Therapy of Crohn's Disease: Digestion

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Therapy of Crohn’s Disease

Guest Editor

Pierre Michetti, Lausanne

1 table, 2005

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

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

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 2005 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7931–4

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

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Vol. 71, No. 1, 2005

Contents

Preface 5 Special Topic Issue Devoted to the Management

of Crohn’s Disease Beglinger, C. (Basle); Goeke, B. (Munich)

Introduction 6 The European Panel on the Appropriateness of

Crohn’s Disease Therapy Caprilli, R. (Rome); Michetti, P. (Lausanne)

26 Fistulizing Crohn’s Disease Felley, C.; Mottet, C.; Juillerat, P. (Lausanne); Froehlich, F. (Lausanne/Basle); Burnand, B.; Vader, J.-P.; Michetti, P.; Gonvers, J.-J. (Lausanne) 29 Obstructive Fibrostenotic Crohn’s Disease Froehlich, F. (Lausanne/Basle); Juillerat, P.; Mottet, C.; Felley, C.; Vader, J.-P.; Burnand, B.; Gonvers, J.-J.; Michetti, P. (Lausanne) 31 Extraintestinal Manifestations of Crohn’s Disease Juillerat, P.; Mottet, C. (Lausanne); Froehlich, F. (Lausanne/ Basle); Felley, C.; Vader, J.-P.; Burnand, B.; Gonvers, J.-J.; Michetti, P. (Lausanne) 37 Treatment of Gastroduodenal Crohn’s Disease Mottet, C.; Juillerat, P.; Gonvers, J.-J.; Michetti, P.; Burnand, B.; Vader, J.-P.; Felley, C. (Lausanne); Froehlich, F. (Lausanne/Basle)

Reviews 8 Drug Safety in the Treatment of Crohn’s Disease Juillerat, P.; Felley, C.; Mottet, C. (Lausanne); Froehlich, F. (Lausanne/Basle); Vader, J.-P.; Burnand, B.; Gonvers, J.-J.; Michetti, P. (Lausanne) 13 Therapy of Mild to Moderate Luminal Crohn’s

Disease Michetti, P.; Juillerat, P.; Mottet, C.; Gonvers, J.-J.; Burnand, B.; Vader, J.-P. (Lausanne); Froehlich, F. (Lausanne/Basle); Felley, C. (Lausanne) 19 Severe and Steroid-Resistant Crohn’s Disease Michetti, P.; Mottet, C.; Juillerat, P.; Felley, C.; Vader, J.-P.; Burnand, B.; Gonvers, J.-J. (Lausanne); Froehlich, F. (Lausanne/Basle)

41 Maintenance of Remission in Crohn’s Disease Gonvers, J.-J.; Juillerat, P.; Mottet, C.; Felley, C.; Burnand, B.; Vader, J.-P.; Michetti, P. (Lausanne); Froehlich, F. (Lausanne/ Basle) 49 Treatment of Postoperative Crohn’s Disease Froehlich, F. (Lausanne/Basle); Juillerat, P.; Felley, C.; Mottet, C.; Vader, J.-P.; Burnand, B.; Michetti, P.; Gonvers, J.-J. (Lausanne) 54 Pregnancy and Crohn’s Disease Mottet, C.; Juillerat, P.; Gonvers, J.-J. (Lausanne); Froehlich, F. (Lausanne/Basle); Burnand, B.; Vader, J.-P.; Michetti, P.; Felley, C. (Lausanne)

62 Author and Subject Index

© 2005 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/dig_issues

18.03.2005 15:36:59

Preface Digestion 2005;71:5 DOI: 10.1159/000084138

Published online: February 23, 2005

Special Topic Issue Devoted to the Management of Crohn’s Disease

Due to the ever-expanding progress in several disciplines that cannot be confined to a single review article on the management of Crohn’s disease, it has become difficult to keep track of the different developments. What is standard of care? What is evidence-based? Where do we lack enough information? The main issue for physicians and patients at present is therefore the decision for the best management choice. The editors of Digestion were therefore happy that Pierre Michetti accepted to act as a Guest Editor for a special topic issue presenting in a coordinated set of short review articles the different aspects of managing patients with Crohn’s disease. Pierre Michetti was a member of the organisation of a panel which assessed the various strategies in the different areas of Crohn’s disease using the RAND-UCLA appropriateness method. All articles were reviewed by at least nine experts. Very few other areas of gastroenterology have experienced the type of rapid growth in terms of understanding disease pathogenesis, genetic predisposition and, most importantly, translation to novel approaches to therapy, as has been witnessed in Crohn’s disease. This issue provides valuable short reviews on the current state of the art for the different clinical aspects of managing Crohn’s disease patients, with particular attention being paid to the most recent literature. These reviews should be of immediate benefit to the practicing physician. Christoph Beglinger, Basel Burkhart Goeke, Munich February 2005

© 2005 S. Karger AG, Basel 0012–2823/05/0711–0005$22.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/dig

Introduction Digestion 2005;71:6–7 DOI: 10.1159/000083864


The European Panel on the Appropriateness of Crohn’s Disease Therapy Renzo Caprillia Pierre Michettib a b

Gastrointestinal Unit, Department of Clinical Science, University of Rome La Sapienza, Rome, Italy, and Division of Gastroenterology and Hepatology, Lausanne University Medical Center, Lausanne, Switzerland

The management of Crohn’s disease (CD) remains a challenge for the practicing physician, as high-grade evidence is lacking for many therapeutic decisions in clinical practice. In addition, where information from randomized clinical trials is available, it may be difficult to translate it for the care of an individual patient. The arrival in the armamentarium of novel biological therapies, exemplified by the case of infliximab, has further increased the complexity of therapeutical decision-making in CD. Indeed, while high-quality evidence established the high benefit/risk ratio of this compound in selected patient groups [1], the lack of comparative studies between this novel drug and more classical therapies is a limitation in the design of evidence-based treatment strategies. In such circumstances, the development of criteria to assess the appropriateness of therapeutical options has the potential to assist clinicians in their practical decision-making. To develop those criteria, however, validated and well-accepted methods should be used. The RAND Appropriateness Method (RAM), which integrates a systematic review of the medical literature with personal experience of experts in the field, is a well-accepted method to define appropriateness and necessity criteria of medical care [2]. This approach is designed not to create evidence but to bridge gaps in our knowledge in areas where high-grade evidence is lacking. Appropriateness criteria may serve as a basis for guidelines concerning



therapy and to assist individual clinicians in their treatment choices. This second goal may be facilitated by making the criteria interactive thanks to the information technology and the Internet. Furthermore, appropriateness and necessity criteria may be applied to patient databases in outcome research projects, to evaluate the appropriate use as well as the overuse and underuse of the various strategies defined by the criteria. The RAM has been used successfully in many areas of medicine, including gastroenterology. In this field, appropriateness and necessity criteria were developed for upper and lower gastrointestinal diagnostic endoscopies [3, 4]. The application of these criteria to patient databases revealed that the overuse of these procedures was as prevalent as their underuse, indicating that better resource utilization may result from the use of such criteria, without overall increase in costs [5]. The RAM approach has also recently been used to develop guidelines for the appropriate use of anti-inflammatory drugs, COX-2 inhibitors and proton pump inhibitors in patients requiring chronic anti-inflammatory therapy [6]. Practically the RAM requires specific procedural steps [7]. The first step is a systematic and critical review of the literature, with a grading of the quality of the evidence according to preset criteria. Based on this review, clinical situations, or scenarios, are derived. The literature review and the clinical scenarios are then submitted to a panel

Prof. Pierre Michetti Division of Gastroenterology and Hepatology Lausanne University Medical Center Rue du Bugnon 46, CH–1011 Lausanne (Switzerland) Tel. +41 21 314 0690, Fax +41 21 314 0707, E-Mail [email protected]

of representative experts. These experts comment the literature review and perform a first rating of the appropriateness of each of the proposed clinical scenarios. After their comments are integrated, final literature documents and clinical scenarios are prepared and a second expert rating takes place after extensive discussion during a formal meeting of the expert panel. The European Panel on the Appropriateness of Crohn’s Disease Therapy (EPACT) has been organized with the aim to apply the RAM approach to the treatment of CD, and performed under the auspices of the European Crohn’s and Colitis Organisation (ECCO). ECCO is an organization that includes most of the European IBD Study Groups. The main aim of ECCO is to promote and coordinate international research and education in the field of IBD. ECCO recognized the need for guidelines in the therapy of CD and its role in fostering research in this area in Europe. The panel brought together was thus mainly composed of national ECCO representatives (11 ECCO members out of 15 experts) complemented by surgeons and general practitioners. As ECCO members are

elected by their respective national gastroenterological societies, this approach fulfilled the RAM claim for representative experts. The collaboration with ECCO is further valuable as the criteria defined by this panel, which convened in March 2004 in Lausanne, Switzerland, will need regular updates. The ongoing collaboration with ECCO is likely to facilitate greatly the continuation of this work. In this issue of Digestion the literature review produced for the purpose of the EPACT panel is presented. This literature review has been evaluated in depth by the 15 experts participating in the panel, resulting in substantial improvements of these reviews, further highlighting the prominent role played by ECCO in the whole EPACT endeavor. These reviews have been assembled by going back to each original publication in the treatment of CD, with the attention centered on reporting the original data with as a little interpretation as possible. In that sense they may provide an opportunity for the reader to remember the data associated with evidence-based therapy of CD.

References 1 Rutgeerts P, Van Assche G, Vermeire S: Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology 2004; 126: 1593–1610. 2 Naylor CD: What is appropriate care? N Engl J Med 1998;338:1918–1920. 3 Seematter-Bagnoud L, Vader JP, Wietlisbach V, Froehlich F, Gonvers JJ, Burnand B: Overuse and underuse of diagnostic upper gastrointestinal endoscopy in various clinical settings. Int J Qual Health Care 1999;11:301–308.

The European Panel on the Appropriateness of CD Therapy

4 Vader JP, Pache I, Froehlich F, Burnand B, Schneider C, Dubois RW, Brook RH, Gonvers JJ: Overuse and underuse of colonoscopy in a European primary care setting. Gastrointest Endosc 2000;52: 593–599. 5 Froehlich F, Pache I, Burnand B, Vader JP, Fried M, Kosecoff J, Kolodny M, DuBois RW, Brook RH, Gonvers JJ: Underutilization of upper gastrointestinal endoscopy. Gastroenterology 1997;112:690–697.

6 Dubois RW, Melmed GY, Henning JM, Laine L: Guidelines for the appropriate use of nonsteroidal anti-inflammatory drugs, cyclo-oxygenase-2-specific inhibitors and proton pump inhibitors in patients requiring chronic antiinflammatory therapy. Aliment Pharmacol Ther 2004;19:197–208. 7 Brook RH, Chassin MR, Fink A, Salomon DH, Kosecoff J, Park RE: A method for the detailed assessment of the appropriateness of medical technologies. Int J Technol Assess Health Care 1986; 2:53–63.

Digestion 2005;71:6–7

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Review Digestion 2005;71:8–12 DOI: 10.1159/000083865


Drug Safety in the Treatment of Crohn’s Disease Pascal Juillerata Christian Felleya Christian Motteta Florian Froehlicha, b John-Paul Vaderc Bernard Burnandc Jean-Jacques Gonversa Pierre Michettia a

Division of Gastroenterology and Hepatology, Lausanne University Medical Center, Lausanne; Gastrointestinal Department, University of Basle, Basle, and c Institute of Social and Preventive Medicine, University of Lausanne, Lausanne, Switzerland b

Key Words Crohn’s disease Inflammatory bowel disease Crohn’s disease, treatment Drugs, safety Treatment adverse events Drug toxicity Immunosuppression

Abstract The management of Crohn’s disease usually consists of a succession of short-term acute phase treatments followed by long-term maintenance therapy. The disease affects young patients and for this reason the long-term safety of the drugs needs to be especially taken into consideration. The safety, dose, duration for optimal efficacy and the most frequent adverse events will be described in this article. Copyright © 2005 S. Karger AG, Basel

(budesonide, prednisone and equivalents), thiopurine (azathioprine and 6-mercaptopurine), methotrexate, infliximab, cyclosporine, tacrolimus and mycophenolate mofetil.

Definitions

5-ASA Mesalamine 3.2–4 g/day or sulfasalazine 3–6 g in splitdose daily treatment with one of the following for at least 2–4 weeks [1]. Antibiotics Metronidazole 10–20 mg/kg/day or ciprofloxacine 1,000–2,000 mg/day or both in daily treatment with one of the following for at least 6–8 weeks with clinical improvement or healing.

Introduction

Among the many drugs that have been used for shortor long-term therapy of Crohn’s disease, only a limited number have been studied precisely in large groups of patients with a similar presentation of the disease. This group of drugs includes 5-ASA compounds, antibiotics (metronidazole and ciprofloxacine), corticosteroids



Corticosteroids Prednisone 40–60 mg (1–1.5 mg/kg/day) or equivalent, or budesonide 9 mg/day for at least 2 weeks with complete or partial clinical response and no regression of clinical symptoms 30 days after corticosteroid treatment was completed [2].

Pierre Michetti, MD Division of Gastroenterology and Hepatology Lausanne University Medical Center Rue du Bugnon 46, CH–1011 Lausanne (Switzerland) Tel. +41 21 3140690, Fax +41 21 3140707, E-Mail [email protected]

Immunosuppressive Therapy Azathioprine 2–2.5 mg/kg/day or 6-mercaptopurine 1–1.5 mg/kg/day treatment with one of the following for at least 2 months with clinical improvement or healing. Methotrexate Methotrexate 10–25 mg/week treatment for at least 2 months with clinical improvement or healing. Infliximab Infliximab 5–10 mg/kg/day treatment at weeks 0, 2 and 6 with clinical improvement or healing, then as maintenance therapy on a symptom-directed or a fixed (every 8 weeks) schedule. Cyclosporine Cyclosporine 2–4 mg/kg/day intravenously or 5–8 mg/ kg/day orally, treatment for at least 2 months with clinical improvement or healing evident after 2 weeks [3, 4]. The drug should not be continued for more than 3–6 months and its main role is as a bridge to azathioprine or 6-mercaptopurine. Tacrolimus Tacrolimus 0.01–0.02 mg/kg/day intravenously for !7 days and then as an oral treatment of 0.1–0.2 mg/kg/day b.i.d. for at least 6 weeks with clinical improvement or healing [5, 6]. Mycophenolate Mofetil Mycophenolate mofetil 0.75–2 g/day or 15 mg/kg/day treatment with clinical improvement or healing [7–9].

Treatment Adverse Events

5-ASA Group Sulfasalazine dose-related side effects, attributed to the sulfapyridine moiety, occur in up to 50% of patients (acetylator status-dependent) and include nausea, abdominal pain and headache. These side effects are often transient, or may be eliminated by dose reduction. Their incidence can also be reduced by gradual dose increase. The other 5-ASA preparations (mesalazine, olsalazine and balsalazide), which lack the sulfapyridine moiety, were purposely developed to avoid such side effects, and are better tolerated than sulfasalazine [10]. Idiosyncratic reactions (= sulfasalazine intolerance), such as nausea, diarrhea and skin rash, occur in about 15% of patients and resolve on drug withdrawal. Many

Drug Safety in the Treatment of Crohn’s Disease

studies report on mesalamine-induced thrombopenia described within the first 3 months of therapy and after reintroduction of this drug indicate an idiosyncratic hypersensitivity reaction [11]. Episodes of nephrotoxicity have been associated with the use of aminosalicylates [12], but seem to be very rare, whereas impairment of male fertility is well documented, and is mainly due to the sulfasalazine moiety [13]. Other adverse events, judged as probably or possibly related to prolonged-release mesalazine treatment include: pancreatitis, pericarditis/myocarditis, elevated liver enzyme levels, diarrhea, and thrombocytopenia [14]. Metronidazole Common adverse events associated with metronidazole include nausea, a metallic taste in the mouth, and coating of the tongue. Peripheral neuropathy, which manifests as distal paraesthesia, can occur with prolonged administration. When taken with alcohol, a disulfiram-like reaction has been described with high dosages of metronidazole [15]. Ciprofloxacine No serious adverse events have been reported in the IBD literature [15]. Quinolones are well tolerated overall, the most common adverse reaction reported during therapy with fluoroquinolone being taste disturbance, gastrointestinal adverse events, CNS reactions such as dizziness and light-headedness in a considerable proportion of patients. Phototoxicity has been described for all quinolones. Juveniles are especially sensitive to chondrotoxicity of quinolones, and the indication for treatment should thus be highly selective in this age group. Other manifestations of the toxic effects of quinolones on connective tissue structures are tendopathies. Tendinitis and tendon rupture have occurred as late as several months after quinolone treatment was terminated. Corticosteroids Many adverse effects have been reported, including weight gain, fluid retention, glucose intolerance, hypertension, proximal myopathy, infections, mood changes, glaucoma, various skin changes, adrenal suppression and growth retardation in children. Significant long-term complications include osteoporosis, cataracts, aseptic bone necrosis [10, 16, 17]. Azathioprine/6-Mercaptopurine Side effects that limit AZA/6-MP use, mostly within the first 3–4 weeks, occur in 10–25% of patients and may


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be dose-dependent or idiosyncratic and may also be considered as major (leukopenia, pancreatitis, infection) or minor (skin rash, nausea, fever, arthralgia, malaise and diarrhea) side effects [18–20]. Bone marrow suppression is dose-related and may be delayed. At the start of azathioprine or mercaptopurine therapy, measurement of TPMT (thiopurine methyltransferase) activity, which is under the control of a genetic polymorphism, is suggested. This status warns of early bone marrow toxicity, leading to the identification of patients who are at risk of early leukopenic episodes, particularly during the initial 4 months of therapy. Only 1 in 300 patients develops severe myelosuppression when treated with standard thiopurine dosages and there is no evidence to suggest a specific role for the measurement of TPMT activity in the management of patients already established on azathioprine/mercaptopurine immunosuppression [21]. In this case, to determine the efficacy of the immunosuppressive therapy, an erythrocyte 6-TG level 1235 pmol was determined as highly correlated with clinical response by Dubinsky et al. [22]. A drug interaction between azathioprine and aminosalicylates, through a mechanism which remains unclear, has been described. This should be taken into account when using azathioprine and aminosalicylates simultaneously [23]. Asymptomatic leukopenia may be treated by dose reduction or drug cessation, whereas a life-threatening leukopenic episode may respond to granulocyte colony-stimulating factor. Bone marrow suppression may occur at any time during treatment and continual monitoring is recommended. There are reports of long-term AZA treatment culminating in chronic liver disease and portal hypertension. Side effects may be minimized with adequate monitoring by full blood count and liver enzyme tests [18]. The frequency of other major side effects in a large cohort has been reported as follows: pancreatitis (3–15%) [15] and infectious complications (7.4%) [24]. The main argument against longer treatment duration is the longterm risk of malignancy. Connell et al. [25] did not observe any increase in the risk of malignancy in 755 patients with inflammatory bowel disease followed for a median of 9 years from the start of azathioprine treatment. Methotrexate Manifestation of early toxicity during methotrexate therapy is primarily gastrointestinal (nausea, abdominal pain, diarrhea and stomatitis) and this is due to its antiproliferative activity. Folate supplements can decrease the gastrointestinal side effects without any decrease in

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therapeutic efficacy. Pancytopenia has been reported in 1–2% of patients, but may be less frequent with the routine use of folate supplements [26]. Methotrexate should not be prescribed to women of child-bearing age because of the risk of teratogenicity [27]. The initial clinical experience with low-dose methotrexate was in patients with psoriasis. Liver fibrosis was observed in a significant number of patients, but liver disease in methotrexate-treated rheumatoid arthritis appeared to be much less frequent [28]. Asymptomatic transaminase elevation is not considered as reflecting or predictive of existing or future hepatic disease [29]. Surveillance liver biopsies, based on cumulative dose, do not appear to be warranted. Pneumonitis has rarely been reported in series of inflammatory bowel disease patients. The risk of malignancy as a complication of methotrexate monotherapy is thought to be low or absent, and opportunistic infections are rare [30]. Infliximab Overall the commonest adverse events following treatment with infliximab are nausea, headache, abdominal pain and upper respiratory tract infections, particularly sinusitis. Another group of common complications are immediate infusion reactions, which occur in 4.8–23% of patients, but are generally mild. Early infusion reactions generally consist of urticaria, skin erythema and sweating. In 0.5% of cases more serious consequences include bronchospasm and stridor. Delayed infusion reactions consist of myalgia, arthralgia, skin rash and malaise [18, 31]. Infections requiring antimicrobial agents are seen in 32% of patients, but severe infection in only 4%. Opportunistic infections, particularly tuberculosis reactivation, have been described within the first 3 months after initiation of therapy, leading to recommendations for tuberculosis screening (PPD skin test and chest X-ray) prior to infliximab treatment [32]. A few deaths occurred following infliximab therapy, not all fully explained. Infliximab therapy can result in the formation of antibodies against infliximab. The incidence did not increase further with repeated infusions and was measured at 61% by Baert et al. [33] in a cohort with 125 patients treated with infliximab. This immunogenicity is associated with an increased risk of infusion reactions and a reduced duration of response to treatment. Immunosuppressed patients show a reduced level of antibodies, that can also be obtained by a single dose of 200 mg of hydrocortisone just before the infusion [34].

Juillerat/Felley/Mottet/Froehlich/Vader/ Burnand/Gonvers/Michetti

Cyclosporine Major complications are reported with a frequency of 0–17%, including renal, infectious and neurotoxic effects. Mild, reversible renal impairment in colitis patients treated with cyclosporine is common, and leads to hypertension. There are only isolated reports of serious acute or chronic renal failure or hemolytic-uremic syndrome. In small case series, abnormal liver function, gingival hyperplasia and hirsutism are described as well as minor neurotoxic side effects such as tremor, burning paraesthesia, headache, blurred vision and malaise. More serious side effects include seizure, coma, spasticity, ataxia, and various other side effects [35, 36]. The profound immunosuppressive effects of cyclosporine result in a significant risk of infection. The risk is dose-dependent and compounded by co-treatment with corticosteroids, and the general condition of the patient. Infections complications reported include opportunistic pathogens. The risk of toxicity can be reduced by using lower doses (2 mg/kg/day intravenously), by oral microemulsion cyclosporine, or by monotherapy without corticosteroids [37]. Pneumocystis prophylaxis with co-trimoxazole should be considered if patients are also on high-dose corticosteroids and/or azathioprine/6-mercaptopurine. Tacrolimus Tacrolimus (previously known as FK506) has an adverse event profile similar to that of cyclosporine: nausea,

disturbance of glucose metabolism, hypercholesterolemia, paresthesia, tremor, increased risk of infection and nephrotoxicity, leading to hypertension. The risk of the latter is largely determined by higher initial doses [6, 15, 38, 39]. Mycophenolate Mofetil Small open studies (no RCT) have used mycophenolate mofetil in highly refractory Crohn’s disease, with modest toxicity being observed. The most reported adverse events were headache, nausea, abdominal pain, arthralgia, pancreatitis, toxidermia and an atypical druginduced colitis [8, 39, 40]. Mycophenolate does not induce bone suppression, but has rarely been reported to cause neutropenia, and has been associated with opportunistic infections [15].

Conclusions

The safety and tolerance of medication should be considered as part of the therapeutic decision. Clinicians use a risk-benefit model to evaluate the appropriateness of the treatment. The RAND method mimics such a decision process. The adverse events of any medication must thus be carefully evaluated before treatment is begun and then closely watched. Many groups are trying to establish guidelines, but when evidence is limited because of controversial data, expert opinion is of prime interest.

References 1 Gisbert JP, et al: Role of 5-aminosalicylic acid in treatment of inflammatory bowel disease: A systematic review. Dig Dis Sci 2002; 47: 471– 488. 2 Rutgeerts P, et al: A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med 1994;331:842–845. 3 Brynskov J, et al: A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn’s disease. N Engl J Med 1989;321:845–850. 4 Hanauer SB, Smith MB: Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993;88:646–649. 5 Ierardi E, et al: Oral tacrolimus long-term therapy in patients with Crohn’s disease and steroid resistance. Aliment Pharmacol Ther 2001; 15:371–377.

Drug Safety in the Treatment of Crohn’s Disease

6 Fellermann K, et al: Steroid-unresponsive acute attacks of inflammatory bowel disease: Immunomodulation by tacrolimus (FK506). Am J Gastroenterol 1998;93: 1860–1866. 7 Hafraoui S, et al: Mycophenolate mofetil in refractory Crohn’s disease after failure of treatments by azathioprine or methotrexate. Gastroenterol Clin Biol 2002;26:17–22. 8 Skelly MM, et al: Toxicity of mycophenolate mofetil in patients with inflammatory bowel disease. Inflamm Bowel Dis 2002;8:93–97. 9 Neurath MF, et al: Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut 1999;44:625–628. 10 Cunliffe RN, Scott BB: Monitoring for drug side-effects in inflammatory bowel disease. Aliment Pharmacol Ther 2002;16:647–662. 11 Bhidayasiri R, Katz JA, Sokos DR: Correction of mesalazine-induced neutropenia with high dose G-CSF. Am J Gastroenterol 2000; 95: 3321–3322.


12 Clemett D, Markham A: Prolonged-release mesalazine: A review of its therapeutic potential in ulcerative colitis and Crohn’s disease. Drugs 2000; 59:929–956. 13 Birnie GG, McLeod TIF, Watkinson G: Incidence of sulfasalazine-induced male infertility. Gut 1981;22:452–455. 14 Marteau P, et al: Adverse events in patients treated with 5-aminosalicyclic acid: 1993– 1994 pharmacovigilance report for Pentasa in France. Aliment Pharmacol Ther 1996; 10: 949–956. 15 Stein RB, Hanauer SB: Comparative tolerability of treatments for inflammatory bowel disease. Drug Saf 2000; 23:429–448. 16 Steinhart A: Corticosteroids for maintaining remission of Crohn’s disease. Update Software. Oxford, The Cochrane Library, 1999. 17 Rutgeerts PJ: The limitations of corticosteroid therapy in Crohn’s disease. Aliment Pharmacol Ther 2001; 15:1515–1525.

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18 Arnott IDR, Watts D, Satsangi J: Azathioprine and anti-TNF- therapies in Crohn’s disease: A review of pharmacology, clinical efficacy and safety. Pharmacol Res 2003;47: 1–10. 19 Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C: Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease (Cochrane review). Update Software. Oxford, The Cochrane Library, 2003. 20 Marion JF: Toxicity of 6-mercaptopurine/azathioprine in patients with inflammatory bowel disease. Inflamm Bowel Dis 1998;4:116–117. 21 Lennard L: TPMT in the treatment of Crohn’s disease with azathioprine. Gut 2002; 51: 143– 146. 22 Dubinsky M, et al: Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;118:705–713. 23 Dewit O, et al: Interaction between azathioprine and aminosalicylates: An in vivo study in patients with Crohn’s disease. Aliment Pharmacol Ther 2002;16: 79–85. 24 Present DH, et al: 6-Mercaptopurine in the management of inflammatory bowel disease: Short- and long-term toxicity. Ann Intern Med 1989;111:641–649.

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25 Connell WR, et al: Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343:1249–1252. 26 Fraser AG, et al: The efficacy of methotrexate for maintaining remission in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16:693–697. 27 Kozlowski RD, et al: Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990;88: 589–592. 28 Whiting-O’Keefe QE, Fye KH, Sack KD: Methotrexate and histologic hepatic abnormalities: A meta-analysis. Am J Med 1991;90: 711–716. 29 Alfadhli AAF MJ, Feagan BG: Methotrexate for induction of remission in refractory Crohn’s disease (Cochrane Review). Update Software. Oxford, The Cochrane Library, 2003. 30 Fraser AG: Methotrexate: First-line or secondline immunomodulator? Eur J Gastroenterol Hepatol 2003;15:225–231. 31 Hanauer SB: Safety of infliximab in clinical trials. Aliment Pharmacol Ther 1999; 13(suppl 4):16–38. 32 Braun J, Sieper J: Overview of the use of the anti-TNF agent infliximab in chronic inflammatory diseases. Expert Opin Biol Ther 2003; 3:141–168.

33 Baert F, et al: Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601–608. 34 Farrell R, et al: Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: A randomized controlled trial. Gastroenterology 2003; 124:917– 924. 35 Haslam N, Hearing SD, Probert CS: Audit of cyclosporin use in inflammatory bowel disease: Limited benefits, numerous side effects. Eur J Gastroenterol Hepatol 2000;12:657–660. 36 Humphreys TR, Leyden JJ: Acute reversible central nervous system toxicity associated with low-dose oral cyclosporine therapy. J Am Acad Dermatol 1993; 29:490–492. 37 Hawthorne AB: Cyclosporin and refractory colitis. Eur J Gastroenterol Hepatol 2003; 15: 239–244. 38 Scott LJ, et al: Tacrolimus, a further update of its use in the management of organ transplantation. Drugs 2003;63: 1247–1297. 39 Forbes A: Alternative immunomodulators. Eur J Gastroenterol Hepatol 2003; 15: 245– 248. 40 Fellermann K, et al: Mycophenolate mofetil: Lack of efficacy in chronic active inflammatory bowel disease. Aliment Pharmacol Ther 2000; 14:171–176.

Juillerat/Felley/Mottet/Froehlich/Vader/ Burnand/Gonvers/Michetti



Therapy of Mild to Moderate Luminal Crohn’s Disease Pierre Michettia Pascal Juillerata Christian Motteta Jean-Jacques Gonversa Bernard Burnandc John-Paul Vaderc Florian Froehlicha, b Christian Felleya a


Key Words Crohn’s disease, review Crohn’s disease, therapy Aminosalicylates Steroids Azathioprine Methotrexate Infliximab

Abstract The management of luminal Crohn’s disease, the most common form of initial presentation of the disease, depends on the location and the severity of the lesions. Mild to moderate disease represents a relatively large proportion of patients with a first flare of luminal disease, which may also be associated with perianal disease. As quality of life of these patients correlates with disease activity, adequate therapy is a central goal of the overall patient management. Treatment options include mainly sulfasalazine, budesonide and systemic steroids, while the role of mesalazine and antibiotics remains controversial. The role of biological therapies in mild to moderate disease has not been thoroughly evaluated and will not be discussed here. Copyright © 2005 S. Karger AG, Basel



Introduction

Several drugs have been evaluated for the treatment of luminal Crohn’s disease (CD), the classical form of the disease. Therapeutic recommendations depend upon the disease location, severity, and complications. A step-up approach still prevails, as no drug will be effective in all patients and because milder forms of therapy usually also present a better side effect profile than stronger medications. The delay between the initiation of a therapy and its onset of action can vary from a few days to several months, further modifying the approach. Prevalence and Incidence In a large population-based study throughout Europe (The European Collaborative Study on Inflammatory Bowel Disease – EC-IBD), the overall incidence per 100,000 at ages 15–64 years (standardized for age and sex) of CD was 5.6 (95% CI 2.8–8.3). Rates of CD in northern countries were 80% higher than those of the south (RR = 1.8 (95% CI 1.5–2.1)). The prevalence of CD in North America ranges from 26.0 to 198.5 cases per 100,000 persons. The incidence rates range from 3.1 to 14.6 cases per 100,000 person-years [1]. Luminal CD is the most common form of initial presentation of the dis-


ease. The disease involves the small intestine only (most frequently the terminal ileum) in 35–40% of the cases, the ileum and the colon in 40–45% of cases, and the colon alone in 25% of cases. Upper gastrointestinal involvement is rare (5%). One-third of patients have perianal disease associated with another location. In addition, most patients with fistulous disease also present some luminal disease. The incidence of CD tends to increase in Southern Europe. Natural History Most patients with luminal CD have a chronic intermittent disease course, while 13% have an unremitting disease course and 10% have a prolonged remission [1]. Disease location is most often stable over time. Over 10 years, only 15.9% of 297 patients had a change in disease location [2]. In the same cohort, disease behavior, however, evolved in a substantial proportion of patients, to either stricturing (27%) or penetrating disease (29%), regardless of age at diagnosis or disease location. Ileal CD evolved more often towards the stricturing pattern, and colonic or ileocolonic CD more often towards penetrating disease. In 163 patients followed for 5 years, a high number of flares was associated with a penetrating pattern, observed in 22% of the patients studied [3]. Active smoking was also associated with a penetrating pattern compared with a non-stricturing non-penetrating pattern only. Despite therapy, complete relief is achieved only in a proportion of patients. In the EC-IBD study, therapy provided complete relief of complaints in 35% of the patients, while a further 45% of patients improved. CD-related death may occur, estimated at around 0.4% in Europe [4]. Quality of Life In a recent analysis of 22 studies extracted from 258 articles, CD patients were found to experience a poorer quality of life than ulcerative colitis patients or healthy controls [5]. Their health status was similar or worse than in many other chronic medical conditions. The healthrelated quality of life was directly correlated with CD activity, and was worse in active disease than in remission, underlying the importance of adequate therapy. The health-related quality of life was improved only in the short term in surgically vs. medically treated CD patients. The presence of psychological disorders (especially anxiety and depression) in CD patients may contribute to poor health-related quality of life, regardless of the severity of the condition, a factor that should be appreciated when taking care of these patients [6].

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Management

The therapy choices for luminal CD depends mainly on disease severity and resistance to prior therapies. Disease severity is usually based on the criteria established by the American College of Gastroenterology [7]. According to these criteria, mild to moderate disease can be defined as ambulatory patients able to tolerate oral alimentation without manifestations of dehydration, toxicity, abdominal tenderness, painful mass, obstruction, or 110% weight loss. Patients in this category but resistant to first-line therapies, including steroids, are to be considered presenting with severe disease. The review below will thus consider first-line treatment options as therapies for mild to moderate disease, and second-line treatment options, therapies indicated for severe disease. An evidence-based approach of the literature is privileged.

First-Line Treatment Options

Evidence Aminosalicylates Sulfasalazine (SFS) The efficacy of SFS has been compared to placebo or to steroids in several controlled trials. In the large US national cooperative trial, Summers et al. [8] compared SFS 1 g/15 kg to prednisone 0.25–0.75 mg/kg, azathioprine, and placebo. After 17 weeks, SFS was found superior to placebo (43 vs. 30%) and to azathioprine (40%), but not to prednisone (60%) in inducing remission. Subgroup analysis suggested that patients previously treated with prednisone failed to respond to SFS, and that patients with disease limited to the colon were the most likely to benefit from SFS. In a similar European study, Malchow et al. [9] randomized patients to SFS, 6-methylprednisolone, both drugs, or placebo. SFS was the least effective as compared to placebo (50 vs. 34%), while methylprednisolone was the most effective regimen (83%). Combination therapy (76%) was not superior to methylprednisolone alone. Steroid therapy was superior in subgroup analysis in patients with small bowel involvement or prior steroid therapy. Other smaller trials have confirmed that SFS 3–6 g/day is superior to placebo in mild to moderate CD [10, 11]. In other well-designed studies, SFS showed no adjunctive effect on prednisone and no steroid-sparing effect [12], while prednisone has an adjunctive effect on SFS [13]. In one uncontrolled retrospective analysis, Goldstein et al. [14] estimated that about 25%

Michetti/Juillerat/Mottet/Gonvers/ Burnand/Vader/Froehlich/Felley

of patients with disease limited to the small bowel benefit from long-term SFS therapy. Mesalamine Mesalamine was compared to placebo in six randomized, double-blind trials in patients with mild to moderate CD. The two first studies investigated 1.5 g of mesalamine (Pentasa, corresponding to 3 g of SFS), given for 16 or 6 weeks, respectively [15, 16]. The authors observed no benefit of mesalamine over placebo (40 vs. 30 or 35%, respectively) in inducing remission of CD. In 38 patients, Tremaine et al. [17] observed that 3.2 g of mesalamine induced a larger number of partial remissions (n = 9) than placebo (n = 4). When combining partial and complete remissions, the difference was significant but there was, however, no benefit in terms of complete remission (CDAI !150 points). This study was performed with Asacol, which has a limited bioavailability in the ileum, and patients with ileocolitis were included in the study. Singleton et al. [18] conducted a total of three 16-week trials comparing mesalamine 1, 2, or 4 g (Pentasa) daily to placebo, with very similar design and inclusion criteria. The 1-gram dose was omitted from the second trial, and only the 4-gram dose was compared to placebo in the third trial. While in the first trial (230 patients), mesalamine 4 g was superior to placebo (remission rate 43 vs. 18% in placebo, p ! 0.01), mesalamine 1 or 2 g showed no benefit. In their second trail (232 patients), however, the same investigators failed to show any benefit or mesalamine over placebo [19]. In a pooled analysis of both trials (545 patients), mesalamine 4 g was found significantly better than placebo in reducing CDAI values, but the complete data of the second trial were never published in full [19]. The third trial (310 patients) was reported more recently, with a meta-analysis of the three studies [20]. This third trial showed again no benefit of 4 g mesalamine over placebo. The overall meta-analysis showed a significant, but not clinically relevant, 18-point reduction in CDAI in favor of 4 g mesalamine. Because the mesalamine formulation and the location of the disease could be responsible for the controversial results of prior trials, Prantera et al. [21] undertook another trial, comparing mesalamine 4 g daily, as tablets (Asacol) or microgranular preparation (with release in the ileum). A third group received 6-methylprednisolone 40 mg (discussed later). Less than half of the predefined number of patients were enrolled in the study, which showed no significant difference between the mesalamine preparations in terms of CDAI decrease or remission rates during the 12-week trial. The remission rates were 60 and 79% (p = 0.27, NS) for the patients as-

Mild-Moderate Crohn’s Disease

signed to mesalamine tablets and mesalamine microgranules, respectively. Mesalamine was further compared to systemic steroids and to budesonide for the treatment of mild to moderate CD. A number of relatively small trials compared mesalamine to systemic steroids. The largest study, conducted by the German 5-ASA Study Group, compared mesalamine 2 g daily with of 6-methylprednisolone 48 mg (tapered to 8 mg), for 24 weeks [22]. Changes in CDAI were –58 for mesalamine vs. –151 for methylprednisolone (p ! 0.001), and steroids were also significantly better than mesalamine in inducing remission of CD. The Prantera trial described above similarly lacked the statistical power to define the non-inferiority of mesalamine over systemic steroids [21]. Mesalamine was compared to the non-systemic steroid budesonide in one large randomized, double-blind study. Mesalamine 2 g (Pentasa) twice daily was compared to budesonide 9 mg once daily (and placebo once daily) for 16 weeks [23]. 182 patients were enrolled in this high-quality study. At each time point, budesonide induced more remissions than mesalamine, reaching 62 vs. 36% (p ! 0.001) at 16 weeks. Time to remission was shorter in the budesonide group. Rate of remission decreased in both groups with higher severity of disease at entry, and with colonic involvement. Steroids Systemic Corticosteroids Prednisone and 6-methylprednisolone were shown to be efficacious in two large multicentric placebo-controlled studies, and superior to SFS [8, 9]. These results were confirmed in other smaller studies [12, 13]. Details about these studies are provided above, in the SFS section. Budesonide To take advantage of the established efficacy of corticosteroids in CD, without their associated adverse events, budesonide preparations were developed. This corticosteroid has a high affinity for the glucocorticoid receptor, and undergoes extensive first-pass metabolism in the liver. Two formulations are available on the European market, Entocort®, a gelatin capsule containing acid-stable microgranules of budesonide (Eudragit L100-55) with slow release in the ileum and right colon, and Budenofalk®, an oral pH-modified release (pH 16.4) formulation of budesonide, not approved in the USA. Budesonide (Entocort®) has been tested for its ability to induce remission of mild to moderate CD in several large, controlled, double-blind, multicenter studies. Two

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of these trials were placebo-controlled trials. Greenberg et al. [24] compared budesonide 3, 9, and 15 mg daily to placebo in 258 patients with mild to moderate CD and showed significantly higher remission rates for budesonide 9 mg (51%) and 15 mg (43%) vs. placebo (20%). The other trial, despite similar design and patient population, did not achieve the primary endpoint to show that budesonide 4.5 or 9 mg daily was better than placebo in inducing remission in 200 patients [25]. The difference in mean change from baseline in CDAI between the combined budesonide groups and placebo was, however, significant. In both trials, no difference in adverse events was observed between budesonide and placebo, but decreased plasma cortisol concentrations occurred in patients treated with budesonide. A recent meta-analysis found that budesonide induced remission more frequently than placebo, with an odds ratio of 1.85 [26]. Budesonide was also compared to mesalamine and to conventional corticosteroids. As previously described, budesonide (Entocort®) 9 mg was found superior to mesalamine 4 g in one large and well-designed study [23]. Further analysis of the results of this trial indicated that budesonide improved patients’ quality of life better than mesalamine [27]. In their meta-analysis, Kane et al. [26] evaluated that budenoside was more likely to induce remission than mesalamine, with an odds ratio of 1.73. Four trials compared budenoside with conventional steroids. In two trials with Entocort®, Campieri et al. [28] and Rutgeerts et al. [29] reported that budenoside was equivalent to prednisolone in inducing remission of mild to moderate CD. In the first trial, prednisone decreased CDAI score significantly more than budenoside, and subgroup analysis suggested that prednisolone was superior in patients with high baseline CDAI scores. Budenofalk 9 mg daily was compared to prednisone 40 mg (tapered to 5 mg) and to 6-methylprednisolone 48 mg (tapered to 8 mg) [30, 31]. In both studies, no differences in remission rates were observed between this form of budesonide and conventional steroids. All these four trials, however, were not formal non-inferiority trials. In meta-analysis, conventional steroids were found to induce remission more frequently than budesonide, with a significant odds ratio of 0.87, the difference disappearing in patients with lower CDAI scores [26]. Three out of the four trials, as well as the meta-analysis reported lower corticosteroidrelated adverse event rates with budesonide than with conventional steroids.

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Antibiotics Metronidazole, ciprofloxacin, cotrimoxazole, and clarithromycin have been evaluated for the treatment of mild to moderate CD. Most of the studies included small numbers of patients, and few were randomized, doubleblind, controlled trials. In the largest randomized trial, by Sutherland et al. [32] compared metronidazole in two doses (10 or 20 mg/ kg) to placebo. Although only 56 out of 105 patients completed the study, both doses of metronidazole induced significant improvements in CDAI levels from baseline as compared to placebo (–97 points for 20 mg/kg, –67 points for 10 mg/kg, –1 point for placebo, p = 0.002). In subgroup analysis, improvement was better in patients with disease limited to the colon or affecting both ileum and colon, but not in patients with small bowel disease alone. In three smaller placebo-controlled trials metronidazole (0.8–1.0 g daily) was not found to be better than placebo [33, 34, 36], except in subgroup analysis for patients with isolated colonic disease in one study [34]. In an additional randomized trial of 52 patients with ileocolitis published in German, metronidazole monotherapy was compared with a combination of SFS and cortisone, and of metronidazole, SFS, and cortisone [35]. No differences were observed between the two treatment groups, but metronidazole, alone or in combination, was found to be superior to SFS and cortisone in patients with discharging fistulae. In a double-blind, randomized, multicenter study, metronidazole 0.8 g and SFS 3 g were compared in a cross-over design [36]. No differences were observed between the two groups, but in both groups patients with colonic disease responded better to therapy. Ciprofloxacin was shown efficacious in reducing CDAI scores when added to the current treatment regimen of patients with moderately active, but treatment-resistant CD [37]. In this trial, 47 patients were randomly assigned to ciprofloxacin 1 g daily or placebo for 6 months. In a larger study, however, metronidazole and ciprofloxacin (1 g/day each) given with budesonide 9 mg/day was not superior to budesonide only in a well-designed study that included 134 patients with mild to moderate CD [38]. Again, subgroup analysis suggested a benefit of antibiotic therapy in patients with colonic involvement (53% remission in the antibiotic group vs. 25% in placebo, p = 0.10). Two additional studies showed no difference between ciprofloxacin and mesalamine [39], and between ciprofloxacin plus metronidazole and 6-methylprednisolone [40]. Due to the small sample size of these studies, there is a high risk of type II errors in these studies that did not have a design adequate for equivalence studies.


Comments Aminosalicylates Two large and rigorous, and several smaller studies have shown that SFS is modestly effective in inducing remission of CD, but inferior to systemic steroids. Furthermore, SFS offers no adjunctive benefit to steroid therapy. SFS is most effective against colonic disease, which is in accordance with its need for colonic bacteria to release the active moiety of the drug – mesalamine – that is then only topically active. As the sulfapyrimidine carrier moiety of SFS is non-active and associated with most of its side effects, mesalamine formulations devoid of sulfa moieties were developed. The efficacy of these mesalamine formulations, however, has not been demonstrated in clinical trials, most of them of inadequate quality. Only two trials showed efficacy of mesalamine 3.2 and 4 g over placebo. In one trial, however, an unusual endpoint was used, a combination of partial and complete remission, and about half of the patients were on concomitant steroid therapy [17]. The results of the other trial, performed on 230 patients [18], could not be repeated by the same investigators with the same compound during two subsequent trials [19, 20]. Thus, despite its frequent use in practice over SFS, mesalamine cannot be recommended for the treatment of mild to moderate CD. Steroids The efficacy of conventional steroids is well demonstrated for induction of remission of mild to moderate CD, and both prednisone and 6-methylprednisolone are unequivocally effective in this indication. However, their side effects are also well documented. Budesonide has shown similar primary efficacy to conventional steroids in clinical trials, but in meta-analysis, its efficacy, as compared to classical steroids, is inferior in patients with high baseline CDAI scores [26]. The safety profile of budenoside is better than steroids. Budesonide efficacy is limited, however, in patients with disease restricted to the colon.

Conclusion

The traditional, non-evidence-based stepwise approach for mild to moderate CD has been to start with mesalamine, and then to move up to antibiotics, and then to steroids. Budenoside has more recently been inserted in this progressive scheme, just before conventional steroids are considered. A novel evidence-based approach has recently been proposed as an alternative, that takes into account disease location, as some therapies will act topically and in specific segments of the gut only [41]. This new proposition recommends first-line therapy with SFS 3–6 g/day for 16 weeks for disease limited to the colon, and budesonide 9 mg/day for 8–16 weeks, followed by a tapering schedule over 2–4 weeks by 3-mg increments, for disease located in the terminal ileum and right colon. If the patient shows no improvement, a reclassification as moderate to severe disease should be considered, and therapies aimed at the management of moderate to severe disease initiated. If patients fail to improve with SFS, budesonide, or antibiotics if they have been introduced, or if the patient presents initially with moderate to severe disease as defined by the American College of Gastroenterology [7], conventional steroids, immunosuppressive drugs, or the newly introduced biological therapies should be considered. These patients are also considered as patients with moderate to severe disease.

Antibiotics Although widely used in practice for patients presenting with mild to moderate CD, there is little evidence to support the use of antibiotics, and in particular metronidazole and ciprofloxacin. Indeed, controlled trials have not consistently shown their efficacy. The quality of the evidence to rule out their benefit in patients with colonic disease may, however, not be adequate due to small number of patients and post-hoc analysis.

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References 1 Loftus EV, Schoenfeld P, Sandborn WJ: The epidemiology and natural history of Crohn’s disease in population-based patient cohorts from North America: A systematic review. Aliment Pharmacol Ther 2002;16:51–60. 2 Louis E, et al: Behaviour of Crohn’s disease according to the Vienna classification: Changing pattern over the course of the disease. Gut 2001;49:777–782. 3 Louis E, et al: Early development of stricturing or penetrating pattern in Crohn’s disease is influenced by disease location, number of flares, and smoking but not by NOD2/CARD15 genotype. Gut 2003;52:552–557. 4 Witte J, et al: Disease outcome in inflammatory bowel disease: Mortality, morbidity and therapeutic management of a 796-person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (ECIBD). Scand J Gastroenterol 2000; 35: 1272– 1277. 5 Cohen RD: The quality of life in patients with Crohn’s disease. Aliment Pharmacol Ther 2002;16:1603–1609. 6 Guthrie E, et al: Psychological disorder and severity of inflammatory bowel disease predict health-related quality of life in ulcerative colitis and Crohn’s disease. Am J Gastroenterol 2002;97:1994–1999. 7 Hanauer SB, Sandborn W: Management of Crohn’s disease in adults. Am J Gastroenterol 2001;96:635–643. 8 Summers RW, et al: National Cooperative Crohn’s Disease Study: Results of drug treatment. Gastroenterology 1979;77:847–869. 9 Malchow H, et al: European Cooperative Crohn’s Disease Study (ECCDS): Results of drug treatment. Gastroenterology 1984; 86: 249–266. 10 Anthonisen P, et al: The clinical effect of salazosulphapyridine (Salazopyrin®) in Crohn’s disease. A controlled double-blind study. Scand J Gastroenterol 1974;9:549–554. 11 Van Hees PA, et al: Effect of sulphasalazine in patients with active Crohn’s disease: A controlled double-blind study. Gut 1981; 22: 404– 409. 12 Singleton JW, et al: A trial of sulfasalazine as adjunctive therapy in Crohn’s disease. Gastroenterology 1979;77: 887–897. 13 Rijk MC et al: Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease. A double-blind, randomized, multicenter trial. Ann Intern Med 1991; 114:445–450. 14 Goldstein F, et al: Favorable effects of sulfasalazine on small bowel Crohn’s disease: A long-term study. Am J Gastroenterol 1987;82: 848–853.

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15 Rasmussen SN, et al: 5-Aminosalicylic acid in the treatment of Crohn’s disease. A 16-week double-blind, placebo-controlled, multicentre study with Pentasa. Scand J Gastroenterol 1987;22: 877–883. 16 Mahida YR, Jewell DP: Slow-release 5-aminosalicylic acid (Pentasa) for the treatment of active Crohn’s disease. Digestion 1990; 45: 88– 92. 17 Tremaine WJ, et al: A randomized, doubleblind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn’s colitis and ileocolitis. J Clin Gastroenterol 1994; 19: 278– 282. 18 Singleton JW, et al: Mesalamine capsules for the treatment of active Crohn’s disease: Results of a 16-week trial. Pentasa Crohn’s Disease Study Group. Gastroenterology 1993;104: 1293–1301. 19 Singleton J: Second trial of mesalamine therapy in the treatment of active Crohn’s disease. Gastroenterology 1994; 107:632–633. 20 Hanauer SB, Stromberg U: Oral Pentasa in the treatment of active Crohn’s disease: A metaanalysis of double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol 2004;2:379– 388. 21 Prantera C, et al: Mesalamine in the treatment of mild to moderate active Crohn’s ileitis: Results of a randomized, multicenter trial. Gastroenterology 1999;116:521–526. 22 Gross, V et al: Comparison between high dose 5-aminosalicylic acid and 6-methylprednisolone in active Crohn’s ileocolitis. A multicenter randomized double-blind study. German 5ASA Study Group. Z Gastroenterol 1995; 33: 581–584. 23 Thomsen OO, et al: A comparison of budesonide and mesalamine for active Crohn’s disease. International Budesonide-Mesalamine Study Group. N Engl J Med 1998;339: 370–374. Erratum appears in N Engl J Med 2001;345:1652. 24 Greenberg GR, et al: Oral budesonide for active Crohn’s disease. Canadian Inflammatory Bowel Disease Study Group. N Engl J Med 1994;331:836–841. 25 Tremaine WJ, et al: Budesonide CIR capsules (once or twice daily divided-dose) in active Crohn’s disease: A randomized placebo-controlled study in the United States. Am J Gastroenterol 2002;97: 1748–1754. 26 Kane SV et al: Systematic review: The effectiveness of budesonide therapy for Crohn’s disease. Aliment Pharmacol Ther 2002;16:1509– 1517. 27 Thomsen OO, et al: Budesonide and mesalazine in active Crohn’s disease: A comparison of the effects on quality of life. Am J Gastroenterol 2002; 97:649–653.

28 Campieri M, et al: Oral budesonide is as effective as oral prednisolone in active Crohn’s disease. The Global Budesonide Study Group. Gut 1997;41:209–214. 29 Rutgeerts P, et al: A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med 1994;331:842–845. 30 Bar-Meir S, et al: Budesonide versus prednisone in the treatment of active Crohn’s disease. The Israeli Budesonide Study Group. Gastroenterology 1998;115:835–840. 31 Gross V, et al: Oral pH-modified release budesonide versus 6-methylprednisolone in active Crohn’s disease. German/Austrian Budesonide Study Group. Eur J Gastroenterol Hepatol 1996;8:905–909. 32 Sutherland L, et al: Double-blind, placebo-controlled trial of metronidazole in Crohn’s disease. Gut 1991;32:1071–1075. 33 Allan R, Cooke WT: Evaluation of metronidazole in management of Crohn’s disease. Gut 1977; 18:A422–A422. 34 Blichfeldt P, et al: Metronidazole in Crohn’s disease. A double-blind cross-over clinical trial. Scand J Gastroenterol 1978;13:123–127. 35 Schneider MU, et al: Metronidazole in the treatment of Crohn disease. Results of a controlled randomized prospective study. Dtsch Med Wochenschr 1985; 110:1724–1730. 36 Ursing B, et al: A comparative study of metronidazole and sulfasalazine for active Crohn’s disease: The cooperative Crohn’s disease study in Sweden II. Result. Gastroenterology 1982; 83: 550–562. 37 Arnold GL, et al: Preliminary study of ciprofloxacin in active Crohn’s disease. Inflamm Bowel Dis 2002;8:10–15. 38 Steinhart AH, et al: Combined budesonide and antibiotic therapy for active Crohn’s disease: A randomized controlled trial. Gastroenterology 2002;123:33–40. 39 Colombel JF, et al: A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn’s disease. Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). Am J Gastroenterol 1999;94: 674–678. 40 Prantera C, et al: An antibiotic regimen for the treatment of active Crohn’s disease: A randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996; 91: 328–332. 41 Sandborn WJ, Feagan BG: Mild to moderate Crohn’s disease – Defining the basis for a new treatment algorithm. Aliment Pharmacol Ther 2003;18:263–277.


Review Published online: February 4, 2005

Digestion 2005;71:19–25 DOI: 10.1159/000083867

Severe and Steroid-Resistant Crohn’s Disease Pierre Michettia Christian Motteta Pascal Juillerata Christian Felleya John-Paul Vaderc Bernard Burnandc Jean-Jacques Gonversa Florian Froehlicha, b a


Key Words Crohn’s disease, therapy Crohn’s disease, review Steroids Azathioprine Methotrexate Infliximab Biological therapies

Abstract Patients with moderate to severe disease and patients with steroid-refractory or steroid-dependent disease differ in their management, as the latter groups usually include patients with less acute situations. Systemic corticosteroids represent the mainstay of the management of moderate to severe disease and remain the first-line therapy in this setting. Infliximab is the choice alternative for patients who do not respond to steroids or in whom steroids are contraindicated. Purine analogues, methotrexate and infliximab have shown efficacy in achieving steroid-free remission in patients with steroid-refractory or -dependent disease. Other fast-acting immunosuppressors showed little benefit. Surgery may be indicated in this setting. Nataluzimab may prove useful in patients refractory to infliximab. Copyright © 2005 S. Karger AG, Basel

Introduction

The treatment of an acute moderate to severe Crohn’s disease (CD) differs from the management of steroid-dependent or steroid-resistant CD that are less acute situations. The former acute situation includes a fulminant form, which will be discussed separately in this review. This stratification takes into account the ability of the various therapies to induce remission as well as the delay between their initiation and their onset of action. Disease severity is based on the criteria established by the American College of Gastroenterology (ACG) [1]. According to these criteria, moderate to severe disease applies to patients who have failed to respond to treatment for mild to moderate disease or those with more prominent symptoms such as fever, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia. Severe disease refers to patients with persisting symptoms despite the introduction of steroids as outpatients, or individuals presenting with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess. The definition of severe disease should probably also include resistance to infliximab. Natural History When considering a patient with a severe form of CD, one should recognize the presence of factors that contrib-




ute to the disease relapse, severity and possible steroid resistance or dependence. For instance, non-steroidal anti-inflammatory agents, smoking and intercurrent infection may alter response to steroid therapy. Other factors, such as bile salt malabsorption or the presence of an infectious complication (abscess or mass) or of an obstruction should be recognized before one considers treatment resistance or failure. A large proportion of patients started on steroids will become dependent or resistant to this therapy [2, 3], a situation that deserves special attention. Smoking, colonic disease, and non-fibrostenotic disease have been associated with a higher risk of steroid dependence [4]. Several therapies have been evaluated in their ability to allow steroid withdrawal.

Moderate to Severe and Severe Disease

The ACG guidelines define patients with moderate to severe disease as patients who have failed to respond to treatment for mild to moderate disease or those with more prominent symptoms such as fever, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia. According to the ACG guidelines, severe disease refers to patients with persisting symptoms despite the introduction of steroids as outpatients, or individuals presenting with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess. Patients refractory to infliximab should probably be included in this definition. General Management While moderate to severe disease patients are mostly managed as outpatients, severe disease patients should be hospitalized. Surgical consultation is warranted for patients with obstruction or tender abdominal mass. An abdominal mass should be evaluated via ultrasound or computerized tomography to exclude an abscess. Abscesses require percutaneous or surgical drainage. Supportive or resuscitative therapy with fluid and electrolytes is indicated for dehydrated patients. Antibiotics are recommended in these patients if there is evidence of sepsis, inflammatory mass, or severe perianal disease. Transfusions are necessary in the setting of anemia and active hemorrhage. Oral feeding may be continued, as tolerated, for patients without obstructive manifestations or severe abdominal pain. More severely ill patients or those with evidence of obstruction should be treated with bowel rest and parenteral nutritional support [5, 6].

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First-Line Treatment Options Evidence Corticosteroids As first-line therapies, steroids induced remission in about 70% of patients in two large multicenter randomized high-quality trials [7, 8]. Although there is no strong evidence, intravenous administration in severely ill patients obviates concerns about poor absorption in patients with active disease or prior resections [9]. Parenteral corticosteroids are indicated for patients with severe or fulminant CD [1]. Dose-ranging studies have not been performed to define an optimal dose or schedule of administration although most clinicians administer parenteral corticosteroids equivalent to 40– 60 mg of prednisone in divided doses or as a continuous infusion [10]. A retrospective study confirmed the safety and efficacy of this approach [9]. Intravenous ACTH is equally as effective as intravenous corticosteroids but is potentially complicated by adrenal hemorrhage [11]. Infliximab Infliximab, a monoclonal chimeric antibody to TNF-, was first tested in an initial pilot uncontrolled study as a single infusion of 10 mg/kg, given to moderate to severe patients refractory to steroid therapy. Improvement occurred in 8 out of 10 patients within 2 weeks [12]. This observation prompted double-blind, placebo-controlled trials. In the first of these trials, patients unresponsive to steroids, azathioprine or 6-mercaptopurine were randomized to infliximab 5, 10 or 20 mg/kg. At 4 weeks, 64% of the infliximab-treated patients showed a clinical response vs. 17% in the placebo group [13]. In this study, the 5 mg/kg dose was numerically superior to the higher doses. The results of this study were confirmed by several clinical series [14, 15], and more recently in a large study, the ACCENT I trial, that included 573 patients. All the patients enrolled in this trial received, before randomization, an initial infusion of infliximab 5 mg/kg, in a non-blinded setting. At week 2, 58% of patients presented a clinical response to 5 mg/kg infliximab [16]. There are no data on the utility of infliximab in severe or fulminant CD. Infliximab administration is associated with the development of antibodies to the medication in a large proportion of patients (36–68%) [17, 18]. Risk factors for this complication that may lead to poor tolerance to the drug and loss of efficacy are the absence of concurrent immunosuppression or prednisone below 20 mg/day. Isolated single infusion may also predispose to antibody develop-

Michetti/Mottet/Juillerat/Felley/Vader/ Burnand/Gonvers/Froehlich

ment. In a small randomized, placebo-controlled trial, hydrocortisone 200 mg premedication at the time of infliximab infusion reduced levels and occurrence of antibodies to infliximab [18]. Comments Oral corticosteroids remain the mainstay of the management of moderate to severe CD. Infliximab should be administered according to procedures likely to decrease the risk of antibody to this medication. Infliximab is a well-studied alternative for patients with moderate to severe disease intolerant of or unresponsive to oral steroids. Several contraindications to infliximab should be considered, including the presence of abscesses and sepsis. Severe and even lethal infections have occurred with this medication. The presence of prior exposure to tuberculosis, or evidence of cardiac failure, are contraindications to infliximab. Infliximab therapy may also precipitate obstruction in patients with stenosis. Attention should be directed to avoiding the development of antibodies to infliximab, by giving the medication in patients already on immunosuppression, or by concurrent administration of hydrocortisone. In this context, three initial infusions should be preferred to a single infusion. Propositions Although oral systemic steroids and budesonide have showed equal efficacy in clinical trials, most clinicians are reluctant to use budesonide in patients with severe disease, a setting where budesonide utility is less clear. Prednisone 1 mg/kg p.o. should be administered initially, followed by a rapidly tapering schedule. Infliximab represents an alternative in this situation. If oral steroids and/or infliximab are ineffective, or in patients with severe or fulminant disease, intravenous steroids may be given at the same dose as oral steroids. Corticotrophin may represent an alternative in patients not previously exposed to steroids. Budesonide may have a role after remission is obtained by oral or parenteral systemic steroids, as a followup therapy in patients poorly tolerant of steroids, or with side effects of systemic steroids, as a bridge to long-term strategies. Infliximab should be considered in patients refractory to steroids or in patients in whom steroids are contraindicated. Patients should be evaluated for prior exposure to tuberculosis. Infliximab should be administered with a strategy aimed at preventing occurrence of anti-infliximab antibodies.

Severe Crohn’s Disease

Second-Line Treatment Options Evidence Immunosuppressive Therapy Numerous controlled and uncontrolled studies reported the use of immunosuppressive therapies for CD. The best studied compounds are azathioprine, 6-mercaptopurine and methotrexate. These drugs act slowly, however, and the mean time to respond in patients with CD is about 3 months for thiopurine analogues, and 2 months for methotrexate. These agents therefore only have a limited role in the management of an acute attack of the disease. Their value in the management of CD patients with active disease will be included in the section on steroidresistant disease (below). More recently, cyclosporine and methotrexate have been used in patients with acute, steroid-refractory disease. Cyclosporine Anecdotal reports suggest a benefit of cyclosporine in patients with active CD refractory to conventional agents. The advantage of this agent is its rapid onset of action, within 2–3 weeks of treatment. The first randomized trial with this agent included 71 patients with active chronic CD who were resistant to or intolerant of corticosteroids, to treatment with oral cyclosporine (5–7.5 mg/kg per day) [19]. At the end of the treatment period, 22 of the 37 cyclosporine-treated patients (59%) had improvement, as compared with 11 of the 34 placebo-treated patients (32%) (p = 0.032). In three further placebo-controlled randomized trials of excellent quality, however, and despite substantial differences in trial designs, cyclosporine did not confirm its efficacy in chronically active CD [20–22]. In later small case series, intravenous cyclosporine showed benefit in patients with severe refractory disease [23–25]. Other Fast-Acting Immunosuppressors Tacrolimus, a macrolide frequently used in transplant patients refractory to cyclosporine, induced remission in 3 patients with proximal or complicated CD [26]. Randomized trials are not available to be able to determine the utility of this medication in CD. Mycophenolate mofetil showed limited benefit in patients intolerant of or unresponsive to conventional immunosuppressors such as azathioprine or methotrexate [27–29]. However, treatment of patients with highly active CD (CDAI 1300) with a combination of mycophenolate and prednisone caused a significant clinical response earlier than azathioprine/cortisone treatment [30].

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Diet Several controlled and uncontrolled studies evaluated the benefit of elemental or non-elemental diets for induction of remission in CD [31–37]. Their results, somewhat conflicting, prompted three meta-analyses that concurred in concluding that dietary approaches were less effective than steroids in inducing remission of CD in adults [38– 40]. No difference between elemental and polymeric diets was shown in these analyses. Surgery For patients with ileal disease that is limited in extent, early surgery is an option. Indeed, surgery induces remission by ablation of the inflamed segment. Relapse occurs post-surgery at a rate of about 15% per year, approximately half the relapse rate following medically induced remission [41]. In a population-based study of 907 patients, resection rates were 61, 77 and 83% at 1, 5 and 10 years respectively after the diagnosis. Relapse rates were 28 and 36% 5 and 10 years after the first resection. The presence of perianal CD and long resection segments increased the incidence of recurrence, and resection for a palpable mass and/or abscess decreased the recurrence rate. Another large follow-up study after surgery associated perforating disease and long-standing CD with early recurrence [42]. For terminal ileitis, a functional end-toend anastomosis is considered as the most attractive option [43]. Stapled anastomosis may be associated with a lower rate of complications than sutured anastomosis. Conservative surgery using stricturoplasty compares to resection in terms of 5- and 10-year recurrence rate, but may not be indicated in the setting of penetrating disease. A randomized trial showed that laparoscopic surgery is as safe as laparotomy and may shorten hospital stay [44]. A retrospective study in 80 patients showed that 78% of patients would have preferred earlier surgery, with a median time of 12 months [45]. Comments and Propositions Parenteral steroid therapy is accepted as the first-line therapy for severe or fulminant disease, after exclusion of CD complications precluding its use. Antibiotics are frequently added at this stage. Patients with severe disease who do not respond to parenteral steroids may respond to intravenous cyclosporine or tacrolimus, although there are no controlled or dose-response data. Infliximab may be used in severe disease, but its value in fulminant disease is not established. Although elemental diets and possibly liquid polymeric diets have demonstrable clinical benefits and reduce

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inflammatory features of active CD, the long-term course of disease is not altered, compliance is difficult in adults, and the cost is considerable. Their value in patients with fulminant disease is unclear. Surgery should be considered in patients with disease of limited extension, especially in a perforating disease phenotype or in patients with risk factors or contraindication for medical therapy. Surgery is associated with a low rate of complications in CD. The abiding principle of surgery for inflammatory CD is a conservative approach, with resection of the least amount of bowel possible, to reduce future risk of short bowel syndrome. Stricturoplasty and laparoscopic approaches are possible alternative to resection by laparotomy.

Steroid-Refractory and Steroid-Dependent Disease

Twenty to forty-five percent of patients initially responding to steroids will relapse when this medication is tapered or withdrawn [2, 46]. In addition, 20–30% of patients will not respond to steroid therapy [2, 7, 8].

First-Line Treatment Options Evidence Purine Analogues Azathioprine (2–2.5 mg/kg) or its metabolite, 6-mercaptopurine (0.5–1 mg/kg), are frequently used in patients with steroid-dependent or steroid-refractory disease. These two medications have the same mode of action, and eight controlled trials showed that these drugs are effective in patients with active steroid-refractory disease [8, 47–53]. The steroid-sparing effect of these drugs was a study endpoint in four of these studies [47, 49, 51, 53]. A meta-analysis associated these drugs with an odds ratio of 3.09 (95% CI 2.45–3.91) of response in active disease [54]. The authors of the meta-analysis calculated that 56% of patients responded to the drugs, vs. 32% in the placebo groups. In this analysis, treatment for more than 17 weeks improved response rate. Five studies included data on the ability to reduce steroids, measured either by ability to follow a fixed steroidtapering schedule, or by reaching a dose of steroids below 10 mg/day without relapse [47, 49, 51–53]. Another study included patients stable on azathioprine and various other drugs, including steroids and randomized them to azathioprine withdrawal or continuation [55]. These studies


showed that azathioprine or 6-mercaptopurine were useful in maintaining remission while withdrawing steroids. A Cochrane review confirmed this indication of purine analogues, with an odds ratio of 3.86 (95% CI 2.14–6.96) [56]. Methotrexate Three randomized placebo-controlled trials have evaluated methotrexate therapy in CD. Two studies employed low-dose oral methotrexate (12.5–22.5 mg weekly doses), and showed no efficacy in steroid-dependent or refractory CD patients as compared to placebo [48, 57]. A third trial employed 25 mg methotrexate per week by intramuscular injections in 141 patients with chronic active disease despite steroid therapy, i.e. steroid-refractory patients [58]. At 16 weeks, 39% of patients were in remission as compared to 19% in the placebo group, with a significant decrease in the steroid dose. Seventeen percent of the methotrexate-treated patients withdrew from therapy because of adverse events. Additional reports on the utility of methotrexate in steroid-refractory patients are available, but these reports are mostly case series [59–61]. The remission rate in these three series which included mostly patients intolerant of or refractory to purine analogues was about 70%. Comments and Propositions Purine analogues are effective in patients with steroidrefractory or steroid-dependent patients. Although adverse events leading to drug withdrawal occurred in 9.3 and 2.3% for azathioprine and 6-mercaptopurine, respectively [56], these medications should be considered as the first option in patients with these two disease presentations. Methotrexate is less well studied, but represents an alternative for patients unresponsive to or intolerant of purine analogues. Parenteral administration, which can be in the form of self-administered subcutaneous injection, is recommended due to unpredictable absorption by the oral route.

roids at enrollment. In this trial, infliximab responders at week 2 after first infusion were randomized to repeated infusion (5 or 10 mg/kg every 8th week, or placebo). At week 54 of the follow-up, 29% of all infliximab-treated patients were steroid-free vs. 9% in the placebo group (odds ratio 4.2; 95% CI 1.5–11.5). In addition, steroid withdrawal was faster in the infliximab groups combined. In addition, steroid-sparing effect of infliximab was observed in four case series, in which 40–90% of patients could be weaned off steroids during various observation periods [14, 62–64]. These series included not only patients with active disease, but also patients in remission on steroids. Surgery In colonic CD, urgent colectomy may be required after failure of medical therapy, or in presence of complications such as peritonitis or abscess. Elective colectomy may also be indicated in poorly controlled disease [65]. In the acute setting a subtotal colectomy with double ileostomy and sigmoidostomy is indicated, with later construction of an ileo-rectal (or -sigmoid) anastomosis or coloproctectomy with terminal ileostomy. In elective situation, one-step procedures are preferred. The status of the rectum is central to the choice of the final surgery, and the presence of perianal disease.

Evidence Infliximab One large randomized placebo-controlled trial, in patients with moderate to severe disease despite prior therapies, had steroid withdrawal as a secondary study endpoint [16]. Fifty-one percent of the patients were on ste-

Natalizumab Two randomized trials have shown that natalizumab, an anti-4-integrin antibody, can induce remission in CD patients with moderate to severe disease [66, 67]. In the trial by Ghosh et al. [66], 248 patients were randomized to three treatment schedules with natalizumab, or placebo. Although the primary endpoint of the study was not achieved (remission at week 6), natalizumab was superior to placebo at most time points after week 2. About half of the patients were on corticosteroids at the time of inclusion with CDAI ranging from 220 to 450. In the second trial, 30 patients were randomized to a single 3-mg infusion. Thirty-nine percent of natalizumab-treated patients achieved remission at week 2, vs. 8% in the placebo group. Natalizumab was well tolerated in both trials. A third large randomized trial was reported at EUGW 2003 in Madrid [68]. In this study of 905 patients, the primary endpoint (clinical response at week 10) was not achieved, but 62% of natalizumab patients vs. 53% placebo patients met this endpoint at week 12. Subgroup analyses showed that natalizumab was superior to placebo in patients on concurrent immunosuppressors, in patients with prior


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Second-Line Treatment Options

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exposure to infliximab, and in patients with elevated CRP at baseline. Comments and Propositions Infliximab has demonstrated a steroid-sparing effect in steroid-refractory patients. This drug may be used in this indication as a second-line therapy. Its utility in steroid-dependent patients is less clear, as only a limited number of patients in uncontrolled studies have been treated with infliximab for this indication. Surgery may be indicated in severe refractory disease, especially in colonic disease. Surgical options depend of the clinical situation and should not be delayed if medical

therapy is not promptly effective or does not lead to complete remission. Natalizumab is not yet approved by European and American government agencies for the treatment of CD. The results so far are interesting, although the two major trials did not meet their primary endpoint, partly because of high placebo responses. These placebo-response rates may reflect poor selection of patients (with low CRP) or the high expectations of patients enrolled in the testing of these new therapies. The observation that this drug may work in patients who lost response to infliximab is of interest.

References 1 Hanauer SB, Sandborn W: Management of Crohn’s disease in adults. Am J Gastroenterol 2001;96:635–643. 2 Munkholm P, et al: Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 1994;35: 360–362. 3 Faubion WA Jr, et al: The natural history of corticosteroid therapy for inflammatory bowel disease: A population-based study. Gastroenterology 2001;121:255–260. 4 Franchimont DP, et al: Clinical pattern of corticosteroid dependent Crohn’s disease. Eur J Gastroenterol Hepatol 1998;10: 821–825. 5 Bernstein CN, Shanahan, F: Critical appraisal of enteral nutrition as primary therapy in adults with Crohn’s disease. Am J Gastroenterol 1996;91: 2075–2079. 6 Han PD, et al: Nutrition and inflammatory bowel disease. Gastroenterol Clin North Am 1999;28:423–443, ix. 7 Malchow H, et al: European Cooperative Crohn’s Disease Study (ECCDS): Results of drug treatment. Gastroenterology 1984; 86: 249–266. 8 Summers RW, et al: National Cooperative Crohn’s Disease Study: Results of drug treatment. Gastroenterology 1979;77:847–869. 9 Shepherd HA, Barr, GD, Jewell DP: Use of an intravenous steroid regimen in the treatment of acute Crohn’s disease. J Clin Gastroenterol 1986;8:154–159. 10 Felder JB, Adler DJ, Korelitz BI: The safety of corticosteroid therapy in Crohn’s disease with an abdominal mass. Am J Gastroenterol 1991; 86:1450–1455. 11 Chun A, et al: Intravenous corticotrophin vs. hydrocortisone in the treatment of hospitalized patients with Crohn’s disease: A randomized double-blind study and follow-up. Inflamm Bowel Dis 1998;4:177–181. 12 Van Dullemen HM, et al: Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109:129–135.

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13 Targan SR, et al: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor- for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997; 337: 1029–1035. 14 Farrell RJ, et al: Clinical experience with infliximab therapy in 100 patients with Crohn’s disease. Am J Gastroenterol 2000; 95: 3490– 3497. 15 Cohen RD, Tsang JF, Hanauer SB: Infliximab in Crohn’s disease: First anniversary clinical experience. Am J Gastroenterol 2000; 95: 3469–3477. 16 Hanauer SB, et al: Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet 2002;359:1541–1549. 17 Baert F, et al: Autoimmunity associated with anti-tumor necrosis factor- treatment in Crohn’s disease: A prospective cohort study. N Engl J Med 2003;348:601–608. 18 Farrell RJ, et al: Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: A randomized controlled trial. Gastroenterology 2003; 124:917– 924. 19 Brynskov J, et al: A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn’s disease. N Engl J Med 1989;321:845–850. 20 Jewell DP, Lennard-Jones JE, and the Cyclosporine Study Group of Great Britain and Ireland: Oral cyclosporine for chronic active Crohn’s disease. A multicenter controlled trial. Eur J Gastroenterol Hepatol 1994;6:499–505. 21 Feagan BG, et al: Low-dose cyclosporine for the treatment of Crohn’s disease. The Canadian Crohn’s Relapse Prevention Trial Investigators. N Engl J Med 1994;330:1846–1851. 22 Stange EF, et al: European trial of cyclosporine in chronic active Crohn’s disease: A 12- month study. The European Study Group. Gastroenterology 1995;109:774–782.

23 Hermida-Rodriguez C, et al: High-dose intravenous cyclosporine in steroid refractory attacks of inflammatory bowel disease. Hepatogastroenterology 1999;46:2265–2268. 24 Santos JV, et al: Intravenous cyclosporine for steroid-refractory attacks of Crohn’s disease. Short- and long-term results. J Clin Gastroenterol 1995; 20:207–210. 25 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. 26 Sandborn WJ: Preliminary report on the use of oral tacrolimus (FK506) in the treatment of complicated proximal small bowel and fistulizing Crohn’s disease. Am J Gastroenterol 1997; 92: 876–879. 27 Hafraoui S, et al: Mycophenolate mofetil in refractory Crohn’s disease after failure of treatments by azathioprine or methotrexate (in French). Gastroenterol Clin Biol 2002;26: 17– 22. 28 Hassard PV, et al: Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn’s disease. Inflamm Bowel Dis 2000;6:16–20. 29 Miehsler W, et al: Is mycophenolate mofetil an effective alternative in azathioprine-intolerant patients with chronic active Crohn’s disease? Am J Gastroenterol 2001;96:782–787. 30 Neurath MF, et al: Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut 1999;44:625–628. 31 Gonzalez-Huix F, et al: Polymeric enteral diets as primary treatment of active Crohn’s disease: A prospective steroid controlled trial. Gut 1993; 34:778–782. 32 Fukuda Y, et al: Efficacy of nutritional therapy for active Crohn’s disease. J Gastroenterol 1995;30(suppl 8):83–87.


33 Lindor KD, et al: A randomized prospective trial comparing a defined formula diet, corticosteroids, and a defined formula diet plus corticosteroids in active Crohn’s disease. Mayo Clin Proc 1992;67: 328–333. 34 Lochs H, et al: Comparison of enteral nutrition and drug treatment in active Crohn’s disease. Results of the European Cooperative Crohn’s Disease Study. IV. Gastroenterology 1991; 101:881–888. 35 Malchow H, et al: Feasibility and effectiveness of a defined-formula diet regimen in treating active Crohn’s disease. European Cooperative Crohn’s Disease Study III. Scand J Gastroenterol 1990;25: 235–244. 36 O’Keefe SJ, et al: Steroids and bowel rest versus elemental diet in the treatment of patients with Crohn’s disease: The effects on protein metabolism and immune function. JPEN J Parenter Enteral Nutr 1989;13:455–460. 37 O’Morain C, Segal AW, Levi AJ: Elemental diet as primary treatment of acute Crohn’s disease: A controlled trial. Br Med J Clin Res Ed 1984;288:1859–1862. 38 Fernandez-Banares F, et al: How effective is enteral nutrition in inducing clinical remission in active Crohn’s disease? A meta-analysis of the randomized clinical trials. JPEN J Parenter Enteral Nutr 1995;19: 356–364. 39 Griffiths AM, et al: Meta-analysis of enteral nutrition as a primary treatment of active Crohn’s disease. Gastroenterology 1995; 108: 1056–1067. 40 Messori A, et al: Defined-formula diets versus steroids in the treatment of active Crohn’s disease: A meta-analysis. Scand J Gastroenterol 1996;31:267–272. 41 Bernell O, Lapidus A, Hellers G: Risk factors for surgery and recurrence in 907 patients with primary ileocaecal Crohn’s disease. Br J Surg 2000;87:1697–1701. 42 Lautenbach E, Berlin JA, Lichtenstein GR: Risk factors for early postoperative recurrence of Crohn’s disease. Gastroenterology 1998; 115:259–267. 43 Poggioli G, et al: Review article: Indication and type of surgery in Crohn’s disease. Aliment Pharmacol Ther 2002;16(suppl 4):59–64.


44 Milsom JW, et al: Prospective, randomized trial comparing laparoscopic vs. conventional surgery for refractory ileocolic Crohn’s disease. Dis Colon Rectum 2001;44: 1–9. 45 Scott NA, Hughes LE: Timing of ileocolonic resection for symptomatic Crohn’s disease – The patient’s view. Gut 1994;35:656–657. 46 Binder V, Hendriksen C, Kreiner S: Prognosis in Crohn’s disease based on results from a regional patient group from the county of Copenhagen. Gut 1985; 26:146–150. 47 Present DH, et al: Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980;302:981–987. 48 Oren R, et al: Methotrexate in chronic active Crohn’s disease: A double-blind, randomized, Israeli multicenter trial. Am J Gastroenterol 1997;92: 2203–2209. 49 Willoughby JM, et al: Controlled trial of azathioprine in Crohn’s disease. Lancet 1971;ii:944–947. 50 Rhodes J, et al: Controlled trial of azathioprine in Crohn’s disease. Lancet 1971;ii:1273– 1276. 51 Ewe K, et al: Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology 1993;105:367–732. 52 Candy S, et al: A controlled double-blind study of azathioprine in the management of Crohn’s disease. Gut 1995;37: 674–678. 53 Klein M, et al: Treatment of Crohn’s disease with azathioprine: A controlled evaluation. Gastroenterology 1974;66:916–922. 54 Pearson DC, et al: Azathioprine and 6-mercaptopurine in Crohn’s disease – A meta-analysis. Ann Intern Med 1995; 123:132–142. 55 O’Donoghue DP, et al: Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet 1978; ii:955–957. 56 Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C: Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease (Cochrane review). Update Software. Oxford, The Cochrane Library, 2003.

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57 Arora S, et al: Methotrexate in Crohn’s disease: Results of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology 1999; 46:1724–1729. 58 Feagan BG, 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. 59 Vandeputte L, et al: Methotrexate in refractory Crohn’s disease. Inflamm Bowel Dis 1999; 5: 11–15. 60 Lemann M, et al: Methotrexate for the treatment of refractory Crohn’s disease. Aliment Pharmacol Ther 1996;10:309–314. 61 Kozarek RA, et al: Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110:353–356. 62 Ricart E, et al: Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic: The first 100 patients. Am J Gastroenterol 2001; 96: 722–729. 63 Cohen RD: Efficacy and safety of repeated infliximab infusions for Crohn’s disease: Oneyear clinical experience. Inflamm Bowel Dis 2001; 7(suppl 1):17–22. 64 Hommes DW, et al: Infliximab treatment for Crohn’s disease: One-year experience in a Dutch academic hospital. Inflamm Bowel Dis 2002; 8:81–86. 65 Panis Y: Prise en charge chirurgicale des maladies inflammatoires chroniques de l’intestin: les consensus et les controverses. Gastroenterol Clin Biol 2003;27(suppl 3):92–97. 66 Ghosh S, et al: Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24–32. 67 Gordon F, et al: A randomized placebo-controlled trial of a humanized monoclonal antibody to 4 integrin in active Crohn’s disease. Gastroenterology 2001;121:268–274. 68 Rutgeerts P, et al: Subanalyses from a phase 3 study on the evaluation of natalizumab in active Crohn’s disease therapy-1 (ENACT-1). Gut 2003;52(suppl 6):A239

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Fistulizing Crohn’s Disease Christian Felleya Christian Motteta Pascal Juillerata Florian Froehlicha, b Bernard Burnandc John-Paul Vaderc Pierre Michettia Jean-Jacques Gonversa a


Key Words Crohn’s disease Fistula Antibiotics Azathioprine Infliximab Methotrexate Cyclosporine Tacrolimus Internal fistulas, surgery

Abstract Fistulas are common in Crohn’s disease. A populationbased study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%). Medical therapy is the main option for perianal fistula once abscesses, if present, have been drained, and should include antibiotics (both ciprofloxacin and metronidazole) and immunomodulators. Infliximab should be reserved for refractory patients. Surgery is often necessary for internal fistulas. Copyright © 2005 S. Karger AG, Basel

Introduction

Three main patterns have been described in the presentation of Crohn’s disease. Some patients have predominantly fistulizing disease, whereas other patients have either inflammatory or stricturing disease. Fistulas occur either in the perianal region or are internal, between



intestinal structures or between the intestine and other organs such as the bladder or the abdominal wall. Perianal fistulas can be classified as low (below the dentate line) or high (above the dentate line). A perianal fistula will furthermore be classified as simple if it is low, has a single external opening, is not painful, with no evidence of rectovaginal fistula and with no evidence of anorectal stricture [1]. A complex fistula is high, may have multiple external openings, may be associated with pain, with the presence of a rectovaginal fistula, anorectal stricture or active rectal disease at endoscopy. The diagnostic modalities may include examination under general anesthesia, fistulography, pelvic MRI and anorectal endoscopic ultrasound.

Natural History

The lifetime risk for developing fistulas in patients with Crohn’s disease has been reported to be between 20 and 40% in referral-center cohorts [2–4]. There are also two population-based studies [5, 6]. The Swedish study looked only at perianal fistulas and showed that their cumulative incidence was 23%. The American study analyzed any type of fistula and observed a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal

Christian Felley, MD Division of Gastroenterology and Hepatology Lausanne University Medical Center Rue du Bugnon 44, CH–1011 Lausanne (Switzerland) Tel. +41 21 3142394, Fax +41 21 3144718, E-Mail [email protected]

fistulas were the most common (54%). The second most common were entero-enteric (24%). Many of the patients (44%) developed a fistula at or before the diagnosis of Crohn’s disease. Most fistulizing episodes (83%) required operations. In contrast to referral-based studies, only 34% of patients developed recurrent fistulas.

Treatment

Available Treatments The main therapeutic options are medical therapy and surgical management. Simple fistulas can be treated with antibiotics, infliximab or fistulostomy. Complex fistulas should be treated with infliximab combined with azathioprine/6-mercaptopurine. The insertion of non-cutting setons is reserved for patients in whom medical therapy has failed. Treatment 1: Antibiotics An uncontrolled study evaluating 21 patients with fistulas showed an initial clinical response in 20 patients receiving metronidazole [7]. With a maintenance treatment, complete healing occurred in 10 out of 18. A follow-up study demonstrated that dosage reduction was associated with exacerbation in all patients and that the fistulas healed again promptly when the full dosage was resumed. However, the drug could be discontinued in only 28% of those in whom cessation was attempted. The major problem with metronidazole is that a high number of patients taking this agent have difficulty in tolerating it, complaining of nausea, fatigue and presenting peripheral neuropathy, especially if doses are 1750 mg daily [8]. In another uncontrolled study, Turunen et al. [9] studied 10 patients with fistulas and showed a 70% response by using 1–1.5 g of ciprofloxacin for a minimum of 3 months. Solomon et al. [10] retrospectively showed that the combination of ciprofloxacin and metronidazole in 14 patients with perianal fistulas healed the fistula in 3 patients and improved 85% of them. We can conclude from these studies that antibiotics are efficacious in the treatment of perianal fistulas, without inducing complete healing. Furthermore, withdrawal of these agents leads to re-exacerbation of the disease.

patients. 31% of the fistulas closed completely during the treatment with 6-mercapturine versus only 6% with placebo. The onset of response was often delayed, with 32% of the patients taking longer than 3 months to respond. These data were further expanded in an uncontrolled manner showing complete closure in 39%, improvement in 26% and no response in 35% [12]. A meta-analysis confirmed these results, showing that fistulas improved with azathioprine and 6-mercaptopurine (OR 4.44; CI 1.50–13.20) [13]. We can conclude from these studies that azathioprine/6-mercaptopurine are effective agents both in closing and in maintaining closure of fistulas. Treatment 3: Infliximab Infliximab is a chimeric monoclonal antibody against TNF-. An international study included 94 patients who were randomized to receive 3 infusions of either 5 mg/kg or 10 mg/kg infliximab versus placebo [14]. The primary end-point was a reduction in the number of draining fistulas of 50% or more on two consecutive visits and was achieved in 62% of patients with a 5-mg/kg dose. A complete closure was observed in 46% compared to 13% with placebo. A maintenance study has been published as an abstract [15]. All patients who responded to the first three infusions were then randomized to receive either infliximab 5 mg/kg or placebo every 8 weeks. Patients who were on treatment with infliximab had higher rates of fistula closure, as well as longer duration of fistula closure, compared to placebo. Treatment 4: Methotrexate In a small study in 16 patients with fistulizing disease, 4 (25%) had complete closure of fistulas and 5 (31%) a partial response [16]. With this limited evidence in mind, if a patient does not respond to azathioprine/6-mercaptopurine or does not tolerate it, methotrexate should be tried.

Treatment 2: Azathioprine/6-Mercaptopurine In 1980, Present et al. [11] described the efficacy of 6mecaptopurine in the treatment of Crohn’s disease. Among this collective, 40 fistulas were observed in 36

Treatment 5: Cyclosporin A Using intravenous cyclosporin A 4 mg/kg, Present and Lichtiger [17] showed that 14 out of 16 patients (88%) responded. Complete closure was observed in 7 (44%) and a moderate improvement in the other 7 (44%). Other uncontrolled studies obtained similar results [18, 19]. On the basis of these studies, it is reasonable to use cyclosporin A in the treatment of fistulizing Crohn’s disease. All patients treated in the acute phase with cyclosporin A should receive concomitant azathioprine/6-mercaptopurine or methotrexate for maintenance treatment.

Fistulas in Crohn’s Disease

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Treatment 6: Tacrolimus (FK506) A randomized placebo-controlled study on the use of tacrolimus for the treatment of perianal and enterocutaneous fistulas in patients with Crohn’s disease was recently published [1]. Oral tacrolimus at an initial dose of 0.2 mg kg–1 day–1 was effective for fistula improvement but not fistula remission in patients with perianal Crohn’s disease. The authors found no evidence of efficacy in patients with abdominal fistulas. Treatment 7: Surgical Management There are no controlled trials comparing surgical treatment with medical therapy. The majority of perianal fistulas are initially associated with an abscess which either drains spontaneously or must be drained surgically. Patients with low anal fistulas can be treated by fistulotomy [20]. However, there is the risk of a non-healing wound following this procedure. This is the reason why some surgeons are in favor of a non-cutting seton in such a situation, especially when there is an active inflammation of the rectosigmoid colon. In patients with high fistulas, non-cutting setons are the procedure of choice [21].

If the disease is refractory to currently available treatment, proctectomy may be necessary to allow an adequate quality of life. Furthermore, internal fistulas are usually associated with a more aggressive disease and surgery is thus more often required than in perianal fistulas.

Synthesis

The management of fistulizing Crohn’s disease necessitates a close collaboration between the gastroenterologist and the surgeon. A review has recently proposed an algorithm for the diagnosis and treatment of perianal Crohn’s fistula [22]. Abscesses should always be drained, preferably by a colorectal surgeon. Antibiotics are indicated and both ciprofloxacin and metronidazole should be given. Immunomodulators such as azathioprine/6mercaptopurine or methotrexate should be given early in the disease. In the case of resistance to immunomodulators, infliximab should be given. Cyclosporin A or tacrolimus should be tried in patients who fail to respond to infliximab.

References 1 Sandborn WJ, et al: Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: A randomized, placebo-controlled trial. Gastroenterology 2003; 125:380–388. 2 Steinberg DM, Cooke WT, Alexander-Williams J: Abscess and fistulae in Crohn’s disease. Gut 1973; 14:865–869. 3 Farmer RG, Hawk WA, Turnbull RB Jr: Clinical patterns in Crohn’s disease: A statistical study of 615 cases. Gastroenterology 1975;68: 627–635. 4 Rankin GB, et al: National Cooperative Crohn’s Disease Study: Extraintestinal manifestations and perianal complications. Gastroenterology 1979;77: 914–920. 5 Hellers G, et al: Occurrence and outcome after primary treatment of anal fistulae in Crohn’s disease. Gut 1980;21:525–527. 6 Schwartz DA, et al: The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology 2002; 122: 875– 880. 7 Bernstein LH, et al: Healing of perineal Crohn’s disease with metronidazole. Gastroenterology 1980;79:357–365. 8 Brandt L, et al: Metronidazole therapy for perineal Crohn’s disease: A follow-up study. Gastroenterology 1982;83:383–387.

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9 Turunen U, et al: Long-term outcome of ciprofloxacin treatment in severe perianal or fistulous Crohn’s disease. Gastroenterology 1993; 104:A793 (abstract). 10 Solomon MJ, et al: Combination ciprofloxacin and metronidazole in severe perianal Crohn’s disease. Can J Gastroenterol 1993; 7: 571– 573. 11 Present DH, et al: Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980;302:981–987. 12 Korelitz BI, Present DH: Favorable effect of 6-mercaptopurine on fistulae of Crohn’s disease. Dig Dis Sci 1985;30: 58–64. 13 Pearson DC, et al: Azathioprine and 6-mercaptopurine in Crohn’s disease – A meta-analysis. Ann Intern Med 1995; 123:132–142. 14 Present DH, et al: Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340:1398–1405. 15 Sands B, et al: Maintenance infliximab is safe and effective in fistulizing Crohn’s disease: Results from the ACCENT II trial. Am J Gastroenterol 2002; 97:787.

16 Mahadevan U, Marion JF, Present DH: The place for methotrexate in the treatment of refractory Crohn’s disease. Gastroenterology 1997; 112:A1031. 17 Present DH, Lichtiger S: Efficacy of cyclosporine in treatment of fistula of Crohn’s disease. Dig Dis Sci 1994;39:374–380. 18 Hanauer SB, Smith MB: Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993; 88:646–649. 19 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. 20 Williamson PR, et al: Twenty-year review of the surgical management of perianal Crohn’s disease. Dis Colon Rectum 1995;38: 389–392. 21 Faucheron JL, et al: Long-term seton drainage for high anal fistulas in Crohn’s disease – A sphincter-saving operation? Dis Colon Rectum 1996;39:208–211. 22 Schwartz DA, Pemberton JH, Sandborn WJ: Diagnosis and treatment of perianal fistulas in Crohn’s disease. Ann Intern Med, 2001; 135: 906–918.

Felley/Mottet/Juillerat/Froehlich/ Burnand/Vader/Michetti/Gonvers



Obstructive Fibrostenotic Crohn’s Disease Florian Froehlicha, b Pascal Juillerata Christian Motteta Christian Felleya John-Paul Vaderc Bernard Burnandc Jean-Jacques Gonversa Pierre Michettia a


Key Words Crohn’s disease Stenosis Obstruction Strictures Surgical resection Stricturoplasty Balloon dilation

Abstract Crohn’s disease is often complicated by gastrointestinal strictures. Postoperative recurrence at the anastomotic site is common and repeated surgical interventions may be necessary. Medical treatment may relieve active inflammation (see chapter on active luminal disease) but fibrous strictures will not respond to this. Mechanical treatment methods consist of endoscopic balloon dilation, stricturoplasty or surgical resection. Fibrostenotic Crohn’s disease does not respond to medical therapy and requires endoscopic or surgical treatment. Copyright © 2005 S. Karger AG, Basel

Introduction

Obstructive symptoms are the main indication for surgery in Crohn’s disease affecting the small intestine or the ileocecal region [1]. Strictures are generally silent until the luminal caliber is so reduced that it causes obstruction. Strictures are a common complication of Crohn’s disease



and occur mostly in the ileocecal region. Recurrence of disease after surgery is common (see chapter 6, postoperative maintenance of Crohn’s disease). Not all obstructive situations in Crohn’s disease are caused by a fibrotic stricture; edema may also enhance the degree of stenosis. Unless there is a clear-cut positive response to anti-inflammatory therapy (steroid test [2]), it may be extremely difficult to differentiate between a fibrostenotic and an inflammatory stricture [3].

Treatment

Available Treatments Treatment 1: Surgical Resection Limited surgical resection effectively relieves obstruction in symptomatic stenotic Crohn’s disease. However, recurrence of inflammation and fibrosis and the need for repeated surgery increases the risk of short bowel syndrome. Resection is typically used when it is the first surgery for Crohn’s disease. Wide resection margins do not seem to be helpful. Thus, a prospective randomized study in 131 patients found similar recurrence rates whether margins were 2 or 12 cm [4]. Resection with or without stricturoplasty has a significant beneficial impact on patients’ quality of life [5]. This chapter does not address

Florian Froehlich, MD Division of Gastroenterology and Hepatology Lausanne University Medical Center Rue du Bugnon 44, CH–1011 Lausanne (Switzerland) Tel. +41 32 4662255, Fax +41 32 4662955, E-Mail [email protected]

the issue of resective surgery for acute or chronic active Crohn’s disease which is resistant to medical treatment or of anorectal disease. Treatment 2: Stricturoplasty Surgery is seldom curative in Crohn’s disease and thus more conservative methods than resection alone were developed. Stricturoplasty consists of increasing the diameter of the lumen without resection. Stricturoplasty is useful in patients with extensive disease with fibrotic strictures who may have undergone previous resections and are susceptible to the short bowel syndrome [6]. Stricturoplasty is contraindicated in patients with active sepsis or fistula. Surgical stricturoplasty is as effective as resection of the diseased segment for treatment of obstructive symptoms; reoperation rates and time to recurrence of symptoms are comparable (see chapter 6, postoperative maintenance of Crohn’s disease) [7–9]. Treatment 3: Endoscopic Balloon Dilation In endoscopically accessible strictures, balloon dilation has the advantage of being minimally invasive and of preserving intestinal length. There are no randomized trials comparing the different methods of dilation. In a

study by Couckuyt et al. [10], 55 patients with ileocolonic strictures were prospectively followed during a median time period of 33 months after endoscopic balloon dilation. Dilation was technically successful in 90%, and the endoscope could pass the stricture in 73% of the dilations. The total long-term success rate (symptom relief, no need for surgery) was 62%. 38% of the patients were operated on because of persistent obstructive symptoms. Complications occurred in 6 patients (11%). In this series, the presence of active disease was not associated with poor response to dilation [10]. A retrospective study by Dear and Hunter [11] in 22 patients with strictures and a follow-up period of nearly 7 years showed pain relief in 16 patients (72%). Surgery was ultimately required in 6 patients (27%). The authors did not report on complications. A third recently published study [12] was a retrospective case note review over 16 years (median follow-up 29 months) in 59 patients with 124 dilations. 41% of the patients achieved long-term relief while 59% required surgery for their stricture during follow-up. Two perforations occurred. Dilation followed by intralesional steroid injection has not been studied in any series in more than 12 patients [1].

References 1 Legnani PE, Kornbluth A: Therapeutic options in the management of strictures in Crohn’s disease. Gastrointest Endosc Clin N Am 2002;12: 589–603. 2 Sandborn WJ, et al: A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology 2002; 122:512–530. 3 Sands BE: Crohn’s Disease. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, ed 7. New York, Elsevier, 2002, pp 2005– 2038. 4 Fazio VW, et al: Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. A randomized controlled trial. Ann Surg 1996; 224:563–573.

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5 Thirlby RC, et al: Effect of surgery on healthrelated quality of life in patients with inflammatory bowel disease: A prospective study. Arch Surg 1998;133:826–832. 6 Fazio VW, et al: Long-term follow-up of strictureplasty in Crohn’s disease. Dis Colon Rectum 1993;36: 355–361. 7 Dietz DW, et al: Safety and long-term efficacy of strictureplasty in 314 patients with obstructing small bowel Crohn’s disease. J Am Coll Surg 2001;192:330–338. 8 Sayfan J, et al: Recurrence after strictureplasty or resection for Crohn’s disease. Br J Surg 1989;76: 335–338.

9 Cristaldi M, et al: Long-term results and multivariate analysis of prognostic factors in 138 consecutive patients operated on for Crohn’s disease using ‘bowel-sparing’ techniques. Am J Surg 2000;179:266–270. 10 Couckuyt H, et al: Efficacy and safety of hydrostatic balloon dilatation of ileocolonic Crohn’s strictures: A prospective long-term analysis. Gut 1995;36:577–580. 11 Dear KL, Hunter JO: Colonoscopic hydrostatic balloon dilatation of Crohn’s strictures. J Clin Gastroenterol 2001;33:315–318. 12 Thomas-Gibson S, et al: Colonoscopic balloon dilation of Crohn’s strictures: A review of longterm outcomes. Eur J Gastroenterol Hepatol 2003; 15:485–488.

Froehlich/Juillerat/Mottet/Felley/Vader/ Burnand/Gonvers/Michetti



Extraintestinal Manifestations of Crohn’s Disease Pascal Juillerata Christian Motteta Florian Froehlicha, b Christian Felleya John-Paul Vaderc Bernard Burnandc Jean-Jacques Gonversa Pierre Michettia a


Key Words Crohn’s disease Inflammatory bowel disease Extraintestinal manifestations Ankylosing spondylitis Pyoderma gangrenosum Primary sclerosing cholangitis Uveitis Extraintestinal manifestations of CD, treatment

Abstract In each case of extraintestinal manifestations of Crohn’s disease, active disease, if present, should be treated to induce remission, which may positively influence the course of most concomitant extraintestinal manifestations. For some extraintestinal manifestations, however, a specific treatment should be introduced. This latter part of disease management will be discussed in this chapter, in particular for pyoderma gangrenosum, uveitis, spondylarthropathy – axial arthropathy – and primary sclerosing cholangitis, which have also been described in quiescent Crohn’s disease. Few new drugs for the treatment of extraintestinal manifestations of Crohn’s disease have been developed in the past and only the role of infliximab has increased in Crohn’s disease-related extraintestinal manifestations. Drugs specifically aimed at this treatment, stemming from a few randomized controlled studies or case series, are sulfasalazine, 5-ASA, corticoste-



roids, azathioprine or 6-mercaptopurine, methotrexate, infliximab, dapsone and cyclosporine or tacrolimus. Copyright © 2005 S. Karger AG, Basel

Introduction

Because many inflammatory bowel disease (IBD) patients will develop an extraintestinal manifestation (EIM) at least once in the course of their illness and the occurrence of a first EIM predisposes to additional hits [1, 2], it is thus very important to consider and accurately diagnose the extraintestinal clinical presentations of Crohn’s disease (CD). Erythema nodosum, iridocyclitis, and peripheral asymmetric oligoarthritis are generally associated with a flare of the intestinal disease and are managed by treating the intestinal disease. Given that EIMs of CD mainly run parallel to the intestinal disease, using a specific treatment for EIM is rare and happened only with primary sclerosing cholangitis (PSC), pyoderma gangrenosum (PG), ankylosing spondylitis (AS) and uveitis, which may have an independent course. The management of these latter EIMs is the main subject of this chapter. Because of the low prevalence of some of these clinical situations, the treatment of EIMs has almost never been


studied in well-designed randomized controlled trials and thus most therapy regimens are empiric or deduced from studies in patients presenting these EIMs in association with other underlying diseases. In the context of this chapter, which mainly considers the independent forms of EIMs of CD, it is important to consider the potential harmful effects when choosing a therapy.

Definitions

Extraintestinal Manifestations of Crohn’s Disease Inflammatory manifestations outside of the digestive tract, related to underlying disease activity (peripheral arthritis, erythema nodosum or aphtous ulcers, episcleritis), or independent (PG, uveitis, spondylarthropathy – axial arthropathy, PSC) [3]. Extradigestive associated diseases (gallstones, nephrolithiasis) and non-disease-specific complications (amyloidosis, osteoporosis, thromboembolic complications) are not included [4]. Extraintestinal side effects of CD therapy are excluded.

Occurrence

EIMs occur in 21–36% of patients with IBD during their disease history [1, 5–9]. Joint involvement is the most frequent manifestation, with a prevalence of 10– 35%. Peripheral arthritis is very common, whereas AS (spondylarthropathies) affects 2–8% [1, 5–8, 10]. Cutaneous EIMs, not including perianal cutaneous lesions of CD such as fistulas and anal fissures, consist essentially of erythema nodosum (6–15% of CD patients) [8, 11], and PG (0.1–1.2%) [12–14]. PSC (with a prevalence of 2.5– 7.5%) is associated with colonic involvement in IBD [15]. Finally, anterior uveitis (or iridocyclitis), already mentioned by Crohn and Oppenheimer [16] in 1932, is described in 4–6% of CD patients [1, 5, 6, 8] with a higher prevalence in patients with joint (AS, HLA-B27-positive patients) and skin abnormalities.

Treatment

Treatment of Ankylosing Spondylitis It is generally accepted that the treatment of the intestinal disease must take precedence, as in many cases this will reduce joint inflammation as well. When the arthropathy exists, or persists, independently of the intestinal

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disease, it should be treated with caution as a primary articular disease so as not to aggravate intestinal CD. For example, non-steroidal anti-inflammatory drugs (NSAIDs) [17], including COX-2-selective inhibitors, which may potentially activate IBD [18–20], should, if possible, be replaced by acetaminophen or tramadol for pain control. The first-choice therapy for axial involvement of arthritis is sulfasalazine, associated with rest and physiotherapy [21]. At least ten double-blind studies have evaluated the efficacy of sulfasalazine, but none included patients with IBD arthropathies. A meta-analysis of five randomized controlled studies in 1990 concluded that there are some beneficial effects of sulfasalazine therapy [22] in AS, but this was followed by two large multicenter trials showing that efficacy of this treatment was limited to the peripheral joint involvement of the disease [23– 25]. While less well evaluated, the use of mesalamine is supported by the results of two small studies [21, 26, 27]. The first, conducted by Thomson et al. [26] in 30 patients with AS, was a 16-week open-label study with a mesalamine dose range between 1,500 and 4,000 mg. The treatment was well tolerated and all clinical and laboratory measures indicated efficacy of mesalamine in treating AS. In the second study, 20 AS patients under sulfasalazine treatment were switched to 5-ASA, with the same effectiveness. In selected cases of severe forms of AS, the use of corticosteroid therapy could be required [28]. The use of intravenous steroid therapy is poorly documented. In 1992, Peters et al. [29] described in a double-blind study a dose-independent relief of symptoms, using a high dose (1,000 mg) and a low dose (375 mg) of methylprednisolone given intravenously. To reduce long-term side effects, an MRI-guided corticosteroid injection in the sacroiliac joint could be appropriate [30]. The only report on azathioprine for the treatment of AS was (published as an abstract) a controlled doubleblind study versus sulfasalazine. In this study, Brandt et al. [31] reported, in a small group of 32 patients, the same response rate (66%) for both drugs, but a significantly higher level of adverse events for azathioprine. Methotrexate alone or in a combined therapy with infliximab has a well-documented effectiveness in rheumatological disease such as rheumatoid arthritis [32]. However, for AS, a large placebo-controlled trial is lacking. Thus, methotrexate should rather be used for patients in whom analgesics and anti-inflammatory drugs proved to be insufficient [25, 33]. The safety and efficacy of infliximab therapy was explored in several clinical situations associated with CD.

Juillerat/Mottet/Froehlich/Felley/Vader/ Burnand/Gonvers/Michetti

Van den Bosch et al. [34] reported the first results, an improvement of articular manifestations in 4 patients suffering from CD-associated spondylarthropathy. In the last 5 years, two randomized controlled trials have shown good evidence for the effectiveness of the use of infliximab in the treatment of AS [35, 36]. Infliximab is now approved for the treatment of AS, not IBD-associated and insufficiently treated with NSAIDs and sulfasalazine. One randomized controlled multicenter study in 70 patients [35] was performed in Germany and completed by an observational study to evaluate the safety and longterm efficacy of infliximab [37]. In this study, the primary outcome (a 50% improvement in rheumatological disease activity) was achieved in 53% (18/34) of patients treated with infliximab compared to 9% (3/35) on placebo (p ! 0.0001). Van den Bosch et al. [36] conducted another randomized controlled trial with 40 patients with spondylarthropathies, of whom 19 patients had AS. At study endpoint, a significant clinical and laboratory improvement was observed in the infliximab group, but not in the placebo group. Maksymowych et al. [38] recently published a randomized controlled double-blind dose-response intravenous trial with pamidronate in 84 patients with NSAIDrefractory AS. A placebo-controlled trial was in fact not possible because of significant post-infusion arthralgia and myalgia. Patients were assigned to two groups receiving respectively 10 and 60 mg of pamidronate on a monthly basis over 6 months. At 6 months, significantly greater reduction (p = 0.003) in the mean AS disease activity scores (BASDAI, BASFI, BASGI, BASMI) were observed in the 60-mg group. This study confirms prior results obtained by the same group in an open study in 16 patients [39] and a prior report on the clinical and radiological assessment of the efficacy of pamidronate in axial joint involvement [40]. These results suggest that bisphosphonate therapy, underused in IBD patients because of frequent gastrointestinal adverse events, should probably be considered as an alternative for the treatment of SPA. Treatment of Pyoderma gangrenosum Topical treatment alone is usually insufficient in patients with PG, either associated with systemic disease or occurring alone [13, 14] and should thus only be considered as an adjuvant to a combined therapy. Measures directed at cleaning the ulcer and preventing bacterial overgrowth are, however, important. More invasive surgical debridement should be discouraged as it may trigger new lesions (pathergy) [41–43].

Extraintestinal Manifestations of Crohn’s Disease

Topical use of 5-ASA has been reported [44] for PG, but only in 1 CD patient receiving concomitant systemic steroid therapy. In many reports on other drugs, patients who develop PG also receive 5-ASA compounds, a treatment which seems to bring only a limited benefit, possibly only in treating associated intestinal disease. Steroids are the most effective and the first-intention treatment for acute and subacute forms of PG, described in association with IBD [13, 45, 46]. High-dose intravenous steroid pulse therapy is recommended for refractory cases [47]. Prystowsky et al. [48] noted good clinical results in 6 of 8 PG patients treated with methylprednisolone over 3–5 days. Cyclosporine and tacrolimus are also effective drugs for PG [46, 49–51]. After low-dose cyclosporine, 10 of 11 patients cleared rapidly and completely their PG [52]. In a retrospective analysis of 11 steroid-refractory IBD-associated (5 UC, 6 CD) PG cases, a closure of the PG within 4–5 days, independently of intestinal disease activity, was observed with cyclosporine. This analysis further suggests the use of 6-mercaptopurine or azathioprine as maintenance therapy [53]. Azathioprine could be used in the long-term treatment of PG for its steroid-sparing activity [13, 54]. The effectiveness of infliximab for CD-associated PG is reported in many articles and abstracts [55–60]. Tan et al. [61] reported the first promising results in 2 PG-associated CD patients. Then, two groups, in Sweden [57] and North America [62] respectively, described in small retrospective series of patients with PG-associated CD that infliximab had a therapeutic potential for skin manifestations associated with IBD. However, they observed that successful treatment may require repeated courses of infliximab and that the majority of patients had to be maintained on infliximab. Dapsone can be prescribed alone or in combination with systemic steroids for the treatment of recurrent PG [63, 64]. Its use is probably deduced from its effectiveness in other skin diseases with abnormal accumulation of leukocytes, such as dermatitis herpetiformis and Sweet syndrome [46]. Clofazidime – used to treat leprosy – is not recommended for the treatment of IBD-associated PG, as it could lead to an exacerbation of the disease [65–67]. Treatment of Primary Sclerosing Cholangitis In a randomized placebo-controlled study in 100 patients at the Mayo Clinic receiving ursodeoxycholic acid (UDCA 10–15 mg/kg/day) as monotherapy, significant improvement of serum transaminase levels was observed

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[68]. However, during a 2-year follow-up period, no success in clinically relevant end-points such as ascites, encephalopathy and death were observed. Adding budesonide to UDCA therapy was superior to UDCA alone in a 2-year prospective controlled double-blind study in terms of laboratory values and liver histology [69]. In contrast, however, a randomized double-blind study with 104 PSC patients conducted by van Hoogstraten et al. [70] suggested only minor and short-term benefits on symptoms and liver enzymes with prednisone-UDCA combined treatment, and no benefit with budesonide-UDCA. The efficacy of methotrexate has been compared to placebo in 24 patients over a 2-year period by Knox and Kaplan [71], and a combination therapy of methotrexate and UDCA was attempted prospectively at the Mayo Clinic [72]. These two studies did not show any therapeutic efficacy. Combination therapy had substantial toxicity (20% of patients discontinued therapy). In a 1-year double-blind trial, 26 PSC patients associated with ulcerative colitis (UC) were randomized to receive low-dose cyclosporine (4.1 mg/kg/day, n = 16) or placebo (n = 10). The results confirmed the effectiveness of low-dose cyclosporine in the maintenance treatment of intestinal disease in mild-moderate UC patients with PSC [73]. Tacrolimus was used in a 10-patient open trial and showed a rapid decrease in liver enzyme levels (from 70 to 86%), but no histological improvement after 1 year [74]. Treatment of Anterior Uveitis (Iridocyclitis) Topical steroid and cycloplegics application is usually sufficient to treat anterior uveitis and is therefore the most commonly employed therapy [75]. However, longterm topical application may exacerbate cataract and glaucoma. The use of immunosuppression, azathioprine in particular, for uveitis associated with IBD, was described by Soukiasian et al. [76], who reported a limited effectiveness after NSAID failure. A successful treatment for IBD-associated uveitis with infliximab was described in 1 CD patient having an extraintestinal constellation (sacroileitis and uveitis) [77]. Retrospective small-scale reports including patients with uveitis and associated rheumatic disease and patients with Behçet’s disease and sight-threatening uveitis have also been published [78–80]. Finally, a number of abstracts suggest that inhibition of tumor necrosis factor- may be effective in uveitis associated with rheumatoid disease [81– 83].

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Synthesis

Treatment of EIM is often empirical. The first step is to determine whether or not intestinal disease activity is responsible for the EIM, which could orient subsequent management. Mesalamine has no real proven efficacy, outside of musculoskeletal manifestations. Its use relies rather on the reputation of sulfasalazine. The acute development of EIM in CD, even if intestinal disease activity is low, is in practice an indication for systemic corticosteroid therapy [84], but this should be limited to topical use (eyedrops, cutaneous or intra-articular injections), or short-term treatment, given their toxicity. Other immunosuppressive agents, such as azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus are reported in small case series and may be considered as good alternative treatments or as steroid-sparing agents. Infliximab should be considered when conventional therapy fails to control the musculoskeletal, cutaneous or ocular manifestations of CD. The medical management of PSC treatment remains unsatisfactory [15]. No immunosuppressive agent has been proven successful and, in most cases, PSC progresses insidiously, leading to cirrhosis. PSC is an important risk factor for cholangiocarcinoma (8–15%/year), which can only be prevented by hepatic transplantation [4, 15, 75, 85]. It is also associated with an increased risk of colorectal cancer, which may be prevented with UDCA [86].

Limitations

Due to the low prevalence of EIMs of CD described in this chapter, treatment remains empirical and is only supported by small case series in the literature. The lack of evidence is particularly notable for PSC and uveitis.


References 1 Rankin GB, et al: National Cooperative Crohn’s Disease Study: Extraintestinal manifestations and perianal complications. Gastroenterology 1979;77: 914–920. 2 Gasché C: Extraintestinale Manifestationen der chronisch entzündlichen Darmerkrankungen. Chir Gastroenterol 1998;14: 120–125. 3 Parsi MA, et al: Extraintestinal manifestations of Crohn’s disease respond to infliximab. Am J Gastroenterol 2002;97:S265. 4 Adler G, et al: Extraintestinal manifestations (in German). Z Gastroenterol 2003; 41: 54– 61. 5 Su CG, Judge TA, Lichtenstein GR: Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Clin North Am 2002; 31:307–327. 6 Greenstein AJ, Janowitz HD, Sachar DB: The extraintestinal complications of Crohn’s disease and ulcerative colitis: A study of 700 patients. Medicine 1976; 55:401–412. 7 Farmer RG, Hawk WA, Turnbull RB, Jr: Clinical patterns in Crohn’s disease: A statistical study of 615 cases. Gastroenterology 1975;68: 627–635. 8 Veloso FT, Carvalho J, Magro F: Immune-related systemic manifestations of inflammatory bowel disease. A prospective study of 792 patients. J Clin Gastroenterol 1996;23: 29–34. 9 Triantafillidis JK, et al: Clinical patterns of Crohn’s disease in Greece: A follow-up study of 155 cases. Digestion 2000;61: 121–128. 10 Katz JP, Lichtenstein GR: Rheumatologic manifestations of gastrointestinal diseases. Gastroenterol Clin North Am 1998; 27: 533– 562. 11 Bernstein CN, et al: The prevalence of extraintestinal diseases in inflammatory bowel disease: A population-based study. Am J Gastroenterol 2001;96:1116–1122. 12 Tromm A, et al: Cutaneous manifestations in inflammatory bowel disease. Z Gastroenterol 2001;39:137–144. 13 Chow RK, Ho VC: Treatment of pyoderma gangrenosum. J Am Acad Dermatol 1996; 34: 1047–1060. 14 Powell FC, Su WP, Perry HO: Pyoderma gangrenosum: Classification and management. J Am Acad Dermatol 1996;34: 395–412. 15 Raj V, Lichtenstein DR: Hepatobiliary manifestations of inflammatory bowel disease. Gastroenterol Clin North Am 1999;28: 491–513. 16 Crohn BB, Ginzburg L, Oppenheimer GD: Regional enteritis: A pathological and clinical entity. JAMA 1932;99: 1323–1329. 17 Hayllar J, et al: Side effects of non-steroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104:1832–1847. 18 McCartney SA, et al: Selective COX-2 inhibitors and human inflammatory bowel disease. Aliment Pharmacol Ther 1999; 13: 1115– 1117.

Extraintestinal Manifestations of Crohn’s Disease

19 Cipolla G, et al: Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: Current perspectives. Pharmacol Res 2002;46: 1–6. 20 Evans J, et al: Non-steroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease. Gut 1997;40: 619–622. 21 Fornaciari G, et al: Musculoskeletal manifestations in inflammatory bowel disease. Can J Gastroenterol 2001;15:399–403. 22 Ferraz MB, et al: Meta-analysis of sulfasalazine in ankylosing spondylitis. J Rheumatol 1990; 17:1482–1486. 23 Clegg DO, et al: Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis – A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39: 2004–2012. 24 Dougados M, et al: Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995;38:618–627. 25 Dougados M, et al: Conventional treatments for ankylosing spondylitis. Ann Rheum Dis 2002;61: 40–50. 26 Thomson GT, et al: Clinical efficacy of mesalamine in the treatment of the spondyloarthropathies. J Rheumatol 2000;27: 714–718. 27 Dekker-Saeys BJ, Dijkmans BA, Tytgat GN: Treatment of spondyloarthropathy with 5aminosalicylic acid (mesalazine): An open trial. J Rheumatol 2000;27:723–726. 28 Salvarani C, et al: Musculoskeletal manifestations in inflammatory bowel disease. Eur J Intern Med 2000; 11:210–214. 29 Peters ND, Ejstrup L: Intravenous methylprednisolone pulse therapy in ankylosing spondylitis. Scand J Rheumatol 1992; 21:134–138. 30 Maugars Y, et al: Assessment of the efficacy of sacroiliac corticosteroid injections in spondylarthropathies: A double-blind study. Br J Rheumatol 1996;35: 767–770. 31 Brandt J, et al: Efficacy of treatment of sulfasalazine versus azathioprine in ankylosing spondylitis. J Rheumatol 2000; 27(suppl 59): 55. 32 Maini R, et al: Infliximab (chimeric anti-tumour necrosis factor- monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomised phase III trial. Lancet 1999; 354: 1932–1939. 33 Van Bodegraven A, Pena A: Treatment of extraintestinal manifestations in inflammatory bowel disease. Curr Treat Options Gastroenterol 2003; 6:201–212. 34 Van den Bosch F, et al: Crohn’s disease associated with spondyloarthropathy: Effect of TNF blockade with infliximab on articular symptoms. Lancet 2000;356:1821–1822. 35 Braun J, et al: Treatment of active ankylosing spondylitis with infliximab: A randomised controlled multicentre trial. Lancet 2002;359: 1187–1193.

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36 Van den Bosch F, et al: Randomized doubleblind comparison of chimeric monoclonal antibody to tumor necrosis factor- (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum 2002;46:755–765. 37 Brandt J, et al: Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: An open, observational, extension study of a three-month, randomized, placebocontrolled trial. Rheumatology 2003;42:1018– 1020. 38 Maksymowych WP, et al: A six-month randomized, controlled, double-blind, dose-response comparison of intravenous pamidronate (60 vs. 10 mg) in the treatment of nonsteroidal anti-inflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum 2002;46:766–773. 39 Maksymowych WP, et al: An open study of pamidronate in the treatment of refractory ankylosing spondylitis. J Rheumatol 1998; 25: 714–717. 40 Maksymowych WP, et al: Clinical and radiological amelioration of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy. J Rheumatol 2001; 28: 144– 155. 41 Bernstein CN: Treatment of the extraintestinal manifestations of inflammatory bowel disease. Curr Gastroenterol Rep 2002; 4:513–516. 42 Rozen SM, Nahabedian MY, Manson PN: Management strategies for pyoderma gangrenosum: Case studies and review of literature. Ann Plast Surg 2001;47:310–315. 43 Kaddoura IL, Amm C: A rationale for adjuvant surgical intervention in pyoderma gangrenosum. Ann Plast Surg 2001;46:23–28. 44 Sanders CJ, Hulsmans RF: Successful treatment of pyoderma gangrenosum with topical 5-aminosalicylic acid. Cutis 1993; 51: 262– 264. 45 Futami H, et al: Pyoderma gangrenosum complicating ulcerative colitis: Successful treatment with methylprednisolone pulse therapy and cyclosporine. J Gastroenterol 1998; 33: 408–411. 46 Eisen AZ: Fitzpatrick’s Dermatology in General Medicine, ed 5. New York, McGraw-Hill, 2000, pp 1140–1148. 47 Johnson R, Lazarus G: Pulse therapy: Therapeutic efficacy in the treatment of pyoderma gangrenosum. Arch Dermatol 1982; 11: 76– 84. 48 Prystowsky JH, Kahn SN, Lazarus GS: Present status of pyoderma gangrenosum – Review of 21 cases. Arch Dermatol 1989;125:57–64. 49 Jolles S, Niclasse S, Benson E: Combination oral and topical tacrolimus in therapy-resistant pyoderma gangrenosum. Br J Dermatol 1999; 140:564–565. 50 Abu-Elmagd K, et al: Efficacy of FK506 in the treatment of recalcitrant pyoderma gangrenosum. Transplant Proc 1991;23:3328–3329.

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51 Schuppe HC, et al: Topical tacrolimus for pyoderma gangrenosum. Lancet 1998;351:832. 52 Matis WL, et al: Treatment of pyoderma gangrenosum with cyclosporine. Arch Dermatol 1992;128:1060–1064. 53 Friedman S, et al: Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease. Inflamm Bowel Dis 2001;7:1–7. 54 Rapini RP: Cytotoxic drugs in the treatment of skin disease. Int J Dermatol 1991; 30: 313– 322. 55 Arnott ID, et al: Clinical use of infliximab in Crohn’s disease: The Edinburgh experience. Aliment Pharmacol Ther 2001; 15: 1639– 1646. 56 Hong JJ, Merel NH, Hanauer SB: Treatment of pyoderma gangrenosum complicating Crohn’s disease with infliximab. Gastroenterology 2001; 120:3153. 57 Ljung T, et al: Pyoderma gangrenosum associated with Crohn’s disease: Effect of TNF- blockade with infliximab. Scand J Gastroenterol 2002; 37: 1108–11010. 58 Regueiro M, et al: Successful treatment of IBDassociated pyoderma gangrenosum with infliximab. Gastroenterology 2002;122:W1357. 59 Triantafillidis JK, et al: Favorable response to infliximab treatment in a patient with active Crohn’s disease and pyoderma gangrenosum. Scand J Gastroenterol 2002;37: 863–865. 60 Foster EN, et al: Cutaneous manifestations of inflammatory bowel disease improve with infliximab therapy. Gastroenterology 2002;122: W1366. 61 Tan MH, et al: Improvement of pyoderma gangrenosum and psoriasis associated with Crohn’s disease with anti-tumor necrosis factor- monoclonal antibody. Arch Dermatol 2001;137:930–933. 62 Regueiro M, et al: Infliximab for treatment of pyoderma gangrenosum associated with inflammatory bowel disease. Am J Gastroenterol 2003;98:1821–1826. 63 Brown RE, Lay L, Graham D: Bilateral pyoderma gangrenosum of the hand: Treatment with dapsone. J Hand Surg [Br] 1993;18: 119– 121.

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64 Zhu YI, Stiller MJ: Dapsone and sulfones in dermatology: Overview and update. J Am Acad Dermatol 2001;45:420–434. 65 Brandt L, et al: Pyoderma gangrenosum associated with regional enteritis. Improvement in defective granulocyte function and healing of skin lesions during administration of clofazimine. Acta Med Scand 1977; 201:141–144. 66 Kaplan B, et al: Treatment of pyoderma gangrenosum with clofazimine. Int J Dermatol 1992;31: 591–593. 67 Kark EC, Davis BR: Clofazimine treatment of pyoderma gangrenosum. J Am Acad Dermatol 1981;5:346–348. 68 Lindor KD: The Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group: Ursodiol for Primary Sclerosing Cholangitis. N Engl J Med 1997;336:691–695. 69 Leuschner M, et al: Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: Results of a prospective doubleblind trial. Gastroenterology 1999; 117: 918–925. 70 Van Hoogstraten HJF, et al: Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: A randomized double-blind pilot study. Am J Gastroenterol 2000;95:2015–2022. 71 Knox TA, Kaplan MM: A double-blind controlled trial of oral-pulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology 1994; 106:494–499. 72 Lindor KD, et al: Ursodeoxycholic acid and methotrexate for primary sclerosing cholangitis: A pilot study. Am J Gastroenterol 1996;91: 511–515. 73 Sandborn W, et al: Ulcerative colitis disease activity following treatment of associated primary sclerosing cholangitis with cyclosporin. Gut 1993;34:242–246. 74 Van Thiel DH, et al: Tacrolimus (FK506), a treatment for primary sclerosing cholangitis: Results of an open-label preliminary trial. Am J Gastroenterol 1995; 90:455–459. 75 Seibold F, Oneta CM, Michetti P: Traitement des pathologies intestinales inflammatoires chroniques et de leurs complications. Forum Méd Suisse 2002;48:1115–1118.

76 Soukiasian SH, Foster CS, Raizman MB: Treatment strategies for scleritis and uveitis associated with inflammatory bowel disease. Am J Ophthalmol 1994; 118:601–611. 77 Fries W, et al: Treatment of acute uveitis associated with Crohn’s disease and sacroileitis with infliximab. Am J Gastroenterol 2002; 97: 499–500. 78 Smith JR, et al: Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001; 45: 252–257. 79 Sfikakis PP, et al: Effect of infliximab on sightthreatening panuveitis in Behçet’s disease. Lancet 2001; 358:295–296. 80 Joseph A, et al: Infliximab in the treatment of refractory posterior uveitis. Ophthalmology 2003;110:1449–1453. 81 Banares A, Abasolo L, Macarron P: Treatment of refractory posterior uveitis with anti-TNF- (infliximab). Arthritis Rheum 2001;44:S90. 82 El-Shabrawi Y, Hermann Graz J: Anti-TNF therapy with infliximab in the treatment of HLA-B27 associated acute anterior uveitis: A one-year follow up. Arthritis Rheum 2001: S123. 83 Martin TMP, Smith JRMP, Rosenbaum JTMD: Anterior uveitis: Current concepts of pathogenesis and interactions with the spondyloarthropathies. Curr Opin Rheumatol 2002; 14: 337–341. 84 Schreiber S: Guidelines of the DGVS. Extraintestinal manifestations. German Society of Digestive and Metabolic Diseases (in German). Z Gastroenterol 2001;39: 63–65. 85 Dvorchik I, et al: Effect of liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis. Hepatology 2002;35:380–384. 86 Tung BY, et al: Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 2001;134: 89–95.




Treatment of Gastroduodenal Crohn’s Disease Christian Motteta Pascal Juillerata Jean-Jacques Gonversa Pierre Michettia Bernard Burnandc John-Paul Vaderc Christian Felleya Florian Froehlicha, b a


Key Words Crohn’s disease Esophagus Stomach Duodenum Stenosis Therapy

Abstract Symptomatic gastroduodenal manifestations of Crohn’s disease (CD) are rare, with less than 4% of patients being clinically symptomatic. Gastroduodenal involvement may, however, be found endoscopically in 20% and in up to 40% of cases histologically, most frequently as Helicobacter pylori-negative focal gastritis, usually in patients with concomitant distal ileal disease. In practice, the activity of concomitant distal CD usually determines the indication for therapy, except in the presence of obstructive gastroduodenal symptoms. With the few data available, it seems correct to say that localized gastroduodenal disease should be treated with standard medical therapy used for more distal disease, with the exception of sulfasalazine and mesalanine with pH-dependent release. Presence of symptoms of obstruction needs aggressive therapy. If medical therapy with steroids and immunomodulatory drugs does not alleviate the symptoms, balloon dilation and surgery are the options to consider. Copyright © 2005 S. Karger AG, Basel



Introduction

Gastroduodenal involvement in Crohn’s disease may be found endoscopically in 20% [1] and up to 40% of cases histologically [2, 3], most frequently as a Helicobacter pylori-negative focal gastritis, and is commonly encountered in patients with concomitant distal disease locations, usually ileal. On the other hand, in a patient not known to have Crohn’s disease, a histological H. pylorinegative focal gastritis has a high positive predictive value of 94% for Crohn’s disease [2, 3]. Symptomatic gastroduodenal manifestations of Crohn’s disease are, however, rare, as less than 4% of patients are clinically symptomatic [4–6]. Dysphagia, odynophagia, pyrosis for esophageal involvement, and nausea, anorexia, epigastric pain, dyspepsia for duodenal and gastric involvement are the most frequent symptoms. The presence of symptoms of obstruction such as epigastric distress, early satiety, postprandial vomiting and weight loss indicates more severe disease and lies at the heart of the therapeutic decisional tree. As no high-quality-level evidence-based data are available on the medical and surgical management of gastroduodenal Crohn’s disease, therapy propositions rely mostly on small uncontrolled retrospective case series or anecdotal reports, clinical experience, pathophysiological theories and result extrapolation from studies performed on more distal disease. An important point to stress is the fact that in practice the activity of concomitant distal Crohn’s disease usually determines the indication for

Christian Mottet, MD Division of Gastroenterology and Hepatology Lausanne University Medical Center Rue du Bugnon 46, CH–1011 Lausanne (Switzerland) Tel. +41 21 3140683, Fax +41 21 3140707, E-Mail [email protected]

therapy, except in the case of obstructive gastroduodenal symptoms.

Treatment

Available Treatments Treatment 1: Proton-Pump Inhibitors No data are available on this topic but it is generally recommended to try a proton-pump inhibitor as initial treatment of a presumed diagnosis of gastritis, peptic ulcer disease or gastroesophageal reflux disease. As gastric acid may also perpetuate Helicobacter pylori-negative Crohn’s gastroduodenal ulcers, proton-pump inhibitors are, from a theoretical point of view, indeed also recommended for this condition. However, acid suppression alone probably does not control the idiopathic mucosal inflammatory process. In theory, a combined approach with both acid suppression and anti-inflammatory/immunosuppressive therapy therefore seems appropriate. Treatment 2: Sulfasalazine This azo-bound drug releases its 5-aminosalicylic-active compound in the distal ileum or in the colon and therefore probably has no place in the management of proximal Crohn’s disease. In any case, no data have been published with regard to this indication. Treatment 3: Mesalamine The same can be said concerning the mesalamine preparation with pH-dependent release. Slow-release mesalamine embedded in methylcellulose granules (Pentasa) is partly released in the proximal small intestine [7] and might therefore be useful in gastroduodenal disease, but this has not been tested in clinical trials. Treatment 4: Steroids A small retrospective study in 10 patients with symptomatic gastroduodenal involvement [8] showed, in every patient, a good clinical response with oral corticosteroids, 1 patient had 6-mercaptopurine and 3 had H2-receptor antagonists as adjunct therapy. Nugent and Roy [9] reported similar results in a retrospective case series. Out of 46 patients treated with steroids for non-obstructing disease, 42 had good to excellent results, some of them were on concomitant medication with sulfasalazine, an H2-receptor blocking agent or intermittently with azathioprine or metronidazole. There are no data on the use of budesonide for this indication.

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Treatment 5: Azathioprine, 6-Mercaptopurine For patients who remained symptomatic on steroids, who are steroid-dependent or who necessitate maintenance therapy, the introduction of immunomodulatory drugs such as azathioprine or 6-mercaptopurine is indicated, although only anecdotal clinical experience has been published to support it for this indication. Korelitz et al. [10] reported 20 years of clinical experience with 6mercaptopurine. In a subgroup analyzed, they described a 100% therapeutic goal achievement in healing or marked improvement of Crohn’s disease of the stomach and duodenum. In another study of 12 patients with upper gastrointestinal tract involvement treated with azathioprine, prednisone could be discontinued in 7 of them after 4–6 months. A significant decrease in Crohn’s disease activity index (CDAI) score was also observed [11]. Treatment 6: Infliximab Heller et al. [12] as well as Ho et al. [13] described a case of severe esophageal disease with esophagogastric vs. esophagobronchial fistula that clinically resolved with infliximab therapy. Grubel et al. [14] reported 4 cases of severe isolated Crohn’s-like disease of the gastroduodenal tract, 2 were treated with infliximab, 1 healed and the other did not improve. There is one case report of the successful use of infliximab for severe gastric and duodenal Crohn’s disease with diffuse thickening and ulceration throughout the antrum and duodenum [15]. Treatment 7: Balloon Dilation The presence of a stenosis with obstruction indicates a severe disease presentation that necessitates a more aggressive treatment. If the aforementioned medical therapy with steroid and immunomodulatory drugs does not alleviate the symptoms, balloon dilation or surgery are indicated in proportion to the severity of the symptoms and the technical feasibility. Matsui et al. [16] reported 5 patients with successful dilatation for obstructive gastroduodenal Crohn’s disease. Three patients developed recurrent obstructive symptoms which were alleviated by repeated balloon dilations in the absence of any steroid or immunomodulatory medication. Murthy [17] and Kelly and Hunter [18] also reported successful dilation of obstructive gastroduodenal Crohn’s disease. Treatment 8: Surgery Indications for surgery of gastroduodenal disease have been reviewed by Reynolds and Stellato [19], who sum-

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marized 6 series [9, 20–23] with a total of 108 patients: 90 (83%) underwent surgery for obstruction, 12 (11%) for refractory pain and 5 (5%) for massive bleeding. Gastrojejunostomy, duodenojejunostomy and gastroduodenostomy bypass operations are preferred to stomach or duodenum resection because resection is associated with an increase in morbidity, as shown in the case series by Murray et al. [24] at the Lahey Clinic (4-fold higher morbidity). Stricturoplasty has been a useful adjunct in managing short stenosis in the jejunum and the ileum [25] but only two retrospective reports of 13 patients each [22, 23] have compared stricturoplasty with bypass surgery for gastroduodenal obstruction. Worsey et al. [24] reported equal rates of reoperation between stricturoplasty (2/13, 15%, selected cases, median follow-up of 42 months) as compared to bypass (2/21, 10%, median follow-up of 96 months). Yamamoto et al. [25], however, reported higher reoperative rates with stricturoplasty (9/13, 69%, median follow-up of 143 months) compared to bypass (6/13, 46%, median follow-up of 192 months). A definitive recommendation for one approach over the other cannot be made because of the limited data. Salky [26] advocates the use of laparoscopic gastrojejunostomy bypass surgery in obstructive gastroduodenal Crohn’s disease in the discussion section of his 12 published cases because of the minimal invasive approach, the shorter length of stay and the cosmetic advantages in

this especially young patient population. One patient required open surgery to correct a wrongly placed anastomosis, which attests to the complexity of this type of surgery. The role of surgery in esophageal Crohn’s disease has been reviewed by Davidson and Sawyers [27, 28]. The literature is however limited to case reports. They identified 20 patients, 12 had stenosis or obstruction on barium studies and 4 fistulae were present. Thirteen patients underwent esophagectomy, 2 deaths occurred.

Conclusions and Summary

In summary, there is no high-quality level evidencebased data to guide the medical and surgical management of gastroduodenal Crohn’s disease. Therapeutic options rely either on small poor-quality level case series without proper controls or on results extrapolated from more distal disease or on rational but theoretical hypotheses. With the data available it seems correct to say that one should treat these patients with standard medical therapy as would be used for more distal disease, with few exceptions. Medical therapy is indeed the best option for treatment of the majority of patients with gastroduodenal Crohn’s disease, because most patients do not present with obstructive symptoms – the main indication for surgery in this collective.

References 1 Alcantara M, et al: Endoscopic and bioptic findings in the upper gastrointestinal tract in patients with Crohn’s disease. Endoscopy 1993;25:282–286. 2 Oberhuber G, Hirsch M, Stolte M: High incidence of upper gastrointestinal tract involvement in Crohn’s disease. Virchows Arch 1998; 432:49–52. 3 Oberhuber G, et al: Focally enhanced gastritis: A frequent type of gastritis in patients with Crohn’s disease. Gastroenterology 1997; 112: 698–706. 4 Fielding JF, et al: Crohn’s disease of stomach and duodenum. Gut 1970;11:1001–1006. 5 Wagtmans MJ, et al: Crohn’s disease of the upper gastrointestinal tract. Neth J Med 1997;50: S2–S7. 6 Wagtmans MJ, et al: Clinical aspects of Crohn’s disease of the upper gastrointestinal tract: A comparison with distal Crohn’s disease. Am J Gastroenterol 1997;92:1467–1471.

Treatment of Gastroduodenal Crohn’s Disease

7 Healey JN: Gastrointestinal transit and release of mesalazine tablets in patients with inflammatory bowel disease. Scand J Gastroenterol Suppl 1990; 172:47–51. 8 Griffiths AM, Alemayehu E, Sherman P: Clinical features of gastroduodenal Crohn’s disease in adolescents. J Pediatr Gastroenterol Nutr 1989;8:166–171. 9 Nugent FW, Roy MA: Duodenal Crohn’s disease: An analysis of 89 cases. Am J Gastroenterol 1989; 84:249–254. 10 Korelitz BI, et al: Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol 1993; 88: 1198– 1205. 11 Miehsler W, et al: Impact of different therapeutic regimens on the outcome of patients with Crohn’s disease of the upper gastrointestinal tract. Inflamm Bowel Dis 2001; 7:99–105. 12 Heller T, et al: Treatment of severe esophageal Crohn’s disease with infliximab. Inflamm Bowel Dis 1999;5:279–282.

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13 Ho IK, et al: Infliximab treatment of an esophagobronchial fistula in a patient with extensive Crohn’s disease of the esophagus. J Clin Gastroenterol 2002;34: 488–489. 14 Grubel P, et al: Severe isolated Crohn’s-like disease of the gastroduodenal tract. Dig Dis Sci 2003;48:1360–1365. 15 Firth JJ, Prather C: Unusual gastric Crohn’s disease treated with infliximab. A case report. Am J Gastroenterol 2002;97:S190. 16 Matsui T, et al: Long-term outcome of endoscopic balloon dilation in obstructive gastroduodenal Crohn’s disease. Endoscopy 1997; 29: 640–645. 17 Murthy UK: Repeated hydrostatic balloon dilation in obstructive gastroduodenal Crohn’s disease. Gastrointest Endosc 1991; 37: 484– 485. 18 Kelly SM, Hunter JO: Endoscopic balloon dilatation of duodenal strictures in Crohn’s disease. Postgrad Med J 1995;71:623–624.

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19 Reynolds HL Jr, Stellato TA: Crohn’s disease of the foregut. Surg Clin North Am 2001; 81: 117–135, viii. 20 Farmer RG, Hawk WA, Turnbull RB Jr: Crohn’s disease of the duodenum (transmural duodenitis): Clinical manifestations. Report of 11 cases. Am J Dig Dis 1972;17: 191–198. 21 Poggioli G, et al: Duodenal involvement of Crohn’s disease: Three different clinicopathologic patterns. Dis Colon Rectum 1997; 40: 179–183.

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22 Worsey MJ, et al: Strictureplasty is an effective option in the operative management of duodenal Crohn’s disease. Dis Colon Rectum 1999; 42:596–600. 23 Yamamoto T, et al: Outcome of strictureplasty for duodenal Crohn’s disease. Br J Surg 1999; 86:259–262. 24 Murray JJ, et al: Surgical management of Crohn’s disease involving the duodenum. Am J Surg 1984;147:58–65.

25 Pace BW, Bank S, Wise L: Strictureplasty. An alternative in the surgical treatment of Crohn’s disease. Arch Surg 1984;119:861–862. 26 Salky B: Severe gastroduodenal Crohn’s disease: Surgical treatment. Inflamm Bowel Dis 2003; 9:129–130. 27 Davidson JT 3rd, Sawyers JL: Surgical management of Crohn’s disease: Experience with 135 patients. Am Surg 1982;48: 16–19. 28 Davidson JT, Sawyers JL: Crohn’s disease of the esophagus. Am Surg 1983;49: 168–172.

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Maintenance of Remission in Crohn’s Disease Jean-Jacques Gonversa Pascal Juillerata Christian Motteta Christian Felleya Bernard Burnandc John-Paul Vaderc Pierre Michettia Florian Froehlicha, b a


Key Words Crohn’s disease Maintenance treatment Mesalamine Azathioprine Methotrexate Infliximab

Abstract When remission of Crohn’s disease is achieved, the next goal is to maintain long-term remission. Aminosalicylates may be recommended for maintenance remission, even though the results are less consistent than those observed in ulcerative colitis. The benefit is mainly observed in the post-surgical setting and in patients with ileitis, and with a prolonged disease duration. Corticosteroids are not effective in maintaining remission and should not be used for this indication. Azathioprine and 6-mercaptopurine are effective in maintaining remission. Maintenance benefits remain significant for patients who continued with the therapy for up to 5 years. Methotrexate has also been found to be effective in maintaining remission in Crohn’s disease in patients who have responded acutely to methotrexate. Cyclosporine has not been found to be an effective maintenance agent. Mycophenolate mofetil could be considered a therapy in patients who are either allergic to azathioprine or in whom azathioprine failed to induce remission. The



use of infliximab may change the future approach to maintenance therapy for Crohn’s disease. Patients who responded clinically to infliximab have maintained their clinical response when receiving repeat infusions at 8week intervals. In patients refractory to other therapies, infliximab may be effective in maintaining remission. Copyright © 2005 S. Karger AG, Basel

Introduction

Of patients with Crohn’s disease who have not previously undergone surgical treatment, and who are in symptomatic remission, 25–50% will experience symptom recurrence within 2 years [1, 2]. Because of the high rate of recurrence, safe and effective treatment regimens have long been sought to maintain remission in patients with Crohn’s disease. Clinical remission (Crohn’s Disease Activity Index (CDAI) !150) refers to patients who are asymptomatic or without inflammatory sequelae and includes patients who have responded to acute medical intervention [3]. Relapse is defined as both CDAI 1150 points and a minimum increase in the baseline CDAI score 170 points [4].

Jean-Jacques Gonvers, MD Division of Gastroenterology and Hepatology Lausanne University Medical Center Rue du Bugnon 44, CH–1011 Lausanne (Switzerland) Tel. +41 21 3144719, Fax +41 21 3144718, E-Mail [email protected]

Factors Influencing the Relapse of Patients with Crohn’s Disease

Factors recognized to exacerbate Crohn’s disease include: intercurrent infections (both upper respiratory tract and enteric infections, including Clostridium difficile), cigarette smoking [5] and non-steroidal anti-inflammatory drugs [6]. Smoking increases the risk of Crohn’s disease. A metaanalysis of seven suitable studies of Crohn’s disease confirmed a pooled OR and a 95% CI of 2.0 (1.65–2.47) for current smokers compared to lifetime non-smokers [7]. Smoking also appears to have an adverse effect on the clinical course of the disease. Duffy et al. [8] monitored patients with Crohn’s disease for 6 months. Smokers had a 34% higher relapse rate than non-smokers. In the study by Timmer et al. [9], oral contraceptive use and smoking are associated with an increased risk of relapse in patients with Crohn’s disease. Non-steroidal anti-inflammatory drug use is now a well-recognized cause of exacerbation of disease [10].

Definitions

Clinical remission (CDAI !150), confirmed if necessary by endoscopy, refers to patients who are asymptomatic or without any inflammatory sequelae, and includes patients who have responded to acute medical intervention [3]. Relapse is defined as both CDAI 1150 and a minimum increase in the baseline CDAI score 170 points [4].

Treatment

When remission is achieved, the next goal is to maintain long-term remission. A wide range of drugs have been used and these will be reviewed here. Available Treatments In this chapter, the following treatments will be reviewed: aminosalicylates, steroids, azathioprine and 6mercaptopurine, methotrexate, infliximab, cyclosporine, mycophenolate mofetil, antibiotics, probiotics, diet and cessation of smoking. Treatment 1: Aminosalicylates Crohn’s disease maintenance trials with aminosalicylates have resulted in less consistent results than have been observed in ulcerative colitis. In this literature re-

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view, we have selected five studies which showed a favorable effect of 5-ASA [11–15], four studies which did not show that 5-ASA prevented relapse [16–19] and, finally, three meta-analyses which appeared in 1994 and 1997 were also examined [20–22]. The International Mesalazine Study Group treated 248 patients with 3 ! 500 mg/day of 5-ASA or placebo. Cumulative life-table relapse was lower in the 5-ASA patients compared to placebo (22.4 vs. 36.2%; p = 0.0395). The 12-month relapse estimate in the 5-ASA group was also lower in patients with ileal disease and in patients with previous bowel resection [11]. In the study by Prantera et al. [15], 125 patients with inactive Crohn’s disease were treated either by 5-ASA 3 ! 800 mg daily or placebo for up to 12 months, or until relapse of symptoms. At 12 months, relapse rate was 34 vs. 55% (p = 0.02). A significant decrease in the risk of relapse was found in patients with ileitis, in those with previous bowel resection and in those with prolonged pre-study remission. In the French study by Gendre et al. [14], 161 patients in remission were randomized to receive either Pentasa 2 g daily or placebo in a 2-year double-blind multicenter trial. Pentasa was shown to be an effective maintenance treatment for Crohn’s disease when given within 3 months of achieving remission. In a small study of 59 patients, Arber et al. [13] treated 59 patients with mesalazine 2 ! 500 mg daily or placebo. The end-points were 1 year of follow-up or clinical relapse. Mesalazine had a significant advantage over placebo (p ^ 0.05) only in the subgroup of patients with ileal Crohn’s disease and in those aged 130 years. In another French study, Modigliani et al. [12] randomized 129 patients in clinical remission after oral prednisolone to Pentasa 4 g daily or placebo. At the end of the trial, 25% of patients receiving placebo and 29% of patients who received mesalamine were in remission. After adjusting for risk factors such as high CDAI, white blood cell count 19 [9] at weaning, Pentasa was found to be superior to placebo. Thomson et al. [16] compared the efficacy of oral mesalazine 1.5 g twice daily with placebo in the maintenance of remission in 286 patients with Crohn’s disease in a multicenter study conducted in 11 countries. The relapse rate of Crohn’s disease was similar for !12 months in both the 5-ASA and placebo groups. In another large multicenter Canadian study [18], 293 patients with Crohn’s disease in remission were treated either with mesalamine 750 mg four times daily for 48 weeks or placebo. Mesalamine treatment reduced relapse compared to placebo treatment, but statistical significance was not achieved. The time to relapse was 119 days for the mesalamine-treated

Gonvers/Juillerat/Mottet/Felley/Burnand/ Vader/Michetti/Froehlich

patients compared with 109 days for placebo-treated patients (n.s.). In an Italian multicenter study, de Franchis et al. [17] treated patients with Crohn’s disease having achieved remission on steroids either with 5-ASA 3 g daily or placebo, while steroids were doubled over 6 weeks. In this study, 5-ASA did not prevent relapse in Crohn’s disease patients (relapse rate after 20 months was 58% in the 5-ASA group and 52% in the placebo group). Olsalazine consists of two 5-ASA molecules linked by an AZO bond. The role of olsalazine in maintenance of remission in Crohn’s colitis and/or ileocolitis has been investigated by Mahmud et al. [19]. A total of 328 patients were treated with olsalazine or placebo for 82 weeks. No differences in the frequency of termination due to relapse or time to termination due to relapse were noted between the two treatment groups (olsalazine 48.5% vs. placebo 45%). Three meta-analyses showed a diminution of relapse risk for Crohn’s disease with 5-ASA therapy [20–22]. In the most recently published meta-analysis of 15 randomized controlled trials, adjusted for confounding variables, it was shown that mesalazine maintenance therapy significantly reduced the risk of symptomatic relapse of Crohn’s disease. The benefit was mainly observed in the post-surgical setting, in patients with ileitis and with prolonged disease duration [22]. In conclusion, mesalamine may be recommended for maintaining remission of quiescent Crohn’s disease. The benefit is mainly observed in the post-surgical setting, in patients with ileitis and with prolonged disease duration. Treatment 2: Corticosteroids Corticosteroids are the most effective therapy for active Crohn’s disease. The remission rate ranges from 60 to 92% [1, 2]. Patients treated acutely with corticosteroids are unlikely to remain well after 1 year without some maintenance therapy [23]. Despite their efficacy in active disease, there is no evidence that prolonged low-dose corticosteroid therapy will prevent symptomatic relapse in Crohn’s disease in remission [1, 2, 24]. There continues to be confusion regarding the issues of ‘steroid maintenance’ vs. ‘steroid dependence’. The former applies to ‘clinical trials’ evidence of a therapy that prevents relapse in the population of patients. The latter is a clinical observation pertaining to individual patients unable to take steroids below a certain dose without developing symptoms [3]. In the study by Smith et al. [24], 64 patients with Crohn’s disease who were free from symptoms were randomized to receive either prednisone 7.5 mg daily or pla-

cebo. The study found no overall difference in the withdrawal rate between the prednisone- and the placebotreated groups. In addition, of the 26 patients with previous resection and no residual disease, only 2 experienced a disease relapse, 1 in each of the prednisone and placebo groups. In part 2 of the National Cooperative Crohn’s Disease Study [1], of a total of 274 patients who had quiescent disease, either after surgical resection within the previous year (n = 48) or by medical therapy (n = 226), 101 were randomized to receive placebo and 61 were randomized to receive prednisone 0.25 mg/kg per day. Patients were followed for up to 2 years and were considered treatment failures if they had a CDAI 1150, required surgery, developed a new fistula, had persistent fever or showed significant worsening of barium X-rays. Results of the study showed no difference between placebo- and prednisone-treated groups with respect to outcome ranking scores and to the proportion of patients in remission. In the European Cooperative Crohn’s Disease Study [2], a total of 237 patients with quiescent Crohn’s disease were randomized to receive either placebo (n = 52), 6-methylprednisolone 8 mg/day (n = 66), sulfasalazine or a combination of 6-methylprednisolone and sulfasalazine. Patients were followed for up to 24 months. According to the life-table analysis method for the outcome of failure and relapse, no statistical difference was found between the placebo- and the 6-methylprednisolone groups with respect to the proportion of patients remaining in remission over the 2-year study period. Budesonide is a corticosteroid with high topical antiinflammatory activity and low systemic activity due to a rapid hepatic metabolism via the cytochrome P450 CYP3 to metabolites with less than 1% glucocorticoid activity. Three studies have evaluated oral budesonide for maintenance of remission in patients with quiescent Crohn’s disease [25–27]. All these trials were randomized, multicenter, double-blind and placebo-controlled. They evaluated oral budesonide 3 and 6 mg/day for 1 year. In the Canadian study by Greenberg et al. [25], the relapse rate at 1 year was 61% in patients of the 6-mg/day group, 70% in the 3-mg/day group and 67% in the placebo group (p = 0.75). In the European study by Lofberg et al. [26], 90 patients with Crohn’s disease were studied. Therapeutic failure occurred in 47% in the 6-mg group, 68% in the 3-mg group and in 63% in the placebo group (p = 0.22). However, budesonide 6 mg/day was found to be significantly more efficacious than placebo in prolonging the time to relapse or discontinuation of therapy in Crohn’s disease (58 days in the 6-mg/day group, 139 days in the 3-mg/day group and 92 days in the placebo group)

Remission Maintenance

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(p = 0.021). In 1998, Ferguson et al. [27] randomly allocated 75 patients to receive budesonide 6 mg/day, 3 mg/ day or placebo for 1 year. During the 12 months of treatment, the relapse rates were 48% in the 6-mg/day group, 46% in the 3-mg/day group and 60% in the placebo group (n.s.). In the German study by Gross et al. [28], 179 patients with steroid-induced remission of Crohn’s disease received either 3 mg budesonide (n = 84) or placebo (n = 95) for 1 year. Budesonide at a dose of 3 mg/day was not effective for maintaining steroid-induced remission. The relapse rate was 67% in the budesonide group and 65% in the placebo group. The mean time to relapse was 93.5 days in the budesonide group and 67 days in the placebo group. Two meta-analyses [29, 30] of six trials comparing budesonide to placebo for the maintenance of quiescent Crohn’s disease (four for preventing recurrence after medical remission and two after surgical remission) were analyzed. In both studies, budesonide was as effective as placebo for preventing relapse in medically induced remission. In conclusion, routine use of corticosteroid therapy for the maintenance of remission in Crohn’s disease cannot be recommended based upon the available evidence. This applied to conventional corticosteroids as well as to controlled-release budesonide. Treatment 3: Azathioprine and 6-Mercaptopurine Crohn’s disease is characterized by recurrent exacerbations and remissions. Corticosteroids have been the mainstay of therapy for the induction of remission; however, 20% of patients become steroid-dependent. To avoid prolonged steroid therapy, because of the frequency and severity of adverse events, sparing agents such as azathioprine and 6-mercaptopurine have been used. Five randomized double-blind, placebo-controlled studies have been published [1, 31–34]. In the study by Willoughby et al. [31], 22 patients were treated with azathioprine 2 mg/kg per day or placebo for 24 weeks. Ten of 11 patients on azathioprine remained in remission and completed the trial, whereas 8 of 11 receiving placebo were withdrawn early because of relapse (p ^ 0.01). In the study by Rosenberg et al. [32], 20 patients with Crohn’s disease requiring at least 10 mg of prednisone per day to control disease activity received either 3 mg/kg of azathioprine or placebo for 26 weeks, while taking prednisone. There were 7 relapses in the placebo group and 2 relapses in the azathioprine group. The average reduction in steroid dosage in the azathioprine group at the end of the trial was significantly greater than in the placebo-

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treated group (p ^ 0.05). O’Donoghue et al. [33] dealt exclusively with quiescent disease. Fifty-one patients in remission on azathioprine were allocated either to a group in which azathioprine was continued at 2 mg/kg per day or a group in which a placebo was substituted. The cumulative probability of relapse at 1 year was 5% among those on azathioprine compared to 41% among those in the control group (p ^ 0.01). In a recent study, Candy et al. [34] allocated 63 patients in remission either to 2.5 mg/kg per day of azathioprine or placebo for 15 months. At 15 months, there was a highly significant difference in the proportion of patients in remission (42% for patients receiving azathioprine vs. 7% for patients receiving placebo; p = 0.001). Bouhnik et al. [35] followed 190 patients in clinical remission treated with either azathioprine or 6mercaptopurine for more than 6 months. The time to relapse was analyzed in those on treatment and in those who stopped treatment for reasons other than relapse. In the 157 patients who continued to take therapy, cumulative probability of relapse at 1 and 5 years was 11 and 32%, respectively. In the 42 patients who stopped therapy, probability of relapse at 1 and 5 years was 38 and 75%. Only one study has failed to show benefit from azathioprine given for 2 years, but the dose used in that trial was half that of other trials [1]. In a prospective doubleblind, placebo-controlled trial in 55 children with Crohn’s disease, Markowitz et al. [36] showed that the addition of 6-MP to a regimen of corticosteroids significantly lessens the need for prednisone and improves maintenance of remission. Only 9% in the 6-MP group relapsed compared to 47% of controls (p = 0.007). A meta-analysis of azathioprine and 6-mercaptopurine in Crohn’s disease has been performed by Pearson et al. [37]. The authors selected nine randomized placebo-controlled trials of azathioprine or 6-mercaptopurine. Two of these trials consisted solely of patients with quiescent Crohn’s disease. Azathioprine had a positive effect on maintenance of remission. The OR for maintenance of remission was 2.16 (CI 95%, 1.35–3.47). A higher dose improved response and a steroid-sparing effect was noted. Life-table analysis shows that maintenance azathioprine is effective for up to 5 years of treatment [38]. There is no suggestion that the effectiveness of treatment tapers off after a specific duration. There is nothing to support the concept that treatment should be stopped after 3–4 years [35]. The main argument against longer durations of treatment is the long-term risk of malignancy. Connell et al. [39] did not observe any increase in risk of malignancy in 755 patients with inflammatory bowel disease


followed for a median of 9 years from the start of azathioprine treatment. In conclusion, azathioprine and 6-mercaptopurine are effective in treating active Crohn’s disease and in maintaining remission. There is evidence of a steroid-sparing effect. 6-Thioguanine was prescribed, in a pilot study, to 10 patients with Crohn’s disease that was resistant to 6-mercaptopurine. Seven patients out of the 10 showed remission after 16 weeks [40]. A study over a longer period of time showed that 29 of the 111 patients treated (26%) subsequently developed hepatic function test perturbations. Fine-needle liver biopsy tests in this group of patients revealed a regenerative nodular hyperplasia of the liver in 76% of patients [41], while a French study did not report this type of complication [42]. For the moment, we do not feel able to recommend the use of thioguanine for the treatment of inflammatory bowel disease in view of its known toxicity. Treatment 4: Methotrexate The interest in methotrexate for the treatment of Crohn’s disease originated from an uncontrolled study by Kozarek et al. [43]. In an uncontrolled study in 21 patients with chronically active disease (14 with Crohn’s disease and 7 with ulcerative colitis), methotrexate was administered at a dose of 25 mg once a week, with conversion to a maintenance dose of 15 mg per os in patients who responded to therapy. Approximately two-thirds of patients showed an improvement in symptoms and a steroid-sparing effect was also documented. Feagan et al. [44] conducted a double-blind, placebocontrolled multicenter study of patients with chronically active Crohn’s disease who had entered remission after treatment with 25 mg of methotrexate given intramuscularly once a week. After 40 weeks, 65% of the patients receiving methotrexate were in remission in the methotrexate group as compared to 39% in the placebo group (p = 0.04). No serious adverse effects were observed in this study. Although this trial represents a landmark study, that clearly shows the efficacy of methotrexate in the maintenance treatment of Crohn’s disease, it must be stressed that the benefit of methotrexate was achieved in a highly selected group of patients who had already demonstrated responsiveness to methotrexate and who also tolerated the drug at the higher induction dose. Whether methotrexate would be as efficacious and tolerable in patients whose remission is achieved surgically or by other drugs (e.g., corticosteroids, infliximab) remains unclear from this study and needs further investigation.


Treatment 5: Infliximab Tumor necrosis factor- (TNF-) is a proinflammatory cytokine that has a significant role in the pathogenesis of Crohn’s disease. Infliximab, a chimeric antiTNF- monoclonal antibody, binds to TNF- with high affinity, thereby neutralizing its biological activity. When given as a 5-mg/kg i.v. infusion, infliximab induces remission in patients with moderately to severely active Crohn’s disease [45, 46]. Clinical experience has shown that patients can relapse after a single infusion of infliximab. Retreatment with infliximab maintained the clinical benefit up to 8 weeks after the last infusion in nearly all patients who responded to an initial dose of treatment [47]. In the ACCENT I randomized trial, Hanauer et al. [48] randomized 335 patients to repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group 1), repeat infusions of 5 mg/kg infliximab at the same time-points (group 2) or 5 mg/kg at weeks 2 and 6, followed by 10 mg/kg (group 3). At weeks 30, 23 of 110 (21%) group 1 patients were in remission compared to 44 of 113 (39%) of group 2 (p = 0.003) and 50 of 112 (45%) of group 3 (p = 0.0002). In conclusion, the results of the ACCENT I study showed that patients with Crohn’s disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids and to maintain their response for a longer period of time if infliximab therapy is maintained every 8 weeks. Treatment 6: Cyclosporine and Mycophenolate Mofetil Three large controlled trials of low-dose oral cyclosporine (5 mg/kg per day) for treatment of chronically active Crohn’s disease and Crohn’s disease remission maintenance did not show a beneficial treatment effect [49–51]. In conclusion, in Crohn’s disease, cyclosporine at low doses appears to be virtually useless for maintenance of remission. In a comparative controlled trial using azathioprine as a positive control, Neurath et al. [52] reported that mycophenolate mofetil (15 mg/kg per day) or azathioprine (2.5 mg/kg per day) in combination with a decreasing dose of corticosteroids was equally efficacious in inducing and maintaining remission of active Crohn’s disease. There was a trend towards a more rapid response with mycophenolate mofetil compared to azathioprine in those patients with the greatest disease activity. The possible use of mycophenolate mofetil in patients with poor tolerance of or lack of response to azathioprine

Digestion 2005;71:41–48

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has been studied. One study showed a success rate of only 20% in such a situation and that the treatment was poorly tolerated in 25% of cases [53, 54]. Treatment 7: Antibiotics Antibiotics have been widely used for active Crohn’s disease and fistulous disease. Metronidazole alone, or in combination with cotrimoxazole, was compared to placebo or cotrimoxazole alone as relapse prevention therapy in a small study. No significant difference was found between the groups [55]. Treatment 8: Probiotics Saccharomyces boulardii is a non-pathogenic yeast reportedly able to protect the intestine against Clostridium difficile and cholera toxins. In a pilot study, a preparation of S. boulardii was found to be superior to placebo in promoting reduction of both frequency of bowel movements and best indexed in a small group of patients with minimally active Crohn’s disease [56]. The possible role of S. boulardii in the maintenance treatment of Crohn’s disease has been evaluated by Guslandi et al. [57]. Thirtytwo patients with Crohn’s disease in clinical remission were randomly treated for 6 months with either mesalamine 1 g 3 times per day or mesalamine 1 g twice 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 probiotic agents. However, in view of the products’ cost, further control studies are needed to confirm these preliminary data. Promising results have also come from a pilot study in which a non-pathogenic Escherichia coli strain Missle 1917 was tested for efficacy and tolerance in maintaining remission in patients with colonic Crohn’s disease. Twenty-eight patients participated in this study [58]. In the prednisone and E. coli group of patients in remission, 33.3% had a relapse during the year of treatment, compared to 63.6% in the group receiving prednisone and placebo. Further control studies are required to look more carefully at the efficacy and benefit of these therapies in the microbiologic treatment of IBD. Treatment 9: Diet Therapy Several controlled studies indicate that an elemental diet can induce remission in patients with active Crohn’s disease, but none has demonstrated that an elemental diet can maintain long-term remission [59, 60].

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Treatment 10: Cessation of Smoking Smoking cigarettes is associated with Crohn’s disease and has a negative effect on the cause of Crohn’s disease [61]. Smoking increases the risk of Crohn’s disease [61]. A meta-analysis on seven suitable studies of Crohn’s disease confirmed a pooled OR of 2 (95% CI 1.65–2.47) for current smokers compared to lifetime non-smokers and 1.83 (95% CI 1.33–2.51) for former smokers compared to lifetime non-smokers [7]. Smoking also appears to have an adverse effect on the clinical course of the disease [8, 62, 63]. Duffy et al. [8] monitored patients with Crohn’s disease for 6 months. Smokers had a 34% higher relapse rate than non-smokers. Cottone et al. [62] studied the influence of smoking on the clinical course of Crohn’s disease in 182 patients followed over a 20-year period. After surgery, the risk of recurrence was increased in smokers compared to nonsmokers. In the study by Timmer et al. [9] of a cohort of 152 patients, oral contraceptive use and smoking are associated with an increased risk of relapse in patients with Crohn’s disease. In conclusion, Crohn’s disease patients should be strongly dissuaded from smoking, although none of the studies published adequately explained the observed clinical pattern.

Recommendations of the American College of Gastroenterology

Guidelines were developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee, and published in the American Journal of Gastroenterology [3]. Concerning maintenance therapy, the recommendations based on the data available at the time of the production of the document were that corticosteroids should not be used long-term as agents for preventing relapse of Crohn’s disease, that azathioprine/6-mercaptopurine have demonstrable maintenance benefits after induction therapy with corticosteroids, and that mesalamine or azathioprine/6-mercaptopurine should be considered after ileocolonic resection to reduce the likelihood of symptomatic recurrence.

Conclusions

Routine use of corticosteroid therapy for the maintenance of remission in Crohn’s disease cannot be recommended. This applies to conventional corticosteroids as well as to controlled-release budesonide.


An immunosuppression therapy should be instigated when relapse is rapid or frequent after remission has been obtained with medication. Azathioprine and 6-mercaptopurine have been shown to be effective in maintaining remission and there is also evidence of a corticosteroidsparing effect. Methotrexate may be used as an alternative treatment in patients unable to tolerate azathioprine or 6-mercaptopurine.

Repeat doses of infliximab every 8 weeks can prolong remission duration in patients who responded well to an initial dose, as well as increasing the chances of being able to cease administration of corticosteroids. Aminosalicylates are less effective in preventing relapse of Crohn’s disease than of relapse in ulcerative colitis. The benefit in Crohn’s disease is observed mainly in the post-surgical setting.

References 1 Summers RW, et al: National Cooperative Crohn’s Disease Study: Results of drug treatment. Gastroenterology 1979;77:847–869. 2 Malchow H, et al: European Cooperative Crohn’s Disease Study (ECCDS): Results of drug treatment. Gastroenterology 1984; 86: 249–266. 3 Hanauer SB, Sandborn W: Management of Crohn’s disease in adults. Am Gastroenterol 2001;96:635–643. 4 Sandborn WJ, et al: A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology 2002; 122:512–530. 5 Rutgeerts P, et al: Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990; 99:956–963. 6 Miner PB Jr: Factors influencing the relapse of patients with inflammatory bowel disease. Am Gastroenterol 1997;92(suppl 12):1–4. 7 Calkins BM: A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989;34: 1841–1854. 8 Duffy LC, et al: Cigarette smoking and risk of clinical relapse in patients with Crohn’s disease. Am J Prev Med 1990;6:161–166. 9 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. 10 Kaufmann HJ, Taubin HL: Nonsteroidal antiinflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987; 107:513–516. 11 Thomson ABR: Coated oral 5-aminosalicylic acid versus placebo in maintaining remission of inactive Crohn’s disease. Aliment Pharmacol Ther 1990;4:55–64. 12 Modigliani R, et al: Mesalamine in Crohn’s disease with steroid-induced remission: Effect on steroid withdrawal and remission maintenance, Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. Gastroenterology 1996;110:688–693. 13 Arber N, et al: A controlled double-blind multicenter study of the effectiveness of 5-aminosalicylic acid in patients with Crohn’s disease in remission. J Clin Gastroenterol 1995; 20: 203–206.


14 Gendre JP, et al: Oral mesalamine (Pentasa) as maintenance treatment in Crohn’s disease: A multicenter placebo-controlled study. The Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives (GETAID). Gastroenterology 1993;104:435–439. 15 Prantera C, et al: Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn’s disease. The Italian IBD Study Group. Gastroenterology 1992;103:363–368. 16 Thomson AB, et al: Mesalazine (Mesasal/Claversal) 1.5 g bd vs. placebo in the maintenance of remission of patients with Crohn’s disease. Aliment Pharmacol Ther 1995;9:673–683. 17 De Franchis R, et al: Controlled trial of oral 5-aminosalicylic acid for the prevention of early relapse in Crohn’s disease. Aliment Pharmacol Ther 1997; 11:845–852. 18 Sutherland LR, et al: A randomized, placebocontrolled, 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. 19 Mahmud N, et al: Olsalazine is not superior to placebo in maintaining remission of inactive Crohn’s colitis and ileocolitis: A double-blind, parallel, randomised, multicentre study. Gut 2001;49: 552–556. 20 Messori A, et al: Effectiveness of 5-aminosalicylic acid for maintaining remission in patients with Crohn’s disease: A meta-analysis. Am J Gastroenterol 1994;89:692–698. 21 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. 22 Camma C, et al: Mesalamine in the maintenance treatment of Crohn’s disease: A metaanalysis adjusted for confounding variables. Gastroenterology 1997;113:1465–1473. 23 Greenberg GR, et al: Oral budesonide for active Crohn’s disease. Canadian Inflammatory Bowel Disease Study Group. N Engl J Med 1994;331:836–841. 24 Smith RC, et al: Low dose steroids and clinical relapse in Crohn’s disease: A controlled trial. Gut 1978;19:606–610.

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25 Greenberg GR, et al: Oral budesonide as maintenance treatment for Crohn’s disease: A placebo-controlled, dose-ranging study. Canadian Inflammatory Bowel Disease Study Group. Gastroenterology 1996;110:45–51. 26 Lofberg R, 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. 27 Ferguson A, et al: Oral budesonide as maintenance therapy in Crohn’s disease – Results of a 12-month study. Global Budesonide Study Group. Aliment Pharmacol Ther 1998; 12: 175–183. 28 Gross V, et al: Low dose oral pH modified release budesonide for maintenance of steroidinduced remission in Crohn’s disease. The Budesonide Study Group. Gut 1998; 42: 493– 496. 29 Papi C, et al: Budesonide in the treatment of Crohn’s disease: A meta-analysis. Aliment Pharmacol Ther 2000;14:1419–1428. 30 Kane SV, et al: Systematic review: The effectiveness of budesonide therapy for Crohn’s disease. Aliment Pharmacol Ther 2002; 16:1509– 1517. 31 Willoughby JM, et al: Controlled trial of azathioprine in Crohn’s disease. Lancet 1971; ii:944–947. 32 Rosenberg JL, et al: A controlled trial of azathioprine in Crohn’s disease. Am J Dig Dis 1975;20:721–726. 33 O’Donoghue DP, et al: Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet 1978;P ii:955–957. 34 Candy S, et al: A controlled double-blind study of azathioprine in the management of Crohn’s disease. Gut 1995;37:674–678. 35 Bouhnik Y, et al: Long-term follow-up of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet 1996; 347:215–219. 36 Markowitz J, Wyllie R, Markowitz G: Don’t be sidelined. Managing exercise-induced asthma in children. J Pediatr 2000;137:192–196. 37 Pearson DC, et al: Azathioprine and 6-mercaptopurine in Crohn’s disease – A Meta-Analysis. Ann Intern Med 1995;123:132–142.

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38 Fraser AG, Orchard TR, Jewell DP: The efficacy of azathioprine for the treatment of inflammatory bowel disease: A 30-year review. Gut 2002;50:485–489. 39 Connell WR, et al: Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994;343:1249–1252. 40 Dubinsky MC, et al: An open-label pilot study using thioguanine as a therapeutic alternative in Crohn’s disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis 2001; 7:181–189. 41 Dubinsky M, et al: 6-Thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 2003; 125: 298–303. 42 Bonaz B, et al: Tioguanine in patients with Crohn’s disease intolerant or resistant to azathioprine/mercaptopurine. Aliment Pharmacol Ther 2003;18: 401–408. 43 Kozarek RA, et al: Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989;110:353–356. 44 Feagan BG, 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. 45 Targan SR, et al: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor- for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997; 337: 1029–1035.

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46 Cohen RD, Tsang JF, Hanauer SB: Infliximab in Crohn’s disease: First anniversary clinical experience. Am Gastroenterol 2000;95:3469– 3477. 47 Rutgeerts P, 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. 48 Hanauer SB, et al: Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet 2002; 359:1541–1549. 49 Feagan BG, et al: Low-dose cyclosporine for the treatment of Crohn’s disease. The Canadian Crohn’s Relapse Prevention Trial Investigators. N Engl J Med 1994;330:1846–1851. 50 Jewell DP, Lennard-Jones JE, and the cyclosporine study group of Great Britain and Ireland: Oral cyclosporine for chronic active Crohn’s disease. A multicenter controlled trial. Eur J Gastroenterol Hepatol 1994; 6:499–505. 51 Stange EF, et al: European trial of cyclosporine in chronic active Crohn’s disease: A 12-month study. The European Study Group. Gastroenterology 1995;109:774–782. 52 Neurath MF, et al: Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut 1999; 44:625–628. 53 Hafraoui S, et al: Mycophenolate mofetil in refractory Crohn’s disease after failure of treatments by azathioprine or methotrexate (in French). Gastroenterol Clin Biol 2002; 26:17– 22. 54 Skelly MM, et al: Toxicity of mycophenolate mofetil in patients with inflammatory bowel disease. Inflamm Bowel Dis 2002; 8:93–97.

55 Ambrose NS, et al: Antibiotic therapy for treatment in relapse of intestinal Crohn’s disease. A prospective randomized study. Dis Colon Rectum 1985;28:81–85. 56 Plein K, Hotz J: Therapeutic effects of Saccharomyces boulardii on mild residual symptoms in a stable phase of Crohn’s disease with special respect to chronic diarrhea – A pilot study. Z Gastroenterol 1993;31: 129–134. 57 Guslandi M, et al: Saccharomyces boulardii in maintenance treatment of Crohn’s disease. Dig Dis Sci 2000;45:1462–1464. 58 Malchow HA: Crohn’s disease and Escherichia coli. A new approach in therapy to maintain remission of colonic Crohn’s disease? J Clin Gastroenterol 1997;25: 653–658. 59 O’Morain C, Segal AW, Levi AJ: Elemental diet as primary treatment of acute Crohn’s disease: A controlled trial. Br Med J Clin Res Ed 1984;288:1859–1862. 60 Saverymuttu S, Hodgson HJ, Chadwick VS: Controlled trial comparing prednisolone with an elemental diet plus non-absorbable antibiotics in active Crohn’s disease. Gut 1985; 26: 994–998. 61 Somerville KW, et al: Smoking and Crohn’s disease. Br Med J 1984;289:954–956. 62 Cottone M, et al: Smoking habits and recurrence in Crohn’s disease. Gastroenterology 1994; 106:643–648. 63 Sutherland LR, et al: Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology 1990;98:1123–1128.




Treatment of Postoperative Crohn’s Disease Florian Froehlicha, b Pascal Juillerata Christian Felleya Christian Motteta John-Paul Vaderc Bernard Burnandc Pierre Michettia Jean-Jacques Gonversa a


Key Words Crohn’s disease Postoperative treatment Maintenance treatment Relapse prevention Mesalamine Azathioprine Immunosuppressive treatment

ment as initial short-term prevention therapy rather than for long-term use. Conventional corticosteroids, budesonide or probiotics have no proven role in postoperative prophylaxis. Infliximab has not as yet been studied for use in the prevention of relapse after surgery. Copyright © 2005 S. Karger AG, Basel

Abstract At 1 year after a first resection, up to 80% of patients show an endoscopic recurrence, 10–20% have clinical relapse, and 5% have surgical recurrence. Smoking is one of the most important risk factors for postoperative recurrence. Preoperative disease activity and the severity of endoscopic lesions in the neoterminal ileum within the first postoperative year are predictors of symptomatic recurrence. Mesalamine is generally the first-line treatment used in the postoperative setting but still provokes considerable controversy as to its efficacy, in spite of the results of a meta-analysis. Immunosuppressive treatment (azathioprine, 6-MP) is based on scant evidence but is currently used as a second-line treatment in postsurgical patients at high risk for recurrence, with symptoms or with early endoscopic lesions in the neoterminal ileum. Nitroimidazole antibiotics (metronidazole, ornidazole) are also effective in the control of active Crohn’s disease in the postoperative setting. Given their known toxicity, they may be used as a third-line treat-



Introduction

There are currently no guidelines on postoperative maintenance therapy in Crohn’s disease and considerable uncertainty remains as to the efficacy of such treatments. The development of explicit criteria of appropriateness of the use of various postoperative treatment regimens will be a useful aid to clinical decision-making in this context.

Natural History of Postoperative Crohn’s Disease

Approximately 75% of Crohn’s disease patients require surgery within the first 20 years after symptom onset [1, 2]. Surgery is rarely curative as more than 80% of patients with Crohn’s disease develop endoscopic recurrence 1 year after surgery, almost invariably on the ileal

Florian Froehlich, MD Division of Gastroenterology and Hepatology Lausanne University Medical Center Rue du Bugnon 44, CH–1011 Lausanne (Switzerland) Tel. +41 32 4662255, Fax +41 32 4662955, E-Mail [email protected]

side of the ileocolonic anastomosis [3]. A significant proportion of patients with recurrent endoscopic lesions do not show any patent clinical symptoms [4]. Clinical relapse occurs in 30% of patients 3 years after surgery and in up to 60% after 10 years [5, 6] and by 5 years approximately 50% of patients have a clinical recurrence [7]. Half of these patients subsequently need surgery at some point in their life. Endoscopic recurrence after ileocolonic resection was detected very early after surgery [4, 8]. At 3 months after surgery, approximately 60% of patients had endoscopic signs of ileal recurrence; at 1 and 2 years, the endoscopic recurrence rate was 71 and 77% respectively [4, 8]. The severity of early recurrence of inflammation impacts on the subsequent course of disease [4]. Endoscopy 6–12 months after surgery has thus been recommended in Crohn’s disease patients with a lower risk of recurrence in order to direct postoperative medical prophylaxis towards those patients with moderate or severe endoscopic lesions while giving no treatment to those with mild lesions or no lesions at all. The need for repeated surgery is fortunately lower, varying at 10 years after resection between 16 and 65% [9, 10].

Risk Factors for Postoperative Recurrence

Specific risk factors for postoperative recurrence have not previously been well defined. Rutgeerts et al. [4] followed up prospectively a cohort of 89 patients after surgery for Crohn’s disease in order to study the natural course of early postoperative lesions. The main clinical parameter which influenced outcome was preoperative disease activity while the number of resections was not found to be an independent risk factor but rather reflected preoperative disease activity. The most powerful variable determining symptomatic recurrence was the severity of endoscopic lesions in the neoterminal ileum during the first year after surgery. In this study, outcome was poor in patients with high disease activity preoperatively and severe early endoscopic recurrence [4]. Colonoscopy performed at 6–12 months after surgery may therefore permit targeting patients at high risk of symptomatic recurrence [11]. An important retrospective cohort study in 1,936 patients showed that female gender, perianal fistulas and continuous ileocolonic disease increase the relative risk of recurrence after surgery [3].

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Smoking is the most important external risk factor and increases the probability of postsurgical recurrence and of further surgical intervention [12–14]. Smoking is the only risk factor that has been related to both endoscopic and clinical recurrence. Ex-smokers have a risk probability comparable to that of non-smokers [12]. Several other risk factors have been identified. Patients having undergone surgery at a younger age or with a disease history of less than 10 years have a higher recurrence rate [15, 16]. Multiple-site bowel involvement seems to be associated with an increased risk [17]. Patients with ileocolonic disease have a higher recurrence rate than those with predominantly ileal [18] or with isolated colonic disease [19]. The time from onset of symptoms to the first operation for Crohn’s disease was found to be shortest in patients with ileocolitis [2]. The length of bowel involved in postoperative recurrence was correlated to the length of diseased intestine before surgery, and more extensive disease predicted a recurrence after a shorter follow-up period [20]. The pattern of disease recurrence (perforating or non-perforating) is consistent with the type of disease before surgery [21]. A perforating indication for surgery was predictive of earlier postoperative recurrence [22, 23] as compared to a non-perforating indication. Neither radical resections with wide resection margins nor disease-free margins seem to have a positive impact on postoperative recurrence [24–26]. The number of prior resections did not significantly impact on the probability of postoperative recurrence [2, 27] and was not identified as an independent predictor of postoperative recurrence [4]. End-to-end anastomosis seems to be associated with a higher risk of relapse than side-toside or end-to-side anastomosis [19].

Treatment

Available Treatments Treatment 1: Mesalazine Evidence The efficacy of mesalamine in preventing postoperative recurrence in Crohn’s disease is controversial as shown by the varying results of several studies. Caprilli et al. [28] randomly allocated mesalamine (2.4 g/day) or no treatment to 110 Crohn’s patients at first resection and followed them over 2 years to study endoscopic recurrence. Patients underwent colonoscopy at 6 months and thereafter at yearly intervals. Severe endoscopic recurrence was observed in 17% in the mesalamine

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group and in 38% in the control group. Brignola et al. [29] reported on 87 patients randomly receiving mesalamine (Pentasa) 3 g/day or placebo within 1 month after surgery. After a follow-up of 1 year, clinical relapse occurred in 16% in the mesalamine group and in 23% in the placebo group (NS). Severe endoscopic recurrence was however recorded less frequently in the treatment group (14%) than in the placebo group (50%; p ! 0.002). Mesalamine (Pentasa, 3,000 mg/day, 106 patients) introduced 15 days after ‘curative’ resection did not reduce the rate of endoscopic recurrence at 3 months, compared to placebo (50 vs. 63%, p = 0.16) [30]. McLeod et al. [31] randomized 163 patients who underwent surgical resection without residual disease to 3 g of mesalamine or placebo within 8 weeks of surgery. The symptomatic recurrence rate (defined as symptoms plus endoscopic and/or radiological confirmation of disease) was 31% in the treatment group compared to 41% in the control group (p = 0.03). The relative risk of developing recurrent disease or of endoscopic recurrence was 0.62 (95% CI 0.40–0.97) and 0.65 (95% CI 0.47–0-91) in favor of mesalamine. Another randomized placebo-controlled trial in 246 patients, with both medically and surgically induced remission (mesalamine 3,000 mg/day), did not find a statistically significant difference between mesalamine (relapse in 25%) and placebo (relapse in 36%, p = 0.056). Subgroup analysis revealed that women and patients with ileocolonic disease had distinctly fewer relapses at 2 years’ follow-up (19 vs. 41%, p = 0.003; 21 vs. 41%, p = 0.018) [32]. In a randomized placebo-controlled trial, Lochs et al. [33] assessed mesalamine 4 g/day started within 10 days after resection for a duration of 18 months in 318 patients. The cumulative relapse rates after 18 months were 24.5% in the mesalamine group and 31.4% in the placebo group (p = 0.10). However, in a retrospective analysis, this study found a benefit with mesalamine treatment in a subgroup of patients with isolated small bowel disease and resection. A meta-analysis showed a modest but significant risk reduction of recurrence in the postoperative setting (absolute risk reduction for mesalamine compared with placebo 13.1%, 95% CI 4.5–21.8%) although not in patients without prior surgery for Crohn’s disease. Multivariate analysis of these data showed the most benefit in patients with ileitis and prolonged disease duration [34]. The difference between mesalamine and placebo remained significant after adding the data obtained 3 years later by Lochs et al. [33] to this meta-analysis. The absolute risk difference was

Treatment after Surgical Intervention

then 10% (95% CI 17–3%) and the number needed to treat to prevent one relapse was found to be 10 [35]. Mesalazine 4 g/day does not have any significant advantage over mesalazine 2.4 g/day with respect to endoscopic or clinical recurrence rates (62 vs. 46% at 1 year after surgery, NS) [36] and it still remains unclear which is the best dosage to use. Historically, sulfasalazine is effective in preventing postoperative recurrence at 2 years, compared to placebo [26], but is rarely used in the postoperative setting. Treatment 2: Immunosuppressive Therapy Evidence Very few studies on immunosuppressive therapy have been performed. 6-Mercaptopurine has been found to be effective in preventing postoperative relapse in a multicenter study that has only to date been published in abstract form [37] in which 131 patients were randomized to either 6-MP, 5-ASA or placebo. 6-MP was found to be superior to placebo and mesalamine in preventing clinical, endoscopic and radiographic postoperative relapse at 2 years after resection surgery. The clinical recurrence rate in the group receiving 6-MP was 53% at 24 months compared to 70% in the placebo group (p ! 0.05). Endoscopic recurrence with more severe lesions was found in 68% at 24 months in the 6-MP group, compared to 90% in the placebo group (p ! 0.05). In a small trial in 21 patients, azathioprine (50 mg/day) was compared to mesalamine (3 g/day). There was no difference in the clinical or endoscopic relapse rate after 1 year, but the dosage of azathioprine was obviously too low [38]. In a case series of 15 patients receiving azathioprine and undergoing colonoscopy at least 6 months after weaning from steroids, immunosuppressive therapy induced mucosal healing in the neoterminal ileum in most patients [39]. Despite the fact that little evidence is available, immunosuppressive therapy has become a mainstay in postoperative Crohn’s disease in patients with high risk of recurrence, severe symptoms or severe early endoscopic lesions. Treatment 3: Metronidazole Evidence Fecal bacteria probably play a major role in the pathogenesis of recurrence [40]. The role of metronidazole was assessed in a trial in which 60 patients were randomized to receive either metronidazole for 3 months, starting within 1 week of ileal resection, or placebo [41]. Recurrent lesions in the neoterminal ileum occurred in 52% in

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the metronidazole group and in 75% in the placebo group (p = 0.09); severe endoscopic lesions were found more frequently in the placebo group (43%) as compared to the metronidazole group (13%; p = 0.02). Metronidazole reduced the clinical recurrence rate significantly at 1 year (4 vs. 25%) while reduction at 2 years (26 vs. 43%) and 3 years (30 vs. 50%) was not significant. Metronidazole therapy for 3 months decreases the rate and severity of early postoperative recurrence. However, the known toxicity of metronidazole may not be compatible with longterm use. The same group performed a similar trial using randomly either ornidazole 1 g/day or placebo in 80 patients within 1 week after resection (only published in abstract form [42]). Patients underwent endoscopic follow-up at 3 and 12 months, and clinical follow-up at 12, 24 and 36 months. At 12 months, the endoscopic recurrence rate was 54% with ornidazole compared to 79% with placebo (p = 0.04). Clinical recurrence at 12 months was 8% with active treatment and 37% with placebo (p = 0.002) while there was no significant difference in relapse rate at 24 and 36 months. Nitroimidazole antibiotics (metronidazole, ornidazole) are also effective in the control of active Crohn’s disease in the postoperative setting. They may be used as an initial short-term prevention therapy rather than longterm given their known toxicity. There are no major clinical trials regarding the use of Infliximab in the setting of postoperative Crohn’s disease. Colombel et al. [43] retrospectively studied 26 patients with an initial diagnosis of ulcerative colitis who subsequently developed complications compatible with Crohn’s disease, such as fistula or prepouch ileitis. In these highly selected patients, Infliximab produced a complete clinical response in 62% in the short term, and a good or acceptable response in 58% after 21 months.

the clinical or endoscopic recurrence rate or the severity of endoscopic lesions at 1-year follow-up, as compared to placebo [45]. The efficacy of interleukin-10 (IL-10) was assessed in a randomized placebo-controlled study in 65 patients. IL10 was well tolerated, but did not prevent the endoscopic recurrence at 12 weeks after surgery for Crohn’s disease (recurrence rate 52% in the placebo group, 46% in the IL10 group) [46].

Conclusions

In practice, mesalamine is generally the first-line treatment used in the postoperative setting despite considerable controversy as to its efficacy. Immunosuppressive treatment (azathioprine, 6-MP) is currently used as a second-line treatment in patients at high risk of recurrence, with symptoms or with early endoscopic lesions in the neoterminal ileum. Nitroimidazole antibiotics (metronidazole, ornidazole) may be used as a third-line treatment as an initial short-term prevention therapy rather than for long-term use. While immunosuppressive therapy is generally introduced in patients at high risk of recurrence, colonoscopy performed 6–12 months after surgery may permit targeting of treatment to patients at higher risk of recurrence by confirmation of the severity of endoscopic lesions [11].

Inefficacious Treatments Conventional steroids have no role in postoperative prophylaxis. Budesonide 3 mg/day, introduced within 2 weeks after surgery [25], or 6 mg/day [44], was also ineffective in preventing endoscopic or clinical relapse 1 year after surgery in two randomized placebo-controlled trials. In patients with disease activity as the indication for surgery, the endoscopic recurrence rate was lower in the budesonide group at 12 months as compared to placebo (32 vs. 65%, p = 0.047) [44]. No difference in adverse event patterns was found between the two groups. A probiotic therapy with lactobacillus given per os during 1 year in 55 patients did not positively affect either

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References 1 Becker JM: Surgical therapy for ulcerative colitis and Crohn’s disease. Gastroenterol Clin North Am 1999;28:371–390, viii–ix. 2 Mekhjian HS, et al: National Cooperative Crohn’s Disease Study: Factors determining recurrence of Crohn’s disease after surgery. Gastroenterology 1979; 77:907–913. 3 Bernell O, Lapidus A, Hellers G: Risk factors for surgery and postoperative recurrence in Crohn’s disease. Ann Surg 2000;231:38–45. 4 Rutgeerts P, et al: Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956–963. 5 Sachar DB: The problem of postoperative recurrence of Crohn’s disease. Med Clin North Am 1990;74:183–188. 6 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. 7 Banerjee S, Peppercorn MA: Inflammatory bowel disease. Medical therapy of specific clinical presentations. Gastroenterol Clin North Am 2002;31:185–202. 8 Rutgeerts P, et al: Natural history of recurrent Crohn’s disease at the ileocolonic anastomosis after curative surgery. Gut 1984;25:665–672. 9 Greenstein AJ, et al: Reoperation and recurrence in Crohn’s colitis and ileocolitis crude and cumulative rates. N Engl J Med 1975;293: 685–690. 10 Whelan G, et al: Recurrence after surgery in Crohn’s disease. Relationship to location of disease (clinical pattern) and surgical indication. Gastroenterology 1985; 88:1826–1833. 11 D’Haens G: Prevention of postoperative recurrence in Crohn’s disease. Curr Gastroenterol Rep 1999;1:476–481. 12 Cottone M, et al: Smoking habits and recurrence in Crohn’s disease. Gastroenterology 1994;106:643–648. 13 Sutherland LR, et al: Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology 1990;98: 1123–1128. 14 Borley NR, Mortensen NJ, Jewell DP: Preventing postoperative recurrence of Crohn’s disease. Br J Surg 1997;84:1493–1502. 15 Hellers G: Crohn’s disease in Stockholm County, 1955–1974. Acta Chir Scand 1979; 5(suppl 490):81. 16 Baker WN: The results of ileorectal anastomosis at St Mark’s Hospital from 1953 to 1968. Gut 1970;11:235–239. 17 Michelassi F, et al: Primary and recurrent Crohn’s disease. Experience with 1,379 patients. Ann Surg 1991;214:230–240. 18 Griffiths AM, et al: Factors influencing postoperative recurrence of Crohn’s disease in childhood. Gut 1991;32:491–495.

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19 Caprilli R, et al: Prognostic factors for postoperative recurrence of Crohn’s disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Dis Colon Rectum 1996; 39: 335– 341. 20 D’Haens GR, Gasparaitis AE, Hanauer SB: Duration of recurrent ileitis after ileocolonic resection correlates with presurgical extent of Crohn’s disease. Gut 1995;36: 715–717. 21 Greenstein AJ, et al: Perforating and non-perforating indications for repeated operations in Crohn’s disease: Evidence for two clinical forms. Gut 1988;29:588–592. 22 Lautenbach E, Berlin JA, Lichtenstein GR: Risk factors for early postoperative recurrence of Crohn’s disease. Gastroenterology 1998; 115:259–267. 23 Aeberhard P, et al: Surgical recurrence of perforating and nonperforating Crohn’s disease. A study of 101 surgically treated patients. Dis Colon Rectum 1996;39:80–87. 24 Fazio VW, et al: Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. A randomized controlled trial. Ann Surg 1996;224:563–573. 25 Ewe K, et al: Low-dose budesonide treatment for prevention of postoperative recurrence of Crohn’s disease: A multicentre randomized placebo-controlled trial. German Budesonide Study Group. Eur J Gastroenterol Hepatol 1999;11: 277–282. 26 Ewe K, et al: Postoperative recurrence of Crohn’s disease in relation to radicality of operation and sulfasalazine prophylaxis: A multicenter trial. Digestion 1989;42:224–232. 27 Nygaard K, Fausa O: Crohn’s disease. Recurrence after surgical treatment. Scand J Gastroenterol 1977;12:577–584. 28 Caprilli R, et al: Oral mesalazine (5-aminosalicylic acid; Asacol) for the prevention of postoperative recurrence of Crohn’s disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Aliment Pharmacol Ther 1994; 8:35– 43. 29 Brignola C, et al: Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn’s disease. Italian Cooperative Study Group. Gastroenterology 1995; 108: 345–349. 30 Florent C, et al: Placebo-controlled clinical trial of mesalazine in the prevention of early endoscopic recurrences after resection for Crohn’s disease. Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). Eur J Gastroenterol Hepatol 1996; 8: 229–233. 31 McLeod RS, et al: Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology 1995; 109:404–413.

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32 Sutherland LR, et al: A randomized, placebocontrolled, 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. 33 Lochs H, et al: Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine: European Cooperative Crohn’s Disease Study VI. Gastroenterology 2000;118:264–273. 34 Camma C, et al: Mesalamine in the maintenance treatment of Crohn’s disease: A metaanalysis adjusted for confounding variables. Gastroenterology 1997;113:1465–1473. 35 Cottone M, Camma C: Mesalamine and relapse prevention in Crohn’s disease. Gastroenterology 2000;119:597. 36 Caprilli R, 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. 37 Korelitz B, et al: Post-operative prophylaxis with 6-MP, 5-ASA or placebo in Crohn’s disease: A 2-year multicenter trial. Gastroenterology 1998;114:A1011. 38 Nos P, et al: Azathioprine and 5-ASA in the prevention of postoperative recurrence of Crohn’s disease. Gastroenterol Hepatol 2000; 23: 374–378. 39 D’Haens G, et al: Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn’s disease. Gastroenterology 1997; 112:1475–1481. 40 D’Haens G, et al: Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998;114:262–267. 41 Rutgeerts P, et al: Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995;108:1617–1621. 42 Rutgeerts P: infliximab maintenance strategy results in mucosal healing in patients with Crohn’s disease. Gastroenterology 2002; 122: W1356. 43 Colombel JF, et al: Management of Crohn’s disease of the ileoanal pouch with infliximab. Am J Gastroenterol 2003;98:2239–2244. 44 Hellers G, et al: Oral budesonide for prevention of postsurgical recurrence in Crohn’s disease. The IOIBD Budesonide Study Group. Gastroenterology 1999;116:294–300. 45 Prantera C, et al: Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: A randomised controlled trial with Lactobacillus GG. Gut 2002; 51: 405–409. 46 Colombel JF, et al: Interleukin-10 (Tenovil) in the prevention of postoperative recurrence of Crohn’s disease. Gut 2001;49: 42–46.

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Pregnancy and Crohn’s Disease Christian Motteta Pascal Juillerata Jean-Jacques Gonversa Florian Froehlicha, b Bernard Burnandc John-Paul Vaderc Pierre Michettia Christian Felleya a


Key Words Crohn’s disease Pregnancy and Crohn’s disease Crohn’s disease, therapy

Abstract Crohn’s disease commonly affects women of childbearing age. Available data on Crohn’s disease and pregnancy show that women with Crohn’s disease can expect to conceive successfully, carry to term and deliver a healthy baby. Control of disease activity before conception and during pregnancy is critical, to optimize both maternal and fetal health. Generally speaking, pharmacological therapy for Crohn’s disease during pregnancy is similar to pharmacological therapy for non-pregnant patients. Patients maintained in remission by way of pharmacological therapy should continue it throughout their pregnancy. Most drugs, including sulfasalazine, mesalazine, corticosteroids, and immunosuppressors such as azathioprine and 6-mercaptopurine, are safe, whereas methotrexate is contraindicated. Copyright © 2005 S. Karger AG, Basel



Introduction

As the peak age of onset of Crohn’s disease coincides with the peak age for conception, physicians regularly have to care for pregnant Crohn’s patients. Patient management is challenging and necessitates a multidisciplinary approach by an obstetrician and a gastroenterologist familiar with Crohn’s disease and its treatment. Control of disease activity before conception and during pregnancy is critical to optimize both maternal and fetal health, as fetal outcome from mothers with Crohn’s disease is not essentially different from that in the general population, except in the presence of active disease. Most drugs, including sulfasalazine, mesalazine, corticosteroids, and immunosuppressors such as azathioprine and 6-mercaptopurine (6-MP), are safe and allow a better fetal outcome than untreated active disease. The use-inpregnancy ratings for drugs categorize drug risk to the fetus. These categories run from ‘A’ (controlled studies show no risk), ‘B’ (no evidence of risk in humans: animal findings show risk but human studies do not, or animal studies are negative but there are no adequate human studies), ‘C’ (risk cannot be ruled out: animal studies positive or lacking, human studies lacking), ‘D’ (positive evidence of risk: can still be used if benefit outweighs risk) to ‘X’ (known danger, contraindicated during pregnancy). All the available data on Crohn’s disease medication and pregnancy rely, however, almost exclusively on case series or case-control studies with only very few prospec-

Christian Mottet, MD Division of Gastroenterology and Hepatology Lausanne University Medical Center Rue du Bugnon 46, CH–1011 Lausanne (Switzerland) Tel. +41 21 3140683, Fax +41 21 3140707, E-Mail [email protected]

tive, although not randomized studies and on extrapolations from the use of immunomodulatory medication in pregnancy for other medical conditions, mostly in transplantation.

Results

Two important factors determine the management of a pregnancy in the presence of Crohn’s disease: the disease activity (quiescent vs. active) and when a flare-up occurs, i.e. before (fertility), during (early and late pregnancy), or after pregnancy (nursing). Crohn’s Disease and Fertility A retrospective [1] case-control study in women showed a normal fertility rate when the disease was quiescent and a reduced fertility in proportion to disease activity and in the presence of a history of prior abdominal operations, ovary and fallopian tube involvement and perianal disease with secondary dyspareunia. Infertility may be also observed in men under sulfasalazine therapy, as sulfasalazine [2, 3] but not 5-ASA compounds [2] or azathioprine [4] causes reversible oligospermia, reduced sperm motility and abnormal sperm morphology. There is conflicting data on the effect of oral contraception on Crohn’s disease. In one prospective study [5], women under oral contraception were 1.8 times more likely to develop Crohn’s disease than those not taking these agents. However, another case-control study has not found any association between the use of oral contraceptives and the development of Crohn’s disease [6] and oral contraceptives did not appear to influence the disease course of patients with established Crohn’s disease [7]. Given the uncertainty, it is reasonable to continue oral contraception in patients with Crohn’s disease who are doing well, while cessation of oral contraception should be considered in those who remain symptomatic despite conventional drug therapy. Crohn’s Disease and Pregnancy Two main questions are of interest in the context of pregnancy and Crohn’s disease: does pregnancy affect the activity of the disease? and reciprocally, does Crohn’s disease or its treatment affect the outcome of pregnancy?

Crohn’s disease activity at the time of conception as a quiescent disease (spontaneous or under maintenance therapy) at the time of conception remained quiescent in twothirds of the cases, whereas an active disease continued to be active in 60–70% and only improved in a third of cases [9]. This stresses the importance of a careful planning of pregnancy at a time when the disease is in remission. Pregnancy termination should never be considered as a therapeutic option for Crohn’s flare-up as there is no evidence to suggest that induced abortion improves disease activity. Effect of Crohn’s Disease on Pregnancy Outcome No data has been published demonstrating an increased risk of congenital abnormalities in quiescent Crohn’s disease. Four retrospective studies [10–13] have, however, shown higher incidences of low birth weight and pre-term birth, but made no correlation to disease activity. Another study [14] observed a correlation between length of bowel resection or active disease at the time of conception and an increased risk of spontaneous abortion as compared to a reference population and to women with ulcerative colitis. The best mode of delivery still remains controversial as no randomized prospective studies have been published. Generally speaking, the method of delivery should be dictated by obstetric necessity and indication. Standard practice is vaginal delivery for women with quiescent or mild disease [15] and cesarean delivery for active perianal disease. Avoidance of episiotomy is recommended as a high rate of perineal involvement seems to follow vaginal delivery with episiotomy in patients with Crohn’s disease according to a retrospective study with methodological limitations [16]. Course of Crohn’s Disease after Pregnancy The impression expressed by some clinicians of higher rates of flare-up in postpartum is not documented in the literature. A survey by Mogadam et al. [17] in 1981 reported that the course of inflammatory bowel disease is not adversely affected by concurrent pregnancy or postpartum.

Effect of Pregnancy on Crohn’s Disease An inaugural manifestation of Crohn’s disease only rarely occurs during pregnancy [8]. The evolution of Crohn’s disease during pregnancy depends mostly on

Treatment Options Most therapy regimens proposed are empiric and rely on observational prospective cohort or retrospective case (controlled) series as evidenced-based therapy from experimental, well-designed, randomized controlled trials is almost absent. Since treatment modalities differ, it is important to differentiate between treatments aimed at

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maintaining remission (quiescent disease) with treatment of flare-up. Proactive maintenance of quiescent disease is generally preferred to reactive treatment of disease flares as pregnancy outcomes are best for controlled disease at the time of conception. Timing of conception should therefore be planned during a phase of remission. Active disease is commonly accepted as a greater threat to the mother and the fetus than the standard medication used to treat and prevent it, with few exceptions! Generally speaking, pharmacological therapy for Crohn’s disease during pregnancy is similar to pharmacological therapy for non-pregnant patients and patients maintained in remission by way of pharmacological therapy should continue it throughout their pregnancy, with few exceptions! Unfortunately, the conclusions of most studies have to be considered with caution because of the retrospective nature of data collection, the small sample size, the lack of a truly normal control group and the lack of information regarding disease activity and comorbidity. The studies with the greatest sample collective about drug safety for corticosteroids and immunomodulators such as azathioprine and 6-MP have not been conducted in Crohn’s disease patients, the extrapolation of these results for Crohn’s disease should therefore also be considered with caution. Safety of Drugs (table 1) Antibiotics (Metronidazole, Ciprofloxacin) Metronidazole (pregnancy category B) and ciprofloxacin (pregnancy category C) are currently the most frequently used antibiotics in the treatment of Crohn’s disease. Although some animal studies have shown a teratogenicity of metronidazole [18], two meta-analyses [19, 20] and a recent prospective controlled cohort study failed to show any birth defect increase in the treatment group [21]. These studies were however not specifically designed for patients with Crohn’s disease. The same is valid for ciprofloxacin. Loebstein et al. [22] prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that of 200 controls matched for age and for smoking and alcohol consumption habits. Rates of major congenital malformation did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk 0.85; 95% confidence interval 0.21–3.49). They concluded that the use of fluoroquinolones during embryogenesis was not associated with an increased risk of major malformation [22].

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Table 1. Fetal safety of medication used for Crohn’s disease

Safe

Probably safe

Mesalamine Sulfasalazine Ampicillin Cephalosporines Metronidazol1 Prednisone Hydrocortisone Methylprednisolone Loperamide

Azathioprine Infliximab 6-MercaptoOlsalazine purine Ciprofloxacin1 Budenoside

1

Very Contralimited data indicated Methotrexate

In second or third trimester.

Metronidazole [23, 24] and ciprofloxacin [25] are excreted into breast milk, but only scant data are available [24] about their safety for breast-fed infants. Sulfasalazine (Pregnancy Category B) A case-control study [26] within the Hungarian Case Control Surveillance of Congenital Abnormalities based on newborn infants or fetuses with congenital abnormalities, and babies without any detected congenital abnormalities (control group), found only 17 pregnant women (0.07%) treated with sulfasalazine in the case group and 26 (0.07%) in the control group. Although limited, the data does not indicate any significant increased prevalence of selected congenital abnormalities among the exposed compared to the not-exposed fetus. To determine the safety of corticosteroids and sulfasalazine in pregnancy associated with inflammatory bowel disease, Mogadam et al. [27] reviewed the outcome of 531 such pregnancies in a national survey. Two hundred and eighty-seven pregnancies (172 ulcerative colitis and 115 Crohn’s disease) were treated with either or both drugs, whereas 244 (137 ulcerative colitis and 107 Crohn’s disease) received neither. As the frequency of fetal complications was significantly lower in both ‘treated’ and ‘untreated’ groups than the reported rates in the general pregnant population, they concluded that the use of corticosteroid and sulfasalazine in pregnancy associated with ulcerative colitis were unlikely to increase fetal morbidity or mortality. A single study showed a correlation between congenital malformation and sulfasalazine medication with sulfasalazine being taken by the parents in 29 of the 39 mal-

Mottet/Juillerat/Gonvers/Froehlich/ Burnand/Vader/Michetti/Felley

formations which occurred. The statistical analysis performed in this questionnaire-based study has, however, some serious limitations as other factors such as age at the time of conception and activity of disease are not taken into account and the study is based on an 81% response rate with consequently a possible selection-bias [28]. The amount of sulfasalazine found in the breast milk and serum of nursing babies is minimal [29, 30]. It is therefore generally admitted that sulfasalazine may be used in lactating women although no proper data are available. As the sulfapyridine moiety in sulfasalazine can cause inhibition of folate absorption, and could therefore theoretically cause neural tube defects as well as cardiovascular and urinary tract abnormalities and oral cleft, pregnant women under sulfasalazine therapy are advised to take an additional folate supplementation (2 mg/day) throughout pregnancy. Sulfasalazine can furthermore cause reversible oligospermia in men [2, 3] as discussed above. Because of the high rate of side effects (nausea, vomiting, rash, fever, diarrhea) the drug should be started at a low dose of 0.5 g/day to the goal of 4–6 g/day in divided doses over several days for acute illness or 3–4 g/ day for maintenance therapy. 5-Aminosalicylic Acid (5-ASA) Drugs Mesalazine (pregnancy category B) seems to be safe for use during pregnancy and nursing. Habal et al. [31] reported that 18 out of 19 pregnancies under mesalazine medication resulted in full-term delivery with no fetal abnormalities. One patient had a miscarriage, but she had miscarried on four previous occasions before taking mesalazine. The study by Diav-Citrin et al. [32] prospectively enrolled and followed up 165 women with inflammatory bowel disease exposed to mesalazine during pregnancy, 146 of whom had first trimester exposure. Pregnancy outcome was compared with that of a control group, who were counseled for non-teratogenic exposure. There was no increase in major malformations (1 of 127 [0.8%] for mesalazine vs. 5 of 131 [3.8%] for non-teratogenic controls; p = 0.23). An increase in the rate of preterm deliveries (13.0% for mesalazine vs. 4.7% for nonteratogenic controls; p = 0.02), and a decrease in the mean birth weight (3,253 8 546 g for mesalazine vs. 3,461 8 542 g for non-teratogenic controls; p = 0.0005) were observed, but no data on disease activity are reported. A questionnaire case report study analyzed the fate of pregnancy and fetal outcome in women taking 1–4 g/day of mesalazine microgranules for inflammatory bowel dis-


ease. The study covered a total of 123 pregnancies (126 fetuses). The following abnormalities were observed: ectopic pregnancy (1), spontaneous abortion (2), fetal death (1), premature delivery (8), congenital malformation (4) and 1 case of lethal oxalosis. The abnormalities observed were not considered to be related to mesalazine [33]. To examine the risk of malformations, stillbirths, preterm births, and low birth weight from the use of 5-ASA drugs mesalazine and olsalazine during pregnancy, Norgard et al. [34] analyzed data from the population-based prescription registry, the Danish Birth Registry, and the Hospital Discharge Registry. The study included 60 pregnancies exposed to 5-ASA drugs 30 days before pregnancy or in the first trimester and 88 pregnancies exposed during the entire pregnancy. The outcomes were compared with those of 19,418 pregnancies in which no drugs were prescribed for mothers during the study period. They found an increased risk of stillbirth and pre-term birth in women who had been prescribed 5-ASA drugs during pregnancy but no substantial increased risk of malformation. With the data available it was, however, impossible to distinguish the specific effects of disease activity and 5-ASA drugs. One case of renal insufficiency in a child born after mesalazine therapy, consisting of 4 g/day during the third trimester, has been reported [35, 36]. The recommended dose of mesalazine is 2.4–4.8 g/ day. As 5-ASA compounds may increase the effective dose of azathioprine and 6-MP [37], because inhibition at the detoxification pathway has been described [38], careful monitoring is advised. The safety of other compounds such as balsalazide has not been tested in pregnant women. The committee on drugs of the American Academy of Pediatrics [39] recommend caution as one case of bloody diarrhea has been reported with sulfasalazine and one case of diarrhea with 5-ASA. Corticosteroids (No FDA Pregnancy Category Rating) Glucocorticoids are the most effective treatment for severe acute flares in Crohn’s disease but have no place as maintenance therapy. No data are specifically available concerning the use of glucocorticoids in Crohn’s disease and pregnancy. In a 1968 Lancet study, 34 pregnancies of women receiving prednisolone resulted in 8 stillbirths in comparison to 1 stillbirth and 3 premature babies in 34 control pregnancies with similar general diseases not treated with prednisolone [40].

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57

Park-Wyllie et al. [41] prospectively collected and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant control women for the rate of major birth defects. No statistical difference was found in the rate of major anomalies between the corticosteroid-exposed and control groups. A well-performed meta-analysis of the data of all publications registered in the Medline database from 1966 to 1999 and Current Contents in 1999 retrieved by the following search ‘(congenital anomalies or drug-induced or teratogen or birth defect) and glucocorticosteroid’ showed, however, a marginally increased risk of major malformation (mostly oral cleft malformation) after first trimester exposure to corticosteroids. The odds ratio was 3.03 (95% confidence interval 1.08, 8.54) [41]. Glucocorticoids can cross the placenta. As short-acting prednisone, prednisolone and methylprednisolone are more efficiently metabolized by the placenta and therefore reach lower concentrations in the fetus than the longer acting dexamethasone and betamethasone, the former are preferred for the treatment of maternal conditions necessitating glucocorticosteroids. Standard dosage is 1 mg/kg oral prednisone for a week then tapered slowly over 8 weeks. Patients with left-sided colitis or proctosigmoiditis may benefit from enema, foam or suppository preparations. These topical therapies have fewer steroid side effects. There is, however, no specific data available for pregnancy. Budesonide (Pregnancy Category C) No specific data are available for Crohn’s disease and pregnancy. The only available data concern inhaled budesonide by asthma patients. Data from the Swedish Medical Birth Register identified 2,968 mothers who reported use of inhaled budesonide for asthma during early pregnancy. They gave birth to infants of normal gestational age, birth weight and length, with no increased rate of stillbirth or multiple births [42]. Another study from the Swedish Medical Birth Register identified 2,014 infants whose mother had used inhaled budesonide. No increase in the rate of congenital malformation was observed [43]. Immunomodulators: Azathioprine and 6-MP (Both Pregnancy Category D) Despite a pregnancy class D rating, these drugs have been used very successfully to induce or maintain remission in pregnancy. The greatest experience with azathioprine and 6-MP and pregnancy comes from the renal

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transplant literature [44, 45]. No significant increase in congenital anomalies have been described. The few available published literature about Crohn’s disease and pregnancy, although retrospective and limited by the lack of proper control group and information regarding comorbidity, suggest that these drugs are safe and well tolerated during pregnancy. The retrospective analysis of the outcome of 16 pregnancies in 14 women receiving azathioprine for inflammatory bowel disease by Alstead et al. [46] identified one infectious complication of pregnancy (hepatitis B virus infection), but there were no congenital abnormalities or subsequent health problems in the children. Francella et al. [47] reviewed the records of 485 men and women who had taken or were currently taking 6-MP. 155 had conceived at least once after developing IBD. Pregnancies were analyzed as to whether the patient had taken 6-MP before, or at the time of, conception. These data were compared with IBD patients who had their pregnancies before taking 6-MP. There was no statistical difference in spontaneous abortion, abortion secondary to a birth defect, major congenital malformation, neoplasia, or increased infection (relative risk = 0.85 [0.47–1.55], p = 0.59). Standard dosage is 2–2.5 mg/kg/day for AZA and 1– 1.5 mg/kg/day for 6-MP. These should not be used during nursing as they are transmitted at low levels in breast milk. Azathioprine and its metabolites are transferred to breast milk at a low level. The use of azathioprine and 6-MP in nursing mothers is not recommended, because of the theoretical potential for immunosuppression, growth retardation and carcinogenesis. Cyclosporine (Pregnancy Category C) Cyclosporine has a beneficial therapeutic effect in patients with chronic active Crohn’s disease and resistance to or intolerance of corticosteroids [48–50] but none for maintenance therapy [51, 52]. The data on the safety of cyclosporine during pregnancy in humans is primarily derived from transplant recipients. One large series evaluated 154 pregnancies in 115 renal transplant recipients treated with cyclosporine in addition to other immunosuppressive agents (prednisone and azathioprine); the results were compared to pregnancies in which cyclosporine was not given [44]. The administration of cyclosporine was associated with lower birth weight and a higher incidence of maternal diabetes, hypertension, and renal allograft rejection. The last three complications may represent a patient selection-bias, since the women treated with cyclosporine may have been at greater risk of graft


rejection and other morbidity. Overall, the complication rate in the newborns was slightly lower in the cyclosporine group and no malformations were seen. There are no data available on the specific topic of cyclosporine medication in pregnant patients with Crohn’s disease. Methotrexate (Pregnancy Class X) It is generally accepted that methotrexate is absolutely contraindicated in pregnancy and that female as well as male patients should avoid conception during methotrexate medication and for 6 months afterwards. Kozlowski et al. [53] reported, however, on 8 women with a total of 10 pregnancies while under methotrexate therapy. The mean duration of methotrexate medication during gestation was 7.5 weeks (range 2–20). Outcome of pregnancy included 5 full-term babies, 3 spontaneous abortions, and 2 elective abortions. All offspring were of normal height and weight at birth with no physical abnormalities. All children reached growth, development, and intellectual stages normally, to the mean age of 11.5 years at the time of publication. Infliximab (Pregnancy Category B) In murine models, no evidence of embryotoxicity or teratogenicity has been observed. However, anti TNF- antibodies are species-specific and limited information is available regarding pregnancy outcome in humans. Burt et al. [54] reported a successful pregnancy that had resulted from intercourse 3 days prior to Infliximab infusion. Srinivasan [55], however, reported the case of a patient who received Infliximab around the time of conception and a second infusion 2 weeks later. She delivered a prematurely born baby at 23 week (birth weight 681 g), who died 3 days later from intracerebral and intrapulmonary bleeding. Srinivasan commented that it was difficult to separate the effect of Infliximab from that of the active disease and concurrent medication (mesalazine, metronidazole, azathioprine). Katz et al. [56] have reported data extracted from the Infliximab post-marketing surveillance database regarding exposure to Infliximab before or during pregnancy. Of 35 pregnancies with a known outcome, 26 (74%) resulted in a live birth, 1 with a congenital anomaly (tetralogy of Fallot) and another baby who died soon after due to prematurity and low weight; there were also 5 miscarriages and 4 terminations.


Others Loperamide (pregnancy category B) medication, even in the fist trimester, was not associated with an increased risk of major malformation in a prospective case-control study comparing 105 women taking loperamide medication to a similar group of pregnant women matched for age, smoking, alcohol and other exposure [57]. All patients who are pregnant should be encouraged not to smoke as smoking patients have higher rates of flare-up [58]. Nutritional depletion and deficiencies in oligo elements and vitamins in pregnancy carries an increased fetal risk and should be avoided and treated if recognized. Folate deficiency is observed in approximately 40% of adults with Crohn’s disease [59]. As already mentioned above, treatment with sulfasalazine may exacerbate folate deficiency since the drug’s sulfa moiety can bind folate in the gut lumen, leaving it unavailable for absorption. Patients should therefore take a higher amount (2 mg/day) of folic acid supplementation. Vitamin B12 deficiency, which occurs frequently in Crohn’s disease involving the terminal ileum, should be corrected although no data are available. With the data currently available, it is also not possible to give evidence-based advice on whether, or how, to treat iron-deficiency anemia, which affects 25–40% of those with Crohn’s disease. Fat-soluble vitamin supplementation (vitamins A, E, and K, and especially D) should also be considered, even though no evidence-based data are available, because deficiencies can occur secondary to bile acid deficiency due to terminal ileal disease or resection. If indicated, parenteral nutrition seems to be safe in pregnancy according to case reports [60–63].

Conclusions

Available data on Crohn’s disease and pregnancy, mostly from case series and case-control studies, show that women with Crohn’s disease can expect to conceive successfully, carry to term and deliver a healthy baby. Control of disease activity before conception and during pregnancy is critical to optimize both maternal and fetal health. Generally speaking, pharmacological therapy for Crohn’s disease during pregnancy is similar to pharmacological therapy for non-pregnant patients and patients maintained in remission by way of pharmacological therapy should continue it throughout their pregnancy, with few exceptions! Available human data suggest that drugs such as sulfasalazine, mesalazine, metronidazole, cipro-

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59

floxacin, corticosteroids, azathioprine and 6-MP can safely be used. All the available data on Crohn’s disease medication and pregnancy rely, however, almost exclusively on case series or case-control studies, with only a

very few prospective, although not randomized, studies and on extrapolations from the use of immunomodulatory medication in pregnancy for other medical conditions, mostly in transplantation.

References 1 Hudson M, et al: Fertility and pregnancy in inflammatory bowel disease. Int J Gynaecol Obstet 1997; 58:229–237. 2 Shaffer JL, Kershaw A, Berrisford MH: Sulphasalazine-induced infertility reversed on transfer to 5-aminosalicylic acid. Lancet 1984;1(8388):1240. 3 Levi AJ, et al: Male infertility due to sulphasalazine. Lancet 1979;2(8137):276–278. 4 Dejaco C, et al: Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology 2001;121:1048–1053. 5 Vessey M, et al: Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: Findings in a large cohort study of women of childbearing age. Br Med J (Clin Res Ed) 1986;292:1101–1103. 6 Lashner BA, Kane SV, Hanauer SB: Lack of association between oral contraceptive use and Crohn’s disease: A community-based matched case-control study. Gastroenterology 1989; 97: 1442–1447. 7 Cosnes J, et al: Oral contraceptive use and the clinical course of Crohn’s disease: A prospective cohort study. Gut 1999;45:218–222. 8 Hill J, Clark A, Scott NA: Surgical treatment of acute manifestations of Crohn’s disease during pregnancy. J R Soc Med 1997;90: 64–66. 9 Rogers RG, Katz VL: Course of Crohn’s disease during pregnancy and its effect on pregnancy outcome: A retrospective review. Am J Perinatol 1995;12: 262–264. 10 Kornfeld D, Cnattingius S, Ekbom A: Pregnancy outcomes in women with inflammatory bowel disease – A population-based cohort study. Am J Obstet Gynecol 1997; 177: 942– 946. 11 Norgard B, et al: Birth outcomes of women with ulcerative colitis: A nationwide Danish cohort study. Am J Gastroenterol 2000; 95: 3165–3170. 12 Fonager K, et al: Pregnancy outcome for women with Crohn’s disease: A follow-up study based on linkage between national registries. Am J Gastroenterol 1998;93:2426–2430. 13 Dominitz JA, Young JCC, Boyko EJ: Outcomes of infants born to mothers with inflammatory bowel disease: A population-based cohort study. Am J Gastroenterol 2002; 97: 641–648. 14 Nielsen OH, et al: Pregnancy in Crohn’s disease. Scand J Gastroenterol 1984; 19: 724– 732. 15 Ilnyckyji A, et al: Perianal Crohn’s disease and pregnancy: Role of the mode of delivery. Am J Gastroenterol 1999;94:3274–3278.

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16 Brandt LJ, Estabrook SG, Reinus JF: Results of a survey to evaluate whether vaginal delivery and episiotomy lead to perineal involvement in women with Crohn’s disease. Am J Gastroenterol 1995;90:1918–1922. 17 Mogadam M, et al: The course of inflammatory bowel disease during pregnancy and postpartum. Am J Gastroenterol 1981; 75: 265– 269. 18 Roe FJ: Toxicologic evaluation of metronidazole with particular reference to carcinogenic, mutagenic, and teratogenic potential. Surgery 1983;93: 158–164. 19 Caro-Paton T, et al: Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol 1997;44: 179–182. 20 Burtin P, et al: Safety of metronidazole in pregnancy – A meta-analysis. Am J Obstet Gynecol 1995;172:525–529. 21 Diav-Citrin O, et al: Pregnancy outcome after gestational exposure to metronidazole: A prospective controlled cohort study. Teratology 2001;63: 186–192. 22 Loebstein R, et al: Pregnancy outcome following gestational exposure to fluoroquinolones: A multicenter prospective controlled study. Antimicrob Agents Chemother 1998; 42: 1336– 1339. 23 Heisterberg L, Branebjerg PE: Blood and milk concentrations of metronidazole in mothers and infants. J Perinat Med 1983; 11: 114–120. 24 Passmore CM, et al: Metronidazole excretion in human milk and its effect on the suckling neonate. Br J Clin Pharmacol 1988;26: 45–51. 25 Gardner DK, Gabbe SG, Harter C: Simultaneous concentrations of ciprofloxacin in breast milk and in serum in mother and breast-fed infant. Clin Pharm 1992;11: 352–354. 26 Norgard B, et al: Population-based case control study of the safety of sulfasalazine use during pregnancy. Aliment Pharmacol Ther 2001;15: 483–648. 27 Mogadam M, et al: Pregnancy in inflammatory bowel disease: Effect of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology 1981;80: 72–76. 28 Moody GA, et al: The effects of chronic ill health and treatment with sulphasalazine on fertility amongst men and women with inflammatory bowel disease in Leicestershire. Int J Colorectal Dis 1997;12:220–224. 29 Esbjorner E, Jarnerot G, Wranne L: Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation. Acta Paediatr Scand 1987;76:137–142.

30 Jarnerot G, Into-Malmberg MB: Sulphasalazine treatment during breast feeding. Scand J Gastroenterol 1979;14: 869–871. 31 Habal FM, Hui G, Greenberg GR: Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: Safety and clinical course. Gastroenterology 1993;105:1057–1060. 32 Diav-Citrin O, et al: The safety of mesalamine in human pregnancy: A prospective controlled cohort study. Gastroenterology 1998;114: 23– 28. 33 Marteau P, et al: Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules. Aliment Pharmacol Ther 1998;12: 1101– 1108. 34 Norgard B, et al: Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy: A Danish cohort study. Gut 2003;52:243– 247. 35 Colombel JF, et al: Renal insufficiency in infant: Side effect of prenatal exposure to mesalazine? Lancet 1994; 344:620–621. 36 Marteau P, Devaux CB: Mesalazine during pregnancy. Lancet 1994;344:1708–1709. 37 Dewit O, et al: Interaction between azathioprine and aminosalicylates: An in vivo study in patients with Crohn’s disease. Aliment Pharmacol Ther 2002;16:79–85. 38 Szumlanski CL, Weinshilboum RM: Sulphasalazine inhibition of thiopurine methyltransferase: Possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 1995; 39:456–459. 39 American Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–789. 40 Warrell DW, Taylor R: Outcome for foetus of mothers receiving prednisolone during pregnancy. Lancet 1968;1(7534):117–118. 41 Park-Wyllie L, et al: Birth defects after maternal exposure to corticosteroids: Prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62:385–392. 42 Norjavaara E, de Verdier MG, Normal pregnancy outcomes in a population-based study including 2,968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003;111: 736–742. 43 Kallen B, Rydhstroem H, Aberg A: Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999; 93:392–395.


44 Armenti VT, et al: National Transplantation Pregnancy Registry – Outcomes of 154 pregnancies in cyclosporine-treated female kidneytransplant recipients. Transplantation 1994; 57:502–506. 45 Ramsey-Goldman R, Schilling E: Immunosuppressive drug use during pregnancy. Rheum Dis Clin North Am 1997;23: 149–167. 46 Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJ, Clark ML: Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 1990;99:443–446. 47 Francella A, et al: The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: A retrospective cohort study. Gastroenterology 2003;124:9–17. 48 Brynskov J, et al: A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn’s disease. N Engl J Med 1989; 321:845–850. 49 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.


50 Hermida-Rodriguez C, et al: High-dose intravenous cyclosporine in steroid refractory attacks of inflammatory bowel disease. Hepatogastroenterology 1999;46:2265–2268. 51 Feagan BG, et al: Low-dose cyclosporine for the treatment of Crohn’s disease. The Canadian Crohn’s Relapse Prevention Trial Investigators. N Engl J Med 1994;330:1846–1851. 52 Stange EF, et al: European trial of cyclosporine in chronic active Crohn’s disease: A 12-month study. The European Study Group. Gastroenterology 1995;109:774–782. 53 Kozlowski RD, et al: Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990;88: 589–592. 54 Burt MJ, Frizelle FA, Barbezat GO: Pregnancy and exposure to infliximab (anti-tumor necrosis factor- monoclonal antibody). J Gastroenterol Hepatol 2003;18: 465–466. 55 Srinivasan R: Infliximab treatment and pregnancy outcome in active Crohn’s disease. Am J Gastroenterol, 2001;96:2274–2275. 56 Katz JA, et al: Outcome of pregnancy in women receiving Remicade® (infliximab) for the treatment of Crohn’s disease or rheumatoid arthritis. Gastroenterology 2001;120:366.

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57 Einarson A, et al: Prospective, controlled, multicentre study of loperamide in pregnancy. Can J Gastroenterol 2000;14:185–187. 58 Thomas GA, Rhodes J, Green JT: Inflammatory bowel disease and smoking – A review. Am J Gastroenterol 1998; 93:144–149. 59 Seidman E, et al: Nutritional issues in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1991; 12:424–438. 60 Gatenby SJ: Maintenance of pregnancy in Crohn’s disease by parenteral nutrition: A case study. Hum Nutr Appl Nutr 1987; 41: 345– 349. 61 Robin P, et al: Parenteral nutrition for Crohn’s disease in the third trimester of pregnancy. Apropos of a case (in French). J Gynecol Obstet Biol Reprod (Paris) 1987; 16:379–382. 62 Jacobson LB, Clapp DH: Total parenteral nutrition in pregnancy complicated by Crohn’s disease. JPEN J Parenter Enteral Nutr 1987; 11: 93–96. 63 Hiki M, et al: A case report of Crohn’s disease maintained on parenteral nutrition for almost the whole period of pregnancy (in Japanese). Nippon Shokakibyo Gakkai Zasshi 1986; 83: 2238–2242.

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Author Index Vol. 71, No. 1, 2005

Beglinger, C. 5 Burnand, B. 8, 13, 19, 26, 29, 31, 37, 41, 49, 54 Caprilli, R. 6 Felley, C. 8, 13, 19, 26, 29, 31, 37, 41, 49, 54 Froehlich, F. 8, 13, 19, 26, 29, 31, 37, 41, 49, 54 Goeke, B. 5 Gonvers, J.-J. 8, 13, 19, 26, 29, 31, 37, 41, 49, 54

Juillerat, P. 8, 13, 19, 26, 29, 31, 37, 41, 49, 54 Michetti, P. 6, 8, 13, 19, 26, 29, 31, 37, 41, 49, 54 Mottet, C. 8, 13, 19, 26, 29, 31, 37, 41, 49, 54 Vader, J.-P. 8, 13, 19, 26, 29, 31, 37, 41, 49, 54

Subject Index Vol. 71, No. 1, 2005

Adverse events, treatment 8 Aminosalicylates 13 Ankylosing spondylitis 31 Azathioprine 13, 19, 26, 41, 49 Balloon dilation 29 Biological therapies 19 Budesonide 13 Ciprofloxacin 26 Cyclosporine 26 Drug safety 8 – toxicity 8 Duodenum 37 Esophagus 37 Extraintestinal manifestations 31 Fistula 26 Immunosuppression 8, 49 Inflammatory bowel disease 8, 31 Infliximab 13, 19, 26, 41 Internal fistulas, surgery 26

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

© 2005 S. Karger AG, Basel


Maintenance treatment 41, 49 Mesalamine 41, 49 Methotrexate 13, 19, 26, 41 Metronidazole 26 Obstructive symptoms 29 Postoperative treatment 49 Pregnancy 54 Primary sclerosing cholangitis 31 Pyoderma gangrenosum 31 Relapse prevention 49 Stenosis 29, 37 Steroids 13, 19 Stomach 37 Strictures 29 Stricturoplasty 29 Sulfasalazine 13 Surgical resection 29 Tacrolimus 26 Uveitis 31

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