VOLUME 7 NUMBER 3 2007 INFLAMMATORY BOWEL DISEASE MONITOR Commentary and analysis on advances in the understanding and management of inflammatory bowel disease

EDITORS-IN-CHIEF Stephen Hanauer, Chicago, IL, USA Jack Satsangi, Edinburgh, UK

LEADING ARTICLES Novel Anti-inflammatory Mechanisms of 5-ASAs in Ulcerative Colitis Cécile Vignal, Christel Rousseaux, Laurent Peyrin-Biroulet, Laurent Dubuquoy, Philippe Chavatte, and Pierre Desreumaux Capsule Endoscopy in the Diagnosis of Crohn’s Disease Michel Delvaux and Gérard Gay

CLINICAL REVIEWS MEETING REPORTS ACG 2006 UEGW 2006 The First European Symposium on Pediatric IBD

www.ibdmonitor.com

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Kentucky College of Medicine and Remedica. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky is an equal This journal is supported by an opportunity university. educational grant from Shire New Gastroenterology Titles from Remedica

IMMUNOLOGY AND THE INFLAMMATORY BOWEL DISEASES OF THE GUT DISEASE YEARBOOK VOLUME 3

Published: September 2006 Published: September 2006 ISBN: 978 1 901346 88 9 ISBN: 978 1 901346 56 0 ISSN: 1472-4626 Price: US$35/£20/€30 Price: US$45/£25/€40 Extent: 160 pages Extent: 216 pages Format: Paperback Format: Hardback

AUTHORS AUTHORS Thomas T MacDonald: Barts and the London School of A Hillary Steinhart (Canada), Severine Vermeire (Belgium), Medicine, UK; Adrian C Bateman: Southampton General Gert Van Assche (Belgium), Paul Rutgeerts (Belgium), David A Hospital, UK Schwartz (USA), Steven R Brant (USA), Amir Karban (Israel), Jürgen Schölmerich (Germany), Ernest G Seidman (Canada), DESCRIPTION Devendra K Amre (Canada), William J Sandborn (USA) This book unravels the subject of immunology into three clear areas: immunology itself, gut immunology, and inflammation. DESCRIPTION These areas are explored with detailed and easy-to-understand The Inflammatory Bowel Disease Yearbook Volume 3 is explanations and a focus on the aspects of immunology that Remedica's third instalment in the 'Inflammatory Bowel are particularly important for the gut. In addition, this book Disease Yearbook' series. In this volume, the authors (from contains an illustrated A-to-Z listing of over 35 commonly Europe, Canada, and North America) discuss the current encountered gastroenterological disorders (including chronic status of topics such as IBD genetics, diagnostic blood testing, granulomatous disease, Crohn's disease, graft-versus-host- and biological therapies. In keeping with previous titles, disease, pernicious anemia, reflux disease, and ulcerative this book provides clinicians and scientists in IBD research colitis). Detailed descriptions of each disorder include with a thorough understanding of recent data in the context information on clinical features, epidemiology, diagnosis, of the disease as a whole. immunopathogenesis, and treatment. CONTENTS CONTENTS • Therapy: purine analogs and methotrexate • A beginner's guide to immunology • Blood tests in IBD: which are necessary? • A beginner's guide to gut immunology • Progress in IBD genetics • A beginner's guide to inflammation • Crohn’s perianal fistulas: current treatment paradigms • Gastrointestinal diseases with an immunological component • Pediatric IBD: novel investigative approaches for diagnosis • Glossary and follow-up • Biological therapies

In the US: In the UK: Phone: 1-800-247-6553 or 1-800-266-5564 Phone: +44 (0)161 273 6799 (or 1-419-281-1802 from Canada) Fax: +44 (0)161 273 6261 Fax: 1-419-281-6883 [email protected] Email: [email protected] www.remedicabooks.com ✂ ACCREDITATION Answers should be recorded in the spaces provided overleaf. This activity has been planned and implemented One answer is correct for each question. in accordance with the Essentials Areas and policies γ of the Accreditation Council for Continuing Medical Novel Anti-Inflammatory Mechanisms 9. In ulcerative colitis, PPAR expression is: 5. Which of the following statements is correct of 5-ASAs in Ulcerative Colitis A. Downregulated in macrophages regarding double balloon enteroscopy? Education through the joint sponsorship of the Vignal C, Rousseaux C, Peyrin-Biroulet L, B. Upregulated in macrophages A. Biopsy of intestinal lesions is not possible University of Kentucky College of Medicine and Dubuquoy L, Chavatte P, and Desreumaux P. C. Downregulated in colonic epithelial cells during double balloon enteroscopy Remedica Medical Education and Publishing. Inflamm Bowel Dis Monit 2007;7(3):90–8. D. Upregulated in colonic epithelial cells B. Double balloon enteroscopy prevents The University of Kentucky College of Medicine E. A and C capsule retention CME is accredited by the ACCME to provide continuing 1. To be effective during colonic inflammation, C. The frequency of capsule blockade is 5-aminosalicylic acid (5-ASA) should have: 10. 5-ASA is: increased by double balloon enteroscopy A. A novel ligand of PPARγ medical education for physicians. A. A systemic effect D. Biopsy of intestinal lesions may be possible B. Able to induce PPARγ expression

CME B. A specific effect on the small bowel during double balloon enteroscopy in epithelial cells The University of Kentucky College of Medicine C. A specific effect on the colon C. Able to induce PPARγ activation E. B and D designates this educational activity for a maximum D. Been in contact with intestinal in epithelial cells epithelial cells of two (2.0) AMA PRA Category 1 Credits™. D. Able to bind PPARγ expressed by 6. Conditions in which elemental lesions similar E. C and D lamina propria mononuclear cells to those of Crohn’s disease are found include: Physicians should only claim credit commensurate E. All of the above A. Mesenteric ischemia with the extent of their participation in the activity. 2. The active form of 5-ASA is: B. Celiac disease A. Acetylated-5-ASA Capsule Endoscopy in the Diagnosis C. Nonsteroidal anti-inflammatory The University of Kentucky College of Medicine B. Free 5-ASA of Crohn’s Disease drug-related intestinal damage Delvaux M and Gay G. presents this activity for educational purposes only. C. 4-ASA D. Cryptogenetic multifocal ulcerous D. 3-ASA Inflamm Bowel Dis Monit 2007;7(3):99–105. stenosing enteritis Participants are expected to utilize their own E. 2-ASA E. All of the above expertise and judgment while engaged in the 1. Capsule endoscopy is used in the diagnosis of Crohn’s disease. Which of the following 3. Peroxisome proliferator activator receptor γ practice of medicine. The content of the statements is true? 7. Radiological analyses are effective for: (PPARγ) is: presentations is provided solely by presenters A. Capsule endoscopy examines the gut wall A. Investigation of intestinal stenoses who have been selected for presentations A. Expressed only by adipocytes in the same way as classical endoscopy B. Examination of large ulcers B. Expressed only by epithelial cells B. Capsule endoscopy allows the simultaneous C. Detection of apthae because of recognized expertise in their field. C. A nuclear receptor examination of multiple lesions D. A and C D. A coactivator C. Only short segments of gut are visualized E. A and B DISCLOSURES E. A corepressor at one time point using capsule endoscopy D. Insufflation of air during capsule endoscopy Dr Desreumaux has received funding for research 8. Capsule retention is a complication of capsule 4. The synthetic ligands of PPARγ, glitazones allows close examination of the mucosa from Giuliani Pharma, Milan, Italy. Drs Vignal, endoscopy. Which of the following statements have been developed as: E. A and B is correct? Rousseaux, Peyrin-Biroulet, Dubuquoy, and A. A treatment for type 2 diabetes A. Capsule retention is defined as the absence Chavatte have no relevant financial interests B. An anti-inflammatory drug 2. Capsule endoscopy detects intestinal lesions of natural excretion of the capsule within to disclose. C. An antineoplastic compound of Crohn’s disease. Which of the following statements are correct? the 7 days post-procedure D. A hypolipemic drug A. Radiological methods have been found B. Capsule retention is defined as the natural E. A hormonal therapy Drs Delvaux and Gay have no relevant financial to detect more intestinal lesions than excretion of the capsule within the 7 days capsule endoscopy post-procedure interests to disclose. γ 5. PPAR is: B. Capsule endoscopy has been shown C. Capsule retention is defined as the failure A. Regulated by the luminal flora to detect more intestinal lesions than of the capsule to reach the cecum during INSTRUCTIONS FOR OBTAINING CME CREDIT B. Weakly expressed in the small bowel push-enteroscopy the 8-h recording Participation in this activity should be completed compared to the colon C. Capsule endoscopy has been shown D. A and C in approximately 2.5 h. To successfully complete C. Mainly expressed by colonic epithelial cells to detect fewer intestinal lesions than E. B and C D. A key element in the regulation small-bowel follow through this program and receive credit, participants must D. A and B of bacteria-induced colitis 9. Regarding capsule retention, which of the follow these steps: E. A and C E. All of the above following statements is true? 1. Read the learning objectives. A. The frequency of capsule retention is γ 3. Indications for capsule endoscopy include: 2. Read the articles’ text and tables and review 6. The anti-inflammatory effect of PPAR greater in Crohn’s disease patients than has been demonstrated in: A. To diagnose Crohn’s disease in patients the figures. who are suspected of having the disease in patients investigated for obscure A. Colonic epithelial cells 3. Complete the registration information on the in the clinic, but have normal radiological gastrointestinal bleeding B. Lymphocytes B. The frequency of capsule retention is form included. test results C. Macrophages B. The further diagnosis of indeterminate colitis greater in patients investigated for obscure 4. Read, complete, and submit answers to the D. Monocytes C. To detect early disease recurrence after surgery gastrointestinal bleeding than in Crohn’s self-assessment questions. Participants must E. All of the above D. To evaluate lesions in the small bowel disease patients respond to all program evaluation questions in patients with known Crohn’s disease C. The frequency of capsule retention is 7. What are the main mechanisms sustaining E. All of the above similar in Crohn’s disease patients, to receive a certificate by mail. the anti-inflammatory effect of PPARγ: and in those investigated for obscure 5. Complete the registration form, post-test answer A. Inhibition of nuclear factor-κB 4. Morphological investigations of the small gastrointestinal bleeding sheet, and evaluation form at the back of this B. Inhibition of nuclear factor of activated bowel are performed using radiological and D. Capsule retention can lead to surgical journal and return to the address provided. T cells endoscopic methods. Which of the following procedures in Crohn’s disease patients who statements is correct? are not otherwise indicated for surgery Alternatively, visit the journal web site C. Inhibition of activator protein-1 D. Inhibition of cyclic AMP response A. Radiological and endoscopic investigations E. A and D www.ibdmonitor.com and follow the element binding protein are equally effective for the detection of links to CME. E. A, B, and C tiny mucosal lesions and apthae 10. The presence of an intestinal stenosis may B. Endoscopic methods more frequently be a contraindication to capsule endoscopy. detect tiny mucosal lesions and apthae, 8. In epithelial cells, expression of PPARγ Which of the following methods has been Please note that the website provides the option compared with radiological methods is regulated by: proposed to avoid this problem? to print out a PDF of the answers, which requires C. A combination of endoscopic and A. Its ligands A. A patency capsule participants to fax or mail their responses to the radiological methods can increase the B. Glucagons diagnostic success in patients with B. Magnetic resonance imaging University of Kentucky. C. Microorganisms suspected intestinal disease C. Computed tomography-enteroclysis D. A and B D. A and C D. Surgery E. A and C E. B and C E. Nonsteroidal anti-inflammatory drugs ✂

INFLAMMATORY BOWEL DISEASE MONITOR Vol 7 No 3 2007 ✂ Complete the post-test answer sheet, evaluation form, and registration form, return to: NEEDS ASSESSMENT Inflammatory Bowel Disease Monitor, a CME-accredited Attn: Distance Education educational program, systematically identifies, evaluates, UKCPMCE [MEN07077-02] and places into clinical context the most important recent One Quality Street, 6th Floor studies into the science and medicine of inflammatory Lexington, KY 40517, USA bowel disease. It provides rapid access for busy specialists Fax: (859) 323-2920 to a critical and clinically relevant review of the developments that will have most impact on their

day-to-day practice and is designed to provide CME Alternatively the form can be downloaded from www.ibdmonitor.com by following the links to CME. management options for clinicians to allow them Registration is required, but is free to physicians and healthcare professionals. to better diagnose and treat patients with IBD.

CME EXAMINATION ANSWERS Each issue of Inflammatory Bowel Disease Monitor will Record your answers here by filling in the blank with the correct letter for the corresponding question: present carefully constructed review articles, written by practicing specialists in gastroenterology and related disciplines and developed to equip readers with practical Novel Anti-Inflammatory Mechanisms of 5-ASAs in Ulcerative Colitis. Vignal C, Rousseaux C, Peyrin-Biroulet L, Dubuquoy L, knowledge of the area under discussion. These articles are Chavatte P, and Desreumaux P. Inflamm Bowel Dis Monit 2007;7(3):90–8 commissioned to support particular educational themes identified by the Editors-in-Chief, Editorial Advisory Board, 1. ____ 2. ____ 3. ____ 4. ____ 5. ____ 6. ____ 7. ____ 8. ____ 9. ____ 10. ____ and readers. This issue of Inflammatory Bowel Disease Monitor presents two such leading articles. Capsule Endoscopy in the Diagnosis of Crohn’s Disease Delvaux M and Gay G. Inflamm Bowel Dis Monit 2007;7(3):99–105. INTENDED AUDIENCE 1. ____ 2. ____ 3. ____ 4. ____ 5. ____ 6. ____ 7. ____ 8. ____ 9. ____ 10. ____ This activity is designed to meet the educational needs of multidisciplinary clinicians and healthcare professionals Participants will receive a confidential report of their results along with the correct answers to each question. involved in the care of patients with inflammatory bowel disease. A certificate of credit will be sent to those who successfully complete the examination with a score of 80% or higher. LEARNING OBJECTIVES EVALUATION FORM Strongly agree Strongly disagree Novel Anti-Inflammatory Mechanisms of 5-ASAs in 1. The activity provided new information I had not yet acquired. 12345 Ulcerative Colitis. Vignal C, Rousseaux C, Peyrin-Biroulet L, Dubuquoy L, Chavatte P, and Desreumaux P. 2. The activity helped increase my knowledge and skills. 12345 Inflamm Bowel Dis Monit 2007;7(3):90–8. 3. The activity content was educational and understandable 12345 Goal: To educate the reader on recent insights into 4. The activity content met its objectives. 12345 the molecular mechanisms of action of 5-ASAs in ulcerative colitis. 5. The amount of information presented was adequate for my needs. 12345 Objectives: After reading this article the reader should 6. I felt I absorbed a reasonable amount of the presented materials. 12345 be able to discuss: • The metabolism of 5-ASA and its consequences 7. The technical quality of the activity was acceptable. 12345 on drug efficacy in the gut. 8. I would recommend this program to my peers. 12345 • Anti-inflammatory effects mediated by peroxisome- proliferator activated receptor γ (PPARγ). 9. Funding for this activity may have come from commercial sponsors. • Evidence for a role for PPARγ in the anti-inflammatory Do you think you were adequately informed of commercial sponsorship or faculty conflict of interest? Yes No effects of 5-ASA in ulcerative colitis. 10. Do you think the overall activity was biased toward certain commercial products or services? Yes No Capsule Endoscopy in the Diagnosis of Crohn’s Disease. Delvaux M and Gay G. REGISTRATION FORM Inflamm Bowel Dis Monit 2007;7(3):99–105.

Name: ...... Goal: To educate the reader on the role of capsule endoscopy in the diagnosis of Crohn’s disease. Affiliation: ...... Objectives: After reading this article the reader should be able to discuss: Office Address: ...... • The role of capsule endoscopy alongside ...... other imaging modalities for the diagnosis of Crohn’s disease. City: ...... State: ...... Zip Code: ...... • The current indications for capsule endoscopy. • The risks associated with capsule endoscopy. Office Phone: ...... Home Phone: ...... Date of release: March 2007 Email: ...... Period of validity: Until March 2008 Last 4 Digits of Social Security Number (optional) ...... (for recordkeeping only)

By signing this certificate, I attest that I have attended the above named continuing medical education program.

Signature: ...... Credit Hours: ...... ✂

INFLAMMATORY BOWEL DISEASE MONITOR Vol 7 No 3 2007 Editors-in-Chief Stephen Hanauer Contents University of Chicago, Chicago, IL, USA Leading Articles Jack Satsangi Novel Anti-inflammatory Mechanisms Western General Hospital, Edinburgh, UK of 5-ASAs in Ulcerative Colitis Editors Cécile Vignal, Christel Rousseaux, Laurent Peyrin-Biroulet, Laurent Dubuquoy, Ian Arnott Philippe Chavatte, and Pierre Desreumaux 90 Western General Hospital, Edinburgh, UK Federico Balzola Capsule Endoscopy in the Diagnosis Azienda Ospedaliera San Giovanni Battista di Torino, of Crohn’s Disease Turin, Italy Michel Delvaux and Gérard Gay 99 Charles Bernstein University of Manitoba, Winnipeg, MB, Canada Clinical Reviews Simon Murch Pathogenesis 106 University of Warwick, Coventry, UK Clinical Observations 111 Editorial Advisory Board Treatment and Clinical Practice 117 Zane Cohen Mount Sinai Hospital, Toronto, ON, Canada Epidemiology 120 Jean-Frédéric Colombel Meeting Reports Hôpital Huriez, Lille, France American College of Gastroenterology Anders Ekbom Annual Scientific Meeting 2006 Karolinska Institute, Stockholm, Sweden (ACG 2006) Brian Feagan Corey A Siegel and David T Rubin 121 University of Western Ontario, London, ON, Canada Claudio Fiocchi United European Gastroenterology Week Cleveland Clinic, Cleveland, OH, USA (UEGW) 2006 John O’Leary Séverine Vermeire 125 Coombe Women’s Hospital, Dublin, Ireland The First European Symposium on Roy E Pounder Royal Free and University College Medical School, Pediatric Inflammatory Bowel Disease London, UK Richard K Russell 130 Paul C Rutgeerts Universitaire Ziekenhuizen Leuven, UZ Gasthuisberg, Leuven, Belgium Ernest G Seidman Hôpital Sainte-Justine, Université de Montréal, Montreal, QC, Canada Stephan Targan Cedars-Sinai Medical Center, Los Angeles, CA, USA William J Tremaine Mayo Clinic, Rochester, MN, USA

Subscription Information Publisher’s Statement Inflammatory Bowel Disease Monitor (ISSN 1466-7401) is published four times per year. © Remedica Medical Education and Publishing 2007. Subscriptions are available at the following rates: Europe €150, USA, Canada and all other All rights reserved. No part of this publication may be reproduced, stored in a retrieval system territories US$200 per year. Additional subscription information is available from the publisher. or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior permission of the copyright owners. While every effort is made by Editorial Policy the publishers and editorial board to see that no inaccurate or misleading data, opinions, Inflammatory Bowel Disease Monitor is an independent journal published by Remedica Medical or statements appear in this journal, they wish to make it clear that the material contained in the Education and Publishing Ltd. The aim is to provide an up-to-date overview of the recent literature publication represents a summary of the independent evaluations and opinions of the authors compiled by an international team of practising physicians. Leading articles commissioned by the and contributors. As a consequence, the board, publishers and any sponsoring company accept Editors-in-Chief review new therapeutic techniques and emerging technologies, and news from no responsibility for the consequences of any such inaccurate or misleading data or statements. major international meetings is reported. Editorial control is vested entirely in the Editors-in-Chief, Neither do they endorse the content of the publication or the use of any drug or device in a way Editors, and Editorial Advisory Board. that lies outside its current licensed application in any territory. For detailed information on any drugs or devices discussed in this publication, readers are Any queries regarding the content of the journal should be addressed to: Remedica Medical advised to consult the Physicians Circular issued by the manufacturer. Education and Publishing Ltd, 20 N. Wacker Drive, Suite 1642, Chicago, IL 60606, USA. Editorial Team: Rhian Phillips, Scott Millar Tel: +1 (312) 372 4020, Fax +1 (312) 372 0217. Email: [email protected] Editorial Director: Reghu Venkatesan Design and Artwork: AS&K Skylight Creative Services ISSN 1466-7401 Publishers: Ian Ackland-Snow, Simon Kirsch Novel Anti-inflammatory Mechanisms of 5-ASAs in Ulcerative Colitis

Cécile Vignal, Christel Rousseaux, Laurent Peyrin-Biroulet, Laurent Dubuquoy, Philippe Chavatte, and Pierre Desreumaux INSERM U795, University of Lille 2, and Digestive Tract Diseases and Nutrition Department, Huriez Hospital, Lille, France LEADING ARTICLE

5-aminosalicylic acid (5-ASA) is among the medications that are most commonly prescribed by gastroenterologists for the treatment of patients with IBD. Despite a 30-year period of development and >2000 publications referenced in scientific databases, an integrated understanding of the mechanisms of action of 5-ASA has only recently emerged; this involves the nuclear receptor peroxisome-proliferator activated receptor γ (PPARγ). The current review describes how 5-ASA interacts with PPARγ, inducing its activation in epithelial cells and lamina propria mononuclear cells of the colon. 5-ASA is now considered to be a PPARγ ligand, able to regulate many key elements of inflammation such as the nuclear factor-κB signaling pathway, the production of cytokines and chemokines, and the expression of adhesion molecules. These findings create a new perspective for the rational development of optimized 5-ASA-like molecules with an increased efficacy in the induction and maintenance treatment of IBD patients. Inflamm Bowel Dis Monit 2007;7(3):90–8.

5-ASA discovery 5-ASA moiety [1]. The recognition that 5-ASA was the 5-aminosalicylic acid (5-ASA), which is also called mesalamine active component and that the side effects were related to or mesalazine, is among the oldest medication prescribed by the sulfapyridine carrier molecule explained why many gastroenterologists for patients with IBD. The first decisive countries replaced sulfasalazine with 5-ASA as first-line phase of 5-ASA development was the discovery of the curative therapy in the management of active mild-to-moderate action of certain sulfonamide-containing azo compounds. ulcerative colitis (UC) and for the maintenance of remission. Developing the extensive work of Professor Nanna Svartz, Today, 5-ASA represents the most commonly prescribed these compounds were synthesized by the chemists Joseph treatment in IBD patients (50–65% of UC patients and Klarer and Fritz Mietzsch, and eventually led to the awarding 30–75% of Crohn’s disease [CD] patients) for an estimated of the Nobel Prize for Physiology or Medicine to Gerhard market of US$750 million per year (Pierre Desreumaux, Domagk in 1939. At that time, the most effective sulfonamide personal communication). compounds, known as prontosil rubrum and prontosil solubile, were used for their curative action against streptococcal 5-ASA metabolism infections of man and also in diverse inflammatory diseases The therapeutic effect of 5-ASA is obtained through a local believed to be of bacterial origin, including rheumatic action on colonic epithelial cells, rather than by a systemic polyarthritis, colitis, and regional enteritis. Combined with an effect, when an effective and clinically relevant luminal antibiotic, sulfapyridine, in 1942 to form a molecule named concentration of pure, non-acetylated 5-ASA reaches sulfasalazine (sulfapyridine linked to 5-ASA by an azo bond) 5–100 mM [2,3]. (Fig. 1), it was only in 1977 that Azad Khan et al. demonstrated that the efficacy of sulfasalazine depended on the splitting Drug concentration of the diazo bond in the molecule by the action of bacteria At a pH of 6–8, 5-ASA is present in the colonic lumen in the large bowel, releasing the pharmacologically active as a zwitterion, sharing an intramolecular hydrogen bond between its hydroxyl and carboxylate groups (Fig. 1). 5-ASA Address for correspondence: Pierre Desreumaux, INSERM U795, concentration is an important determinant of the response Hôpital Swynghedauw, Rue A. Verhaeghe, F-59037 Lille cedex, France. to treatment as the efficacy of 5-ASA is related to its local Email: [email protected] concentration in the colon [4]. Therefore, factors such as

90 INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 NOVEL ANTI-INFLAMMATORY MECHANISMS OF 5-ASASINUC

Figure 1. 5-aminosalicylic acid (5-ASA) chemical structures. A: Semi-developed chemical structure of 5-ASA. B: Chemical structure of sulfasalazine, which is a prodrug that combines the antibiotic sulfapyridine and 5-ASA. Sulfapyridine is linked to 5-ASA by an azo bond that is metabolized in the intestine. C: 5-ASA is supposed to form a zwitterion, sharing an intramolecular hydrogen bond between hydroxyl and carboxylate groups.

A B C O O H S 11 12 O O NH O – O H C11 N O N 1 OH N 6 2 2 N + 5 3 HH OH 4 H3N 5 O OH 5-ASA Sulfasalazine: 5-ASA zwitterion Sulfapyridine + 5-ASA

intestinal metabolism and elimination, which affect tissue the drug’s mode of action are not clear, but colonic epithelial delivery, may be crucial in determining drug efficacy. Previous cells absorb and acetylate 5-ASA rapidly (Fig. 2) [6,9]. Orally studies examining the intestinal absorption of 5-ASA have administered N-acetyl 5-ASA has consistently been shown indicated that the drug is better absorbed in the upper than to be ineffective, probably due to an absence of absorption the lower intestine [5], thus motivating the development by epithelial cells. From previous work on intestinal and of sustained-release drug preparations to minimize systemic systemic N-acetylation of 5-ASA, there appear to be some 5-ASA absorption in the proximal intestine and to deliver unresolved questions regarding intestinal metabolic capacity more drugs to the diseased colon. After oral or rectal and the fate of the intestinal metabolite in relation to administration, some 5-ASA is absorbed in the colon by systemic 5-ASA elimination. In situ jejunal perfusion studies epithelial cells, but most remains within the lumen and is of 5-ASA in the rat demonstrate that at a low concentration passed in the stool (Fig. 2) [6]. In IBD patients receiving in the intestinal lumen, 5-ASA is transported in epithelial standard 5-ASA maintenance treatment, the median mucosal cells via a carrier identified as an intestinal organic anion concentration of 5-ASA is 16 ng/mg, ranging from 3 to transporter [5]. At these low concentrations, the carrier 50 ng/mg of wet colonic tissue [2]. More importantly than transports 5-ASA into the epithelial cell cytosol where a the tissue concentration of 5-ASA in the colon, the major fraction (60%) is metabolized to N-acetyl 5-ASA, therapeutic effect of 5-ASA depends on the direct contact which is then secreted predominantly into the intestinal of the molecule with the epithelium of the colon, implying lumen. Absorbed 5-ASA that is not metabolized by epithelial that a high perimucosal concentration of 5-ASA is a cells enters the circulation and is subject to hepatic prerequisite for its action [7]. It has previously been reported metabolism and subsequent renal elimination [4]. At higher in conventionally treated patients, that stool concentrations concentrations of 5-ASA in the intestinal lumen, carrier- of 5-ASA are in the median order of 30 mM, ranging from mediated drug absorption is saturated and paracellular 10 to 100 mM, which correspond to luminal concentrations absorption dominates, leading to an enhancement of 5-ASA of 5-ASA that are 100-times greater than those in the in the systemic circulation. In this case, systemic metabolism colonic mucosa [2,3]. has a greater role in drug elimination through N-acetylation in the liver. N-acetyl 5-ASA formed in intestinal epithelia is Drug acetylation and cell absorption secreted only in the luminal direction, whereas N-acetyl 5-ASA is metabolized by N-acetylation, which is an important 5-ASA in the systemic circulation is unlikely to be secreted metabolic pathway for the elimination of carcinogenic amines from plasma into the intestinal lumen. It should also be occurring primarily in the liver through the action of noted that N-acetyl 5-ASA is not absorbed after luminal N-acetyltransferase (NAT), and also along the intestinal administration, and intravenous administration of 5-ASA tract [8]. The principal site of acetylation and its relevance to results in essentially complete elimination of N-acetyl

INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 91 C VIGNAL, C ROUSSEAUX, L PEYRIN-BIROULET ET AL

Figure 2. 5-ASA metabolism. After oral absorption of SR-5-ASA, the 5-ASA that reaches the distal ileum and the colon is mostly absorbed by epithelial cells, where it undergoes acetylation to N-Ac-5-ASA by NAT1. Ac-5-ASA may be secreted back into the lumen and excreted in the feces. Both free and acetylated forms of 5-ASA present in epithelial cells may also be absorbed systemically into the blood and excreted in the urine (preceded by an acetylation step in the liver for the free form).

Liver Ac 5-ASA Ac 5-ASA

Kidney

5-ASA Ac 5-ASA

Epithelial cells

NAT1 Ac 5-ASA

5-ASA

Ac 5-ASA Ac 5-ASA Lumen 5-ASA 5-ASA

SR-5-ASA SR-5-ASA X-ASA

5-ASA: 5-aminosalicylic acid; Ac-5-ASA: N-acetyl-5-ASA; NAT1: N-acetyl transferase 1; SR-5-ASA: sustained-release 5-ASA; X-ASA: other metabolites/not defined. Redrawn with permission from [6].

Figure 3. Progression in the literature on 5-ASA. Data were 5-ASA in the urine. Thus, N-acetyl 5-ASA is unlikely to enter obtained using a computerized medical literature search of intestinal cells. all English language articles selected from the “PubMed” In conclusion, 5-ASA concentration and the route of online database with the keywords “aminosalicylate”, administration determine the acetylation and elimination “mesalamine”, and “mesalazine”, from 1986–2005. profiles of the compound, two major determinants of 5-ASA efficacy that appear not to be impaired during intestinal inflammation in IBD patients. 700 600 New anti-inflammatory mechanisms of 5-ASA 500 Despite a large and escalating number of publications demonstrating diverse effects of 5-ASA on cytokine and lications b 400 chemokine production, signal transduction pathways, reactive 300 oxygen metabolites, leukocyte chemotaxis, cyclooxygenase-2, er of pu

b leukotrienes, and prostaglandins, the primary mechanisms 200 of action of 5-ASA have remained largely unknown (Fig. 3). Num 100 Due to functional similarities between 5-ASA and the peroxisome-proliferator activated receptor γ (PPARγ), as well 0 1986–1990 1991–1995 1996–2000 2001–2005 as structural analogies between 5-ASA and the known ligands of this nuclear receptor, it has been hypothesized 5-ASA: 5-aminosalicylic acid. that 5-ASA may be a new ligand of PPARγ, driving its

92 INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 NOVEL ANTI-INFLAMMATORY MECHANISMS OF 5-ASASINUC

Figure 4. PPARγ structure and activation. A: The general structure of nuclear receptors is characterized by two main domains: a central DBD and a carboxy-terminal domain that mediates ligand-binding, dimerization, and transactivation functions. Ligand- dependent transcription requires a highly conserved motif, termed AF-2, located at the C-terminus of the LBD. B: While activated by its ligand, PPARγ must form a heterodimer with another nuclear receptor known as the RXRα, leading to a binding of this heterodimer to specific DNA sequence elements termed PPRE. C: The LBD of PPARγ forms a particularly large pocket that can accept a high variety of ligands.

A N-terminus DBD LBD C-terminus

AF-1Dimerization AF-2

B PPAR RXR DNA PPRE

Regulation of gene expression

C

PPARγ

5-ASA PPARγ LBD 5-ASA

AF-2: activating function-2; DBD: DNA-binding domain; LBD: ligand-binding domain; PPAR: peroxisome proliferator activated receptor; PPRE: peroxisome proliferator response elements; RXR: retinoid X receptor. anti-inflammatory effect in the colon. Taken together, with another nuclear receptor known as the retinoid these observations led to the characterization of the X receptor α (RXRα) (Fig. 4), leading to the binding of potential anti-inflammatory effect of 5-ASA through PPARγ this heterodimer to specific DNA sequence elements, expression and activation. termed peroxisome proliferator response elements [11]. Ligand-dependent transcription requires a highly conserved PPARγ structure and expression motif, termed activating function-2 (AF-2), located at the PPARγ belongs to the nuclear receptor family consisting C-terminus of the LBD [12]. PPARγ is an essential nuclear of a group of approximately 50 transcription factors receptor controlling the expression of a large number of characterized by a common structure [10]. The PPARγ regulatory genes for lipid metabolism and insulin sensitization, structure is characterized by a central DNA-binding domain as well as inflammation and cell proliferation [13,14]. (DBD) and a carboxy-terminal domain that mediates ligand High levels of PPARγ expression have been reported in binding (LBD), dimerization, and transactivation functions. both colonic and adipose tissues. It was originally described In order to be functional, PPARγ must form a heterodimer as a receptor expressed by adipose tissue – where it plays a

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Figure 5. Regulation of PPARγ expression in intestinal concentrations, their in vivo intestinal effects through epithelial cells. PPARγ expression is induced in epithelial PPARγ activation remain hypothetical; this is because the cells by three major factors: probiotics such as bacteria concentrations of these fatty acids within colonic cells are

and yeast, nutrients (e.g. tocopherol), and PPARγ agonists unknown [25]. The eicosanoid 15-deoxy-prostaglandin J2

(e.g. rosiglitazone). With regard to bacteria, a component of (15d-PGJ2) is also proposed to be a natural ligand of PPARγ

the Gram-negative wall, LPS, has been shown to increase [26]. However, the physiological role of 15d-PGJ2 in PPARγ PPARγ expression after activation of the TLR4. Butyrate, activation in the colon remains open for debate as the

which is produced by colonic bacteria, is able to induce minimal concentrations of 15d-PGJ2 required to activate PPARγ expression in colonocytes. PPARγ are approximately 10–150-fold higher than those found in human intestinal epithelial cells [27]. Recently, the

unsaturated fatty acid derivative nitrolinoleic acid (LNO2), Microorganisms: which is generated via nitric oxide-dependent oxidative Bacteria Saccharomyces boulardii inflammatory reactions, has been identified as a new PPARγ agonist [28]. Present in the vascular cell wall as the most abundant bioactive oxide of nitrogen and also in the blood of healthy individuals at concentrations of approximately

Nutrients: 500 nM, LNO2 is considered to be one of the most potent LPS Butyrate Tocopherol physiological endogenous natural ligands of PPARγ at TLR4 present, efficacious at nM concentrations. Apex Concerning synthetic ligands, two main different groups of chemical compounds have been developed; these are glitazones, which bind selectively to PPARγ, and glitazars, Agonists: PPARγ which have the ability to bind both PPARα and PPARγ. Rosiglitazone Numerous glitazone molecules have been developed, and 5-ASA two (rosiglitazone, Avandia® [GlaxoSmithKline, Research ® Intestinal epithelial cell Base Triangle Park, NC, USA] and pioglitazone, Actos [Takeda Pharmaceuticals, Osaka, Japan]) are already approved in the US and Europe for the treatment of type 2 diabetes (Fig. 6). 5-ASA: 5-aminosalicylic acid; LPS: lipopolysaccharide; PPAR: peroxisome Due to their systemic effects, the most well known adverse proliferator activated receptor; TLR4: Toll-like receptor 4. events of glitazones observed in patients with diabetes are weight gain and, infrequently, hepatotoxicity. Glitazars are a role in adipocyte differentiation and in the regulation of novel family of dual-acting PPARα/γ agonists developed as insulin responses; in the colon, PPARγ is mainly expressed by on oral treatment for insulin resistance-related glucose and epithelial cells located at the luminal surface and, to a lesser lipid abnormalities associated with type 2 diabetes and the degree, in lamina propria mononuclear cells [15–19]. metabolic syndrome [29]. Nonsteroidal anti-inflammatory Regulation of PPARγ expression remains poorly investigated. drugs are also reported to be PPARγ ligands in vitro, but In adipocytes, different in vitro studies have demonstrated their binding affinities of 0.1 mM are 1000-fold higher than a synergistic effect of insulin and corticosteroids [20,21]. the mean concentrations found in patients conventionally In the colon, where PPARγ is overexpressed compared with treated with these drugs [30]. the small bowel, microorganisms such as bacteria and yeast are able to increase expression and/or activation of this 5-ASA: a prototype of a new class of PPARγ agonists nuclear receptor (Fig. 5) [17,22–24]. Recently, the current authors published studies showing functional, biological, pharmacological, and chemical evidence Classical ligands of PPARγ that aminosalicylates were a new functional synthetic ligand The LBD of PPARγ is particularly large and can accept a high of PPARγ in colonic epithelial cells [31]. They showed that variety of natural and synthetic ligands. Many natural chemically induced colitis in mice heterozygous at the PPARγ endogenous lipophilic species such as the polyunsaturated locus (PPARγ+/–) was refractory to 5-ASA therapy, arguing for fatty acids (PUFAs) and eicosanoids are classically proposed a major role of PPARγ in mediating the anti-inflammatory as natural PPARγ ligands (Fig. 6) [25,26]. Although many effect of 5-ASA in the gut. In addition, they found that 5-ASA PUFAs activate PPARγ in micromolar concentrations and induced PPARγ expression in the HT-29 human colonic are recorded as functional in human plasma at these epithelial cell line. 5-ASA is also able to bind PPARγ to induce

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Figure 6. PPARγ natural and synthetic ligands. PPARγ is activated by natural ligands such as PUFAs, eicosanoids, and other naturally produced compounds. Concerning the synthetic compounds, the antidiabetic thiazolidinediones (glitazones), the PPARα/γ dual agonists glitazars, certain NSAIDs, and L-tyrosine-derived compounds are able to activate PPARγ.

Natural PPARγ modulators Synthetic PPARγ modulators PUFAs: Eicosanoids: Glitazones: NSAIDs: Omega 3 8S-hydroxyeicosapentaenoic ac. Omega 3 Indomethacin α-linolenic ac. 12-hydroxyeicosatetraenoic ac. Rosiglitazone Flufenamic acid γ-linolenic ac. 15-hydroxyeicosatetraenoic ac. Ciglitazone Fenoprofen eicosapentanic ac. 9-hydroxyoctodecadienoic ac. Troglitazone Ibuprofen docohexanoic ac. 15dPGJ2 Pioglitazone Omega 6 Netoglitazone (MCC-555) L-Tyrosine derived linoleic ac. Miscellaneous: compounds: dihomo-γ-linolenic ac. Swientenia mahagony extract Glitazars: FMOC-L-Leu arachidonic ac. Lysophosphatidic acid Muraglitazar Omega 9 9-tetrahydrocannabinol Tesaglitazar Miscellaneous: palmitoleic ac. Soy isoflavavone Farglitazar 5-ASA oleic ac. Ragaglitazar CDDO Derivatives COOH Conjugated linoleic ac. (CLA) Triphenyltin Nitrolinoleic ac. (LNO2) BADGE Nitrooleic ac. (OA-NO2)

PPAR RXR DNA PPRE

Regulation of gene expression

ac: acid; 5-ASA: 5-aminosalycilic acid; BADGE: bisphenol A diglycidyl ether; CDDO: 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid; COOH: 2-(2-(4-phenoxy-2- propylphenoxy) ethyl)indole-5-acetic acid; FMOC-L-Leu: fluorenylmethyloxycarbonyl-L-leucine; NSAIDs: nonsteroidal anti-inflammatory drugs; PPAR: peroxisome proliferator activated receptor; PPRE: peroxisome proliferator response element; PUFAs: polyunsaturated fatty acids; RXR: retinoid X receptor. its translocation from the cytosol of epithelial cells to the monocytes and mouse peritoneal macrophages, through nucleus, to promote a PPARγ conformational change, and to an inhibition of transcription driven by nuclear factor-κB recruit a coactivator named vitamin D receptor-interacting (NF-κB) and activator protein-1 transcription factors [32,33]. protein (Fig. 7). Docking simulations showed a binding The first evidence of the involvement of PPARγ in the regulation mode of 5-ASA very similar to the crystal orientation of the of intestinal inflammation came from the use of the PPARγ thiazolidinedione head group of rosiglitazone. 5-ASA fitted synthetic agonist thiazolidinedione in mice with colitis tightly with the PPARγ LBD, interacting through hydrogen induced by oral administration of dextran sodium sulfate bonding with His-323, His-449, Tyr-473, and Ser-289, [34]. In that study, the two different thiazolidinediones, which are considered the key molecular determinants troglitazone and rosiglitazone, dramatically reduced the required for ligand recognition and PPARγ activation [31]. disease severity in mice by 47–70%. These results were Taken together, these data show that PPARγ is an essential confirmed and extended several months later in another receptor mediating the common 5-ASA activities in IBD. mouse model of experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Anti-inflammatory properties Thiazolidinediones given preventively or in treatment of PPARγ in the colon mode have a therapeutic effect in reducing the mortality Preclinical data rate, and also reduce the intensity of macroscopic and In vitro studies have shown that PPARγ is able to limit histological lesions and levels of biological markers of the production of inflammatory mediators, such as pro- colonic inflammation, including the NF-κB and stress kinase inflammatory cytokines produced by human activated pathways involved in the transduction of inflammation [35].

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Figure 7. PPARγ activation by 5-ASA and subsequent anti-inflammatory effects. In the cytoplasm of the epithelial cell, 5-ASA binds to PPARγ inducing its translocation to the nucleus and a conformational change. This rearrangement promotes the recruitment of the co-activator DRIP and the assembly of the active heterodimer PPAR-RXR leading to the activation of PPRE. Subsequently, PPARγ blocks major inflammatory signaling pathways such as NF-κB or JNK pathways that are involved in cytokine, chemokine, and adhesion molecule expression, as well as in cell proliferation, which ultimately decrease cell recruitment in inflamed tissues.

p65 IκB JNK p38 calcineurin p50

5-ASA Cell membrane CBP CBP CBP p65 p50 Jun fos Jun fos NFAT NF-κB AP-1 AP-1

5-ASA Cytokines Chemokines Cell proliferation Cytoplasm Adhesion molecules PPAR EC

Adhesion molecules DRIP (VCAM-1 ICAM-1, E- and P-selectins)

5- ASA PPAR RXR EC activation

Nucleus PPRE

Migration of inflammatory cells in tissues

AP-1: activator protein-1; 5-ASA: 5-aminosalycilic acid; CBP: cyclic AMP-response element binding-binding protein; DRIP: vitamin D receptor-interacting protein; EC: endothelial cell; ICAM-1: intercellular adhesion molecule-1; JNK: c-jun-N terminal kinase; NFAT: nuclear factor of activated T cells; NF-κB: nuclear factor-κB; PPAR: peroxisome proliferator activated receptor; PPRE: PPARγ response element; RXR: retinoid X receptor; VCAM-1: vascular cell adhesion molecule-1.

In addition, the genetic involvement of PPARγ in the both epithelial cells and macrophages for regulation of protection against inflammation of the colon was shown by intestinal inflammation during experimental colitis [42,43]. the increased susceptibility of PPARγ heterozygous mice (PPARγ+/–) to TNBS-induced inflammation compared with PPARγ in patients with UC their wild-type littermates [35]. At present, >20 published Despite in vitro and in vivo evidence of the anti-inflammatory studies have reported similar prophylactic and therapeutic functions of the PPARγ/RXR heterodimer in the colon, effects of PPARγ in animal models. These include acute very few studies have assessed the roles of PPARγ in UC colitis induced by chemical compounds, bacteria, or [17,40,44]. As PPARγ is mainly expressed in the colon by ischemia-reperfusion in different strains of mice, rats, epithelial cells, the expectation might be that a decreased or pigs, and also in chronic colitis occurring after the transfer expression of this receptor may be found in an inflammatory of immunocompetent T cells to severe combined immuno- disorder confined to superficial layers of the intestine and deficient mice or spontaneously in interleukin-10-deficient limited to the colon, such as UC. A decreased expression mice and SAMP1/YitFc animals [34–41]. Recently, two of PPARγ was observed at the mRNA and protein levels in studies have shown the importance of PPARγ expression in the colons of UC patients compared with individuals who

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Figure 8. Double immunostaining for PPARγ (green) and TLR4 (red) in colonic mucosa of UC and CD patients, and control subjects. In contrast to CD, in which a double PPARγ/TLR4 staining is observed, UC patients present an impaired PPARγ expression, suggesting an imbalance between pro-inflammatory and anti-inflammatory signals in epithelial cells from UC patients, which might explain the colonic inflammation observed in UC patients.

UC CD Control PPAR: TLR4: Anti-inflammatory Pro-inflammatory

CD: Crohn’s disease; PPAR: peroxisome proliferator activated receptor; TLR4: Toll-like receptor 4; UC: ulcerative colitis. had CD and control subjects [17]. This impaired expression maintenance of remission is due to PPARγ activation in was found in both healthy and inflamed colons and was epithelial cells; however, during active disease, when the limited to epithelial cells, suggesting that the perturbed epithelium is disorganized, 5-ASA might also act through levels of PPARγ in UC is not secondary to the inflammatory activation of PPARγ expressed by lamina propria macrophages process. The etiology underlying the impaired PPARγ and T lymphocytes. expression in colonic epithelial cells of UC patients remains To date, only one open-label, pilot trial has evaluated unknown. Comparable levels of PPARγ in the peripheral the efficacy of the PPARγ ligand rosiglitazone (4 mg orally, mononuclear cells of IBD patients and controls, and the twice daily) in 15 patients with active UC, refractory to absence of specific mutations of the PPARγ gene or its conventional treatment with either corticosteroids or promoter in UC patients, suggest that epigenetic events immunomodulators and 5-ASA [44]. After 12 weeks of may account for the impaired PPARγ expression in UC treatment with rosiglitazone, a substantial decrease in patients [17]. Another attractive possibility may be that disease activity index score was reported, with clinical and the Toll-like receptor 4 (TLR4) signaling to PPARγ is endoscopic remission (27% and 20%, respectively) or a impaired in UC, and an imbalance between elevated partial response (27%) in eight patients. This study in IBD levels of TLR4 and the impaired expression of PPARγ in patients has led to new clinical trials in IBD with these epithelial cells of UC patients may alter mucosal tolerance to chemical compounds, and may lead to the development of luminal lipopolysaccharide, resulting in superficial colonic safer PPARγ agonists that have topical effects and selectively inflammation (Fig. 8) [17]. More generally, it could be targeting the colon. hypothesized that impaired expression of PPARγ in UC may be secondary to non-functional regulation of PPARγ Conclusion and perspectives expression in epithelial cells due to abnormal signaling Anti-inflammatory effects of 5-ASA are mainly mediated pathways and/or a lack of luminal stimuli induced by natural through PPARγ, a key receptor expressed by epithelial cells ligands or microorganisms. Further study is required to that regulates bacterial-induced inflammation. Present investigate more precisely the complex regulation of PPARγ knowledge supports the concept that the therapeutic effect expression by epithelial cells in UC patients. It is possible of 5-ASA in UC patients is mainly mediated through a that the 5-ASA effect observed in UC patients for the normalization of PPARγ expression and its activation in

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colonic epithelial cells. This may also explain why 5-ASA is 17. Dubuquoy L, Jansson EA, Deeb S et al. Impaired expression of peroxisome proliferator less effective in CD, which is a condition characterized by activated receptor gamma in ulcerative colitis. Gastroenterology 2003;124:1265–76. 18. Spiegelman BM. PPARgamma in monocytes: less pain, any gain? Cell 1998;93:153–5. transmural inflammation affecting predominantly the small 19. Tontonoz P, Nagy L, Alvarez JG et al. PPARgamma promotes monocyte/macrophage bowel, where the levels of PPARγ expression remain low differentiation and uptake of oxidized LDL. Cell 1998;93:241–52. (Fig. 8). The description of 5-ASA as a new PPARγ ligand 20. Vidal-Puig AJ, Considine RV, Jimenez-Linan M et al. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation also opens an avenue for the rational development of novel by insulin and glucocorticoids. J Clin Invest 1997;99:2416–22. molecules that have a local effect and better affinity for 21. Rieusset J, Andreelli F, Auboeuf D et al. Insulin acutely regulates the expression of the peroxisome proliferator-activated receptor-gamma in human adipocytes. Diabetes PPARγ in colonic epithelial cells. Together with the 1999;48:699–705. development of new galenic formulations designed to 22. Eun CS, Han DS, Lee SH et al. Attenuation of colonic inflammation by PPAR-gamma in intestinal epithelial cells: effect on TLR pathways. Gastroenterology 2005;128:T1526. facilitate prolonged exposure of the active compound into 23. Lee SK, Kim HJ, Chi SG et al. [Saccharomyces boulardii activates expression of peroxisome TM the colonic mucosa, such as the MMX technology, we can proliferator-activated receptor-gamma in HT-29 cells]. Korean J Gastroenterol 2005;45:328–34. expect new 5-ASA optimized molecules with higher anti- 24. Konturek PC, Kania J, Kukharsky V et al. 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98 INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 LEADING ARTICLE 99 3 2007 O 7 N OL V (3):99–105. 7 Morphological investigations of the small bowel, both Morphological investigations of the and infusion Examinations performed with enteroclysis ONITOR M 2007; the presence of extra-intestinal manifestations of the disease of extra-intestinal manifestations the presence patients with clinical without typical colonic lesions, and in at colonoscopy. symptoms not explained by lesions found improved radiological and endoscopic, have dramatically tomography (CT), over the last two decades. Computed imaging (MRI), and abdominal magnetic resonance examination of the effective ultrasound allow for a more with small bowel with that achieved small bowel compared series [3,4]. follow-through the further increase of water into the lumen of the gut Following on from diagnostic yield of CT and MRI. in the 1980s [5], the development of push-enteroscopy capsule endoscopy in 2000 [6] of wireless the emergence [7], have enteroscopy double balloon recently, and, more small enabled the endoscopic examination of the entire interventions are biopsies and therapeutic bowel. Moreover, Radiological possible during double balloon enteroscopy. in exploring intestinal stenoses, effective investigations are such as ulcers, and extra-intestinal manifestations large or fistulae. In contrast, abscesses, sclerolipomatosis, detect tiny frequently endoscopic examinations more mucosal lesions such as aphthae and erosions. Thus, the combination of these investigations has significantly to investigate the small bowel in the capacity increased in a dramatic increase clinical settings. This has also resulted in the diagnostic yield in patients with suspected intestinal diseases, and has enabled the diagnostic and therapeutic to several conditions to be modified. approach ISEASE D OWEL B Inflamm Bowel Dis Monit NFLAMMATORY I

Endoscopic investigations of the small bowel must be Address for Correspondence: Michel Delvaux, Department of Michel Delvaux, Department for Correspondence: Address Hôpitaux de Brabois, Internal Medicine and Digestive Pathology, France. les Nancy, F-54511 Vandoeuvre CHU de Nancy, Email: [email protected] considered in several clinical situations including in patients considered suspected of strongly with known CD or those who are limited to the small bowel, in having CD, when lesions are Crohn’s disease (CD) was initially described as “terminal Crohn’s of patients suffering ileitis” and endoscopic investigations the disease focused mainly on the colon and the from accessible to colonoscopy. terminal ileum, which are of the small bowel lesions in other segments Until recently, poorly investigated in the absence of specific were an intestinal stenosis. symptoms, such as obstruction due to bowel of CD patients Elemental lesions found in the small multiple and can be distributed along the whole small are status and duration bowel. Depending on the inflammatory will be characterized of the disease, endoscopic findings mucosal fissures, of aphthae, erosions, by the presence stenoses, or inflammatory pseudo-polyps [1]. The fibrotic endoscopic pattern may be highly suggestive of CD, but diagnosis between this in many instances the differential and other conditions will be challenging as, individually, 1). these elemental lesions may not be specific to CD (Table to establish a firm diagnosis [2]. Biopsies will be required Examples of endoscopic findings in patients with CD and in those who have diseases with endoscopic patterns similar to 1 and 2. shown in Figures CD are The development of capsule endoscopy over recent years has significantly improved investigations of the small bowel in has significantly improved investigations capsule endoscopy over recent years The development of of the multiple morphological investigations those suspected of having CD. Although disease (CD) patients, and in Crohn’s shown to detect significantly of CD, capsule endoscopy has been required for a definitive diagnosis small bowel may be or classical endoscopic follow-through, entero-CT scanning, other modalities such as small bowel more lesions than of CD in a number of important indications, for example, to support a diagnosis procedures. Capsule endoscopy has the suspicion of CD and a negative classical endoscopic work-up. Furthermore, patients with a clinical and/or biological evaluated repeated during follow-up. This review summarizes the studies that have procedure is well tolerated and can be with the CD to date, and discusses the specific clinical issues that are associated capsule endoscopy in patients with procedure, along with its indications. Michel Delvaux and Gérard Gay Michel Delvaux France Nancy, Hospital of Nancy, University Medicine and Digestive Pathology, Department of Internal Diagnosis of Crohn’s Disease of Crohn’s Diagnosis Capsule Endoscopy in the in the Endoscopy Capsule MICHEL DELVAUX AND GÉRARD GAY

Figure 1. Elemental lesions constituting the endoscopic pattern of Crohn’s disease, as seen by capsule endoscopy. A: Deep ulcer; B: Apthoid erosion; C: Ulcerated mucosa with edema; D: Deep ulcer with surrounding edema; E: Ulcerated stenosis; F: Inflammatory mucosa with pseudopolyps.

A B C

D E F

Capsule endoscopy has predominantly been evaluated in Table 1. Intestinal diseases showing elemental lesions similar comparative controlled studies, and its success in the to those of CD. diagnosis of patients with obscure gastrointestinal bleeding Frequency has been demonstrated to be consistently higher than that CD ++++ of other modalities [8,9]. In these studies, in >85% of patients the capsule was shown to enter into the cecum by Drug-related injuries (NSAIDs) +++ the end of the 8-h recording period, and thus, had Mesenteric ischemia ++ examined the entire intestinal mucosa. However, the role of Celiac disease (jejunitis) ++ capsule endoscopy in the diagnosis of CD has not yet been Cryptogenetic multifocal ulcerous fully elucidated. The clinical situation of patients presenting stenosing enteritis + with CD are variable and the diagnostic assessment must be Radiational enteritis + tailored to the current status of the disease (level of activity, Lymphoma, ulcerated cancer + main symptoms, and surgical history). Therefore, it is not Vasculitus (lupus, polyarthritis, PAN) + possible to design a simple algorithm to define the role of Behçet’s disease +/– capsule endoscopy. Indications must be discussed case by case, and further studies are clearly needed to validate a Eosinophilic enteritis +/– specific strategy. Infections (CMV, yersinia) +/–

Consequently, the aim of this review is to summarize the +/–: Indicates the frequency of intestinal lesions in the disease compared with results of studies that have evaluated capsule endoscopy in CD; CD: Crohn’s disease; CMV: cytomegalovirus; NSAID: nonsteroidal anti- patients with CD, to discuss the specific clinical issues related inflammatory drug; PAN: polyarteritis nodosa.

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Figure 2. Diseases with an endoscopic pattern similar to that of Crohn’s disease and requiring a careful differential diagnosis. A: Nonsteroidal anti-inflammatory drug (NSAID)-related ulcer; B: NSAID-related stenosis; C: Vasculitis: Churg–Strauss syndrome; D: Ulcerous jejunitis complicating celiac disease; E: Cytomegalovirus infection after heart transplantation; F: Whipple’s disease.

A B C

D E F

to the use of capsule endoscopy in this disease setting, and The Minimal Standard Terminology for Digestive finally, to outline its possible indications. Endoscopy, which is a structured language for the description of the lesions observed during endoscopic procedures Elemental lesions of CD at capsule endoscopy was proposed and validated in 2000 [10]. More recently, The endoscopic diagnosis of CD is based on the presence of an adapted version named Capsule Endoscopy Structured a spectrum of elemental lesions, which can occur either in Terminology (CEST), which takes into account the specificity the small bowel or in the colon. During classical endoscopy, of capsule endoscopy for the small bowel, was designed insufflation of air distends the lumen of the organ and allows [11]. The CEST is based on the principle of a separate the immediate examination of long segments of the gut, description of the elemental lesions (e.g. ulcers, stenosis, thus allowing the simultaneous identification of multiple aphthae, and erosions) and a diagnosis that is based on the lesions presented in an endoscopic pattern that may be global understanding of all the findings. Terms describing highly suggestive of CD. Capsule endoscopy examines the the lesions are listed, and each of these be can further gut wall in a distinct way to classical endoscopy. Due categorized according to specific attributes. Similarly, the to the absence of air insufflation during the former diagnosis can be specified by indicating the confidence level procedure, the mucosa is closely observed and only a short that it can be assigned. The objective is to promote segment of the gut can be viewed on each frame. Therefore, standardized descriptions to be used in the reports of most of the time, the lesions will be observed and described capsule endoscopy. In the setting of CD, this effort is separately. At the end of the analysis, the endoscopist of considerable importance, as an accurate description of will consider all of the findings in order to formulate the lesions observed by the capsule will support a better a diagnosis. outcome of the studies evaluating the diagnostic capability

INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 101 MICHEL DELVAUX AND GÉRARD GAY

of the technique. Moreover, individual intestinal or colonic yield 42%), entero-CT scanner (incremental yield 38%), and lesions are not pathognomonic of CD and can be observed ileo-colonoscopy (incremental yield 15%). in a number of conditions (Table 1). In addition, some minimal lesions can also be observed in healthy subjects, as Capsule endoscopy and double shown by Goldstein et al., who found mucosal breaks and balloon enteroscopy erosions in 14% of healthy subjects (not taking nonsteroidal A diagnosis of CD can be suggested by a typical endoscopic anti-inflammatory drugs [NSAIDs]) [12]. This highlights the pattern, the association of endoscopic lesions with positive clinical importance of capsule findings. serological tests, or the combined findings from biological, In summary, the diagnosis of these lesions presents radiological, and endoscopic analyses that are not individually a real challenge for the endoscopist as they are not specific typical of CD, but together indicate the presence of the to CD, and a firm diagnosis may require the pathological disease. In the latter case, the diagnosis will require examination of the biopsies. Clinical relevance can be confirmation by biopsies. Intestinal lesions may be accessible ascertained by the severity of the lesions, their number, and to biopsy during double balloon enteroscopy [25]. By the diffuse involvement of the mucosa. However, isolated, combining the oral and the anal routes, the whole small minute lesions should be more cautiously interpreted to bowel can be examined, and biopsies or therapeutic avoid over-diagnosis of CD. interventions performed as easily as during colonoscopy. However, it is difficult to define the actual number of cases in Diagnostic yield of capsule endoscopy which the entire small bowel can be examined by double and comparison with other investigations balloon enteroscopy. In the study of Yamamoto et al., Initial studies of capsule endoscopy were predominantly examination of the entire small bowel was reported in performed in patients with obscure gastrointestinal approximately 25% of the patients using a combined bleeding (reviewed in [13]). However, over the same time procedure (oral plus anal routes) [25]; however, these authors period, several studies involving small series of CD patients did not have access to capsule endoscopy at this time. were published. The limitations of these early studies In CD, double balloon enteroscopy may be proposed are the number of patients included, the choice of the after capsule endoscopy has identified lesions that require comparator subjects, and often the use of small bowel biopsies, for example, pseudopolyps. In this situation, follow-through, which should no longer be regarded as the capsule endoscopy can direct the choice of route to be used, most effective radiological investigation for the small bowel and therefore avoid unnecessary double examinations [9]. in view of advances in abdominal ultrasound, CT, and MRI In patients who are at a risk of capsule blockade – a frequent with enteroclysis [14,15]. Capsule endoscopy detects more issue in patients with CD – double balloon enteroscopy may intestinal lesions of CD compared with any radiological be proposed as the initial investigation for detection of modality (small bowel follow-through, entero-CT scanning, intestinal lesions. In this indication, double balloon entero-MRI) or other classical endoscopic procedures enteroscopy has been shown to detect intestinal lesions in (oesophago-gastro-duodenoscopy [OGD], ileo-colonoscopy, about one-third of patients who are suspected of having CD push-enteroscopy) [16–22]. The diagnostic yield of capsule by biological analyses, but have a normal classical endoscopic endoscopy in this indication has been reported to be as high assessment (OGD plus colonoscopy) [26]. Moreover, double as 40–74% and even 93% in some of these studies. balloon enteroscopy may have a therapeutic application in Furthermore, detection of intestinal lesions of CD by some patients with symptomatic intestinal strictures that can capsule endoscopy may modify the management of the be dilated with a hydrostatic balloon [27]. patient. Studies by Voderholzer et al. [18] and Chong et al. [21] showed that capsule endoscopy significantly influences Indications of capsule endoscopy the therapeutic strategy in at least 25% of patients in patients with CD undergoing investigations for known CD. Finally, in a recent To date, indications for capsule endoscopy in patients with CD report, capsule endoscopy influenced the choice of therapy have remained under evaluation, and the current literature in 17 patients who underwent surgery (ileo-cecal resection) needs to be scrutinized before a standard of practice for CD, as the presence of intestinal ulcers at capsule is defined. The most extensively evaluated application is endoscopy was predictive of disease recurrence [23]. for the investigation of the patient with a clinical and/or These results were recently summarized in a meta- biological suspicion of CD and a negative classical endoscopic analysis that considered all published studies [24]. This work-up, including OGD and ileo-colonoscopy. In such analysis found that capsule endoscopy detects more lesions patients, capsule endoscopy may detect intestinal lesions in up compared with small-bowel follow through (incremental to 70% of individuals [18,19,22,29]. In the study by

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Voderholzer et al. [18], capsule endoscopy was more effective that capsule endoscopy may, in the future, be used to assess than CT with enteroclysis for detection of lesions in the small the efficacy of immunosuppressive treatments, which are bowel, but not in the terminal ileum. This result may be increasingly prescribed to patients with CD. explained by the frequent association of CD lesions in the terminal ileum with sclerolipomatosis, which is easily Tolerance of capsule endoscopy: recognized by CT. The studies of Voderholzer et al. and the risk of capsule retention Chong et al. demonstrated that the detection of intestinal Capsule retention is defined by the absence of natural lesions by capsule endoscopy resulted in adaptation of excretion of the capsule within 7 days following capsule treatment in 25% [18] and 70% [21] of patients, respectively. endoscopy. It must be distinguished from cases in which the Patients with indeterminate colitis may benefit from an capsule did not reach the cecum during the 8-h recording investigation with capsule endoscopy. In a study of 21 patients period, but was naturally excreted in a normal time. Capsule with unclassified colitis, the detection of intestinal lesions retention has been shown to occur in approximately led to a diagnosis of CD in five subjects [29]. Similar findings 1.5–1.8% of patients investigated for obscure gastro- were reported by Whitaker et al. [30]. intestinal bleeding [32,33]. However, the frequency of Another potential indication for capsule endoscopy capsule retention is dramatically higher in patients with CD, is during the follow-up of patients having undergone an ileo- observed in up to 5% of the patients [19,20,34,35]. cecal resection for CD. Two studies have shown that capsule The experience from the literature shows that patients may endoscopy may detect early recurrence of disease after surgery be contraindicated for capsule endoscopy, due to either an [23,31]. According to these studies, recurrence occurs within intestinal stenosis demonstrated by a radiological the first year in two out of three patients. Capsule endoscopy investigation, or clinical signs suggesting such a stenosis, and colonoscopy are equally effective for diagnosis of lesions which is subsequently confirmed by radiology. In patients located around the ileo-colonic anastomosis [23]. However, with CD, the consequence of capsule retention may be capsule endoscopy detected jejunal lesions in 60% of the dramatically different from that in patients with an intestinal patients and allowed the diagnosis of recurrence in an tumor. The latter will most likely undergo surgery to treat additional two patients compared with those diagnosed by the lesion and the capsule removed at the same time, ileo-colonoscopy. In the study by Biancone et al., capsule whereas in patients with CD, surgery would not necessarily endoscopy appeared equally as effective as colonoscopy or be indicated, but performed only to remove the capsule. contrast-enhanced ultrasonography for the diagnosis of There is no clear indicator of the presence of an intestinal recurrence [31]. The main advantage of capsule endoscopy in stenosis in patients undergoing capsule endoscopy. this indication is its excellent tolerance by the patient; Radiological assessment of the small bowel by abdominal therefore, it can be easily repeated during the follow-up in ultrasound [36], CT-enteroclysis, or MRI [37] is impaired these subjects, who undergo frequent investigations. To by low sensitivity and operator-dependent results. The summarize, capsule endoscopy may be indicated in four correlation between radiological and intra-operative findings different clinical situations in patients with CD: has been shown to be weak [38]. Clinical suspicion is based mainly on the careful recording of the patient’s medical history, • To add support to a potential diagnosis of CD i.e. history of abdominal surgery, use of NSAIDs, or the in patients with a clinical and/or biological suspicion presence of obstructive symptoms. To overcome this problem, of the disease, but who have normal results of Given Imaging (Yoqneam, Israel) developed a “patency radiological and classical endoscopic procedures. capsule” to test the patency of the gastrointestinal tract. • The diagnosis of disease recurrence after surgery. However, three studies published in 2005, by Spada et al. in • To evaluate the extent of the lesions in the small Italy [39], Boivin et al. in Germany [40], and Delvaux et al. in bowel in patients with known CD, although the France [41], found that this system did not meet the influence that this may have on patient management expectations of clinicians. Indeed, the envelope of the has not been demonstrated. dissolved capsule was itself responsible for an intestinal • To further diagnose undetermined colitis by detection occlusion requiring surgery in three patients who did not have of intestinal lesions, thus directing a double balloon prior signs of obstruction and who would not otherwise have enteroscopy, with biopsies. required surgery at that time. Although prior radiological investigations had suggested the presence of a stenosis in the In contrast, capsule endoscopy has no indication in study by the current authors [41], the patients who underwent patients in whom the diagnosis of CD can be firmly obtained surgery had a long fibrotic stenosis in which the envelope of by the way of classical investigations. One could envisage the dissolved capsule had become impacted.

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In view of this experience, a second-generation patency References capsule has been developed: the AGILETM patency capsule 1. Lee SD, Cohen RD. Endoscopy of the small bowel in inflammatory bowel disease. Gastrointest Endosc Clin N Am 2002;12:485–93. (Given Imaging). This has a timer plug at each end of the 2. Stange EF, Travis SP, Vermeire S et al.; European Crohn’s and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohn’s disease: capsule, which allows the dissolution to be more easily definitions and diagnosis. Gut 2006;55:i1–15. triggered, even if one of the plugs is trapped in a tight 3. Gourtsoyiannis NC, Papanikolaou N, Karantanas A. Magnetic resonance imaging evaluation stenosis. Clinical studies are ongoing, but patients with CD of small intestinal Crohn’s disease. Best Pract Res Clin Gastroenterol 2006;20:137–56. 4. Wiarda BM, Kuipers EJ, Heitbrink MA et al. MR Enteroclysis of inflammatory small-bowel who are considered for an AGILE patency capsule should diseases. Am J Roentgenol 2006;187:522–31. always be informed of the risk of retention, as there is no 5. Gay GJ, Delmotte JS. Enteroscopy in small intestinal inflammatory diseases. Gastrointest Endosc Clin N Am 1999;9:115–23. radiological investigation that allows the detection of these 6. Iddan G, Meron G, Glukhovsky A et al. Wireless capsule endoscopy. Nature 2000;405: 417. stenoses with a high sensitivity. Therefore, indications of 7. Yamamoto H, Sekine Y, Sato Y et al. Total enteroscopy with a non-surgical steerable double-balloon method. Gastrointest Endosc 2001;53:216–20. capsule endoscopy should be discussed cautiously in patients 8. Triester SL, Leighton JA, Leontiadis GI et al. A meta-analysis of the yield of capsule with known CD, taking into account a careful evaluation of endoscopy compared to other diagnostic modalities in patients with obscure gastrointestinal bleeding. Am J Gastroenterol 2005;100:2407–18. the risk/benefit ratio. Contrary to some advice previously 9. Delvaux M, Fassler I, Gay G. Clinical usefulness of the endoscopic video capsule as the initial intestinal investigation in patients with obscure digestive bleeding: validation of a diagnostic expressed in the literature [42], surgery is frequently not strategy based on the patient outcome after 12 months. Endoscopy 2004;36:1067–73. mandatory in patients with CD, and the retention of the 10. Delvaux M, Crespi M and the Computer Committee of ESGE. Minimal Standard capsule must be regarded as a serious adverse event when it Terminology in Digestive Endoscopy. Version 2.0. Endoscopy 2000;32:159–88. 11. Korman LY, Delvaux M, Gay G et al. Capsule endoscopy structured terminology (CEST): requires a surgical procedure that is otherwise not indicated. proposal of a standardized and structured terminology for reporting capsule endoscopy procedures. Endoscopy 2005;37:951–9.

12. Goldstein JL, Eisen GM, Lewis B et al.; Investigators. Video capsule endoscopy to Conclusion prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and Capsule endoscopy is now assuming a prominent role in the placebo. Clin Gastroenterol Hepatol 2005;3:133–41. 13. Delvaux M, Gay G. Capsule endoscopy in 2005: facts and perspectives. Best Pract Res investigation of patients with CD. Although it should not be Clin Gastroenterol 2006;20:23–39. proposed systematically, indications can currently be refined 14. Pallotta N, Tomei E, Viscido A et al. Small intestine contrast ultrasonography: an alternative to radiology in the assessment of small bowel disease. Inflamm Bowel Dis 2005;11:146–53. from data in the literature. Capsule endoscopy can be used in 15. Schmidt S, Lepori D, Meuwly JY et al. Prospective comparison of MR enteroclysis with patients with a clinical and/or biological suspicion of CD and a multidetector spiral-CT enteroclysis: interobserver agreement and sensitivity by means of “sign-by-sign” correlation. Eur Radiol 2003;13:1303–11. negative classical endoscopic work-up, in patients followed 16. Rieber A, Wruk D, Potthast S et al. Diagnostic imaging in Crohn’s disease: comparison of after surgical ileo-cecal resection, or in patients with abnormal magnetic resonance imaging and conventional imaging methods. Int J Colorectal Dis 2000;15:176–81. radiological findings requiring further investigations. Capsule 17. Albert TG, Martiny F, Krummenerl A et al. Diagnosis of small bowel Crohn’s disease: a prospective comparison of capsule endoscopy with magnetic resonance imaging and endoscopy may also be useful in patients with undetermined fluoroscopic enteroclysis. Gut 2005;54:1721–7. colitis. However, capsule endoscopy must be integrated in a 18. Voderholzer WA, Beinhoelzl J, Rogalla P et al. Small bowel involvement in Crohn’s disease: a prospective comparison of wireless capsule endoscopy and computed tomography graduated and multidisciplinary approach. The combination of enteroclysis. Gut 2005;54:369–73. radiological and endoscopic investigations – capsule endoscopy 19. Fireman Z, Mahajna E, Broide E et al. Diagnosing small bowel Crohn’s disease with wireless capsule endoscopy. Gut 2003;52:390–2. and/or double balloon enteroscopy – with advanced 20. Buchman AL, Miller FH, Walter A et al. Videocapsule endoscopy versus barium contrast immunological and biological tests has significantly improved studies for the diagnosis of Crohn’s disease recurrence involving the small intestine. Am J Gastroenterol 2004;99:2171–5. the differential diagnosis of intestinal diseases. 21. Chong AK, Taylor A, Miller A et al. Capsule endoscopy vs push-enteroscopy and enteroclysis Capsule endoscopy and double balloon enteroscopy are in suspected small bowel Crohn’s disease. Gastrointest Endosc 2005;61:255–61. 22. Dubenco E, Jeejeboy KN, Petroniene R et al. Capsule endoscopy findings in patients with well tolerated by patients and can be repeated during the established and suspected small-bowel Crohn’s disease: correlation with radiologic, follow-up in chronic diseases such as CD. The information endoscopic and histologic findings. Gastrointest Endosc 2005;62:538–44. 23. Bourreille A, Jarry M, D’Halluin PN et al. Wireless capsule endoscopy versus obtained will modify the knowledge about the involvement ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn’s disease: a prospective study. Gut 2006;55:978–83. of the small bowel, which appears to be more diffuse or 24. Triester SL, Leighton JA, Leontiadis GI et al. A meta-analysis of the yield of capsule more frequent than previously described [43]. The frequency endoscopy compared to other diagnostic modalities in patients with non-stricturing small bowel Crohn’s disease. Am J Gastroenterol 2006;101:954–64. of CD cases limited to the small bowel also seem to be more 25. Yamamoto H, Sekine Y, Sato Y et al. Total enteroscopy with a non-surgical steerable frequent than previously reported – when investigations double-balloon method. Gastrointest Endosc 2001;53:216–20. 26. Oshitani N, Yukawa T, Yamagami H et al. Evaluation of deep small bowel involvement by were almost exclusively limited to the colon and terminal double-balloon enteroscopy in Crohn’s disease. Am J Gastroenterol 2006;101:1484–9. ileum. Future studies need to demonstrate, in homogenous 27. Sunada K, Yamamoto H, Kita H et al.Clinical outcomes of enteroscopy using the double- balloon method for strictures of the small intestine. World J Gastroenterol 2005;11:1087–9. groups of patients, that this earlier work-up will result in a 28. Goldfarb NI, Pizzi LT, Fuhr JP Jr et al. Diagnosing Crohn’s disease: an economic analysis better outcome. comparing wireless capsule endoscopy with traditional diagnostic procedures. Dis Manag 2004;7:292–304. 29. Maunoury V, Bourreille A, Ben Soussan E et al. The value of wireless capsule endoscopy Disclosures in indeterminate colitis. Gut 2005;54:A73 (abstract). 30. Whitaker DA, Hume G, Radford-Smith GC. Can capsule endoscopy help differentiate The authors have no relevant financial interests to disclose. the aetiology of indeterminate colitis? Gastrointest Endosc 2004;59:117 (abstract).

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31. Biancone L, Calabrese E, Bozzi RM et al. Small intestine contrast ultrasonography 37. Schmidt S, Lepori D, Meuwly JY et al. Prospective comparison of MR enteroclysis with versus videocapsule endoscopy for assessing Crohn’s disease post-operative recurrence: multidetector spiral-CT enteroclysis: interobserver agreement and sensitivity by means a prospective longitudinal study. Gastroenterology 2006;130:A204 (abstract). of “sign-by-sign” correlation. Eur Radiol 2003;13:1303–11. 32. Barkin JS, O’Loughlin C. Capsule endoscopy contraindications: complications and 38. Otterson MF, Lundeen SJ, Spinelli KS et al. Radiographic underestimation of small bowel how to avoid their occurrence. Gastrointest Endosc Clin N Am 2004;14:61–5. stricturing Crohn’s disease: a comparison with surgical findings. Surgery 2004;136:854–60. 39. Spada C, Spera G, Riccioni M et al. A novel diagnostic tool for detecting functional 33. Rosch T, Ell C. [Position paper on capsule endoscopy for the diagnosis of small bowel patency of the small bowel: the Given patency capsule. Endoscopy 2005;37:793–800. disorders]. Z Gastroenterol 2004;42:247–59. 40. Boivin ML, Lochs H, Voderholzer WA. Does passage of a patency capsule indicate 34. Mow WS, Lo SK, Targan SR et al. Initial experience with wireless capsule enteroscopy small-bowel patency? A prospective clinical trial? Endoscopy 2005;37:808–15. in the diagnosis and management of inflammatory bowel disease. Clin Gastroenterol 41. Delvaux M, Ben Soussan E, Laurent V et al. Clinical evaluation of the use of the M2A Hepatol 2 2004; :31–40. patency capsule system before a capsule endoscopy procedure, in patients with known 35. Herrerias JM, Caunedo A, Rodriguez-Tellez M et al. Capsule endoscopy in patients or suspected intestinal stenosis. Endoscopy 2005;37:801–7. with suspected Crohn’s disease and negative endoscopy. Endoscopy 2003;35:564–8. 42. Swain P. Wireless capsule endoscopy and Crohn’s disease. Gut 2005;54:323–6. 36. Fraquelli M, Colli A, Casazza G et al. Role of US in detection of Crohn disease: 43. Kornbluth A, Colombel JF, Leighton JA et al. ICCE consensus for inflammatory bowel meta-analysis. Radiology 2005;236:95–101. disease. Endoscopy 2005;37:1051–4.

INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 105 CLINICAL REVIEWS Commentary and Analysis on Recent Key Papers

Clinical reviews were prepared by Ian Arnott, Federico Balzola, Charles Bernstein, and Simon Murch

PATHOGENESIS To establish the importance of MUC2 in the development of gastrointestinal inflammation, the authors generated Muc2-deficient mice in which goblet cells were absent. It is Muc2-deficient mice spontaneously develop colitis, of interest that the development of small-bowel adenomas and indicating that MUC2 is critical for colonic protection carcinomas is a feature of these mice. The mice were challenged Van der Sluis M, De Koning BA, De Bruijn AC et al. with dextran sodium sulfate (DSS) to induce an experimental Gastroenterology 2006;131:117–29. colitis. Wild-type (Muc2+/+), heterozygous (Muc2+/–), and homozygous deficient (Muc2–/–) mice were studied, and Mucins are produced by goblet cells in the gut, and groups of mice were sacrificed at 5, 8, 12, and 16 weeks. are a major component of the protective mucus layer. The authors demonstrated that the Muc2–/– mice showed The authors of this study generated mice deficient in clinical signs of colitis from week 5, becoming more severe as MUC2 (the predominant mucin type) and assessed the the mice grew older. This was manifest as weight loss, diarrhea, development and course of disease in experimentally overt rectal bleeding, and rectal prolapse. Microscopic analysis –/– induced colitis in the knockout (Muc2–/–) compared with of the colon of Muc2 mice showed mucosal thickening, heterozygous (Muc2+/–), and wild-type (Muc2+/+) mice. increased proliferation, and superficial erosions. Colonic goblet MUC2 deficiency resulted in inflammation of the colon, cells in the Muc2–/– mice were negative for MUC2, but trefoil which occurred at an earlier time point and was more factor 3 (a protein also expressed by goblet cells in the intestine severe when an experimental colitis was induced. that plays a role in the maintenance and repair of the mucosa) was still detectable. In Muc2–/– mice, transient de novo An appreciation that defects in mucosal protection may be expression of Muc6 mRNA was observed in the distal colon. critical in the development of IBD is increasing rapidly. This is On day 2 of DSS treatment, the histological damage was more of relevance in both ulcerative colitis (UC) and Crohn’s disease severe in Muc2+/– versus Muc2+/+ mice, but the disease activity (CD). The association of defensin deficiency in carriers of index was not different at this stage. By day 7, the disease NOD2 gene variants is a pertinent example. The defensins, a activity index and histological score were significantly elevated family of antimicrobial peptides, are secreted by paneth cells in Muc2+/– compared with Muc2+/+ mice. The disease activity deep in the epithelial crypt, and are important in mucosal index of the Muc2–/– mice was higher (versus both Muc2+/+ protection. However, it is clear that the products of goblet and Muc2+/– mice) throughout DSS treatment. The histological cells are also important, and the major products of these cells damage in the DSS-treated Muc2–/– mice was different are mucins, which are the building blocks of the protective compared with Muc2+/+ and Muc2+/– mice, with many crypt mucus layer. The mucus layer is a hydrated polymeric gel of abscesses seen, rather than mucosal ulcerations. a thickness of 50–800 μm, and is composed of two layers: The authors concluded that MUC2 deficiency is a cause a loosely adherent layer that is removable by suction, and of inflammation of the colon and, when combined with an a layer firmly attached to the mucosa. In humans, mice, and experimental colitis, this occurs earlier and is more severe. rats, MUC2 is the predominant mucin type secreted in large This study is an important demonstration of the significance amounts from apical granules within the goblet cell. of the barrier function of the intestinal mucosa. Further data Damage to the epithelium, in particular events affecting the are awaited with interest. protective properties conferred by the secretory products Address for reprints: IB Renes, Laboratory Pediatrics, Erasmus MC and of the goblet cells, is a likely cause of inflammation. An Sophia Children’s Hospital, Room Ee 15.71A, Dr. Molewaterplein 50, illustration of this is the goblet cell depletion seen in UC. 3015 GE Rotterdam, The Netherlands. Email: [email protected]

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Serological and DNA-based evaluation biopsies of CD (27%) compared with non-inflamed biopsies of Chlamydia pneumoniae infection (8%). Among CD patients, the NOD2/CARD15 mutation in inflammatory bowel disease was present in 33% of C pneumoniae DNA-positive patients Müller S, Arni S, Varga L et al. and in 47% of C pneumoniae DNA-negative patients. Eur J Gastroenterol Hepatol 2006;18:889–94. These data demonstrate that there is no direct involvement of Chlamydia in the etiology of IBD. Nevertheless, the It has been suggested that Chlamydia pneumoniae can results suggest that this agent has an important influence on trigger autoimmune events. Thus, the authors of this inflammation in CD patients. study assessed the relationship between Chlamydia Address for reprints: F Seibold, Division of Gastroenterology, infection and IBD. No significant differences in the serum Inselspital Bern, Freiburgstrasse, 3010 Bern, Switzerland. titers of anti-C pneumoniae immunoglobulin G or the Email: [email protected] presence of C pneumoniae DNA were found between healthy controls and patients with IBD, although Identification of novel virulence determinants inflamed biopsies from Crohn’s disease patients were in Mycobacterium paratuberculosis by screening significantly more likely to contain C pneumoniae DNA a library of insertional mutants compared with biopsies from non-inflamed tissue. Shin SJ, Wu CW, Steinberg H et al. Infect Immun 2006;74:3825–33. Chlamydia pneumoniae is an obligate intracellular Gram- negative bacterium that has emerged as an important The Mycobacterium avian subspecies paratuberculosis pathogen in humans over the last decade. It is one of the (MAP) has been proposed to play a role in the pathogenesis most common causes of eye, respiratory tract, genital tract, of Crohn’s disease. The authors of this study identified joint, and vasculature infections, occurring in millions of several novel virulence determinants of MAP during people every year. More recently, it has been suggested that screening of a library of mutants. These determinants of C pneumoniae triggers autoimmune events. Although the virulence may represent novel targets for drug development. exact mechanism is still unknown, Chlamydia shares some epitopes with certain reactive proteins (e.g. myelin basic Mycobacterium avian subspecies paratuberculosis (MAP) is protein) and, for this reason, is potentially involved in the the cause of Johne’s disease in cattle and other ruminants, etiology or pathogenesis of autoimmune disorders. As which is a worldwide problem for dairy farming. The role of Chlamydia has also been found in the intestinal mucosa of this organism in the pathogenesis of Crohn’s disease (CD) IBD patients and healthy controls, a possible role for the remains controversial. Consistent data have demonstrated a bacteria in the pathogenesis of IBD has been proposed, but higher frequency of the MAP insertion sequence IS900 in not yet confirmed. patients than in healthy controls but there has been very little The current authors measured the titers of scientific proof that this is a causative organism rather than a immunoglobulin G (IgG) antibodies against C pneumoniae bystander. A randomized control trial of antituberculous and tested for C pneumoniae DNA in the sera and mucosal therapy in patients with CD has yielded negative results [1]. biopsies, respectively, of 78 patients with Crohn’s disease The mechanisms of virulence of MAP remain poorly (CD) and 24 with ulcerative colitis (UC). Moreover, CD understood and the key steps for developing paratuberculosis patients with mutations in NOD2/CARD15 (a gene involved remain elusive. Characterization of these pathways could in the immune reactivity to intracellular bacterial antigens) lead to the development of vaccines or other treatments were selected in order to assess possible correlations with the that, in turn, may have relevance to IBD. In an attempt to presence or absence of C pneumoniae DNA. The blood of identify virulence factors in MAP organisms, Shin et al. 73 family members and the sera and biopsies of 20 healthy constructed a library of 5060 transposon mutants using subjects were also evaluated as control groups. The results Tn5367 insertion mutagenesis. They analyzed a total of showed that IgG antibodies against C pneumoniae were 1150 mutants, and 970 unique insertion sites were identified. present in 41%, 46%, 48%, and 45% of the CD, UC, The authors found that insertion of Tn5367 was more unaffected family members, and healthy control groups, prevalent in genomic regions with a G+C content that was respectively. C pneumoniae DNA was found in 23% and 31% lower than the average G+C content of the MAP genome. of the biopsies from patients with CD and UC, respectively. Disruptions in genes involved in iron, tryptophan, and mycolic Surprisingly, even in the 35% of intestinal biopsies from acid metabolic pathways were demonstrated to confer unique healthy controls, C pneumoniae DNA was present. In addition, growth characteristics. Bioinformatic analyses of disrupted C pneumoniae DNA was more frequently found in inflamed genes identified several potential virulence determinants,

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which subsequently underwent further testing in vivo. type 1 diabetes. They examined six single nucleotide Infection studies in mice showed a significant decrease in polymorphisms (SNPs) across OCTN1/2 in 295 subjects with tissue colonization by mutants with a disruption of specific type 1 diabetes and 508 healthy controls. TaqMan® (Applied genes. Furthermore, these “attenuation phenotypes” were Biosystems, Foster City, CA, USA) was used to genotype the tissue-specific, and the time-course of infection progression SNPs slc2F2 (rs3792876), slc2F11 (rs2306772), T306I varied according to the mutant, suggesting that certain (rs272893), L503F (rs1050152) (all OCTN1), OCTN2-intron genes may be involved in distinct virulence mechanisms. (rs274559), and an OCTN2 promoter polymorphism. The novel virulence determinants identified in this study The authors demonstrated that, when analyzed represent new functional classes that may be necessary for independently, one SNP in the SLC22A4 gene at position mycobacterial survival during infection; these could provide 1672 (L503F) showed a significant association with type 1 suitable targets for new drug development. diabetes. It is of note that this was not the variant associated 1. Borody TJ, Clancy R, Wettstein A et al. Anti-MAP therapy in the treatment of active with CD or rheumatoid arthritis (although the high linkage Crohn’s disease. J Gastroenterol Hepatol 2005;20(suppl):A2. disequilibrium across this region should be kept in mind). Address for reprints: AM Talaat, Department of Animal Health The overall comparison of the inferred haplotypes was and Biomedical Sciences, University of Wisconsin – Madison, significantly different between patients and control subjects, 1656 Linden Drive, Madison, WI, USA. Email: [email protected] with one of the haplotypes showing a protective effect for type 1 diabetes (odds ratio 0.62; p=0.02). Evidence for the association of the SLC22A4 In summary, this Spanish group presented some and SLC22A5 genes with type 1 diabetes: interesting data on the possible role of this cytokine cluster a case control study in type 1 diabetes. It is clear from their data that OCTN1/2 Santiago JL, Martinez A, de la Calle H et al. may not be the causative genes and that, in addition to BMC Med Genet 2006;7:54. confirmation in other populations, further genetic, functional, and expression data are required to address this issue. Santiago et al. performed a case–control study in order However, when complete, this work may have significant to identify polymorphisms in the IBD5 region of implications for many important diseases. 1. Peltekova VD, Wintle RF, Rubin LA et al. Functional variants of OCTN cation transporter chromosome 5 in a group of patients with type 1 genes are associated with Crohn disease. Nat Genet 2004;36:471–5. diabetes. They identified one single nucleotide poly- morphism that was significantly associated with type 1 Address for reprints: EG de la Concha, Immunology Department, diabetes; however, this was different to the recently Hospital Universitario San Carlos, Madrid, Spain. identified organic cation transporters 1 and 2 (OCTN1/2) Email: [email protected] polymorphisms associated with Crohn’s disease. Patients with inflammatory bowel disease The cluster of cytokine genes located on chromosome 5q31 are at risk for vaccine-preventable illnesses (IBD5) has attracted much interest in recent months with the Melmed GY, Ippoliti AF, Papadakis KA et al. description of variants in organic cation transporters 1 and 2 Am J Gastroenterol 2006;101:1834–40. (OCTN1/2) in Crohn’s disease (CD). However, the strong linkage disequilibrium that occurs across this region has Although immunization therapies are potentially always been a barrier to the clarification of individual important in immunosuppressed patients such as those candidate genes. In a study by Peltekova et al., the CD with IBD, there is a lack of available data regarding susceptibility haplotype (the so-called TC haplotype) was vaccination in this population. The authors of this study seen to be independent of other markers in the IBD5 region evaluated the immunization history and exposure to [1]. Subsequent studies from different geographical locations viral risk factors in a cohort of IBD patients, using a have confirmed the association of OCTN1/2 with CD but self-administered questionnaire. They conclude that have not been able to substantiate the independence of this there is a low rate of immunization of IBD patients, association, and, hence, questions remain regarding the role probably due to lack of patient awareness and concerns of OCTN1/2 as the causative genes. regarding side effects of immunization therapies. The OCTN genes encode proteins that function as carnitine transporters (with the transporter activity of OCTN2 being During the past two decades, medical therapy for Crohn’s much greater than that of OCTN1). Carnitine is important disease (CD) and ulcerative colitis (UC) has expanded to for lipid and energy metabolism; therefore, Santiago et al. incorporate a variety of long-term immunosuppressive agents postulated that OCTN1/2 could be susceptibility genes in or biological therapies to control the inflammatory course of

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the disease. Simultaneously, new information regarding the Comparative study of the intestinal mucous abnormal mechanism of the mucosal immune response, which barrier in normal and inflamed colon could underlie IBD, has become available. The relationship Swidsinski A, Loening-Baucke V, Theissig F et al. between host susceptibility to infection and the safety and Gut 2006; [Epub ahead of print]. efficacy of immunization for vaccine-preventable diseases has been explored in other immune-mediated disease, but rarely The authors of this study examined the interaction in IBD. The paucity of available data highlights how vaccines of the microbial flora with the mucus layer in healthy are underused in this group of patients, notwithstanding and inflamed tissue. In biopsies from healthy subjects that these individuals are at risk for acquired infections, which the mucosal surface beneath the mucus layer was free are potentially preventable using immunization therapies. of bacteria in ≥80% of cases; however, in patients Using a self-administered questionnaire, the authors evaluated with colitis or ulcerative colitis there was deep mucosal the immunization history and exposure to known viral risks infiltration with bacteria and leukocytes, with a thinning factors (influenza, pneumococcus, viral hepatitis, and varicella) of the mucus layer, and epithelial defects. in a group of IBD patients who attended the Cedars-Sinai Inflammatory Bowel Disease Center (Los Angeles, CA, USA). A distinct approach to examine the importance of the mucus Of the 196 patients enrolled, 169 completed the study, layer in IBD was taken by Swidsinski et al. The mucus layer is showing the following results: the site of interaction between the host and the enteric bacteria, and these bacteria are essential for the development • 86% of patients were at risk for infection as and perpetuation of chronic IBD. Although changes in the they had been treated with immunosuppressive mucus layer have been described in inflammation, the medications or had frequent hospitalizations. significance of this remains unclear. The authors of this study • Only 28% of patients received routine influenza used advances in specimen fixation and techniques including vaccinations and only 9% had been immunized fluorescent in situ hybridization to examine the interaction against pneumococcus (despite the recommendations of the microbial flora with the mucus layer in healthy and for immunosuppressed patients). inflamed tissue. They aimed to minimize the bias that is • Only 45% of patients recalled receiving tetanus often encountered in specimen collection by using enema immunization within the past 10 years. preparation of the left colon and by using appendix specimens • 44% of patients showed an increased risk for hepatitis B from individuals who had not been treated with antibiotics. infections (having at least one known risk factor), but Biopsy samples from 20 healthy individuals, 20 patients with only 28% had been vaccinated against hepatitis B. self-limiting colitis, and 20 patients with ulcerative colitis (UC) were examined. In addition, biopsy samples from The most frequent causes cited by patients for not being 60 randomly selected appendices were examined. vaccinated against influenza were lack of awareness (49%) The main findings of the study were that the mucosal and concerns about side effects (18%). surface beneath the mucus layer was free of bacteria in As the efficacy of immunization may be diminished in ≥80% of the non-inflamed appendices and biopsy samples some patients in whom the immune status is compromised from healthy subjects. The thickness of the mucus layer, by immunosuppression therapy, additional larger studies are and its spread, decreased with increasing severity of the required to assess the protection conferred by immunization. inflammation; the epithelial surface showed bacterial These are also required to convince patients that, with adherence, and epithelial tissue defects and deep mucosal the exception of live agent vaccines, the majority of infiltration with bacteria and leukocytes were observed. immunizations may be safely administered and provide Bacteria and leukocytes were found within the mucus in all long-term efficacy. Interestingly, the low rate of biopsy samples from patients with UC, self-limiting colitis, immunization of IBD patients demonstrated in this study is and acute appendicitis. The concentration of bacteria similar to the rate in the general population, which possibly within the mucus was inversely correlated with the number reflects a deficiency in the communication of information by of leukocytes. clinicians to patients regarding vaccine-preventable illnesses, The authors concluded that the normal mucus layer rather than patients concerns (lack of awareness of possible provides an effective barrier between the luminal microbial infections or concerns about side effects). flora and the mucosa, and prevents contact in all parts of the colon. They effectively showed that in colonic inflammation Address for reprints: GY Melmed, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Thalians Building, 8730 Alden Drive, this process is disrupted, with regular mucosal breaks and Los Angeles, CA 90048, USA. contact of microbes with the mucosa. Although the process

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of inflammation functions to reduce the number of bacteria of cells number in inactive disease and a tripling in within the mucus, it is unable to prevent bacterial migration, active disease. adherence, and invasion. Considerable interest remains in This study was undoubtedly limited by the small identifying the initiating event for these processes. numbers of patients included, and it is unclear how many of the 10 subjects within each group were in relapse or Address for reprints: A Swidsinski, Humboldt University, Charité, CCM, 10098 Berlin, Germany. Email: [email protected] remission; however, the differences between the CD and UC groups were apparent. The localization of these MCTC cells Immunohistochemical study of chymase-positive in CD was consistent with a direct role in fibrosis, as mast cells in inflammatory bowel disease previously suggested [2]. Thus, further characterization in Andoh A, Deguchi Y, Inatomi O et al. subgroups of CD patients with different propensities for Oncol Rep 2006;16:103–7. stricturing would be interesting in order to determine whether the mast cells may become a therapeutic target in This analysis of mast cells in IBD demonstrates that patients with a history of stricturing. 1. Soderholm JD, Yang PC, Ceponis P et al. Chronic stress induces mast cell-dependent differences are observed between Crohn’s disease bacterial adherence and initiates mucosal inflammation in rat intestine. and ulcerative colitis with regard to the numbers Gastroenterology 2002;123:1099–108. 2. Gelbmann CM, Mestermann S, Gross V et al. Strictures in Crohn’s disease are of mast cells that are immunoreactive for chymase. characterised by an accumulation of mast cells colocalised with laminin but not This type of mast cell is implicated in fibrosis. with fibronectin or vitronectin. Gut 1999;45:210–7. Address for reprints: A Andoh, Department of Internal Medicine, Much of the early literature on mast cells focuses on their Shiga University of Medical Science, Seta Tukinowa, Otsu 520-2192, role in allergic responses. Indeed, the release of mediators Japan. Email: [email protected] from these cells in response to the cross-linking of membrane-bound immunoglobulin E remains a central Bosentan, an endothelin receptor antagonist, component of the type I allergic response. However, there is reduces leucocyte adhesion and inflammation increasing evidence that mast cells play a broader role in in a murine model of inflammatory bowel disease immunopathogenesis, and that their release of cytokines Anthoni C, Mennigen RB, Rijcken EJ et al. such as tumor necrosis factor-α may be critical in non- Int J Colorectal Dis 2006;21:409–18. allergic disease processes. Activated mast cells can release a number of proteinases, notably tryptase, chymase, and The authors of this report describe a potentially novel carboxypeptidase. Two types of mast cells may be identified therapeutic approach to treatment of IBD – through on the basis of staining for proteinases – those producing inhibiting production of endothelin-1. The observed tryptase but not chymase (MCT cells) and those producing therapeutic effects may be mediated by inhibiting both tryptase and chymase (MCTC cells). The latter type has leukocyte recruitment. a particular role in fibrogenesis, due to the role that chymase plays in the generation of angiotensin II, which promotes Endothelins, which are structurally related to the sarafotoxins fibroblast proliferation and matrix production. of scorpion venom, are the most potent vasoconstrictors Previous studies have shown an essential role for mast discovered to date, and are thought to play a fundamental cells in models of stress-induced colitis in rats [1], and also role in vascular biology. Their pressor effects are counteracted that their number is increased within the mucosa in IBD, by nitric oxide (NO), and the balance between endothelin particularly at sites of stricturing [2]. Thus, the authors of the and NO concentrations may determine vascular tone at the present study aimed to localize chymase-positive MCTC cells local level. Four endothelins, endothelin-1 (ET-1), ET-2, ET-3, within the mucosa from 10 patients with Crohn’s disease and ET-4 mediate their effects through two receptors (ETA

(CD) and 10 with ulcerative colitis (UC), in view of their and ETB), and may be generated in situ from precursor pro- particular role in stricturing. endothelins. A role is emerging for endothelins in inflammatory Clear differences were seen between the tissues of disorders, and leukocytes such as macrophages may produce patients with UC and those with CD. In comparison with endothelin within tissues. the histologically normal resection margin tissues from A possible role for endothelins in the pathogenesis of IBD patients with colon carcinoma, patients with UC in relapse was suggested several years ago following identification of actually showed a reduction in MCTC cell density within a significant upregulation of ET-1 within the mucosa in both the mucosa, although those in remission showed a normal Crohn’s disease (CD) and ulcerative colitis (UC) patients, density of cells. In contrast, patients with CD (either active and in Crohn’s submucosa, often associated with perivascular or inactive) showed a substantial increase, with a doubling macrophage aggregates [1]. The plasma levels of ET-1 are

110 INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 CLINICAL OBSERVATIONS also increased in active IBD [2], although other studies have CLINICAL OBSERVATIONS not confirmed an increase of ET-1 mRNA in IBD [3]. The relevance of endothelins as potential therapeutic targets in IBD has been underlined by the identification The efficacy of corticosteroid therapy in of a role for these mediators in leukocyte recruitment to the inflammatory bowel disease: analysis intestine, and the observed improvement in colonic damage of a 5-year UK inception cohort in a model of rodent colitis upon administration of the Ho G-T, Chiam P, Drummond H et al. endothelin receptor blocker bosentan [4]. The current study Aliment Pharm Ther 2006;24:319–30. develops these earlier observations, with the aim of assessing the effects of bosentan in greater detail, using the Ho et al. evaluated the outcomes at 1 year of an dextran sodium sulfate (DSS) mouse model of colitis. inception cohort of newly diagnosed IBD patients. Employing a daily disease activity index, the authors Of these subjects, 63% of ulcerative colitis patients were able to establish that intraperitoneal bosentan and 75% of Crohn’s disease (CD) patients were treated administration rapidly induced clinical improvement of with corticosteroids. In CD, 60% of those requiring established disease. Histological examination of tissues corticosteroids were either corticosteroid-dependent showed some evidence of inflammation, but this was by 1 year or had required surgery within the first year. substantially milder than that observed in tissue from untreated animals, with an approximate 40% reduction in All new diagnoses of ulcerative colitis (UC) and Crohn’s severity upon quantitation. The changes that occurred were disease (CD) that had been made at the Western General found to relate particularly to the vasculature, with increased Hospital, Edinburgh, UK between 1998 and 2003, were venular diameter and measured blood flow in the bosentan- analyzed retrospectively. Of 216 newly diagnosed IBD treated animals. Leukocyte adhesion, studied by in vivo patients, 63% of those with UC (n=136) and 75% of CD microscopy, was significantly lower in the bosentan-treated patients (n=80) required corticosteroid therapy. At 30 days, group than in animals with untreated DSS-induced colitis, there was complete, partial, or no response to corticosteroid and indeed was at the level of that observed in animals treatment in 51%, 31%, and 18% of UC patients, without colitis. Leukocyte rolling velocity was significantly respectively. In comparison, there was complete, partial, or increased in the bosentan-treated mice compared with no response to corticosteroid treatment at 30 days in 40%, untreated mice with DSS-induced colitis. 35%, and 25% of CD patients, respectively. At 1 year, the The key finding of this study is that the blockade of prolonged response was 55% and 38% in the UC and CD endothelin activity with bosentan induces a therapeutic groups, respectively. Furthermore, corticosteroid dependence effect in experimental colitis by reducing leukocyte was 17% in the UC group and 24% in the CD group, and recruitment to the lesion. Whether this effect is due to surgery was required in 21% of UC and 35% of CD patients prevention of endothelin-mediated upregulation of cell by 1 year. Extensive UC was a predictor of surgery by 1 year adhesion molecules remains to be determined. The (odds ratio [OR] 15.2, 95% confidence interval [CI] importance of the experimental design is that, for the first 3.7–62.4), whereas inflammatory activity was negatively time, bosentan treatment was shown to ameliorate fully associated with surgery (OR 0.13, 95% CI 0.02–0.7). established colitis. Orally administered bosentan has been In the UC group, 72% did not initially require used in a variety of human studies, mainly in cardiovascular corticosteroids or were in a prolonged remission off- disease, and appears to be a well-tolerated medication. corticosteroids at 1 year. Of those who required corticosteroids There seems to be sufficient preliminary evidence to suggest early, 55% were in a prolonged remission at 1 year. that clinical efficacy in IBD should be assessed in future. However, in the CD group, only 54% of patients did not 1. Murch SH, Braegger CP, Sessa WC et al. High endothelin-1 immunoreactivity initially require corticosteroids or were in a prolonged in Crohn’s disease and ulcerative colitis. Lancet 1992;339:381–5. 2. Letizia C, Boirivant M, De Toma G et al. Plasma levels of endothelin-1 in patients remission at 1 year. Of the CD patients who did require with Crohn’s disease and ulcerative colitis. Ital J Gastroenterol Hepatol corticosteroids at an early stage, 59% were corticosteroid- 1998;30:266–9. 3. McCartney SA, Ballinger AB, Vojnovic I et al. Endothelin in human inflammatory dependent or required surgery. However, 33% of the UC bowel disease: comparison to rat trinitrobenzenesulphonic acid-induced colitis. Life Sci 2002;71:1893–904. group was prescribed azathioprine following diagnosis, 4. Hogaboam CM, Muller MJ, Collins SM et al. An orally active non-selective endothelin which limited the conclusions that could be drawn regarding receptor antagonist, bosentan, markedly reduces injury in a rat model of colitis. Eur J Pharmacol 1996;309:261–9. corticosteroid treatment alone. Only 13% of the CD group was prescribed concomitant azathioprine. Address for reprints: C Anthoni, Department of General Surgery, Westfalian Wilhelm’s University, Muenster, Germany. This study serves as a reminder that approximately 55% Email: [email protected] of patients with newly diagnosed CD either do not require

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corticosteroids or are in a prolonged remission at 1 year to have UC than CD, and only 9% ultimately changed from following a course of corticosteroids. This information the initial diagnosis. should be heeded by those who advocate a “top down” Address for reprints: M Henriksen, Department of Internal Medicine, approach, with an early introduction of biological agents Østfold Central Hospital, 1535 Moss, Norway. Email: [email protected] to all who present with disease. Ulcerative colitis and clinical course: results Address for reprints: G-T Ho, Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh of a 5-year population-based follow-up study EH4 2XU, UK. Email: [email protected] (the IBSEN Study) Henriksen M, Jahnsen J, Lygren I et al. Change of diagnosis during the first five years after Inflamm Bowel Dis 2006;12:543–50. onset of inflammatory bowel disease: results of a prospective follow-up study (the IBSEN study) Patients who were diagnosed with IBD, or possible IBD, Henriksen M, Jahnsen J, Lygren I et al. in southeastern Norway in the early 1990s were more Scand J Gastroenterol 2006;21:1037–43. likely to be diagnosed with ulcerative colitis than with Crohn’s disease. When followed-up over a 5-year The authors of this study evaluated an inception cohort period from diagnosis, only 7.5% had colectomies and of 843 newly diagnosed IBD patients from 1990–1994 ≤41% of patients were off-medication. Although and found that, by 5 years, only five individuals had a approximately 50% relapsed in any 1 year, few had changed diagnosis. It was more common for patients disease symptoms that interfered with their daily to be diagnosed with ulcerative colitis (UC). A switch living activities. of diagnosis to UC from Crohn’s disease (CD) or indeterminate colitis was also more likely than for initial Patients diagnosed with definite or possible ulcerative colitis UC or indeterminate colitis to evolve into CD. (UC) in southeastern Norway from 1990–1993 were followed prospectively over 5 years. Definite UC was The authors of this study assessed the accuracy of first diagnosed in 454 patients who were alive and available for diagnosis of IBD in an inception cohort enrolled during follow-up at 5 years. Of this cohort, 7.5% had a colectomy, 1990–1993, with a 5-year follow-up. The initial diagnoses with 71% of these individuals undergoing surgery during for the 843 enrolled patients were: the first 2 years following diagnosis. Within 5 years:

• Ulcerative colitis (UC) in 518. • 43% of patients had used corticosteroids. • Crohn’s disease (CD) in 221. • 19% of patients had not used 5-aminosalicylates. • Indeterminate colitis in 40. • 28% of patients initially diagnosed with proctitis had • Possible IBD in 64. progressed to proctosigmoiditis, left-sided colitis, or extensive colitis. Clinical information was available for 94% of patients at 5 years. Of those initially diagnosed with UC, 8.9% had At the 5-year review, 41% were off-medications, only changed diagnoses: 6.2% to non-IBD and 2.7% to CD. Of 7% had symptoms that interfered with their daily activities, those initially diagnosed with CD, 8.6% had a changed and 22% of patients had a relapse-free course. There was diagnosis: 3.2% to UC and 5.4% to non-IBD. Thus, it was no correlation between the extent of the disease and the more common to change diagnosis to non-IBD than to UC number of patients reporting symptoms, or the severity of or CD. Of the 40 patients initially classified as having these symptoms. Furthermore, the relapse rate in the first indeterminate colitis, 42.5% were classified at 5 years as year of follow-up was similar to the fifth year, at approximately having UC, 12.5% as having CD, and 22.5% as non-IBD. 50%, and was not correlated with disease extent. Of those with possible IBD, 30% proved to have UC, Of interest, only 200 of the 843 patients assessed with 5% were found to have CD, and 50% were deemed to not newly diagnosed or possible IBD were ultimately diagnosed have IBD. Hence, in those diagnosed with UC or CD, only with Crohn’s disease (CD), whereas 454 patients were 2.8% of patients switched from one diagnosis to the other diagnosed with UC. Therefore, UC continued to have a at 5 years. Of those initially diagnosed with UC or CD, higher incidence rate than CD during the early 1990s in 6% proved to have non-IBD. In southeastern Norway in the southeastern Norway. mid-1990s more patients had UC than CD, more patients Address for reprints: M Henriksen, Department of Internal Medicine, who were undifferentiated at presentation eventually proved Østfold Central Hospital, 1535 Moss, Norway. Email: [email protected]

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Long-term effectiveness of azathioprine follow-up was too short to determine whether or not patients in IBD beyond 4 years: a European multicenter can remain in remission after discontinuing azathioprine. study in 1176 patients Address for reprints: MF Neurath, 1 Medical Clinic, University Holtmann MH, Krummenauer F, Claas C et al. of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Dig Dis Sci 2006;51:1516–24. Email: [email protected]

This was a retrospective assessment of 1176 patients Adverse events leading to modification who used azathioprine for the treatment of IBD. The of therapy in a large cohort of patients intent was to discern if azathioprine could be safely with inflammatory bowel disease withdrawn after 4 years of use; however, the study Hindorf U, Lindqvist M, Hildebrand H et al. design did not allow for a proper assessment of Aliment Pharmacol Ther 2006;24:331–42. this endpoint. The authors of this study assessed adverse events Charts of 1176 patients with IBD who had been using related to thiopurine methyltransferase (TPMT) levels azathioprine for ≥6 months were reviewed from 16 different and thiopurine metabolite levels in thiopurine users. Low centers in Germany, Holland, and Belgium. Patients were TPMT levels were associated with a marked leukopenia divided according to length of azathioprine use into groups in five out of six patients. Intermediate or normal levels of <3 years, 3–4 years, or >4 years of treatment. of TPMT did not predict adverse events. Thiopurine Azathioprine dosing was 2.0–2.5 mg/kg. There was a total metabolite levels of >400 pmol/8×108 red blood cells follow-up time following discontinuation of azathioprine were associated with adverse events, although there of 462 years for 818 Crohn’s disease (CD) patients and was an overlap of levels in those with and without 153 years for 358 ulcerative colitis (UC) patients. This adverse events. The high prevalence of thiopurine equates to an average follow-up of approximately 0.5 years therapy-related adverse events led to drug for each patient, which was a short time period to analyze discontinuation in 31% of patients in this study. the effects of drug discontinuation. In 6% of patients, azathioprine was prescribed for post- Patients with IBD who were treated with purine analogue operative maintenance of remission. This is a very different therapy (n=364) were assessed for adverse events related to indication than the maintenance of remission following thiopurine methyltransferase (TPMT) levels and thiopurine steroid withdrawal or for treatment of active disease, and metabolite levels. Adverse events were more common such patients should have been excluded from the analysis. in adults than in children (40% vs. 15%, respectively; A flare was defined as an increase in steroid dose. The p<0.001), although both groups were on similar doses median flare incidence in patients with CD prior to adjusted for weight, and had similar TPMT levels. Adverse azathioprine therapy in the groups treated for <3 years, events were more common in subjects with low-to- 3–4 years, and >4 years was 1.32, 1.2, and 1.44, intermediate TPMT levels (≤9 U/mL red blood cells) and in respectively. Flare incidence decreased in all groups during those with 6-thioguanine levels >400 pmol/8×108 red blood azathioprine therapy to a median of zero flares. Minimal cells or methylated thioinosine monophosphate (meTIMP) flares were evident after azathioprine was discontinued. In levels >11 450 pmol/8×108 red blood cells. Low TPMT activity 179 patients who continued azathioprine for >4 years, was evident in six patients (1.6%) and intermediate activity sustained improvement was illustrated by further reduction was evident in 45 patients (12%). Adverse events occurred in flares and steroid dosing. The authors conclude that in 83% of patients with low TPMT activity, 42% with azathioprine treatment for CD could be safely stopped after intermediate TPMT activity, and 32% with normal TPMT 4 years in those in remission and off-steroids, but should be activity. On average, patients with adverse events were continued in those with active disease and still using older than those without adverse events (mean age 34 years steroids. In UC patients, azathioprine use decreased flare and 24 years, respectively; p<0.001). Patients who experienced incidence and steroid requirement. However, when adverse events were also more likely to be using corticosteroids azathioprine was discontinued after 4 years there was a than those who did not (60% vs. 34%; p<0.001). Patients trend toward more flares and increased steroid use. who experienced adverse events were on lower doses of This study has a number of flaws. For example, its azathioprine at the time of occurrence than those who did retrospective design led the authors to a fairly simple definition not experience any adverse events (1.5 mg/kg vs. 1.9 mg/kg; of disease flare, and some flares might have been successfully p<0.001). There was no difference between those with and treated without steroids. Furthermore, the duration of without adverse events in terms of age or disease diagnosis.

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Of those who experienced adverse events, 71% did so event that necessitated drug discontinuation, this would within the first 3 months of drug therapy. The most common occur regardless of thiopurine metabolite levels, and a adverse events were: decision to try an alternate thiopurine may be made regardless of the metabolite levels. However, if there were • Allergic/systemic reactions (9%). uncertainties regarding drug efficacy, the combination of • Myelotoxicity (8%). high metabolite levels (associated with more adverse events) • Gastrointestinal upset (8%). and a lack of any therapeutic response would encourage • Hepatotoxicity (5%). drug discontinuation. In addition, pre-administration TPMT • Pancreatitis (4%). level measurements seem warranted in a population with a high prevalence of low TPMT levels, in order to avoid Allergic/systemic reactions occurred at a median of profound leukopenia. 40 days (range 20–188 days) while pancreatitis occurred Address for reprints: U Hindorf, Department of Clinical Sciences, at a median of 21 days (range 17–28 days). Myelotoxicity Division of Gastroenterology, Faculty of Medicine, Lund University, occurred at a median of 104 days (range 54–490 days). SE-22185 Lund, Sweden. Email: [email protected] Adverse events led to drug discontinuation in 31% of patients. A shift to 6-mercaptopurine therapy was successful Determinants of vitamin D status in adult in 48% of azathioprine intolerant patients and in all cases of Crohn’s disease patients, with particular patients suffering azathioprine-induced myalgias or arthralgias. mphasis on supplemental vitamin D use One patient was successfully shifted from 6-mercaptopurine Gilman J, Shanahan F, Cashman KD. to azathioprine. Eur J Clin Nutr 2006;60:889–96. The authors conclude that the determination of TPMT status prior to treatment could help predict the likelihood of This study evaluated vitamin D intake and serum adverse events. However, this is only likely to be true for a levels in 58 patients with Crohn’s disease. Levels were small minority of patients with TPMT deficiency (low levels). significantly lower in the winter than in the summer In this study, the prevalence of deficiency was higher than and, not surprisingly, vitamin D supplement use expected. Furthermore, patients with intermediate levels correlated with serum levels in both seasons. were as likely to have an adverse event as those with normal levels, and the time to the adverse event tended to be Of 58 Crohn’s disease (CD) patients in the Republic of Ireland, longer in the group with intermediate TPMT levels than in 50% were vitamin D deficient in winter and 19% were the group with normal TPMT levels. In patients with vitamin D deficient in summer. Vitamin D deficiency was recorded thiopurine metabolite levels (50/124 with adverse defined as serum levels of <50 nmol/L 25-hydroxyvitamin events and 214/240 without adverse events), there was no D. At the first visit, 36% of patients were taking vitamin D difference in thioguanine (TG) or meTIMP levels between supplements. The mean dietary intake plus supplemental those who experienced adverse events and those who did intake of vitamin D was 7.1 μg/day (standard deviation [SD] not. However, there were higher TG levels in patients with 5.2 μg/day) and calcium intake was 1482 mg/day (SD gastrointestinal side effects than those without adverse 728 mg/day). These intakes are high compared with other events (332 vs. 170 pmol/8×108 red blood cells; p=0.03). In previously reported western populations, but the large SD addition, higher meTIMP levels were observed in patients reflects a large variance of intake. Multiple regression analysis with myelotoxicity than in those who did not experience showed that summer vitamin D levels were positively adverse events (2650 vs. 1500 pmol/8×108 red blood cells; associated with supplement use (p=0.033), and negatively p=0.02). However, the ranges of TG and meTIMP levels associated with smoking (p=0.006). In the summer, serum overlapped between the adverse event group and no levels of vitamin D did not differ between supplement users adverse event group, raising doubts about the usefulness of versus non-users. However, vitamin D levels were positively individual metabolite measurements in predicting adverse associated with supplement use (p=0.04) and negatively events. Furthermore, the authors recommend that associated with small intestinal involvement (p=0.005) 6-mercaptopurine therapy should be attempted in patients during the winter. Age, steroid use, calcium, and vitamin D with azathioprine intolerance except in cases where dietary intake did not correlate with vitamin D serum levels. intolerance relates to profound leukopenia. However, when the cut-off for vitamin D deficiency was The results of this study do not support the use of increased to 80 nmol/L 25-hydroxyvitamin D, 64% of thiopurine metabolite level measurements to determine the patients in late summer and 84% of patients in late winter course of therapy. If a patient were to experience an adverse were classed as being vitamin D deficient.

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This study design suffers from small sample size, and during the 1960s and 1970s), but is also likely to be affected thus the real effects of some of the variables tested may by the greater difficulties experienced with chronic intestinal have been missed. However, it does suggest that vitamin D diseases during family planning. Spontaneous abortions deficiency is common and that vitamin D supplementation is occurred in 13% of the pregnancies following IBD diagnosis effective in raising intake levels and serum levels. Therefore, (similar to the background population of 10–13%); routine supplementation should be considered in all CD however, the frequency of spontaneous abortion was patients, not just in those using corticosteroids. significantly lower in women not yet diagnosed with IBD (6.5%). Furthermore, spontaneous abortion was more Address for reprints: KD Cashman, Department of Food and Nutritional Sciences, University College, Cork, Ireland. Email: [email protected] frequent in women following diagnosis with CD (4.1% before diagnosis vs. 19.1% after diagnosis; p<0.001) than Does pregnancy change the disease course? in women diagnosed with UC (7.5% before diagnosis vs. A study in a European cohort of patients with 9.2% after diagnosis; non significant). Prior to IBD inflammatory bowel disease diagnosis, vaginal delivery rates were similar for patients Riis L, Vind I, Politi P et al.; European Collaborative with CD and UC (87.7% and 93.6%, respectively) but study group on Inflammatory Bowel Disease. were dramatically reduced following diagnosis (CD 28.6% Am J Gastroenterol 2006;101:1539–45. and UC 28.7%) with significantly more cesareans being performed. This appears to reflect a growing trend in the The aim of this study was to describe the effect of general population rather than the recommendation of pregnancy on disease outcome in a European cohort of cesarean delivery in the subgroup of CD patients with active IBD patients. Pregnancy before or during the course of perianal disease. Interestingly, half of the patients were IBD did not influence the disease phenotype and disease receiving 5-aminosalicylates or corticosteroids at the time of locations at time of the diagnosis. Moreover, in women conception or during pregnancy, but these treatments were who conceived ≥3 years after diagnosis, the numbers of not implicated in any of the four birth defects observed relapses per year were significantly reduced in the 3 years (in 1.4% of pregnancies prior to IBD diagnosis and 2.7% following pregnancy compared with the 3 years prior of pregnancies after IBD diagnosis), which were similar to to pregnancy. This suggests that the maternal immune the rate of birth defects in the general population. response to paternal human leukocyte antigens plays Two further points are very interesting. Firstly, pregnancy a role in pregnancy-induced remission of disease. before or during the course of IBD did not influence the disease phenotype and disease locations at time of the In IBD, the outcome of pregnancy is dependent mostly on the diagnosis. Specifically, terminal ileum involvement was activity of the disease. An increase in adverse events including similar for pregnant following diagnosis (n=38) and never fetal loss, stillbirth, preterm delivery, low birth weight, and pregnant following diagnosis (n=63) women (66% and developmental defects have been reported in patients with 52%, respectively; p=0.19). In addition, resection rates were active disease at the time of conception or during pregnancy. not significantly affected by pregnancy following diagnosis, Conversely, few data are available on the influence of compared with non-pregnancy following diagnosis pregnancy on disease course and IBD phenotype. (53% vs. 43%; p=0.37). Secondly, in women who conceived This interesting report describes the prospective ≥3 years after diagnosis and for whom there were sufficient evaluation over a 10-year follow-up period of 206 women follow-up data (n=40), the numbers of relapses per year with ulcerative colitis (UC) and 110 women with Crohn’s were significantly reduced in the 3 years following disease (CD) using a European IBD database. Of this cohort, pregnancy compared with the 3 years prior to pregnancy 266 women reported a total of 580 pregnancies; 191 (72%) (0.17 flares/year vs. 0.46 flares/year; p<0.001). women were pregnant for the first time prior to diagnosis This study appears to confirm mechanisms proposed in whereas the remaining 75 (28%) became pregnant after studies of other autoimmune conditions, which suggest that the discovery of the disease. the maternal immune response to paternal human leukocyte The analysis of patient files confirmed some predictable antigens plays a role in pregnancy-induced remission. information but also disclosed new and unexpected findings. Moreover, it also demonstrates that the improved knowledge Women having their first pregnancy after the diagnosis of of the disease permits better treatment and quality of life for IBD were older and had fewer children compared with the pregnant patients, who are no longer advised against ones who were pregnant before diagnosis. This may reflect a conception by clinicians or parents/family. general trend in the European population (several of the Address for reprints: L Riis, Department of Medical Gastroenterology, women who were pregnant before diagnosis were pregnant Herlev Hospital, Herlev Ringvej 75, 2730 Herlev, Denmark.

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Phenotype at diagnosis predicts recurrence documented here is relatively mild, with 57% of patients rates in Crohn’s disease experiencing only two recurrences in the 10-year period Wolters FL, Russel MG, Sijbrandij J et al. of analysis. This may represent anomalies in data collection Gut 2006;55:1124–30. or a genuinely milder spectrum of disease. However, the phenotypic data – although of interest – will not provide This study from the European Collaborative Study Group physicians with very much indication of the future course of on IBD (EC-IBD) attempted to identify factors at diagnosis the disease. It is possible that further investigation of genetic that would predict more rapid clinical recurrence of Crohn’s and serological data will provide additional details. disease and the need for surgery. A total of 358 patients Address for reprints: FL Wolters, Department of Gastroenterology and who were classified for phenotype at diagnosis were Hepatology, PO Box 5800, 6202 AZ Maastricht, The Netherlands. available for analysis of disease recurrence. Interestingly, Email: [email protected] the disease documented was relatively mild, with 57% of patients experiencing just two recurrences during the The bacteriology of biopsies differs between 10-year period of analysis. Although these phenotypic newly diagnosed, untreated, Crohn’s disease data are of interest, they do not provide significant and ulcerative colitis patients information regarding the future course of the disease. Bibiloni R, Mangold M, Madsen KL et al. J Med Microbiol 2006;55:1141–9. The stratification of risk is an important issue in the treatment of IBD. There has always been a need to give individual patients Using molecular biology methods, the authors of this the correct treatments; however, as more vigorous initial study found that distinct differences in the numbers and treatment regimens become popular, there is an increasing types of mucosa-associated bacteria are seen in Crohn’s need for reliable markers to identify individuals who will do disease and ulcerative colitis. less well with these regimens. The availability of such markers will enable a reduction of treatment-related morbidity and The advent of techniques allowing molecular analysis of the mortality rates, particularly in the era of biological therapies. intestinal flora has uncovered a hugely complex ecosystem This study from the European Collaborative Study Group with much greater diversity than might have been on IBD (EC-IBD) aimed to identify factors at diagnosis that considered using current bacterial culture techniques. would predict more rapid clinical recurrence of Crohn’s Indeed, only a minority of species found in the gut lumen disease (CD) and the need for surgery. Between 1991 and can be cultured by present methods. It appears to be a task 1993, the group assembled a prospective and uniformly of significant complexity to determine those elements of diagnosed inception cohort consisting of 2201 patients with the flora that may be driving inflammatory responses of the IBD from 12 European countries. There were originally mucosal immune system in individual patients. In general, 706 patients with CD. In the detailed follow-up, 10 out it is unlikely that a single species will emerge as dominant of 13 centers were able to achieve the required minimal inducers of IBD. response rate of 60%, giving a total of 380 patients. The authors of this study used the techniques of A total of 358 subjects who were classified for denaturing gradient gel electrophoresis (DGGE) and analysis phenotype at diagnosis were available for analyses of of clone libraries prepared using bacterial 16S RNA to detect recurrence; 262 (73.2%) patients had a first recurrence and specific groups of bacteria within mucosal biopsies in IBD 113 (31.6%) patients had a first surgical operation during patients, in comparison with those taken from healthy the first 10 years after diagnosis. The authors demonstrated subjects. Biopsies were obtained from 20 patients with that those with upper gastrointestinal disease at diagnosis newly diagnosed Crohn’s disease (CD), 15 individuals with had an increased risk of recurrence (hazard ratio 1.54, 95% ulcerative colitis (UC), and 14 healthy control subjects. confidence interval [CI] 1.13–2.10) and those who had CD A feature observed in the three groups was that biopsy- diagnosed at age ≥40 years experienced fewer recurrences associated profiles, as assessed by DGGE, were similar within (hazard ratio 0.82, 95% CI 0.70–0.97). Colonic disease an individual, regardless of the site of biopsy. An average of was a protective factor for surgery (hazard ratio 0.38, 25 densely stained DNA fragments were obtained from each 95% CI 0.21–0.69). Interestingly, more frequent surgery patient, showing essentially identical band patterns in biopsies was observed in patients from Copenhagen, Denmark from the terminal ileum and colon. Even in inflamed IBD tissue, (hazard ratio 3.23, 95% CI 1.32–7.89). band appearances were similar to those found in an analysis This study provides useful data from a Europe-wide of uninflamed biopsies from the same individual. In contrast, cohort of patients with IBD. It is clear that the disease the band patterns differed greatly between individuals.

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Using group-specific polymerase chain reaction techniques, nonsteroidal anti-inflammatory drug exposure. However, its the authors were able to exclude the presence of sulfate- potential ease of utilization for both clinicians and patients reducing bacteria, Helicobacter species, and the Mycobacterium are factors that may lead to an expansion of its use for the avium subspecies paratuberculosis in all cases. Patients with diagnosis of other gastrointestinal diseases or symptoms. UC had higher numbers of bacteria associated with biopsies The authors of this report retrospectively evaluated than patients with CD or healthy control subjects. Clone libraries consecutive unselected capsule endoscopy examinations generated from patients with CD and UC differed from each (37 children, 63 adults; age range 7–86 years), which were other, and those of normal controls. Unclassified species of performed at the Homerton Hospital, London, UK, during Bacteroidetes were notably more prevalent in CD than in 2003–2005 when there were no local referral guidelines the other groups, and may represent a target for future in place. This retrospective assessment for unrestricted studies. In addition, unclassified Verrucomicrobia species indications allowed the authors to identify diagnoses that may were found only in CD patients, while Porphyromonadaceae have been missed by adherence to recommended guidelines. were found only in patients with UC. The authors suggest Of the 100 patients, 30 underwent capsule endoscopy for that future metagenomic studies will be needed, in order to non-NICE recommended indications such as abdominal pain, study antigens present in such uncultivatable bacteria. vomiting, arthritis, poor growth, lymphangiectasia, and intussusceptions. Interestingly, pathology was found in Address for reprints: GW Tannock, Department of Agricultural, Food and Nutritional Science, University of Otago, PO Box 56, Dunedin, >60% of the 16 patients with abdominal pain (seven had New Zealand. Email: [email protected] inflammation/ulcers, one had angiodysplasia, and one had lymphoid nodular hyperplasia); in the remainder of the patients with abdominal pain, a normal bowel was present. One patient TREATMENT AND CLINICAL PRACTICE with vomiting had widespread lymphangectasia, one with poor growth showed lymphoid nodular hyperplasia, one with an indication of lymphangectasia had this confirmed, while one Guidelines for capsule endoscopy: subject with arthritis and one with intussusception had a diagnoses will be missed normal intestinal pattern. In five patients who underwent Makins R, Blanshard C. investigations for celiac disease, two demonstrated persistent Aliment Pharmacol Ther 2006;24:293–7. villous atrophy, one had jejunal inflammation, one had delayed gastric empting, and one had colitis, confirming the role of The authors of this study retrospectively evaluated the this examination for disease follow-up. No complications outcome of capsule endoscopy in 100 patients at the (capsule retention or obstructive symptoms) were reported. Homerton Hospital, London, UK. Their aim was to identify In conclusion, this procedure confirmed the supposed possible indications for the use of the procedure, which are diagnosis in 83 patients who were examined for standard not currently recommended by regulatory bodies. Capsule indications. Nevertheless, in the remaining 17 patients who endoscopy identified pathologies in >60% of patients with underwent capsule endoscopy for non-NICE-recommended abdominal pain who were examined for non-conventional indications, several pathologies were identified by chance indications, suggesting that this imaging modality may (eight mucosal ulcers, one worm infection, seven delayed be useful for an extensive range of indications. gastric empting, and one biliary bleeding); these may have been missed using conventional techniques. Moreover, Capsule endoscopy has revolutionized the management of capsule endoscopy was able to identify pathologies in >60% digestive tract diseases by providing a new, non-invasive, of patients with abdominal pain who were examined for and well-tolerated method for directly viewing the entire non-conventional indications. These results support the use small bowel mucosa. This method is considered superior to of this procedure as a safe and effective diagnostic method other standard imaging techniques. Thus far, it has been for an extended range of indications. In addition, new performed in >200 000 patients worldwide. At present, the lesions or patterns that are unexpectedly discovered with indications for its use are limited by the UK National Institute this direct vision of the bowel (unseen by other diagnostic of Health and Clinical Excellence (NICE) and the European tools), are crucial as they may uncover novel interactions Society of Gastrointestinal Endoscopy (ESGE) guidelines. The between gastrointestinal symptoms, signs, or diseases that approved indications comprise obscure gastrointestinal were previously not suspected to be related. bleeding, iron deficiency anemia, suspected Crohn’s disease, Address for reprints: R Makins, Department of Gastroenterology, small-bowel tumors, and, more recently, celiac disease Whipps Cross University Hospital, Whipps Cross Road, Leytonstone, follow-up and evaluation of pathologies secondary to London, E11 1NR, UK. Email: [email protected]

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Use of antibiotics in the treatment could represent a preferred tool for manipulating enteric of inflammatory bowel disease flora in patients with IBD. Preliminary data suggest their Perencevich M, Burakoff R. beneficial effects in the treatment of active ulcerative colitis Inflamm Bowel Dis 2006;12:651–64. (and pouchitis) and mild-to-moderate colonic CD, as well as for the prevention of post-operative IBD recurrence. There is increasing evidence that the gut flora has an Lastly, these authors present two interesting treatment important role in the pathogenesis of IBD. The authors algorithms for active CD, which may be useful for of this article review the current literature on the role clinical practice. of the intestinal flora and the use of antibiotics in the Address for reprints: R Burakoff, Division of Gastroenterology, management of patients with IBD. In addition, they Brigham and Women’s Hospital, Boston, MA 02115, USA. present a clinical model for the use of antibiotics for the Email: [email protected] treatment of IBD. Therapeutic efficacy of leukocytapheresis in a A growing volume of evidence indicates that the intestinal pregnant woman with severe active ulcerative colitis flora plays a pathogenic role in IBD; hence, manipulation of Okada H, Makidono C, Takenaka R et al. the luminal content of the gut using antibiotics or probiotics Digestion 2006;74:15–8. represents a potentially effective therapeutic option. Notwithstanding the fact that no specific infectious agent The authors of this report describe the use of weekly has been found to be behind the etiology of IBD, the altered leukocytapheresis for treatment of an exacerbation of composition of the gut microflora (dysbiosis), together ulcerative colitis (UC) in a pregnant woman. The patient with evidence for an aberrant immune response to this (in demonstrated a rapid recovery following the first susceptible individuals with genetic variants of the NOD2 treatment, with an almost complete remission within gene), has encouraged the use of antimicrobial agents. 2 weeks. After the fourth treatment, leukocytapheresis Antibiotics are effective for the treatment of the septic was discontinued due to the improvement in clinical complications of IBD, and their frequent use for perianal and activity index. No side effects were observed. post-operative Crohn’s disease (CD), and for the treatment Furthermore, the pregnancy continued normally and prevention of pouchitis are common in clinical practice. and the patient delivered a healthy baby. However, their optimal use as a primary therapy for active mild-to-moderate IBD remains controversial. Leukocytapheresis has recently been used to induce For these reasons, the authors of this interesting article remission in patients with ulcerative colitis (UC) who fail to reviewed the current antibiotic approaches to the manage- respond to corticosteroids. Three methods are currently used ment of patients with IBD, summarizing the efficacy and to perform leukocytapheresis: centrifugation, filtration, and side-effects data thus far reported. Whereas the results of passage through a granulocyte and monocyte removal studies with anti-tubercular agents remain inconclusive, column. The mechanisms by which these treatments induce antibiotic treatment, usually with metronidazole (active clinical remission are still not well understood; one against Gram-positive and Gram-negative anaerobes), or hypothesis is that the removal of peripheral activated ciprofloxacin (active against enteric Gram-negative and leukocytes would interrupt the communication between aerobic bacteria), or both, appears to be more effective in those cells and those attacking the colonic mucosa. The colonic compared with ileal IBD. Controlled trials are limited method of selective removal of granulocytes, monocytes, and, although both antibiotics appear to provide clinical and macrophages with columns has showed an benefit, definitive conclusions cannot be drawn and precise immunomodulating effect characterized by the reduction of therapeutic guidelines cannot be decisively recommended. pro-inflammatory cytokines, downregulation of L-selectin Moreover, because of the obvious need for lifelong or long- (which is responsible for the adhesion of leukocytes to the term therapy to maintain disease remission, the tolerability endothelial cells), and an increase of anti-inflammatory of antibiotics – which has been shown to be poor due to the cytokines including interleukin-1 receptor antagonist, tumor appearance of systemic side effects – remains an important necrosis factor soluble receptors I and II, and hepatocyte consideration. For these reasons, the use of non-absorbable growth factors. anti-bacterial agents such as rifaximin (which is poorly The authors of this case study are the first to report absorbed and is an effective antibiotic for most Gram-positive treatment of a pregnant woman with centrifugation and Gram-negative bacteria, including aerobes, anaerobes, leukocytapheresis for an exacerbation of UC. The patient and some mycobacterium) or probiotics are encouraging and was diagnosed as having an exacerbation of UC at the

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seventh week of pregnancy. After showing no response to 2003 study examining the use of intravenous cyclo- 1.5 g/day of mesalazine, she responded to 60 mg/day of phosphamide (CPM) in patients with acute, severe CD [1]. intravenous prednisolone in combination with mesalazine. CPM has been widely used in the treatment of systemic However, a reduction of the prednisolone dose to 40 mg/day vasculitides, Wegener’s granulomatosis, and systemic lupus was followed by an exacerbation of UC. The patient refused erythematosus for several years. Its mode of action is a any increase beyond 40 mg/day of prednisolone and direct cytotoxic effect of the metabolite, chloroacetaldehyde, additional immunosuppressive agents due to the increased on activated and resting lymphocytes. There has always risk of fetal abnormalities. Her clinical activity index was been some concern regarding the side effect profile of the 12 out of a possible 21. The patient was subsequently drug. Mesna (2-mercaptoethanesulfonic acid) is given recommended for weekly leukocytapheresis. Such a treatment routinely during the infusion to prevent hemorrhagic cystitis, has previously been performed in pregnant women, only for but there is a significant frequency of opportunistic the treatment of chronic myeloid leukemia. Side effects of infections, neutropenia, and other side effects. these procedures are those connected with an extracorporeal The authors enrolled 16 patients with steroid-refractory circulation, with the possibility of a variation in blood volume CD. All had suffered a relapse and were inpatients who had of approximately 400–500 mL during the procedures along failed to respond to 7 days of treatment with intravenous with a slight reduction of hemoglobin levels, which could be steroids. Their CD activity index (CDAI) values ranged from critical for these patients. This patient did not experience any 228–550. All were treated with 750 mg CPM. Treatments side effects. Furthermore, she demonstrated a rapid and were given monthly; all patients received two infusions and, dramatic recovery following the first treatment (decrease in if they responded, received further infusions. The median mucus-containing bloody stools), with an almost complete number of infusions was four. Some patients received six remission within 2 weeks. After the fourth treatment, infusions. The patients were also started on azathioprine or leukocytapheresis was discontinued as the clinical activity methotrexate if they were not already taking them. Seven of index had decreased to 4; 2 weeks later the patient was the 16 subjects were described in the current authors’ discharged from hospital. Pregnancy continued normally and previous report of short-term CPM efficacy [1]. It is of note the patient delivered a healthy baby by uncomplicated that the authors defined a response as a rather modest vaginal delivery, while maintaining remission of UC. 70-point reduction in CDAI. At 8 weeks following the first treatment, 13 of the Address for reprints: H Okada, Department of Medicine and Medical Science Okayama University Graduate School of Medicine and 16 patients had achieved clinical remission (CDAI ≤150). Dentistry 2-5-1, Shikata-cho, Okayama 700-8558, Japan. There was a steady reduction in the mean CDAI over this Email: [email protected] time period. Once achieved, remission was maintained for a median of 19 months. There were particularly good Cyclophosphamide pulse therapy followed responses in patients who had extra-intestinal manifestations by azathioprine or methotrexate induces of CD and it is also noteworthy that there appeared to be long-term remission in patients with better responses in those who were immunomodulator naïve. steroid-refractory Crohn’s disease Adverse events occurred in six patients and comprised Schmidt C, Wittig BM, Moser C et al. opportunistic infections (specifically candidal esophagitis and Aliment Pharmacol Ther 2006;24:343–50. a urinary tract infection) and relatively mild neutropenia. In summary, the authors have demonstrated efficacy of The authors of this study report the results of a small CPM in a small group of patients with steroid-refractory, number of patients with steroid-refractory Crohn’s acute CD. This group of subjects represents a highly selected disease (CD) who received monthly cyclophosphamide population of CD patients. Moreover, they were treated by (CPM). At 8 weeks after the first infusion of CPM, a study group that has considerable experience with the use >80% of the patients were in clinical remission, which of this drug. Further assessment by randomized controlled was maintained for a median of 19 months. These data trial is required before definitive conclusions regarding the suggest that CPM may be a useful adjunctive treatment drug’s efficacy can be made; nonetheless, it may represent in this subgroup of CD patients, although larger, a useful adjunct therapy in a small number of individuals. 1. Stallmach A, Wittig BM, Moser C et al. Safety and efficacy of intravenous pulse controlled trials are required. cyclophosphamide in acute steroid refractory inflammatory bowel disease. Gut 2003;52:377–82. The search for an effective immunosuppressive regimen for Address for reprints: A Stallmach, Department of Gastroenterology, the treatment of diseases such as Crohn’s disease (CD) Hepatology and Infectiology, Friedrich Schiller-University, Erlanger Allee continues. Schmidt et al. report on an extension of their 101, 07740 Jena, Germany.Email: [email protected]

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EPIDEMIOLOGY more, even though data are limited, the incidence of pediatric IBD in developing countries appears to be lower compared with industrialized countries. Although all of Epidemiology of inflammatory bowel diseases the published epidemiological studies have led to better in childhood understanding of IBD, most of these focused on the Ravikumara M, Sandhu BK. incidence/prevalence of disease, with substantial local and Indian J Pediatr 2006;73:717–21. regional variables including geographical, ethnic, and demographic influences. In addition, the different inclusion This review evaluated the current opinion on incidence, criteria or design of many studies resulted in data and age and gender distribution, geographical variation, conclusions that could not be directly compared between trends over time, presenting features, and disease studies; implications for clinical practice are therefore limited. distribution, from analysis of the epidemiological For these reasons, the IBD working group of the European studies of pediatric IBD published to date. Society of Paediatric Gastroenterology, Hepatology and Nutrition published the “Porto Criteria”, which detail The incidence of pediatric IBD has been increasing in consensus diagnostic criteria for the management of Western countries in recent decades, and now comprises childhood IBD. The aim was to prospectively create a almost 30% of the total cases of IBD. In parallel with the uniform database to characterize the incidence, prevalence, overall population trends, younger people showed a disease behavior, genetic characteristics, risk factors, drug predominant colonic Crohn’s disease (CD) compared with therapy, health outcomes, social and economics aspects of ulcerative colitis (UC), with a familial pattern of disease the disease, in order to better understand the disease. concordance. An atypical clinical manifestation that differs This review highlighted discrepancies between from the classical abdominal pain, diarrhea, and weight loss epidemiological studies of pediatric IBD, and underlined the symptoms of CD has been described in a high proportion of difficulties in obtaining homogeneous and comparable data. these patients. Many studies have reported an unexplained Addressing these differences in order to produce uniform preponderance of males with early onset CD (with an equal results that may be validated in other studies is extremely gender distribution in pediatric UC) and an increased important as it could lead to improvement in the clinical amount of indeterminate colitis, although these findings management and understanding of a disease, which begins are not universal. Understanding the difference between at a critical period of growth and development in childhood. these forms of disease is crucial as there are significant Address for reprints: BK Sandhu, Department of Pediatric Gastroenterology, implications, including the choice of medical treatment, Bristol Children’s Hospital, Upper Maudlin Street, Bristol, BS2 8BJ, UK. timing of surgery, prognosis, and disease course. Further- Email: [email protected]

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Las Vegas, NV, USA, 20–25 October, 2006

Corey A Siegel1 and David T Rubin2 1Section of Gastroenterology and Hepatology, Inflammatory Bowel Disease Center, Dartmouth–Hitchcock Medical Center, Dartmouth Medical School, Lebanon, NH; 2University of Chicago Hospitals, Inflammatory Bowel Disease Center, Chicago, IL, USA

The American College of Gastroenterology (ACG)’s Annual and no new safety concerns were observed. No delayed- Scientific Meeting for 2006 took place in Las Vegas, hypersensitivity reactions occurred over the course of NV, USA, from October 20–25, 2006. The Vegas strip the study, and the presence or absence of human anti- was an exciting backdrop for gastroenterologists to get chimeric antibodies (HACA) did not influence efficacy. updated on the “state of the art” advances in the care The authors concluded that adalimumab rapidly and of patients with IBD. Here, we present the highlights of significantly induced clinical remission and response in this the scientific presentations related to the treatment and patient population and that there was no cross-reactivity diagnosis of IBD, along with the “bottom line” take-home to antibodies against infliximab. message from each. Adalimumab appears to be a safe and effective option Therapeutics in CD patients who have lost response or had a hyper- Biological therapy sensitivity reaction to infliximab. William Sandborn (Mayo Clinic, Rochester, MN, USA) commenced the IBD presentations with results of the GAIN (Gauging Adalimumab Efficacy in Infliximab Non-Responders) Further data on adalimumab from the CHARM (Crohn’s study [1]. GAIN was a randomized, controlled trial of Trial of the Fully Human Antibody Adalimumab for adalimumab, a self-injectable, fully human anti-tumor Remission Maintenance) study were presented by Stephen necrosis factor (anti-TNF) monoclonal antibody in patients Hanauer (University of Chicago, Chicago, IL, USA). CHARM with moderate-to-severe Crohn’s disease (CD) who had was a 56-week study of the maintenance of remission previously received infliximab but had either lost the of CD, which was initially presented in Los Angeles, CA, response to the drug or developed a hypersensitivity USA, in May 2006 at Digestive Disease Week [2]. The reaction. This was the first trial studying the efficacy and investigators of this post hoc analysis evaluated the benefit safety of switching from one anti-TNF agent to another in of concomitant immunosuppressant therapy (IMM) while CD. A total of 325 patients were randomized to receive patients received maintenance injections (every 2 weeks) of either adalimumab 160 mg subcutaneously at week 0 and adalimumab for 1 year [3]. Of 778 randomized patients, 80 mg subcutaneously at week 2, or placebo at both time 58% responded to treatment with adalimumab at 4 weeks. points. The primary endpoint was clinical remission at week By 56 weeks, 41% of the responders receiving IMM were in 4. At this time point, 21% of patients in the adalimumab clinical remission compared with 49% who were not arm were in clinical remission compared with 7% of those receiving IMM; 17% of those receiving placebo were in who received placebo (p≤0.001). In addition, 38% of remission. The conclusion of this post hoc analysis was patients responded to treatment (a decrease in CD activity that adalimumab is superior to placebo in inducing index [CDAI] of ≥100 points) compared with 25% in the remission of moderate-to-severely active CD irrespective of placebo group (p≤0.01). The medication was well tolerated concomitant IMM.

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Adalimumab may be equally effective with or without held true for patients who had previously failed infliximab concomitant immunosuppression. Additional data therapy. There were no cases of PML in this follow-up. are needed to determine the long-term outcomes of this approach. Patients achieving remission with natalizumab are highly likely to maintain that remission with ongoing treatment for up to 2 years. Certolizumab pegol is a new anti-TNF agent that will, most likely, soon be available for our patients. The previously presented PRECiSE 2 (Pegylated Antibody in Crohn’s disease 5-aminosalicylates Safety and Efficacy Fragment Evaluation) trial found that Information on 5-aminosalicylates (5-ASAs) presented at ACG certolizumab pegol has a similar efficacy to infliximab and included effects of delayed-release mesalamine on mucosal adalimumab for maintenance of remission of moderate-to- healing, and safety data for the new Multi Matrix System severely active CD [4]. At this year’s ACG, Dr Sandborn and (MMX™, Shire Pharmaceuticals, Wayne, PA, USA; licensed colleagues presented a unique subgroup analysis from from Giuliani S.p.A., Milan, Italy) delivery of mesalamine. PRECiSE 2 that evaluated response rates stratified by disease Pooling data from two previously presented Phase III, duration [5]. With a similar trial design to ACCENT 1 multicenter, randomized, double-blind controlled studies, (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New David Rubin (University of Chicago, Chicago, IL, USA) and Long-Term Treatment Regimen) and CHARM, all patients colleagues reported rates of mucosal healing in moderately initially received open-label drug, and then the responders active ulcerative colitis (UC) using delayed-release oral (68%) were randomized to receive maintenance certolizumab mesalamine at either 2.4 g/day or 4.8 g/day [8]. They found pegol or placebo every 4 weeks. At 26 weeks, patients who that at 6 weeks, 67% of patients who had achieved treatment had had CD for <1 year achieved response and remission success also achieved mucosal healing. This was independent rates of 89% and 68%, respectively. This is in contrast to of dose. Interestingly, there was a poor correlation between response and remission rates of 57% and 44%, respectively, mucosal healing and symptom improvement. for patients who had been diagnosed with CD for ≥5 years. These data suggest benefit of early, rather than late, use of Treatment with mesalamine can induce mucosal healing certolizumab pegol. in UC as early as 3 and 6 weeks. However, endoscopic healing and improvement in UC symptoms were not These data mirror the higher therapeutic response rates well-correlated. seen in pediatric IBD patients (compared with adults) and lend support to the concept of “top-down” therapy; that we can improve outcomes by using Gary Lichtenstein (University of Pennsylvania, Philadelphia, biological therapy earlier in the course of CD. PA, USA) and an international group of collaborators presented safety data on MMX mesalamine used in UC patients at either 2.4 g/day or 4.8 g/day [9]. They pooled data from three 8- Natalizumab is a monoclonal antibody designed to bind week studies that included 560 patients with mild-to-moderate α4 integrin, which is a key intestinal adhesion molecule. It UC who were treated with MMX mesalamine and 179 patients has previously been shown to induce and maintain remission who were treated with placebo. Rates of serious adverse events in patients with moderately-to-severely active CD, but safety were very low in all groups and similar to placebo. Only concerns based on the report of three cases of progressive pancreatitis (two cases, one in each mesalamine group) was multifocal leukoencephalopathy (PML) led to a hold on seen more commonly in the MMX mesalamine group, but this further clinical trials. At this meeting, Remo Panaccione and is a previously described rare side-effect of mesalamine. colleagues (University of Calgary, Calgary, AB, Canada) presented follow-up, open-label extension data from the MMX mesalamine appears to be well tolerated in previously reported ENACT-2 (Evaluation of Natalizumab as patients with UC up to 4.8 g/day. Continuous Therapy) trial [6,7]. The purpose of this study was to examine the ability of natalizumab to maintain remission for an additional year after the conclusion of ENACT-2 Novel treatments (2 years in total). With continued infusions, 86% of patients There was a paucity of data on novel IBD drug therapies in remission at 1 year successfully maintained this remission presented at this meeting, but two “procedural” treatments for 2 years. This high percentage of remission maintenance appear to show promise for patients refractory to standard

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interventions. For the most refractory, end-stage patients multicenter, observational study enrolled 323 patients with IBS with CD, Kareem Abu-Elmagd and colleagues (University of and 241 controls (no symptoms of IBS and no history of IBD). Pittsburgh, Pittsburgh, PA, USA) reported their experience with They were tested for the presence of perinuclear antineutrophil intestinal transplant (IT) in patients with intestinal failure [10]. cytoplasmic antibodies, immunoglobulin A (IgA) and IgG anti- Of their series of 196 patients who underwent IT for various Saccharomyces cerevisiae antibodies, and anti-Escherichia coli causes of intestinal failure, 38 had a history of complicated outer membrane porin C (anti-OmpC). A total of 31% of IBS CD. All CD patients were recalcitrant to previous therapy, patients and 28% of the control population had measurable had undergone multiple surgeries, and failed total parenteral titers to at least one marker (p=0.6). The high false-positive nutrition (TPN). The overall survival of CD patients undergoing rate (30% overall) and low positive predictive value (0.62%) IT was 85% at 1 year, and 62% at 3 years. Survival rates results in a low specificity for IBD serological testing in this improved to 92% at 1 year and 78% at 3 years with the patient population. The authors concluded that serological addition of induction immunosuppression, which was used in markers of IBD are frequently present in patients without CD the more recent IT recipients. All survivors achieved full or UC. Of note, they did not report the test performance of nutritional autonomy with an unrestricted oral diet. Disease combinations of markers or how new computer heuristic recurrence occurred in 7.5% of recipients at 18 months. algorithmic approaches may impact these results.

Intestinal transplantation is an option for the most These results reinforce the importance of understanding refractory CD patients who have failed medical and the population prevalence of IBD when interpreting surgical therapy and can no longer be maintained serology results, and suggest that in a low-risk patient on TPN, but is not a “cure” for their disease. population, serological testing may not be an effective screening tool for IBD.

Perhaps the most interesting presentation regarding IBD treatment at the conference was that by Jane Onken (Duke A group from the Mayo Clinic (Rochester, MN, USA) Clinical Research Institute, Durham, NC, USA). Dr Onken and examined cumulative radiation exposure from radiological colleagues studied the effect of PROCHYMAL™ (Osiris testing in patients with CD and UC [15]. Their aim was to Therapeutics Inc, Baltimore, MD, USA), ex vivo cultured adult quantify the amount of ionizing radiation received by IBD human mesenchymal stem cells, for patients who had CD that patients over the course of their disease. The significance is was refractory to standard therapeutic options [11]. that higher doses of radiation have been associated with an PROCHYMAL has anti-TNF activity, and has previously been increased risk of cancer. They reported on an Olmsted County shown to induce colonic mucosal healing in patients with acute inception cohort of 220 patients with IBD (115 with CD and graft-versus-host disease [12]. They reported open-label data on 105 with UC) who were diagnosed between 1990 and 2001. nine patients who received two infusions of PROCHYMAL, The mean follow-up time was just over 10 years. The mean administered 7 days apart. Three patients (33%) achieved the cumulative effective radiation dose received from radiographic primary endpoint of clinical response (a decrease in CDAI of ≥100 testing over this 10-year period was 36.9 millisieverts (mSv). points) by day 14. All three of these patients had previously failed As a comparison, the average annual radiation exposure in infliximab treatment. All infusions were well tolerated and the USA is 3.0 mSv. Patients with CD had a significantly there were no treatment-related serious adverse events. higher mean dose than those who had UC, primarily resulting from nearly twice the number of abdominopelvic PROCHYMAL may be a promising novel therapy for computed tomography scans. When annualizing their data, patients with CD, but further safety and pharmacokinetic the authors found that the radiation exposure in the IBD data are needed before its potential is fully understood. population was not much higher than the annual background dose in the US population. However, a subset of IBD patients had substantially higher exposure. Diagnostics Scientific presentations of interest related to the evaluation of To decrease a possible increased carcinogenic risk, IBD patients included data on the utility of serological markers alternative imaging modalities (e.g. ultrasound or and radiation exposure associated with radiographic imaging. magnetic resonance imaging) should be considered for A collaborative group studied the diagnostic accuracy of IBD IBD patients destined to undergo multiple radiographic serological markers in patients meeting Rome II criteria [13] tests (i.e. younger or sicker patients). for irritable bowel syndrome (IBS) [14]. This prospective,

INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 123 COREY A SIEGEL AND DAVID T RUBIN

3. Hanauer SB, D’Haens GR, Colombel JF et al. Sustained clinical remission in patients with Conclusion moderate to severe Crohn’s disease with adalimumab, regardless of anti-TNF history Presentations at ACG 2006 focused on optimizing available or concomittant immunosuppressant threrapy. Am J Gastroenterol 2006;101(9):S457. 4. Schreiber S, Khaliq-Kareemi M, Lawrance I et al. Certolizumab pegol, a humanised anti- biological therapies. While we await further data on novel TNF PEGylated Fab’ fragment is safe and effective in the maintenance of response and approaches for the treatment of IBD, we hope that this new remission following induction in active Crohn’s disease: a Phase III study (PRECiSE). Gut 2005;54(Suppl VII):A82. information will translate into more effective and safe use of 5. Sandborn WJ, Colombel JF, Panes J et al. Higher remission rate and maintenance of the currently available (and hopefully soon to be available) response rates with subcutaneous monthly certolizumab pegol in patients with recent- medications. We look forward to ACG 2007 in Philadelphia, onset Crohn’s disease: Data from PRECiSE 2. Am J Gastroenterol 2006;101(9):S434. 6. Sandborn WJ, Colombel JF, Enns R et al. Natalizumab induction and maintenance therapy PA, USA. for Crohn’s disease. N Engl J Med 2005;353:1912–25. 7. Panaccione R, Colombel JF, Enns RA et al. Natalizumab maintains remission for 2 years in patients with moderately to severely active Crohn’s disease and in those with prior Disclosures infliximab exposure: Results from an open-label extension study. Am J Gastroenterol Dr Siegel has served on advisory boards of Abbott and UCB 2006;101(9):1152. 8. Rubin DT, Yacyshyn BR, Ramsey D et al. Endoscopically measured mucosal healing Pharmaceuticals and on speakers’ bureaus for Prometheus Labs, correlated with response to therapy in moderately active UC. Am J Gastroenterol Salix Pharmaceuticals, and Shire, has served as a consultant for Elan 2006;101(9):S442. 9. Lichtenstein GR, Kamm MA, Sandborn WJ et al. MMX mesalamine is well tolerated in Pharmaceuticals and has received grant support from Procter and patient with active mild-to-moderate ulcerative colitis: pooled analysis of adverse events Gamble. Dr Rubin has served as a consultant for Abbott, Given Imaging, from three randomized studies. Am J Gastroenterol 2006;101(9):S432. 10. Abu-Elmagd K, Wu T, Bond G et al. Intestinal transplantation for end stage Crohn’s Procter & Gamble, Prometheus Labs, Salix, Shire, and UCB Pharmaceuticals, disease: therapeutic efficacy and risk of recurrence. Am J Gastroenterol 2006;101(9):S468. and has served on speakers’ bureaus for Abbott, Procter and Gamble, 11. Onken J, Gallup D, Hanson J et al. Successful outpatient treatment of refractory Crohn’s disease using adult mesenchymal stem cells. Late breaking abstract. Presented at ACG Prometheus Labs, and Salix Pharmaceuticals. Dr Rubin has received 2006; October 20–25, 2006; Las Vegas, NV, USA. grant support from Given Imaging and Prometheus Labs. 12. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815–22. 13. Thompson WG, Longstreth GF, Drossman DA et al. Functional bowel disorders and References functional abdominal pain. Gut 1999;45(Suppl 2):II43–7. 1. Sandborn WJ, Rutgeerts P, Enns RA et al. Adalimumab rapidly induces clinical remission 14. Andrews AH, Cash BD, Lee DH et al. The high false positive rate of inflammatory and response in patients with moderate to severe Crohn’s disease who had a secondary bowel disease serologic markers in patients with irritable bowel syndrome. failure to infliximab: Results of the GAIN study. Am J Gastroenterol 2006;101(9):S448. Am J Gastroenterol 2006;101(9):S475. 2. Colombel JF, Sandborn WJ, Rutgeerts P et al. Adalimumab induces and maintains clinical response and remission in patients with active Crohn’s disease: results of the CHARM trial. 15. Peloquin JM, Pardi DS, Sandborn WJ et al. Exposure to diagnostic ionizing radiation Program and abstracts of the Digestive Disease Week; May 20–25, 2006; Los Angeles, in a population-based cohort of patients with inflammatory bowel disease. CA, USA. Am J Gastroenterol 2006;101(9):S448.

124 INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 MEETING REPORT 125 3 per day with no ≤ Classification of UC based on 3 2007 : “Extent of Disease”. The extent O 7 N OL V Three examples of ECCO guidelines on the management Three ONITOR ECCO Statement management. Disease of UC influences the patient’s modality and extent influences the treatment is initiated determines if oral and/or topical therapy start and (EL1b, RG B). Disease extent influences of surveillance (EL2, RG B). Therefore, frequency to extent of disease is a classification according classification (EL5, RG D). The preferred recommended proctitis is an endoscopic classification into ulcerative left-sided colitis (up to the (limited to the rectum), maximal and extensive colitis, and by splenic flexure) extent upon follow-up (EL5, RG D). ECCO Statement: disease severity is useful for clinical practice and dictates management (EL1b, RG B). Disease the patient’s modality and severity influences the treatment therapy determines if no, oral, intravenous, or surgical is initiated. Indices of disease severity have not been imaging and adequately validated. Clinical, laboratory, endoscopic parameters, including histopathology assist physicians in patient management (EL 2; RG B). There The best is no fully validated definition of remission. is a combination of clinical way of defining remission parameters (i.e. stool frequency bleeding) and a normal mucosa at endoscopy (EL5, RG D) (majority vote). M consensus meeting prior to UEGW with 61 European consensus meeting prior to UEGW Consensus was opinion leaders and experts on IBD present. defined as >80% agreement. The full publication of these guidelines given below. of UC are is expected early in 2007. ISEASE D OWEL B NFLAMMATORY I

Recently, ECCO published European evidence-based ECCO published European Recently, consensus guidelines on the diagnosis and management of consensus guidelines on the diagnosis ECCO is a forum for specialists disease (CD) [1–3]. Crohn’s Stange (Robert countries. Eduard 22 European in IBD from Bosch Hospital, Stuttgart, Germany), the driving force behind the consensus guidelines on CD, has now repeated [4]. The aim of the UC consensus was for UC this exercise perspective on the management of a European to promote the disease. The main statements and recommendations The during the last day of the congress. presented were published was very similar to that of the previously process parties for 13 topics consensus on CD [1–3]. Working (including diagnosis, classification, active disease, maintenance of disease, complementary and alternative and pouchitis) circulated medicine, pediatrics, pathology, “expert opinion”. The content to quantify questionnaires on systematic literature was based of the questionnaires statements with an Oxford Finally, on each topic. search were evidence level (EL) and guideline recommendations drafted [5]. All statements, levels of evidence, and grades during a 2-day reviewed (RG) were of recommendation ECCO UC consensus guidelines in their generated to assist physicians Clinical guidelines are of patients. Although they have no automatic daily care individual not intended to override legal mandate and are will, in general, clinical judgment, evidence-based guidelines good medical care. assure The annual United European Gastroenterology Week (UEGW) Week Gastroenterology The annual United European 21–25 October from 2006 was held in Berlin, Germany 103 countries were 2006. A total of 9955 people from highlights several report for the meeting. This registered on some of the most active presented abstracts that were and also discusses the European of IBD research, areas (ECCO) consensus and Colitis Organisation Crohn’s details of which were guidelines for ulcerative colitis (UC), during the last day of the congress. presented Séverine Vermeire Leuven, Belgium Hospital Gasthuisberg, University Department of Gastroenterology, Berlin, Germany, 21–25 October 2006 21–25 Berlin, Germany, (UEGW) 2006 2006 (UEGW) United European Gastroenterology Week Gastroenterology European United SÉVERINE VERMEIRE

ECCO Statement: Left-sided active UC of mild-to- Figure 1. Induction study design of the GAIN (Gauging moderate severity should initially be treated with topical Adalimumab Efficacy in Infliximab Non-Responders) study. aminosalicylates [EL1b, RG B] combined with oral mesalazine ≥2 g/day [EL1a, RG A]. Topical steroids or Double-blind, mesalazine alone are also effective, but less effective placebo-controlled period than combination therapy [EL1b, RG B]. Topical Week Week Week mesalazine is more effective than topical steroid [EL1a, 0 2 4

RG A]. Oral aminosalicylates alone are less effective n=166 Primary endpoint [EL1a, RG A]. Systemic corticosteroids are appropriate Placebo Placebo 325 if symptoms of active colitis do not respond rapidly to Patients mesalazine [EL1b, RG C]. Severe left-sided colitis is usually an indication for hospital admission for intensive n=159 treatment with systemic therapy [EL1b, RG B]. 160 mg 80 mg adalimumab adalimumab

IBD therapeutics Besides new and interesting data on the available and upcoming anti-tumor necrosis factor (anti-TNF) biological Adalimumab Efficacy in Infliximab Non-Responders) study agents (infliximab, adalimumab, and certolizumab pegol), assessed the efficacy and safety of adalimumab versus placebo and 5-aminosalicylates, this year’s UEGW also reported for the induction of clinical remission in patients with some encouraging results for some novel molecules for moderate-to-severe CD (CD activity index [CDAI] 220–450) treatment of CD and UC. A summary of these is presented who had lost the response or had reactions to infliximab. The in the following section. results were presented by Paul Rutgeerts on behalf of the GAIN study investigators [8]. This was a 4-week, double-blind, Anti-TNF-agents placebo-controlled trial with patients randomized to either Walter Reinisch and colleagues (University of Vienna, Vienna, adalimumab (160 mg) at week 0 and 80 mg at week 2, or Austria) presented the results of the impact of infliximab on placebo at weeks 0 and 2 (Fig. 1). The primary endpoint, UC-related hospitalizations and UC-related hospitalizations defined as the induction of remission (CDAI <150) at week 4, requiring high-dose corticosteroids (a surrogate measure of was reached in 21% of the adalimumab-treated patients acute, severe flare of UC requiring hospitalization in ACT 1 compared with just 7% of patients that received placebo (Active UC Trial 1) and ACT 2 [6]. A total of 728 patients (p<0.001). Secondary endpoints included a 70 (CR-70) were included in the ACT studies, the results of which were or 100 (CR-100) point decrease in the CDAI. A CR-70 and published in 2005 [7]. At week 30 (for both studies CR-100 response was seen in 52% and 38% of patients combined), infliximab-treated patients showed significantly treated with adalimumab, and 34% and 25% of patients less UC-related hospitalizations (2.7/100 patients) compared receiving placebo, respectively (p<0.01). The effect was with patients receiving placebo (7.8/100 patients; p=0.025). observed as early as week 1 with response rates of 35% and At week 54 (ACT 1 patients only), the respective numbers 21% for adalimumab and placebo, respectively (p<0.005). of UC-related hospitalizations were 4.1/100 and 11.6/100 Adalimumab was well tolerated with an overall lower incidence (p=0.055). Therefore, maintenance therapy with infliximab of adverse events compared with placebo. is associated with a reduced number of hospitalizations Despite their extensive use, the precise mechanisms requiring high-dose corticosteroids. of action of all anti-TNF agents remain incompletely As a result of its chimeric properties, treatment with understood. Although complement activation, antibody- infliximab may be associated with antibody formation and risk dependent cell mediated cytotoxicity (ADCC), and induction of acute infusion reactions and loss of response. Treatment of apoptosis have been shown to be important in explaining with the fully human monoclonal antibody adalimumab may the mechanisms of action of infliximab and adalimumab, be effective and safe in these patients. Adalimumab is an certolizumab pegol does not induce ADCC or apoptosis but immunoglobulin G1 (IgG1) isotype monoclonal antibody that has shown similar efficacy in recent clinical trials in CD. This is structurally identical to naturally occurring human antibodies, has led to further investigations of the mechanisms of action and is therefore less likely to engender an immune response. Its of these drugs. It has been suggested that anti-TNF agents half-life is 12–14 days, and the drug is administered every 2 induce signaling via membrane-bound TNF-α, which results weeks by subcutaneous injection. The GAIN (Gauging in an inhibitory effect on lipopolysaccharide (LPS)-induced

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cytokine production. Gianluca Fossati and colleagues (UCB, Stefan Schreiber (Christian Albrechts Universität, Kiel, Slough, Berkshire, UK) compared certolizumab pegol (an Germany) and colleagues presented data on the safety and antibody Fab’ fragment conjugated with polyethylene tolerability of MMX mesalazine in patients with mild-to- glycol) with other anti-TNF agents in terms of their effect moderate UC, which were pooled from the three studies on LPS-stimulated production of TNF-α and interleukin-1β (SPD476-202, SPD476-301, and SPD476-302). A total of (IL-1β) [9]. Human monocytes were selected from the 560 patients received MMX mesalazine 2.4 g/day (n=191), peripheral blood of healthy blood donors and were pre- 4.8 g/day (n=190), or placebo (n=179). Only 10 patients incubated with etanercept, certolizumab pegol, adalimumab, (<2%) reported 13 serious adverse events (seven with infliximab, or control buffer. After washing, monocytes were placebo, four with MMX mesalazine 2.4 g/day [aggravated then incubated with LPS or buffer, and supernatants were UC, pancreatitis, perianal abscess, and urinary retention], collected to measure cytokine levels using an enzyme-linked and two with MMX mesalazine 4.8 g/day [viral gastroenteritis immunosorbent assay. Etanercept was much less efficient and pancreatitis]) [14]. than all other anti-TNF agents in inhibiting LPS-stimulated A poster by Dr Kamm and colleagues described 4-month production of TNF-α and IL-1β, while certolizumab interim safety data from an open-label, extension study appeared to be 100-fold more potent than adalimumab (SPD476-303) to evaluate the long-term safety and tolerability or infliximab at inhibiting the release of TNF-α and IL-1β of MMX mesalazine. Patients who were not in remission by monocytes. The potent inhibition by certolizumab pegol following the 8-week SPD476-301 and SPD476-302 studies of cytokine production by monocytes may represent an received MMX mesalazine 4.8 g/day for 8 weeks (acute important mechanism of action in CD. phase). Subjects from the SPD476-301, -302, or -303 studies who achieved remission were randomized in an extension Mesalazine study to receive MMX mesalazine 2.4 g/day for 12 months. A number of presentations from Michael Kamm (University At 4 months, 146/458 patients who entered the maintenance College London, London, UK) and colleagues discussed pivotal phase reported at least one treatment-emergent adverse data from the multicenter, randomized, placebo-controlled, event (TEAE), the majority of which were gastrointestinal and Phase III trials (SPD476-301 and SPD476-302) of MMXTM were mild or moderate. A total of 55 treatment-related adverse (Shire Pharmaceuticals, Wayne, PA, USA; licensed from Giuliani events and 21 serious adverse events were reported [15]. S.p.A., Milan, Italy) mesalazine in which patients with mild-to- These Phase III studies demonstrate that MMX mesalazine moderate UC (UC disease activity index [DAI] 4–10) were is well tolerated, with a safety profile similar to other randomized to receive MMX mesalazine 2.4 g/day once daily mesalazine formulations, and is effective for the induction (study 302) or twice daily (study 301), MMX mesalazine 4.8 of remission of mild-to-moderate UC at both doses tested. g/day once daily (both studies), or placebo. The MMX form- It is anticipated that MMX mesalazine may improve patient ulation of mesalazine utilizes Multi Matrix System technology to compliance and enhance the overall treatment success. delay and extend delivery of the active drug throughout the Chyon Yeh (Procter and Gamble Pharmaceuticals, Mason, colon. The primary endpoint of these studies was clinical and OH, USA) and colleagues assessed the effects of mesalamine endoscopic remission defined according to the criteria described on creatinine clearance using 6-week data from the ASCEND I in the previously published Phase II study of MMX mesalazine and II (Assessing the Safety & Clinical Efficacy of a New Dose in patients with mild-to-moderate UC (SPD476-202) [10]. In of 5-ASA), multicenter, randomized, Phase III clinical trials of the two Phase III trials, at week 8, remission was achieved by a delayed-release oral mesalamine (Asacol®, Procter & Gamble significantly greater number of patients receiving MMX Pharmaceuticals, Cincinnati, OH, USA) in patients with mesalazine 2.4 g/day (37.2% [64/172]; p<0.001) or MMX moderate UC. In patients with predominantly normal renal mesalamine 4.8 g/day (35.1% [61/174]; p<0.001) compared function at baseline, no detrimental effects on creatinine with placebo (17.5% [30/171]) [11]. Similar findings were clearance were observed [16]. A separate presentation by Dr obtained from patients with moderate disease, indicating that Yeh and colleagues demonstrated that this modified-release MMX mesalazine is effective for the induction of remission of oral mesalamine induced mucosal healing in >50% of patients both mild and moderate UC [12]. with moderately active UC (a total of 391 patients from A post hoc analysis of pooled data from SPD476-301 and ASCEND I and II were included in this analysis) [17]. SPD476-302 found that a significant induction of remission was achieved in patients with mild-to-moderate UC who Novel molecules and approaches for Crohn’s disease switched from a low-dose formulation of mesalamine (or who CCX282-B were previously 5-ASA-naïve/had discontinued 5-ASAs) to Satish Keshav and colleagues (University College London, subsequent treatment with MMX mesalazine [13] London, UK) presented the results of a Phase II study of

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CCX282-B, an orally active inhibitor of the chemokine Novel molecules for treatment of UC receptor, CCR9, in moderate-to-severe CD [18]. The ligand Phosphatidylcholine for CCR9 is CCL25, which is selectively expressed in the Phosphatidylcholine was studied in a randomized, double- digestive tract. CCX282-B is an orally bioavailable specific blind, placebo-controlled trial of 60 patients with steroid- CCR9 antagonist that was found to be well tolerated in a dependent, chronic, active UC [21]. Patients received either previous Phase I study in healthy volunteers [19]. In this 0.5 g of phosphatidylcholine (PC) or placebo daily for study, the safety and tolerability of CCX282-B in 71 patients 12 weeks. The primary endpoint was steroid withdrawal and with CD was assessed. Patients were randomized in a 2:1 clinical remission (defined as a disease activity index of ≤3), ratio to either CCX282-B or placebo. CCX282-B was well or a ≥50% clinical activity index improvement. This was tolerated and the only transient side effect seen more achieved in 15 patients (50%) in the PC group compared frequently in the group that received CCX282-B was with only three (10%) in the placebo group (p=0.002). headache. The investigators found encouraging evidence of Therefore, retarded-release PC seems effective in steroid clinical benefit in CD patients, although strictly speaking no withdrawal of chronic, active, steroid-dependent UC and statistical significance was reached. However, there was promotes a parallel improvement of clinical activity. an observed decrease of 4.4±3.7 mg/L in the levels of C-reactive protein in the group that received CCX282-B Curcumin after 28 days of therapy, while an increase of 6.7±4.2 mg/L Curcumin is a plant-derived natural substance present in was seen in the placebo group (p=0.07). This study was not turmeric. Curcumin is known to have tumor suppressing designed to measure the efficacy of the drug; this should be actions, as well as anti-inflammatory and anti-microbial evaluated in subsequent studies. activities. These activities are explained in part by inhibition of nuclear factor-κB. In the double-blind, randomized study Fibrin glue presented by Hiroyuki Hanai and colleagues (Hamamatsu Fibrin glue was presented as a new option for treatment of University School of Medicine, Hamamatsu, Japan), the anal fistulas [20]. It is a simple technique that may be clinical efficacy of curcumin in combination with 5-ASA or repeatedly used and will not affect anal sphincter function. sulphasalazine was tested [22]. A total of 89 patients with This multicenter, randomized study assessed the efficacy UC in remission were randomized to receive curcumin plus and safety of fibrin glue injected in the fistula tracts of CD sulphasalazine or 5-ASA, or placebo plus sulphasalazine or patients. All patients received a baseline magnetic 5-ASA for 6 months. The relapse rate during the 6 months resonance imaging scan or endoscopic ultrasound to rule of therapy was significantly lower in the curcumin group out the presence of abscess. Stable doses of concomitant (4.55%) compared with the placebo group (20.51%; treatment were allowed, but anti-TNF agents were p=0.04). Curcumin treatment improved the clinical activity excluded. Patients were randomized to receive either fibrin index as well as the endoscopic index after 6 months and glue injection or no treatment. The primary endpoint was may prove to be a promising treatment for maintaining complete response at week 8, defined as the absence of remission in patients with UC. Further studies of this agent perianal pain and absence of draining fistulas. At week 8, are essential. patients randomized to the no treatment group who had no response could receive active treatment. At this stage, re- IBD epidemiology treatment was possible in the group randomized to fibrin Long-term outcome of infliximab therapy glue. A total of 77 patients with a mean duration of CD Data on the long-term outcome of treatment with infliximab of 6.7 years were enrolled. At week 8, 38% of the fibrin are scarce. A large population-based registry of all patients glue group had a complete response compared with 16% in treated with infliximab in 22 medical centers between the no treatment group (p<0.05). The significant results 1998–2005 were included in the Danish Crohn Colitis were only observed in the subgroup of patients treated with Database [23]. A total of 648 patients (615 with CD, a simple fistula (53% of all patients). In those who were 16 with UC, and 17 with indeterminate colitis) were treated defined as fibrin-glue responders at week 8, 83% with infliximab. The duration of the disease at the first maintained remission at week 16. Therefore, fibrin glue infliximab treatment was a median of 5 years (range appears to be an effective therapy for achieving complete 0–38 years) and 64 patients were aged <18 years. A median closure of anal fistulas in patients with CD. The procedure of three infusions per patient (range 1–30 infusions) were appears safe and should be regarded as a good option in administered, giving a total of 3320 infusions. Maintenance patients with persisting or relapsing perineal fistulas without therapy was given to 26% of patients and 33% had on- intestinal symptoms. demand therapy. Overall response rates for CD were 84.7%

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(luminal disease) and 82.6% (fistulizing disease), and, for References UC, the response rate was 69.2%. Five patients were 1. Stange EF, Travis SP, Vermeire S et al.; European Crohn’s and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohn’s disease: diagnosed with cancer, but only one was possibly related to definitions and diagnosis. Gut 2006;55(Suppl 1):i1–15. the use of infliximab. In total, 13 patients died; two of these 2. Travis SP, Stange EF, Lemann M et al.; European Crohn’s and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohn’s disease: may have been related to infliximab (0.3%). The authors current management. Gut 2006;55(Suppl 1):i16–35. concluded that, in this large database, infliximab is an 3. Caprilli R, Gassull MA, Escher JC et al.; European Crohn’s and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohn’s disease: efficacious treatment for IBD with response rates of >80%. special situations. Gut 2006;55(Suppl 1):i36–58. This was in spite of 33% of patients being treated episodically. 4. Stange E, Travis SP, Vermeire S et al. ECCO consensus on the management of ulcerative colitis. Gut 2006;55(Suppl V). 5. Centre for Evidence Based Medicine, Oxford. Levels of evidence and grades of Biological therapies and pregnancy recommendation. Available at: http://www.cebm.net/levels_of_evidence.asp. The increased use of biologics such as anti-TNFs in the 6. Reinisch W, Sandborn WJ, Yan S et al. Infliximab reduces UC-related hospitalizations treatment of IBD and other immune-mediated diseases requiring high-dose corticosteroids: the ACT trial experience in ambulatory patients with moderately to severely active UC. Gut 2006;55(Suppl V):A23. raises the question of safety for developing fetuses. A 7. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance question that is frequently asked by young (female) patients therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76. relates to the use of anti-TNF agents during pregnancy. The 8. Rutgeerts P, Sandborn WJ, Enns R et al. Adalimumab rapidly induces clinical response and remission in patients with moderat to severe Crohn’s disease who had secondary preliminary data from the Organization of Teratology failure to infliximab therapy: results of the GAIN study. Gut 2006;55(Suppl V):A20. Information Specialists (OTIS) Autoimmune Diseases in 9. Fossati G, Brown D, Nesbitt A. Effects of certolizumab pegol, etanerceprt, adalimumab and infliximab on lipopolysaccharide-induced cytokine production by human peripheral Pregnancy Project were presented [24]. OTIS is a non-profit blood monocytes. Gut 2006;55(Suppl V):A18. organization that was founded in 1988 and has an overall 10. D’Haens G, Hommes D, Engels L et al. Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study. Aliment Pharmacol objective to help prevent birth defects and improve public Ther 2006;24:1087–97. health. The organization conducts pregnancy exposure 11. Kamm MA, Lichtenstein GR, Sandborn WJ et al. Combined data from two pivotal, randomised, placebo-controlled, Phase III studies show that MMX mesalazine, a novel cohort studies. Specialists provide current information about formulation given once or twice daily, is effective for the induction of remission of mild- the possible effects on pregnancies of patient exposure to to-moderate ulcerative colitis. Gut 2006;55(Suppl V):A126. various agents, including prescription and over-the-counter 12. Schreiber S, Lichtenstein GR, Kamm MA et al. Once- and twice-daily MMX mesalazine, a novel, high-strength formulation of 5-ASA, induces remission of both mild and moderate medications, alcohol and illicit drugs, diseases and infections, ulcerative colitis: a prespecified analysis of combined data from two pivotal, randomised, placebo-controlled, Phase III studies. Gut 2006;55(Suppl V):A132. and occupational and paternal exposures. The current target 13. Kamm MA, Lichtenstein GR, Sandborn WJ et al. MMX mesalazine, a novel, high-strength diseases include rheumatoid arthritis, ankylosing spondylitis, 5-ASA formulation induces remission of active, mild-to-moderate ulcerative colitis in patients who are changed from low-dose oral 5-ASA therapy or are 5-ASA-naive or psoriatic arthritis, and psoriasis. This prospective, observational discontinued: an analysis of pooled data from two Phase III, randomised, placebo cohort study, presented by Christina Chambers and colleagues controlled studies. Gut 2006;55(Suppl V):A126. 14. Schreiber S, Kamm MA, Lichtenstein G et al. MMX mesalazine, a novel formulation of (University of California, San Diego, CA, USA) compared 5-ASA given once or twice daily, is well tolerated in patients with active mild-to-moderate pregnancy outcomes in women with these diseases with a ulcerative colitis: an analysis of adverse events in combined data from three randomised studies. Gut 2006;55(Suppl V):A132. disease-matched control group and a non-diseased control 15. Kamm MA, Schreiber S, Butler T et al. Safety analysis of MMX mesalazine for the group. The current US Food and Drug Administration maintenance of remission of mild-to-moderate ulcerative colitis: results of 4-month interim data analysis. Gut 2006;55(Suppl V):A126. pregnancy label category of both infliximab and adalimumab 16. Sandborn W, Yeh C, Magowan S. Mesalazine 2.4 & 4.8 g/day demonstrates no difference is B. In this study, 19 women with a target disease were in creatinine clearance (CrCl) in moderately active ulcerative colitis patients over a 6 week adalimumab-exposed, while 32 adalimumab-exposed women treatment period. Gut 2006;55(Suppl V):A20. 17. Lichtenstein G, Rubin D, Regalli G et al. Endoscopy measured mucosal healing of did not meet cohort criteria but were enrolled (eight of whom modified-release oral mesalazine 4.8 g/day versus 2.4 g/day. Gut 2006;55(Suppl V):A127. were using adalimumab for CD). There was one spontaneous 18. Keshav S, Wolf D, Katz S et al. CCX282-B, an orally active inhibitor of chemokine receptor CCR9, in a randomized, double-blind, placebo-controlled phase 2 study in moderate abortion in the adalimumab cohort group and one in the to severe Crohn’s disease. Gut 2006;55(Suppl V):A22. group of women from the adalimumab registry. No 19. http://chemocentryx.com/product/CCR9.html developmental abnormalities were seen. These preliminary 20. Grimaud J, Munoz-Bongrand N, Siproudhis L et al. Fibrin glue injection for perianal fistulas findings do not suggest an increased risk for adverse in Crohn’s disease: a randomized controlled trial. Gut 2006;55(Suppl V):A40. 21. Stremmel W, Autschbach F, Schafer S et al. Retarded release phosphatidylcholine in steroid pregnancy outcomes with exposure to adalimumab early in dependent ulcerative colitis. Gut 2006;55(Suppl V):A22. pregnancy. Of course, definite conclusions await the 22. Hanai H, Iida T, Takeuchi K et al. Curcumin, a promising drug for long-term maintenance therapy in patients with ulcerative colitis: results from a multicenter, randomized double- accumulation of a sufficient sample size in the cohort study. blind placebo-controlled clinical trial. Gut 2006;55(Suppl V):A23. 23. Elkjaer M, Caspersen S, Pedersen N et al. Longterm outcome of inflixmab treatment Disclosures in the national Danish Crohn and colitis database. Gut 2006;55(Suppl V):A41. Dr Vermeire has received honoraria from Abbott, Ferring, 24. Chambers CD, Johnson DL, Jones KL; OTIS collaborative Research Group. Adalimumab and pregnancy outcome: preliminary data from the OTIS auto-immune diseases in Schering-Plough, and UCB Pharmaceuticals. pregnancy project. Gut 2006;55(Suppl V):A71.

INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 129 MEETING REPORT patients from the“pre-IBD state” totheperiodwhenIBD studies shouldbepopulation-based, and,ifpossible,follow retrospective studiesandfocus onprospective studies.These advances inIBDepidemiology wastoabandonanyfurther Colombel outlinedthatthe wayforward withregard to of children’s studies,smokingwasnotdiscussed.Professor ulcerative colitis(UC)[2].Ashewasproviding anoverview adolescents aged<20yearswithareduced risk of developing linking appendicectomyforappendicitisinchildren and Colombel deemedthattheonlytrulyrobust datawere those produced conflictingandinconsistentdata.Professor knowledge andhighlightedthat,inthemain,studieshave involving children. Hesummarizedthecurrent stateof published todateonIBD,focusingparticularlystudies eloquently summarizedalloftheenvironmental data Jean-Frédéric Colombel(HôpitalHuriez,Lille,France) Epidemiology Journal ofPediatricGastroenterologyandNutrition invited lectures hasbeenpublishedasasupplementofthe abstract presentations. Thefullprogram ofabstracts and on newandemerging informationdescribedinlectures and meeting infinedetail;therefore, thisreport willconcentrate 20–30 years. contributors toadvancesinpediatricIBDfrom thepast of speakersresembled a“who’s who”ofthemajor held inRome,Italy, andattendedby>300delegates.Thelist Pediatric Gastroenterology, HepatologyandNutrition.Itwas by Salvatore CucchiaraonbehalfoftheItalianSocietyfor Hepatology andNutrition[NASPGHAN]),washosted the NorthAmericanSocietyforPediatricGastroenterology, Gastroenterology, HepatologyandNutrition[ESPGHAN] and NorthAmerica(theEuropean SocietyforPaediatric meeting ofthepediatricgastroenterology societiesofEurope The FirstEuropean SymposiumonPediatricIBDwasajoint Edinburgh, Scotland,UK. Department ofPaediatricGastroenterology andNutrition,RoyalHospitalforSickChildren, Richard KRussell Rome, Italy, 23–25November, 2006 Pediatric InflammatoryBowelDisease The FirstEuropean Symposiumon 130 It isbeyondthescopeofthisreview todiscussthewhole I NFLAMMATORY B OWEL [1]. D ISEASE Animal modelsofIBD multidrug resistance 1( exceptions were highlighted:theC3435Tallelein lack ofconsistencyinreplication studies.However, two on candidategenesthatwere, ingeneral,variable,witha up-to-date overviewofIBDgenetics[6].Hedescribeddata ever susceptibilitygeneforIBD( responsible fortheground-breaking workdescribingthefirst U458, HôpitalRobertDebré,Paris,France),whowas The pioneerofIBDgenetics,Jean-Pierre Hugot(INSERM Genetics potential therapeutictarget inpatientswithIBD. data complementgenetic(seebelow),offering anovel, the intestinalinflammationinIBDandthesenewexperimental have beenpublishedthisyear[3–5].IL-23isakeyplayerin with interleukin-23(IL-23).Severalkeypapersinthisfield of TcellsintoTh17andtheirimportantrelationship Th1/Th2 paradigm,describingthefurthersub-classification highlighted recent datathataddtothewell-established evolution ofIBDderivedfrom animalmodels.Professor Murch others discussedtheevidenceforpathogenesisand Simon Murch (UniversityofWarwick, Warwick, UK)and diagnosis phase–achallengeindeed. protracted periodoftime,forseveraldecadesinthepost- develops. Patientsshouldthenundergo follow-upovera used genome-wideassociation studieswhichhaveused index populationsare stilltobeundertaken. gene are new, replication studiesincohortsoutsideof the increase intheriskofUC[8]. As thesedataonthe celiac disease,butisnowalsoassociatedwithamodest which wasinitiallyimplicatedinincreased susceptibilityto and theA1011SalleleinmyosinIXB( susceptibility toUCinarecently publishedmeta-analysis[7], M ONITOR Professor Hugotthenwentontohighlight more recently V OL 7 N O 3 2007 MDR1 ) gene,whichdemonstrates NOD2 / CARD15 MY09B ) gavean MY09B ) gene, THE FIRST EUROPEAN SYMPOSIUM ON PEDIATRIC IBD

several hundred thousand single nucleotide polymorphisms studies have been performed in children, with several to map across the entire genome, in order to identify novel prospective studies now underway. The difficulties of the genes associated with disease susceptibility in patients with differential diagnosis after identifying small-bowel lesions, IBD. This has resulted in the identification of an association and the issue of retention of capsules in patients with between variants in the TNFSF gene and Crohn’s disease strictures (around 5% in patients with established CD, (CD) in the Japanese population [9], and an association quoted by Dr Seidman) are still being resolved. between the IL-23 receptor gene and a protective effect in In a separate abstract presentation, Dr Seidman patients with ileal CD [10]. described retrospective data collected over a period of Thomas Walters (The Hospital for Sick Children, 5 years, on 57 patients who were strongly suspected of University of Toronto, Toronto, ON, Canada) presented new having CD, but in whom imaging (small-bowel radiography) genetic data from an analysis of 380 children with IBD from and endoscopic examination (upper GI endoscopy and ileo- the Canadian population. He produced data from IBD trios colonoscopy) had not confirmed CD. This analysis found to show that susceptibility to UC is increased in patients that 37% of the patients had small-bowel lesions in keeping possessing variants of the G2677T allele of the MDR1 gene, with CD, and a further 9% were suspected, but not but not for the C3435T allele or for variants in the discs confirmed, as having CD. Of the 57 patients, two required large homologue 5 (DLG5; G113A and C4136A), Toll-like the capsule to be placed endoscopically and two had a receptor 4 (TLR4; D299G and T399I), or NOD1/CARD4 retained capsule (these retained capsules resolved upon (E266K) genes. Dr Walters also described phenotypic treatment with steroids). Therefore, this technique may associations of the G2677T MDR1 allele and D299G TLR4 be especially useful in children who are strongly suspected allele with isolated colonic CD, and of the C3435T MDR1 of having CD, but in whom findings from conventional allele with a more complicated disease course. investigations are negative (as techniques used in adults, such as push enteroscopy, are not generally available Disease assessment scores for children). Dan Turner (The Hospital for Sick Children, University of Toronto) gave a very interesting presentation on the Therapeutics development of a novel pediatric UC activity index (PUCAI). A cohort study of 27 patients with CD who were unresponsive At the present time there is no UC disease activity index that to azathioprine treatment was presented by Pamela Rogers can be used for clinical assessment in children with UC. He (Department of Paediatric Gastroenterology and Nutrition, developed an initial disease activity index after employing Royal Hospital for Sick Children, Edinburgh, Scotland, UK). the Delphi consensus method, taking into account the All patients were initially treated with subcutaneous opinion of 48 experts, combined with a thorough literature methotrexate (15 mg/m2) for induction of remission, and review that generated an initial list of 41 potential items for responders subsequently received the drug for the the activity index. The score was reduced to 11 key items maintenance of remission. In total, 85% of those who were and was subsequently prospectively tested on a cohort of treated entered clinical remission as defined by a pediatric 157 children with UC. After further statistical analysis, the CD activity index score of <15. A number of patients score was modified, and the resulting eight-item score was subsequently relapsed and thus the number of patients in then validated in a further 48 patients with UC. The final maintained remission for ≥12 months was 30%. disease assessment activity score that has now been A half-day of the meeting was devoted to discussion on developed for use in children with UC is based on six items the use of biological therapy in children with IBD. There and requires neither endoscopic assessment nor the continues to be debate within the pediatric IBD community performing of blood tests, making it an excellent and most regarding the development of hepatosplenic T cell lymphomas needed tool for use in the childhood UC population. in children with IBD treated with azathioprine, with or without infliximab. This has been discussed in previous Diagnostic methods meeting reports in this journal [12,13]. Jeffrey Hyams The latest data on wireless capsule endoscopy were (Connecticut Children’s Medical Center, Hartford, CT, USA) presented by Ernest Seidman (Sainte-Justine Hospital, provided an update on this subject. There have been a University of Montreal, Montreal, QC, Canada). A recent total of 14 reports in the medical literature, describing meta-analysis in adults has identified that a capsule is predominantly children who have developed this lymphoma superior to all other current imaging modalities of the small while receiving azathioprine/6-mercaptopurine. There have bowel, especially for disease in the small bowel proximal to been a further four case reports in the literature of this the terminal ileum [11]. However, only a limited number of lymphoma in patients with CD receiving azathioprine/

INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 131 RICHARD K RUSSELL

6-mercaptopurine. In addition, a further eight patients have organization of lengthy follow-up of patients, and in the been reported through post-marketing surveillance – these persuasion of funding bodies to support such research. The patients were taking immunomodulators in combination next meeting is planned for 2008. with infliximab, and developed this lymphoma. The consensus opinion at the meeting was that Disclosures treatment with these agents should continue, but The author has no relevant financial interests to disclose. consideration should be given to an early withdrawal of azathioprine/6-mercaptopurine treatment in patients who References will continue to receive maintenance (but not episodic) 1. First European Symposium on Pediatric Inflammatory Bowel Disease, November 23–25, 2006, Rome, Italy. J Pediatr Gastroenterol Nutr 2006;43:S1–55. infliximab therapy. Séverine Vermeire (University Hospital 2. Andersson RE, Olaison G, Tysk C et al. Appendectomy and protection against ulcerative Gasthuisberg, Leuven, Belgium) presented data on 80 adult colitis. N Engl J Med 2001;344:808–14. 3. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest patients receiving maintenance treatment with infliximab, 2006;116:1218–22. half of whom had immunomodulators withdrawn at 4. Kullberg MC, Jankovic D, Feng CG et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 2006;203:2485–94. 6 months after commencing infliximab. The clinical relapse 5. Hue S, Ahern P, Buonocore S et al. Interleukin-23 drives innate and T cell-mediated rate at 24 months after commencing infliximab was not intestinal inflammation. J Exp Med 2006;203:2473–83. 6. Hugot JP, Chamaillard M, Zouali H et al. Association of NOD2 leucine-rich repeat variants significantly different between the group that continued to with susceptibility to Crohn’s disease. Nature 2001;411:599–603. receive immunomodulators and patients who did not. 7. Annese V, Valvano MR, Palmieri O et al. Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis. World J Gastroenterol 2006;12:3636–44. 8. Van Bodegraven AA, Curley CR, Hunt KA et al. Genetic Variation in Myosin IXB Is Summary Associated With Ulcerative Colitis. Gastroenterology 2006;131:1768–74. The overriding theme emerging from the meeting was that 9. Yamazaki K, McGovern D, Ragoussis J et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet 2005;14:3499–506. a collaborative, prospective approach to investigating and 10. Duerr RH, Taylor KD, Brant SR et al. A genome-wide association study identifies IL23R treating pediatric patients with IBD is now required if the as an inflammatory bowel disease gene. Science 2006;314:1461–3. 11. Triester SL, Leighton JA, Leontiadis GI et al. A meta-analysis of the yield of capsule questions raised at the symposium are to be answered at endoscopy compared to other diagnostic modalities in patients with non-stricturing small any stage in the future. This entails studying disease from bowel Crohn’s disease. Am J Gastroenterol 2006;101:954–64. 12. Lees CW, Gaya DR. Digestive Diseases Week 2006 (DDW 2006). Inflamm Bowel Dis early childhood over the following several decades, and the Monit 2006;7:41–8. establishment of multicenter treatment trials. This presents 13. Russell RK, Van Limbergen J. 39th Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Inflamm Bowel Dis Monit significant challenges for investigators with regard to the 2006;7:86–8.

132 INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007 INFLAMMATORY BOWEL DISEASE MONITOR

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