(TGF-b) 15, 126, 159 T regulatory cells (T regs) 159–161 deﬁcient 144 Trichuris 5 Trimethoprim-sulfa 114 tRNA suppressor associated antigenic protein (tRNP(Ser)Sec) 157 TRNP(Ser)Sec 123 Tropheryma whipplei 114 Tru-cut biopsies 19 Trypsinogen 37 Tuberculosis. See Mycobacterial infection Tumor necrosis factor-a 5, 126, 159, 171, 180, 249 Tunica media 85, 86 Tuning. See Biochemical tuning Type 2 (Th2) cytokine, pathway 126 Tyrosine phosphatase CD45 gene, mutation of 125, 126

Index

U Ubiquitin ligases 8 UDCA therapy 146, 147 UGA tRNA 157 Ulceration 67, 110, 111 Ulcerative colitis (UC) 66, 231, 238, 249 Ulcer bleeding 245, 247 incidence 254 Ultrasonography. See Ultrasound (US) Ultrasound (US) 15–16 Unmethylated CpG dinucleotides 9 Uraemia 31 Ureterohydronephrosis, bilateral 33, 35 Uridine diphosphate glucuronosyltransferase (UGT) 237 Uridine triphosphate glucuronosyltransferase 123 Ursodeoxycholic acid (UDCA) 181–183 US. See Ultrasound (US)

V Vagous nerve 5 Valdecoxib 253, 256 Vasa vasorum 85, 86 Vascular anatomy, visualization of 19–20 cell adhesion molecule-1 (VCAM-1) 84, 85 Vasculature, mesenteric and hepatic 89 Vasculitic appendicitis 90 lesions, in HBV 196 Vasculitis 64, 67, 104 acute intestinal 83 hypersensitivity 84 necrosis of the bowel wall due to 104 primary and secondary 83 spontaneous perforation associated with 104, 106 Venous thrombosis, deep 39, 41 Venules 89, 90 V gene segments, of TCR 173

295

VGT-MF pattern 157 VGT patterns 157 Vidarabine 199 Videoﬂuoroscopy 15 Videomanometry 65, 66 Villous atrophy 66 Villus–crypt unit 4 Vioxx Gastrointestinal Outcomes Study (VIGOR) 251–253, 255 Viral hepatitides, B and C 154 Vitamin D receptor (VDR) gene 125 Volume rendering (VR) 20

W Watermelon stomach. See Gastric antral vascular ectasia (GAVE) Wegener’s granulomatosis (WG) 89 Welsh community survey 244 WG etanercept trial (WGET) 92 Whipple’s disease 112, 114 Wilson disease 154, 155 Wiskott-Aldrich syndrome 8

X Xanothomatous biliary cirrhosis 141 Xanthelasma 146 Xenobiotics 144 Xerophtalmia 212 Xerostomia 102, 212 X protein, in HBV 192

Y Yersinia enterocolitica 110 Yersinia pseudotuberculosis 110

Z Zenker’s diverticula 65

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Pulmonary Involvement in Systemic Autoimmune Diseases, Volume 2 (Handbook of Systemic Autoimmune Diseases)

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