Inflammatory bowel disease, Volume 21

Inflammatory Bowel Diseases Editor Jürgen Schölmerich, Regensburg 23 figures, 2 in color, and 28 tables, 2003 Basel...

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Inflammatory Bowel Diseases

Editor

Jürgen Schölmerich, Regensburg

23 figures, 2 in color, and 28 tables, 2003

Basel 폷 Freiburg 폷 Paris 폷 London 폷 New York 폷 Bangalore 폷 Bangkok 폷 Singapore 폷 Tokyo 폷 Sydney

S. Karger Medical and Scientific Publishers Basel 폷 Freiburg 폷 Paris 폷 London New York 폷 Bangalore 폷 Bangkok Singapore 폷 Tokyo 폷 Sydney

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2003 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7647–1

Vol. 21, No. 2, 2003

Contents

Editorial 83 Inflammatory Bowel Diseases 2003 – From Genetics to Biological Therapy Schölmerich, J. (Regensburg)

Review Articles 85 Genetics of Inflammatory Bowel Diseases – Past, Present, and Future Peña, A.S. (Amsterdam) 91 Environmental Influences on Inflammatory Bowel Disease

Manifestations. Lessons from Epidemiology Timmer, A. (Regensburg) 105 Rationale for Probiotic and Antibiotic Treatment Strategies in

Inflammatory Bowel Diseases Schultz, M.; Schölmerich, J.; Rath, H.C. (Regensburg) 129 New Diagnostic Avenues in Inflammatory Bowel Diseases. Capsule

Endoscopy, Magnetic Resonance Imaging and Virtual Enteroscopy Schreyer, A.G.; Gölder, S.; Seitz, J.; Herfarth, H. (Regensburg) 138 Osteoporosis and Other Extraintestinal Symptoms and Complications

of Inflammatory Bowel Diseases Reinshagen, M.; von Tirpitz, C. (Ulm) 146 Standard Therapy of Crohn’s Disease Miehsler, W.; Gasche, C. (Vienna) 157 Standard Treatment of Ulcerative Colitis Gionchetti, P.; Rizzello, F. (Bologna); Habal, F. (Toronto); Morselli, C.; Amadini, C.; Romagnoli, R.; Campieri, M. (Bologna) 168 Surgery for Inflammatory Bowel Diseases McLeod, R.S. (Toronto) 180 Biological Therapy in IBD. Anti-Tumor Necrosis Factor-Alpha and Others Schölmerich, J.; Huber, G. (Regensburg)

192 Author Index and Subject Index

© 2003 S. Karger AG, Basel Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

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Editorial Dig Dis 2003;21:83–84 DOI: 10.1159/000073240

Inflammatory Bowel Diseases 2003 – From Genetics to Biological Therapy Jürgen Schölmerich Department of Internal Medicine I, University Medical Center Regensburg, Regensburg, Germany

Although chronic inflammatory bowel diseases (IBD) have been described in the modern medical literature for more than 100 years, their etiology and pathogenesis are still not completely understood. In spite of this, prognosis has improved significantly. While in the 1950s only about 80% of patients survived more than 10 years, in the mean time age-adapted survival has become almost or completely normal. The last decade has evidenced much progress in the field and new findings regarding genetic susceptibility, environmental influences, the role of bacteria, new diagnostic techniques and, in particular, new treatments have evolved. This issue of Digestive Diseases comprises a series of articles dedicated to the state of the art of the etiology, pathogenesis, diagnosis, clinical presentation, and treatment of IBD. There is an abundance of evidence for a polygenic susceptibility to IBD. Most recently, the first gene where a mutation leads to manifestation of Crohn’s disease was described, and several other candidates are being discussed. The most recent developments and the limitations of the information on the genetic basis of IBD are also discussed. The fact that a number of temporal and geographical trends and distributions point to risk factors associated with defined life-styles has led to the suspicion that environmental factors play an important role in disease manifestation and, in addition, regarding the course and prognosis. Numerous studies have been performed on factors such as diet, smoking and infectious agents. Lately, the

ABC

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‘hygiene hypothesis’ which indicates that childhood exposure to a high hygienic level increases the risk of developing Crohn’s disease later in life has gained wide acceptance. Smoking has been found to increase the risk of Crohn’s disease and decrease that of ulcerative colitis. Furthermore, appendectomy seems to decrease the risk of developing ulcerative colitis later in life. All these genetic and environmental effects have not yet been set up completely into a defined picture, but the mosaic seems to be gaining pieces. Both data from genetic and environmental studies point to the role played by bacterial flora in the manifestation and perpetuation of intestinal inflammation. Numerous animal experiments have proven that the presence of intestinal bacteria seems to be a necessary prerequisite for the manifestation of inflammation in almost all models of IBD. Furthermore, the effects of antibiotics and probiotics in experimental models and in some aspects of clinical IBD support an important role of bacteria in the pathophysiology of IBD. During the last decade, imaging procedures such as computed tomography and magnetic resonance imaging have provided us with amazing possibilities. In addition, capsule endoscopy has opened up avenues enabling visualization of the small bowel way beyond earlier expectations. Although it is not yet clear to what extent conventional radiological techniques or even endoscopy will be substituted by these new modalities, it is obvious at the moment that small bowel imaging will probably be done using magnetic resonance imaging and/or capsule endos-

Prof. Dr. Jürgen Schölmerich Department of Internal Medicine I, University Medical Center Regensburg DE–93042 Regensburg (Germany) Tel. +49 0 941 944 7001, Fax +49 0 941 944 7002 E-Mail [email protected]

copy. In contrast, the large bowel will probably remain the domain of endoscopy as biopsy taking is only possible with real endoscopy. It is not clear at the moment to which extent magnetic resonance imaging will be able to replace other techniques regarding the assessment of disease activity. There are a number of extraintestinal symptoms and complications in IBD. Among them, osteoporosis, which can be due to the disease itself or to treatment, remains prominent. There is still no consensus on the treatment of osteoporosis in patients with IBD and there is a lack of sufficient knowledge regarding the treatment of some extraintestinal manifestations. In contrast, extraintestinal complications which are due to the lack of gut function can be detected and treated accordingly when the pathophysiological principles are known to the patients or physicians. Standard treatment of Crohn’s disease and ulcerative colitis is relatively uniform and agreed upon worldwide. It has been tested for safety and efficacy in controlled clinical trials. However, there is the need and opportunity to adapt therapies to individual cases based on scientific facts and recent thinking, weighing up the potential effects against any side effects. Treatment concepts regarding active disease and maintenance of remission have been agreed upon in consensus guidelines; 5-aminosalicylic acid, corticosteroids, immunosuppressants, probiotics and antibiotics and Infliximab, an anti-TNF antibody, play a role. In spite of the success of these conventional treatments, surgical therapy is still required in a large proportion of patients with ulcerative colitis and Crohn’s disease

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at some time during their life. The need for surgery should probably not be perceived as a failure of medical therapy but rather be viewed as a reasonable part of the therapeutic arsenal for those disorders. Improvements in surgical therapies have certainly added to the normalization of lifetime prognosis in both patient populations. ‘Biological therapies’ based on new knowledge of pathophysiology are being tested worldwide to a surprising extent. Only infliximab, a chimeric antibody to tumor necrosis factor-·, has been introduced into the routine arsenal. Many of the approaches have not been found to be clinically relevantly effective although they show ‘biological activity’. This may be due to the fact that the arsenal of inflammatory cells and mediators is comparable to an orchestra which will not be silenced by eliminating a single instrument. The conductor of the orchestra has not yet been found and it seems doubtful that it will ever be when we consider different genotypes and consequently phenotypes of those disorders which are the basis of different effects of drugs. In summary, there is much progress regarding inflammatory bowel disease. We still need to define more of the genotypes which will be much easier due to the knowledge of the human genome. We will then have to define treatments for the different genotypes/phenotypes and thus improve the quality of life of our patients which nowadays have a normal life expectancy. It is to be hoped that this issue of Digestive Diseases provides the necessary information for clinicians and researchers to advance our knowledge on IBD and its treatment possibilities.

Schölmerich

Review Article Dig Dis 2003;21:85–90 DOI: 10.1159/000073241

Genetics of Inflammatory Bowel Diseases – Past, Present, and Future A.S. Peña Gastroenterology and Immunogenetics, VU University Medical Center, Amsterdam, The Netherlands

Key Words Inflammatory bowel disease W Ulcerative colitis W Crohn’s disease W Genetics W Genetic epidemiology W Candidate gene approach W Genome-wide screening

Abstract In this review, the evidence to support the multifactorial and polygenic nature of the disease is briefly described. The past of genetics of inflammatory bowel disease (IBD) is characterized by unfulfilled promises and is now closed with a new vision and a new promise coming from a genetic epidemiology approach. The genomewide screening has led to the first gene of IBD and has given a new insight into the regulation of chronic inflammation. The future of IBD will be under scrutiny of the visionaries, but also the skeptics and the enthusiasts. Copyright © 2003 S. Karger AG, Basel

Introduction

Ulcerative colitis and Crohn’s disease are complex diseases of unknown etiology. Several genes are involved in the susceptibility. To suffer from these diseases, certain genes in different chromosomes are necessary, but they are not sufficient by themselves to cause these diseases. There is firm evidence that inflammatory bowel diseases

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(IBDs) are multifactorial and polygenic in nature. Within the multifactorial component, the risk factors that have been identified up to date are not strongly associated with either ulcerative colitis or Crohn’s disease. It is very likely that both serological markers and genetic factors which have been described in different patient populations, identify subgroups of patients who may not have been properly identified and defined [1, 2]. For example, IgG perinuclear antineutrophil cytoplasmic antibody (pANCA), IgA and IgG against Saccharomyces cerevisiae mannan antibodies (ASCA), antibodies against pancreas (PAB) were shown to be independently associated with early age at onset of the disease, as well as fibrostenosing and internal penetrating disease behaviors. Higher ANCA levels were associated with later age at onset of disease and ulcerative colitis-like behavior. Substratification of the Crohn’s disease population has been possible by using the presence of high levels of ANCA and ASCA expression: (1) this combination has identified homogeneous subgroups which manifested similar disease location and inflammation behavior, and (2) identified patient subgroups with more aggressive small bowel disease [3]. To minimize invasive diagnostic procedures, which is important particularly in children with IBD, the combined testing of ANCA and ASCA represent a valuable tool in the differential diagnosis between ulcerative colitis and Crohn’s disease.

Prof. A.S. Peña Gastroenterology and Immunogenetics, VU University Medical Center Amsterdam (The Netherlands) Tel. +31 20 444 705, Fax +31 20 444 737, E-Mail [email protected]

The sole monitoring of ANCA, its specificity and titer determination does not add to the information obtained with standard procedures. Testing for specific IgE to food allergens may be considered in individual patients [4]. The combination of a positive ASCA and a negative pANCA predicts Crohn’s disease in 80% of patients with indeterminate colitis and the combination of ASCA-negative and pANCA-positive predicts ulcerative colitis in 63.6% of these patients. Interestingly, 48.5% of patients do not show antibodies against ASCA or pANCA. Most of these patients remain diagnosed with indeterminate colitis during their further clinical course; possibly they form a distinct clinical-serological subgroup [5]. In 279 patients with Crohn’s disease who had been treated with infliximab, neither the presence of ASCA nor pANCA has been able to predict a response to the treatment. However, the combination of pANCA-positive and ASCA-negative in patients with refractory luminal disease may warrant further investigation of these markers as to predicting a nonresponse [6]. When compared with healthy controls and patients with infectious enterocolitis, the prevalence of ASCA was significantly increased in patients with Crohn’s disease and first-degree relatives [7]. The combination of positive ANCA, negative ASCA and negative serum agglutinating antibodies to anaerobic coccoid rods increased the positive predictive value and specificity in ulcerative colitis, the combination of negative ANCA and positive ASCA with positive antibodies to coccoid rods increased the positive predictive value and specificity in Crohn’s disease. In this disease, the presence of positive pANCA was correlated with colonic involvement. No correlation was found between the presence of any of these three different antibodies and the disease activity, the duration, the behavior of the inflammation or the response to medical treatment [8]. The role of these antibodies in the pathophysiology of IBD still needs to be assessed as well as the need to identify the ASCA immunogen(s) that gives rise to the antibody response [9]. There is accumulating evidence that the inflammatory response in patients with IBD is abnormal. Therefore, the study of genes that are involved in the regulation of the inflammation may help to clarify the pathogenesis of the disease. Recent advances in the treatment of IBD have contributed to enhance the significance of the studies directed to unravel the genetics of the immune response. Some of the new biological agents are directed to modulate the TH1 and TH2 balance of the inflammatory response. One way to monitor their efficacy could be to study the effects of these therapeutical agents on the cytokine levels and/or production. Unfortunately, this meth-

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od is not recommendable in general because of the lack of a good correlation between blood levels of cytokines and the intestinal inflammation. Also, it is not always possible to measure local cytokine levels and even when possible, invasive techniques would be needed. Nevertheless, stable variations in the production rates of cytokines between individuals have been observed. Also, significant increases within both high and low producers of cytokines in response to infections or other proinflammatory stimuli are reproducible. The interindividual differences in cytokine production are associated with polymorphisms of cytokine genes that regulate the transcription or translation of the cytokines. The genetic variability of the inflammatory process could be the basis to select patients for specific immunomodulation therapy. This hypothesis is based on observations suggesting that polymorphisms involved in the regulation of inflammation such as HLA and cytokine gene polymorphisms, will determine the heterogeneity of the disease and prognosis. Genetic studies will contribute to define multifactorial diseases more precisely. The classification of diseases will be based on subgroups of patients with different prognosis and etiology.

The Past: Unfulfilled Promises

The expectations were that functional polymorphisms of cytokine genes and HLA profiles would help the doctor to select and monitor ‘old and new’ specific therapies. Also, that specific immunomodulatory therapy might not only be more effective for certain patients but less harmful in patients with intolerance to a specific biological agent. The so-called tailor-made medicine would then be made possible. Examples of this aspect in research are the phenotype frequencies of the HLA-DRB1 alleles in selected groups of patients and matched controls: 35 unrelated patients with Crohn’s disease with confirmed perianal fistulas showed a striking decrease of the HLA-DRB1*03 allele in comparison with healthy controls. The HLADRB1*03 allele is in strong linkage disequilibrium with a polymorphism at position -308 in the promoter region of the TNF-· gene (TNF-·-308*2). Surprisingly, the phenotype frequency of TNF-·-308*2 was 29%. The frequency was not different from the one observed in 98 matched healthy controls. This finding still needs confirmation in a larger sample size [10]. Other studies confirmed that HLA-DRB1*0103 and HLA-DR2 (DRB1*1502) are involved in the susceptibility for ulcerative colitis. HLADRB1*03 and HLA-DR4 may be markers for resistance

Peña

to treatment in Crohn’s disease and ulcerative colitis, respectively [11]. The biological significance of the determination of HLA studies to understand the variability of the inflammatory process can be seen in other diseases; HLA-DRB1 and HLA-DRB3 specificities in sarcoidosis patients identified that the presence of HLA-DRB1*03 favors a course of disease which is associated with Lofgren’s syndrome [12]. Also the presence of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly associated with the presence of HLA-DRB1*03 and HLADQB1*02 in patients with primary Sjögren’s syndrome [13].

The Importance of Subgroups in IBD

In the past, in the present and in the future one of the more important aspects for treatment of patients with inflammatory bowel disease is the search for the identification of patient subgroups. This is not only important for the management of acute and subacute episodes but also for establishing the long-term prognosis, particularly for those patients at risk of frequent relapses. In spite of the introduction in the 1950s of glucocorticosteroids for the treatment of acute attacks which has decreased the mortality rate of the disease, not all patients respond. The prevention of relapse and recurrence continues to be a challenge. The search for biological markers is not easy. Findings of associations of markers with subgroups of patients are influenced by selection bias, recall bias, misclassification and confounding. Timmer and Sutherland [14] have summarized the importance of identifying patient subgroups as follows: (1) Aid in the interpretation and design of clinical trials. (2) Control of confounding risk factors by study design or analysis will enhance comparability of studies. (3) Inclusion of patients with a high risk of relapse will only increase the efficiency and power of randomized clinical trials on maintenance therapy in IBD. (4) Could guide treatment decisions. (5) Improve the cost-benefit relationship. (6) The overall prognosis of the disease could be improved through lifestyle changes. (7) The prediction of relapse may alleviate the psychological burden that constant fear of incapacitating phases of disease activity poses to the often young and active patient. IBD research in association studies on candidate genes has been characterized by non-replication of results and the inclusion of a limited number of genes. The vision expressed by Tabor et al. [15] in relation to the candidategene approach in multifactorial diseases is very relevant

Genetics of Inflammatory Bowel Disease

in IBD. These authors have argued that the use of epidemiological principles in the selection, analysis and interpretation of candidate genes and DNA sequence variants should also be applied to candidate-gene studies. The biological plausibility, the strength of association, the doseresponse relationship and the consistency are the rules of the game.

Epidemiological Criteria for Gene-Association Studies According to Tabor and Coworkers

Biological plausibility of association and its consistency with existing knowledge about biology and disease etiology are evaluated. Is the candidate gene likely to be involved in the phenotype? Are the single-nucleotide polymorphisms (SNPs) likely to have functional effects on the protein? The strength of the association between the risk factor and the disease is examined. When considering multiple SNPs in a candidate gene, the ones with strongest association are most likely to be causally related. The dose-response relationship of the association is considered. For example, individuals with two copies of a variant might be at greater risk of disease than individuals with one copy of the variant. The consistency of the association across past and future studies, and across different populations, is an important consideration. Consistent replication in different populations is strong evidence of causality. Lack of replication does not necessarily imply lack of causality, but might point to the need for more studies in certain populations or more detailed study of the function of a particular gene. The above-mentioned rules should not be ignored and it is obvious that the lack of adherence to these genetic epidemiological principles explain the unfulfilled promises of the expectations of the past.

The Present: Incomplete Knowledge; Genetic Research Provides a New Focus

The genome-wide approach studies lead to a gene coding for NOD2, the now called CARD15 gene, the first gene involved in the susceptibility of Crohn’s disease. The genome-wide studies in IBD have already confirmed the polygenic and multifactorial nature of the diseases [16–18]. It was originally thought that CARD15/ NOD2 was only expressed in monocytes but recent evi-

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dence demonstrates its expression in intestinal epithelial cells as well [19, 20]. It is now known that mutations in the CARD15 gene may serve as a key component of innate mucosal responses to luminal bacteria. Failure in this activity may contribute to the development of Crohn’s disease [19]. Mutations of intestinal genes regulating the innate immunity are influenced by the microbiological ecology of the individual. Therefore, the frequency of the mutations will vary in different populations. For example, a single nucleotide polymorphism (Asp299Gly) in the Toll-like receptor-4 (TLR-4) gene that affects the responsiveness to lipopolysaccharide in humans is present in about 10% of the western population [21], but this mutation could not be detected in 275 subjects of the Japanese population [22], neither in a similar number of subjects in China [Xia Bing, Wuhan, pers. commun.]. Similarly, concerning the NOD2/CARD15 mutations, a novel haplotype conferring risk for Crohn’s disease has been found only in Ashkenazi Jews [23], and the frequent mutations found in the western population do not exist in the Japanese [24, 25], Korean [26] or in the Cretan populations of patients with Crohn’s disease [27].

D299G mutation, affecting the LRR domain of TLR4, is associated with a blunted response to inhalated LPS with a dominant genetic effect. An increased expression of this receptor in the epithelial cells of patients with IBD is related to intestinal flora [29]. Other products of intestinal bacterial flora such as peptidoglycan of gram-positive bacteria are able to stimulate specific receptors, the family of NOD proteins of the cytoplasm of antigen-presenting cells, which are also characterized by the presence of LRRs. Both receptors are able to stimulate the NF-ÎB, a key immunoregulatory molecule that regulates the inflammatory response [36]. The presence of caspase-activating regions in NOD proteins suggests their importance in apoptosis [31, 37, 38]. From the clinical significance point of view and from the basic science, the story is still incomplete. At present it can be concluded that the findings of the research in the genetics and immunology (immunogenetics) are leading to a deeper understanding of the biology and pathophysiology of inflammatory bowel disease.

The Future: The Visionary, the Enthusiast, and the Skeptic [39] The Importance of the Innate Immunity in IBD

The findings on the genetic susceptibility of Crohn’s disease have shifted the focus of research in this disease from the acquired immunity to the innate immunity [28– 31]. Advances on the innate immunity and its relationship with the acquired immunity are providing a good insight in the mechanisms that control the inflammation in the gut. The identification and functional characterization, including the discovery of mutants which completely abolish nuclear factor-ÎB (NF-ÎB) signal transduction, like the extracellular Toll-like receptors (TLRs) and the intracellular NOD/CARD receptors, are providing a new insight into the relationship of the bacteria and the host and into the relationship of the bacteria and the development of disease [32, 33]. The Toll-related proteins, of which 10 have been identified, are highly conserved through evolution and are expressed in both enterocyte and immune cells. They recognize specific microbial components through leucine-rich region domains (LRRs), such as surface determinants, lipopolysaccharide (LPS) of gram-negative bacteria (TLR2 and TLR4) and unmethylated CpG DNA sequences (TLR9). Their activation induces the production of T-helper 1 (TH1) cytokines through a process dependent on NF-ÎB [34, 35]. LPS and the lipid A fraction of LPS is recognized by TLR4. The

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‘Gene Expression Data have the Potential to aid accurate, individualised, prognosis’ Gene predictors, The Lancet 2003, 361 (9369)

IBD is clinically heterogeneous, with varying natural history and response to treatment. As described in the previous sections, despite much effort to identify genetic, serological markers and clinical measures of risk, methods to accurately predict a patient’s clinical course are not yet available. Gene-expression profiling by DNA microarrays produce gene-expression measurements for thousands of genes simultaneously. It is to be expected that genetic information from DNA and RNA microarrays will lead to a deeper understanding of the molecular pathways that cause chronic inflammation and in turn will help to design drugs with a clearer rationale. As Gordon Duff [39] has stated: ‘The ability to screen for genetic susceptibility, brings with it the possibility of modifying risk by chemoprevention, dietary manipulation, choice of work environment, and lifestyle adjustments.’ These ideas with the advances in new technology have contributed to stimulate the clinical investigators interested in the genetics of IBD in this direction. Although a note of caution has been raised by Dr. N. Holtzman: ‘Exaggerating the importance of genetic factors stops people

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thinking about the need to clean up the environment and tackle socioeconomic inequity’ [39], I firmly believe that the creation of a network or several networks of experts is necessary to support the multidisciplinary collaboration of gastroenterologists, practitioners, immunologists, geneticists, bio-medical informatic experts and patient organizations to integrate all existing knowledge in order to generate the necessary number of patients required to qualify for a meaningful statistical approach. If successful, this will allow the implementation of a new way of working with new information technology tools to improve the understanding of the nature of IBD. A multidisciplinary approach involving universities, hospitals and industrial collaboration using cutting edge technologies arising from genotype-phenotype interaction, genomics, proteomics, clinical and biomedical informatics research will achieve health care progress and cost reduction. This approach will improve a more precise diagnosis and permit the development of personalized medicine. The progress in treatment of patients will partially be related to the genetic knowledge generated with the candidate gene approach. The recently developed diagnostic tools in imaging tech-

nology and microarray systems will enable clinicians to achieve an early diagnosis. It will then possibly allow the physicians to classify patients in prognostic groups, relevant for a more rational and less expensive approach to patients’ management. This underlines the importance to store, exchange and retrieve data in order to transform data into higher quality information, to help professionals to monitor and analyze processes. Proposals to achieve this aim have been submitted to the FP6th program of the EU, but have not been successful. It is to be hoped that in the future the reviewers, scientists and politicians alike will recognize the importance of IBD, and the need to obtain a deeper knowledge in these diseases which affect a great proportion of Europeans in their most productive years.

Acknowledgements The editor chose the title of the review and the author built his theme on the interesting approach of Tessa Richards of the BMJ as stated in reference 39. The author’s research in IBD for 2002–2003 was supported in part by funding from the Crohn’s and Colitis Foundation of America (CCFA).

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25 Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y: Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet 2002;47:469–472. 26 Croucher PJ, Mascheretti S, Hampe J, Huse K, Frenzel H, Stoll M, et al: Haplotype structure and association to Crohn’s disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet 2003;11:6–16. 27 Roussomoustakaki M, Koutroubakis I, Vardas EM, Dimoulios P, Kouroumalis EA, Baritaki S, et al: NOD2 insertion mutation in a Cretan Crohn’s disease population. Gastroenterology 2003;124:272–273. 28 Aderem A, Ulevitch RJ: Toll-like receptors in the induction of the innate immune response. Nature 2000;406:782–787. 29 Cario E, Podolsky DK: Differential alteration in intestinal epithelial cell expression of tolllike receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 2000;68: 7010–7017. 30 Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al: A Toll-like receptor recognizes bacterial DNA. Nature 2000;408:740– 745. 31 Beutler B: Autoimmunity and apoptosis: The Crohn’s connection. Immunity 2001;15:5–14. 32 Hecht G: Innate mechanisms of epithelial host defense: Spotlight on intestine. Am J Physiol 1999;277:C351–358.

33 Cho JH: The Nod2 gene in Crohn’s disease: Implications for future research into the genetics and immunology of Crohn’s disease. Inflamm Bowel Dis 2001;7:271–275. 34 Miettinen M, Lehtonen A, Julkunen I, Matikainen S: Lactobacilli and Streptococci activate NF-kappa B and STAT signaling pathways in human macrophages. J Immunol 2000;164: 3733–3740. 35 Korhonen R, Korpela R, Saxelin M, Maki M, Kankaanranta H, Moilanen E: Induction of nitric oxide synthesis by probiotic Lactobacillus rhamnosus GG in J774 macrophages and human T84 intestinal epithelial cells. Inflammation 2001;25:223–232. 36 Chen LW, Egan L, Li ZW, Greten FR, Kagnoff MF, Karin M: The two faces of IKK and NFkappaB inhibition: Prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med 2003;9:575–581. 37 Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, et al: Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappa B. J Biol Chem 1999;274:14560–14567. 38 Inohara N, Nunez G: The NOD: A signaling module that regulates apoptosis and host defense against pathogens. Oncogene 2001;20: 6473–6481. 39 Burn J, Duff G, Holtzman N: Three views of genetics: the enthusiast, the visionary, and the sceptic. Interview by Tessa Richards. BMJ 2001;322:1016.

Peña

Review Article Dig Dis 2003;21:91–104 DOI: 10.1159/000073242

Environmental Influences on Inflammatory Bowel Disease Manifestations Lessons from Epidemiology

Antje Timmer Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, Germany

Key Words Inflammatory bowel diseases W Risk factors W Epidemiology W

Abstract Environmental factors play an important role in the disease manifestation, course and prognosis of inflammatory bowel disease. Observations on temporal trends and geographical distribution point at risk factors associated with a Western lifestyle. A large number of studies have been performed on various factors such as diet, smoking, and several infectious agents. Childhood exposures modifying immune responses in later life form a particularly interesting field. However, so far, only smoking in Crohn’s disease, and smoking cessation in ulcerative colitis can be considered established as risk factors for the manifestation of the disease. Smoking is also associated with a poor prognosis in Crohn’s disease. A strong negative association of appendectomy with ulcerative colitis has been very consistent across many studies; however, the implications of this finding are still obscure. Copyright © 2003 S. Karger AG, Basel

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Accessible online at: www.karger.com/ddi

Introduction

The etiology of the inflammatory bowel diseases is still unknown but seems to be multifactorial. The last few years have seen important advances in the study of genetically predisposing factors. The volume of literature in this field has risen exponentially, and currently, hopes are high to gain essential insights into the etiopathogenesis of inflammatory bowel disease. In contrast, progress feels slow in the study of environmental factors. After many decades of extensive epidemiological research, the identification and interpretation of specific factors remains a challenge. Many compelling hypotheses never met convincing evidence. On the other hand, causal explanations are still speculative for those few factors for which consistent associations were shown. Nevertheless, the impact of environmental factors on the manifestation, course and prognosis of inflammatory bowel diseases is well supported by a number of observations. Initially, these focused on secular and geographic trends in the incidence of these diseases. Subsequently, a large number of studies were published examining various potential risk factors, mostly those related to Western life-style.

Dr. A. Timmer Medizinische Klinik 1, Universitätsklinikum Regensburg DE–93053 Regensburg (Germany) Tel. +49 0941 944 7010, Fax +49 0941 944 7002 E-Mail [email protected]

Fig. 1. Incidence of Crohn’s disease, tempo-

ral trends [6, 12, 61, 62].

Twin studies, studies on familial aggregation and patterns of segregation underline the relative importance of the environment and other factors for the manifestation of inflammatory bowel diseases even in the presence of a genetic predisposition [1]. Concordance rates between identical twins are about 37% for Crohn’s disease and 10% in ulcerative colitis, as compared to 7 and 3% in dizygotic twins. Having a family member with the disease is the strongest risk factor for the manifestation of inflammatory bowel diseases. On the other hand, this risk factor is only present in about 10% of all patients with inflammatory bowel diseases. As an example, the genotype-related relative risk attributed to carriers of a CARD 15 mutation seems to be similar to the relative risk of smokers for developing Crohn’s disease (OR 2.6, 95% CI 1.5–4.5, vs. OR 2.0, 95% CI 1.7–2.5) [2, 3]. Taking into account the much higher prevalence of smoking in the population as compared to the allele prevalence of CARD 15 mutations it is obvious that the proportion of all cases attributable to smoking by far exceeds the contribution of CARD 15, even if a lack of valid population data on the genetic epidemiology prevents reliable calculation of population attributable risk proportions [4]. Therefore, in the context of identifying predisposing factors careful consideration of the impact of environmental factors remains an important issue. Similarly, lab-based experimental research has previously added impetus to the study of epidemiology of inflammatory bowel disease, and continues to do so. For example, evidence of an inappropriate response to fecal bacteria has led to a search for exposures capable of influencing immune function and development [5].

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I will first present some data on the descriptive epidemiology of inflammatory bowel disease, pointing at influences from the environment. Potential risk factors reviewed thereafter include those associated with lifestyle, such as smoking and dietary factors. Other factors relate to various hypotheses on immunological priming in childhood.

Incidence and Demographic Factors

Temporal Trends and Geographical Distribution A steep rise in the incidence of Crohn’s disease beginning after WW II and leveling out in the 1980s was reported from a number of centers in Scandinavia, the UK and Iceland [6] (fig. 1). As an example, in Copenhagen, the incidence of Crohn’s disease increased sixfold from less than 1/105/year in the early 1960s to 4.1/105/ year in the 1979–1987 period [7]. For ulcerative colitis, the data are less consistent (fig. 2). Generally, it is assumed that a rise in the incidence of ulcerative colitis preceded Crohn’s disease. In most centers, ulcerative colitis is about twice as common as Crohn’s disease. From countries outside Scandinavia and the UK, epidemiological data on the frequency of inflammatory bowel disease are only available from the 1970s on. Within Europe, as well as within the US, a North-South gradient became obvious [6, 8]. For Crohn’s disease the highest incidence rates are now reported from Manitoba (14.6/ 105/year) and North-West Scotland (11.6/105/year) [9, 10]. The highest rates for ulcerative colitis come from Iceland (24.3/105/year), Crete (16.6/105/year) and Norway

Timmer

Fig. 2. Incidence of ulcerative colitis, tem-

poral trends [6, 12, 61, 62].

(15.6/105/year) [11]. Outside Europe and North America, inflammatory bowel disease seemed to be very rare. Recent reports observed a rising incidence in Westernizing countries, e.g. from Asia [12]. At the same time, a large European cooperative study found differences between the North and South much smaller than expected, in fact, these may well be spurious [11] (fig. 3, 4). Genetic susceptibility patterns may show geographic variation, but are not likely to change as fast. Rather, the observed trends seem to point at environmental factors associated with a Western life-style and improved socioeconomic circumstances. Age and Sex There have been only minor inconsistencies on the age and sex distribution in the literature [6]. The EC-IBD study is the largest prospectively assembled populationbased inception cohort and may be regarded the most reliable source on age and sex distribution [11]. For Crohn’s disease, the highest age-specific incidence was described for persons aged 15–24. Ulcerative colitis affects people on average about 10 years later. There was no evidence for a bimodal age distribution as occasionally described previously by smaller studies. A preponderance for women in Crohn’s disease was small but statistically significant. In contrast, men suffer from ulcerative colitis slightly more often (age standardized risk ratios for women vs. men: 1.2 in Crohn’s disease, 0.8 in ulcerative colitis). Ethnic Differences The differences in the incidence of inflammatory bowel disease between countries may relate to life-style factors

Epidemiology of Inflammatory Bowel Disease

as well as to genetic factors. In this context, incidence studies in populations with a high proportion of immigrants are of considerable interest. Most population-based studies from Europe and North-America were based on ethnically homogenous groups. Within the USA, lower rates were reported for persons of Asian origin [6]. AfroAmericans showed hospital admission rates similar to people of Caucasian origin. There are also several studies on Asian minority groups in the UK, as well as in a few other countries [12, 13]. Life-style factors seem to be responsible for at least some of the differences. For example, in the UK, Hindu and Sikh people have a low incidence of Crohn’s disease, while Muslims originating from the same areas in Asia had a risk similar to the white UK background population. This pattern corresponds to the smoking behavior of the various groups. Unfortunately, in these minority group studies, adequate assessment of the contribution of potential risk factors to the variability in incidence was not possible on the individual level, either because case numbers were too small, or because the information was not available (or both). In contrast, the evidence is strong for an increased risk in Ashkenazi Jews. Odds ratios of about 2–4, as compared to the non-Jewish background population have been shown consistently in a large number of studies from different countries and periods [6]. There was no association with the degree of orthodoxy; the increased risk is usually considered to be genetically determined. Interestingly, Israel is a country with a relatively low incidence of inflammatory bowel disease [11]. Crohn’s disease is much lower in Jewish residents of Israel as compared to US American Jews. In Israel, Crohn’s disease is very rare in

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Fig. 3. Incidence of Crohn’s disease across

Europe, 1991–1993 [11].

Fig. 4. Incidence of ulcerative colitis across Europe, 1991–1993 [11].

the Arabic population. For first generation Jewish immigrants, there is a gradient based on the country of origin: The incidence is highest in immigrants from North America and Western Europe. Jewish people immigrating from Central and Eastern Europe, but especially immigrants from countries outside Europe and North America have a lower risk of developing inflammatory bowel disease. These difference are not observed in second generation immigrants [14]. Generally spoken, the incidence of inflammatory bowel disease in immigrant populations is often different

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from the incidence in the indigenous, host population. It does not correspond exactly to the incidence in the region of origin either. Complex interactions between risk factors working in different periods of life, possibly including a genetic predisposition as well as culturally determined life-style factors, seem to take place prior to the manifestation of inflammatory bowel disease.

Timmer

Life-Style Factors Urban vs. Rural Residency

There have been several reports on a lower incidence of inflammatory bowel disease in rural as compared to urban areas. Some of this may be due to differences in health care seeking behavior or failure to control for variations in age structure. With an increasingly mobile population differences in life-style between urban and rural areas are likely to level out and will be more difficult to study. However, a gradient was also reported in several well designed recent reports, such as those from Olmsted county and Manitoba [15, 16]. The interpretation of these associations is difficult. Age and smoking status could be adjusted for, but innumerous other factors are conceivable to be associated with residency, including differences in antigen exposure due to crowding or exposure to animals, dietary factors, or exposure to agents of pollution. Dietary Factors It seems a logical conclusion to assume a causative role for dietary factors in diseases involving the gastrointestinal tract. Dietary habits changed fast over the decades of rising incidence of inflammatory bowel disease and vary between countries and ethnic groups. Unfortunately, however, the study of dietary factors is particularly difficult in case control studies on inflammatory bowel disease. One of the major problems is the long delay which may occur between symptom onset and diagnosis. Even if restricting case groups to newly incident cases, it is likely that a number of patients have already changed dietary habits because of abdominal symptoms. Furthermore, patients with diarrhea or abdominal discomfort and pain tend to seek the culprit within their diet. Recall bias can hardly be avoided. Among the associations most often replicated is an increased consumption of sugar by patients with both ulcerative colitis and Crohn’s disease, reported as early as 1976 by Martini, or more recently in a study from Maastricht [17, 18]. Fruits, especially citrus fruits, have occasionally shown to be negatively associated with having inflammatory bowel disease. Several hypotheses have been put forward to explain these associations. Personally, to me the idea that sugar offers fast energy without putting much strain on the intestines is the most appealing, meaning increased sugar consumption is in fact a consequence of having inflammatory bowel disease rather than a risk factor. This view is supported by results from a small interventional study, which showed that eating a low-sugar diet rich in fiber did not improve inflammatory

Epidemiology of Inflammatory Bowel Disease

bowel disease, but rather, led to increased discomfort in some of the probands [19]. Many other dietary acquisitions coming into common use during the 2nd half of the 20th century were examined for any associations with the manifestation of inflammatory bowel disease, such as margarine, corn flakes, toothpaste, chewing gum, chocolate and coca cola [18]. However, in spite of a large body of publications on this topic, there is still no conclusive evidence on the role of dietary factors. Smoking The importance of smoking as a risk factor for the manifestation of Crohn’s disease is well established. For smokers a twofold risk of developing Crohn’s disease has been a consistent finding in many case control, as well as several prospective cohort studies. These were summarized in a meta-analysis, performed as early as 1989, [3] (fig. 5). Current, as well as previous, smoking was associated with the development of Crohn’s disease. Unfortunately, most studies did not provide detailed data on the duration or the intensity of smoking. Therefore, even in the meta-analysis, it was not possible to prove a doseeffect relationship. More recently, in a large case-control study restricted to incident cases, Corrao found the risk for smokers increased by 1.7 [20]. In quitters, the risk for Crohn’s disease stayed increased for about 5 years. Thereafter, risks were similar between never and previous smokers. For ulcerative colitis, the meta-analysis by Calkins suggested a protective effect of smoking (fig. 5). The pooled OR for smokers vs. never smokers was calculated to be 0.4 (95% CI 0.3–0.5). In contrast, ex-smokers were at an increased risk for the disease (OR 1.6, 95% CI 1.4–2.0). A dose response was evident – the more people smoked before cessation, the higher the risk. For current smoking, the risk of manifesting ulcerative colitis decreased with increasing dosage of smoking. There may have been some inaccuracies in the way how smoking was reported. The study by Corrao did not confirm the protective association of smoking, but showed strong evidence for a robust and dose-dependent adverse effect of smoking cessation. The risk was highest during the year following cessation, but stayed raised for several years. Possibly, smoking protects the mucosa from developing ulcerative colitis in predisposed individuals. Several hypotheses have been put forward to explain the effect of smoking in inflammatory bowel disease; especially Crohn’s disease. In Crohn’s disease one group suggest inflammatory processes in the bowel wall follow-

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Fig. 5. Meta-analyses of observational studies in IBD: pooled OR for smoking, oral contraceptives and appendectomy [3, 23, 41].

ing minor infarction from thrombosed small vessels [21]. In ulcerative colitis, an immunosuppressive effect of smoking or changes to the structure of mucins have been suggested [22]. Oral Contraceptives An adverse effect of contraceptives, especially in smokers, may fit into the minor infarction hypothesis. In addition, the predilection of young women and clinical observations have drawn attention to the role of oral contraceptives as potential risk factors in Crohn’s disease; possibly also ulcerative colitis. A number of previous studies showed conflicting results; usually power was insufficient. A meta-analysis discovered small positive associations with ulcerative colitis as well as Crohn’s disease (OR 1.3, 95% CI 0.9–1.8; OR 1.4, 95% CI 1.1–1.9) [23] (fig. 5). Weak effects such as these could be completely explained by bias. If there is any at all, it is not likely that the association between oral contraceptive use and inflammatory bowel disease is very strong. Occupation and Socioeconomic Status Diseases affecting people at a young age or in early adulthood are not likely to be caused by occupational factors. It seems more likely that disease symptoms, time spent in hospital, etc., impact on decisions concerning schooling and career choices. Nevertheless, there have been a couple of analyses published, mostly based on administrative data [24, 25]. The notion of an increased risk of inflammatory bowel disease in white-collar jobs

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was coined by Sonnenberg. Specifically, the risk of inflammatory bowel disease seemed to be associated with working shifts, exposure to artificial light, little physical activity, sitting, working indoors, and higher prestige. Ecological analyses observed a positive correlation between income and incidence of inflammatory bowel disease [16]. As pointed out before, there is not much to support a causal role of these factors – temporal relationships are not clear, there is no plausible biological explanation, the strength of the effects is small, and the study designs used were not optimal. There is a lack of subsequent case control studies, specifically designed to test the various potentially adverse factors individually. Similarly, high socioeconomic status, although quite consistently linked to an increased risk of inflammatory bowel disease, is a concept which is difficult to grasp. A number of potential risk factors may be associated with higher socioeconomic status.

Psychological Factors

Ulcerative colitis was originally counted among the classical psychosomatic diseases. There has been an understanding that both ulcerative colitis and Crohn’s disease affect people with specific behavioral or personality traits more often. There is no valid evidence to support this cliché.

Timmer

Table 1. Studies on childhood factors in IBD

First author

Year of Study design publication

Source of controls

Cases of Crohn’s disease

Cases of ulcerative colitis

Whorwell [30] Gilat [32] Ekbom [29] Gent [35] Wurzelmann [31] Duggan [36] Thompson [45]

1979 1987 1990 1994 1994 1998 1998

mixed mixed birth cohort GP patients neighbors surgical patients birth cohort

57 302 93 133 322 110 26

51 197 164 231 181 213 29

Feeney [37] Hampe [38]

2002 2003

functional GI disease relatives

139 120 IBD

137

case control case control retrospective cohort case control case control case control prospective/ nested case control case control case control

Childhood Factors

As inflammatory bowel diseases typically manifest themselves in early adulthood or before, events in early childhood have been attracting attention as potential risk factors for subsequent development of inflammatory bowel disease. More research in perinatal events was motivated when Ekbom described birth cohort effects, not only by year of birth, but even varying by seasons [26, 27]. These data were never convincingly replicated. Most did not find any evidence for birth cohorts, while others identified cohorts but arrived at different conclusions. More recently, based on disease specific death rates, Delco identified those born around 1890 to have been at highest risk for dying of inflammatory bowel disease [28]. The analysis of data on duodenal ulcers had similar results, while death from gastric cancer was more common for those born about a decade earlier. Overall, the birth cohort theme is not well supported by the literature. However, the concept that events in early childhood may modify immune responses, leading to the manifestation of inflammatory bowel disease in later life, possibly under the effect of immunologically challenging exogenous factors is still attractive. Two contrasting hypotheses have been followed. Ekbom originally focused on infectious events occurring perinatally. In contrast, the sheltered child hypothesis assumes delayed exposure to immunologically challenging events in early childhood. Both hypotheses still motivate interesting research, and neither have ever been refuted, even though they may seem contradictory (tables 1–5). Size of sibship and appendectomy may also modify the response to exogenous factors in later life, but due to conflicting results may serve either of the

Epidemiology of Inflammatory Bowel Disease

two concepts and will therefore be considered separately. Breastfeeding is another factor which is likely to be of importance for priming immunological responses. Early Infections Exceptional data linkage possibilities enabled Ekbom et al. [29] to examine perinatal events based on maternity hospital records for all patients with inflammatory bowel diseases, and controls, born at Uppsala University hospital between 1924 and 1957. In this analysis, perinatal health events were strongly associated with both Crohn’s disease and ulcerative colitis (tables 2, 3). Separate analyses for specific infections are not reported. The authors felt that febrile viral infections contributed most to the increased risk of inflammatory bowel disease. Even before, in a short report of 1979, Whorwell [30] found that patients with Crohn’s disease were more likely to report early gastroenteritis. Later, Wurzelmann et al. [31] confirmed the association of early childhood infections with development of inflammatory bowel disease in later life, providing a detailed analysis of various common infections (tables 2, 3). In contrast to the importance of viral infections assumed by Ekbom, in this analysis, bacterial infections, in particular pharyngitis and tonsillitis were the strongest risk factors for Crohn’s disease. This was validated by an increased rate of tonsillectomy and treatment with antibiotics in patients with Crohn’s disease, as had been previously shown by Gilat [32]. Among the viral infections, perinatal measles infections have received the most attention, as recently summarized by Robertson and Sandler [33]. A number of interesting studies and hypotheses, including Crohn’s disease representing a slow virus infection, have been put

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Table 2. Evidence of childhood infections and atopic disease in Crohn’s disease (see previous table for study details) Whorwell [30] Prenatal infectious event Postnatal infection (child) Any bacterial infection Otitis Pharyngitis Scarlet fever Tonsillitis Respiratory infections Gastroenteritis Measles Mumps Rubella Varicella Whooping cough Colds Serological status Helicobacter pylori IgG Hepatitis A IgG Treatment with antibiotics Appendectomy Tonsillectomy Eczema Any other allergies

Gilat [32]

Ekbom [29]

Gent [35]

Wurzelmann [31]a

Duggan [36]

3.6 (1.6–8.2) 9.2 (2.7–33.0)

Thompson [45]

Feeney [37]

1.3 (0.3–5.3) 4.7 (2.7–3.2) 1.6 (0.9–2.8) 2.1 (1.3–2.0) 1.2 (0.7–2.2) 1.6 (1.0–2.6)

13.3 (1.5–300)

1.3 (0.9–1.9) n.s. n.s. n.s.

1.3 (0.8–2.3) 1.0 (0.7–1.5) 1.1 (0.7–1.7) 1.1 (0.6–2.0)

1.1 (0.4–3.5) 0.9 (0.3–2.4)

2.4 (0.9–6.2) 2.4 (1.4–4.2) 0.9 (0.5–1.6) positive 1.6 (1.0–2.6) n.s. positive n.s.

1.4 (0.6–3.4)

1.8 (1.0–3.3) ‘not increased’ 1.3 (0.7–2.3) 1.5 (1.1–2.2) 1.2 (0.7–2.1)

0.2 (0.1–0.5) 0.9 (0.4–2.0) 0.0 (0.0–3.8)b 1.5 (0.5–4.2)

0.5 (0.2–1.7) 2.8 (1.2–6.4)

All OR represent associations if factor present vs. absence of factor. For original data using presence of factor as reference value, reciprocals were calculated for comparability. n.s. = No association, not significant; positive = positive association; inverse = negative association. a For infections: frequent vs. fewer. b 0/26 of cases vs. 15/207 had had appendectomy.

forward. There have also been attempts to link measles vaccination campaigns to cohort effects in Crohn’s disease. Overall, there is no conclusive evidence to support any of the various measles hypotheses. The role of mycobacteria has also been extensively studied. However, there are hardly any data from epidemiology; most reports focused on technical microbiological methods for isolating evidence of mycobacterial infection [34]. The Sheltered Child Hypothesis The infectious hypothesis seems to collide with the fact that the incidence of inflammatory bowel disease is higher in more developed countries, and that there may be a positive association with higher economic status. In 1987, Gilat [32] was one of the first to discuss what he called the sheltered child hypothesis, based on data from a large international case-control study (tables 4, 5). He did not yet examine the effect of the later notorious hot water tap, but used several markers of hygiene and early exposure to infections. Unfortunately, the results are not reported in much detail. Several markers were included in a ‘shelter score’. The risk of inflammatory bowel disease was associ-

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ated with ‘extreme’ shelter scores, i.e. those particularly sheltered were at a higher risk, as well as those likely to be particularly exposed to early antigen exposure, while the middle category was less likely to develop inflammatory bowel disease. Later, two different studies found the availability of a hot water tap the most useful marker of early childhood hygiene, and described a rather strong risk effect on the manifestation of Crohn’s disease in later life (tables 4, 5) [35, 36]. Other studies did not support this association [37, 38]. However, as Feeney [38] points out, growing up without running hot water is now very rare in Western countries. For mere statistical reasons it has become difficult to adequately assess this risk factor. The failure to detect associations in the most recent analysis may also be due to insufficient power. The confidence interval for ‘hot water tap’ in this study included 2, i.e. exceeded the effect described by Duggan (1.8). Also, in this study, cases with ulcerative colitis and Crohn’s disease were mixed. Patients with a genetic background were overrepresented, as the group had originally been assembled for linkage analysis. There is some evidence that genetically predisposed

Timmer

Table 3. Evidence of childhood infections and atopic disease in ulcerative colitis Whorwell [30] Prenatal infectious event Postnatal infection (child) Any bacterial infection Otitis Pharyngitis Scarlet fever Tonsillitis Respiratory infections Gastroenteritis Measles Mumps Rubella Varicella Whooping cough Colds Helicobacter pylori IgG Hepatitis A IgG Treatment with antibiotics Appendectomy Tonsillectomy Eczema Any other allergies

Gilat [32]

Ekbom [29]

Gent [35]

Wurzelmann [31]a

Duggan [36]

2.7 (1.5–4.8) 6.1 (2.6–14.3)

Thompson [45]

Feeney [37]

0.8 (0.1–4.5) 2.4 (1.2–4.7) 0.6 (0.3–1.3) 1.4 (0.8–2.5) 1.8 (0.8–4.0) 0.9 (0.5–1.7)

1.6 (1.0–2.6) 8.6 (0.9–200) n.s. n.s. n.s. inverse

1.5 (0.5–5.5) 1.0 (0.4–2.4)

1.3 (0.8–2.3) 1.0 (0.6–1.8) 1.9 (0.6–2.9)

1.6 (0.7–3.7) 0.9 (0.6–1.5) n.s. 0.3 (0.1–0.8) n.s. n.s. n.s.

0.3 (0.1–0.6)

n.s. 0.3 (0.1–1.1)

0.2 (0.1–0.4) 0.8 (0.5–1.2)

0.9 (0.4–2.2) 1.2 (0.6–2.5) 2.3 (0.7–7.5) 1.2 (0.5–3.2)

0.1 (0.0–0.5) 1.8 (0.7–4.6)

All OR represent associations if factor present vs. absence of factor. For original data using presence of factor as reference value, reciprocals were calculated for comparability. n.s. = No association, not significant; positive = positive association; inverse = negative association. a For infections: frequent vs. fewer.

patients are less susceptible to environmental influences, although the hypothesis needs to be further explored. Also, the use of relatives as controls compromise the comparability of these results with previous studies. A number of markers used to describe domestic hygiene are listed in tables 4 and 5. In addition, perinatal mortality has been considered to reflect antigen exposure in early childhood. The incidence of Crohn’s disease has been described to be negatively correlated to perinatal mortality [39]. Caution needs to be applied to the interpretation of correlational studies. Other indirect markers include seroprevalence of Helicobacter pylori, a germ associated with poor sanitary conditions and crowding. A strong inverse association was recently described by Feeney [37] which seems to confirm this concept. The same effect is not shown for hepatitis A, although similar mechanism would have been expected to play a role. Also, the data from the literature concerning a relationship between H. pylori infection and inflammatory bowel disease have shown conflicting results. Appendectomy Appendectomy rates have initially been included in risk factor analyses as another marker for childhood infec-

Epidemiology of Inflammatory Bowel Disease

tions (tables 2, 3) [32]. A series of mostly smaller studies examined the effect of appendectomy on the manifestation of Crohn’s disease, some suggesting a small positive association. However, overall, the results were considered inconclusive, especially as reverse causation could not always be excluded – incipient Crohn’s disease may be misdiagnosed for appendicitis. Eventually, earlier this year a large register based retrospective cohort study from Sweden was published which sheds more light on this relationship [40]. Results were presented separately by discharge diagnoses following appendectomy, i.e. perforated appendicitis, non-perforated appendicitis, mesenteric lymphadenitis, and nonspecific abdominal pain. In addition, the investigators examined the effect of the temporal relationship between appendectomy and diagnosis of inflammatory bowel disease, as well as follow-up data with respect to the subsequent course of the disease in inflammatory bowel disease patients. Some findings are still somewhat confusing, such as an inverse relationship between childhood appendectomy (age at operation !10 years, OR 0.5, 95% CI 0.2–1.0) and Crohn’s disease, contrasting the results for all other age groups (overall, OR 1.5, 95% CI 1.2–1.7). Also, the incidence rates observed seem unusually high, even in controls (up to 11.3/105/

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Table 4. The sheltered child hypothesis: studies on early childhood factors in Crohn’s disease Gilat [32] OR for disease (95% CI) ‘Poor amenities’ Hot water tap Fixed bath/bathroom Flush/inside toilet Mains drainage Sharing bedrooms Sharing bed Nursery attendance Frequent use of pool Urban environment Rural residence Central heating Pets in home Higher social class

Ekbom [29]

Gent [35]

Wurzelmann [31]

Duggan [36]

Thompson [45]

Feeney [37]

Hampe [38]

1.8 (1.1–3.3) 0.6 (0.3–1.3) 0.8 (0.4–1.4)

.

1.3 (0.8–2.0)

0.9 (0.6–1.4) 1.0 (0.6–1.6)

1.1 (0.2–5.0)

1.3 (0.4–3.5) 5.0 (1.4–17.3) 3.3 (1.3–8.3) 1.1 (0.5–2.6) 2.6 (0.9–7.3) n.s.

n.s.

1.4 (0.8–2.4)

n.s.

0.6 (0.3–1.4) 2.9 (1.2–6.9) 0.6 (0.3–1.4)

positive 1.3 (0.7–2.3)

1.3 (0.8–2.1) n.s. 1.4 (1.0–1.8)

a

0.4 (0.1–1.1)

n.s.

All OR represent associations if factor present vs. absence of factor. For original data using presence of factor as reference value, reciprocals were calculated for comparability. n.s. = No association, not significant; positive = positive association; inverse = negative association. a Various pets, OR ranging from 0.7 to 1.8, all CI including 1.

Table 5. Studies on early childhood factors in ulcerative colitis Gilat [32] OR for disease (95% CI) ‘Poor amenities’ Hot water tap Fixed bath/bathroom Flush/inside toilet Mains drainage Sharing bedrooms Sharing bed Nursery attendance Frequent use of pool Urban environment Rural residence Central heating Pets in home Higher social class

Ekbom [29]

Gent [35]

Wurzelmann [31]

Duggan [36]

Thompson [45]

Feeney [37]

Hampe [38]

0.6 (0.2–1.6) 1.3 (0.7–2.2) 1.3 (0.7–2.4) 1.4 (0.7–2.4) 1.2 (0.7–2.5) n.s.

0.8 (0.5–1.2) 1.0 (0.6–1.5) 1.1 (0.3–1.6) n.s.

0.8 (0.6–1.2) 1.1 (0.8–1.6)

n.s.

1.1 (0.7–1.7)

1.3 (0.8–2.0) 1.4 (0.8–2.4) 1.2 (0.5–3.3) 0.5 (0.2–1.2) 1.2 (0.6–2.6) 1.0 (0.4–2.2)

no trend n.s. 1.0 (0.6–1.6)

n.s. 0.8 (0.5–1.3)

1.3 (0.8–2.1) n.s. n.s.

0.3 (0.1–0.8)

All OR represent associations if factor present vs. absence of factor. For original data using presence of factor as reference value, reciprocals were calculated for comparability.

year). However, the positive association with Crohn’s disease was particularly strong for the most robust diagnosis (perforated appendicitis, OR 2.1, 95% CI 1.2–3.8). In addition, the relative stability of the association irrespective of the time period chosen between operation and diagnosis of inflammatory bowel disease, and some evidence for a role of appendicitis on the subsequent course of the disease support the validity of the results. Based on

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this study, there seems to be now sufficient evidence to assume a positive association between appendicitis and subsequent manifestation of Crohn’s disease. In contrast, a strong negative association of appendectomy with ulcerative colitis is one of the most consistent findings in the epidemiological literature on inflammatory bowel disease. Based on a meta-analysis including 13 case control studies, the pooled odds ratio is 0.3 (95% CI

Timmer

0.2–0.4) [41]. As for Crohn’s disease, the Swedish study group of Andersson et al. [42] have reported detailed analyses including the effects of variable follow-up periods, type of appendiceal disease, and age at appendectomy. As compared to the results of the meta-analysis and most previous studies, the overall effect observed was slightly smaller but still marked, especially following perforated appendicitis (OR 0.6, 95% CI 0.4–0.9). Non-perforated appendicitis and mesenteric lymphadenitis were also significantly associated with developing ulcerative colitis later, but appendectomy without evidence for inflammation was not (OR 1.1, 95% CI 0.7–1.5). In accordance with several other studies, the protective effect of appendectomy was only shown if the operation was performed in childhood (before age 20). Do the associations observed represent causal relationships? For ulcerative colitis, the strength and consistency of the effect as well as an obvious temporal relationship seem to support this view. There is also experimental evidence from animal research [43]: T cell receptor-·-deficient mice which usually develop a ulcerative colitis like colitis in over 80% of cases could be efficiently protected by appendectomy at an early age. The authors concluded that appendix lymphoid tissue plays an important role in the development of inflammatory bowel disease. It has been suggested that removal of the appendix leads to a shift in the balance of T helper and suppressor cells, modifying the immune response and hereby exerting an influence on the manifestation and type of inflammatory bowel disease. Based on the Swedish data, Andersson et al. [42] argue that the appendiceal inflammation is crucial for the association, not the removal. A T-helper 1 cellmediated response type would constitute a predisposition for appendicitis as well as Crohn’s disease, while the inappropriate response in ulcerative colitis is said to be characterized by a T-helper 2 cell-mediated type. In this view, appendicitis and ulcerative colitis are considered to represent alternative inflammatory responses that are genetically or environmentally determined. From the epidemiological view, there are interesting parallels in the incidence and risk factors of appendicitis, such as infectious hypotheses, the relevance of crowding, domestic hygiene, socioeconomic status, etc. As argued from the immunological perspective, there is the possibility that the associations between appendicitis and inflammatory bowel disease are in fact due to confounding by yet unknown factors, although the causative mechanisms suggested also have some appeal. More experimental research is needed.

Birth Rank Having brothers and sisters has been used as a marker of early childhood exposure patterns to antigens in several studies. Generally, it may be assumed that children with siblings are more frequently exposed to infections. Antigen exposure is also likely to occur at an earlier age, especially in the presence of older siblings. Based on the sheltered child hypothesis, an only child would be expected to be at higher risk of developing Crohn’s disease later. The number of, especially older, siblings should be inversely correlated with Crohn’s disease occurrence. While this seems a reasonably straight forward hypothesis, reality is more complex. Other factors associated with the number and spacing of offspring, such as the age of the parents, rural vs. urban residency, economic status, breastfeeding, attitudes towards vaccination, etc., may also play a role. Also, studies have used differing designs and risk factor classifications, further compromising the interpretation of results. It is not surprising, therefore, that so far, there have been conflicting results. The largest study examining birth rank as a risk factor for inflammatory bowel disease used population-based registries, including a nationwide multi-generation family data base in Sweden [44]. In contrast to what would have been expected, for Crohn’s disease a negative, dosedependent association with the number of younger siblings was observed, especially if the younger siblings were born at least 5 years after the index cases. This analysis was restricted to children with no older siblings. There was no association with having older, but not younger siblings. For ulcerative colitis, in contrast, having older siblings, but not younger siblings, was associated with a higher risk for developing the disease later. Unfortunately, this study used somewhat unusual categories and head jumped to trend analyses. Data on the effects of having brothers and sisters at all, or having older siblings at all, are not presented. In view of the contrasting results by type of inflammatory bowel disease described in this study, it is somewhat irritating that cases with ulcerative colitis and Crohn’s disease were combined in a more recent analysis by Hampe et al. [38]. Most likely, the majority of patients in this report had Crohn’s disease, but the proportion is not given. The results are therefore somewhat difficult to interpret. Higher birth rank was associated with a lower risk of inflammatory bowel disease (OR 0.7). Also, one child families were excluded from the analysis. The effect of being an only child, possibly the most important sibship factor, could therefore not be assessed.

Epidemiology of Inflammatory Bowel Disease

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Fig. 6. Relapse in Crohn’s disease – impact

of smoking status [54].

In contrast to the report by Hampe, the majority of studies looking at birth rank and number of siblings did not find a significant association [37, 45]. Gilat [32] found patients with Crohn’s disease to be more likely to be last born, as compared to controls. Given these conflicting results, a strong association between birth rank and the risk for inflammatory bowel disease is not likely. Early Weaning As early as 1961, early weaning was suspected to increase the risk for developing ulcerative colitis in later life [46]. Later, using sib controls, Koletzko found a positive association between early weaning and Crohn’s disease, but failed to confirm this finding for ulcerative colitis [47, 48]. More recently, in a methodologically sound large case control study from Italy, using incident patients, early weaning was associated with an increased risk of both ulcerative colitis (OR 1.5, 95% CI 1.1–2.1) and Crohn’s disease (OR 1.9, 95% CI 1.1–3.3) [20]. There is some evidence for a dose response of the protective effect of breastfeeding by duration [49]. Other studies did not find a significant association [29, 32, 38]. However, small sample size or methodological problems preclude any definite conclusions in most of the ‘negative’ studies. It seems that early weaning may be a risk factor for developing Crohn’s disease, but the evidence is still weak. For ulcerative colitis, results are conflicting.

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Childhood Exposure to Smoking The prominent relevance of smoking status for the development of inflammatory bowel disease in adults prompted research into the effects of environmental tobacco exposure in childhood. Naturally, this is more difficult to study. Provided active smoking has been controlled for the effect of passive smoking is not expected to be as consistent and strong as evident in adult active smoking. However, there have been singular positive findings on the protective effect of passive smoking in childhood in ulcerative colitis (OR 0.5, 95% CI 0.3–1.0) [50], as well as on a harmful effect in Crohn’s disease (OR 1.5, 95% CI 1.0–2.3) [51].

Prognostic Factors in Inflammatory Bowel Disease

Excellent data on the long-term prognosis in inflammatory bowel disease are now available from populationbased inception cohorts, prospectively followed up for up to 35 years [52, 53]. Unfortunately, in these studies the impact of environmental factors was rarely assessed. With respect to short time prognosis, an adverse role of smoking in Crohn’s disease is firmly established. Smoking has consistently been shown to about double the risk of various outcomes, including surgical recurrence, clinical relapse, and use of immunosuppressants, irrespective of the study design [54–58]. An example is shown in figure 6.

Timmer

A prospective cohort study by Cosnes et al. [59] nicely demonstrated reversibility of the adverse effect by following up a group of patients following smoking cessation. Successful quitters suffered less relapses and required fewer medications. Data for ulcerative colitis are less convincing [60]. Theoretically, the hypothesis that nicotine is associated with a better prognosis in ulcerative colitis is amenable to testing by clinical trials. However, trials using nicotine patches, gum or other preparations have not shown convincing results [22]. Compliance is often a problem due to a significant prevalence of side effects. Oral contraceptives may also be associated with a worse short time prognosis in Crohn’s disease [54]. However, the evidence is weak. Most studies did not find a significant association, but none was large enough to exclude an effect comparable to the one found for smoking. A dose response relationship or reversibility has not been demonstrated. Other factors suspected to precipitate relapse in inflammatory bowel disease include intestinal infection, NSAIR, and psychological factors, but there are no controlled data to support this. So far, there is no justification for general advice against specific dietary components, or the use of the oral contraceptive. However, patients with Crohn’s disease should definitely not smoke, especially if

also taking oral contraceptives. There is no drug available for maintenance of remission in Crohn’s disease coming close to the effect expected from smoking cessation.

Conclusions

Environmental factors seem to play an important role in the manifestation of inflammatory bowel diseases. There is evidence pointing at factors associated with a modern, Westernized life-style. So far, only smoking was established as a risk factor for Crohn’s disease. This factor is also adversely associated with prognosis. In contrast, the risk for developing ulcerative colitis increases with smoking cessation. In addition to adult life-style factors, the manifestation of IBD seems to be influenced by environmental factors impacting on early childhood development of immunological response patterns. These factors are likely to be infectious. More research is needed combining methods from molecular genetics, microbiology and immunological research with epidemiologically sound risk factor analyses to advance our understanding of the manifestation and etiopathogenesis of ulcerative colitis and Crohn’s disease.

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8 Sonnenberg A, McCarty DJ, Jacobson SJ: Geographic variation of inflammatory bowel disease within the United States. Gastroenterology 1991;100:143–149. 9 Kyle J: Crohn’s disease in the northeastern and northern Isles of Scotland: An epidemiological review. Gastroenterology 1992;103:392–399. 10 Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A: Epidemiology of Crohn’s disease and ulcerative colitis in a central Canadian province: A population-based study. Am J Epidemiol 1999;149:916–924. 11 Shivananda S, Lennard-Jones JE, Logan R, et al: Incidence of inflammatory bowel disease across Europe: Is there a difference between North and South? Results of the European collaborative study on inflammatory bowel disease (EC-IBD). Gut 1996;39:690–697. 12 Yang SK, Loftus EV Jr, Sandborn WJ: Epidemiology of inflammatory bowel disease in Asia. Inflamm Bowel Dis 2001;7:260–270. 13 Probert CS, Jayanthi V, Rampton DS, Mayberry JF: Epidemiology of inflammatory bowel disease in different ethnic and religious groups: Limitations and aetiological clues. Int J Colorectal Dis 1996;11:25–28.

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14 Odes H S, Fraser D, Krawiec J: Inflammatory bowel disease in migrant and native Jewish populations of Southern Israel. Scand J Gastroenterol 1989;170:36–38. 15 Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR: Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: Incidence, prevalence, and survival. Gut 2000;46:336–343. 16 Blanchard JF, Bernstein CN, Wajda A, Rawsthorne P: Small-area variations and sociodemographic correlates for the incidence of Crohn’s disease and ulcerative colitis. Am J Epidemiol 2001;154:328–335. 17 Martini GA, Brandes JW: Increased consumption of refined carbohydrates in patients with Crohn’s disease. Klin Wochenschr 1976;54: 367–371. 18 Russel MG, Engels LG, Muris JW, et al: ‘Modern life’ in the epidemiology of inflammatory bowel disease: A case-control study with special emphasis on nutritional factors. Eur J Gastroenterol Hepatol 1998;10:243–249.

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19 Ritchie JK, Wadsworth J, Lennard-Jones JE, Rogers E: Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn’s disease. Br Med J 1987;295: 517–520. 20 Corrao G, Tragnone A, Caprilli R, et al: Risk of inflammatory bowel disease attributable to smoking, oral contraception and breastfeeding in Italy: A nationwide case-control study. Cooperative Investigators of the Italian Group for the Study of the Colon and the Rectum (GISC). Int J Epidemiol 1998;27:397–404. 21 Wakefield AJ, Dhillon AP, Rowles PM, Sayerr AM, Pittilo RM, Lewis AA M: Pathogenesis of Crohn’s disease: Multifocal gastrointestinal infarction. Lancet 1989;i:1057–1062. 22 Sandborn WJ: Nicotine therapy for ulcerative colitis: A review of rationale, mechanisms, pharmacology, and clinical results. Am J Gastroenterol 1999;94:1161–1171. 23 Godet PG, May GR, Sutherland LR: Metaanalysis of the role of oral contraceptive agents in inflammatory bowel disease. Gut 1995;37: 668–673. 24 Sonnenberg A: Occupational distribution of inflammatory bowel disease among German employees. Gut 1990;31:1037–1040. 25 Sonnenberg A: Disability from inflammatory bowel disease among employees in West Germany. Gut 1989;30:367–370. 26 Ekbom A, Zack M, Adami H O, Helmick C: Is there clustering of inflammatory bowel disease at birth? Am J Epidemiol 1991;134:876–886. 27 Ekbom A, Helmick C, Zack M, Adami HO: The epidemiology of inflammatory bowel disease: A large, population-based study in Sweden. Gastroenterology 1991;100:350–358. 28 Delco F, Sonnenberg A: Exposure to risk factors for ulcerative colitis occurs during an early period of life. Am J Gastroenterol 1999;94: 679–684. 29 Ekbom A, Adami HO, Helmick CG, Jonzon A, Zack MM: Perinatal risk factors for inflammatory bowel disease: A case-control study. Am J Epidemiol 1990;132:1111–1119. 30 Whorwell PJ, Holdstock G, Whorwell GM, Wright R: Bottle feeding, early gastroenteritis, and inflammatory bowel disease. Br Med J 1979;i:382. 31 Wurzelmann JI, Lyles CM, Sandler RS: Childhood infections and the risk of inflammatory bowel disease. Dig Dis Sci 1994;39:555–560. 32 Gilat T, Hacohen D, Lilos P, Langman MJ: Childhood factors in ulcerative colitis and Crohn’s disease. An international cooperative study. Scand J Gastroenterol 1987;22:1009– 1024. 33 Robertson DJ, Sandler RS: Measles virus and Crohn’s disease: A critical appraisal of the current literature. Inflamm Bowel Dis 2001;7:51– 57.

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34 El-Zaatari FA, Osato MS, Graham DY: Etiology of Crohn’s disease: The role of Mycobacterium avium paratuberculosis. Trends Mol Med 2001;7:247–252. 35 Gent AE, Hellier MD, Grace RH, Swarbrick ET, Coggon D: Inflammatory bowel disease and domestic hygiene in infancy. Lancet 1994; 343:766–767. 36 Duggan AE, Usmani I, Neal KR, Logan RF: Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: A case control study. Gut 1998; 43:494–498. 37 Feeney MA, Murphy F, Clegg AJ, Trebble TM, Sharer NM, Snook JA: A case-control study of childhood environmental risk factors for the development of inflammatory bowel disease. Eur J Gastroenterol Hepatol 2002;14:529– 534. 38 Hampe J, Heymann K, Krawczak M, Schreiber S: Association of inflammatory bowel disease with indicators for childhood antigen and infection exposure. Int J Colorectal Dis. DOI 10.1007/s00384-003-0484-1 (e-preprint) 39 Montgomery SM, Pounder RE, Wakefield AJ: Infant mortality and the incidence of inflammatory bowel disease. Lancet 1997;349:472– 473. 40 Andersson RE, Olaison G, Tysk C, Ekbom A: Appendectomy is followed by increased risk of Crohn’s disease. Gastroenterology 2003;124: 40–46. 41 Koutroubakis IE, Vlachonikolis IG: Appendectomy and the development of ulcerative colitis: Results of a metaanalysis of published casecontrol studies. Am J Gastroenterol 2000;95: 171–176. 42 Andersson RE, Olaison G, Tysk C, Ekbom A: Appendectomy and protection against ulcerative colitis. N Engl J Med 2001;344:808–814. 43 Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK: Role of appendix in the development of inflammatory bowel disease in TCR-alpha mutant mice. J Exp Med 1996;184:707–715. 44 Montgomery SM, Lambe M, Wakefield AJ, Pounder RE, Ekbom A: Siblings and the risk of inflammatory bowel disease. Scand J Gastroenterol 2002;37:1301–1308. 45 Thompson NP, Montgomery SM, Wadsworth ME, Pounder RE, Wakefield AJ: Early determinants of inflammatory bowel disease: Use of two national longitudinal birth cohorts. Eur J Gastroenterol Hepatol 2000;12:25–30. 46 Acheson ED, Truelove SC: Early weaning in the aetiology of ulcerative colitis. Br Med J 1961;2:929–933. 47 Koletzko S, Griffiths A, Corey M, Smith C, Sherman P: Infant feeding practices and ulcerative colitis in childhood. Br Med J 1991;302: 1580–1581.

48 Koletzko S, Sherman P, Correy M, et al: Role of infant feeding practices in development of Crohn’s disease in childhood. Br Med J 1989; 298:1617–1618. 49 Rigas A, Rigas B, Glassman M, et al: Breastfeeding and maternal smoking in the etiology of Crohn’s disease and ulcerative colitis in childhood. Ann Epidemiol 1993;3:387–392. 50 Sandler RS, Sandler DP, McDonnell CW, Wurzelmann JI: Childhood exposure to environmental tobacco smoke and the risk of ulcerative colitis. Am J Epidemiol 1992;135:603– 608. 51 Persson P-G, Ahlbom A, Hellers G: Inflammatory bowel disease and tobacco smoke: A casecontrol study. Gut 1990;31:1377–1381. 52 Jess T, Winther KV, Munkholm P, Langholz E, Binder V: Mortality and causes of death in Crohn’s disease: Follow-up of a populationbased cohort in Copenhagen County, Denmark. Gastroenterology 2002;122:1808–1814. 53 Timmer A: Natural history and prognosis: An evidence based approach; in Satsangi J, Sutherland LR (eds): Inflammatory Bowel Diseases. Edinburgh, Churchill-Livingstone, 2003. 54 Timmer A, Martin F, Sutherland LR, The Canadian Mesalamine for Remission of Crohn’s Disease Study Group: Smoking and use of oral contraceptives are risk factors for relapse in Crohn’s disease. Gastroenterology 1998;114: 1143–1150. 55 Duffy LC, Zielezny MA, Marshall JR, et al: Cigarette smoking and risk of clinical relapse in patients with Crohn’s disease. Am J Prev Med 1990;6:161–166. 56 Sutherland LR, Ramcharan S, Bryant H, Fick GH: Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology 1990;98: 1123–1128. 57 Cottone M, Rosselli M, Orlando A, et al: Smoking habits and recurrence in Crohn’s disease. Gastroenterology 1994;106:643–648. 58 Cosnes J, Carbonnel F, Beaugerie L, Le Quintrec Y, Gendre J-P: Effects of cigarette smoking on the long-term course of Crohn’s disease. Gastroenterology 1996;110:424–431. 59 Cosnes J, Beaugerie L, Carbonnel F, Gendre JP: Smoking cessation and the course of Crohn’s disease: An intervention study. Gastroenterology 2001;120:1093–1099. 60 Beaugerie L, Massot N, Carbonnel F, Cattan S, Gendre J P, Cosnes J: Impact of cessation of smoking on the course of ulcerative colitis. Am J Gastroenterol 2001;96:2113–2116. 61 Russel MG: Changes in the incidence of inflammatory bowel disease: What does it mean? Eur J Intern Med 2000;11:191–196. 62 Logan RF: Inflammatory bowel disease incidence: Up, down or unchanged? Gut 1998;42: 309–311.

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Review Article Dig Dis 2003;21:105–128 DOI: 10.1159/000073243

Rationale for Probiotic and Antibiotic Treatment Strategies in Inflammatory Bowel Diseases Michael Schultz Jürgen Schölmerich Heiko C. Rath Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

Key Words Inflammatory bowel disease W Antibiotics W Probiotics

Abstract Inflammatory bowel diseases (IBD), commonly referred to as Crohn’s disease and ulcerative colitis are chronic aggressive disorders which share many similarities concerning pathomechanism and clinical course, but have very distinct features. Both entities are mainly located in areas with high bacterial concentrations, such as the terminal ileum and cecum in Crohn’s disease and the rectum in ulcerative colitis. In recent years, overwhelming evidence accumulated, supporting the hypothesis that IBD are characterized by a genetically determined, overly aggressive immune response towards ubiquitous luminal antigens, especially commensal bacteria and their products. Trials in both human IBD and experimental colitis have demonstrated that broad-spectrum antibiotics may influence the course of ulcerative colitis and Crohn’s disease and antibiotics with narrow activity against the anaerobic fraction of the flora can prevent relapse in Crohn’s disease after surgically induced remission. Since relevant antibiotic strategies can be associated with some side effects, the ongoing research recently focused on alternative methods to modify the

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0212–0105$19.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ddi

intestinal flora in patients with IBD. Clinical observations including few controlled trials, basic research, and animal studies have suggested a potential role for probiotic bacteria within the treatment regimens for IBD. However, the mode of action of these organisms is still largely unclear and in vitro studies are inconclusive. This review summarizes recent in vitro and in vivo data regarding the role of the intestinal microflora in the pathogenesis of chronic intestinal inflammation and possible therapeutic mechanisms of probiotic bacteria relevant to IBD. Furthermore, we will review clinical trials examining the efficacy of antibiotic and probiotic treatment strategies in IBD. Copyright © 2003 S. Karger AG, Basel

Introduction

Crohn’s disease and ulcerative colitis, collectively referred to as inflammatory bowel diseases (IBD), are chronic aggressive disorders, which affect approximately 35–55/100,000 people in western Europe. Incidence and prevalence varies substantially between regions of the world with regard to different standards in lifestyle and hygiene. The disease normally starts in childhood or youth with a peak between 20 and 30 years of age.

Michael Schultz, MD Department of Internal Medicine I, University of Regensburg DE–93053 Regensburg (Germany) Tel. +49 941 944 7001, Fax +49 941 944 7002 E-Mail [email protected]

Although there are many similarities concerning pathomechanisms and clinical course, the disorders have very distinct features. Ulcerative colitis is characterized by inflammation with superficial ulcerations limited to the mucosa of the colon. It normally starts in the rectum and continuously spreads throughout the large intestine. Crohn’s disease, however, is characterized by a discontinuous pattern, potentially affecting the whole gastrointestinal tract. In contrast to ulcerative colitis, the inflammation is transmural with large ulcerations and occasional granuloma. Both entities are mainly located in areas with high bacterial concentrations, such as the terminal ileum and cecum in Crohn’s disease and the rectum in ulcerative colitis. Here, bacterial concentrations are as high as 1012 per gram dry weight of luminal content. Modern categorizing techniques reveal 300–400 distinct bacterial organisms, of which only few are well known, most are unculturable, unnamed and only described by shape and staining features. It is the enormous bacterial concentration and the close contact to the gastrointestinal mucosa, the largest surface of the body, equipped with a highly sophisticated immune system, which always incriminated luminal bacteria in the pathogenesis of IBDs. Since the first descriptions by Samuel Wilks in 1859 and Burrell B. Crohn in 1932, extensive studies have tried to identify a specific pathogen that could be of etiologic importance for ulcerative colitis and Crohn’s disease. Research in this field was intensified by the fact that Helicobacter pylori was found to be the cause for peptic ulcer disease. Results including bacterial culture, antibody response, and PCR techniques have always been controversial and did not reveal strong evidence for single pathogens as the cause of IBD. On the other hand, overwhelming evidence accumulated, supporting the hypothesis that IBDs are characterized by a genetically determined, overly aggressive, immune response to ubiquitous luminal antigens, including commensal bacteria and their products. However, not all bacterial subsets of the luminal flora possess equal pro-inflammatory properties. It has been suggested that the flora can be divided into three functional categories: neutral organisms (e.g. Escherichia coli sp.), health-promoting organisms (probiotics, e.g. Lactobacilli, Bifidobacteria, etc.), and potentially pathogenic organisms (e.g. Bacteroides sp.) [1]. Antibiotic trials in both IBD [2] and experimental colitis have demonstrated that mainly Crohn’s disease can be attenuated with broadspectrum antibiotics or antimicrobial agents affecting primarily the anaerobic fraction of the flora [3–6]. Also, fecal stream diversion and bowel rest seem to be an effective

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tool to reduce the bacterial load in an affected area and promote wound healing [7]. Since any antibiotic therapy can be associated with major or minor side effects, the focus of ongoing research was recently shifted towards alternative methods to alter the intestinal flora in patients with IBD. As early as in 1907, Elias Metchnikoff suggested that intestinal bacteria, and especially lactic acid bacteria, play a beneficial role regarding the health of patients [8]. These beneficial microorganisms are commonly called probiotics and are defined as living food supplements which beneficially affect the health status of the host [9]. Preferably, they should be of human origin, nonpathogenic, resistant to technical processes as well as to gastric acid and bile salts, adhere to intestinal epithelial cells, persist for some time in the gut lumen, modulate the immune response and produce antimicrobial substances [10]. Since then, probiotic activity has been associated mainly with lactic acid bacteria, bifidobacteria, and other nonpathogenic strains, including certain Enterococci, E. coli, and non-bacterial organisms such as Saccharomyces boulardii [11]. However, comprehensive comparison of probiotic performance and safety assessment has not been performed yet. Clinical observations including few controlled trials, basic research, and animal studies have suggested a potential role for probiotic bacteria within the treatment regimens for IBD [12, 13]. So far, it is known that different probiotics act differently regarding the local effect on the intestinal flora, and the modulation of the immune system. In that respect, few studies have been conducted using probiotic microorganisms in combination. While the clinical efficacy was well demonstrated, the mode of action of these organisms is still largely unclear and in vitro studies are inconclusive. This review summarizes recent in vitro and in vivo data regarding the role of the intestinal microflora in the pathogenesis of chronic intestinal inflammation and possible therapeutic mechanisms of probiotic bacteria relevant to IBD. Furthermore, we will review clinical trials examining the efficacy of antibiotic and probiotic treatment strategies in IBD.

Genetic Susceptibility towards Intestinal Bacteria

There is strong evidence that IBD depends on a specific genetic background, as demonstrated by the different susceptibility of various animal strains to experimental colitis, increasing frequency of IBD in affected families, higher concordance between monozygotic twins com-

Schultz/Schölmerich/Rath

pared with dizygotic twins, and chromosomal alterations in patients with Crohn’s disease. Host response to commensal bacteria may also be genetically engineered. Lewis rats, injected with purified PG-PS into subserosal lymphoid aggregates, as described earlier in this chapter, spontaneously develop a relapse of chronic granulomatous enterocolitis with extraintestinal liver and joint manifestations, after an initial acute phase and consecutive remission, but Buffalo and Fischer rats display only mild local inflammation, and no extraintestinal manifestations [14]. Lewis rats with predominantly anaerobic bacterial overgrowth in a jejunal self-filling blind loop develop spontaneous hepatobiliary inflammation but not Fischer and Buffalo rats [15]. Wistar rats exhibit a delayed inflammatory response. Lewis rats, injected subcutaneously with indomethacin develop chronic ulcerative small intestinal inflammation with hepatic manifestation, whereas this injury in Fischer rats spontaneously resolves and is only restricted to the midsmall bowel in contrast to the above rat strains [16]. Lewis rats have a defective neuroimmunologic driven antiinflammatory response, with low corticosterone levels in the mucosal tissue [17], low activation of plasma kallikrein and abnormal high bradykinin liberation compared with Buffalo and Fischer rats [14]. Recently various inbred strains of mice (C3H/HeJ, C3H/HeJBir, C57BL/6J, DBA/2J, NOD/LtJ, NOD/LtSz-Prkdc(scid)/ Prkdc(scid), 129/SvPas, NON/LtJ, and NON.NODH2g7) were screened for genetically determined differences in susceptibility to DSS-induced colitis. This study demonstrated major differences in genetic susceptibility to DSS-induced colitis among inbred strains of mice [18]. C3H/HeJ mice developed severe colitis only after challenge with DSS, whereas the C3H/HeJBir mouse strain developed spontaneous colitis. However, it is not clear whether this goes together with defects or deletions of the Toll-like receptor 4 locus [19]. Most recently, a polymorphism in the NOD2 gene was described as a member of a super family of apoptosis regulators, which is expressed in monocytes, and activates nuclear factor NFÎB. It was concluded that this activation is regulated by an intracellular receptor for components of microbial pathogens; however, this topic is still under investigation. To date it is not entirely clear how the NOD2 mutation creates the phenotype seen in IBD [20, 21].

Rationale for Probiotic and Antibiotic Treatment Strategies in IBD

Persistent Pathogenic Microbes in the Pathogenesis of IBD

Macroscopically and histologically, Crohn’s disease can barely be distinguished from ileocecal and rectal manifestations of abdominal tuberculosis, featuring ulcers, abscesses and fistula. Salmonella, Yersinia enterocolitica, Shigella and Campylobacter are other pathogens leading to intestinal inflammation resembling Crohn’s disease or ulcerative colitis. Although no evidence exists that an infection with these pathogens can initiate IBD, clinical observations demonstrate that certain intestinal and extraintestinal bacterial infections sometimes precede or reactivate chronic intestinal inflammation. Possible disease-modifying mechanisms of transient pathogens are the disruption of the mucosal barrier, allowing increased uptake of luminal antigens, mimicry of self-antigens and permanent modulation of the mucosal immune system via the activation of the NF-ÎB pathway. There are few persistent pathogens under current investigation, but none have been proven to be relevant in IBD.

Alteration of the Mucosal Barrier and the Possible Impact of Probiotic Therapy

A major task of the intestine is to form a defensive barrier to prevent absorption of damaging substances from the external environment. There is evidence, that this permeability is increased in most patients with Crohn’s disease and even in 10–20% of their clinically healthy relatives [22]. If this precedes the onset of the gastrointestinal manifestation of IBD or is simply an unspecific epiphenomenon is still subject of discussion [23]. The abnormal leakiness of the mucosa in Crohn’s patients and their relatives can be amplified by oral administration of non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin [24]. A broken mucosal barrier may then result in increased uptake of bacteria and their products [25] and lead to chronic inflammation and entering a vicious circle when bacterial products, such as FMLP, will undergo enterohepatic circulation and by itself reduce the mucosal barrier even further [26]. Important contributors to the mucosal barrier are epithelial tight junctions and the superficial mucus. Defective tight junctions in dominant negative N-cadherin transgenic mice lead to focal chronic intestinal inflammation and adenomas [27]. It has furthermore been shown in experimental models, that NSAIDs may disrupt the homeostasis of the intestinal flora and induce overgrowth of some bacterial species which

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exacerbate NSAID-induced mucosal injury [28–30]. Elliott et al. [31] studied the effect of bacterial colonization on ulcer healing in rats. Gastric ulcers were induced by serosal injection of acetic acid. Within 6–12 h of their induction, gastric ulcers were colonized by a variety of bacteria. Suppression of colonization with streptomycin and penicillin markedly accelerated healing. The induction of Lactobacillus colonization with oral administration of lactulose also accelerated the healing process, suggesting a protective effect by these bacterial species. Administration of an antibiotic-resistant E. coli strain reversed the beneficial effect of antibiotics. The positive effect of Lactobacillus GG ingestion on the gastrointestinal mucosal barrier was studied in detail by several investigators. The intestinal permeability of 14day-old suckling rats was greatly enhanced by daily gavage with cow’s milk, as documented at 21 days by increased absorption of intact horseradish peroxidase, but the addition of Lactobacillus GG to cow’s milk counteracted this permeability disorder significantly [32]. Gotteland et al. [33] showed that heat-killed Lactobacillus GG did not modify the indomethacin-induced increase of gastrointestinal permeability in human volunteers; however, live bacteria significantly reduced the alteration of gastric but not intestinal permeability. Oral administration of Lactobacillus plantarum 299v to an animal model of spontaneous bacterial peritonitis due to portal hypertension did not inhibit the bacterial translocation of intestinal E. coli and did therefore not change the course of the disease but other experimental settings showed contradictionary results, especially in models for acute liver injury [34; and R. Wiest, pers. commun.]. Recent pilot studies have demonstrated that the new probiotic compound, VSL#3, is efficacious as maintenance therapy in pouchitis and ulcerative colitis [35, 36] but mechanisms remained unclear. The aim of a further study was therefore to determine the efficacy of VSL#3 as a primary therapy in the treatment of colitis in the IL10–/– mouse model, while mechanisms of action were investigated in T-84 monolayers in vitro. Treatment with VSL#3 resulted in normalization of colonic barrier integrity in conjunction with a reduction in mucosal secretion of TNF-· and IFN-Á and an improvement in histologic disease. In vitro studies showed that epithelial barrier function and resistance to Salmonella invasion could be enhanced by exposure to a protein-like soluble factor secreted by the bacteria found in VSL#3. Since VSL#3 is a compound of different bacteria, it remains unclear, which member of the preparation is responsible for the observed mechanism [37].

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Pro- and Anti-Inflammatory Capabilities of Commensal Bacteria

IBD as the Result of an Aberrant Intestinal Microflora? In a healthy body, the intestinal microbial flora forms an immunologically balanced symbiosis with the mucosal immune system. This genetically engineered delicate balance between the host defense and the potentially aggressive luminal content is disrupted in patients with IBD. Data from different groups suggest that the bacterial profile might be genetically determined and is relatively stable throughout live [38]. There is evidence for the possibility that the fecal flora differs in patients with active IBD compared to quiescent disease or healthy volunteers. This was demonstrated by Giaffer et al. [39]: while the total concentration of anaerobic organisms in IBD was not different compared to normal controls, Bifidobacteria seemed to be decreased, whereas Bacteroides vulgatus and Bacteroides fragilis were increased. The intestinal flora in IBD was studied in more detail by other investigators, who in contrast demonstrated a significant decrease in the number of anaerobic bacteria and Lactobacilli in patients with active but not inactive ulcerative colitis [40, 41]. In Crohn’s disease, Enterobacteriaceae were observed significantly more frequently than in healthy patients, while there was no difference between active and quiescent disease [42]. Furthermore, a decrease in fecal concentrations of Bifidobacteria in Crohn’s disease and in patients with active pouchitis has been reported [43]. The hypothesis of bacterial influence on the pathogenesis of IBD is strongly supported by the attenuation or complete absence of colitis in a germ-free environment in a variety of animal models of chronic intestinal inflammation [44]. Germ-free and disease-free HLA-B27 transgenic rats as well as IL-10 knockout (IL-10 –/–) and to some extent IL-2 knockout (IL-2 –/–) mice, contaminated with a specific pathogen-free flora develop colitis and gastritis correlating with the time of contamination [45–47]. However, not all bacteria have equal proinflammatory capabilities as demonstrated by selective colonization in a gnotobiotic environment. HLA-B27 transgenic rats, raised under germ-free conditions, develop only moderate colitis and gastritis if colonized with a cocktail of 5 different bacterial strains including Bacteroides vulgatus, and neither colonic nor gastric inflammation if colonized with the same cocktail excluding B. vulgatus [45]. Interestingly, monoassociation with B. vulgatus leads to colonic inflammation to the same degree as the whole cocktail including B. vulgatus, but not to gastritic inflammation implicating, that some bacteria, although not involved in the induction

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of disease at the primary site, may account for secondary inflammation at remote sites of the gut [48]. Reports of B. vulgatus-induced colitis also exist from carrageenanfed guinea pigs [4] and TCR· –/– mice [49]. The response to selective subsets of the enteric flora may be genetically determined and therefore host depending. Gnotobiotic IL-10 –/– mice, colonized with the cocktail as described above including B. vulgatus developed only mild colitis [46], while mice monoassociated with Enterococcus fecalis exhibited moderate colitis and a selective in vitro T cell response [50]. The more aggressive colitis in animal models colonized with a specific pathogen-free flora suggests synergistic effects of different strains. This is supported by the failure of metronidazole, which is selectively active against anaerobic bacteria, to attenuate established intestinal inflammation but to prevent the onset in different animal models for experimental colitis [51, 52]. Treatment with broad-spectrum antibiotics (vancomycin/imipenem) reduced established intestinal inflammation to almost normal degree [51]. The pathomechanism by which intestinal bacteria exert their proinflammatory influence is not completely understood. It is still controversial whether commensal bacteria and their products induce chronic intestinal inflammation and extraintestinal manifestation through antigens, such as peptidoglycan-polysaccharides (PG-PS), lipopolysaccharides (LPS), or bacterial DNA motifs (CpGs), which abnormally interact with the mucosal immune system or whether bacteria simply secondarily invade ulcers in inflamed areas and perpetuate established disease. Liu et al. [53] have detected E. coli, Listeria and Streptococcus antigen in Crohn’s disease ulcers using immunohistochemistry. Macrophages and giant cells immunolabeled for this antigen were distributed underneath ulcers, along fissures, around abscesses, within the lamina propria, in granulomas, and in the germinal centers of mesenteric lymph nodes. More recently, quantitative competitive polymerase chain reaction (PCR) of paraffin-embedded intestinal specimens from 212 patients showed that Pseudomonas fluorescens DNA was present in 43% of colonic lesions in Crohn’s disease but only in 9% in lesions of ulcerative colitis and 5% of non-IBD specimens [54]. This was prevalent regardless of disease status. Enzyme-linked immunosorbent assay analysis (ELISA) showed IgA seroreactivity in 54% Crohn’s disease patients, but only in 4% of normal controls. There is also strong evidence that commensal bacteria from the distal intestine produce proinflammatory agents which activate the mucosal immune system. Bacterial cell

wall polymers, such as LPS and PG-PS can induce experimental colitis in susceptible animal models [44]. PG-PS, subserosally injected in the cecum of rats, can induce chronic, spontaneously relapsing, granulomatous disease, with local enterocolitis and associated extraintestinal manifestations such as distal arthritis and granulomatous hepatitis [55]. PG-PS may also account for hepatobiliary manifestations induced by experimental bacterial overgrowth in jejunal self-filling blind loops in genetically susceptible Lewis rats [56]. Formylated oligopeptides, such as N-formyl-methionyl-leucyl-phenylalanine (FMLP), synthesized by colonic bacteria could be important in the pathophysiology of colonic inflammation and is frequently associated with hepatobiliary complications [25]. An enterohepatic circulation of synthetic FMLP has been demonstrated in the rat. Following colonic instillation of FMLP, the mean biliary excretion was almost 10-fold higher in rats with colitis compared with non-inflamed controls and could be attributed to the increased mucosal permeability [26]. Recently, some attention has been drawn to CpG motifs of bacterial DNA which stimulate a variety of immunecompetent cells to a TH1-dominated response. Using the dextran-sodium sulfate (DSS) mouse model, Obermeier et al. [57] could demonstrate that CpGs aggravated the inflammation if given in the acute or chronic phase of intestinal inflammation, but pretreatment with CpGs resulted in reduced inflammation suggesting induction of tolerance to bacterial antigens. Whether the intestinal microflora can be drastically altered by oral administration of high concentrations of probiotic microorganisms is still unclear. This would depend in part on the resistance of the administered strains to gastric acid, bile salts, and pancreatic enzymes, but the fate of the probiotic organism within the intestinal tract is known for only a few strains. Lactobacillus rhamnosus strain GG (Lactobacillus GG), for example, can be detected in stool samples as viable bacteria for up to one week after the oral administration has ceased [58, 59] and Lactobacillus acidophilus (Lactobacillus johnsonii strain La1) and Bifidobacterium sp. can be found in ileal fluid following oral administration [60, 61]. Survival in gastric acid is also known for most other lactic acid bacteria, including Lactobacillus reuteri (various strains), Lactobacillus gasseri strain ADH, Lactobacillus plantarum 299, with the exception of Lactococcus lactis, which is largely inactivated in the duodenum by bile salts [62]. In a later study however, this Lactococcus lactis was engineered to secrete biologically active murine IL-10 in the colon. The anti-inflammatory effect was documented in the treat-

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ment of murine chronic colitis induced by DSS and in prevention of spontaneous colitis in IL-10 –/– mice [63]. The ability to adhere to human intestinal epithelial cells might also be important for a suggested impact on the composition of the luminal flora. Most studies have been using in vitro settings with immortalized cell lines of human origin (HT-29 and Caco-2) to address this question. However, Alander et al. [64] were able to demonstrate adherence of Lactobacillus GG to human colonocytes in vivo. The test subjects consumed a whey drink fermented with Lactobacillus GG for 12 days. The presence of Lactobacillus GG was then checked both in the fecal samples and in the colonic biopsies obtained from various locations in the large intestine following evacuation of the colon using laxatives. In all patients, Lactobacillus GG was the dominant fecal lactic acid bacterium, and in 4/5 patients, Lactobacillus GG could also be recovered from the biopsies, while in one patient, who suffered from ulcerative colitis, no Lactobacillus GG was isolated from biopsies. All other volunteers had no intestinal disorders. Furthermore, it has been shown that several L. acidophilus strains (LB, LA1) and Lactobacillus GG bind to enterocyte-like Caco-2 cell lines [65–67], while Lactobacillus bulgaricus and several other Bifidobacterium and Lactobacillus strains showed none or very weak adhesive properties. Additionally, it was shown that L. acidophilus LA1 inhibits cell attachment and invasion by enterotoxigenic and enteropathogenic E. coli, and Salmonella typhimurium and cell invasion by Yersinia pseudotuberculosis [66]. This was also documented for E. coli strain Nissle. While in vivo experiments have suggested a protective effect of E. coli strain Nissle against S. typhimurium infection, it was shown that it directly inhibits the invasion of this pathogen and of adherent-invasive E. coli, using the human epithelial cell line INT407 [68, 69]. Several other lactic acid bacteria and E. coli strain Nissle 1917 have also been demonstrated to effectively inhibit the in vitro growth of many enteric pathogens including S. typhimurium, Staphylococcus aureus, enteropathogenic E. coli, Clostridium perfringens, Clostridium difficile, Listeria monocytogenes, and Candida albicans [70–72]. Different mechanisms have been described, responsible for this antimicrobial effect, which will strengthen the position of a probiotic organism in a highly competitive environment such as the intestinal microflora. For Lactobacillus GG, the secretion of a microcin has been documented [70] which is active against a wide range of other intestinal bacterial inhabitants, such as anaerobic bacteria (Clostridium spp., Bacteroides spp., Bifidobacterium spp.) and members of the family Enterobacteriaceae, Pseudomonas

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spp., Staphylococcus spp., Streptococcus spp. as demonstrated by a microbiological assay. However, it did not inhibit other lactobacilli. Lactobacillus plantarum 299v enhances intestinal mucin gene expression (MUC2, MUC3) to inhibit the adherence of enteropathogenic E. coli to HT-29 cells [73], but other mechanisms to enhance survival in a highly populated environment are also suggested [72]. Due to feasibility aspects, most studies of the human intestinal microflora usually involve analyses of the bacterial composition in fecal samples. Therefore, studies on the impact of oral administration of probiotic microorganisms on the intestinal microflora are limited. Tannock et al. [74] recently analyzed the fecal microflora of human subjects consuming Lactobacillus rhamnosus strain DR20. Lactobacillus and enterococcal contents of the intestinal flora were only transiently altered, without markedly affecting biochemical and other bacteriological factors. Similarly, Venturi et al. [35] demonstrated significant changes of the composition of the luminal flora but just affecting a small fraction. Patients with ulcerative colitis in remission were treated with a probiotic preparation (VSL#3) p.o. for 12 months, containing large numbers of seven different bacterial strains (4 strains of lactobacilli, 3 strains of bifidobacteria, and 1 strain of Streptococcus salivarius ssp. thermophilus). Throughout the treatment period, increased fecal concentrations of the administered strains (S. salivarius spp. thermophilus, bifidobacteria and lactobacilli) were found in all patients, but returned to basal levels only 15 days after administration had ceased. Concentrations of Bacteroides, clostridia, coliforms, total aerobic and anaerobic bacteria did not change significantly during treatment.

Immune Effects of Commensal Bacteria

It is still unknown how the immune system is able to distinguish between own and foreign, good and bad, health-promoting and pathogenic luminal contents. Since the impact on the intestinal microflora by probiotics is limited, and the clinical relevance of the increased gut permeability in IBD is unclear, interest recently shifted towards the influence of probiotics on the host’s immune system. Animal experiments document that the commensal microflora is the major stimulus to the gut immune system and is also a potent regulator of the innate immune system [75–77]. The current hypothesis of the interaction between the intestinal microflora and the mucosal immune system

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suggests a central role for M cells located in the area of Peyer’s patches to take up antigenic material [78]. The small intestine, where Peyer’s patches are situated, is populated by a relatively small number of microorganisms (103–8 CFU/g fecal content), compared to the large intestine (1011–14 CFU/g fecal content). It seems possible that the oral intake of approximately 1010 probiotic microorganisms daily can influence the gut immune system by uptake through Peyer’s patches [79]. Further evidence of host-depending immunologic response to residual bacterial flora was provided by Duchmann et al. [80]. Mononuclear cells from spleen, small and large bowel of mice did not proliferate when exposed to autologous bacterial sonicates, but proliferated when exposed to bacterial sonicates derived from a heterologous intestine. Moreover, it was shown that both local and systemic tolerance to autologous flora were broken in TNBS-induced colitis. Tolerance to autologous flora could be restored and colitis abrogated in mice systemically treated with IL-10 or antibodies to IL-12 suggesting a TH1-type of immunoresponse, but the treatment did not influence the proliferation induced by heterologous flora. It was furthermore shown that LPMC isolated from inflamed areas of the intestine of patients with active IBD strongly proliferated after co-culture with sonicated autologous flora in contrast to LPMC from noninflamed areas from the same patients and PBMC from patients with IBD or controls [81]. These cells from controls, however, strongly proliferated after co-culture with bacterial sonicates from heterologous intestinal contents. T-cells play an important role in IBD. In particular, TH1-mediated cytokines such as IL-2 and IFN-Á have been detected in the mucosa of Crohn’s disease patients while in ulcerative colitis the profile of mucosal cytokines seems to belong to the TH2 type with increased production of IL-4 and IL-10 [82]. This has largely been confirmed by animal models with experimental colitis [83]. The T cell response in experimental colitis is characterized by a TH1 profile, as demonstrated by the induction of spontaneous chronic colitis in SCID mice after transfer of CD45RBhigh cells, derived from BALB/c donors [84]. This was confirmed in IL-10 –/– mice which develop colitis and express high IL-12 and IFN-Á levels in the presence of conventional flora. The disease is attenuated in specific pathogen free environment and completely absent under germ-free conditions [46]. This TH1 response is directed against luminal bacteria, as demonstrated by IFN-Á secretion of T cells of CD3Â transgenic mice substituted with bone marrow cells after in vitro stimulation with sonicates of normal luminal flora [85]. The importance of T cells was fur-

ther illustrated by experiments with HLA-B27 transgenic rats. Creation of a self-filling blind loop of the cecum leads to highly aggravated inflammation with mainly anaerobic bacterial overgrowth. Exclusion of the cecum from the fecal stream, with subsequent decrease of total bacterial counts, does not only result in complete resolution of the local inflammation but also of the gastritis [86], suggesting primary response of T cells, located in the lymphoid aggregates of the cecal tip. These findings are further supported by attenuated colitis in T cell receptor · –/– mice after appendectomy [87]. When TCR-· –/– mice underwent appendectomy at 3–5 weeks, the number of mesenteric lymph node cells at 6–7 months was significantly less than in the sham-operated TCR-· –/– controls. Furthermore, appendectomy at 1 month of age suppressed the development of colitis at 6–7 months of age, leaving only 3% of knockout mice with intestinal inflammation, compared with 80% of controls. These results supported that lymphoid follicles located in the appendix may play an important role in the development of chronic colitis. There is a large body of evidence for the modulation of cytokine production by probiotic bacteria. While it could be demonstrated in both human IBD and animal models with experimental colitis that levels of certain proinflammatory cytokines (IFN-Á, TNF-·) decrease following the administration of probiotic preparations [88–90], it remains unclear whether this effect is due to the attenuation of the disease or directly influenced by the probiotic microorganism. To overcome this problem, human intestinal cell lines [91] and peripheral blood mononuclear cells [92] were stimulated with nonpathogenic and pathogenic bacteria, and cytokine responses as well as cytokine gene transcription were measured. According to recent studies by Miettinen et al. [93, 94], lactic acid bacteria induce the production of several cytokines, including IL12, IL-18, IFN-Á, TNF-·, IL-6 and IL-10 in human monocytes and additionally activate NF-ÎB and STAT signalling pathways [95], but not resulting in a clear pro- or antiinflammatory profile. Lammers et al. [96] analyzed different probiotic Gram-positive and Gram-negative bacteria regarding their ability to induce IL-8 secretion in the human HT29/19A cell line. While the Gram-positive microorganisms Lactobacillus GG and lactobacilli and bifidobacteria from VSL#3 did not induce IL-8 secretion, the Gram-negative E. coli strain Nissle induced a dosedependent secretion, further suggesting that probiotic bacteria exert their beneficial effects on the host by a different mechanism of action. We were able to confirm these results and observed a significant induction of NF-

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ÎB-mediated IL-8 secretion of HT-29 cells upon stimulation with the probiotic microorganism E. coli strain Nissle, but not with Lactobacillus GG, Lactobacillus reuteri, L. acidophilus or Saccharomyces boulardii [unpubl. data]. In vivo, there was no effect by repeated oral exposure to viable or nonviable L. acidophilus, Lactobacillus GG, or Streptococcus thermophilus on basal cytokine mRNA expression in Peyer’s patches, spleen or mesenteric lymph nodes of mice [97]. Recently, the probiotic compound VSL#3 has been studied in in vivo and in vitro settings regarding the impact on the cytokine profile in pouchitis. For this purpose, pouch biopsy samples were obtained from 7 patients with chronic active pouchitis before and after antibiotic (ciprofloxacin and rifaximin) and probiotic treatment. Tissue samples from 5 patients with a normal pouch have been used as control. Tissue levels of TNF-· were increased (p ! 0.01) in active pouchitis compared to the uninflamed pouch and reduced after antibiotic and probiotic treatment. Also IFN-Á and IL-10 tissue levels were augmented in pouchitis and also decreased following treatment. Levels of IL-4 and IL-10 were unchanged in inflamed pouches, and unaffected by antibiotic treatment. However, IL-10 increased following probiotic treatment. Moreover, inflamed pouches had higher levels of inducible nitric oxide synthase and gelatinase activities which decreased following treatment [88]. Regarding humoral immune responses within the intestinal tract, it is noteworthy that there is evidence of a local overproduction of IgG with a relative mucosal IgA deficiency in patients with Crohn’s disease [98]. There have been several reports describing the effects of probiotics on sIgA, and especially several Lactobacilli sp. were shown to enhance IgA immune responses [99, 100]. Malin et al. [101] studied the effect of oral bacteriotherapy with human Lactobacillus GG in children with Crohn’s disease (n = 14) and juvenile arthritis (n = 9). The mean number of antibody-secreting cells in the IgA class to ß-lactoglobulin and casein increased significantly following 10 days of treatment. This indicates that orally administered Lactobacillus GG has the potential to increase the gut immune response and thereby promotes the gut immunological barrier. Furthermore, Kaila et al. [102] could demonstrate a significantly enhanced non-specific humoral immune response during the acute phase of rotavirus infection in children, reflected by increased numbers of IgG-, IgA- and IgM-secreting cells due to treatment with Lactobacillus GG. At convalescence, 90% of the study group versus 46% of the placebo group had developed a specific response to rotavirus.

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While it is difficult to assess innate immunity, several studies have suggested an enhancement with probiotic bacteria. Nonspecific immunity was measured by determining phagocytosis as well as a modified cytokine production [103–105]. We were able to demonstrate a modulated cytokine response by peripheral blood mononuclear cells stimulated by intestinal bacteria in volunteers following 5 weeks of daily oral Lactobacillus GG intake with an increase of IL-10 secretion and a significant decrease of the proinflammatory cytokines TNF-· and IL-6, while IFN-Á showed a trend towards decreased secretion [106]. Schiffrin et al. [107] demonstrated enhanced leukocyte phagocytosis of E. coli sp. following the administration of L. acidophilus strain La1 or Bifidobacterium bifidum strain Bb12 for 3 weeks in healthy volunteers. Most of the described effects on the human immune response are mediated by viable bacteria only, while the administration of nonviable bacteria or bacterial components had no effect. However, the underlying mechanisms have not yet been identified. Recently, Neish et al. [108] demonstrated that a non-pathogenic strain of Salmonella is able to abrogate synthesis of inflammatory cytokines by gut epithelial cells. The bacteria accomplish this by blocking degradation of IÎB, an inhibitor of the master transcription factor NF-ÎB. It has been concluded, that the normal gut flora is therefore able to induce a distinctive form of tolerance in gut epithelial cells. However, whether this is the mode of action for probiotic bacteria to mediate the clinically observed anti-inflammatory effects intestinal diseases remains unclear.

Clinical Rationale for Probiotic Therapy

Clinical data support the experimental evidence of the crucial role for luminal bacteria in the pathogenesis of IBD. Since recurrent aphthous lesions in the neoterminal ileum of Crohn’s disease patients are observed within a few months after curative resection of the distal ileum, fecal components were incriminated in the pathogenesis. Following curative ileal resection and ileocolonic anastomosis in 5 patients with Crohn’s disease, a diverting terminal ileostomy was constructed 25–35 cm proximal to the anastomosis. Six months following exclusion, none of the 5 patients had endoscopic lesions in the neoterminal ileum, but 6 months after reanastomosis all patients had significant recurrence of disease [109]. To further investigate the requirement of intestinal components in the course of mucosal inflammation,

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D’Haens et al. [110] reinfused autologous intestinal luminal contents into the excluded ileum in 3 patients with Crohn’s disease following ileocolonic resection and creation of a proximal loop ileostomy, and determined inflammatory changes by histology and electron microscopy. Eight days after infusion focal infiltration of mononuclear cells, eosinophils, and neutrophils into the lamina propria, small vessels, and epithelium was observed. Additionally, markers for epithelial transformation and lymphocyte recruitment were elevated, further emphasizing that intestinal components may trigger postoperative recurrence of Crohn’s disease. Although previously the requirement of viable bacteria was suggested there is evidence that humoral and, more likely, cellular immune responses to bacterial components are the main mediators of chronic intestinal inflammation. Duchmann et al. [111] performed an analysis of T cell clones from peripheral blood, and non-inflamed and inflamed intestinal tissue from IBD patients and control individuals. He could demonstrate, that all T cell clones reacted selectively to bacterial stimuli and only !3% were cross-reactive. These specific T cell clones were more frequently isolated from inflamed tissue than from peripheral blood or non-inflamed intestinal tissue. He could further demonstrate that broken tolerance towards autologous bacteria could be a central feature of patients with IBD as outlined in detail earlier in this review [81]. Mucosal immunoglobulins were isolated from endoscopic washings from Crohn’s disease patients, patients with ulcerative colitis, inflammatory and non-inflammatory controls. Total mucosal IgG was significantly higher in active Crohn’s disease and ulcerative colitis compared with non-inflamed controls. However, no difference was detected compared to patients with nonspecific inflammation. But specificity to proteins of a range of nonpathogenic commensal fecal bacteria was significantly higher in active Crohn’s disease than in ulcerative colitis and non-IBD inflammation or non-inflammatory controls [112]. These results further supported the hypothesis of a breakdown of tolerance to the normal commensal flora of the gut in patients with active IBD, especially Crohn’s disease. The etiopathogenic role of B cell response in chronic intestinal inflammation remains unclear, since it does not play a significant role in chronic experimental colitis. Therefore, it cannot be excluded that elevated immunoglobulins are a secondary phenomenon due to a broken intestinal barrier in active disease.

The discussion about a potential role of pathogenic or commensal bacteria in the pathogenesis of IBD has led to multiple trials with therapeutic approaches using a variety of antimicrobial or probiotic agents. Most studies were performed under uncontrolled conditions. Only few trials, however, met the rigorous criteria of evidencebased medicine. These trials represent bridges from bench results to bedside application.

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Antibiotics against Commensal Intestinal Bacteria (table 1)

Metronidazole Back in 1978, Blichfeldt et al. [113] reported, in a placebo-controlled, double-blind, crossover study, significant improvement of symptoms and laboratory values with metronidazole 1 g daily over 4 months in patients with active Crohn’s disease, restricted to the colon. All patients were additionally treated with salazosulfapyridin or prednisone. In a Swedish randomized, double-blind, crossover trial 78 patients with active Crohn’s disease were investigated for two 4-month periods [114]. To compare the efficacy of metronidazole with sulphasalazine the Crohn’s Disease Activity Index (CDAI) by Best et al. [115] and plasma levels of orosomucoid were evaluated. In the first 4 months no difference in CDAI and erythrocyte sedimentation rate was found between the treatment groups. However, the plasma orosomucoid level was significantly reduced in the metronidazole group. In the patients who had active disease throughout the first period, a significant reduction of the CDAI could be observed in those who switched to metronidazole in the second 4 months, but not for those who switched to sulphasalazine. Those patients who responded already in the first period remained stable in the second phase regardless of the treatment procedure. However, the plasma concentration of orosomucoid increased significantly in patients treated with sulphasalazine but not in the metronidazole group. These data suggest that the antimicrobial capabilities of metronidazole are slightly more effective than sulphasalazine in the treatment of Crohn’s disease. In 1991, Sutherland et al. [116] included 105 patients with Crohn’s disease in a double-blind, randomized, placebo-controlled study investigating the efficacy of metronidazole in two doses (20 and 10 mg/kg) over a 14week period. There was a significant improvement in CDAI, C-reactive protein concentrations, and serum orosomucoid in both metronidazole groups compared to

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Table 1. Antibiotic therapy in IBD Type of study

Aim of clinical trial

Outcome

Reference

22

randomized double-blind cross-over

effect on symptoms and laboratory values in patients with active Crohn’s disease

significant improvement only in the 6/22 patients with colonic involvement

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78

randomized double-blind cross-over

cross-over trial to compare the efficacy of metronidazole with sulphasalazine in active Crohn’s disease

significant reduction of CDAI in patients who had active disease in the first 4 months and were switched to metronidazole

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105

randomized double-blind placebo-controlled

comparison of different doses in Crohn’s disease

greater improvement in disease activity receiving 20 mg/kg/ day compared to 10 mg/kg/day (NS), but 21 were withdrawn for deterioration of symptoms, 17 for adverse experiences, and 11 for protocol violation

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Ciprofloxacin

40

randomized

efficacy of ciprofloxacin compared with mesalazine in active Crohn’s disease

this study suggests that ciprofloxacin is as effective as mesalazine in treating mild to moderate flare-up of Crohn’s disease

126

Metronidazole/ ciprofloxacin

41

randomized partially masked

efficacy and safety of the combination of metronidazole and ciprofloxacin compared with methylprednisolone in active Crohn’s disease

45.5% in the antibiotic group and 63% receiving steroids went into clinical remission at the end of the 12-week treatment period (NS)

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233

retrospective

efficacy of metronidazole and/or ciprofloxacin in the treatment of acute Crohn’s disease

70.6% of the patients treated with the antibiotic combination achieved clinical remission, 72.8% with metronidazole, 69.0% with ciprofloxacin; remission lasted 1 year in each group; severe side effects, were observed in 20% of patients

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72

open

efficacy of the combination of ciprofloxacin and metronidazole in active Crohn’s disease

clinical response in 84% of patients with or without ileal involvement in comparison to 64% with ileal disease alone and in 86% without resection compared to 61% of those with previous resection

129

Rifampicin/ ethambutol

27

randomized double-blind crossover

efficacy of antimycobacterial therapy in active Crohn’s disease

no significant difference of CDAI or any clinical indicator of disease activity between the treatment groups

135

Rifampicin/ isoniazid/ ethambutol

130

randomized double-blind

efficacy of triple-antimycobacterial therapy in active Crohn’s disease

no difference between the two groups regarding radiological changes; in a follow-up after 5 years there was no evidence of consistent benefit or disadvantage from the antibiotic therapy regarding the number of acute relapses, surgical episodes, hospital admissions, disease activity, blood tests, or medication required

136, 137

Ethambutol/ clofazimine/ dapsone/ rifampicin

40

randomized, double-blind, crossover

efficacy of antimycobacterial therapy in refractory, steroid- dependent Crohn’s disease

3/19 patients on medication relapsed during the study period, compared with 11/17 on placebo; there was no substantial endoscopical or radiological effect

131

Clarithromycin

15

randomized, double-blind, crossover

efficacy of antimycobacterial therapy in active Crohn’s disease

5/7 patients receiving clarithromycin achieved remission compared with 1/8 patients in the placebo group; crossover revealed an effect only in 1/7 patients from the former placebo group now receiving clarithromycin

138

Clarithromycin/ ethambutol

31

placebo-controlled

effect on mucosal permeability

no difference between at the end of the treatment period and the 1-year follow up

139

Ornidazole

25

open

clinical effect in active disease

75% of patients; were clinically in remission after four weeks of treatment

121

Antibiotic therapy

Patients

Active Crohn’s disease Metronidazole

placebo. Patients receiving metronidazole 20 mg/kg/day had a greater improvement in disease activity than those receiving 10 mg/kg/day. However, this was not significant, probably due to the small sample size. 17 patients were withdrawn due to adverse events, but there was no

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difference between the groups. Subgroup analysis revealed a higher efficacy in patients with involvement of the large intestine or affecting both small and large bowel than in those with small bowel disease only.

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Table 1 (continued) Antibiotic therapy

Patients

Type of study

Aim of clinical trial

Outcome

Reference

Postoperative Crohn’s disease Metronidazole

60

randomized double-blind placebo-controlled

prevention of recurrence of Crohn’s disease in the neoterminal ileum

75% patients in the placebo, compared with 52% patients in the metronidazole group at 3 month group had recurrent lesions in the neoterminal ileum; antibiotic therapy significantly reduced the clinical recurrence rates at 1 year

117

Ornidazole

71

double-blind, placebo-controlled

prevention of postoperative recurrence of Crohn’s disease

Significantly increased rate of severe endoscopic lesions in patients on placebo in comparison with ornidazole treated patients at 3 and 12 months, but no data on tolerability and clinical outcome

120

Metronidazole

13

double-blind placebo-controlled crossover

effect on diarrhea in chronic pouchitis

significant decrease in stool frequency, but no effect on histological or serological marker

122

Rifaximin/ Ciprofloxacin

18

open

clinical effect on chronic active, treatment resistant pouchitis

88.8% patients either significantly improved or went into remission

130

83

randomized placebo-controlled

long term effect of ciprofloxacin to induce and maintain remission of ulcerative colitis

Clinical relapse rate 21% in the ciprofloxacin-treated group and 44% in the placebo group; endoscopic and histological findings demonstrated differences only at 3 months but not at 6 months

124

55

randomized placebo-controlled

to assess the therapeutic role of ciprofloxacin as an adjunct to corticosteroids in acute severe ulcerative colitis

a short course of intravenous ciprofloxacin does not seem to augment the effect of corticosteroids for patients with acute, severe ulcerative colitis

125

Chronic pouchitis

Ulcerative colitis Ciprofloxacin

More recently, Rutgeerts et al. [117] included 60 patients after curative ileal resection and primary anastomosis within 1 week after surgery in a double-blind, placebocontrolled trial using metronidazole to prevent recurrence of Crohn’s disease in the neoterminal ileum (fig. 1). For the treatment period of 3 months 30 patients received metronidazole (20 mg/kg) and the remaining patients placebo. After treatment was discontinued, 75% patients in the placebo group had recurrent lesions in the neoterminal ileum, compared with 52% patients treated with metronidazole. The severity of relapse was significantly reduced in the metronidazole-treated patients. Although discontinued after 12 weeks, metronidazole therapy statistically significantly reduced the clinical recurrence rates at 1 year, while the relapse rates at 2 and 3 years were not significantly different although sharing a similar trend. Nine patients dropped out due to side effects, 7 in the metronidazole group and 2 in the placebo arm. This study revealed the most compelling evidence of efficacy of metronidazole in Crohn’s disease patients. It demonstrated the prophylactic capabilities of metronidazole to prevent early relapse in patients in remission. This is consistent with experiments in three different animal models

of spontaneous and inducible colitis, where metronidazole prevented the onset of chronic colitis, but was unable to treat established intestinal inflammation [51, 52], incriminating a more narrow spectrum of predominantly anaerobic bacteria in the induction of relapse in Crohn’s disease than in perpetuating of acute inflammation. Widespread concern exists regarding severe permanent adverse events, especially peripheral neuropathy by the use of metronidazole. The specific bactericidal effect of metronidazole is probably due to the reduction of the 5-nitro group to a hydroxylamine group, which is able to bind to DNA, and thereby inhibiting further cell division. This mechanism is restricted to an environment only present in anaerobic micro-organisms. There is evidence that metabolic products of metronidazole also bind to neuronal RNA causing peripheral axonal degeneration [118], but reports on peripheral neuropathy are inconsistent in the literature. No symptoms have been reported in the use of a cumulative dose of less than 30 g. Most symptoms were mild and transient and related to daily doses higher than 20 mg/kg/day [119]. Discontinuation or dose reduction resulted in most cases in the resolution of symptoms.

Rationale for Probiotic and Antibiotic Treatment Strategies in IBD

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60 patients following ileal resection and primary anastomosis

Metronidazole 20 mg/kg body weight n = 30 Drop out n=7

Placebo n = 30 Drop out n=2

3 months

Recurrent lesions 12/23 patients 52%

Recurrent lesions 21/28 patients 75%

Severe lesions 12/28 patients 43%*

Severe lesions 3/23 patients 13% Clinical recurrence: 4%

1 year

Clinical recurrence: 25%*

Clinical recurrence: 26%

2 years

Clinical recurrence: 43%

Clinical recurrence: 30%

3 years

Clinical recurrence: 50%

Fig. 1. Controlled trial of metronidazole treatment for prevention of postoperative Crohn’s recurrence.

Due to these concerns, ornidazole was tested for the prevention of postoperative recurrence of Crohn’s disease. In the interim analysis, the authors reported on a significantly increased rate of severe endoscopic lesions in patients on placebo in comparison with ornidazoletreated patients at the 3- and 12-month intervals, but no data on tolerability and clinical outcome was given [120]. In an open trial, Triantafillidis et al. [121] studied the clinical effect of ornidazole in 25 patients with active Crohn’s disease (CDAI 1150 points). At the end of the 4-week treatment period, 75% of the patients were clinically in remission, while only minimal side effects were reported. Although clinical experience in ulcerative colitis reveals a dramatic benefit of a broad-spectrum antibiotic regimen adjunctive to conventional steroid therapy, in some patients with severe disease, the efficacy of antibiotic therapy, especially metronidazole is somehow discouraging. Patients with ulcerative pouchitis usually benefit from an antibiotic therapy. Metronidazole 400 mg three times daily for 7 days was given to patients with chronic pouchitis in a double-blind,

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placebo-controlled, crossover study [122]. At entry all patients had symptomatic pouchitis. Metronidazole decreased the number of bowel movements whereas placebo increased stool frequency. However, there was no significant change in the macroscopic or histological grade of inflammation or serum C-reactive protein level. Nonsevere side effects were observed in 52% of the patients. In an uncontrolled observation in 52 patients with pouchitis, clinical response to antibiotic treatment with metronidazole was 96% [123]. Some small uncontrolled trials report benefit of local instillation with 40 mg metronidazole suspension without detectable systemic concentrations and side effects. Ciprofloxacin An alternative to metronidazole is ciprofloxacin. Although it is not effective against facultative Gram-negative anaerobes such as Bacteroides spp., it covers a broad spectrum of intestinal bacteria and in contrast to metronidazole has some proven beneficial effect in patients with ulcerative colitis. In a controlled trial, Turunen et al. [124] evaluated the role of ciprofloxacin to induce and maintain remission of ulcerative colitis in patients previously poorly responding to conventional therapy with steroids and mesalazine. The patients were initially treated with high doses of prednisone on a tapering regime and maintenance treatment with mesalazine was commenced. Ciprofloxacin or placebo were administered for 6 months. During the treatment period, the relapse rate was 21% in the ciprofloxacintreated group and 44% in the placebo group. This difference was detected using predominantly clinical criteria. Endoscopic and histological findings demonstrated differences only at 3 months but not at 6 months. These modest results could not be confirmed in short-term treatment of acute ulcerative colitis [125]. In another randomized controlled trial Colombel et al. [126] investigated the efficacy of ciprofloxacin 1 g/day compared with mesalazine 4 g/day for 6 weeks in the treatment of active Crohn’s disease. Complete remission was observed in 56% of patients treated with ciprofloxacin and 55% of patients treated with mesalazine, suggesting ciprofloxacin to be equally effective as mesalazine in the treatment of mild-to-moderate active Crohn’s disease. Prantera et al. [127] conducted several trials using antibiotics in the treatment of active Crohn’s disease. In 1996 they investigated the efficacy and safety of the combination of metronidazole and ciprofloxacin compared with methylprednisolone in a randomized, partially masked trial including 41 consecutive patients with active

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Crohn’s disease. Patients were randomized to receive either ciprofloxacin 500 mg twice daily plus metronidazole 250 mg four times daily for 12 weeks, or methylprednisolone 0.7–1 mg/kg/day, with variable tapering to 4 mg daily. 45.5% in the antibiotic group and 63% receiving steroids went into clinical remission at the end of the 12week treatment period. The difference did not reach statistical significance, probably due to the small sample size. Five patients in both groups were considered treatment failures. Side effects were observed in 27.3% of antibiotic-treated patients and 10.6% on steroids. More recently, the same group retrospectively evaluated the efficacy of metronidazole and/or ciprofloxacin in the treatment of acute Crohn’s disease [128]. The clinical records of 233 inpatients treated for active Crohn’s disease with metronidazole and/or ciprofloxacin (1 g/day each) during the period 1984–1996 were reviewed. 70.6% of the patients treated with the antibiotic combination achieved clinical remission, 72.8% with metronidazole, and 69.0% with ciprofloxacin. Remission lasted about 1 year in each group. Side effects, requiring discontinuation of therapy, were observed in 20% of patients. The efficacy of the combination of ciprofloxacin and metronidazole in active Crohn’s disease was further studied in a open trial by Greenbloom et al. [129]. At the end of the 10-week treatment period, 49/72 patients reached clinical remission (68%) and 55/72 patients showed a clinical response (76%). The effect was even greater in patients with colonic disease with or without ileal involvement (84%) in comparison to patients with ileal disease alone (64%) and in patients without resection (86%) compared with those with previous resection (61%). In view of these data, it could be concluded that the combination of metronidazole and ciprofloxacin has some beneficial effect, but the antimicrobial effect is not broad and strong enough to reduce the bacterial load to the degree needed to reliably inhibit the inflammatory process. Other Antibiotics Local therapy with rifaximin together with oral ciprofloxacin might be an acceptable alternative in chronic active, treatment-resistant pouchitis. Gionchetti treated 18 patients with rifaximin 1 g b.i.d. and ciprofloxacin 500 mg b.i.d. for 15 days [130]. 88.8% patients either significantly improved or went into remission. No side effects could be observed. The fact that rifaximin plasma levels and urinary excretion were not measurable suggested a primarily topical effect. A significant reduction of total anaerobes and aerobes was observed.

Rationale for Probiotic and Antibiotic Treatment Strategies in IBD

There are also reports of a beneficial effect of amoxycillin/clavulanic acid, tetracycline and erythromycin. Based on these data it is obvious that some patients, especially those with large bowel involvement, may benefit from a reduction of the bacterial load. Therefore, differential antibiotic strategies are required, taking into account whether the patient is in remission or in active disease. Metronidazole alone should be restricted to maintenance strategies of remission, especially after surgery. Broad-spectrum combinations, such as ciprofloxacin and metronidazole may be of benefit as adjunctive therapy to standard protocols in the acute phase of inflammation. In some cases of colitis refractory to standard procedures including immunosuppressive drugs, accompanied with severe systemic disease, a bowel decontamination as described by Prantera et al. [131] may be considered.

Antimycobacterial Therapy

In 1913, Dalziel [132] reported similarities between ileocecal tuberculosis and granulomatous enterocolitis in ruminants (Johne’s disease) and a human idiopathic enterocolitis which was later described as Crohn’s disease. The debate about a pathogenic role for Mycobacterium tuberculosis in IBD was resurrected following the detection in resected Crohn’s disease tissues by direct culture and PCR as well as immunologic data and results from antibiotic trials. However, later studies, using highly sophisticated techniques revealed variable results and many failed to detect any evidence [133]. Furthermore, no evidence for a cell-mediated immune response towards mycobacteria has been gathered from patients with IBD [134]. Unfortunately, therapeutic approaches did not reduce the confusion regarding M. paratuberculosis in IBD. Several studies have been conducted, using classical antimycobacterial regimens, but most were open uncontrolled trials with little or no effect. Only three controlled trials are reported. 27 patients with active Crohn’s disease were included in a 2-year randomized, double-blind, crossover, controlled trial with rifampicin and ethambutol [135]. Fourteen patients completed the trial, while 4 patients were withdrawn due to adverse effects. There was no significant difference of CDAI or any clinical indicator or disease activity between the treatment groups. Swift et al. [136] Included 130 patients with active symptoms of Crohn’s disease in a double-blind, random-

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ized, controlled trial with rifampicin, isoniazid, and ethambutol, or identical placebos over a peroid of 2 years. Seventeen patients in the antibiotic group had side effects compared with 3 patients on placebo. There was no significant difference between groups regarding radiological changes of the extent of the disease. In a follow-up investigation after 5 years there was no evidence of a consistent benefit or disadvantage from the antimicrobial chemotherapy regarding the number of acute relapses, surgical episodes, hospital admissions, disease activity, blood tests, or medication required for Crohn’s disease [137]. Using a very broad spectrum of antimycobacterial drugs, 40 patients with refractory, steroid-dependent Crohn’s disease were randomized to receive 2 months of tapering steroids plus either a 9-month regimen of ethambutol, clofazimine, dapsone and 1-day dose only of rifampicin, or identical placebo, in a double-blind, placebocontrolled, crossover trial [131]. 3/19 patients on active medication relapsed during the study period, compared with 11/17 on placebo. Nine patients with relapse or persistent activity of the disease on placebo were crossed over to the active drug; five achieved sustained remission, two failed, and two were withdrawn for side effects. There was no substantial endoscopic or radiological effect. Data on clarithromycin, an antibiotic agent, effective against atypical mycobacteria, such as M. paratuberculosis, in the treatment of Crohn’s disease are rare and contradictory. In 1995, Graham et al. [138] performed a randomized, placebo-controlled, crossover trial to test clarithromycin 500 mg b.i.d. over 3 months in 15 patients with active Cronh’s disease with 1-year follow-up. 5/7 patients receiving clarithromycin achieved remission at the end of the treatment period compared with 1/8 patients in the placebo group. Crossover therapy revealed an effect only in 1/7 patients from the former placebo group. Once in remission no relapse was reported within the 1-year follow-up. On the other hand, the same group conducted a second controlled trial randomizing 31 patients into the treatment group with clarithromycin 500 mg b.i.d. and ethambutol 15 mg/kg/day or placebo over 3 months [139]. There was no difference between both groups at the end of the treatment period and the 1-year follow up. In summary, it is still unclear whether Mycobacteria paratuberculosis plays a role in chronic IBD in a small group of patients, or, as an environmental pathogen, is a matter of superinfection of Crohn’s disease-associated ulcers.

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Probiotic Therapy in Experimental Colitis

Beside in vitro experiments, the effects of probiotic microorganisms are often tested in animal models for experimental colitis. IL-10 –/– mice raised in a SPF environment spontaneously develop a chronic colitis, resembling human Crohn’s disease [140]. Madsen et al. documented a decreased concentration of colonic Lactobacillus sp., and an increase in colonic mucosal adherent bacteria in neonatal IL-10 –/– mice. Restoring Lactobacillus sp. to normal levels of control animals by oral administration of lactulose and rectal swabbing with Lactobacillus reuteri reduced colonic mucosal adherent bacteria and prevented the development of colitis [141]. These beneficial effects by Lactobacillus sp. to prevent experimental colitis were confirmed by other investigators. Healthy IL-10 –/– mice, when transferred from a GF environment into SPF conditions will develop a rapidly progressing intestinal inflammation within 4 weeks [46]. We were able to demonstrate that the disease can be significantly attenuated if the mice are colonized with Lactobacillus plantarum 299v 2 weeks prior to the transfer. This effect was accompanied by a significant reduction of IFN-Á secreted by stimulated mesenteric lymph node cells and colonic IL-12, however, administration of L. plantarum at the time of transfer had no effect [90]. Dieleman et al. [142] showed that the administration of Lactobacillus GG does not prevent colitis in HLA-B27 transgenic rats or treat established disease, but is superior to Lactobacillus plantarum 299v in the prevention of recurrent colitis after antibiotic treatment with vancomycin and imipenem. This was demonstrated by a significant reduced histological score, and biochemical markers. In another preventative setup, both probiotic preparations VSL#3 and Lactobacillus GG were shown to ameliorate colitis induced by iodoacetamide, but had no effect on the toxic, immunemediated DNBS-colitis in rats [143]. Another aspect of probiotic therapy is the question whether the use of prebiotics together with probiotics enhances the anti-inflammatory effects. Therefore, prebiotic oatbase is often administered together with lactobacilli. Recently, we were able to demonstrate an effect of oral administration of a new pre- and probiotic preparation of the treatment of established experimental colitis in HLA-B27 rats. The preparation consists of inulin as the prebiotic compound, and a combination of the probiotic microorganisms L. acidophilus La-5, and Bifidobacterium Bb-12 with a total bacterial concentration of 8 ! 107 CFU/ml. At 4 months of age, following 2 months of treatment, untreated rats had severe colitis in all colonic seg-

Schultz/Schölmerich/Rath

ments, but the inflammation was significantly diminished in the colon of rats treated with the pre- and probiotic preparation. However, since the probiotic microorganisms, added by the manufacturer, were not detectable in fecal samples of treated rats, inulin might be the relevant compound in this preparation [144]. To study the effect of fermentation, acute colitis in rats was induced by methotrexate, resembling a major side effect of many chemotherapeutic agents. Administration of lactobacilli, but not oatbase, decreased the intestinal myeloperoxidase level, and reestablished intestinal microecology. Both lactobacilli and oatbase reduced plasma endotoxin levels, but the effects of lactobacilli were greater with fermentation than without fermentation or oatbase alone, while Lactobacillus plantarum was more effective in reducing intestinal pathogens than Lactobacillus reuteri [145]. The effect on acute experimental colitis was furthermore confirmed by Holma et al. [146], but significant strain differences were documented, with Lactobacillus reuteri R2LC being superior to Lactobacillus rhamnosus GG in reducing the severity of acetic acid-induced colitis in rats. Various in vitro and in vivo studies have suggested possible mechanisms of probiotic bacteria which might counteract underlying pathophysiological causes of human IBD. Most intriguing is the fact that IBD seems to be due to an intolerance of the immune system towards ubiquitous intestinal bacteria. Therefore, it appears logical to intervene by modulation of this intestinal flora. Results of in vivo experiments using animal models for experimental colitis also suggested a potential use of probiotics to treat Crohn’s disease and ulcerative colitis. It became quite evident, that the tested organisms varied in the probiotic performance, depending on the experimental model. Clinical studies will show whether a combination of various probiotic microorganisms will lead to better results than the use of single strains.

Probiotic Therapy of IBDs (table 2)

Despite many years of extensive research, the mechanisms responsible for initiation and perpetuation of IBD remain unclear. The main theory is that IBD might result from a lack of tolerance to members of the intestinal microflora leading to an overreactive immune response. A specific therapy is still not available. Accumulating research suggests that probiotics might offer an alternative by alteration of the intestinal flora and modulation of the immune response [147–150].

Rationale for Probiotic and Antibiotic Treatment Strategies in IBD

Single-Strain Therapy

The treatment with well-defined single strains offers the advantage of better handling and control, and the resulting therapeutic effects can be clearly attributed to the administered substance. However, as outlined above, the various health promoting aspects of probiotic therapy are not equal among all used microorganisms. Therefore, each strain might be useful for specific indications only, which have to be defined by clinical trials. Among the best studied organisms are lactic acid bacteria; however, there is evidence of successful use of E. coli and non-bacterial microorganisms such as Saccharomyces boulardii.

Lactobacillus GG

Lactobacillus GG is probably the best studied probiotic bacterium [151] since it has been first described by Gorbach et al. [152] in 1987. Its clinical potential has been documented for diarrheal disorders such as traveler’s diarrhea [153, 154], treatment of recurrent infection with Clostridium difficile [155], antibiotic-associated diarrhea [156], and rotavirus infection in children [157, 158], but few studies have been conducted to evaluate its potential in IBD. While effects have been documented only in children with Crohn’s disease [159, 160], several clinical trials have been initiated to study the effect in adult disease. The effect of oral human Lactobacillus GG was investigated in 14 children with Crohn’s disease in remission. Following 10 days of oral administration, the gut immune response was measured by determining the number of IgA-secreting cells in peripheral blood samples. While no report was given regarding clinical effects or side effects, the results indicate that orally administered Lactobacillus GG has the potential to increase the gut IgA immune response and thereby to promote the gut immunological barrier [101]. More recently, an open-label study by Gupta et al. [160] examined the effect of Lactobacillus GG in 4 children with mildly to moderately active Crohn’s disease. Changes in intestinal permeability were measured by a double sugar permeability test and clinical activity was determined by measuring the pediatric Crohn’s disease activity index. A significant improvement in clinical activity 1 week after starting Lactobacillus GG could be documented, which was sustained throughout the study period. Median pediatric Crohn’s disease activity index scores at 4 weeks were 73% lower than baseline and intestinal permeability improved in an almost parallel fashion.

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Table 2. Clinical trials with probiotic microorganisms in IBD Probiotic microorganism

Patients

Type of study

Aim of clinical trial

Outcome

Reference

Saccharomyces boulardii

20

randomized double-blind placebo-controlled

effect on diarrhea in Crohn’s disease in remission

significant reduction in the frequency of bowel movements

170

32

randomized, double-blind

comparison of mesalamin to mesalamine plus probiotic in maintenance of remission in Crohn’s disease

rate of relapse significantly reduced

171

14

open

effect on gut immune response in children with Crohn’s disease

significant increase of gut IgA-secreting cells

101

4

open

effect on intestinal permeability and clinical activity in children with mildly active Crohn’s disease

significant improvement of clinical activity and intestinal permeability

160

10

open

effect on chronic pouchitis

complete suppression of symptoms and reversal of macroscopic endoscopic alterations

161

45

randomized, double-blind

prevention of surgically induced remission in Crohn’s disease

clinical recurrence in 16.6%, endoscopic recurrence in 60% with Lactobacillus GG compared to clinical recurrence in 10.5%, endoscopic recurrence in 35.3% on placebo

162

120

randomized, double-blind

comparison to mesalazine to maintain remission in ulcerative colitis

comparable relapse-free period on either medication

164

116

randomized, double-blind

comparison to mesalazine to maintain remission in ulcerative colitis

comparable relapse-free period on either medication

165

327

randomized, double-blind

comparison to mesalazine to maintain remission in ulcerative colitis

Equivalence of the maintenance effects of E. coli strain Nissle 1917 and mesalamine

166

28

randomized, double-blind

maintenance of remission in Crohn’s disease after medical induction

no difference in the number of patients reaching remission but fewer relapses on probiotic medication

167

40

randomized, double-blind, placebo-controlled

maintenance of remission in chronic pouchitis

Remission was maintained in 85% on probiotic treatment vs. 0% on placebo

36

40

randomized, double-blind

prophylaxis of pouchitis onset

2/20 patients on VSL#3 and 8/20 patients on placebo had an acute episode of pouchitis

173

20

open

maintenance of remission in ulcerative colitis

15/20 patients maintained remission on probiotic treatment

35

40

randomized, double-blind

prevention of post-operative recurrence in Crohn’s disease

4/20 relapsed on probiotic treatment compared to 8/20 on mesalamine

174

Lactobacillus GG

E. coli strain Nissle 1917

VSL#3

In a further open-label study, Friedman et al. [161] reported that administration of Lactobacillus GG twice daily and fructooligosaccharide as a prebiotic for one month induced remission in 10 patients with chronic pouchitis as documented by complete suppression of symptoms and reversal of macroscopic endoscopic alterations. In a recent study, Prantera et al. [162] demonstrated the ineffectiveness of Lactobacillus GG in preventing the recurrence of surgically induced remission of Crohn’s disease. Forty-five patients received either Lactobacillus GG or placebo for 1 year following the curative resection for Crohn’s disease. Clinical recurrence was ascertained in 16.6% of patients taking the probiotic and in 10.5% of patients on placebo. However, 60% of patients in clinical

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remission, taking Lactobacillus GG had endoscopic recurrence compared with 35.3% of patients on placebo.

E. coli Strain Nissle 1917

Infectious diarrheal diseases were a severe problem for soldiers during World War I. In 1917 Alfred Nissle isolated a specific Escherichia coli, later named strain Nissle, from the feces of a soldier who seemed to be immune against this spreading disease [163]. In the following years, various in vivo and in vitro studies confirmed the probiotic potential of this microorganism.

Schultz/Schölmerich/Rath

In an initial clinical trial by Kruis et al. [164], a total of 120 patients with inactive ulcerative colitis were included in a double-blind, double-dummy fashion to compare mesalazine 500 mg t.d.s. to an oral preparation of viable E. coli strain Nissle (Serotype 06: K5: H1) for 12 weeks with regard to the efficacy in preventing a relapse of the disease. Life table analysis showed a relapse-free time of 103 B 4 days for mesalazine and 106 B 5 days for E. coli Nissle 1917 (nonsignificant). These promising results were later confirmed in a pilot study by Rembacken et al. [165] and finalized by Kruis et al. [166] in a multicentric, randomized, double-blind study including 327 patients with ulcerative colitis in remission (fig. 2). All patients received either mesalazine (500 md t.i.d.) or E. coli Nissle 1917 (200 mg) and were followed up for a maximum of 12 months. Relapse rates were 36.4% under E. coli Nissle 1917 and 33.0% under mesalazine. The statistical analysis showed significant equivalence (p = 0.004) of the maintenance effects of E. coli Nissle 1917 and mesalamine. It was therefore concluded that E. coli strain Nissle offers an alternative to mesalamine to prevent relapse in ulcerative colitis, especially to those patients allergic or unresponsive to mesalamine. Malchow et al. [167] included 28 patients with active Crohn’s disease (CDAI 1150). The disease had to be limited to the large intestine. Following a 1-year treatment period, combining a tapering regimen of steroids with E. coli strain Nissle or placebo, there was no difference in the number of patients reaching remission. However, in the E. coli Nissle group, fewer patients relapsed (33.3% vs. 63.6%).

Saccharomyces boulardii

S. boulardii is a nonpathogenic yeast that has been successfully used as a biotherapeutic agent to prevent antibiotic-associated diarrhea [168, 169] and to treat other types of infection-related diarrhea. Pein and Hotz [170] performed a pilot, double-blind, controlled study of the efficacy of S. boulardii on symptoms of Crohn’s disease. Twenty patients with active, moderate Crohn’s disease were randomly assigned to receive either S. boulardii or a placebo for 7 weeks in addition to the standard treatment. A significant reduction in the frequency of bowel movements and in disease activity was observed in the group receiving the probiotic agent, but not in the placebo group. In a later study, Guslandi et al. [171] included 32 patients with Crohn’s disease in clin-

Rationale for Probiotic and Antibiotic Treatment Strategies in IBD

327 patients with ulcerative colitis in remission

222 patients per protocol

Mesalazine 500 mg t.i.d. n = 112

E. coli Nissle 1917 n = 110

12 months

Relapse rate 33.0%

Relapse rate 36.4%*

*p = 0.004 (tested for equivalence)

Fig. 2. E. coli strain Nissle 1917 versus mesalazine for remission

maintenance in ulcerative colitis.

ical remission (CDAI !150). They were randomly treated for 6 months with either mesalamine 1 g three times a day or mesalamine 1 g two times a day plus a preparation of S. boulardii 1 g daily. Clinical relapses as assessed by CDAI values were observed in 37.5% of patients receiving mesalamine alone and in 6.25% of patients in the group treated with mesalamine plus the probiotic agent. The results of these two studies suggest that S. boulardii may represent a useful tool in the maintenance treatment of Crohn’s disease.

Other Single Strain Therapies

Despite the fact that plenty of in vitro work was done to evaluate the probiotic properties of various L. acidophilus strains, no clinical trial has been conducted yet regarding the effects on patients with IBD. There is one report on a clinical observation that the orally administered prebiotic substrate lactulose is split by bacteria in the large intestine, leading to a reduction in fecal pH and creating intestinal conditions beneficial to L. acidophilus and inhibitory to coliform bacteria, Bacteroides sp., Salmonella and Shigella. The authors conclude that lactulose may

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be used for treatment of IBD as bacteria and bacterial endotoxin might have an important role in the pathogenesis of this disease [172].

Multi-Strain Therapy

While single strain therapies might be easier to handle, and the observed clinical effect can be clearly attributed to the administered probiotic preparation, mixtures of probiotic strains might have the advantage of combining several probiotic properties and lead to better clinical results.

VSL#3

VSL#3 has been the first product, combining different probiotic microorganisms studied in a scientific manner. While the selection criteria are not available, VSL#3 has been successfully used to maintain remission in ulcerative colitis, Crohn’s disease and pouchitis. Furthermore, Gionchetti et al. [173] have combined clinical trials with mechanistic studies to explain the observed effects. In a first trial, the efficacy of VSL#3 was evaluated in maintenance of remission of chronic pouchitis compared to placebo. Forty patients with pouchitis in clinical and endoscopic remission were randomized to receive either VSL#3, 6 g/day, or an identical placebo for 9 months. All patients received 1 month of antibiotic treatment (1 g ciprofloxacin and 2 g rifaximin daily) prior to probiotic/ placebo treatment. Patients were assessed clinically every month and endoscopically and histologically every 2 months or in the case of a relapse. At the end of the study period, 3 patients (15%) in the VSL#3 group had relapses within the 9-month follow-up period, compared with 20 (100%) in the placebo group (p ! 0.001) [36]. Later, the same group demonstrated the effective prophylaxis of pouchitis onset with administration of VSL#3. Fourty consecutive patients who underwent ileal pouch-anal anastomosis for ulcerative colitis were randomized to receive either VSL#3 or placebo immediately after the operation for 1 year. The patients were assessed clinically, endoscopically, and histologically after 1, 3, 6, 9 and 12 months. During the observation period, 2 of the 20 patients (10%) treated with VSL#3 had an episode of acute colitis, compared to 8 of the 20 patients (40%) on placebo (p ! 0.05) [173]. In an uncontrolled clinical trial a similarly beneficial effect on ulcerative colitis was documented by Venturi et

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al. [35]. To evaluate the effects on intestinal microflora and the clinical efficacy of VSL#3, 20 patients with ulcerative colitis in remission and intolerant or allergic to 5ASA, have been treated for 12 months. Fecal samples for stool culture were obtained from the patients at the beginning of the trial and after 10, 20, 40, 60, 75, 90 days, 12 months and at 15 days after the end of the treatment. As a result, 15/20 treated patients remained in remission during the study, 1 patient was lost to follow-up, while the remaining relapsed. In another study, the authors compared the efficacy of VSL#3 combined with an antibiotic treatment to mesalamine in prevention of post-operative recurrence of Crohn’s disease. Forty patients were randomized to receive either rifaximin 1.8 g/day for 3 months followed by VSL#3 or mesalamine 4 g/day for 12 months. Endoscopic examination was performed after 3 and 12 months. After 1 year 4 patients in the antibiotic/probiotic group had a severe endoscopic recurrence compared to 8 patients in the mesalamine group, while no side effects were reported in the antibiotic/probiotic group [174].

Other Probiotic Combinations

No other combination of probiotic microorganisms has been clinically studied to date, but there is evidence that the combination of pre- and probiotics might have an advantage [141, 161] over single- or multi-strain combinations. Another promising therapeutic concept is the use of prebiotics alone, and by that the enhancement of the endogenous probiotic microflora. This has been demonstrated by the use of germinated barley foodstuff (GBF) containing glutamine-rich protein and the hemicelluloserich fiber which was made from brewer’s spent grain by physical isolation (milling and sieving). Both in vivo [175] and in vitro [176] studies demonstrated that the fiber fraction of GBF supports maintenance of epithelial cell populations, facilitates epithelial repair, and suppresses epithelial NF-kB-DNA binding activity through generating increased short-chain fatty acid (especially butyrate) production by luminal microflora which includes Bifidobacterium and Eubacterium, thereby preventing experimental colonic injury. Based on these observations, clinical studies were initiated in patients with mild to moderate active ulcerative colitis. The patients who had been unresponsive or intolerant to standard treatment received 30 g of GBF feeding daily in a nonrandomized, open-label fashion. At 4 weeks, this treatment resulted in a signifi-

Schultz/Schölmerich/Rath

Commensal bacteria Transient pathogens

initiate

Transit time pH Sulfate SCFA

Bacterial products

Proinflammatory compounds

Dysbiosis

Probiotics

Sulfide

Bacteriocins Mucin gene expr. Bacterial adhesion

Inflammation

Broken barrier TH2 cytokines Restore

TH1-cytokines Broken tolerance

Uptake

IgA B cells

IgG T cells

MØ

Genetic background Lymphatic circulation

Extraintestinal manifestations

Blood circulation

Enterohepatic circulation

Manifestations in remote parts of the gut

Fig. 3. Pathogenic mechanism of chronic inflammatory bowel disease in genetically susceptible hosts, commensal

bacteria and their products are a constant challenge to a disequilibrated overly aggressive immune system.

cant clinical and endoscopic improvement independent of disease extent. The improvement was associated with an increase in stool butyrate concentrations and in luminal Bifidobacterium and Eubacterium levels [177].

Summary and Concluding Remarks

In summary, despite the fact that probiotic properties of ubiquitous luminal bacteria have been suspected for almost a century, it was not until recently that the scientific background was investigated. While probiotics were first used in veterinary medicine to fight concomitant infections in industrialized animal farms, clinical observations followed soon. It was a long way from single case reports to first clinical trials conducted in a randomized, placebo-controlled, double-blind fashion to evaluate the clinical effects of probiotic preparations in comparison to standard medication.

Rationale for Probiotic and Antibiotic Treatment Strategies in IBD

IBDs seem to be an ideal indication to use probiotic preparations for treatment (fig. 3). Since there is abundant evidence for the important role of luminal bacteria in the pathogenesis of IBD, the alteration of the intestinal microflora by probiotic microorganisms should lead to clinical improvement of the condition. Furthermore, immunomodulatory effects of probiotics, as documented in various in vitro studies, as well as the stabilization of the intestinal barrier should be able to counteract some suspected pathomechanisms in IBD. While most data regarding the role of intestinal bacteria in the pathogenesis of IBD were acquired in animal models for experimental intestinal inflammation, few experiments were performed to study the effect of probiotics in treatment or prevention. It was documented that oral administration of different strains was able to prevent or at least significantly attenuate the disease, however, treatment of established colitis seemed difficult. Further studies showed that the combination with antibiotic therapy might even enhance the effect.

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The immunomodulatory effects of probiotic preparations were documented on human intestinal cell lines or peripheral blood mononuclear cells. While a definite effect on cytokine production was obvious, no clear picture regarding a TH1- or TH2-mediated cytokine response was seen. Promising in vivo and in vitro results lead to first clinical trials. The few trials published to date document the possible use of probiotics in IBD, however, more studies were conducted in the treatment of infectious intestinal disorders such as refractory Clostridium difficile or rotavirus infections. So far, E. coli strain Nissle 1917 and S. boulardii have shown promising clinical effects in the maintenance of remission in IBD, and can be recom-

mended at least for patients allergic or intolerant to mesalamine. Most intriguing is the fact that the combination of different probiotic microorganisms as in VSL#3 produced exciting results. More clinical trials are currently on the way to evaluate the effect in various conditions such as postoperative maintenance of remission and the treatment of acute IBD. In the near future, it will be necessary to learn more about the interaction of probiotic microorganisms with cells of the host, e.g. epithelial and other immunocompetent cells. Furthermore, the effects of combinations of various probiotics should be evaluated, to design more powerful preparations, using the different probiotic potentials of single strains to enhance the clinical effect.

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171 Guslandi M: Saccharomyces boulardii in the maintenance of Crohn’s disease. Can J Gastroenterol 2000;14:32. 172 Liao W, Cui XS, Jin XY, Floren CH: Lactulose: A potential drug for the treatment of IBD. Med Hypotheses 1994;43:234–238. 173 Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, et al: Prophylaxis of pouchitis onset with probiotic therapy: A double-blind, placebo-controlled trial. Gastroenterology 2003;124:1204–1209. 174 Campieri M, Rizzello F, Venturi A, Poggioli G, Ugolini F, Helwig U, et al: Combination of antibiotic and probiotic treatment is efficacious in prophylaxis of post-operative recurrence of Crohn’s disease: A randomized controlled study vs. mesalamine. Gastroenterology 2000;118:A4179. 175 Kanauchi O, Nakamura T, Agata K, Mitsuyama K, Iwanaga T: Effects of germinated barley foodstuff on dextran sulfate sodium-induced colitis in rats. J Gastroenterol 1998;33: 179–188. 176 Kanauchi O, Andoh A, Araki Y, Mitsuyama K, Toyonaga A, Sata S, et al: The mechanism of germinated barley foodstuff in attenuating intestinal inflammation in colitis. Gastroenterology 2000;118:A73. 177 Mitsuyama K, Saiki T, Kanauchi O, Iwanaga T, Tomiyasu N, Nishiyama T, et al: Treatment of ulcerative colitis with germinated barley foodstuff feeding: A pilot study. Aliment Pharmacol Ther 1998;12:1225–1230.

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Review Article Dig Dis 2003;21:129–137 DOI: 10.1159/000073244

New Diagnostic Avenues in Inflammatory Bowel Diseases Capsule Endoscopy, Magnetic Resonance Imaging and Virtual Enteroscopy

Andreas G. Schreyer a Stefan Gölder b Johannes Seitz a Hans Herfarth b Departments of a Radiology and b Internal Medicine I, University of Regensburg, Regensburg, Germany

Key Words Crohn’s disease W Inflammatory bowel disease W Capsule endoscopy W Magnetic resonance imaging W Virtual endoscopy W Enteroscopy

Abstract The modalities for diagnostic imaging in patients with inflammatory bowel disease (IBD) have dramatically changed in the last decade. Several years ago the only methods to assess the small bowel were conventional enteroclysis or a small bowel ‘follow through’. Nowadays, wireless capsule endoscopy as well as magnetic resonance imaging (MRI) with virtual endoscopy represent new evolving methods to depict and assess the small bowel. This article describes these recently introduced methods in the diagnostic assessment of the small bowel and discusses the clinical significance based on the current literature.

Introduction

Diagnostic imaging has one of the key roles in the diagnosis and management of patients suffering of IBD. The application of conventional radiological imaging studies, abdominal ultrasound or granulocyte scintigraphy may be indicated in the initial evaluation of the patient for the purpose of establishing a diagnosis, in the preoperative patient to determine the full extent of the disease, during clinical exacerbations to determine if complications are present and to evaluate extraintestinal manifestations of IBD. Additionally, interventional radiographic procedures may become necessary in patients with intraabdominal abscesses. Newer techniques, which will be reviewed in the following chapter, include the application of magnetic resonance imaging, virtual enteroscopy as well as capsule endoscopy in the evaluation of patients with IBD.

Copyright © 2003 S. Karger AG, Basel

Capsule Endoscopy

The first images of the wireless capsule endoscopy (CE) were published in May 2000 in the journal Nature [1]. Since then the familiarity with this system has continued to rise steadily especially since the Food and Drug admin-

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istration (FDA) gave it market clearance in mid-2001 as well as extensive marketing by the manufacturing company. The development of the Given’s Diagnostic System®, which took place between 1992 until mid 1999 [2, 3], offers the potential to examine the whole small intestine with its 4–5 meters length. The Given’s Diagnostic System consists of 3 components: the ‘capsule endoscope’ (11 ! 26 mm and weighing 3.7 g) containing a miniature camera with a short focal lens camera, batteries, a radio transmitter, an external receiving antenna with attached portable hard drive and a personal computer workstation for review and interpretation of images (fig. 1). The capsule endoscope proceeds passively through the GI tract and is only propelled by peristalsis. The video images are transmitted using radiotelemetry to an array of aerials attached to the body which allows image capture. The examination is completely painless and the patients are free to continue their daily routine during the examination. Besides numerous reports of seldom or less seldom diseases and their ‘typical capsule images’ [4–6], up to now the most investigated indication for CE, is obscure gastrointestinal bleeding. Apart from multiple abstracts, several pilot studies (total 72 patients) have been already published in peer-reviewed journals investigating the value of CE compared to push enteroscopy and/or radiologic imaging of the small bowel in patients with obscure gastrointestinal bleeding [7–9]. However, despite these efforts even for this clinical situation, the positioning of the CE in an appropriate diagnostic algorithm has not been definitely solved [10]. Compared to these studies, data of prospective controlled trials in patients with Crohn’s disease are still sparse. Most of the information is only published in abstract form. Two studies including a total of 37 patients were published until May 2003. Fireman et al. [11] investigated 17 patients with suspected Crohn’s disease on the basis of either chronic iron deficiency anemia, chronic abdominal pain, chronic diarrhea or weight loss. The mean duration of the symptoms was 6.3 years. According to the authors, the patients underwent, not longer than 6 months before CE, a diagnostic evaluation including gastroscopy (16/17), small bowel enema (17/17) and colonoscopy (15/17), which were all reported to be negative. Based on the findings of CE, 12 of the 17 patients were diagnosed as having Crohn’s disease of the small bowel. The diagnoses were based on either one of the following visual findings: mucosal erosions, ulcers or strictures (fig. 2). Eliakim et al. [12] performed CE in 20 patients with either suspected or already proven Crohn’s disease. All patients of the study underwent either a com-

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puted tomography (CT) of the small bowel (a so-called entero-CT) or a small bowel follow through before the CE procedure. CE detected additional lesions, which were not found in the radiological procedures in 47% of the cases. However, the clinical significance of these findings is not reported. One has always to keep in mind that the main obstacle in performing CE in patients with suspected or proven Crohn’s disease is the possible presence of clinically asymptomatic strictures. An arrest of the capsule in such a stricture could result in a mechanical ileus, which has been already reported in some studies as well as in oral presentations at several congresses [13]. Therefore, in our opinion CE should only be performed after obtaining a radiological examination of the small bowel, which excludes significant stenoses of the small bowel. In the moment studies testing a so-called ‘patency capsule’, which should be swallowed in a ‘test run’ before performing the real CE are underway. This patency capsule is completely dissolvable but can be detected by X-ray or ultrasound in case of a ‘capsule obstruction’ in front of a stenosis. Another problem is the limited battery capacity resulting in the adequate documentation of the whole small bowel (defined by the visualized passage of the capsule into the cecum on the screen of the workstation) in only about 75–80% of the cases. In our own experience, the capsule stopped transmitting pictures in 35% of the cases before reaching the cecum. This could present a problem in some patients with Crohn’s disease with a solitary involvement of the last segments of the ileum. In conclusion, CE could eventually contribute towards a better diagnostic accuracy in patients with Crohn’s disease. However, the impact of these additional findings on the clinical outcome in patients with Crohn’s disease still needs to be defined. Until the completion of large prospective studies comparing the diagnostic results of established radiological procedures for the small bowel with the findings of CE and evaluating the clinical relevance of this procedure CE should only be performed in the setting of clinical studies.

Magnetic Resonance Imaging in IBD

For the assessment of the small bowel several radiological techniques can be applied: The classical conventional enteroclysis (using the ‘Sellink modification’ [14]) and the detailed per-oral small bowel examination (‘small bowel follow-through’). Using these procedures diagnostically the small bowel peristaltic activity, intra-abdominal bow-

Schreyer/Gölder/Seitz/Herfarth

Fig. 1. The Given’s Diagnostic System®

consists of 3 components: the capsule endoscope, an external receiving antenna with attached portable hard drive and a personal computer workstation for review and interpretation of images.

Fig. 2. Example of an analysis of capsule endoscopy as depicted on the workstation. CE was performed in a 48-year-old patient with long-standing Crohn’s disease. CE depicted two major areas of inflammation. Multiple ulcerations with fibrinous exudates were visible by CE. The localization software screen of the capsule on the left lower part of the screen demonstrates the region of the right lower abdomen.

el distribution, lumen distensability, circular fold morphology and mucosal surface features can be addressed during intermittently sustained fluoroscopic monitoring. The sensitivity and specificity for enteroclysis or small bowel follow-through examination are comparable (sensi-

tivity 85–95%; specificity 89–94%) but strongly depend on the experience of the individual examiner with the procedure [15]. One has to be aware of that even using modern equipment, conventional enteroclysis involves exposure to radiation (6.8 Gy ! cm2, this means an effective

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Fig. 3. a MR-enteroclysis in ‘dark lumen technique’ using water as oral contrast media (T1). b MR-enteroclysis with

positive intraluminal contrast medium (T1) using pineapple juice as oral contrast media.

dose of 1.5 mS) [16]. Sectional imaging techniques such as CT or MRI are able to demonstrate segmental thickening of the bowel wall, stenosis or pre-stenotic dilatation, extraluminal lesions and complications such as fistulae, abscesses and local fatty inflammation. However, subtle manifestations of intestinal diseases in general cannot be detected mainly due to the fact that the small bowel is usually in a collapsed state and cannot be distended with conventional contrast media. Therefore, for the evaluation of patients with IBD, refined procedures for contrasting the small bowel are needed (see below). Comparing CT and MRI as noninvasive diagnostic modalities, the radiation exposure of CT imaging has to be kept in mind. Especially in the mostly young patients with inflammatory bowel disease the lack of radiation exposure of MRI makes MR imaging the preferred modality. MRI provides a better sensitivity to assess severe and advanced Crohn’s lesions than the conventional small bowel examinations and has a comparable sensitivity and specificity with enteroclysis in diagnosing small bowel Crohn’s disease [17]. Furthermore, diagnostic studies report additional information of extraluminal pathologies in 25–58% of the cases [18–20] (fig. 4a). The diagnostic value of MR imaging of the small bowel in patients with inflammatory bow-

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el disease has been extensively assessed in recent years using various contrast media and different techniques, demonstrating a high correlation of this technique with the conventional radiological methods, surgery or endoscopy [17, 19, 21–33].

MRI Techniques for the Evaluation of the Small Bowel

Fast imaging techniques performed within a breath hold are a prerequisite for adequate diagnostic image quality. To gain fast imaging, at least gradients with more than 20 mT/m in scanners with 1.0–1.5 Tesla are required. Additionally, fat saturation techniques are helpful (fig. 4a). These sequences selectively suppress fat signal and allow a better delineation of fluid structures such as subtle wall edemas or small extraluminal fluid collections. A requirement for sufficiently identifying bowel wall pathology is a good contrast difference between the bowel lumen and the wall. Moreover, a complete filling and distension of the small bowel is mandatory. To gain this distension, several groups perform the MRI of the small

Schreyer/Gölder/Seitz/Herfarth

Fig. 4. a MR-enteroclysis in ‘dark lumen technique’, coronal section. Imaging was done using a fat saturation tech-

nique. Note the bowel wall edema in the terminal ileum (arrow). Additionally, an osteochondritis is depicted in the lumbar spine (L4/L5; arrow). The patient reported intermittent back pain in this region. b Axial section of the same patient after application of Gd-DTPA. The MR image demonstrates a marked bowel wall thickening and contrast enhancement of the bowel wall as well as the mesenteric fat tissue in the region of the terminal ileum.

bowel giving contrast media as in conventional enteroclysis after transnasal intubation past the duodeno-jejunal junction [20]. But there are more and more indications that an exclusively oral application of the contrast media gives adequate diagnostic quality [34, 35]. To achieve an adequate bowel distension with oral contrast application, substances such as mannitol [36] or methylcellulosis [37] have to be added to the contrast media. Currently, several intraluminal contrast media (table 1) are used for small bowel MRI. The so-called ‘positive’ intraluminal contrast media (fig. 3b) are T1 shortening materials such as gadolinium (Gd-DTPA) mixtures or manganese containing substances such as pineapple or blueberry juice. Negative intraluminal contrast media are regular water [38] or barium (fig. 3a). When applying positive contrast media (GdDTPA) intravenously to detect inflammatory areas negative intraluminal contrast seems to be superior (fig. 4b), because the enhancing bowel wall can be better appreciated.

New Diagnostic Avenues in Inflammatory Bowel Diseases

Monitoring Intestinal Disease Activity with MRI

Essentially the only criterion for assessing disease activity radiologically represents the typical visible different morphological appearance of the bowel during inflammatory processes. It is believed that an intense wall edema or a strong signal enhancement after GD-DTPA application indicates an acute inflammatory disease of the bowel wall. There are, however, no studies concerning the contrast behavior of a scarring stenosis, which does not respond to steroids. Another problem is a missing reference method to assess disease activity, since the small bowel can currently barely be observed directly using endoscopic methods. Until now the only way to assess parts of the bowel are push enteroscopy or complete colonoscopy with intubation of the terminal ileum. The only exception is CE; however, as mentioned above, prospective studies are needed. Besides a surgical intervention, only with these methods histological specimens can be obtained. There are only a few studies which are investigating the correlation of the disease activity, using clinical parameters such as the Crohn’s disease activity index (CDAI) or laboratory parameters such as C-reactive protein (CRP) or the white cell count.

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Madsen et al. [23] did a study on 8 patients with Crohn’s disease using a low field scanner (0.1 Tesla) to assess contrast enhancement and bowel wall thickening. All patients were examined for a second time 11–120 days after initiation of conservative therapy with steroids. In all patients with clinical response to therapy there was a significant reduction in wall signal intensity and a significant reduction of wall thickening suggesting that MRI of the small bowel might be a noninvasive method in the evaluation of response regarding both disease extension and activity in Crohn’s disease during treatment. In another study the same group demonstrated a good correlation of MRI of the small and large bowel in respect to the extent of the disease with leukocyte scintigraphy, conventional small bowel follow-through, endoscopy or surgery [39]. Additionally, they found a significant correlation of a MRI expression of overall disease activity (calculated by a coefficient which includes the number of diseased bowel segments divided by the total number of segments multiplied by the relative increase of the bowel wall signal intensity after the application of GD-DTPA) and the CDAI (r = 0.51; p ! 0.0001) [40]. Maccioni et al. [26] examined 20 patients with Crohn’s disease. 19 of these 20 patients had no clinical signs of active disease at the time of examination. Typical MRI appearance (wall thickening, contrast enhancement) was compared with a biological activity score (range: activity present or not present) combining white cell count, CRP or orosomucoids. The authors report a significant correlation between the MRI criteria for intestinal inflammation and biological activity score and state that MRI is a good parameter to assess intestinal disease activity. Contrary to this group a study from Mainz describes only a very weak correlation between the signal enhancement of the bowel wall with the CDAI and no correlation with serum CRP levels [21]. Another study comparing findings of MRI with endoscopy or surgery reported a sensitivity of 59% for the identification of all bowel segments that showed active inflammation [28]. However, on a per patient basis, an overall sensitivity of 91% and a specificity of 71% for the detection of active bowel disease were reached. Bowel wall thickening, the enhancement of signal intensity after the application of GD-DTPA as well as an increased mesenteric vascularity was useful in identifying the disease localization. However, no significant correlation between the CDAI and the MR imaging findings was found. In a prospective study, Neurath et al. [38] compared FDG-PET, MRI-enteroclysis and immunoscintigraphy using anti-nonspecific cross-reacting antigen 95 antigranulocyte antibodies in 59 patients. Using PET

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127 bowel segments with inflammation were assessed in 51 of 59 patients. The evaluation of the data was partly based on the endoscopic findings of macroscopic inflammation in the colon and terminal ileum. Based on the endoscopic data, the sensitivity for PET was 85%, for MRI 67 and 41% for scintigraphy. Comparing the localization of the inflamed segments, there was only a minor difference in small bowel assessment between PET and MRI. Applying PET and MRI in the cases with inflamed terminal ileum, PET identified 24 areas whereas MRI depicted 20 lesions. The so-called ‘hot spots’ identified using PET imaging, which were not seen using MRI, were predominantly in the colon. It has to be mentioned that the colon was not prepared for MRI examination, which explains the significant difference between PET and MR imaging. For none of the methods employed in this study (FDG-PET, MRI-enteroclysis and immunoscintigraphy), a correlation with CRP or CDAI could be detected. In summary, currently there are no standardized methods to assess intestinal disease activity in Crohn’s disease. If studies describe correlation of MRI findings with the CDAI index, this correlation is usually low, which is not surprising since the scoring is derived from the mainly subjective symptoms of the patients [41]. It is also known that only a weak correlation exists between serological inflammatory markers and the CDAI. Nevertheless, small bowel MRI has a high diagnostic value in assessing the extent of small bowel disease in Crohn’s disease. More studies addressing the value of monitoring the intestinal disease activity and standardizing the techniques are needed since the ability of monitoring intestinal disease activity in patients with Crohn’s disease using a noninvasive method without radiation exposure may be a promising diagnostic tool for therapeutic stratifications in the future [42, 43]. Nevertheless, MRI of the small bowel has currently become widely accepted in centers dedicated to the diagnosis and treatment of inflammatory bowel disease because of a diagnostic sensitivity which is comparable to conventional radiological methods (enteroclysis or small bowel follow through) but avoids radiation. Additionally, the extraluminal visualization of pathologies such as abscesses or fistulae is superior to the conventional methods in most of the cases.

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Table 1. The signal intensity of different

T1 weighted sequence

T2 weighted sequence

Negative (water, barium)

dark (fig. 3a)

bright

Positive (Gd-DTPA or manganese, blueberry [48], pineapple juice [37], green tea [49])

bright (fig. 3b)

dark

intraluminal contrast media depending on the MRI sequence

Virtual Enteroscopy

Virtual endoscopy [44] is a recently introduced visualization technique based on sectional volumetric image data such as spiral CT or MRI. In sectional imaging, the two-dimensional (2D) pixel (picture element) on every single slice stands for a three-dimensional (3D) voxel (volume picture element) of the data set. So each voxel represents a certain volume of the scanned object. For 3D imaging these slices, respectively voxels have to be connected three-dimensionally. Based on these 3D reconstructions ‘virtual enteroscopy’ represents a computergenerated simulation of an endoscopic perspective. The technique was first described by Vining [45, 46] applying this method in the colon and bronchi respectively. The 3D representation of a virtual endoscopic view is generated by so-called ‘ray casting’ algorithms. Essentially these are parallel rays virtually generated by a source spot, which represents the observer’s eyes at the point the endoscope is positioned. The final virtual endoscopic view of rendered ray casting is a conic field of view using certain simulated optic angles. Presently, the most widely used ‘virtual endoscopy’ application is ‘virtual colonoscopy’. Particularly in the colon there is a potential need for a noninvasive screening method to find polyps as known precursor for carcinoma. Several papers applying MRI for colon screening were published [47]. In most studies a positive intraluminal contrast media is given rectally after standardized bowel preparation equal to conventional colonoscopy. Based on the principles of MRI colonography, virtual enteroscopy of the small bowel can be performed. Our group recently completed a study on 30 patients with Crohn’s disease comparing virtual enteroscopy with MRenteroclysis [37]. In 90% a fair to good image quality was achieved (table 2). In 3 cases fistulae and stenoses were depicted clearly. There was no additional relevant information regarding the disease activity using this new technique. Because just the intraluminal macroscopic surface is depicted, an assessment of the mucosa or a thickening

New Diagnostic Avenues in Inflammatory Bowel Diseases

Table 2. Quality of small bowel virtual endoscopy: 27/30 (90%) were considered fair to good, 3/30 (10%) had poor quality because of motion or filling artifacts of the small bowel: all relevant pathological changes like fistula or stenosis were visualized with fair to good quality [37]

Patients

Visualized pathology fistula

stenosis terminal ileum

Poor Fair Good

3 18 9

– 3 –

– 2 1

Total

30

3

3

of the bowel wall, applying this method, was not possible. Most pathologies such as stenosis of the terminal ileum or fistulas were better shown by 3D rendered external views than by the endoscopic view. Thus, virtual enteroscopy based on high-resolution MRI data is feasible, but its clinical value still has to be tested. Having capsule endoscopy as a new small bowel imaging modality, the MRI-based virtual approach could be re-evaluated having a new gold standard. Combining virtual enteroscopy together with images acquired by capsule endoscopy could lead to a better localization of pathologic changes such as small bowel bleeding or tumors.

Conclusion

Capsule endoscopy is still a new evolving technique, which could contribute towards a better diagnostic accuracy for the small bowel assessment in Crohn’s disease. The most important application could be the detection of subtle small bowel bleedings. More prospective studies are necessary.

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MRI is already accepted as an excellent noninvasive imaging modality to assess the extent of small bowel disease in patients with Crohn’s disease. Additionally, extraluminal complications like abscesses or fistulas can be diagnosed. The value of MRI in assessing the intestinal inflammatory activity in patients with IBD is still not standardized and needs further evaluation. Virtual enteroscopy is currently a fascinating approach to visualize the whole bowel noninvasively. The diagnos-

tic and therapeutic value of the three-dimensional compared to the two-dimensional imaging methods has still to be proven.

Acknowledgment Part of the work was supported by DCCV e.V., Leverkusen, Germany and the Kompetenznetz-Chronisch entzündliche Darmerkrankungen, BMBF.

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13 Rosch T, Ell C: Topical clinical indications for capsule endoscopy – A paper by the Endoscopy Section of DGVS as of 1.11.2002. Z Gastroenterol 2002;40:971–978. 14 Sellink JL: Radiologic examination of the small intestine by duodenal intubation. Acta Radiol Diagn (Stockh) 1974;15:318–332. 15 Ott DJ, Chen YM, Gelfand DW, Van Swearingen F, Munitz HA: Detailed per-oral small bowel examination vs. enteroclysis. II. Radiographic accuracy. Radiology 1985;155:31–34. 16 Hart D, Haggett PJ, Boardman P, Nolan DJ, Wall BF: Patient radiation doses from enteroclysis examinations. Br J Radiol 1994;67:997– 1000. 17 Rieber A, Wruk D, Potthast S, Nussle K, Reinshagen M, Adler G, Brambs HJ: Diagnostic imaging in Crohn’s disease: Comparison of magnetic resonance imaging and conventional imaging methods. Int J Colorectal Dis 2000;15: 176–181. 18 Aschoff AJ, Zeitler H, Merkle EM, Reinshagen M, Brambs HJ, Rieber A: MR enteroclysis for nuclear spin tomographic diagnosis of inflammatory bowel diseases with contrast enhancement. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1997;167:387–391. 19 Holzknecht N, Helmberger T, von Ritter C, Gauger J, Faber S, Reiser M: MRI of the small intestine with rapid MRI sequences in Crohn disease after enteroclysis with oral iron particles. Radiologe 1998;38:29–36. 20 Rieber A, Wruk D, Nussle K, Aschoff AJ, Reinshagen M, Adler G, Brambs HJ, Tomczak R: MRI of the abdomen combined with enteroclysis in Crohn disease using oral and intravenous Gd-DTPA. Radiologe 1998;38:23–28. 21 Schunk K, Kern A, Oberholzer K, Kalden P, Mayer I, Orth T, Wanitschke R: Hydro-MRI in Crohn’s disease: Appraisal of disease activity. Invest Radiol 2000;35:431–437. 22 Madsen SM, Thomsen HS, Munkholm P, Schlichting P, Davidsen B: Magnetic resonance imaging of Crohn disease: Early recognition of treatment response and relapse. Abdom Imaging 1997;22:164–166. 23 Madsen SM, Thomsen HS, Schlichting P, Dorph S, Munkholm P: Evaluation of treatment response in active Crohn’s disease by low-field magnetic resonance imaging. Abdom Imaging 1999;24:232–239.

24 Umschaden HW, Szolar D, Gasser J, Umschaden M, Haselbach H: Small-bowel disease: Comparison of MR enteroclysis images with conventional enteroclysis and surgical findings. Radiology 2000;215:717–725. 25 Maccioni F, Viscido A, Marini M, Caprilli R: MRI evaluation of Crohn’s disease of the small and large bowel with the use of negative superparamagnetic oral contrast agents. Abdom Imaging 2002;27:384–393. 26 Maccioni F, Viscido A, Broglia L, Marrollo M, Masciangelo R, Caprilli R, Rossi P: Evaluation of Crohn disease activity with magnetic resonance imaging. Abdom Imaging 2000;25:219– 228. 27 Shoenut JP, Semelka RC, Magro CM, Silverman R, Yaffe CS, Micflikier AB: Comparison of magnetic resonance imaging and endoscopy in distinguishing the type and severity of inflammatory bowel disease. J Clin Gastroenterol 1994;19:31–35. 28 Koh DM, Miao Y, Chinn RJ, Amin Z, Zeegen R, Westaby D, Healy JC: MR imaging evaluation of the activity of Crohn’s disease. Am J Roentgenol 2001;177:1325–1332. 29 Small WC, DeSimone-Macchi D, Parker JR, Sukerkar A, Hahn PF, Rubin DL, Zelch JV, Kuhlman JE, Outwater EK, Weinreb JC, Brown JJ, de Lange EE, Woodward PJ, Arildsen R, Foster GS, Runge VM, Aisen AM, Muroff LR, Thoeni RF, Parisky YR, Tanenbaum LN, Totterman S, Herfkens RJ, Knudsen J, Bernardino ME, et al: A multisite phase III study of the safety and efficacy of a new manganese chloride-based gastrointestinal contrast agent for MRI of the abdomen and pelvis. J Magn Reson Imaging 1999;10:15–24. 30 Kettritz U, Isaacs K, Warshauer DM, Semelka RC: Crohn’s disease. Pilot study comparing MRI of the abdomen with clinical evaluation. J Clin Gastroenterol 1995;21:249–253. 31 Low RN, Sebrechts CP, Politoske DA, Bennett MT, Flores S, Snyder RJ, Pressman JH: Crohn disease with endoscopic correlation: Singleshot fast spin-echo and gadolinium-enhanced fat-suppressed spoiled gradient-echo MR imaging. Radiology 2002;222:652–660.

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Review Article Dig Dis 2003;21:138–145 DOI: 10.1159/000073245

Osteoporosis and Other Extraintestinal Symptoms and Complications of Inflammatory Bowel Diseases Max Reinshagen Christian von Tirpitz Department of Medicine I, University of Ulm, Ulm, Germany

Key Words Osteoporosis W Inflammatory bowel disease W Crohn’s disease

review the current knowledge of extraintesitnal manifestations and complications in IBD.

Osteoporosis in Inflammatory Bowel Disease Introduction

Patients with Crohn’s disease and ulcerative colitis are confronted with a wide range of extraintestinal symptoms and complications of their disease. Some of these symptoms can occur even before clinical manifestation of the inflammatory bowel disease. Some of the symptoms (e.g. arthralgia) respond to the therapy of Crohn’s disease or ulcerative colitis, whereas other (e.g. PSC, primary sclerosing cholangitis) can progress even after colectomy. Extraintestinal manifestations are especially common when the colon is inflamed. Crohn’s disease patients with small bowel involvement have significantly less extraintestinal manifestations compared to patients with involvement of the colon [1] (table 1). Furthermore, we can distinguish between extraintestinal manifestations (arthralgia/arthritis, skin manifestations, ocular manifestations, primary sclerosing cholangitis) and secondary complications of the disease (osteoporosis, gallstones, kidney stones, coagulation abnormalities) (fig. 1). In this review, we will focus on the problem of osteoporosis in patients with inflammatory bowel disease and

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During the last decade, osteoporosis secondary to inflammatory bowel disease and other chronic gastrointestinal disorders like celiac diseae and primary biliary cirrhosis has been more and more recognized as a clinically relevant problem. Though some of the factors leading to an increased fracture risk in the elderly (e.g. worsening sight and weakness) do not play a major role in patients with gastrointestinal diseases, increased fracture risk is also proven in patients with hepatobiliary and inflammatory bowel disease [2, 3]. According to the WHO guidelines, definition of osteoporosis in absence of manifest fractures is based on measurement of bone mineral density (BMD) with a T-score less than –2.5 [4]. BMD is most commonly assessed by dual energy X-ray absorptiometry (DEXA) with a precision of 1%. Correlation of BMD and fracture risk is well documented in postmenopausal osteoporosis. Therefore, this method is widely used as a screening procedure for osteoporosis in those patients. Since recent data showed a strong association between BMD and the onset of vertebral fractures even in patients with Crohn’s disease [3], this surrogate marker also became the diagnostic standard in this patient group.

PD Dr. Max Reinshagen Department of Medicine I, University of Ulm Robert-Koch-Strasse 8, DE–89081 Ulm (Germany) Tel. +49 731 5002 4305, Fax +49 731 5002 4302 E-Mail [email protected]

Eye Anterior uveitis Episcleritis Skin Erythema nodosum Pyoderma gangraenosum

Liver /biliary system Primary sclerosing cholangitis (PSC) Gallstones

Pancreas Pancreatitis

Joints Arthralgia Arthritis Ankylosing spondylitis

Kidneystones

Fig. 1. Extraintestinal manifestations and complications in patients with IBD.

Quantitative ultrasound (QUS) is accepted as a complementary or alternative tool to absorptiometric techniques in the assessment of postmenopausal osteoporosis due to the absence of ionizing radiation, the low cost and portability of the equipment. Since data of QUS in IBD patients are controversial [5, 6], quantitative ultrasound actually cannot be recommended as a suitable alternative to bone mineral densitometry in those patients. The prevalence of osteoporosis as a complication in patients with inflammatory bowel disease ranges from 5.3 to 38% [7, 8]. While earlier studies have assumed a continuous annual loss of bone density of 3–7% [9, 10], more recent data suggest that patients’ long-term changes in

Table 1. Extraintestinal manifestations on joints, skin and the eye in

Complications of Inflammatory Bowel Diseases

Dig Dis 2003;21:138–145

700 patients with inflammatory bowel disease – relationship between prevalence and involvement pattern (% values)

Joints Skin Eyes

Ulcerative colitis

Crohn’s disease colon

Crohn’s Morbus disease Crohn ileum + colon ileum

26 19 4

39 23 13

26 16 4

14 9 1

From Greenstein et al. [1].

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Table 2. Interventional studies of osteoporosis in inflammatory bowel disease Reference

Patients Duration

Treatment strategy

Type of study

Underlying disease

Results

Vogelsang, 1995 [10]

75

1 year

T: vitamin D (1,000 IU daily) C: no treatment

randomized, controlled

CD

T: unchanged BMD (–0.2%) C: decreased BMD (–7%) T/C: p ! 0.005

Bernstein, 1996 [17]

17

1 year

T: vitamin D (250 IU daily) + calcium (1,000 mg daily) C: placebo

randomized, placebocontrolled

CD and UC

T: increased BMD (+3.4%, n.s.) C: unchanged BMD (+0.6%) T/C: n.s.

v. Tirpitz, 2003 [5, 18]

55

2¼ years

T1: vitamin D (1,000 IU daily) + calcium (800 mg daily) T2: vitamin D (1,000 IU daily) + calcium (800 mg daily) + sodium fluoride (50 mg daily) T3: vitamin D (1,000 IU daily) + calcium (800 mg daily) + ibandronate (1 mg i.v. every 3 months)

randomized, controlled

CD T-score ^1

first year: T1: increased BMD (+2.2%) T2: increased BMD (+4.1%) T3: increased BMD (+3.5%) T2/T1: p = 0.042 second year: T1: unchanged BMD (+0.4%) T2: increased BMD (+1.6%) T3: increased BMD (+1.9%) T2/T1: p = 0.034 T3/T1: p = 0.022

Abitbol, 2002 [19]

94

1 year

T: vitamin D (800 IU daily) + calcium (1,000 mg daily) + sodium fluoride (37.5 mg daily) C: vitamin D (800 IU daily) + calcium (1,000 mg daily) + placebo

randomized, placebocontrolled

CD and UC T-score ^2)

T: increased BMD (+4.8%) C: increased BMD (+3.2%) T/C: n.s.

Haderslev, 2000 [24]

31

1 year

T: vitamin D (400 IU daily) + calcium (1,000 mg daily) + alendronate (10 mg daily) C: vitamin D (400 IU daily) + calcium (1,000 mg daily) + placebo

randomized, placebocontrolled

CD remission T-score ^1

T: increased BMD (+4.6%) C: unchanged BMD (–0.9%) T/C: p ! 0.01

Clements, 1994 [14]

47

2 years

T: hormone replacement therapy

not randomized, CD and UC, T: increased BMD (+2.6%) not controlled postmenopausal women

Robinson, 1998 [25]

107

1 year

T: low impact exercise program C: no intervention

randomized, controlled

CD

T: slightly increased BMD (+1.5%, n.s.) C: unchanged BMD (+0.8%) T/C: n.s. fully compliant patients: increased BMD at trochanter (+7.8%)

T1, T2, ... = Different treatment groups; C = control group; BMD = bone mass density of the lumbar spine; CD = Crohn’s disease; UC = ulcerative colitis; n.s. = not significant.

bone density are quite heterogeneous and cannot be predicted in individual cases [11]. In terms of its pathogenesis, osteoporosis complicating Crohn’s disease and ulcerative colitis differs in several decisive features from that observed in postmenopausal women and in the elderly. The mechanisms contributing to bone loss in those younger patients are not fully understood. Several factors have been implicated, including systemic glucocorticoid administration, proinflammatory cytokines and genetic factors that may disturb the equilibrium of osteoblasts and osteoclasts, leading to a reduction in the osse-

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ous matrix. In addition, bone stability may be adversely affected due to demineralization secondary to bowel resections, malabsorption of vitamin D, lactose intolerance and immobilization. The relative importance of the individual risk factors in the development of osteoporosis in patients with Crohn’s disease has not yet been elucidated. Among patients with inflammatory bowel diseases, osteoporosis is more frequent in Crohn’s disease than in ulcerative colitis at diagnosis [12] and during the course of the disease [13], which underlines the role of systemic inflammation in the pathogenesis of osteoporosis.

Reinshagen/von Tirpitz

Due to this predominant pathogenetic role of proinflammatory cytokines during active disease, low body mass index (BMI) and the use of systemic steroids, effective treatment of the disease itself with agents other than systemic steroids represents the most effective prophylaxis for osteoporosis. Nevertheless, this is not proven by prospective and controlled studies. Most of the treatment modalities for osteoporosis in inflammatory bowel disease were primary established in postmenopausal osteoporosis. Some drugs, especially the selective estrogen receptor modulators (SERM) and aminobisphosphonates, have positive effects on the incidence of new fractures in postmenopausal women. Since IBD patients are generally younger and the pathophysiology of osteoporosis in IBD is presumably different than in postmenopausal women data collected in postmenopausal osteoporosis can therefore only partly be transferred to IBD patients. Several different treatment modalities have also been investigated in IBD with regard to changes of BMD, but up to now there is not one singular study showing a benefit in regard to prevent fractures, which has to be the only clinically relevant endpoint of studies in this context. Interventional trials in IBD patients were mostly performed with small sample sizes and over a short observation period, which may further limit the clinical usefulness of those studies. A summary of interventional trials in patients with osteoporosis associated to inflammatory bowel disease is given in table 2. Efficacy of hormone replacement therapy (HRT) in postmenopausal women with Crohn’s disease is proven only in one not-controlled study (table 2) [14]. The addition of progestin to estrogen reduces the risk of endometrial cancer in postmenopausal women, but it has no positive effect on the increased risk of breast cancer in those patients [15]. Since combined estrogen plus progestin treatment seems to increase the risk of cardiovascular diseases [16], this treatment modality can not be recommended uncritically any longer. Studies about long-term side effects of selective estrogen receptor modulators (SERM) in this context are not available. Supplementation of calcium and vitamin D (800– 1,000 IU) plays an important role in maintaining bone mineral density. The effect of a combined supplementation was investigated in several studies: In two studies BMD in patients treated with calcium [17] or vitamin D [10] remained stable after 1 year, whereas BMD decreased up to 7% in the placebo group [10]. Other studies demonstrated a positive effect on BMD in Crohn’s

disease showing that 800–1,000 mg calcium and 800– 1,000 IU vitamin D daily increased lumbar spine BMD by 2.2–3.2% in the first year [18, 19]. With regard to these data, supplementation of calcium and vitamin D is recommended as prophylaxis in those patients with high inflammatory activity and during treatment with systemic steroids to prevent further bone loss. Sodium fluoride stimulates bone formation and increases bone mass in patients with postmenopausal osteoporosis. Since the increase of BMD has not consistently been associated with a reduction of vertebral fractures [20] and higher doses of the drug (75 mg/day) have been shown to increase the risk of non-vertebral fractures [21], treatment with sodium fluoride is not approved in many countries. Due to the varying pathogenesis of osteoporosis in inflammatory bowel disease, where decreased osteoblast activity plays a major role, sodium fluoride may be a therapeutic alternative in those patients. 50 mg of sustained release sodium fluoride increases bone mineral density in osteopenic patients with Crohn’s disease by 4.1% after 1 year and 5.7% after 2 years, when administered cyclically with a 3-month fluoride-free period after each year of treatment and in addition to calcium supplementation (800 mg daily) [18]. Abitbol et al. [19] found a similar increase of lumbar spine BMD (4.8% per annum) using a smaller daily dose of sodium fluoride (37.5 mg). In this study, sodium fluoride had no additional effect when compared to calcium and vitamin D supplementation alone. On the other hand, fluoride treatment without discontinuing cyclically and without concomitant calcium supplementation leads to excessive formation of unmineralized osteoid and increased risk of nonvertebral fractures which in part may be a further reason for treatment failure demonstrated by Riggs et al. [21]. Several bisphosphonates are well established as effective antiresorptive agents for the prevention and treatment of postmenopausal osteoporosis. In particular, etidronate, alendronate and risedronate are approved as therapies in many countries. In addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of new bone remodelling units, and possibly to enhance osteoid mineralization, may also contribute to the reduction in fractures which could be demonstrated in several studies [22, 23]. Up to now there are only two controlled trials investigating bisphosphonates in patients with Crohn’s disease. In the study published by Haderslev et al. [24], alendronate (10 mg daily) increased lumbar spine BMD by 4.6% after 1 year, whereas in our own study a similar effect could be

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proven when 1 mg ibandronate was given intravenously every 3 months. Ibandronate increased BMD at the lumbar spine by 3.5% after 1 year and by another 1.9% after the second year of treatment, which was superior compared to calcium and vitamin D supplementation only [18]. The importance of exercise in preventing bone loss in inflammatory bowel disease has been shown by Robinson et al. [25]. The authors showed that a 12-month lowimpact exercise program increases bone mass density of the lumbar spine and the hip, which reached significance at the greater trochanter in the subgroup of fully compliant patients.

Joint Manifestations (Arthralgia, Arthritis, Ankylosing Spondylitis)

Peripheral arthralgia and arthritis is common in patients with IBD and predominantly reactive. Inflammation of the colon (ulcerative colitis or colitis Crohn) leads to joint manifestations in 26–39% of patients, whereas patients with Crohn’s ileitis develop joint manifestations in only 14% [1]. This reflects the importance of the colonic bacterial milieu in the pathophysiology of extraintestinal arthritis. Recently, it has been shown that mucosal lymphocytes from patients with active Crohn’s disease bind to human synovia [26] and that identical T cell clones can be identified in patients with active colitis and spondylarthropathy [27]. Arthritis in IBD is non-deforming and usually asymmetric. It involves primarily knees, ankles, wrists and elbows in a migratory pattern. Less often hands and shoulders are involved [28]. Arthralgia starts usually parallel to increased activity of the bowel disease, whereas arthritis may develop as well independent from disease activity. Orchard has proposed to distinguish between type 1 and type 2 arthritis. In type 1 arthritis, less than 5 joints are involved and the attacks are self-limited and mostly associated with active IBD. In type 2, more than 5 joints are involved and the symptoms persist usually more than several months and are generally independent from the activity of the underlying inflammatory bowel disease [29]. Arthralgia and type 1 arthritis are approached by treatment of the flare of the inflammatory bowel disease. Control of the flare of the IBD by steroids [28] or budesonide [30] leads to remission of the arthralgia/arthritis. Arthralgia independent from disease activity should be treated with paracetamol [28, 31] and not by NSAIDS.

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Type 2 arthritis and ankylosing spondylitis which is usually independent from disease activity of the IBD should be treated with sulphasalazin (SASP) or methotrexate [28, 31]. In very severe cases resistant to the latter treatment infliximab has been used successfully in an anecdotal way [32]. Several publications have documented the potential of NSAIDS to induce severe flares of Crohn’s disease and ulcerative colitis [33, for review]. Therefore, in most guidelines NSAIDS are not recommended for treatment of joint manifestations in IBD. Recently, two prospective trials have challenged this common view by stating that NSAID use was not associated with a higher likelihood of active IBD [34, 35]. The safety of selective cyclooxygenase-2 inhibitors has been investigated so far only in a small pilot study [36]. Therefore, the use of NSAIDS or COX-2 selective inhibitors cannot be generally recommended until placebo-controlled trials generate reliable safety and efficacy data.

Skin Manifestations (Erythema nodosum, Pyoderma gangrenosum)

Erythema nodosum is not specific for IBD and can occur in a variety of granulomatous diseases (e.g. sarcoidosis, tuberculosis and yersiniosis as well as in several viral infections). It presents with one or several red and tender subcutaneous nodules with a preference of the lower extremities. It develops in 10–20% of patients (again more often when the colon is involved) usually parallel to a flare of the IBD and is treated empirically by control of the inflammatory bowel disease [31, 37, 38]. Controlled therapy trials do not exist. Pyoderma gangrenosum occurs in 1–10% of patients with IBD (more often in ulcerative colitis than in Crohn’s disease and almost exclusively in patients with colonic involvement) and presents with chronic, sterile ulcerations which develop from pustules or fluctuant nodules. Treatment is started with systemic high-dose steroids, but the response is often limited [31, 38]. Therefore a variety of immunosuppressive/immunomodulating therapies have been reported in steroid-resistant cases including azathioprine, cyclosporine [39], tacrolimus [40, 41], infliximab [42, 43] and granulocyte apheresis [44]. Surgical intervention is contraindicated since it leads to exacerbation of the pyoderma [38]. Thus far no controlled randomized therapy trial of pyoderma gangrenosum in IBD has been published.

Reinshagen/von Tirpitz

Ocular Manifestations (Anterior uveitis, Episcleritis)

Ocular manifestations have been reported in 4–13% of patients with IBD [1, 45]. Acute anterior uveitis (iridocyclitis) presents with symptoms of pain, redness and photophobia. Flares of the IBD usually trigger the ocular inflammation. Therefore, treatment of the acute flare of IBD is initiated. Parallel topical prednisolone is recommended and cycloplegic agents like atropine are topically added to prevent posterior synechiae which could lead to acute glaucoma [46]. Episcleritis responds to treatment with topical corticosteroids [46]. Again this therapy is empiric. Controlled therapy trials have not been performed.

Hepatobiliary Manifestations (Primary Biliary Cholangitis)

Primary biliary cholangitis (PSC) develops in approximately 4% of patients with IBD, particularly ulcerative colitis. PSC is characterized by diffuse strictures of the bile ducts. Mostly, PSC is asymptomatic at diagnosis and abnormal liver function tests (AP, ÁGT) lead to ERCP and subsequently to the diagnosis of PSC [47]. The course of PSC is unpredictable but tends to be progressive and leads to cirrhosis and portal hypertension. 4–10% of patients with PSC develop cholangiocarcinoma. There are no sensitive and specific markers to predict development of cholangiocarcinomas in PSC [48]. Patients are treated with ursodesoxycholic acid (UDCA) in a dose of 12–15 mg/day [31]. A recent pilot study has proposed a higher dose (20 mg/kg) of UDCA, which led to an improvement of the histologic inflammatory scores in 9 of 10 patients [49]. Additionally, dominant strictures of the distal bile ducts should be endoscopically managed by balloon dilatation and/or temporary biliary stenting. Prospective trials have shown that the combination of UDCA therapy and endoscopic therapy slows the progression of the disease in comparison to untreated patients [50, 51]. Immunosuppressive treatment of PSC with azathioprine, cyclosporine, methotrexate or tacrolimus did not show therapeutic benefit [52]. For patients with progressive disease and uncontrollable recurrent cholangitis liver transplantation is the treatment of choice [53, 54].

Complications of Inflammatory Bowel Diseases

Nephrolithiasis, Cholecystolithiasis

Fatty acids resulting from intestinal fat malabsorption bind to free calcium in the colon which diminishes binding of intestinal oxalate to calcium and and fecal excretion of unsoluble calcium oxalate. This raises the intraluminal pool of free oxalate available for absorption. Dehydration is another major contributor to urinary calcium-oxalate precipitation in patients with IBD. Up to 10% of patients with Crohn's disease will develop calcium-oxalate kidney stones during their course of disease [55]. The treatment options for hyperoxaluria are optimal hydration, avoidance of oxalate-rich nutrients, calcium citrate (400–800 mg/day), potassium citrate 30–60 mEq/ day (in patients with normal renal function) and the thiazide diuretic chlortalidone [56] which diminishes calcium excretion. Gallstone disease is significantly increased in patients with IBD. In Crohn’s disease up to 28% of all patients develop gallstones [57]. Gallstone formation is considered to be multifactorial. A potential risk factor may be high bilirubin concentration in the bile, which can be found in patients with resection or severe inflammation of the terminal ileum [58]. Successful prophylactic strategies to avoid gallstone development in Crohn’s disease are not available.

Thrombembolic Complications

Thrombembolic complications are reported to occur in 0.5–6% of patients with IBD [59]. Since thrombembolic complications occur frequently also during quiescent phases of the disease, it is not really clear if activated clotting is only a secondary response to inflammation. Since approximately half of the patients have no other identifiable risk factor, there remains a substantial group of patients with IBD who develop thrombosis for unknown reasons [60, 61].

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26 Salmi M, Jalkanen S: Human leukocyte subpopulations from inflamed gut bind to joint vasculature using distinct sets of adhesion molecules. J Immunol 2001;166:4650–4657. 27 May E, Marker-Hermann E, Wittig BM, Zeitz M, Meyer-zum-Buschenfelde KH, Duchmann R: Identical T-cell expansions in the colon mucosa and the synovium of a patient with enterogenic spondyloarthropathy. Gastroenterology 2000;119:1745–1755. 28 Orchard TR: Arthritis associated with inflammatory bowel disease; in Bayless TM, Hanauer SB (eds): Advanced Therapy of Inflammatory Bowel Disease. Decker, Hamilton, London, 2001, pp 279–288. 29 Orchard TR, Wordsworth BP, Jewell DP: Peripheral arthropathies in inflammatory bowel disease: Their articular distribution and natural history. Gut 1998;42:387–391. 30 Florin TH, Graffner H, Nilsson LG, Persson T: Treatment of joint pain in Crohn’s patients with budesonide controlled ileal release. Clin Exp Pharmacol Physiol 2000;27:295–298. 31 Adler G, Reinshagen M: Extraintestinale Manifestationen. Z Gastroenterol 2003;41:54–61. 32 Sieper J, Braun J: New treatment options in ankylosing spondylitis: A role for anti-TNF· therapy. Ann Rheum Dis 2001;60(suppl 3): iii58–iii61. 33 Bjarnason I, Hayllar J, Macpherson AJ, Russell AS: Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993;104:1832– 1847. 34 Bonner GF, Walczak M, Kitchen L, Bayona M: Tolerance of nonsteroidal anti-inflammatory drugs in patients with inflammatory bowel disease. Am J Gastroenterol 2000;95:1946–1948. 35 Dominitz JA, Koepsell TD, Boyko EJ: Association between analgesic use and inflammatory bowel disease flares (abstract). Gastroenterology 2000;118:A581. 36 Mahadevan U, Loftus EVJ, Tremaine WJ, Sandborn WJ: Safety of selective cyclooxygenase-2 inhibitors in inflammatory bowel disease. Am J Gastroenterol 2002;97:910–914. 37 Nousari HC, Provost TT, Anhalt GJ: Cutaneous manifestations of inflammatory bowel disease; in Bayless TM, Hanauer SB (eds): Advanced Therapy of Inflammatory Bowel Disease. London, B.C. Becker, Hamilton, 2001, pp 271–274. 38 Tromm A, May D, Almus E, Voigt E, Greving I, Schwegler U, Griga T: Cutaneous manifestations in inflammatory bowel disease. Z Gastroenterol 2001;39:137–144. 39 Friedman S, Marion JF, Scherl E, Rubin PH, Present DH: Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease. Inflamm Bowel Dis 2001;7:1–7. 40 Petering H, Kiehl P, Breuer C, Kapp A, Werfel T: Pyoderma gangraenosum: Erfolgreiche topische Therapie mit Tacrolimus (FK506). [Pyoderma gangrenosum: successful topical therapy with tacrolimus (FK506)]. Hautarzt 2001;52:47–50.

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41 Kimble RM, Tickler AK, Nicholls VS, Cleghorn G: Successful topical tacrolimus (FK506) therapy in a child with pyoderma gangrenosum. J Pediatr Gastroenterol Nutr 2002;34: 555–557. 42 Tan MH, Gordon M, Lebwohl O, George J, Lebwohl MG: Improvement of pyoderma gangrenosum and psoriasis associated with Crohn disease with anti-tumor necrosis factor alpha monoclonal antibody. Arch Dermatol 2001; 137:930–933. 43 Hughes AP, Jackson JM, Callen JP: Clinical features and treatment of peristomal pyoderma gangrenosum. JAMA 2000;284:1546–1548. 44 Kanekura T, Maruyama I, Kanzaki T: Granulocyte and monocyte adsorption apheresis for pyoderma gangrenosum. J Am Acad Dermatol 2002;47:320–321. 45 Bernstein CN, Blanchard JF, Rawsthorne P, Yu N: The prevalence of extraintestinal diseases in inflammatory bowel disease: A population-based study. Am J Gastroenterol 2001;96: 1116–1122. 46 Latkany PA, Jabs DA: Ocular manifestations of inflammatory bowel disease; in Bayless TM, Hanauer SB (eds): Advanced Therapy of Inflammatory Bowel Disease. London, Decker, 2001, pp 275–277. 47 Raj V, Lichtenstein DR: Hepatobiliary manifestations of inflammatory bowel disease. Gastroenterol Clins N Am 1999;28:491–513.

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48 Chalasani N, Baluyut A, Ismail A, Zaman A, Sood G, Ghalib R, McCashland TM, Reddy KR, Zervos X, Anbari MA, et al: Cholangiocarcinoma in patients with primary sclerosing cholangitis: A multicenter case-control study. Hepatology 2000;31:7–11. 49 Mitchell SA, Bansi DS, Hunt N, von Bergmann K, Fleming KA, Chapman RW: A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 2001;121:900–907. 50 Stiehl A, Rudolph G, Kloters-Plachky P, Sauer P, Walker S: Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: Outcome after endoscopic treatment. J Hepatol 2002;36:151–156. 51 Stiehl A, Rudolph G, Sauer P, Benz C, Stremmel W, Walker S, Theilmann L: Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenoses in primary sclerosing cholangitis: An 8-year prospective study. J Hepatol 1997;26:560–566. 52 Stiehl A, Benz C, Sauer P: Primary sclerosing cholangitis. Can J Gastroenterol 2000;14:311– 315. 53 Wiesner RH: Liver transplantation for primary sclerosing cholangitis: Timing, outcome, impact of inflammatory bowel disease and recurrence of disease. Best Pract Res Clin Gastroenterol 2001;15:667–680. 54 Dvorchik I, Subotin M, Demetris AJ, Fung JJ, Starzl TE, Wieand S, Abu-Elmagd KM: Effect of liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis. Hepatology 2002;35:380–384.

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55 Buno-Soto A, Torres-Jimenez R, Olveira A, Fernandez-Blanco-Herraiz I, Montero-Garcia A, Mateos-Anton F: Lithogenic risk factors for renal stones in patients with Crohn’s disease. Arch Esp Urol 2001;54:282–292. 56 Ettinger B, Citron JT, Livermore B, Dolman LI: Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol 1988;139:679–684. 57 Lapidus A, Bangstad M, Astrom M, Muhrbeck O: The prevalence of gallstone disease in a defined cohort of patients with Crohn’s disease. Am J Gastroenterol 1999;94:1261–1266. 58 Brink MA, Slors JF, Keulemans YC, Mok KS, De Waart DR, Carey MC, Groen AK, Tytgat GN: Enterohepatic cycling of bilirubin: A putative mechanism for pigment gallstone formation in ileal Crohn’s disease. Gastro 1999;116: 1420–1427. 59 Bernstein CN, Blanchard JF, Houston DS, Wajda A: The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: A population-based cohort study. Thromb Haemost 2001;85:430–434. 60 Koutroubakis IE: Role of thrombotic vascular risk factors in inflammatory bowel disease. Dig Dis 2000;18:161–167. 61 Jackson LM, O’Gorman PJ, O’Connell J, Cronin CC, Cotter KP, Shanahan F: Thrombosis in inflammatory bowel disease: Clinical setting, procoagulant profile and factor V Leiden. QJM 1997;90:183–188.

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Review Article Dig Dis 2003;21:146–156 DOI: 10.1159/000073246

Standard Therapy of Crohn’s Disease Wolfgang Miehsler Christoph Gasche University of Vienna and Vienna General Hospital, Division of Gastroenterology and Hepatology, Vienna, Austria

Key Words Crohn’s disease W Prednisolone W Budesonide W Azathioprine W 6-Mercaptopurine W Mesalamine W Methotrexate W Metronidazole W Infliximab

Abstract Therapy of Crohn’s disease is either counteracting the underlying mechanisms of bowel inflammation or specifically targeting certain complications of disease, e.g. strictures, fistulae, bacterial overgrowth, or anemia. The therapeutic arsenal is well defined and has been tested for safety and efficacy. There is need and opportunity to adapt therapies to individual situations. This is made on the basis of scientific facts that have been collected from randomized controlled trials and on the basis of reasoned thinking that weighs the potential effect against potential side effects in individual cases. In clinical practice, the potency of lifestyle changes such as smoking cessation is still underestimated and not extensively exploited. As the understanding of genetic mutations, their gene function and phenotypic expression grows, we anticipate that future treatment can be tailored to certain genotypes or phenotypes of Crohn’s disease. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0212–0146$19.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ddi

Introduction: Whom Do We Treat?

The robustness of medical therapy in inflammatory bowel disease is based on conclusions from randomized controlled trials. The focus of such trials has been testing the effect of various pharmaceuticals on the clinical disease activity as measured by the Crohn’s disease activity index (CDAI) or similar scores [1]. Further advances in outcome measures led to the implementation of quality of life scores [2] or of endoscopic disease evaluation [3, 4]. When facing the challenges of daily medical practice, additional factors such as compliance, age, social economic status or smoking habits are seminal for therapeutic decisions. Because most patients do not meet the rigorous inclusion criteria, only a small proportion of our daily practice fits into protocols of randomized controlled trials. This is why we need to adapt certain therapies or even tailor treatments to the individual problems of our patients. One more remark: Crohn’s disease is not a 6-week disease! The disease develops silently [5] with aphthous lesions or small ulcers that are not recognized by the patient. As disease progresses over months and years, symptoms or laboratory markers may show up and inflammation may lead to stricture or fistula formation, both of which are considered indications for surgery. Randomized controlled trials usually focus only on short periods of time. This is another reason why the knowledge database from randomized controlled trials has to be bal-

Christoph Gasche Vienna General Hospital, Department of Medicine 4 Währinger Gürtel 18 AT–1090 Vienna (Austria) Fax +43 1 40400 4735, E-Mail [email protected]

Table 1. Active disease Indication

Regimen

Efficacy

Evidence1

Prednisolone

first-line, for severe flares

initial dose 30 mg/day to 1 mg/kg/day tapering over 8–10 weeks

remission in 60–92%

Ib

Budesonide

first-line, for mild-to-moderate flare, location confined to ileum and right colon

9 mg/day, single morning dose for 1–2 months, tapering to 6 and 3 mg/day

remission in 51%

Ia

Mesalamine

first-line, mild-to-moderate flare

3–4 g/day

remission in 40–79%

Ib

Antibiotics

first-line, mild-to-moderate flare

ciprofloxacin 1 g/day, metronidazole 1–1.5 g/day

remission in 46–56%

Ib

Azathioprine and 6-mercaptopurine

second-line, to be considered if 1 2 flares/year steroids for bridging

AZA 2–2.5 mg/kg, 6-MP 1–1.5 mg/kg long-term strategy

OR 3.1 (95% CI 2.5–3.9)

Ia

Infliximab

rescue therapy, if other therapies are not effective

one infusion 5 mg/kg for induction of remission

remission in 58%

Ib

1

Grade of evidence according to the Agency of Health Care Policy and Research (AHCPR); OR = odds ratio.

Steroids The definition of active disease is usually made on the basis of a CDAI above 150, with counts above 220 or 450 being moderately or severely active, respectively [6]. Of course, symptoms produced by strictures or fistulae should not account for disease activity. Because of historical reasons, steroids are the backbone of Crohn’s disease therapy (table 1) and generally used for severe flares [7– 9]. Although the rate of remission seems to be dose dependent, we cannot rely on dose-finding studies [10]. The initial daily dose usually ranges between 30 mg/day and 1 mg/kg/day of prednisolone or equivalent, which is tapered over 8–12 weeks. A dose relationship is unequivocally accepted for short- and long-term side effects. The efficiency of steroids for colonic Crohn’s disease has been questioned in the NCCDS [7]. Endoscopic improvement, however, was observed in a small proportion upon highdose and long-term therapy [10]. Budesonide. Because of steroid-associated side effects, budesonide has emerged as steroid derivative with high topical and low systemic activity based on rapid hepatic

conversion [11]. Budesonide is available as oral, pH-modified or controlled ileal release preparation, both delivering the substance to the terminal ileum, cecum and ascending colon, thereby limiting its applicability to Crohn’s disease confined to these segments. The efficacy of 9 mg budesonide has been tested in a dose finding study and is slightly inferior as compared to prednisolone [12, 13]. No data are available on the local use of budesonide as enema. Sulfasalazine and Mesalamine. Mesalamine and sulfasalazine are alternative options in mild-to-moderate Crohn’s disease. The efficacy is significantly superior to placebo, especially when the colon is involved [14], but it is inferior as compared to prednisolone or budesonide [7, 8, 15]. The combination of sulfasalazine to prednisolone does not result in additional benefit and should be avoided [8, 16]. Mesalamine, which is considered the active moiety of sulfasalazine, has also been studied in active Crohn’s disease. Remission can be achieved in 43% of patients taking 4 g/day, with lesser doses not being effective [17, 18]. Similar to sulfasalazine, the efficacy of mesalamine is inferior as compared to prednisolone [19]. Thus, mesalamine is used in mild disease specifically to avoid steroid-associated side effects. Extensive use over the past years has underscored the safety of mesalamine [20], though high dose use during pregnancy has been questioned [21]. Mesalamine enemas, though sometimes given for left-sided Crohn’s colitis, lack controlled data. Azathioprine and 6-Mercaptopurine. If flare-ups occur repeatedly (two or more flares per year) or disease loca-

Standard Therapy of Crohn’s Disease

Dig Dis 2003;21:146–156

anced with reasoned thinking from a doctor reflecting both long-term outcome and side effects. The scope of this article is to review the current treatment modalities for Crohn’s disease based on both the knowledge database and reasoned thinking.

Active Disease

147

Table 2. Chronic active disease Indication

Regimen

Efficacy

Evidence1

Smoking cessation

first-line lifestyle change

single or repeated advisories

50% long-term benefit

Ib

Prednisolone

useful for bridging to AZA/6-MP

lowest possible dose to control symptoms

Budesonide

prednisolone alterative

3–9 mg/day

68% prednisolone-free

Ib

Azathioprine and 6-mercaptopurine

first-line

AZA 2–2.5 mg/kg 6-MP 1–1.5 mg/kg

steroid-free remission 67%

Ia

Methotrexate

second-line, adverse events or lack of efficacy under AZA/6-MP

25 mg/week i.m., 15 mg/week i.m. for maintenance

steroid-free remission 39%

Ib

Infliximab

third-line, when AZA/6-MP and MTX are ineffective

infusion with 5 mg/kg, repeated infusion and concomitant AZA/6-MP recommended

remission up to 81%

Ia

Antibiotics

colonic disease bacterial overgrowth

ciprofloxacin 1 g/day, metronidazole 1–1.5 g/day

not tested combination better

IV

1

Ib

Grade of evidence according to the Agency of Health Care Policy and Research (AHCPR).

tion is extensive (e.g. L3 or L4 according to the Vienna classification [22]), initiation of immunosuppressive therapy should be considered early. Most of the effects of azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy relate to the long-term benefit. AZA and 6-MP are slow acting drugs and the effect can be expected after 8 weeks at best [23]. Thus, the combination of systemic steroids with AZA/6-MP is the prime choice for active Crohn’s disease, with prednisolone inducing remission rapidly and AZA/6-MP maintaining the remission after tapering of steroids [24–26]. The recommended daily dose of AZA is 2.0–2.5 mg/kg body weight and for 6-MP 1.0–1.5 mg/ kg. Once remission is achieved, the benefit of AZA/6-MP is pertained for over 4 years [27]. There is no reason to use cyclosporine in Crohn’s disease [28, 29]. Antibiotics. Although antibiotics are frequently used in clinical practice, their efficacy in active Crohn’s disease as indicated by controlled trials is rather limited. In mildly active disease, metronidazole seems to have similar activity as compared to sulfasalazine but inferior efficacy as compared to prednisolone [30–32]. As colonic disease (L2) does not well respond to prednisolone, it might benefit the most from metronidazole and sulfasalazine. Also ciprofloxacin (1 g/day) seems to be equally effective to mesalamine (4 g/day) in mild-to-moderate disease [33, 34]. The combination of cirpofloxacin and metronidazole can induce remission but is still inferior to prednisolone [34]. Additionally, it is noteworthy to say that side effects (especially of metronidazole) often necessitate the withdrawal of antibiotics.

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Anti-TNF Therapy. Infliximab, a chimeric monoclonal antibody directed against soluble and membrane bound forms of tumor necrosis factor-· (TNF-·) has emerged as therapeutic option in Crohn’s disease [35]. In the largest trial so far (ACCENT 1), 573 active Crohn’s disease patients received a single infusion of 5 mg/kg resulting in a 58% response rate [36]. Remission was maintained in approximately one third of initial responders by repeated infusions. Although there is no head-to-head trial of infliximab versus prednisolone, the data from ACCENT 1 do not implicate superior activity of infliximab over prednisolone. Given the short term and the potentially immunizing effects of this costly therapy, infliximab is at best a rescue therapy for patients who are refractory, dependent, or intolerant of steroids, AZA/6-MP, mesalamine, or antibiotics.

Chronic Disease Activity

Azathioprine and 6-Mercaptopurine Chronic disease activity is considered when flares recur frequently (two or more times per year), or when steroids cannot be tapered to zero. Some of these cases can be switched to budesonide [37]. A distinct category is steroid refractory disease when patients do not respond to steroids at all. Chronic active disease is important because within a year of steroid treatment almost half of patients will either be steroid dependent or steroid refractory [38]. This large effect is the basis for an early use of AZA/6-MP (table 2). It has long been demonstrated that patients with

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chronic active disease receiving AZA/6-MP achieved steroid-free remission significantly more frequently than with placebo [39, 40]. When using AZA/6-MP, one has to be aware of its side effects, which are divided into the idiosyncratic type (occurring within 10 and 30 days after treatment initiation or immediately after re-challenge) and the non-allergic, dose-dependent toxicity [39]. The most frequent idiosyncratic reaction is acute pancreatitis. The most frequent toxic reaction is profound myelosuppression. One explanation for the occurrence of myelotoxicity are genetic variants of AZA/6-MP metabolizing enzymes, with the thiopurine-methyltransferase (TPMT) being studied best [41]. Homozygote and to a lesser extent also heterozygote individuals are at risk to develop severe myelosuppression or even aplasia. Therefore, if available, measurement of TPMT activity is recommended, but since its negative predictive value is low it does not replace periodical complete blood count checks. 6-Thioguanine (6-TG), acting as a nucleoside analog, has long been considered as the active metabolite of these drugs. Novel studies are now pointing to 6-TG-triphosphate, which inhibits Rac1, a CD28-dependent activator of NFÎB, thereby induces apoptosis in activated T cells [42]. This rather new mechanism would explain why AZA does not increase the rate of malignancies or lymphoma [43]. Still, measurements of 6-TG blood levels are useful to separate true non-responders from those patients with poor drug compliance or poor drug absorption [44, 45]. Safety data on spermatogenesis and pregnancy outcome are in support of using these drugs without specific precautions [46, 47]. Methotrexate Results about the efficacy of methotrexate (MTX) in Crohn’s disease are conflicting. In the study by Feagan et al. [48], 39% achieved steroid-free remission with 25 mg/ week i.m. Sixty-five percent of initial responders were able to maintain remission with 15 mg/week i.m., which means that one quarter of initially treated patients had a long-term benefit [49]. Other trials studying MTX subcutaneously or orally did not show an effect [50–52]. The toxicity of MTX, however, exceeds AZA/6-MP as liver disease, hypersensitivity pneumonitis, potential teratogenicity, and bone marrow depression have to be considered. Thus, MTX is a second line therapy in chronic active Crohn’s disease for AZA/6-MP-intolerant or -refractory cases.

Standard Therapy of Crohn’s Disease

Anti-TNF Therapy Though early studies on infliximab were performed in active Crohn’s disease refractory to any drug such as mesalamine or steroids, the current indication for infliximab is considered chronic active disease refractory or intolerant to AZA/6-MP and MTX [53]. Clinical improvement after infliximab is accompanied by a significant proportion of endoscopic improvement or sometimes healing [3]. However, after 12 weeks half of the initial responders relapse indicating that infliximab has short-term efficacy and repeated infusions are necessary for maintenance of remission [54]. Further details on regimen, efficacy, toxicity and other anti-TNF strategies are found in the article by Scholmerich in this issue [55].

Maintenance of Remission

As mentioned earlier, Crohn’s disease is a chronic disease and maintenance of symptom-free periods is a major objective both after medical and surgical treatment. After an acute flare, we expect 25–50% of patients to relapse within the following year [7, 8]. In general, steroids including budesonide are considered ineffective in maintaining remission [7, 8, 56–61]. Mesalamine Probably because it is the least toxic, most data are available for mesalamine (table 3). Three meta-analyses have been conducted trying to clarify this issue [62–64]. The largest meta-analysis included a total of 2,097 patients with drug-induced remission. Mesalamine reduces the risk of relapse by 4.7%, the number needed to treat being 21 [63]. In view of the considerable costs and the insignificant effects, mesalamine is currently not considered for maintenance of medically induced remission. In the post-surgical setting, however, the meta-analysis demonstrated a benefit of mesalamine in 13% of patients, the number needed to treat being 8 [65, 66]. A benefit in favor of mesalamine could also be demonstrated when patients were followed up by endoscopy [67]. Also a dose relationship was demonstrated by Caprilli et al. [68] who compared 2.4 vs. 4 g/day, the higher dose being more effective. Azathioprine and 6-Mercaptopurine As indicated earlier, AZA/6-MP is effective in inducing and maintaining remission [24]. However, the question remains for how long patients should be treated. It was thought that it is safe to stop AZA after a treatment

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149

Table 3. Maintenance of medically and surgically induced remission in Crohn’s disease Indication

Regimen

Efficacy

Evidence1

Smoking cessation

in all smokers

single or repeated advisories

50% long-term benefit

Ib

Mesalamine

medically induced remission surgically induced remission

3–4 g/day 3–4 g/day

hardly effective, NNT = 21 mild efficacy, NNT = 8

Ia Ia

Azathioprine and 6-mercaptopurine

remission induced with AZA/6-MP post-surgically, not generally recommended (overkill?)

AZA 2–2.5 mg/kg 6-MP, 1–1.5 mg/kg AZA 2–2.5 mg/kg 6-MP, 1–1.5 mg/kg

high long-term efficacy can prevent clinical and endoscopic recurrence

Ia Ib

Methotrexate

remission induced by MTX

15–25 mg/week i.m.

25% long-term benefit

Ib

Infliximab

rescue if refractory to AZA, 6-MP, MTX

5 or 10 mg/kg every 8–12 weeks

30% of initial responders

Ib

1

Grade of evidence according to the Agency of Health Care Policy and Research (AHCPR); NNT = number needed to treat.

period of 4 years [69]. When studied in a randomized prospective manner, however, AZA was still effective even after a period of 4 years [27]. The authors concluded that a treatment cessation is justified in selected patients, probably in those with no laboratory signs of inflammation. The role of AZA/6-MP in the postoperative setting is less clear. In a 2-year follow-up study patients were given 6MP, mesalamine, or placebo developing clinical relapse in 53, 61 and 70%, respectively, and severe endoscopic recurrence in 68, 80 and 90%, respectively [70]. However, AZA/6-MP is potentially toxic. In view of patients who do not develop postoperative recurrence at all, the unselected administration of AZA/6-MP seems to be overkill. An algorithm has been proposed trying to tackle this dilemma (fig. 1) [71]. Patients at high risk for recurrence (ileocolonic anastomosis, continuous smoking, perforating disease, repeated surgery) should receive AZA/6-MP, and patients with low or intermediate risk (fibrostenotic disease, no smoking, first operation) may remain without therapy, followed by ileocolonoscopy after 6 months. Severe endoscopic recurrences may then be treated with AZA/6-MP; intermediate lesions would receive mesalamine (4 g/day). Because of its rational approach, this algorithm is appealing but has not been evaluated in a controlled manner. Antibiotics The best proof of principle for the effect of metronidazole in Crohn’s disease is actually the prevention of postoperative endoscopic recurrence [72]. As a consequence clinical relapse in the metronidazole group was delayed. However, side effects, specifically polyneuropathy, limit its long-term use and its practical application in the postoperative setting.

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Strictures

Strictures mainly consist of inflammatory infiltrate and myofibroblats with a variable degree of collagen deposition. The obstruction associated with this is difficult to overcome by medical means [73–75]. Physical interventions, by either balloon dilatation, strictureplasty, or resection are needed to solve the mechanical problem of obstruction [76]. Concerning the medical management after dilatation, the combination of budesonide and AZA was most effective in preventing recurrence of stenosis [77]. However, this randomized controlled trial has not been published as full report yet. Antibiotics are of anecdotal value in stricturing disease, on one hand because of their effect against stricture-associated bacterial overgrowth and on the other hand because they may prevent the penetrating complications of bowel obstruction (see below).

Fistulae

Fistulae are defined as abnormal communication between the lumen of the gut and the mesentery, and/or another hollow organ, or the abdominal wall and skin [73]. Histologically, fistulae are composed of granulation tissue surrounding a lumen, which is mostly filled by debris, and inflammatory cells, in particular neutrophils. Roughly, fistulae can be divided into perianal and enteric tracts. The actual difference between fistulae (both enteric and perianal) and abscesses is an arbitrary change in diameter, the cut-off being somewhere between 1 and 2 cm [78]. The risk of septic complication relates to the diameter of the lesion, with larger lesions being at higher

Miehsler/Gasche

Fig. 1. Algorithm for maintenance of postsurgical remission in Crohn’s disease. Reprinted with permission from the BMJ publishing group [71].

risk and at need for drainage. Patients benefit from a joint effort between gastroenterologists and surgeons. When enteric fistulae coexist with strictures (which is actually the case in 95% of our pathological series [73], but may be different in other parts of the world), the degree of obstruction defines the treatment. This is the reason why in our hands most enteric fistulae are finally managed surgically.

prolong the effect [80]. Steroids have no effect on fistulae.

Azathioprine and 6-Mercaptopurine Simple perianal fistulae can be treated surgically with low risk of incontinence, but complex perianal tracts usually require a combined surgical (mostly drainage) and medical approach. In the long-term study on the use of 6-MP in Crohn’s disease, 6-MP was more effective in closing fistulae as compared to placebo (31 vs. 6%) [39]. In the follow-up study, fistulae closed completely in 39% of patients whereas another 26% experienced a substantial improvement [79]. Discontinuation of medical therapy led to reopening of fistulae in all patients. Again AZA/ 6-MP is the basis for perianal Crohn’s disease. Also infliximab was studied in fistulizing Crohn’s disease [55]. The combination of AZA/6-MP with infliximab might even

Antibiotics Despite the lack of controlled data, incomplete response to AZA/6-MP and the risk of infectious complication is a good reason for the parallel use of antibiotics in this scenario. Improvement but not healing of perianal fistulae has been reported on ciprofloxacin [81]. Healing of fistulae was seen in approximately half of patients on metronidazole [82, 83] as well as on combination of ciprofloxacin and metronidazole [84]. However, recurrence is a common problem [85] and sustained closure of fistulae needs parallel immunosuppression [86]. The short-term efficacy of cyclosporine was promising in perianal fistulae but long-term efficacy is disappointing since relapse is often seen under therapy after several weeks and occurs in 82% after cessation of treatment [87, 88]. In the only study on MTX in Crohn’s disease that reports the effect on fistulae, 4 of 16 patients achieved closure and 5 achieved improvement, which adds to a 56% overall response rate [89]. However, controlled studies are missing for both, cyclosporine and MTX.

Standard Therapy of Crohn’s Disease

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151

Table 4. Therapy of perianal fistulae in Crohn’s disease Indication

Regimen

Efficacy

Evidence1

Azathioprine and 6-mercaptopurine

first-line, combination with antibiotics

AZA 2–2.5 mg/kg 6-MP 1–1.5 mg/kg

response 55%, complete closure 39% long-term efficacy

IIb

Ciprofloxacin

first-line, combination with AZA/6-MP possible

1 g/day, combination with metronidazole possible

fast improvement but no healing relapse after cessation

IIb

Metronidazole

first-line, combination with AZA/6-MP possible

1–1.5 g/day, combination with ciprofloxacin possible

healing in half of patients frequent relapse after cessation

IIb

Infliximab

second-line, after failure of antibiotics and AZA/6-MP

infusion 5 mg/kg at weeks 0, 2 and 6

reduction of draining fistulae 68% complete closure 55% within 2 weeks median time to relapse 3 months

Ib

Cyclosporin A

in selected cases only

4 mg/kg/24 h i.v. switch to 8 mg/kg/day p.o.

short-term efficacy relapse within weeks

III

Methotrexate

in selected cases only

15–25 mg/week

56% improvement

III

The risk of septic complication of perianal fistulae relates to the presence of the retentions within the lesion (fistula vs. abscess). Since larger retentions need drainage, patients benefit from a joint effort between gastroenterologists and surgeons. 1 Grade of evidence according to the Agency of Health Care Policy and Research (AHCPR).

Anemia

Lifestyle Changes

About one third of patients with inflammatory bowel diseases are anemic and need special attention. Anemia results from a combination of iron deficiency (based on intestinal blood loss, dietary restrictions and sometimes iron malabsorption) and chronic intestinal inflammation, which is then called anemia of chronic disease. During the past decade relevant progress has been made in the understanding and treatment of IBD-associated anemia [90]. It was shown earlier the successful treatment can improve quality of life, cognitive function, and the ability to work but also reduces co-morbidity and mortality. Effective replacement of iron deficits has become the primary goal of anemia therapy in IBD. Intravenous iron preparations such as iron sucrose are safe as a dilute solution (200 mg iron sucrose in 200 ml NaCl 0.9%), and effective alternatives to oral iron compounds [91]. The ability of erythropoietin (150 U/kg, 3 !/week) to interfere with key mechanisms of anemia of chronic diseases also benefits our patients with IBD-associated anemia. Concerns about cost-effectiveness have been raised and weighed to the potential improvement in quality of life.

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Smoking Cessation There is little doubt that environmental factors are causally involved in the pathogenesis of Crohn’s disease. Smoking and may be also oral contraceptives are associated with a higher relapse rate after medically or surgically induced remission [92]. It has been known for a long time that smokers require more glucocorticoids and more immunosuppressants [93]. In our opinion, the first goal in patients with Crohn’s disease is to have them quit smoking. The positive effect of smoking cessation has been recently addressed in a prospective trial [94]. The French group investigated on 474 smokers with Crohn’s disease and tested the hypothesis that smoking cessation improves the clinical course of disease. Smoking cessation was successful in 12% of the study population. As hypothesized, smoking cessation was associated with an improvement in the clinical course of Crohn’s disease similar to patients who never had smoked. Interestingly, the authors identified four factors, which were associated with successful smoking cessation: first, the physician’s role, second, higher socioeconomic (educational) status, third, previous bowel surgery, and last, concomitant use of oral contraceptives. The effect of smoking cessation was much stronger than the effect of mesalamine on maintenance of remission, just without any costs and side effects. Patient’s education and physician’s credibility are most fundamental to achieve this goal.

Miehsler/Gasche

Nutrition Several dietary factors have been suggested to be involved in the pathogenesis of Crohn’s disease, such as refined carbohydrates [95, 96], the proportion of fatty acids [97], omega–3 fatty acids [96, 98], food additives [99], dietary yeast [100], or microparticles [101]. However, none of these factors has definitely been proven to cause disease. The effect of a low carbohydrate diet was tested in a randomized, controlled trial but the results are unclear [96]. Favorable effects were found as long as the patients adhered to the diet, but the question whether the patients relapsed because they increased the carbohydrate intake or because complaints returned and the patients lost faith in the diet is still open. Also, individual exclusion diets have been shown to maintain remission in some trials [102, 103] but showed no [104, 105] or only minor benefits in others [106]. Until now, dietary changes have not added significant progress to the treatment of Crohn’s disease.

Patient-Tailored Medicine

It is general practice to stepwise escalate drugs from less effective, less toxic to more effective, more toxic (fig. 2). Such a stepwise approach is reasonable, because toxic drugs are avoided in the first place. This stepwise approach, however, would not need a doctor for treatment of inflammatory bowel diseases. We may call this ‘method of trial and error’ and its use is strongly discouraged. In fact, each patient has an individual genetic basis, an individual environment and individual disease problems. Individual disease problems mean individual therapeutic challenges. Ineffective therapies should be avoided (e.g. steroids or mesalamine for perianal fistulae) and effective treatment (even if it has higher toxicity) should target the specific problems, which need to be explored

Surgery Infliximab / Biologicals Cyclosporine / Tacrolimus Azathioprine / 6-Mercaptopurine Ciprofloxacin / Metronidazole Budesonide / Prednisolone Sulfasalazine / Mesalamine Diet / Smoking Cessation

Fig. 2. Escalation of Crohn’s therapy: ‘Method of trial and error’. A

general rule in medicine is to prefer less toxic therapies. This leads to the common practice of starting Crohn’s therapy with non-toxic but mostly ineffective drugs. As these drugs proof ineffective, doctors are stepping up the therapeutic pyramid. If such an approach is successful, doctors would be dispensable. It is the so-called ‘method of trial and error’. Instead, ineffective therapies should be avoided in the first place and effective treatment even if it is more toxic should target the individual problems, which need to be defined prior to initiation of treatment.

prior to initiation of treatment. As our understanding of the various genetic mutations, their functional consequence and their phenotypic expression is growing, we still may hope that future therapies can be tailored to the individual genotype and phenotype of Crohn’s disease. Until then, physicians will need to adapt individual therapies to the needs of their patients using both the knowledge database from evidence-based medicine and reasoned thinking.

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Standard Therapy of Crohn’s Disease

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45 Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret Y, et al: Pharmacogenomics and metabolite measurement for 6mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;118:705– 713. 46 Dejaco C, Mittermaier C, Reinisch W, Gasche C, Waldhoer T, Strohmer H, et al: Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology 2001;121: 1048–1053. 47 Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH: The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: A retrospective cohort study. Gastroenterology 2003;124:9–17. 48 Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, et al: Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Engl J Med 1995;332:292–297. 49 Feagan BG, Fedorak RN, Irvine EJ, Wild G, Sutherland L, Steinhart AH, et al: A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North American Crohn’s Study Group Investigators. N Engl J Med 2000;342:1627–1632. 50 Egan LJ, Sandborn WJ, Tremaine WJ, Leighton JA, Mays DC, Pike MG, et al: A randomized dose-response and pharmacokinetic study of methotrexate for refractory inflammatory Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther 1999;13:1597–1604. 51 Oren R, Moshkowitz M, Odes S, Becker S, Keter D, Pomeranz I, et al: Methotrexate in chronic active Crohn’s disease: A double-blind, randomized, Israeli multicenter trial. Am J Gastroenterol 1997;92:2203–2209. 52 Arora S, Katkov W, Cooley J, Kemp JA, Johnston DE, Schapiro RH, et al: Methotrexate in Crohn’s disease: Results of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology 1999;46:1724–1729. 53 Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029–1035. 54 Rutgeerts P, D’Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, et al: Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117:761–769. 55 Schölmerich J, Huber G: Biological therapy in IBD. Anti-tumor necrosing factor-alpha and others. Dig Dis 2003;21:180–191. 56 Smith RC, Rhodes J, Heatley RV, Hughes LE, Crosby DL, Rees BI, et al: Low dose steroids and clinical relapse in Crohn’s disease: A controlled trial. Gut 1978;19:606–610. 57 Greenberg GR, Feagan BG, Martin F, Sutherland LR, Thomson AB, Williams CN, et al: Oral budesonide as maintenance treatment for Crohn’s disease: A placebo-controlled, doseranging study. Canadian Inflammatory Bowel Disease Study Group. Gastroenterology 1996; 110:45–51.

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58 Lofberg R, Rutgeerts P, Malchow H, Lamers C, Danielsson A, Olaison G, et al: Budesonide prolongs time to relapse in ileal and ileocaecal Crohn’s disease: A placebo controlled one year study. Gut 1996;39:82–86. 59 Ferguson A, Campieri M, Doe W, Persson T, Nygard G: Oral budesonide as maintenance therapy in Crohn’s disease: Results of a 12month study. Global Budesonide Study Group. Aliment Pharmacol Ther 1998;12:175–183. 60 Bergman L, Krause U: Postoperative treatment with corticosteroids and salazosulphapyridine (Salazopyrin) after radical resection for Crohn’s disease. Scand J Gastroenterol 1976; 11:651–656. 61 Ewe K, Bottger T, Buhr HJ, Ecker KW, Otto HF: Low-dose budesonide treatment for prevention of postoperative recurrence of Crohn’s disease: A multicentre randomized placebocontrolled trial. German Budesonide Study Group. Eur J Gastroenterol Hepatol 1999;11: 277–282. 62 Camma C, Giunta M, Rosselli M, Cottone M: Mesalamine in the maintenance treatment of Crohn’s disease: A meta-analysis adjusted for confounding variables. Gastroenterology 1997; 113:1465–1473. 63 Messori A, Brignola C, Trallori G, Rampazzo R, Bardazzi G, Belloli C, et al: Effectiveness of 5-aminosalicylic acid for maintaining remission in patients with Crohn’s disease: A metaanalysis. Am J Gastroenterol 1994;89:692– 698. 64 Steinhart AH, Hemphill D, Greenberg GR: Sulfasalazine and mesalazine for the maintenance therapy of Crohn’s disease: A meta-analysis. Am J Gastroenterol 1994;89:2116–2124. 65 Sutherland LR, Martin F, Bailey RJ, Fedorak RN, Poleski M, Dallaire C, et al: A randomized, placebo-controlled, double-blind trial of mesalamine in the maintenance of remission of Crohn’s disease. The Canadian Mesalamine for Remission of Crohn’s Disease Study Group. Gastroenterology 1997;112:1069–1077. 66 Lochs H, Mayer M, Fleig WE, Mortensen PB, Bauer P, Genser D, et al: Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine: European Cooperative Crohn’s Disease Study VI. Gastroenterology 2000;118: 264–273. 67 McLeod RS, Wolff BG, Steinhart AH, Carryer PW, O’Rourke K, Andrews DF, et al: Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology 1995;109:404–413. 68 Caprilli R, Cottone M, Tonelli F, Sturniolo G, Castiglione F, Annese V, et al: Two mesalazine regimens in the prevention of the post-operative recurrence of Crohn’s disease: A pragmatic, double-blind, randomized controlled trial. Aliment Pharmacol Ther 2003;17:517–523. 69 Bouhnik Y, Lemann M, Mary JY, Scemama G, Tai R, Matuchansky C, et al: Long-term followup of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet 1996;347:215–219.

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70 Korelitz B, Hanauer S, Rutgeerts P, Present D, Peppercorn M: Post-operative prophylaxis with 6-MP, 5-ASA or placebo in Crohn’s disease: A 2 year multicenter trial. Gastroenterology 1998;114:A1011. 71 Rutgeerts P: Little benefit from mesalazine taken prophylactically after surgery for Crohn’s disease. Gut 2001;48:452–453. 72 Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R, et al: Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995;108:1617–1621. 73 Oberhuber G, Stangl PC, Vogelsang H, Schober E, Herbst F, Gasche C: Significant association of strictures and internal fistula formation in Crohn’s disease. Virchows Arch 2000;437: 293–297. 74 Tonelli P: Perforation in Crohn’s ileitis and its impact on the natural history of the disease. Note 1. Pathogenic process of the event, its relationship with intestinal obstruction, and its immediate consequences (in Italian). Ann Ital Chir 1995;66:335–347. 75 Tonelli F, Ficari F: Pathological features of Crohn’s disease determining perforation. J Clin Gastroenterol 1991;13:226–230. 76 Couckuyt H, Gevers AM, Coremans G, Hiele M, Rutgeerts P: Efficacy and safety of hydrostatic balloon dilatation of ileocolonic Crohn’s strictures: a prospective longterm analysis. Gut 1995;36:577–580. 77 Raedler A, Peters I, Schreiber S: Treatment with azathioprin and budesonide prevents reoccurrence of ileocolonic stenoses after endoscopic dilatation in Crohn’s disease. Gastroenterology 1997;112:A1067. 78 Gasche C, Moser G, Turetschek K, Schober E, Moeschl P, Oberhuber G: Transabdominal bowel sonography for the detection of intestinal complications in Crohn’s disease. Gut 1999;44:112–117. 79 Korelitz BI, Present DH: Favorable effect of 6mercaptopurine on fistulae of Crohn’s disease. Dig Dis Sci 1985;30:58–64. 80 Ochsenkuhn T, Goke B, Sackmann M: Combining infliximab with 6-mercaptopurine/azathioprine for fistula therapy in Crohn’s disease. Am J Gastroenterol 2002;97:2022–2025. 81 Turunen U, Farkkila M, Seppala K: Long-term treatment of perianal or fistulous Crohn’s disease with ciprofloxacin. Scand J Gastroenterol 1989;24(suppl 158):144. 82 Bernstein LH, Frank MS, Brandt LJ, Boley SJ: Healing of perineal Crohn’s disease with metronidazole. Gastroenterology 1980;79:599. 83 Jakobovits J, Schuster MM: Metronidazole therapy for Crohn’s disease and associated fistulae. Am J Gastroenterol 1984;79:533–540. 84 Solomon MJ, McLeod RS, O’Connor BI, Steinhart AH, Greenberg GR, Cohen Z: Combination of ciprofloxacin and metronidazole in severe perianal Crohn’s disease. Can J Gastroenterol 1993;7:571–573. 85 Brandt LJ, Bernstein LH, Boley SJ, Frank MS: Metronidazole therapy for perineal Crohn’s disease: A follow-up study. Gastroenterology 1982;83:383–387.

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86 Dejaco C, Harrer M, Miehsler W, Vogelsang H, Reinisch W: Clinical outcome of perianal fistulas in Crohn’s disease treated with antibiotics combined with or followed by azathioprine. Gastroenterology 2002;122:A501. 87 Hanauer SB, Smith MB: Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993;88:646–649. 88 Egan LJ, Sandborn WJ, Tremaine WJ: Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn’s disease with intravenous cyclosporine. Am J Gastroenterol 1998;93:442–448. 89 Mahadevan U, Marion JF, Present DH: The place for methotrexate in the treatment of refractory Crohn’s disease. Gastroenterology 1997;112:A1031. 90 Gasche C: Anemia in IBD: The overlooked villain. Inflamm Bowel Dis 2000;6:142–150. 91 Gasche C, Dejaco C, Waldhoer T, Tillinger W, Reinisch W, Fueger GF, et al: Intravenous iron and erythropoietin for anemia associated with Crohn disease: A randomized, controlled trial. Ann Intern Med 1997;126:782–787. 92 Timmer A, Sutherland LR, Martin F: Oral contraceptive use and smoking are risk factors for relapse in Crohn’s disease. The Canadian Mesalamine for Remission of Crohn’s Disease Study Group. Gastroenterology 1998;114: 1143–1150.

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93 Cosnes J, Carbonnel F, Beaugerie L, Le Quintrec Y, Gendre JP: Effects of cigarette smoking on the long-term course of Crohn’s disease. Gastroenterology 1996;110:424–431. 94 Cosnes J, Beaugerie L, Carbonnel F, Gendre JP: Smoking cessation and the course of Crohn’s disease: An intervention study. Gastroenterology 2001;120:1093–1099. 95 Tragnone A, Valpiani D, Miglio F, Elmi G, Bazzocchi G, Pipitone E, et al: Dietary habits as risk factors for inflammatory bowel disease. Eur J Gastroenterol Hepatol 1995;7:47–51. 96 Lorenz-Meyer H, Bauer P, Nicolay C, Schulz B, Purrmann J, Fleig WE, et al: Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn’s disease: A randomized controlled multicenter trial. Study Group Members (German Crohn’s Disease Study Group). Scand J Gastroenterol 1996;31: 778–785. 97 Shoda R, Matsueda K, Yamato S, Umeda N: Epidemiologic analysis of Crohn disease in Japan: Increased dietary intake of n–6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan. Am J Clin Nutr 1996;63:741–745. 98 Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M: Effect of an entericcoated fish-oil preparation on relapses in Crohn’s disease. N Engl J Med 1996;334:1557– 1560. 99 Mahmud N, Weir DG: The urban diet and Crohn’s disease: Is there a relationship? Eur J Gastroenterol Hepatol 2001;13:93–95.

100 Barclay GR, McKenzie H, Pennington J, Parratt D, Pennington CR: The effect of dietary yeast on the activity of stable chronic Crohn’s disease. Scand J Gastroenterol 1992;27:196– 200. 101 Lomer MC, Harvey RS, Evans SM, Thompson RP, Powell JJ: Efficacy and tolerability of a low microparticle diet in a double blind, randomized, pilot study in Crohn’s disease. Eur J Gastroenterol Hepatol 2001;13:101– 106. 102 Jones VA, Dickinson RJ, Workman E, Wilson AJ, Freeman AH, Hunter JO: Crohn’s disease: Maintenance of remission by diet. Lancet 1985;ii:177–180. 103 Riordan AM, Hunter JO, Cowan RE, Crampton JR, Davidson AR, Dickinson RJ, et al: Treatment of active Crohn’s disease by exclusion diet: East Anglian multicentre controlled trial. Lancet 1993;342:1131–1134. 104 Giaffer MH, Cann P, Holdsworth CD: Longterm effects of elemental and exclusion diets for Crohn’s disease. Aliment Pharmacol Ther 1991;5:115–125. 105 O’Brien CJ, Giaffer MH, Cann PA, Holdsworth CD: Elemental diet in steroid-dependent and steroid-refractory Crohn’s disease. Am J Gastroenterol 1991;86:1614–1618. 106 Pearson M, Teahon K, Levi AJ, Bjarnason I: Food intolerance and Crohn’s disease. Gut 1993;34:783–787.

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Review Article Dig Dis 2003;21:157–167 DOI: 10.1159/000073247

Standard Treatment of Ulcerative Colitis Paolo Gionchetti a Fernando Rizzello a Flavio Habal b Claudia Morselli a Cristina Amadini a Rossella Romagnoli a Massimo Campieri a a Department of Internal Medicine, University of Bologna, Bologna, Italy; b Department of Gastroenterology, University of Toronto, Toronto, Ont., Canada

Key Words Ulcerative colitis W 5-Aminosalicylic acid W Topical steroids W Cyclosporine W Infliximab W Immunosuppressors

Abstract Ulcerative colitis (UC) is an idiopathic, chronic inflammation of the colon which may present with a range of mild to severe symptoms. The disease may be localized to the rectum or can be more extensive and involve the left side of the colon or the whole colon. Treatment in UC is directed towards inducing and maintaining remission of symptoms and mucosal inflammation. The key parameters to be assessed for the most appropriate treatment are the severity and extent of the inflammation. Metaanalyses of published trials have shown that topical treatment with 5-aminosalicylic acid (5-ASA) is the treatment of choice in active distal mild-to-moderate UC. Oral aminosalicylates are effective in both distal and extensive mild-to-moderate disease, but in distal disease, the rates of remission are lower than those obtained with topical 5-ASA. New steroids, such as budesonide and beclomethasone dipropionate (BDP), administered as enemas, constitute an alternative to 5-ASA therapy. In some studies, these have been shown to be as effective

as conventional steroids but with significantly lower inhibition of plasma cortisol levels. Patients with unresponsive disease or those with more severe presentation will require oral corticosteroids and sometimes intravenous therapy. Approximately 10% of patients with unresponsive UC have severe attacks requiring hospitalization. Patients with severe disease should be managed jointly by a medical and surgical team, and intensive intravenous treatment should be started with high-dose steroids. Early recognition of failure of therapy will allow the introduction of immunosuppressive therapy with intravenous cyclosporine. Patients who respond are shifted to oral cyclosporine associated with azathioprine/6-mercaptopurine, whereas those who fail will require proctocolectomy. Oral aminosalicylates are the first-line therapy in maintenance of remission. Topical 5-ASA may play a role in distal disease. Patients who are steroid dependent can be started on azathioprine or 6-mercaptopurine although it may take up to 3 months for the treatment to become effective. They may have reversible immediate side effects, such as pancreatitis or bone marrow suppression, which disappear upon discontinuation of therapy. Close monitoring of these hematologic and biochemical parameters will improve safety. The use of biologic therapy with infliximab in more severe disease has not been established. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0212–0157$19.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ddi

Paolo Gionchetti Dipartimento di Medicina Interna, Policlinico S.Orsola via Massarenti 9 IT–40138 Bologna (Italy) Tel. +39 051 6364122, Fax +39 051 392538, E-Mail [email protected]

Introduction

The goal of treatment in ulcerative colitis (UC) is directed towards inducing and maintaining remission of symptoms and mucosal inflammation. Once the diagnosis is confirmed, the key parameters to be assessed are the severity and the extent of the inflammation thus allowing a better approach to treatment.

Management of Mild-to-Moderate Ulcerative Colitis

Mild disease is defined as diarrhea with up to four bowel movements daily associated with intermittent rectal bleeding and mucous discharge. Approximately 90% of all incident cases of UC are mild or moderate in severity, and more than 2/3 of these patients will have endoscopic involvement distal to the splenic flexure [1]. Therefore, a majority of patients with UC could benefit from rectal therapy. However, the therapeutic plan also depends upon patient preference. Topical treatment has a long tradition and offers the advantage of delivering high dosage of the active compound directly to the site of inflammation, minimizing the systemic absorption of the drug to the distal colon and, therefore, limiting the frequency of systemic adverse effects. Topical therapy with a variety of rectal preparations of 5-aminosalicylic acid (5-ASA) is the treatment of choice for mild-moderate distal disease. These preparations have been tested in a variety of clinical trials with several different dosages, and include suppositories, enemas, foams and gel. They differ not only in their chemical properties and dosage, but particularly in their potential delivery to the more proximal areas. Suppositories should be considered the treatment of choice for proctitis and distal sigmoiditis. In fact, scintigraphic studies have demonstrated that the drug is consistently delivered to the rectum and distal sigmoid colon [2, 3], and that suppositories are as effective as enemas but are better tolerated and preferred by patients [4]. Recently, 5-ASA suppositories (400 mg t.i.d) have been shown to produce earlier and significantly better results than oral mesalazine (2.4 g daily) in the treatment of active proctitis [5]. Enemas, foams and gel, thanks to their proximal spread [6–9], should be the treatment of choice for proctosigmoiditis and left-sided colitis. As regards liquid enemas, the volume instilled and the viscosity of the enema

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seem the most important determinants of the proximal spread, and a larger volume has a more consistent proximal spread [8]. Foams and gel may offer the advantage of a more prolonged retention and a more homogeneous coating of the inflamed mucosa [7, 9]. A randomized comparison of 5-ASA foam versus liquid 5-ASA enemas reported that patients found foam easier to retain and that it was more comfortable [10]. More recently, 5-ASA gel enema was shown to be equally effective, but easier to retain and better tolerated than 5-ASA foam [11]. Three recent meta-analyses, which reviewed all therapeutic trials from 1958 to 1997, have clearly shown that rectal 5-ASA therapy is superior to placebo and to rectal corticosteroids in active distal UC [12–14]. There is no evidence supporting a dose-response effect for rectal 5-ASA therapy. Sulfasalazine and the oral aminosalicylates (azo-bond, delayed-release or sustained-release preparations) are also effective in the treatment of mild-to-moderate UC [15]. Compared to rectal 5-ASA preparations oral aminosalicylates are effective in both proximal and distal disease, although in the latter, remission and improvement rates for the rectal 5-ASA therapy were commonly 10–20% higher than those reported for oral 5-ASA compounds. However, combination therapy with rectal plus oral 5ASA may be more effective than a single agent and may be useful in refractory patients [16], although this advantage has not been confirmed more recently [17] (fig. 1). Comparison trials between sulfasalazine and the alternative oral 5-ASA have shown a trend in favor of sulfasalazine but there is no advantage therapeutically, as long as equal amounts of 5-ASA are delivered [18]. Few trials have compared different oral 5-ASA compounds. Two have suggested an advantage of azo compounds over delayed-release mesalazine [19, 20]; however, most data indicate equivalence between the available oral aminosalicylates. The clinical response to sulfasalazine or an alternative aminosalicylate ranges between 40 and 80% but varies considerably between studies because of the difference in patient populations and end-point definitions. A doseresponse effect has been clearly shown for sulfasalazine (between 1 and 4 g/day), and mesalazine preparations (between 1.5 and 4.8 g/day). The azo-bond compounds, olsalazine and balsalazide, have been tested in doses up to 3 and 6.75 g/day (comparable to 3 and 2.4 g/day of mesalazine). With sulfasalazine and olsalazine dose-related side effects offset the dose-response: intolerance occurs with sulfasalazine and diarrhea with olsalazine. A potential therapeutic advantage of mesalazine compounds and bal-

Gionchetti/Rizzello/Habal/Morselli/ Amadini/Romagnoli/Campieri

salazide is that the dose-response effect was not compromised by dose-related side effects. A possible alternative to 5-ASA therapy in mild-tomoderate UC are the new steroids with enhanced topical (mucosal) potency and less systemic activity [21]. Prednisolone-metasulfobenzoate, beclomethasone-dipropionate (BDP), tixocortol pivalate, fluticasone and budesonide have been tested in clinical trials. Budesonide and BDP are the most extensively studied; they have shown, when administered as enemas, to be significantly superior to placebo, and to have an efficacy similar to systemic corticosteroids with significantly less inhibition of the hypothalamic-pituitary adrenal axis, and therefore a minor impact on plasma cortisol levels [22, 23]. An oral preparation of BDP has been recently tested in two recent multicenter Italian trials at a dose of 5 mg/day for 4 weeks. It showed a similar efficacy to oral mesalazine (2.4 g/day) in mild-to-moderate attacks [24], and is significantly superior to placebo in patients not responding after 4 weeks of treatment with 3.2 g/day of oral mesalazine [25]. For patients who are refractory to treatment with 5ASA compounds or those whose symptoms are particularly troublesome, oral conventional steroids are required. Oral prednisone demonstrates a dose-response effect between 20 and 60 mg/day, with 60 mg slightly more effective than 40 mg/day but at the expense of greater side effects [26]. No randomized trials have evaluated the steroid tapering schedules, and experts recommend the use of 40–60 mg/day until a substantial clinical improvement has been obtained and then a dose-tapering of 5–10 mg weekly, until a daily dose of 20 mg is reached; at this point tapering generally proceeds at 2.5–5 mg/week [27]. Controlled trials have shown that Azathioprine, at a dose of 1.5–2.5 mg/kg/day is effective in patients who do not respond to, or cannot be weaned from steroids [28, 29].

5-ASA

Oral formulations pH dependent pH time dependent

Topical formulations

Foam Gel Enema

Azoderivatives Suppository

Fig. 1. 5-ASA formulations.

be confirmed by endoscopy, defined as the presence of spontaneous bleeding, deep ulcerations and mucosal islands [32]. Even though a total colonoscopy seems to be safe in expert hands and useful for a correct evaluation of the disease activity and extension, it is not completely justified [33]. A sigmoidoscopy without preparation and without air insufflation may obtain all the necessary information, while minimizing the risk of acute dilation or perforation of the colon. The major role for colonoscopy is for the decision-making in patients who have incomplete response to treatment and for whom a surgical approach is suggested.

There is no universally accepted definition of severe attacks of UC. The most widely used definition in clinical practice is based on the classical Truelove and Witts [30, 31] criteria. The definition is based on the frequency of bloody bowel movements of up to 10–15 per day associated with the following findings: temperature 137.8 ° C, pulse rate 190/min, hemoglobin !10.5 g/dl or erythrocyte sedimentation rate 130 mm/h. These patients are at a risk of progressing to toxic megacolon. Clinical activity should

Factors Predicting Outcome The introduction of newer therapies in the treatment of severe active UC as an alternative to early colectomy increases the risk of delaying the surgery. This underlines the need to identify clinical and laboratory parameters that may predict the patient outcome. Travis et al. [34] demonstrated that on day three, 85% of patients with more than 8 stools per day and/or 3–8 stools per day and a CRP 145 mg/l fail to respond to treatment. Similarly, Lennard-Jones et al. [35] demonstrated that fever, tachycardia, hypoalbuminemia, number of daily stools and mucosal island or dilation on the plain abdominal radiograph was associated with early treatment failure. Plain abdominal X-ray is essential for the detection of disease-related complications (such as colonic dilation or bowel obstruction or perforation) or for the detection of signs used as risk factors for colectomy. The groups of Caprilli and of Chew demonstrated that an increased amount of intestinal gas measured by pla-

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Management of Severe UC

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nimetry, a small bowel dilation and a dilated colon more than 6 cm in diameter correlated with a failure of medical therapy and the risk of colectomy [36–38].

Treatment

Severe colitis is a serious and potentially life-threatening condition. These patients should be managed by a combined medical and surgical team. Early surgical approach in patients who fail intensive medical therapy will probably decrease morbidity and mortality. The ‘steroid treatment way’, proposed by Truelove and Witts in 1954, dramatically reduced mortality from 31–61% [30] to 3% [31] or even less in referral centers. More recently, cyclosporine has been added as a rescue therapy with a significant decrease in surgical intervention [48–50]. Corticosteroids (CS) Different dosages of hydrocortisone were compared to placebo in the treatment of severe UC attacks, as defined by clinical criteria. About 75% of patients in the cortisone group improved or went into remission compared to 41% in the control group (p ! 0.001). Moreover, the authors analyzed the data to show the differences between first attack and relapses. CS treatment was always significantly better than placebo, but the difference was well marked particularly in the first attack group (p ! 0.001 vs. p ! 0.2) [30]. In 1974, Truelove and Jewell [31] introduced the ‘Intensive Intravenous Regimen’. They treated 49 patients with a severe UC attack with intravenous prednisolone21-phosphate at a dosage of 0.75–1 mg/kg/day up to a maximum of 60 mg/day, topical hydrocortisone, antibiotic therapy, intravenous fluid and ‘nothing by mouth’. This regimen was continued for 5 days with a close observation of the patient. After 5 days, if the patients went into remission, they were switched to an oral regimen. In case of no definite improvement following 5 days of intensive medical therapy, surgical treatment was indicated. Three-quarters (73%) of the patients treated went into remission and were symptom-free and two-thirds of the first-attack patients remained symptom-free during the period of followup. Prolonged treatment with steroids did not show any additional benefit while increasing pre- and post-operative complications. A prolonged treatment of 7–10 days is needed in some patients who may be slow responders. No controlled trials have compared the effectiveness of a single versus multiple or continuous infusion of CS in severe active UC. To reduce the steroid-related side

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effects, CS is usually administered as a single daily dose. In clinical practice, a split-dosing throughout the day is useful in several circumstances. Patients who remain symptomatic after a trial of once daily dosing (particularly if they have nocturnal bowel movements) often benefit from dividing the dosage throughout the day. It is recommended to start with the highest active dose of CS and subsequently to taper the dosage gradually, although there are no controlled data with regard to the best regimen. It is important not to taper CS before a complete response occurred because it is likely to lead to rapid deterioration. Patients whose symptoms improve rapidly can taper prednisone by 5–10 mg/week. Those who are slower to respond or who have a history of rapidly relapsing require a more gradual tapering schedule. No difference in the efficacy was observed comparing CS with intravenous ACTH treatment, particularly in patients firstly receiving steroid. Unfortunately, some cases of death were reported in i.v. ACTH-treated patients, due to adrenal cortical necrosis [40]. The natural history of ulcerative colitis after its first corticosteroid treatment was analyzed by Faubion et al. [41]. Only 34% of 183 patients analyzed required corticosteroid treatment, indicating that the clinical course of UC in the community is relatively mild. At the end of the treatment, 54% of patients were in complete remission, 30% showed a partial response and 16% were refractory and went to colectomy. One year after the end of this first corticosteroid course, 49% of patients had a prolonged response, 22% were steroid-dependent and 29% required a colectomy. Bowel Rest Several trials have demonstrated that bowel rest does not modify the outcome of the attack [42]. Bowel rest is mandatory in the case of complicated active UC (colonic dilatation or ‘impending megacolon’, clinical and radiological findings of bowel obstruction) or in order to reduce the number of daily bowel movements. An oral diet, yet, assures a physiologic nutrition of the mucosa. Antibiotics The role of antibiotics in the treatment of severe active UC is controversial. Several trials have failed to demonstrate a role of antibiotics (metronidazole or ciprofloxacin i.v.) as adjunctive therapy to CS in active UC [43, 44]. Similarly, oral vancomycin 500 mg q.d.s. was shown not to be superior to placebo in patients with moderate to severe active UC treated with prednisone [45]. Oral tobramycin 120 mg t.d.s. as adjunct to oral prednisolone 30–

Gionchetti/Rizzello/Habal/Morselli/ Amadini/Romagnoli/Campieri

60 mg daily in patients with active UC showed a remission rate of 70% in the antibiotic group and 43% in the placebo group (p = 0.008) [46]. Rifaximin 400 mg b.i.d. significantly reduced the number of daily movement and the blood in stools compared to placebo in steroid-refractory severe active UC patients [47]. Oral ciprofloxacin 0.75–1 g/day as adjunct to oral prednisolone and mesalamine was evaluated in a controlled trial in active UC. After the 6-month treatment period, 21% of ciprofloxacin-treated patients had a failure with a subsequent colectomy compared with the 44% in the placebo group (p ! 0.02). The data obtained by Turunen et al. [48] are encouraging but need to be confirmed by larger trials carried-out on a more homogeneous population. Further controlled studies are needed to determine the role of antibiotics. Cyclosporine Patients, who are making only a partial improvement with an intensive intravenous CS regimen, may be candidates for additional treatment with intravenous cyclosporine. Lichtiger and Present [49] have evaluated the efficacy of intravenous cyclosporine 4 mg/kg/day in severe attacks resistant to steroid treatment. In a placebo-controlled trial, 9 of 11 patients treated with cyclosporine had a response within a mean of 7 days versus none of those given placebo, Actis et al. [50] showed that a low dose of cyclosporine (2 mg/kg/day) was effective to induce remission in 7 of 8 steroid-resistant patients. Patients who have responded after seven days of intravenous therapy can be switched to oral therapy at a dosage of 5 mg/kg while gradually tapering the intravenous dosage. Careful monitoring of cyclosporine levels should be performed in order to avoid cyclosporine complications. In spite of these encouraging results, the long-term efficacy does not appear to be as favorable as it was expected. Eight months after being successfully treated with intravenous cyclosporine 44% of patients relapsed and required a colectomy. Because of this high relapse rate, it has been recently proposed to start early with azathioprine or 6mercaptopurine as maintenance therapy for virtually all patients responding to cyclosporine. Prednisone tapering begins after 10–15 days and, after the patients are off steroids, cyclosporine is tapered over the next month and the patient is maintained on aminosalicylate and AZA or 6MP. A prophylaxis with sulphametoxazole/trimetoprim three times weekly is recommended for the prevention of Pneumocystis pneumonia. The use of cyclosporine requires referral centers where it is possible to analyze blood concentrations to avoid toxicity and expert gastroenterologists and surgeons are

Standard Treatment of Ulcerative Colitis

Table 1. Cyclosporine in IBD, toxicity

Flu-like symptoms Bone marrow suppression Allergic reactions Hepatic toxicity Paresthesiae Hypertrophic gingivitis Hypertension Seizures Herpes zoster

available to monitor these patients. Whole blood levels should be maintained between 150 and 300 ng/ml, and evaluated by HPLC assay. It is important to determine blood concentrations of cholesterol and magnesium prior to initiating cyclosporine treatment, since low levels may predispose to seizures. Other side effects include nausea, vomiting, nephrotoxicity, hypertension and paraesthesias. Opportunistic infections, mainly by Pneumocystis carini and Cytomegalovirus could be potentially lifethreatening complications of cyclosporine treatment. Patients should be evaluated also for these complications or a prophylaxis could be started (table 1). Recently, Actis et al. [51] compared the i.v. cyclosporine 2 mg/kg/day with oral micro-emulsion cyclosporine 5 mg/kg/day. The oral formulation was superior in terms of efficacy and of major toxicity compared to the parenteral formulation. Infliximab Antibodies against tumor necrosis factor (TNF) have been proved to be effective in treating steroid-refractory active or fistulizing Crohn’s disease and to maintain the achieved clinical benefit. Several reports and a small controlled trial evaluated the efficacy of Infliximab in the treatment of active UC. Firstly, Chey [52] treated 16 patients with active refractory UC with a single or double infusion of infliximab. Efficacy was assessed by clinical response, endoscopic and histologic outcomes. Clinical, endoscopic, and histologic improvement was observed in 14 of 16 patients (88%) after treatment with infliximab. Surgery was avoided in 6 of 7 surgical candidates (86%). Clinical remission was maintained in 14 of 16 patients (88%) for 64 months, and 4 of 16 patients (25%) for 7–10 months. Most of the treated patients were completely withdrawn from corticosteroid therapy.

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161

Sands et al. [53] conducted a double-blind placebocontrolled trial in active steroid-refractory UC patients. Unfortunately, the study was prematurely closed because of slow enrolment. Four of 8 patients in the infliximab group were considered treatment successes at 2 weeks compared with none in the placebo group. Recently, Kohn et al. [54] presented an open study on infliximab in steroid-resistant active UC patients. 13 patients were enrolled after 7–10 days of steroid treatment (methyl-prednisolone 60 mg/day) and treated with a single infusion of infliximab 5 mg/kg. 10 patients (77%) had a clinical response within 2–3 days after infusion. Nine of 10 patients maintained clinical remission during a mean time of follow-up of 10.1 months free of steroids. Conversely, Probert et al. [55], evaluating the efficacy of infliximab 5 mg/kg at weeks 0 and 2 vs. placebo in patients with active steroid-resistant UC, have shown no difference between the two groups of treatment. Therefore, up to now, no data support the use of infliximab in active UC.

Maintenance of Remission

The use of low-dose steroids is ineffective in lowering the relapse rate and larger doses for longer periods cannot be justified due to the serious side effects. The original study by Misiewicz et al. [56] firstly established the efficacy of sulfasalazine in the maintenance of remission compared to placebo. Seventy-three percent of patients taking placebo relapsed during 1 year of treatment compared to 21% taking the active drug. No difference was reported between 2 and 4 g/daily of sulfasalazine, but a trend in favor of the highest dosages was noted. Dissanayake and Truelove [57] demonstrated that after 3 years of treatment, sulfasalazine-treated patients had a relapse of 12% compared to 50% with placebo. This study suggested continuing the treatment with sulfasalazine indefinitely. In order to identify the active therapeutic moiety of sulfasalazine, Azad Khan [58] compared the enema of sulfasalazine with sulfapyridine or 5-ASA in the treatment of patients with active UC. It was found that pronounced histological improvement occurred equally with sulfasalazine and 5-ASA whereas sulfapyridine had virtually no effect. These findings suggested that sulfasalazine has the capacity to reach the colon intact and then to liberate 5ASA, which is the active agent. The sulfapyridine appeared to act simply as a carrier. The recognition that a large part of the side effects was related to the sulfapyridine component and that 5-ASA

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was the active moiety, led the pharmaceutical industry to prepare a wide range of 5-ASA oral preparations able to reach the lower part of the gastrointestinal tract. In the last two decades, major efforts were employed to find alternative 5-ASA delivery systems [7]. This aim was followed in two ways: by a coating that dissolves at alkaline pH (Eudragit S pH 17; Eudragit L pH 16; microsphere formulation enveloped with ethyl cellulose) as the pH present in the terminal ileum, or by the substitution of sulfapyridine with another carrier that allows to reach the colon and to deliver the active moiety by splitting the diazo-bound through bacteria. Oral aminosalicylate therapy is, today, the ‘first-line’ therapy in maintenance of remission in UC and, in several countries, they completely replaced sulfasalazine. Numerous studies have evaluated the efficacy of these formulations in maintaining remission. Recently, Sutherland et al. [59] have undertaken a meta-analysis of all the controlled studies on 5-ASA containing preparations in this setting. 5-ASA preparations were observed to be significantly more effective than placebo in all the dosage subgroups, but a dose-related trend was observed. More trials comparing sulfasalazine 2 g/day with an equivalent dose of 5-ASA demonstrated a marginal superiority of sulfasalazine in efficacy with no significant difference in side effects. However, most of these trials excluded the patients previously intolerant to sulfasalazine and 2 g is a better tolerated dosage of sulfasalazine. The main advantage offered by 5-ASA preparations is the possibility to increase the dosage. The new 5-ASA preparations would require approximately 40% of the dose compared with the parent compound and a corresponding dose of 5-ASA to up to 10 g of sulfasalazine has been commonly prescribed. An additional advantage of mesalazine compared to sulfasalazine has been the absence of dose-related intolerance or toxicity, which limit the clinical utility of sulfasalazine at the highest dosages. These observations suggest that sulfasalazine is an effective and cheaper therapy that could be used in a subgroup of tolerant patients. There are insufficient clinical trials to distinguish between mesalazine formulations and different dosages. Even if only a dose-related trend was observed, the dosage for maintenance of remission should be the same dosage that induced remission according to the patient’s history, i.e. the patients who have higher frequencies of relapse should be treated with higher dosage. The chronic treatment with mesalazine changes the natural history of the disease, lowering not only the overall number of relapses but particularly the incidence of

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severe relapse and the risk of dysplasia [60]. If the longterm maintenance treatment can be avoided in a subgroup of patients is still an unresolved issue. Ardizzone et al. [61] in a placebo-controlled study evaluated if a maintenance treatment is always necessary according to the length of remission. Patients with longer remission (62 years) showed no differences in the incidence of relapse with or without mesalazine treatment (relapse rate of 18% in the mesalazine group vs. 26% in the placebo group). However in patients with a relapse-free period of ^1 year mesalazine was significantly superior to placebo (relapse rate of 23% in mesalazine group vs. 49% in the placebo group, p ! 0.035). Unfortunately, the small sample size limits the power of this observation and larger studies are warranted to clarify this point. However, it is possible to conclude that the disease history is fundamental to guide our therapeutic choices. Topical 5-ASA plays an important role in maintenance of remission, and Marshall et al. [62], in a recent metaanalysis, showed that 5-ASA enemas or suppositories are superior to placebo. No conclusive data exist for the optimum dosage of rectal 5-ASA, and similar efficacy was shown by daily administration or by three times per week of enema formulations, and with twice daily versus once daily suppositories. The correct answer is probably again to be found in the patient’s history and in the number of relapses per year. Rectal 5-ASA seems to be superior to oral sulfasalazine or 5-ASA for maintaining remission of distal UC whereas a combination of oral plus rectal 5ASA is superior to the single agent. The only side effect reported with topical formulations was local irritation and discomfort. Despite the efficacy and safety of topical preparations, oral treatment was preferred by 80% of patients. The optimization of treatment can improve patient compliance and acceptability.

Table 2. Azathioprine and 6-mercaptopurine in IBD, toxicity

Common Gastrointestinal intolerance Myalgia Uncommon Bone marrow suppression Pancreatitis Allergic reactions Hepatic toxicity Theoretical only Opportunistic infection (unconfirmed) Neoplasm (unconfirmed)

only 1 patient had a relapse and remission was easily restored. Suggesting a benefit of adding azathioprine to patients who respond to cyclosporine, the use of cyclosporine simultaneously with azathioprine was not statistically associated with a major incidence of side effects [63– 66].

Cyclosporine Despite the efficacy of intravenous cyclosporine in severely active steroid-refractory UC, long-term studies failed to demonstrate an efficacy of oral cyclosporine in maintenance of remission. Only 40–50% of patients that responded to cyclosporine during the active phase avoided colectomy during the follow-up. In a recent study, 10 patients with cyclosporineinduced remission were concomitantly treated with azathioprine for a 16-month period. At the end of the study,

Azathioprine/6-Mercaptopurine Immunosuppressive treatment represents the only reliable way to maintain remission in patients allergic or intolerant to sulfasalazine/5-ASA or in those who are steroid-dependent. The initial studies failed to demonstrate the efficacy of these drugs, probably because of the short period of treatment considering the slow pharmacokinetics of these drugs. Subsequent longer studies of more than 3–6 months demonstrated their efficacy and safety. In view of this prolonged period, it is recommended to initiate therapy early on in the disease. The recommended dosage for azathioprine is 2.0–2.5 and 1.5 mg/kg for 6mercaptopurine. The major side effects related to these drugs are bone marrow suppression, hepatitis and pancreatitis. A careful monitoring of white blood cells count, liver and pancreatic enzymes every 10 days in the first 2 months and monthly during the follow-up should avoid these complications. In most cases, discontinuing the drug or reducing the dose should resolve these side effects. Patients who do not tolerate azathioprine can be switched to 6-mercaptopurine after a 10-day wash out period. Patients who develop pancreatitis, hepatitis or other severe reactions should not be switched from one form into the other (table 2). Patients who are unable to discontinue steroids within 6 months despite modest leukopenia, while on immunosuppressors should be deemed failures and alternative

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Immunosuppressors

163

Active ulcerative colitis

Mild to moderate

Distal Topical 5ASA

Improved Maintenance with oral or topical 5ASA

Severe

Extensive Oral 5ASA

Not improved Add oral 5ASA or topical CS

Not improved Add topical 5ASA or oral/topical CS

Not improved Oral prednisolone 40 mg/d

Not improved Oral prednisolone 40 mg/d

Prednisolone 0.7–1 mg/kg/day

Improved Maintenance with oral 5ASA

Not improved Ciclosporine 2–4 mg/kg/day ev + AZA 2 mg/kg/day os

Not improved Surgery

Improved Ciclo 8 mg/kg/day os +AZA 2 mg/kg/day

Improved Tapering steroids Add oral and/or topical 5ASA 3.2–4 g/day

Maintenance with oral 5ASA

Maintenance with AZA

Fig. 2. Management of active UC.

approaches should be considered. The other unanswered question regards the length of treatment with immunosuppressors. The concerns have been about the possible increased risk of neoplasia and their use during pregnancy. A prospective study evaluated patients treated for at least 2 years with immunosuppressors compared with a matched population. The study revealed a slight increase in colorectal cancer which was expected in this population with long-standing disease. In the subgroups of patients with long-standing UC there was no correlation between azathioprine and other cancer incidence associated with immunsuppression [67, 68]. Until recently, women taking azathioprine were advised against pregnancy. Retrospective studies of pregnant women using this medication, however, have not demonstrated significant teratogenesis [69]. Probiotics and Fibers The rationale for using probiotics in IBD is based on evidence implicating intestinal bacteria in the pathogenesis of IBD. More recently, the concept of ‘protective bacteria’ was introduced. These protective bacteria are the probiotics, ‘living organisms, which upon ingestion in certain numbers exert health benefits beyond inherent basic nutrition’ [70].

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Clinical usefulness of probiotics preparations in maintenance of remission in UC was tested in few controlled studies. In three recent controlled studies, a nonpathogenic strain of Escherichia coli Nissle 1917 has been found to exhibit efficacy similar to mesalazine in maintenance treatment of UC. Kruis et al. [71] compared mesalazine 1.5 g/day to an oral preparation of viable E. coli Nissle in maintenance of remission in UC. No differences were noted between the two arms, but the short period of observation limits its statistical significance. Rembacken et al. [72] treated 116 patients with either mesalazine 1.2 g/day or an oral preparation of viable E. coli Nissle for 12 months. At the end of the observational period, no differences were noted between the two drugs but, due to surprisingly high relapse rate (73 vs. 67%) this equivalence is mainly in inefficacy. Finally, Kruis et al. [73] again compared E. coli Nissle versus mesalazine in 327 patients with quiescent UC for twelve months. No difference was observed between the two treatment groups; however, again the low dose of mesalazine used limits the findings of this study. Venturi et al. [74] used a probiotic preparation characterized by a high concentration of bacteria and by a consortium of 8 strains of bacteria (Lactobacilli, Bifidobacteria and Streptococcus salivarius) in patients with quiescent UC intolerant or allergic to 5-ASA or SASP. An effec-

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Table 3. Maintenance therapy of UC

Anatomic extent

Therapy

Proctitis/distal

oral aminosalicylates topical aminosalicylates immunosuppressants (AZA/6-MP) oral aminosalicylates immunosuppressants (AZA/6-MP)

Extensive

Conclusions

tive temporary colonization was demonstrated with an increased concentration of these 3 species over the treatment period. Moreover, after 1 year of treatment, 15 patients were in clinical and endoscopic remission. Fernandez-Banares et al. [75] compared a plantago ovata seeds, 10 g b.i.d. versus mesalazine 1.5 g/day versus the combination in maintenance treatment of UC. At the end of the study, relapse occurred in 37% of patients in the plantago ovata group, in 35% of patients in the mesalazine group and in 23.3% of patients in the combination group. These data suggest that dietary enrichment with probiotics and fibers could have a therapeutic role in UC.

In summary, corticosteroids are the mainstay of treatment for acute severe active UC. The recognition of prognostic parameters allows the early introduction of cyclosporine, azathioprine/6-mercaptopurine or surgery. Infliximab seems not to be an effective therapeutic option, but should be tested in larger controlled trials. Rectal therapy with 5-ASA compounds is the treatment of choice for mild or moderate distal colitis, and the dosage and form should be based on the extent of the inflammation and on patient preference. Oral aminosalicylates are effective both for extensive and distal UC, and combination therapy with rectal 5-ASA may be more effective than a single agent. New topical steroids may represent a useful alternative to 5-ASA therapy and the oral preparations are promising (fig. 2) For patients refractory to therapy with 5-ASA or new steroids, oral conventional steroids are required. Azathioprine or 6-mercaptopurine is effective in patients with chronic active colitis or steroid-dependent patients. Mesalazine represents a valid tool to maintain the remission in most patients using the right dosage and patient’s preference. Immunosuppressors are of proven benefit in patients with chronically active and steroiddependent disease (table 3). Natural bacteriotherapy may represent a simple and attractive way to maintain remission but further controlled studies are needed.

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34 Travis SPL, Farrant JM, Ricketts C, et al: Predicting outcome in severe ulcerative colitis. Gut 1996;38:905–910. 35 Lennard-Jones JE, Ritchie JK, Hilder W, et al: Assessment of severity in colitis: a preliminary study. Gut 1975;16:579–584. 36 Caprilli R, Vernia P, Latella G, et al: Early recognition of toxic megacolon. J Clin Gastroenterol 1987;9:160–164. 37 Chew CN, Nolan DJ, Jewell DP: Small bowel gas in severe ulcerative colitis. Gut 1991;32: 1535–1537. 38 Edward FC, Truelove SC: The course and prognosis of ulcerative colitis. Gut 1963;4:299– 315. 39 Jarnerot G, Rolny P, Sandberg-Gertzen H: Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985;89:1005–1013. 40 Kaplan HP, Portnoy HJ, Binder HJ, et al: A controlled evaluation of intravenous adrenocorticotropin hormone and hydrocortisone in the treatment of acute colitis. Gastroenterology 1975;69:91–95. 41 Faubion WA, Loftus EV, Harmsen WS, et al: The natural history of corticosteroid therapy for inflammatory bowel disease: A populationbased study. Gastroenterology 2001;121;255– 260. 42 Dickinson RJ, Ashton MG, Axon ATR, et al: Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980;79:1199–1204. 43 Chapman RW, Selby WS, Jewell DP: Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986;27:1210–1212. 44 Mantzaris GJ, Petraki K, Archavlis E, et al: A prospective randomized controlled trial of intravenous ciprofloxacin as an adjunct to corticosteroids in acute, severe ulcerative colitis. Scand J Gastroenterol 2001;36:971–974. 45 Dickinson RJ, O’Connor HJ, Pinder I, et al: Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbation of idiopathic colitis. Gut 1985;26:1380– 1384. 46 Burke DA, Axon ATR, Clayden SA, et al: The efficacy of tobramycin in the treatment of ulcerative colitis. Aliment Pharmacol Ther 1990; 4:123–129. 47 Gionchetti P, Rizzello F, Ferrieri A, Venturi A, Brignola C, Ferretti M, Peruzzo S, Miglioli M, Campieri M: Rifaximin in patients with moderate or severe ulcerative colitis refractory to steroid treatment: A double blind, placebo-controlled trial. Dig Dis Sci 1999;44:1220–1221. 48 Turunen UM, Farkkila MA, Hakala K, et al: Long-term treatment of ulcerative colitis with cirpofloxacin: A prospective, double-blind, placebo-controlled study. Gastroenterology 1998; 115:1072–1078. 49 Lichtiger S, Present D, Kornbluth A, et al: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330:1841–1845.

50 Actis GC, Ottobrelli A, Pera A, et al: Continously infused cyclosporine at low dose is sufficient to avoid emergency colectomy in acute attacks of ulcerative colitis without the need for high-dose steroids. J Clin Gastroenterol 1993; 17:10–13. 51 Actis GC, Aimo G, Priolo G et al: Efficacy and efficiency of oral microemulsion cyclosporine versus intravenous and of gelatin cyclosporine in the treatment of severe steroid-refractory ulcerative colitis: An open retrospective trial. Inflamm Bowel Dis 1998;4:276–279. 52 Chey W: Infliximab for patients with refractory ulcerative colitis. Inflamm Bowel Dis 2001;1: s30–33. 53 Sands ES, Tremaine WJ, Sandborne WJ, et al: Infliximab in the treatment of severe, steroidrefractory ulcerative colitis: A pilot study. Inflamm Bowel Dis 2001;7:83–88. 54 Kohn A, Prantera C, Pera A, et al: Anti-tumor necrosis factor alpha (infliximab) in the treatment of severe ulcerative colitis: Result of an open study on 13 patients. Dig Liv Dis 2002; 34:626–630. 55 Probert CSJ, Hearing SD, Schreiber S, et al: Infliximab in steroid-resistant ulcerative colitis: A randomised controlled trial (abstract). Gastroenterology 2002:772. 56 Misiewicz JJ, Lennard-Jones JE, Connell Am, et al: Controlled trial of sulphasalazine in maintenance therapy for ulcerative colitis. Lancet 1965;i:185–188. 57 Dissanayake AS, Truelove SC: A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphasalazine (Salazopyrin). Gut 1973;14:923–926. 58 Azad-khan AK, Piris J, Truelove SC: An experiment to determine the active therapeutic moiety of sulphalasazine. Lancet 1977;ii:892–895. 59 Sutherland L, Roth D, Beck P, et al: Oral 5aminosalicylic acid for maintaining remission in ulcerative colitis. Cochrane Database Syst Rev 2000;2:CD000544. 60 Langholz E, Munkholm P, Davidsen M, et al: Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 1992; 103:1444–1451. 61 Ardizzone S, Petrillo M, Imbesi V, et al: Is maintenance therapy always necessary for patients with ulcerative colitis in remission? Aliment Pharmacol Ther 1999;13:373–379. 62 Marshall JK, Irvine EJ: Putting rectal 5-aminosalicylic acid in its place: The role in distal ulcerative colitis. Am J Gastroenterol 2000;95: 1628–1636. 63 Stack WA, Long RG, Hawkey CJ: Short- and long-term outcome of patients treated with cyclosporin for severe ulcerative colitis. Aliment Pharmacol Ther 1998;12:973–978. 64 Cohen RD, Stein R, Hanauer SB: Intravenous cyclosporin in ulcerative colitis: A five-year experience. Am J Gastroenterol 1999;94:1587– 1592. 65 Fernàndez-Bañares F, Bertran X, Esteve-Comas M, et al: Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporin in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 1996;91: 2498–2499.

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66 Actis GC, Bresso F, Astegiano A, et al: Safety and efficacy of azathioprine in the maintenance of ciclosporin-induced remission of ulcerative colitis. Aliment Pharmacol Ther 2001; 15:1307–1311. 67 Connell WR, kinlen LJ, Ritchie JK, et al: Long term risk of neoplasia in patients treated with azathioprine for inflammatory bowel disease. Lancet 1994;343:1249–1252. 68 Connell WR, Kamm MA, Lennard-Jones JE, et al: Bone marrow toxicity from azathioprine: twenty-seven year experience in inflammatory bowel disease. Gut 1993,34:1081–1085. 69 Alstead EM, Ritchie JK, Lennard-Jones JE, et al: Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 990;99:443–446.

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70 Schaafsma G: State of the art concerning probiotic strains in milk products. IDF Nutr Newslett 1996;5:23–24. 71 Kruis W, Schutz E, Fric P, et al: Double-blind comparison of an oral Echerichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1997;11:853–858. 72 Rembacken BJ, Snelling AM, Hawkey PM, et al: Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: A randomised trial. Lancet 1999;354:635– 639. 73 Kruis W, Fric P, Stolte S: Maintenance of remission in ulcerative colitis is equally effective with Escherichia coli nissle 1917 and with a standard mesalamine (abstract). Gastroenterology 2001;12:A127.

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74 Venturi A, Gionchetti P, Rizzello F, et al: Impact on the faecal flora composition of a new probiotic preparation. Preliminary data on maintenance treatment of patients with ulcerative colitis (UC) intolerant or allergic to 5aminosalycilic acid (5-ASA). Aliment Pharmacol Ther 1999;13:1103–1108. 75 Ferna´ndez-Bañares F, Hinojosa J, SanchezLombraña JL, et al: Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Am J Gastroenterol 1999;94:427–433.

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Review Article Dig Dis 2003;21:168–179 DOI: 10.1159/000073248

Surgery for Inflammatory Bowel Diseases Robin S. McLeod Division of General Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ont., Canada

Key Words Surgery W Inflammatory bowel disease W Crohn’s disease W Ulcerative colitis

Abstract Surgery is required in many patients with inflammatory bowel disease at some point in their disease. In patients with ulcerative colitis, surgery is potentially curative whereas recurrence of Crohn’s disease following surgery is a common occurrence. As a result, the indications and surgical management of the two diseases may be quite different. Surgery is usually reserved for the management of complications or failure of medical treatment in Crohn’s disease. Resection of the diseased segment is the usual procedure performed. While surgery usually results in an improvement in quality of life, recurrence of disease occurs frequently with reported rates of 5–90% at 1 year, depending on the criteria used. To date, there have been no surgical maneuvers which have been shown to decrease the risk of recurrence. Over the past few decades, several advances have been made in the surgical management of Crohn’s disease: use of strictureplasty for extensive disease; use of laparoscopic techniques to perform surgery and the performance of the ileal pouch procedure in very selected patients. Sig-

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nificant advances in the surgical management of ulcerative colitis have been made in the past 50 years. Although there are several options available to patients, the preferred option now is the ileal pouch procedure. With technical modifications and with experience, this procedure can now be performed with a low complication rate, with good functional results and quality of life and excellent long-term outcome. Copyright © 2003 S. Karger AG, Basel

Despite advances in medical therapy, surgical therapy is still required in a large proportion of patients with ulcerative colitis and Crohn’s disease at some time during their lifetimes. The need for surgery should not be perceived as a failure of medical therapy. Rather, one should view the treatment of these diseases as being multimodal – including both surgical and medical therapies and each may be required at different points in the course of the disease. While the manifestations of, and even the surgical procedures performed for ulcerative colitis and Crohn’s disease may be similar, there is a fundamental difference to the surgical approach to these diseases. Because Crohn’s disease is a panintestinal disease, it cannot be eliminated and, indeed, recurrence is one of the most important considerations in the management of Crohn’s disease. Thus,

Dr. R.S. McLeod Mount Sinai Hospital 449–600 University Avenue Toronto, Ontario M5G 1X5 (Canada) Tel. +1 416 586 8534, Fax +1 416 586 8644, E-Mail [email protected]

Bowel Resection For disease involving the terminal ileum, the resection usually encompasses the terminal ileum and cecum since the disease usually extends to or into the cecum. The deci-

sion whether a primary anastomosis should be performed will depend on whether the procedure is performed electively or emergently; the status of the patient including his/her nutritional status, whether he or she is on high doses of steroids or immunosuppressive agents; and the local conditions of the bowel including whether the bowel is obstructed or whether there is an abscess present. In suboptimal conditions, it may be prudent to bring out the proximal end of the bowel as an ileostomy or to perform an anastomosis and a proximal defunctioning ileostomy with the plan to reanastomose the bowel at a later date. Recognizing that recurrence following surgery is a significant problem, surgeons have looked at various maneuvers, which might decrease the risk. There are conflicting data regarding the effect of microscopic disease at the resection margin [2]. However, given that Crohn’s disease is a pan-intestinal disease, that it is focal in distribution, and that histological abnormalities have been demonstrated in segments of bowel which appear to be grossly normal, the significance of microscopic disease at the resection margin is questionable. The length of the resection margin has also generated conflicting and controversial results. In the 1970s, Krause and Bergman [3] advocated a radical approach of excising 10–30 cm of normal bowel proximal and distal to the affected area. This was based on a retrospective study with follow-up ranging from 7 to 19 years where recurrence rates of 29 and 84%, respectively, were reported in patients having radical or limited surgery. However, the two approaches were performed at different hospitals so the possibility of selection biases is real. Fazio et al. [4] recently published the results of a randomized controlled trial where 152 patients were randomized to one of two groups: proximal resection margins of 2 cm in length or 12 cm in length. After a mean follow-up of 56 months, the recurrence rate (as defined by the need for a further resection) was 25% in the limited resection group compared to 18% in the extended resection group, a difference which was not statistically significant. Thus, the approach accepted by most surgeons is to resect the bowel which is grossly involved plus a margin of several centimeters of normal bowel. Frozen sections are usually unnecessary. While there is theoretical concern that obstruction to the fecal stream may be important in the recurrence of Crohn’s disease preanastomotically, at present, there is little evidence to suggest that the type of anastomosis alters the risk. There are two trials that have addressed this issue. Cameron et al. [5] randomized 86 patients who had an ileocolic resection to an end-to-end anastomosis or end-to-side anastomosis. After a mean follow-up of 47

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surgery is most often limited to managing the complications of the disease. On the other hand, ulcerative colitis can be cured and, thus, some of the concerns related to surgery for Crohn’s disease do not apply and improvement in quality of life is a major goal. Obviously, surgery for inflammatory bowel disease is complex and a comprehensive review is beyond the scope of this article. Thus, an attempt will be made to concentrate on some of the newer developments or controversial aspects of surgery for these diseases.

Surgery for Crohn’s Disease

Surgery for Small Bowel and Ileocolic Crohn’s Disease Although Crohn’s disease may affect any part of the small bowel, the terminal ileum is most frequently involved. At the other end of the spectrum there may be multiple skip lesions throughout the small bowel. The pattern of disease may also vary with some patients having primarily fibrostenotic, inflammatory or fistulizing disease. In a review of 500 patients operated on at the Cleveland Clinic between 1966 and 1973, Farmer et al. [1] observed that obstruction was the indication for surgery in 55% and intestinal fistula and abscess in 32% of patients with small bowel disease. The indications in patients with ileocolic disease were similar. Depending on the site of the disease and indication for surgery, the surgical approach may vary. However, resection is the preferred option in most patients with small bowel or ileocolic disease. Although strictureplasty is used in only select patients, it has been a valuable addition to the surgical armamentarium in Crohn’s disease. Bypass procedures (the so-called Eisenhower procedure) were popular in the 1960s but they are rarely performed now because of the high rate of recrudescence of the disease in the short term and the increased risk of small bowel cancer in the long term. At present, the only indication for a bypass procedure would be a gastrojejunostomy for duodenal Crohn’s disease. In the unusual situation where the surgeon felt it was unsafe to resect small intestinal disease, a defunctioning ileostomy would be preferable to a bypass procedure. However, this situation is rarely encountered today because of improved imaging techniques and the ability to percutaneously drain abscesses preoperatively.

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months, the recurrence rates in the 2 groups were similar at 23 and 31%, respectively. Ikeuchi et al. [6] randomized 33 patients to a handsewn end-to end anastomosis and 30 to a stapled functional end-to-end (using the 60-mm linear stapler) or circular stapled anastomosis. There were a variety of anastomotic sites including ilealileal, ileocolic, colocolic and ileorectal anstomoses. Recurrence was based on the need for another operation for recurrence of disease. The recurrence rate was significantly lower in the stapled group (18.9%) compared with the hand-sewn group (37.8%) after a median follow-up of 87 months. It is hypothesized that a side-to-side anastomosis may be wider and therefore lead to less fecal stasis than an endto-end anastomosis. There are no trials comparing sideto-side and end-to-end anastomoses. Munoz-Juarez et al. [7] reviewed the experience of 138 patients who had ileocolic resections at the Mayo Clinic and Birmingham General Hospital. There were 69 patients who had stapled side-to-side anastomoses and they were age and gender matched to 69 who had end-to-end sutured anastomoses. The groups were similar with the exception of mean follow-up (20 vs. 35 months) which may account for the difference in the symptomatic recurrence rates of 18% in the stapled and 48% in the sutured group. Two other studies have reported similar findings [8, 9]. On the other hand, two other studies have found no difference in recurrence rates when the data were analyzed actuarially [10, 11]. The discrepancies in the reports may be due to the studies being retrospective, with variable criteria for diagnosing recurrence and anastomotic techniques and, finally, follow-up may differ between the groups. Strictureplasty Strictureplasty was first advocated in the 1980s for the treatment of fibrotic strictures in Crohn’s disease [12]. Two types of strictureplasties have been described, the socalled Heineke-Mikulicz which is performed for short strictures and the Finney for longer strictures. Recently, Michalessi et al. [13] described a side-to-side isoperistaltic strictureplasty (SSIS) for management of a long segment of disease or multiple strictures in the mid-small bowel. The bowel is divided and a side-to-side anastomosis is performed thus avoiding a resection, a blind loop or a bypassed segment. Their recent report documents the results in 21 patients. One patient had a post-operative bleed. After follow-up of up to 7.5 years, there was evidence of regression of disease in all patients. Another recent report from Poggioli et al. [14] described a strictureplasty where a side-to-side anastomosis is performed between the diseased terminal ileum and the right colon.

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This technique has been used in only 5 patients and therefore its utility has also yet to be determined. Despite the concerns of anastomosing diseased bowel, the short term complication rate following strictureplasty is low with reported complication rates ranging from 1 to 14% [15]. The largest series reported to date is from the Cleveland Clinic [16]. They reported on 314 patients in whom 1,224 strictureplasties were performed. A median of 2 strictureplasties were performed in each patient with a range of 1–19. Sixty-six percent of patients had a synchronous bowel resection. Eighteen percent of patients had complications with 5% having septic complications. Pre-operative weight loss and older age were predictors of complications. With a median follow-up of 7.5 years, 34% of their patients have required further surgery for symptomatic Crohn’s disease. Hurst and Michelassi [17] reported a recurrence of disease necessitating a reoperation of 15 B 6% at 1 year and 22 B 10% at 5 years. Yamamoto and Keighley [18] found that young age at surgery (!37 years) was a poor prognostic variable as did Dietz et al. [16]. Tichansky et al. [15] reviewed 15 series containing 506 patients in whom 1,825 strictureplasties were performed. They found a lower reoperative rate in those patients who had Finney rather than Heineke-Mikulicz strictureplasties (80% of the strictureplasties were Heineke-Mikulicz), in whom the disease was not active and there was no pre-operative weight loss. There are 3 reports of adenocarcinoma arising at or adjacent to a strictureplasty site occurring on average seven years following the surgery [19–21]. One patient presented with anemia, while the other presented with obstructive symptoms. Both patients had longstanding Crohn’s disease and were somewhat older (47 and 78 years of age). Both were treated with resection. The details of the other patients were not reported [21]. Given that the procedure can be performed safely and that a conservative approach to Crohn’s disease is advocated, strictureplasty has an important role in the surgical management of patients with Crohn’s disease. However, at the present time, its use is generally limited to those patients who have multiple skip lesions or who have had multiple resections previously. Tichansky et al. [15] reported that obstruction was the indication for surgery in 92% of patients. It is contraindicated in patients with long strictures, abscesses or fistulizing disease. In the future, however, further evaluation of this procedure compared with resection is warranted especially with respect to longterm outcome. Broering et al. [22] performed an interesting study comparing patients who had a strictureplasty to those who had had a resection. There was no significant

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The pattern of involvement in Crohn’s colitis is quite variable with some patients having predominantly right sided involvement, possibly with small bowel involvement; others having colonic involvement with sparing of the rectum and others having pancolitis. Furthermore, the disease may be complicated by the presence of perianal disease. As a result, the indications for surgery may vary as well as the surgical procedure. Most patients requiring surgery for colonic disease will require a resection. If there is sparing of the rectum and no or minimal perianal disease, then a colectomy and ileorectal or ileosigmoid anastomosis can be performed. Proctocolectomy and ileostomy will be required for patients with pancolitis or those with severe perianal disease. The obvious advantage of performing an anastomosis is that a stoma is avoided. However, the reported recurrence rates are significantly higher in those patients in whom a colectomy and anastomosis is performed. Andrews et al. [23] reported recurrence rates of 46 and 60% at 5 and 10 years, respectively in patients who had ileorectal anastomoses compared with rates of 10 and 21% in those who had a proctocolectomy and ileostomy. Patients with limited disease of the colon may have a segmental resection. Strictureplasty is rarely an option for patients with Crohn’s colitis. Farmer et al. [1] reported that the indication for surgery in patients with colonic Crohn’s disease was poor response to medical therapy in 26%, presence of internal fistula and abscesses in 23%, toxic megacolon in 20% and perianal disease in 19%. Recently, Andersson et al. [24] reported on the changes in surgical management of Crohn’s colitis in Sweden between 1970 and 1997. There were 211 patients followed during this period of time of which 84 underwent surgery. Indications for and outcome of surgery were compared during the time periods 1977 to 1990 and 1991 and 1997. In the early time period, active disease was the indication for surgery in 64% of patients compared to 25% in the more recent time period. With

this, there was a concomitant increase in stricture as the indication for surgery (9 compared with 50%). As well, the median time from diagnosis to operation increased significantly from 3.5 to 11.5 years between the two time periods. Proctocolectomy or colectomy as the primary procedure fell from 69 to 10%, whereas segmental resection increased from 31 to 90%. Only 7% of patients were on postoperative maintenance therapy in the early time period compared with 70% more recently. Despite the higher recurrence rates, colectomy and ileorectal anastomosis (IRA) has an important role in the management of patients with Crohn’s disease since many patients are young and would prefer to avoid having an ileostomy. However, patients must be carefully selected. Patients who have significant perianal disease or severe rectal disease are not candidates. Longo et al. [25] reviewed 131 patients who underwent colectomy and ileorectal anastomosis at the Cleveland Clinic and found that the presence of small bowel disease preoperatively was the only predictive factor of need for further surgery. The age at surgery, duration of disease, steroid use, presence of proctitis and perianal disease did not affect outcome. However, it is quite likely that this was a highly selected group of patients and those with significant rectal or perianal disease would not have been included. From the results of reported series, it can be anticipated that approximately 50–65% of patients will develop recurrence of their disease. In some patients, the recurrence may be confined to the small bowel, so a further resection and anastomosis is possible. Thus, approximately 75% of patients may have a functioning IRA at 5 years and 50% at 10 years [25–28]. Proctocolectomy is the procedure of choice for those patients with pancolitis or extensive perianal disease. In those patients with perianal disease with associated sepsis, it may be prudent to perform a subtotal colectomy and ileostomy and subsequently perform the proctectomy when the sepsis has settled. This may minimize the risk of an unhealed perineal wound. The major complication of this operation is the risk of an unhealed perineal wound which has been reported to occur in up to 20% of patients. Pelvic nerve injury is a rare but important complication. As stated previously, the recurrence rates following proctocolectomy and ileostomy are lower than with colectomy and ileorectal anastomosis. The role of the ileal pouch anal anastomosis in patients with Crohn’s disease is controversial. Crohn’s disease has been considered a contraindication because of the risk of small bowel and perianal involvement. As well, failure rates of 30–50% have been reported in small series of

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difference in the mean scores of the IBDQ in the two cohorts of patients. Another question, which remains unanswered, is whether these patients should receive maintenance therapy. There are no data from randomized controlled trials and opinion seems to be divided on this question. However, since most of these patients do have extensive disease, it has been our practice recently to advise prophylaxis with an immunosuppressive such as imuran.

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patients with Crohn’s disease [29–32]. Only one recent report has suggested that the procedure can be performed safely in patients with Crohn’s disease with a complication rate similar to that in patients with ulcerative colitis [33]. Regimbeau et al. [33] performed ileal pouches in 41 patients with Crohn’s disease who had no evidence of associated anoperineal or small bowel disease. After a mean follow-up of 10 years, 27% had experienced CDrelated complications. However, only 3 (7%) required a definitive ileostomy. Although this report suggests that selected Crohn’s disease patients may have a satisfactory outcome with a pouch procedure, one must be somewhat cautious in the interpretation of these results. Since perianal disease frequently complicates Crohn’s colitis, these patients are a highly selected group or alternatively may have indeterminate colitis. Thus, generally Crohn’s disease remains a contraindication to performing a pouch procedure. However, in patients where there is disease limited to the colon and rectum, this procedure may be considered. Patients must be carefully selected and fully informed that their risk of complications and failure may be higher. As well, maintenance medical therapy may be considered if the diagnosis of Crohn’s disease is suspected. Laparoscopic Surgery for Crohn’s Disease Crohn’s disease is an ideal indication for the laparoscopic approach since it is a benign disease and the concerns related to cancer recurrence do not apply. In addition, it may result in an improved cosmetic result, which is an important consideration in this often young and single patient population. There tends to be less pain and higher patient satisfaction with laparoscopic procedures. On the other hand, there is no consistent evidence that hospital stays are shortened significantly and that patients return to work earlier following laparoscopy. As laparoscopic techniques have become more widely adopted, the indications have widened. Laparoscopic resections may be more difficult in patients who have had previous surgery and have multiple adhesions or have a large inflammatory mass, abscess or fistula. Nevertheless, most procedures in patients with Crohn’s disease can now be attempted laparoscopically and converted to an open procedure if necessary. The laparoscopic approach for performing defunctioning stomas offers real advantages over an open approach. It can be performed easily with the stoma being brought out through one of the port sites. Currently, terminal ileal and right colon resections, segmental resections of the small and large bowel, proctectomy and reconstruction of the gastrointestinal tract follow-

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ing a Hartmann procedure are being performed. Most proponents advocate performing laparoscopic assisted resections so the bowel is exteriorized through a small incision at one of the port sites and the mesentery, which is often thickened, is divided extracorporeally. Several studies have compared outcome in patients having laparoscopic to open ileocolic resections. There are four studies comparing the results of surgery to either historical or concurrent controls who had open surgery [34–38]. In these studies, the complication rates were generally comparable at approximately 10%. However, length of stay was significantly decreased with a savings of 2–5 days in the laparoscopic group. As a result, two studies reported a savings in direct hospital costs [34, 37]. There is one randomized controlled trial comparing open to laparoscopic ileocolic resection. Milson et al. [38] randomized 31 patients to the laparoscopic and 29 to the conventional surgery group. The times to flatus and first bowel movement did not differ significantly. The median length of stay was 5 days after laparoscopic and 6 days after conventional surgery. There was no significant difference in the rate of major complications but there were significantly more minor complications in the conventional surgery group. Two patients in the laparoscopic group were converted to an open procedure. Quality of Life following Surgery for Crohn’s Disease There are several studies documenting outcome in patients pre- and postoperatively using validated instruments which measure quality of life. All have consistently reported significantly improved outcome postoperatively compared with the preoperative status. Thirlby et al. [39] studied 63 patients who had surgery for inflammatory bowel disease. Of these, 36 had Crohn’s disease and all had intractable disease as the indication for surgery. Outcome was measured preoperatively and at 3 months postoperatively using the Medical Outcomes Health Status Questionnaire (SF-36). In this cohort, health-related quality of life (HRQL) was low preoperatively with scores in all 8 scales below the general population whereas scores were significantly improved postoperatively and equal to the general population in most scales. Yazdanpanah and colleagues [40] examined HRQL in 26 patients who had an elective ileocolonic resection for Crohn’s disease. They used a questionnaire comprised of the SF-36 to which was added the Rating Form of Inflammatory Bowel Disease Patients Concerns (RFIPC), a sleep module and 3 questions of pertinence to the French population. This was administered immediately preoper-

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atively and 3 months preoperatively. Again these investigators found that HRQL was significantly better postoperatively although patients’ concerns about having an ostomy bag, surgery, energy level, uncertainty of the disease and pain or suffering were unchanged. Tillinger et al. [41] studied 16 patients preoperatively, and at 3, 6 and 24 months postoperatively using the time trade-off technique and direct questioning of objectives (DQO) to ascertain utilities for their HRQL as well as administering the Crohn’s Disease Activity Index (CDAI), RFIPC, and Beck Depression Index. Again, using these instruments, there was significant improvement in all patients at 3 and 6 months preoperatively. However, at 24 months, 4 patients had developed recurrent disease and their scores were similar to those obtained preoperatively, whereas the other 12 patients continued to have significantly improved scores. Casellas et al. [42] performed a cross-sectional study which included four cohorts of patients: 29 in remission following surgical resection; 48 patients with a medically induced remission; 42 patients with clinically active disease and a control group of 63 healthy individuals. HRQL was measured using the Inflammatory Bowel Disease Questionnaire (IBDQ), the Psychological General Well Being Index (PGWBI) and the EuroQol. Patients with active Crohn’s disease had significantly poorer scores on the IBDQ, PGWBI and EuroQol. Both cohorts of patients with inactive disease (whether it was surgically or medically induced) had better scores on the three instruments than those with active disease.

mal ileitis resulting in high ileostomy outputs. Brooke [43] described the method of maturing an ileostomy as we know it today and with this, the problem was eliminated. Also, advances in the construction of appliances have meant that accidents occur infrequently and the activities of ostomates are relatively unrestricted. Thus, total proctocolectomy and ileostomy has remained the standard procedure for ulcerative colitis. It offers several advantages: it eliminates the disease completely; it may be performed in one stage and has a relatively low complication rate. The obvious disadvantage is that patients are left with a permanent ileostomy. However, despite this, studies have shown that individuals with an ileostomy have a high quality of life. The major surgical complications are unhealed perineal wound and sexual nerve dysfunction. Also, in the long term, approximately 20% of patients may have ileostomy complications, including prolapse, retraction, and peristomal herniation, requiring surgical intervention [44]. Because of the physical and psychological problems encountered by some patients with a stoma, Professor Nils Kock developed the Kock continent ileostomy in the late 1960s [45]. Although it was initially accepted enthusiastically by patients, with the introduction of the pelvic pouch procedure, it is rarely performed, with patients preferring to avoid any stoma at all. In addition, the procedure is technically difficult to perform and the complication rate is high. The most serious complication rate is valve slippage but other complications include prolapse of the valve and peristomal fistulization. Overall, the need for further revision may approach 50%.

There have been tremendous advances in the surgical management of ulcerative colitis in the past 50 years. As a result, surgery is no longer reserved for chronically or acutely sick individuals where there are no other alternatives. Because ulcerative colitis is limited to the colon, surgery is curative meaning that the symptoms of the disease are eliminated, there is no ongoing need for medication and in most cases, regardless of the procedure, and the long-term quality of life is excellent. As well, since the introduction of reconstructive procedures, the normal route of evacuation can be maintained and patients are much more accepting of surgical treatment. The first major advance was made in the early 1950s with the description of the Brooke ileostomy. Prior to that, stomas were matured in various ways but most often became strictured and led to a condition known as presto-

The Pelvic Pouch Procedure In the late 1970s, Parks et al. [46] and Utsonimya et al. [47] independently adapted the ileal reservoir, which had previously been described by Kock, and anastomosed it to the anus, creating what has become known as a restorative proctocolectomy, ilealpouch anal anastomosis or pelvic pouch. Its major advantage over the other procedures is that the normal route of evacuation is maintained and the need for a permanent ileostomy is eliminated. The pelvic pouch procedure is a technically difficult procedure. When it was first introduced, complication rates of 60–70% and failure rates of up to 30% were reported. The complication rate has decreased dramatically, so overall the failure rate now is less than 5% at large centers [48–50]. This is due to modifications in technique as well as increased experience both with the technical aspects of the procedure as well as the management of complications.

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Several types of pouches have been described including the S, J and W pouch. Of these, the J pouch is performed most commonly because of its ease of construction. There does not appear to be any long-term advantage of one design over the others. In the short term, the pouch capacity may be larger in the W or S shaped pouches [51]. The most significant change in technique has been the dissection of the rectum to the level of the levators and then construction of a stapled ileoanal anastomosis approximately 1–2 cm above the dentate line rather than performing a mucosectomy and hand-sewn anastomosis. Again the major advantage is a technical one. Particularly in obese individuals and in heavyset males, it may be extremely difficult to bring the pouch down to the anal outlet to do a hand-sewn anastomosis. There are some data also to suggest that functional results may be improved and the anastomotic leak rate is lower with a stapled anastomosis [48, 52, 53]. The concern has been leaving the short cuff of rectal mucosa and the possibility of continued symptoms due to inflammation or the development of cancer. Although there is persistence of inflammation in this segment of mucosa, so-called symptomatic ‘cuffitis’ requiring medical or surgical therapy is rare. With regards to the development of cancer in the anal outlet, there have been some reported cases, but they have occurred with equal frequency in individuals having had a mucosectomy as those who have had a stapled anastomosis. Lastly, in the initial descriptions of the procedure, a defunctioning stoma was always performed. However, as leak rates have decreased, some authors now routinely omit the ileostomy, while others do so on a selective basis [48,54]. At our institution, an ileostomy is omitted if the patient has previously had a subtotal colectomy and therefore is off all steroids and is nutritionally fit and if a double stapled ileoanal anastomosis is performed. Postoperative deaths are rare, but the reported complication rates following the pelvic pouch procedure are high. There are complications which are common to all major abdominal operations including wound infection, small bowel obstruction and thromboembolic complications. Additionally, there are complications specific to the procedure. The most serious early complication is a leak from the ileoanal anastomosis. This may manifest as a radiological leak, a clinical leak with an intra-abdominal abscess, fistula to another intra-abdominal structure, a perianal abscess or a fistula to the perineum or vagina. Most frequently a leak manifests within a few days of the procedure but may occur many months after the procedure or closure of the ileostomy.

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The reported risk of an anastomotic leak is quite variable. Reported rates vary between 5 and 15%. Heuschen et al. [55] analyzed 706 patients who underwent IPAA and found that 131 (19.2%) of all patients had a pouchrelated septic complication. The rate was 24.4% in patients with ulcerative colitis compared with 9.4% in patients with familial adenomatous polyposis. The most common complication was an identified leak at the ileal pouch-anal anastomosis including an anastomotic separation [20], pouch-anal anastomotic fistula [72] and pouchvaginal fistula [15]. Others included parapouch pelvic abscesses in 11 and proximal pouch fistula in 13. They analyzed various risk factors for sepsis. They found that ulcerative colitic patients receiving more than 40 mg/day of prednisone had a significantly higher risk of septic complications. Tension was a factor in patients with familial adenomatous polyposis [56]. Staging of the procedure may affect the leak rate. In early series, high leak rates were reported in small series of patients who had the procedure performed without a covering ileostomy. Thus, most centers performed a loop ileostomy routinely [57]. However, more recently, some centers have omitted the ileostomy in selected patients. At our own center, we omit the ileostomy in patients who have previously had a subtotal colectomy and ileostomy. This is based on an initial experience of 71 patients who had a pelvic pouch procedure without a defunctioning ileostomy and the leak rate was 18%. Those who had the procedure as a single stage had a leak rate of 32% compared with a 12% leak rate in those who had a previous subtotal colectomy. Similarly, those on steroids had a higher leak rate (33 vs. 14%) [48]. Others, however, continue to perform the IPAA without covering ileostomy and report adequate results [54]. It also seems that a hand-sewn anastomosis is associated with a higher rate of leaks than a stapled anastomosis. Ziv et al. [52] reported a septic complication rate of 10.5% in those having a hand-sewn IPAA compared with 4.6% in those having a stapled IPAA. Anastomotic leaks are significant not only because of their frequency but because they are the commonest reason for pouch excision. In those in whom the pouch is not excised, functional results may be impaired. In our series, of 58 patients requiring excision of the pouch, 39% were because of a leak from the ileoanal anastomosis and 12% because of a leak from the pouch itself [58]. Gemlo et al. [59] reported that perianal sepsis or pouch fistulas were the cause of failure in 24% of their patients requiring excision of the pouch.

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While early in the series, a leak most often led to excision of the pouch, now most pouches can be salvaged. Various modalities can be used including antibiotics and drainage of the pouch (if there is no covering ileostomy), delayed closure of the ileostomy, local techniques for repair of the anastomosis and reconstruction of the pouch with a combined abdominoperineal approach. Heuschen et al. [56] reported on follow-up of 131 patients who had septic complications. An average of 2.2 procedures was performed. Overall, 23.7% lost the pouch and 6.1% were permanently defunctioned. The risk was increased if the initial leak involved the anal sphincter. In our own series, following reconstructive surgery, 75% have functioning pouches [60]. Although construction of an ileostomy may be important to decrease the morbidity from an anastomotic leak, the ileostomy itself may be a source of morbidity [61]. The most common complication is dehydration secondary to high ileostomy outputs. Most often dietary maneuvers, anti-diarrheal agents and fluid replacement will be sufficient. Rarely, early closure of the ileostomy is required. However, this is not a major complication and does not impact on the long-term outcome. Surgical complications such as an anastomotic leak or fistula and obstruction, occurring after closure of the ileostomy, are much more significant complications, occurring in up to 5% of patients. Pouch Failure MacRae et al. [58] reported a failure rate of 10.5% in 551 patients undergoing a pelvic pouch. The risk factors for failure were hand-sewn IAA, tension on the IAA, use of a defunctioning ileostomy, Crohn’s disease, and a leak from the pouch or IAA. Gemlo et al. [59] reported a failure rate of 9.9% in 253 patients having surgery at the University of Minnesota. Poor functional results was the most common cause (28%) followed by unsuspected Crohn’s disease (5%) and pelvic sepsis. Lepisto et al. [50] reported an overall failure rate of 5.3%. The cumulative probability of pouch failure was 1% at 1 year, 5% at 5 years and 7% at 10 years. Fistula was a predictor of failure. These series included patients operated on during the early experience with performing pouches. Currently, failure rates at most large centers are less than 5%.

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Long-Term Complications

Pouchitis Pouchitis is a complication unique to pouches [62]. It is a nonspecific inflammation which manifests as increased stool frequency, lower abdominal pain and occasionally low grade fever. On endoscopy, the pouch is acutely inflamed with evidence of friability, ulceration and mucous discharge. At histology, there should be changes of acute inflammation to make the diagnosis of pouchitis. The cumulative risk of pouchitis may be as high as 30–50%. Fortunately, most episodes begin abruptly and respond quickly to antibiotics, even though the etiology of pouchitis is unknown. In only a few percent of individuals is pouchitis chronic with patients requiring long-term antibiotic therapy and only 1% will require pouch excision. Recently, there are some data to suggest that probiotics may be beneficial in maintaining a remission [63]. Cancer and Dysplasia The other long-term concern has been whether there is an increased risk of dysplasia and cancer in individuals having a pelvic pouch procedure. Potentially, both the residual rectal as well as the pouch mucosa are at risk. With regard to the rectal mucosa, several cases of cancer have been reported. These have occurred in individuals in whom a mucosectomy was performed as well as individuals where a mucosectomy was omitted. Most, however, have occurred in individuals who had a cancer or dysplasia in the colectomy specimen. Thus, regular endoscopy and biopsy of the remaining rectal mucosa should be performed in individuals with a history of ulcerative colitis of more than 10 years duration. On the other hand, while there have been a few reported cases of dysplasia and cancer affecting the pouch mucosa, it still is uncertain whether the risk of cancer is increased in this cohort of patients. As well, it seems that if there is an increased risk, it may be in patients with chronic pouchitis with severe villous atrophy on histology [64]. Sexual Dysfunction and Infertility Males undergoing pelvic surgery are at risk for injury to the pelvic nerves. This may result in difficulty emptying the bladder, retrograde ejaculation or impotence. These symptoms may occur transiently or permanently and may be partial or complete. When surgery is being performed for ulcerative colitis, it is unnecessary to perform a wide pelvic dissection and therefore the risk

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should be significantly lower than in patients having surgery for rectal cancer. Nevertheless, the reported incidence is approximately 1–2%. Recently, studies have documented an increased risk of infertility in females having had a pelvic procedure. The ability to conceive may be decreased by 50% [65]. The mechanism is unknown but likely related to adhesion formation following pelvic surgery. On the other hand, women who do become pregnant do not seem to have problems with either the pregnancy or delivery. The risk of perineal complications is not increased nor are functional results permanently impaired, so the decision whether to have a vaginal delivery or cesarean section may be left up to the woman and her obstetrician [66]. Quality of Life Quality of life is an important issue in assessing the outcome of surgery for ulcerative colitis since the indication for surgery in most patients is failure of medical management or poor quality of life. Although the pelvic pouch procedure is preferred by most patients, there are data to suggest that quality of life is excellent irrespective of the procedure, possibly because physical well-being is improved and it is the main determinant of outcome. Surveys of patients with a conventional ileostomy have revealed that 75–95% of patients are satisfied with their post-operative status. Several groups have attempted to compare quality of life of patients following the various procedures. There are no randomized controlled trials comparing the procedures, so it is likely that there are inherent differences in the patient cohorts which may limit the findings of the studies. Kohler et al. [67] from the Mayo Clinic surveyed 406 patients who had a conventional ileostomy, 403 who had a Kock pouch and 300 who had a pelvic pouch procedure for ulcerative colitis or familial adenomatous polyposis between 1960 and 1980. They reported that more than 90% of patients in all three groups were satisfied with their current status, although 33% of patients with a conventional ileostomy, 11% with a Kock pouch and 3% with a pelvic pouch would have liked to have had a change. In all groups, more than 90% had returned to work or school and more than 60% reported that their attitude had improved since surgery. These patients were also surveyed to assess their ability to partake in social and recreational activities and sports, perform housework, enjoy family relationships and sexual activity and travel. There were no significant differences with the exception that patients with a pelvic pouch scored higher in the areas of sports and sexual activities compared to the

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other two groups. Patients with Kock pouches were more restricted in food intake and their ability to travel. In an attempt to quantitate quality of life following these procedures, our group used two techniques, the time trade-off technique and direct questioning of objectives to derive utilites for patients’ perceived health status [68]. A utility of 1.0 signifies perfect health and death is assigned a utility of 0. Three cohorts of patients were studied: 28 patients with a conventional ileostomy, 28 with a Kock pouch and 37 with a pelvic pouch. The mean utilities were similar for all three groups of patients with utilities ranging from 0.87 to 0.97 depending on the instrument used. Thus, not only did this study suggest that quality of life is close to that of normal, but there appeared to be little difference in quality of life with the different procedures. Subgroup analysis did reveal that the mean utilities were significantly different between those judged to have ‘poorly functioning’ pouches and those with good results. A third study published by Jimmo and Hyman [69] showed that 10 of 12 patients who had a total proctocolectomy and ileostomy and 46 of 55 who had a pelvic pouch procedure were satisfied with the procedure. All patients completed the IBDQ and there was no significant difference between the two groups with respect to the overall score or by category. Two other studies have demonstrated that quality of life following surgery is similar to that of the normal population. Provenzale et al. [70] compared the outcome of 22 patients with a pelvic pouch with that of a normal population using the SF-36. No significant differences were detected. They also reported that the median utility for this cohort was 1.0 signifying normal health-related quality of life. Kohler et al. [71] compared outcome in a cohort of patients who had a pelvic pouch to those who had had a cholecystectomy. Although the pelvic pouch patients had increased stool frequency, and a higher proportion had fecal spotting and concern about their bowel habits, the quality of life of the two cohorts was similar. Also, a similar proportion participated in sports and social and recreational activities, held jobs and were satisfied with their family relationships and sexual activity.

Surgical Management of the Complications of Ulcerative Colitis

Fulminant Colitis Fulminant colitis is one of the more uncommon manifestations of ulcerative colitis. Its frequency has decreased markedly over the past 50 years since Truelove and Witts

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first established their criteria for toxic megacolon so that true toxic megacolon is rarely seen today. Nevertheless, it remains an important complication because of its severity and potentially lethal nature. Patients presenting with fulminant colitis, more than most others, require a team approach with both medical and surgical treatment having a role. In addition to specific measures, supportive measures such as fluid resuscitation, nutritional support and antibiotics play an important role. Patients need to be reassessed frequently and joint decisions made about the timing of various interventions. Intravenous steroids have been the mainstay in the medical management of fulminant ulcerative colitis. However, somewhere between 40 and 60% of patients will fail to respond to a course of steroids [72]. Recently, cyclosporine A was shown to be effective in a small trial of patients who failed to improve on steroids [73]. Nevertheless, subtotal colectomy and ileostomy is necessary in approximately 40–60% of patients. Subtotal colectomy and ileostomy is the preferred surgical procedure for patients with acute colitis having surgery emergently or urgently. Blowhole colostomy and ileostomy as advocated by Turnbull is rarely performed now. Whether the rectal stump is stapled or exteriorized depends on the surgeon’s preference. However, if the disease is fulminant, it is probably safer to exteriorize it. Total proctocolectomy and restorative proctocolectomy

should not be performed since disease will settle with a subtotal colectomy in most patients and the risk of complications with the former procedures is higher. In the long term, preservation of the rectum allows for a reconstructive procedure in the future. Cancer and Dysplasia Unfortunately, the indication for surgery may be cancer in a small proportion of patients with longstanding ulcerative colitis. Depending on the stage of the disease and individual patient preferences, the type of procedure performed may vary. However, for patients with colonic cancer, a pelvic pouch can usually be performed should the patient desire. On the other hand, patients with a low lying rectal cancer may require a total proctocolectomy. Surgical cancer principles should not be compromised in order to perform a reconstructive procedure. A pouch procedure may also not be feasible if the patient requires postoperative radiation. While the risk of cancer occurring in the anal outlet following pouch surgery is extremely low, most of the reported cases have occurred in patients who had dysplasia or cancer in the colectomy specimen. Dysplasia involving the lower rectum is usually a contraindication to performing a pouch procedure and patients who have dysplasia elsewhere in the colon must be informed of the small but definite risk of cancer occurring in the anal outlet subsequently.

References 1 Farmer RG, Hawk WA, Turnbull RB: Indications for surgery in Crohn’s disease. Gastroenterology 1976;71:245–250. 2 Wolff BG: Factors determining recurrence following surgery for Crohn’s disease. World J Surg 1998;22:364–369. 3 Krause U, Ejerblad S, Bergman L: Crohn’s disease: A long-term study of the clinical course in 186 patients. Scand J Gastroent 1985;4:516– 524. 4 Fazio VW, Marchetti F, Church JM, Goldblum JR, Lavery IC, Hull TL, Milsom JW, Strong SA, Oakley JR, Secic M. Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. Ann Surg 1996;224:563–573. 5 Cameron JL, Hamilton SR, Coleman J, Sitzman JV, Bayless TM: Patterns of ileal recurrence in Crohn’s disease. Ann Surg 1992;215: 546–552. 6 Ikeuchi H, Kusunoki M, Yamamura T: Longterm results of stapled and hand-sewn anastomoses in patients with Crohn’s disease. Dig Surg 2000;17:493–496.

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7 Munoz-Juarez M, Yamamoto T, Wolff BG, Keighley MRB: Wide lumen stapled anastomosis versus conventional end-to-end anastomosis in the treatment of Crohn’s disease. Dis Colon Rectum 2001;44:20–25. 8 Hashemi M, Novell JR, Lewis AA: Side-to-side anastomosis may delay recurrence in Crohn’s disease. Dis Colon Rectum 1998;41:1293– 1296. 9 Kusunoki M, Ikeuchi H, Yanagi H, Shoji Y, Yamamura T: A comparison of stapled and hand-sewn anastomosis in Crohn’s disease. Dig Surg 1998;15:679–682. 10 Scott NA, Sue-Ling HM, Hughes LM: Anastomotic configuration does not affect recurrence of Crohn’s disease after ileocolonic resection. Int J Colorectal Dis 1995;10:67–69. 11 Moskovicz D, McLeod RS, Greenberg GR, Cohen: Operative and environmental risk factors for recurrence of Crohn’s disease. Int J Colorectal Dis 1999;14:224–226.

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18 Yamamoto T, Keighley MRB: Factors affecting the incidence of postoperative septic complications and recurrence after strictureplasty for jejunoileal Crohn’s disease. Am J Surg 1999;178:240–245. 19 Marchetti F, Fazio VW, Ozuner G: Adenocarcinoma arising from a strictureplasty site in Crohn’s disease: Report of a case. Dis Colon Rectum 1996;39:1315–1321. 20 Jaskowiak NT, Michelassi F: Adenocarcinoma at a strictureplasty site in Crohn’s disease: Report of a case. Dis Colon Rectum 2001;44:284– 286. 21 Alexander-Williams J, Haynes IG: Up-to-date management of small-bowel Crohn’s disease. Adv Surg 1987;20:245–264. 22 Broering DC, Eisenberger CF, Koch A, Bloechle C, Knoefel WT, Izbicki JR: Quality of life after surgical therapy of small bowel stenosis in Crohn’s disease. Dig Surg 2001;18:124– 130. 23 Andrews HA, Lewis P, Allan RN: Prognosis after surgery for colonic Crohn’s disease. Br J Surg 1989;76:1184–1190. 24 Andersson P, Olaison G, Bodemar G, Nystrom PO, Sjodahl R: Surgery for Crohn colitis over a twenty-eight year period: Fewer stomas and the replacement of total colectomy by segmental resection. Scand J Gastroenterol 2002;37:68– 73. 25 Longo WE, Oakley JR, Lavery IC, Church JM, Fazio VW: Outcome of ileorectal anastomosis for Crohn’s colitis. Dis Colon Rectum 1992;35: 1066–1071. 26 Buchmann P, Weterman IT, Keighley MR, et al: The prognosis of ileorectal anastomosis in Crohn’s disease. Br J Surg 1981;68:7–10. 27 Ambrose NS, Keighley MR, Alexander-Williams J, Allan RN: Clinical impact of colectomy and ileorectal anastomosis in the management of Crohn’s disease. Gut 1984;25:223– 227. 28 Cattan P, Bonhomme N, Panis Y, Lemann M, Coffin B, Bouhnik Y, Allez M, Sarfati E, Valleur P: Fate of the rectum in patients undergoing total colectomy for Crohn’s disease. Br J Surg 2002;89:454–459. 29 Hyman NH, Fazio VW, Tukson WB, Lavery IC: Consequences of ileal pouch-anal anastomosis for Crohn’s colitis. Dis Colon Rectum 1991;34:653–657. 30 Grobler SP, Hosie KB, Affie E, Thompson H, Keighley MRB: Outcome of restorative proctocolectomy when the diagnosis is suggestive of Crohn’s disease. Gut 1993;34:1384–1388. 31 Peyregne V, François Y, Gilly F-N, Descos J-L, Flourie B, Vignal J: Outcome of ileal pouch after secondary diagnosis of Crohn’s disease. Int J Colorectal Dis 2000;15:49–53. 32 Brown CJ, MacLean AR, Asano T, Cohen Z, MacRae HM, O’Connor BI, McLeod RS: Crohn’s disease and indeterminant colitis and the IPAA: Outcomes and patterns of failure. Submitted. 33 Regimbeau JM, Panis Y, Pocard M, Bouhnik Y, Lavergne-Slove A, Rufat P, Matuchansky C, Valleur P: Long-term results of ileal pouch-anal anastomosis for colorectal Crohn’s disease. Dis Colon Rectum 2001;44:769–778.

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34 Duepree HJ, Senagore AJ, Delaney CP, Brady KM, Fazio VW: Advantages of laparoscopic resection for ileocecal Crohn’s disease. Dis Colon Rectum 2002;45:605–610. 35 Bemelman WA, Slors JFM, Dunker MS, van Hogezand RA, van Deventer SJH, Ringers J, Griffioen G, Gouman DJ: Laparoscopic-assisted vs. open ileocolic resection for Crohn’s disease. Surg Endosc 2000;14:721–725. 36 Tabet J, Hong D, Kim CW, Wong J, Goodacre R, Anvari M: Laparoscopic versus open bowel resection for Crohn’s disease. Can J Gastroenterol 2001;15:237–242. 37 Young-Fadok TM, Hall Long K, McConnell EJ, Gomez Rey G, Cabanela RL: Advantages of laparoscopic resection for ileocolic Crohn’s disease: Improved outcomes and reduced costs. Surg Endosc 2001;15:450–454. 38 Milsom JW, Hammerhofer KA, Bohm B, Marcello P, Elson P, Fazio VW: Prospective, randomized trial comparing laparoscopic vs. conventional surgery for refractory ileocolic Crohn’s disease. Dis Colon Rectum 2001;44:1– 9. 39 Thirlby RC, Land JC, Fenster LF, et al: Effect of surgery on health-related quality of life in patients with inflammatory bowel disease: A prospective study. Arch Surg 1998;133:826– 832. 40 Yazdanpanah Y, Klein O, Gambiez L, et al: Impact of surgery on quality of life in Crohn’s disease. Am J Gastroenterol 1997;92:1897– 2000. 41 Tillinger W, Mittermaier C, Lochs H, et al: Health-related quality of life in patients with Crohn’s disease. Dig Dis Sci 1999;44:932– 938. 42 Casellas F, Lopez-Ivancos J, Badia X, et al: Impact of surgery for Crohn’s disease on health-related quality of life. Am J Gastroenterol 2000;95:177–182. 43 Brooke BN: The management of an ileostomy including its complications. Lancet 1952;ii: 102–104. 44 Morowitz DA, Kirsner JB: Ileostomy in ulcerative colitis: A questionnaire study of 1,803 patients. Am J Surg 1981;141:370–375. 45 Kock NG: Intra-abdominal ‘reservoir’ in patients with permanent ileostomy: Preliminary observations on a procedure resulting in fecal ‘continence’ in five ileostomy patients. Arch Surg 1969;99:223–231. 46 Parks AG, Nicholls RJ, Prescatori M, et al: Restorative proctocolectomy with ileal pelvic reservoir for ulcerative colitis and familial adenomatosis: Clinical results in 66 patients followed up to six years. St. Mark’s Hosp Ann Rep 1982, p 49. 47 Utsunomiya J, Iwama T, Imajo M, et al: Total colectomy, mucosal proctectomy and ileoanal anastomosis. Am J Surg 1983;23:459–466. 48 Cohen Z, McLeod RS, Stephen W, Stern HS, O’Connor BI, Reznick R: Continuing evolution of the pelvic pouch procedure. Ann Surg 1992;216:506–512.

49 Fazio VW, Ziv Y, Church JM, Oakley JR, Lavery IC, Milson JW, Schroeder TK: Ileal pouch-anal anastomosis complications and function in 1005 patients. Ann Surg 1995;222: 120–127. 50 Lepisto A, Luukkonen P, Jarvinen HJ: Cumulative failure rate of ileal pouch-anal anastomosis and quality of life after failure. Dis Colon Rectum 2002;45:1289–1294. 51 Nicholls RJ, Pezim ME: Restorative proctocolectomy with ileal reservoir for ulcerative colitis and familial adenomatous polyposis: A comparison of three reservoir designs. Br J Surg 1985;72:470–474. 52 Ziv Y, Fazio VW, Church JM, Lavery IC, King TM, Ambrosetti P: Stapled ileal pouch anal anastomoses are safer than hand-sewn anastomoses in patients with ulcerative colitis. Am J Surg 1996;171:320–323. 53 Johnston D, Holdsworth PJ, Nasmyth DG, Neal DE, Primrose JN, Womack N, et al: Preservation of the entire anal canal in conservation proctocolectomy for ulcerative colitis: A pilot study without mucosal resection with mucosal proctectomy and endo-anal anastomosis. Br J Surg 1987;74:940–944. 54 Sugerman HJ, Newsome HH: Stapled ileoanal anastomosis without a temporary ileostomy. Am J Surg 1994;167:58–66. 55 Heuschen UA, Hinz U, Allemeyer EH, Autschbach F, Stern J, Lucas M, Herfarth C, Heuschen G: Risk factors for ileoanal J pouch-related septic complications in ulcerative colitis and familial adenomatous polyposis. Ann Surg 2002;235:207–216. 56 Heuschen UA, Allemeyer EH, Hinz U, Lucas M, Herfarth C, Heuschen G: Outcome after septic complications in J pouch procedures. Br J Surg 2002;89:194–200. 57 Rothenberger DA, Vermeulen FD, et al: Restorative proctocolectomy with ileal reservoir and ileoanal anastomosis. Dis Colon Rectum 1983;145:82–88. 58 MacRae HM, McLeod RS, Cohen Z, O’Connor BI, Cheong ENC: Risk factors for pelvic pouch failure. Dis Colon Rectum 1997;40:257–262. 59 Gemlo BT, Wong WD, Rothenberger DA, Goldberg SM: Ileal pouch-anal anastomosis. Arch Surg 1992;127:784–787. 60 MacLean AR, O’Connor BI, Parkes R, Cohen Z, McLeod RS: Reconstructive surgery for failed ileal pouch-anal anastomosis: A viable surgical option with acceptable results. Dis Colon Rectum 2002;45:880–886. 61 Feinberg SM, McLeod RS, Cohen Z: Complications of loop ileostomy. Am J Surg 1987;153: 102–107. 62 Mahadevan U, Sandborn WJ: Diagnosis and management of pouchitis. Gastroenterology 2003;124:1636–1650. 63 Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Migliolo M, Campieri M: Prophylaxis of pouchitis onset with probiotic therapy: A double-blind, placebo-controlled trial. Gastroenterology 2003;124:1535–1538.

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64 Veress B, Reinholt FP, Lindquist K, Lofberg R, Liljeqvist L: Long-term histomorphological surveillance of the pelvic ileal pouch: Dysplasia develops in a subgroup of patients. Gastroenterology 1995;109:1090–1097. 65 Ording Olsen K, Juul S, Berndtsson I, Oresland T, Laurberg S: Ulcerative colitis: Female fecundity before diagnosis, during disease, and after surgery compared with a population sample. Gastroenterology 2002;122:226–227. 66 Ravid A, Richard CS, Spencer LM, O’Connor BI, Kennedy ED, MacRae HM, Cohen Z, McLeod RS: Pregnancy, delivery, and pouch function after ileal pouch-anal anastomosis for ulcerative colitis. Dis Colon Rectum 2002;45: 1283–1288.

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67 Kohler LW, Pemberton JH, Zinmeister AR, Kelly KA: Quality of life after proctocolectomy: A comparison of Brooke ileostomy, Kock pouch and ileal pouch-anal anastomosis. Gastroenterology 1991;101:679–681. 68 McLeod RS, Churchill DN, Lock AM, Vanderburgh S, Cohen Z: Quality of life of patients with ulcerative colitis preoperatively and postoperatively. Gastroenterology 1991;101:1307– 1313. 69 Jimmo B, Hyman NH: Is ileal pouch-anal anastomosis really the procedure of choice for patients with ulcerative colitis? Dis Colon Rectum 1998;41:41–45.

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70 Provenzale D, Shearin M, Phillips-Bute B, et al: Health related quality of life of post-colectomy patients-evaluation and assessment of new health status measures. Gastroenterology 1997; 113:7–14. 71 Kohler LW, Pemberton JH, Hodge DO, Zinmeister AR, Kelly KA: Long-term functional results and quality of life after ileal-pouch anal anastomosis and cholecystectomy. World J Surg 1992;16:1126–32. 72 Grant CS, Dzois RR: Toxic megacolon: Ultimate fate of patients after ‘successful’ medical management. Am J Surg 1984;147:106–110. 73 Lichtiger S, Present DH, Kornbluth A, et al: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330:1841–1845.

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Review Article Dig Dis 2003;21:180–191 DOI: 10.1159/000073249

Biological Therapy in IBD Anti-Tumor Necrosis Factor-Alpha and Others

Jürgen Schölmerich Gertrud Huber Department of Internal Medicine I, University Medical Center Regensburg, Regensburg, Germany

Key Words Crohn’s disease W Ulcerative colitis W Tumor necrosis factor-· W T lymphocytes W Anti-sense W Cytokines W Growth factors

Abstract Currently used standard treatment in IBD is effective and sufficient for the majority of patients. Published numbers regarding therapy refractoriness are probably related to referral centers and not representative. Pharmacological optimization of available drugs improves the standard situation further. Biological therapies in a larger meaning are studied intensively, but obviously hopes are to some extent not real. Biological and for some principles clinical effects (i.e. TNF antibodies, CD4 antibodies) are proven, the effects are, however, limited and long-term risks and results are not clarified. Numerous approaches are not clinically relevantly effective which is, in particular, true for those inhibiting single mediators. A number of alternative concepts such as hormones and growth factors could be effective and will be studied further. In particular probiotics may be a development of the future and they belong to the ‘biologic treatments’ in the true sense. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 0257–2753/03/0212–0180$19.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ddi

Although effective and due to pharmacological optimization safe treatments for chronic inflammatory bowel diseases (IBD) are available many new therapeutic principles are studied worldwide. Most of them result from more recent pathophysiological knowledge and belong to the group of ‘biological therapy’. For some principles a biological effect has been proven in men and patients, in many cases effects are unfortunately still limited and longterm results and risks are open. Many approaches have been futile. The concentration on these mostly expensive treatment principles has led to the situation that alternative concepts and approaches are overlooked due to a lack of interest of the pharmaceutical industry. IBD, namely Crohn’s disease (CD) and ulcerative colitis (UC) have a prevalence of 200 to 500 per 100,000 people in western countries and an incidence of 20 per 100,000 per year. Both diseases have lifelong character and due to available treatments are associated with an almost normal life expectancy. During the last decades many pathophysiological mechanisms have been demonstrated using animal models and human cells. However, the real cause is still not definitively clarified although a first susceptibility gene has been found [1, 2]. Probably, due to a defective interaction of the mucosal immune system and the enteric flora in Crohn’s disease, an increased immune response develops where cytokines such as interferon-Á, interleukin-2, interleukin-12 and

Prof. Dr. Jürgen Schölmerich Department of Internal Medicine I, University Medical Center Regensburg DE–93042 Regensburg (Germany) Tel. +49 941 944 7001, Fax +49 941 944 7002 E-Mail [email protected]

interleukin-18 are increasingly expressed and lead to the production of proinflammatory cytokines such as TNF and interleukin-1 (TH1 response). In ulcerative colitis, in contrast, TH2-associated cytokines such as interleukin-4, interleukin-5, interleukin-6, interleukin-10 and interleukin-13 are predominantly expressed. These cytokines present possible targets for a modulation of the immune response although the redundancy of the network makes it improbable that the modulation of a single cytokine will result in significant success. While the current treatment mainly comprises pluripotent substances such as 5-aminosalicylic acid, systemic and local steroids and immunosuppressants such as azathioprine, methotrexate and cyclosporine since a number of years intensive attempts are undertaken to modulate the mucosal immune response. This has been named ‘biological therapy’. The currently available therapy has significantly increased survival which is nowadays almost normal (fig. 1) [3]. The social integration is preserved in more than 90% as evidenced by ability to work, to go to school and to participate in leisure activities [4]. When looking at population-based data, it becomes evident that less than half of all patients with CD and even less of those with UC (34%) ever received steroids (fig. 2) [5]. However, there still is a

Fig. 1. Ten years survival in IBD [3].

Fig. 2. Steroids for IBD – population related data [5].

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181

group of patients which cannot be treated successfully using conventional therapy. In addition, life quality of patients still is less then optimal. Furthermore, the side effects of steroids and other drugs should not be forgotten. Finally, we still have no mucosal healing with conventional treatments, at least not in Crohn’s disease. This means that in Crohn’s disease in particular, the relapse rate is high and there is no effective maintenance treatment available. The picture is even more complicated since genetic as well as clinical analyses demonstrate that Crohn’s disease and probably ulcerative colitis are syndromes rather than diseases which means that different subgroups can be formed which have different etiology and probably different treatment needs [6].

Definition of ‘Biological Therapy’

This rather trendy name which attempts to indicate that no chemical substances are used comprises a large number of very different therapeutic principles. In IBD mostly recombinant peptides or proteins (i.e. interleukin10, interferon-ß, growth factors), partially or almost completely humanized antibodies (i.e. anti-TNF, anti-integrins) or anti-sense constructs (i.e. anti-ICAM-1, antiNFÎB p65) have been tested. The majority of those substances need to be applied intravenously or subcutaneously. More recently, small molecules have been developed which inhibit given steps in signal transduction pathways and have been found by screening of molecule libraries (i.e. MAP-kinase inhibitors). The different approaches can be roughly separated regarding their target and will be presented accordingly in the following.

Interleukin-1

The powerful proinflammatory cytokine interleukin-1 has an endogenous receptor antagonist which has been characterized early and produced recombinantly. It has been licensed in rheumatology [7]. The receptor antagonist inhibits a number of interleukin-1 effects such as hypotension, fever, neutrophilia, lymphocyte proliferation and so on. It has therefore been tested in IBD as well. However, exact data from these studies have never been published and it can only be taken from review articles that they have not been successful [8]. This is probably the first example showing that the inhibition of a single cyto-

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kine is not a very promising approach due to the redundant and complex network of mediators in intestinal inflammation.

Tumor Necrosis Factor-·

Attempts to inhibit another significant proinflammatory cytokine which is involved in mucosal inflammation, namely tumor necrosis factor-·, have also been undertaken early and were successful in animal experiments. Several approaches (different antibodies, a fusion protein containing its p75 receptor as well as the p55 receptor in soluble form, thalidomide, and an inhibitor of MAPkinase) have been studied. Infliximab The first substance which has been clinically tested was the mouse human chimeric monoclonal IgG-1 antibody cA2 meanwhile named Infliximab. After positive pilot studies a larger placebo-controlled study was done [9], where patients with active Crohn’s disease were included. Of those 80% had been treated with steroids and more than 30% with azathioprine without significant improvement. 16% of patients, however, had no such pretreatment. After 4 weeks, 35% of the patients reached remission with Infliximab without a dose-effect relation as compared to 4% with placebo. A response to treatment was found in 66% of Infliximab patients versus 17% with placebo. Surprisingly, the effect was maintained for several weeks and observed side effects were rare. Patients responding in the initial phase of the study were again randomized and retreated with 10 mg/kg Infliximab or placebo every 8 weeks for 36 weeks. 53% of patients with Infliximab in contrast to 20% with placebo maintained remission until week 44. Between 8 and 12 weeks after the last given dose a relapse occurred in the majority of patients [10]. More recently, another study on remission maintenance was published. Patients responding to initial treatment were treated every 8 weeks with 5 or 10 mg/kg Infliximab. Of the initially treated 573 patients, 353 responded. Of those after 54 weeks 24.1% (5 mg/kg) and 32.1% (10 mg/kg) versus 8.9% with placebo were in remission and without steroids. Infections were observed in 32% of the patients, 3.8% were severe. Four patients died (2 from sepsis, 1 from a lymphoma). 49% of patients developed anti-nuclear antibodies with a titer 11:160, and 26 had anti-DNA double-strand antibodies. Infusion reactions such as headache, dizziness, nausea and other symptoms occurred in 3–6% of patients in relation to the

Schölmerich/Huber

Table 1. Long-term effects of Infliximab –

ACCENT I [11]: Responder to first infusion (week 2; 335/573 patients)

54 weeks

Remission %

Response steroid free, %

Remission %

Placebo 5 mg 10 mg

13.6 28.3 38.4

8.9 24.1 32.1

17.0 43.0 53.0

Time to LOR, weeks 19 38* 154*

32% infections, 3.8% serious, 4 deaths (2 sepsis, 1 lymphoma). 49% new ANA (1 1:160), 26% anti-DS DNA AB (61:10). 54% steroids, 24% immunomodulators, 50% 5-ASA!

frequency and dose of the infusion. They were more frequent in patients with proven Infliximab antibodies. Table 1 shows the data [11]. Finally, Infliximab has been used for the treatment of fistulae in Crohn’s disease. 94 patients with draining abdominal or perianal fistulae present since at least 3 months were treated with 5 or 10 mg/kg Infliximab or placebo at weeks 0, 2 and 6. A complete closure of all fistulae which was maintained for at least 4 weeks occurred in 55% of patients with 5 mg/kg and in 38% of those with 10 mg/kg in contrast to only 13% of placebo-treated patients [12]. This study was again complemented by a long-term trial which confirmed these data [13]. It needs to be mentioned that fistula closure is maintained for about 3 months and somewhat more abscesses have been observed in the treatment group due to superficial healing. Sonographic studies have demonstrated that even in patients with complete closure of fistulae the fistula tracts were still present [14]. Since severe side effects, in particular severe infections, such as sepsis, tuberculosis, histoplasmosis, listeriosis and aspergillosis have been reported meanwhile [15, 16], skin testing and, in positive patients, X-ray of the lungs has been recommended. Registration in Europe has been reduced to patients who have been treated with the other available drugs and, in case of fistulae, also surgically. The explanation for this, in contrast to the anti-interleukin-1, in principle successful approach, and at the same time for the severe mostly intracellular infections mentioned may be that the antibody obviously does not act by blocking TNF-· but by binding to membraneexpressed TNF molecules and thereby inducing apoptosis in activated lymphocytes and monocytes [17–19]. Animal experiments demonstrate in a model of experimental sepsis a lethal effect of the antibody when given simultaneously with induction of sepsis by cecal ligation and puncture (fig. 3) [20]. Data regarding an increased appearance of malignant tumors and in particular lym-

Biological Therapy in IBD

Fig. 3. Effects of anti-TNF antibodies on survival after ‘cecal ligation

and puncture’ [20].

phoma are not conclusive. When looking at all studies available a death rate of 0.5 % during treatment seems to be a reliable estimate. Infliximab has been used in patients with ulcerative colitis; however, the largest study available did not show any effect [21]. Other Antibodies or Antagonists CDP571 (Humicade) is another mostly humanized IgG 4 antibody and has just been studied in a number of controlled trials [22–24]. Two of these studies demonstrated a biological effect in active Crohn’s disease; a remission maintenance trial done in accordance to the infliximab trials did not find significant effects for an 8weekly application after 24 weeks. A third study found a remission rate in steroid-dependent patients after 40 weeks of 44% in contrast to 22% with placebo [22]. An uncontrolled study in ulcerative colitis found biological effects [25]. Much less antibodies against the drug (Humicade) and much less double-strand DNA antibodies were

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183

Response (%)

60 50

Placebo

40

Etanercept (n = 23)

(n = 20)

30 20 10

Remission (%)

0 30 25 20 15 10 5 0

0

Fig. 4. Clinical response and remission with

2

Etanercept in moderate to severe active Crohn’s disease [28].

Table 2. CDP 870 an anti-TNF antibody

fragment in ‘active’ Crohn’s disease [26]

4

8

Weeks of treatment

292 patients

Dosing weeks 0, 4, 8

Clinical response week 12, % (CDAI ↓ 1 100) Clinical remission with initial CRP 610 mg/l

placebo

100 mg

200 mg

400 mg

35.6

36.5

36.1

44.4

10.7

35.5

32.1

53.1*

found. More recently, a study with an anti-TNF antibody fragment did not find a difference of 3 different doses versus placebo in a population of 292 patients but did find a difference between the highest dose and placebo when only patients with an initially increased CRP were analyzed. Although this is a post-hoc analysis, it may indicate that we have to select patients for the trials better than we did thus far in order not to overlook effects of biologics which may be helpful in clinical practice for patient subpopulations (table 2) [26].

cebo-controlled trial in 43 patients with active Crohn’s disease did not demonstrate an effect at all (fig. 4) [28]. The receptor p55 in a recombinant soluble form demonstrated in a pilot trial again response in 60% and a remission in 40% of patients [29]. The confirmative study is not yet published. The lack of effects of the soluble receptors and other anti-TNF strategies may be explained by the fact that these neutralize TNF-· but, in contrast to infliximab, do not induce apoptosis [17–19].

Soluble Receptors The application of soluble receptors provides another opportunity for TNF-· blockade. The first product is a recombinant fusion protein which contains the soluble receptor p75 which is fused to an Fc domain of the human IgG1. The protein is completely human and binds human TNF-· as well as lymphotoxin-·. A pilot study found a response in 60% of the patients [27]. The consequent pla-

Thalidomide In contrast to these expensive recombinant proteins, the application of small molecules such as thalidomide which inhibits TNF-· biosynthesis seemed attractive. Initial open studies demonstrated some clinical effect, and the observed side effects did not actually support further development.

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Schölmerich/Huber

Table 3. Interleukin-10 for chronically

active Crohn’s disease [37]

Clinical response, %*

Placebo (n = 66)

Interleukin-10, Ìg/kg/day 1 (n = 67)

4 (n = 64)

8 (n = 65)

20 (n = 67)

23

25

34

35**

27**

* Remission or ¢ CDAI 1 100. ** With 8 and 20 Ìg 46 and 40% hematocrit adjusted.

MAP-Kinase Inhibitors The MAP-kinase inhibitor CNI-1493 which blocks mitogen-activated protein kinase signal transduction and thereby TNF-· gene expression was used in a pilot study [30]. 8 of 9 patients after 4 weeks and 7 of 9 patients after 8 weeks showed responses; remission rates were much lower (3 of 9 patients). The study was terminated due to probable side effects. A currently running larger trial will demonstrate if this approach is useful.

IL-10 (µg/kg/day)

Placebo

1

5

10

20

n

16

15

14

18

21

Remission % (28 days)

13

27

14

6

0

Fig. 5. Interleukin-10 subcutaneously for active Crohn’s disease [36].

Inhibition of NFÎB The transcription factor NFÎB controls expression and release of proinflammatory cytokines, in particular interleukin-1 and TNF-· as well as numerous other immunereactive molecules. Some of the currently used drugs interact with the signal transduction leading to the nuclear translocation of NFÎB, i.e. sulphasalazine, mesalazine, steroids, cyclosporine, tacrolimus and others. A number of animal experiments using different inhibitors of NFÎB activation provided impressive successes in different models [31–33]. Recently, the result of the first human trial was communicated where 11 patients with IBD (5 UC, 6 CD) were treated. 5 of 7 patients treated with the oligonucleotide anti-sense against p65 showed an improvement in 1 week. In 2 steroid-refractory patients a long-lasting steroid-free remission was obtained [34]. The oligonucleotides were applied topically which limits their use. Systemic blockade of NFÎB activation is probably difficult in daily life, as has been demonstrated in animal experiments [32].

Anemia and thrombocytopenia with 10 and 20 Ìg/kg/day. Patients without steroids or 5-ASA, CDAI 1 200 and ^350.

Several strategies inhibiting the shift to a T-helper cell profile 1 have been studied, in particular the T-helper cell type 2 cytokine interleukin-10, antibodies against interleukin-12 and interferon-Á as well as interleukin-18 and finally antibodies against the interleukin-2 receptor.

While initial attempts using interleukin-10 enemas in refractory ulcerative colitis showed an impressive decrease of bowel movements, an improvement of endoscopy and a drastic decrease of TNF-· and interleukin-1 production from mononuclear cells out of biopsies [35] were not successful in consequent studies of Crohn’s disease (fig. 5; table 3) [36–38]. In addition, no relevant effect was found for the prophylaxis of postoperative endoscopic relapse in Crohn’s disease [39]. Finally, results of a study in ulcerative colitis were negative [40]. Since a recent international cooperation demonstrated that local application of interleukin-10 in the colon from genetically modified Lactococci resulted in a high IL-10 concentration in the colon and significant improvements in experimental colitis, such an attempt is currently being done in humans [41]. It may be plausible that the expression of modulating agents at the place of activity may be advantageous in analogy to the galenics of currently used standard drugs [42]. A further approach for modulating the TH1 response is the blockade of interleukin-12. Animal experiments provide interesting data [43]. Currently running human trials have not been published but personal communications

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Modulation of the TH1 Response

185

Table 4. Anti-interferon-Á AB (HuZAF) in Crohn’s disease [45]

Placebo (n = 10)

HuZAF, (mg/kg) 0.1 (n = 6)

1.0 (n = 14)

4.0 (n = 15)

60 40 0

17 0 3

42 25 6

57 50 9

Table 5. Natalizumab (Antegren) for active Crohn’s disease [54]

6 weeks

indicate a positive effect which may be due to the induction of apoptosis by this antibody as well. A further possibility in this context would be the blockade of interferon-Á using respective antibodies. These antibodies were less effective in animal experiments as compared to anti-IL-12 antibodies and similar to antiTNF antibodies. Together with the latter, an additive effect was found [44]. The application of a recombinant interferon antibody (HuZAF) did not find an effect in comparison to placebo in 3 doses in Crohn’s disease (table 4) [45]. Another possibility is the application of antibodies against interleukin-18 which in analogy to interleukin-12 stimulates interferon-Á. In animal models this has been found to be effective; data on patients are not yet available. As discussed before, it seems not to be plausible that the blockade of one of those interleukins alone will demonstrate a relevant clinical effect since at least interleukin12 and interleukin-18 can substitute each other in a redundant way. TH1 lymphocytes produce interleukin-2 as an effector molecule. There are several human receptor antibodies. The only experiments using Basiliximab [46] and Daclizumab in patients with refractory colitis [47] demonstrated some efficacy. However, this has to be proven in larger clinical studies. Inhibition of T Cell Activation T cell activation aside antigen presentation needs additional co-stimulatory signals such as the CD40 system and other molecules on the surface of the T cell and the antigen-presenting cells. A number of those co-stimulatory molecules are known and could be targets of inhibition of T cell activation. A study with a monoclonal antibody against CD40 ligand in patients with Crohn’s disease is running, data are not yet known.

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Antegren 1 ! 3 mg/kg 2 ! 3 mg/kg 2 ! 6 mg/kg

Remission, % CDAI ↓ 1100, % Remission, % SE (‘influenza’), %

Placebo

27

29

46*

31

244 patients randomized. * Significant vs. placebo.

Elimination of Activated T Cells As discussed before, activated T cells play a significant role in perpetuation of intestinal inflammation. The example of a patient with HIV who had a complete remission of his Crohn’s disease led to the conclusion that elimination of CD4+ T-helper cells could be a therapeutic approach. Aside attempts such as leukapheresis and extracorporeal photochemotherapy [48], antibodies against CD4 cells have been used. Initial studies demonstrated a very long-lasting remission in a high percentage of patients with Crohn’s disease and ulcerative colitis [49]. A dose finding study with the same antibody demonstrated an improvement in 75% of the patients [50]. CD4 cell numbers remained constantly below 550/Ìl without opportunistic infections in the patients. In spite of these positive effects, the development was cancelled due to fears of possible long-term problems with immune suppression. Several other antibodies in this context have been tested [51, 52] but their results were less positive. Inhibition of Cell Adhesion and Cell Migration Since obviously an elimination of activated immune cells by Infliximab or respective antibodies has a positive effect it is reasonable to inhibit adhesion molecules and thereby the immigration of inflammatory cells. This approach has been followed using several antibodies and anti-sense oligonucleotides. The recombinant humanized monoclonal IgG 4 antibody Natalizumab is directed against the human ·4 integrin. This approach was effective in the cotton-top tamarin [53] and was also effective in patients with Crohn’s disease [54, 55]. The first study treated 30 patients and demonstrated a reduction in disease activity (39 vs. 8% remission). The second larger trial in 244 patients found that the application of 2 ! 3 mg/kg with 4 weeks delay resulted in 46% remission versus 27% with placebo while higher doses and single application were not effective (ta-

Schölmerich/Huber

Table 6. Epidermal growth factor enemas in distal ulcerative colitis

Table 7. Keratinocyte growth factor (Repifermin) in ulcerative coli-

[63]

tis [64]: 88 patients with moderate UC 1.2 g 5-ASA (orally) + EGF 5 Ìg/100 ml (n = 12)

Remission 2 weeks ¢ Sigmoidoscopy score (0–3) ¢ Histological score (0–3)

10/12 –2 –1

4 weeks placebo (n = 12) 1/12 –0.5 0

ble 5) [54]. This approach has been followed further. An uncontrolled pilot trial in ulcerative colitis demonstrated effects in a few patients [56]. Another recombinant humanized IgG1 antibody against ·4ß7 integrin was also effective in the cotton-top tamarin [57]. Clinical studies demonstrated biological effects in Crohn’s disease and ulcerative colitis [58, 59]. The effects proved better in ulcerative colitis. Another approach is the application of anti-sense oligonucleotides against mRNA for human ICAM-1 leading to a reduced expression of this adhesion molecule. An initial dose-finding study demonstrated a higher remission rate as compared to placebo [60]. Two following trials on larger patient groups did not confirm these effects [61, 62]. It was suggested that higher doses leading to a higher bioavailability would lead to better results, but this was a post-hoc analysis and therefore not really relevant. It remains to be seen if considering the redundancy of adhesion molecules the inhibition of single molecules can be reasonable.

Remission, % Response, %

Placebo (n = 28)

Repifermin, Ìg/kg 1

5

10

25

50

11 36

19 46

9 18

0 33

0 42

0 29

Table 8. Interferon-ß-1a for refractory ulcerative colitis [71]

8 weeks

¢ CAI ¢ CAI 66, % Remission, %

Placebo (n = 31)

Standard treatment + IFNß, 3 ! 3 Mio (n = 34)

IFNß, 3 ! 1 Mio (n = 32)

–4 34 38

–6 56 56

–3 36 30

Variable Substances Several trials have studied the application of interferon-· which is used in the treatment of viral hepatitis. Open pilot trials demonstrated possible positive effects [65, 66]. A prospective study found that there is no significant effect in this indication [67, 68]. With interferon-ß

which has been used for the treatment of multiple sclerosis in Crohn’s disease thus far no effect has been found. A larger trial in ulcerative colitis resulted in a response rate of 50% with interferon-ß versus 14% with placebo [69]. Other studies investigated the application of natural interferon-ß. While a pilot trial resulted in a clinical remission rate in 9 of 16 steroid refractory patients [70], a study on a larger cohort found a higher remission rate (56%) with application of 3 ! 3 million U of interferon-ß/week in comparison to placebo and to a lower dose (table 8) [71]. Human granulocyte colony-stimulating factor (GCSF) as well as human granulocyte macrophage colony-stimulating factor (GMCSF) have been tested in small series. Positive effects have been found [72, 73]. This effect was maintained with repeated administration. However, a daily administration of this growth factor seems to be necessary for remission maintenance which probably will not be useful in daily practice. Interleukin-11 is a cytokine involved in wound healing and maintenance of the intestinal barrier. It has been studied in an initial trial in 76 patients without clearly positive effects [74]. The following study in 148 patients with active Crohn’s disease without steroids demonstrated a higher remission rate (37%) as compared to placebo (16%) which, however, is probably less impressive

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Growth Factors Several growth factors which may influence T cell differentiation have been tested. In a trial in 23 patients epidermal growth factor as enemas demonstrated a remission rate of 82% in comparison to 8% with placebo (table 6) [63]. The keratinocyte growth factor Repifermin was tested in ulcerative colitis without any significant effect (table 7) [64].

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Table 9. ‘Biologic treatments’ for IBD – state of development 05/

2003 Substance IL-1 RA TNF-AB RNF-R 75 and 55 MAP-kinase inhibitor

CD

i

NFÎB p65 antisense Anti-CD4

→

→

EGF KGF INF-· INF-ß GCSF/GMCSF Growth hormone DHEA IL-11

(–) + – ?

? (–) ? ?

(+)

Anti-IL-12 Anti-INF Á Anti-IL-2 R IL-10 Anti-·4 integrin Anti-·4ß7 integrin Anti ICAM-1

UC

(+)

+

?

(–) – (+) (+)

? ? ? ?

(+) (–) –

→

? ?

→ → →

(–) (–) (+) (+) (+) (–)

? (+) ? (+) –

→

– (+) ? ? (+) ?

Table 10. Cyclophosphamide for refractory Crohn’s disease [82]: 10 patients, 4–6 cycles (750 mg, monthly) azathioprine after achieving of remission, steroids tapered

Improvement after 2 cycles Complete remission Steroid free Remission 1 18 months AE: 1 severe leukopenia (transient)

10/10 9/10 9/10 9/10

tive effects on disease activity in ulcerative colitis and Crohn’s disease [77] and is currently tested in larger trials. Finally, Glitazones have been found to be effective in experimental colitis [78] as well as in pilot human studies [79], but larger trials are lacking. In spite of the performance of innumerable controlled trials leading to significant costs, no magic bullet has yet been revealed from the arsenal of ‘biologic therapy’ (table 9). Again and again initially positive pilot trials can not be confirmed in large pivotal studies. The latter are mostly negative or show biological but not clinically relevant effects which do not justify the significant costs of these treatment approaches [80]. Interestingly, the pluripotent immunosuppressants which have been used for years are probably more effective and do not have more side effects than the pathophysiologically based but in a redundant network easy to substitute mediator-targeted approaches. Treatments showing efficacy are either related to an elimination of activated immune cells such as TNF antibodies or anti-CD4 antibodies, or they modulate non-immune-associated signal cascades or wound healing such as growth factors. Therefore, it has to be concluded that the numerous development approaches have not led to the real target and it may be questionable if this will occur in the future [81]. For that reason it is important to realize that treatment with cyclophosphamide in refractory Crohn’s disease shows impressive success rates (table 10) [82]. Completely different approaches result from the analysis of the disturbed epithelial bacterial interaction in the intestinal tract. Induction of immunological tolerance aside from induction of apoptosis using, for example, DNA motifs of intestinal bacteria may be an interesting approach [83]. This relates to the effects of antibiotics [84] and probiotics [85] demonstrating that possibilities to influence this disturbed interaction exist.

than steroids themselves. These negative results were confirmed by another trial [75]. Interestingly, in this case in contrast to the other substances with negative confirmative study here already the pilot trial did not reveal positive results which did not deter the company from conducting further studies. Human growth hormone reduces intestinal permeability. A small trial in 37 patients demonstrated an impressive decrease of disease activity in Crohn’s disease [76]. The ‘anti-aging hormone’ DHEA as a sulfate also has posi-

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56 Gordon FH, Hamilton MI, Donoghue S, Amlot PL, Greenlees C, Rowley-Jones D, Pounder RE: Treatment of active ulcerative colitis with a recombinant humanised antibody to ·4 integrin (AntegrenTM ). Gastroenterology 1999; 116:A726. 57 Hesterberg PE, Winsor-Hines D, Briskin MJ, Soler-Ferran D, Merrill C, Mackay CR, Newman W, Ringler DJ: Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a gut-homing integrin ·4ß7. Gastroenterology 1996;111:1373–1380. 58 Feagan B, Greenberg G, Wild G, McDonald J, Fedorak R, Pare P, Kishimoto K, GuitterezRamos JC, Krop J, Vandervoort M: A randomized controlled trial of a humanized ·4ß7 antibody in ulcerative colitis. Gastroenterology 2003;125:606. 59 Feagan BG, Greenberg G, Wild G, McDonald JWD, Fedorak R, Pare P, Kishimoto K, Gutierrez-Ramos JC, Krop J: Efficacy and safety of a humanized ·4ß7 antibody in active Crohn’s disease. Gastroenterology 2003;124: A25–A26. 60 Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, Tami JA, Bennett CF, Kisner DL, Shanahan WR Jr: A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn’s disease. Gastroenterology 1998;114: 1133–1142. 61 Schreiber S, Nikolaus S, Malchow H, Kruis W, Lochs H, Raedler A, Hahn EG, Krummenerl T, Steinmann G: The German ICAM-1 Study Group. Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn’s disease. Gastroenterology 2001;120: 1339–1346. 62 Yacyshyn BR, Chey WY, Goff J, Salzberg B, Baerg R, Buchman AL, Tami J, Yu R, Gibiansky E, Shanahan WR: ISIS 2302-CS9. Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn’s disease. Gut 2002;51:30–36. 63 Sinha A, Nightingale J, West KP, BerlangaAcosta J, Playford RJ: Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 2003;349:350–357. 64 Sandborn WJ, Sands BE, Wolf DC, Valentine J, Safdi M, Katz S, Isaacs KL, Wruble LD, Katz JA, Present DH, Loftus EV Jr, Odenheimer DJ, Hanauer SB: Repifermin (keratinocyte growth factor 2) for the treatment of active ulcerative colitis: A randomized, double-blind, placebo-controlled, dose-escalation trial. Gastroenterology 2002;122:A61. 65 Hanauer SB, Baert FJ, Robinson M: Interferon treatment in mild to moderate active Crohn’s disease: Preliminary results in an open label study, Gastroenterology 1994;106:A696. 66 Madsen SM, Schlichting P, Davidsen B, Nielsen OH, Federspiel B, Riis P, Munkholm P: An open-labeled, randomized study comparing systemic interferon-alpha-2A and prednisolone enemas in the treatment of left-sided ulcerative colitis. Am J Gastroenterol 2001;96:1807– 1815.

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73 Vaughan D, Drumm B: Treatment of fistulas with granulocyte colony-stimulating factor in a patient with Crohn’s disease. N Engl J Med 1999;340:239–240. 74 Sands BE, Bank S, Sninsky CA, Robinson M, Katz S, Singleton JW, Miner PB, Safdi MA, Galandiuk S, Hanauer SB, Varilek GW, Buchman AL, Rodgers VD, Salzberg B, Cai B, Loewy J, De Bruin MF, Rogge H, Shapiro M, Schwertschlag US: Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn’s disease. Gastroenterology 1999;117:58–64. 75 Sands BE, Winston BD, Salzberg B, Safdi M, Barish C, Wruble L, Wilkins R, Shapiro M, Schwertschlag US: RHIL-11 Crohn’s Study Group. Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn’s disease. Aliment Pharmacol Ther 2002;16:399–406. 76 Slonim AE, Bulone L, Damore MB, Goldberg T, Wingertzahn MA, McKinley MJ: A preliminary study of growth hormone therapy for Crohn’s disease. N Engl J Med 2000;342:1633– 1637. 77 Andus T, Klebl F, Rogler G, Bregenzer N, Schölmerich J, Straub RH: Patients with refractory Crohn’s disease or ulcerative colitis respond to dehydroepiandrosterone (DHEA): A pilot study. Aliment Pharmacol Ther 2003; 17:409–414. 78 Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, Flanigan A, Murthy S, Lazar MA, Wu GD: A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammation response. J Clin Invest 1999;104:383–389.

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79 Lewis JD, Lichtenstein GR, Stein RB, Deren JJ, Judge TA, Fogt F, Furth EE, Demissie EJ, Hurd LB, Su CG, Keilbaugh SA, Lazar MA, Wu GD: An open-label trial of the PPARÁ ligand rosiglitazone for active ulcerative colitis. Am J Gastroenterol 2001;96:3323–3328. 80 Sandborn WJ, Targan SR: Biologic therapy of inflammatory bowel disease. Gastroenterology 2002;122:1592–1608. 81 Schölmerich J: Future developments in diagnosis and treatment of inflammatory bowel disease. Hepatogastroenterology 2000;47:101– 114. 82 Stallmach A, Wittig BM, Moser C, Fischinger J, Duchmann R, Zeitz M: Safety and efficacy of intravenous pulse cyclophosphamide in acute steroid refractory inflammatory bowel disease (IBD). Gut 2003;52:377–382. 83 Obermeier F, Dunger N, Deml L, Herfarth H, Schölmerich J, Falk W: CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur J Immunol 2002;32: 2084–2092. 84 Rutgeerts P, Van Assche G, D’Haens G, Baert F, Noman M, Aerden I, Geboes K, D’Hoore A, Penninckx F: Ornidazole for prophylaxis of postoperative Crohn’s disease: Final results of a double blind placebo controlled trial. Gastoenterology 2002;122:A80. 85 Kruis W, Fric P, Stolte M: The Mutaflor Study Group. Maintenance of remission in ulcerative colitis is equally effective with Escherichia coli Nissle 1917 and with standard mesalamine. Gastroenterology 2001;120:A127.

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Author Index Vol. 21, No. 2, 2003

Amadini, C. 157 Campieri, M. 157 Gasche, C. 146 Gionchetti, P. 157 Gölder, S. 129 Habal, F. 157 Herfarth, H. 129 Huber, G. 180 McLeod, R.S. 168 Miehsler, W. 146 Morselli, C. 157

Peña, A.S. 85 Rath, H.C. 105 Reinshagen, M. 138 Rizzello, F. 157 Romagnoli, R. 157 Schölmerich, J. 83, 105, 180 Schreyer, A.G. 129 Schultz, M. 105 Seitz, J. 129 Timmer, A. 91 Tirpitz, C. von 138

Subject Index Vol. 21, No. 2, 2003

5-Aminosaliyclic acid 157 Antibiotics 105 Anti-sense 180 Azathioprine 146 Budesonide 146 Candidate gene approach 85 Capsule endoscopy 129 Crohn’s disease 85, 129, 138, 146, 168, 180 Cyclosporine 157 Cytokines 180 Enteroscopy 129 Epidemiology 91 Genetic epidemiology 85 Genetics 85 Genome-wide screening 85 Growth factors 180 Immunosuppressors 157 Inflammatory bowel disease 85, 91, 105, 129, 138, 168

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Infliximab 146, 157 Magnetic resonance imaging 129 6-Mercaptopurine 146 Mesalamine 146 Methotrexate 146 Metronidazole 146 Osteoporosis 138 Prednisolone 146 Probiotics 105 Risk factors 91 Surgery 168 T lymphocytes 180 Topical steroids 157 Tumor necrosis factor-· 180 Ulcerative colitis 85, 157, 168, 180 Virtual endoscopy 129