inflammatory bowel disease monitor

Transcription

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
opportunity university.
This journal is supported by an
educational grant from Shire
New Gastroenterology Titles from Remedica
IMMUNOLOGY AND
DISEASES OF THE GUT
THE INFLAMMATORY BOWEL
DISEASE YEARBOOK VOLUME 3
Published: September 2006
ISBN: 978 1 901346 88 9
ISSN: 1472-4626
Price: US$45/£25/€40
Extent: 216 pages
Format: Hardback
Published: September 2006
ISBN: 978 1 901346 56 0
Price: US$35/£20/€30
Extent: 160 pages
Format: Paperback
AUTHORS
AUTHORS
Thomas T MacDonald: Barts and the London School of
Medicine, UK; Adrian C Bateman: Southampton General
Hospital, UK
A Hillary Steinhart (Canada), Severine Vermeire (Belgium),
Gert Van Assche (Belgium), Paul Rutgeerts (Belgium), David A
Schwartz (USA), Steven R Brant (USA), Amir Karban (Israel),
Jürgen Schölmerich (Germany), Ernest G Seidman (Canada),
Devendra K Amre (Canada), William J Sandborn (USA)
DESCRIPTION
This book unravels the subject of immunology into three clear
areas: immunology itself, gut immunology, and inflammation.
These areas are explored with detailed and easy-to-understand
explanations and a focus on the aspects of immunology that
are particularly important for the gut. In addition, this book
contains an illustrated A-to-Z listing of over 35 commonly
encountered gastroenterological disorders (including chronic
granulomatous disease, Crohn's disease, graft-versus-hostdisease, pernicious anemia, reflux disease, and ulcerative
colitis). Detailed descriptions of each disorder include
information on clinical features, epidemiology, diagnosis,
immunopathogenesis, and treatment.
DESCRIPTION
The Inflammatory Bowel Disease Yearbook Volume 3 is
Remedica's third instalment in the 'Inflammatory Bowel
Disease Yearbook' series. In this volume, the authors (from
Europe, Canada, and North America) discuss the current
status of topics such as IBD genetics, diagnostic blood testing,
and biological therapies. In keeping with previous titles,
this book provides clinicians and scientists in IBD research
with a thorough understanding of recent data in the context
of the disease as a whole.
CONTENTS
CONTENTS
•
•
•
•
•
A beginner's guide to immunology
A beginner's guide to gut immunology
A beginner's guide to inflammation
Gastrointestinal diseases with an immunological component
Glossary
In the US:
Phone: 1-800-247-6553 or 1-800-266-5564
(or 1-419-281-1802 from Canada)
Fax: 1-419-281-6883
Email: [email protected]
•
•
•
•
•
Therapy: purine analogs and methotrexate
Blood tests in IBD: which are necessary?
Progress in IBD genetics
Crohn’s perianal fistulas: current treatment paradigms
Pediatric IBD: novel investigative approaches for diagnosis
and follow-up
• Biological therapies
In the UK:
Phone: +44 (0)161 273 6799
Fax: +44 (0)161 273 6261
[email protected]
www.remedicabooks.com
✂
9. In ulcerative colitis, PPARγ expression is:
A. Downregulated in macrophages
B. Upregulated in macrophages
C. Downregulated in colonic epithelial cells
D. Upregulated in colonic epithelial cells
E. A and C
Novel Anti-Inflammatory Mechanisms
Vignal C, Rousseaux C, Peyrin-Biroulet L,
Dubuquoy L, Chavatte P, and Desreumaux P.
Inflamm Bowel Dis Monit 2007;7(3):90–8.
1. To be effective during colonic inflammation,
5-aminosalicylic acid (5-ASA) should have:
A. A systemic effect
B. A specific effect on the small bowel
C. A specific effect on the colon
D. Been in contact with intestinal
epithelial cells
E. C and D
The University of Kentucky College of Medicine
designates this educational activity for a maximum
of two (2.0) AMA PRA Category 1 Credits™.
Physicians should only claim credit commensurate
with the extent of their participation in the activity.
2. The active form of 5-ASA is:
A. Acetylated-5-ASA
B. Free 5-ASA
C. 4-ASA
D. 3-ASA
E. 2-ASA
presents this activity for educational purposes only.
Participants are expected to utilize their own
expertise and judgment while engaged in the
practice of medicine. The content of the
presentations is provided solely by presenters
who have been selected for presentations
because of recognized expertise in their field.
DISCLOSURES
Dr Desreumaux has received funding for research
from Giuliani Pharma, Milan, Italy. Drs Vignal,
Rousseaux, Peyrin-Biroulet, Dubuquoy, and
Chavatte have no relevant financial interests
to disclose.
1. Capsule endoscopy is used in the diagnosis
of Crohn’s disease. Which of the following
statements is true?
A. Capsule endoscopy examines the gut wall
in the same way as classical endoscopy
B. Capsule endoscopy allows the simultaneous
examination of multiple lesions
C. Only short segments of gut are visualized
at one time point using capsule endoscopy
D. Insufflation of air during capsule endoscopy
allows close examination of the mucosa
E. A and B
4. The synthetic ligands of PPARγ, glitazones
have been developed as:
A. A treatment for type 2 diabetes
B. An anti-inflammatory drug
C. An antineoplastic compound
D. A hypolipemic drug
E. A hormonal therapy
Drs Delvaux and Gay have no relevant financial
interests to disclose.
5. PPARγ is:
A. Regulated by the luminal flora
B. Weakly expressed in the small bowel
compared to the colon
C. Mainly expressed by colonic epithelial cells
D. A key element in the regulation
of bacteria-induced colitis
E. All of the above
INSTRUCTIONS FOR OBTAINING CME CREDIT
Participation in this activity should be completed
in approximately 2.5 h. To successfully complete
this program and receive credit, participants must
follow these steps:
1. Read the learning objectives.
2. Read the articles’ text and tables and review
the figures.
3. Complete the registration information on the
form included.
4. Read, complete, and submit answers to the
self-assessment questions. Participants must
respond to all program evaluation questions
to receive a certificate by mail.
5. Complete the registration form, post-test answer
sheet, and evaluation form at the back of this
journal and return to the address provided.
Alternatively, visit the journal web site
www.ibdmonitor.com and follow the
links to CME.
6. The anti-inflammatory effect of PPARγ
has been demonstrated in:
A. Colonic epithelial cells
B. Lymphocytes
C. Macrophages
D. Monocytes
E. All of the above
7. What are the main mechanisms sustaining
the anti-inflammatory effect of PPARγ:
A. Inhibition of nuclear factor-κB
B. Inhibition of nuclear factor of activated
T cells
C. Inhibition of activator protein-1
D. Inhibition of cyclic AMP response
element binding protein
E. A, B, and C
Please note that the website provides the option
to print out a PDF of the answers, which requires
participants to fax or mail their responses to the
University of Kentucky.
8. In epithelial cells, expression of PPARγ
is regulated by:
A. Its ligands
B. Glucagons
C. Microorganisms
D. A and B
E. A and C
10. 5-ASA is:
A. A novel ligand of PPARγ
B. Able to induce PPARγ expression
in epithelial cells
C. Able to induce PPARγ activation
in epithelial cells
D. Able to bind PPARγ expressed by
lamina propria mononuclear cells
E. All of the above
Delvaux M and Gay G.
3. Peroxisome proliferator activator receptor γ
(PPARγ) is:
A. Expressed only by adipocytes
B. Expressed only by epithelial cells
C. A nuclear receptor
D. A coactivator
E. A corepressor
✂
CME
Answers should be recorded in the spaces provided overleaf.
One answer is correct for each question.
2. Capsule endoscopy detects intestinal lesions
of Crohn’s disease. Which of the following
statements are correct?
A. Radiological methods have been found
to detect more intestinal lesions than
capsule endoscopy
B. Capsule endoscopy has been shown
to detect more intestinal lesions than
push-enteroscopy
C. Capsule endoscopy has been shown
to detect fewer intestinal lesions than
small-bowel follow through
D. A and B
E. A and C
3. Indications for capsule endoscopy include:
A. To diagnose Crohn’s disease in patients
who are suspected of having the disease
in the clinic, but have normal radiological
test results
B. The further diagnosis of indeterminate colitis
C. To detect early disease recurrence after surgery
D. To evaluate lesions in the small bowel
in patients with known Crohn’s disease
E. All of the above
4. Morphological investigations of the small
bowel are performed using radiological and
endoscopic methods. Which of the following
statements is correct?
A. Radiological and endoscopic investigations
are equally effective for the detection of
tiny mucosal lesions and apthae
B. Endoscopic methods more frequently
detect tiny mucosal lesions and apthae,
compared with radiological methods
C. A combination of endoscopic and
radiological methods can increase the
diagnostic success in patients with
suspected intestinal disease
D. A and C
E. B and C
INFLAMMATORY BOWEL DISEASE MONITOR
5. Which of the following statements is correct
regarding double balloon enteroscopy?
A. Biopsy of intestinal lesions is not possible
during double balloon enteroscopy
B. Double balloon enteroscopy prevents
capsule retention
C. The frequency of capsule blockade is
increased by double balloon enteroscopy
D. Biopsy of intestinal lesions may be possible
during double balloon enteroscopy
E. B and D
6. Conditions in which elemental lesions similar
to those of Crohn’s disease are found include:
A. Mesenteric ischemia
B. Celiac disease
C. Nonsteroidal anti-inflammatory
drug-related intestinal damage
D. Cryptogenetic multifocal ulcerous
stenosing enteritis
E. All of the above
7. Radiological analyses are effective for:
A. Investigation of intestinal stenoses
B. Examination of large ulcers
C. Detection of apthae
D. A and C
E. A and B
8. Capsule retention is a complication of capsule
endoscopy. Which of the following statements
is correct?
A. Capsule retention is defined as the absence
of natural excretion of the capsule within
the 7 days post-procedure
B. Capsule retention is defined as the natural
excretion of the capsule within the 7 days
post-procedure
C. Capsule retention is defined as the failure
of the capsule to reach the cecum during
the 8-h recording
D. A and C
E. B and C
9. Regarding capsule retention, which of the
following statements is true?
A. The frequency of capsule retention is
greater in Crohn’s disease patients than
in patients investigated for obscure
gastrointestinal bleeding
B. The frequency of capsule retention is
greater in patients investigated for obscure
gastrointestinal bleeding than in Crohn’s
disease patients
C. The frequency of capsule retention is
similar in Crohn’s disease patients,
and in those investigated for obscure
gastrointestinal bleeding
D. Capsule retention can lead to surgical
procedures in Crohn’s disease patients who
are not otherwise indicated for surgery
E. A and D
10. The presence of an intestinal stenosis may
be a contraindication to capsule endoscopy.
Which of the following methods has been
proposed to avoid this problem?
A. A patency capsule
B. Magnetic resonance imaging
C. Computed tomography-enteroclysis
D. Surgery
E. Nonsteroidal anti-inflammatory drugs
Vol 7 No 3 2007
CME
ACCREDITATION
This activity has been planned and implemented
in accordance with the Essentials Areas and policies
of the Accreditation Council for Continuing Medical
Education through the joint sponsorship of the
University of Kentucky College of Medicine and
Remedica Medical Education and Publishing.
is accredited by the ACCME to provide continuing
medical education for physicians.
✂
Complete the post-test answer sheet, evaluation form, and registration form, return to:
Alternatively the form can be downloaded from www.ibdmonitor.com by following the links to CME.
Registration is required, but is free to physicians and healthcare professionals.
EXAMINATION ANSWERS
Each issue of Inflammatory Bowel Disease Monitor will
present carefully constructed review articles, written by
practicing specialists in gastroenterology and related
disciplines and developed to equip readers with practical
knowledge of the area under discussion. These articles are
commissioned to support particular educational themes
identified by the Editors-in-Chief, Editorial Advisory Board,
and readers. This issue of Inflammatory Bowel Disease
Monitor presents two such leading articles.
Record your answers here by filling in the blank with the correct letter for the corresponding question:
Novel Anti-Inflammatory Mechanisms of 5-ASAs in Ulcerative Colitis. Vignal C, Rousseaux C, Peyrin-Biroulet L, Dubuquoy L,
Chavatte P, and Desreumaux P. Inflamm Bowel Dis Monit 2007;7(3):90–8
1. ____ 2. ____ 3. ____ 4. ____ 5. ____ 6. ____ 7. ____ 8. ____ 9. ____ 10. ____
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
This activity is designed to meet the educational needs
of multidisciplinary clinicians and healthcare professionals
involved in the care of patients with inflammatory
bowel disease.
1. ____ 2. ____ 3. ____ 4. ____ 5. ____ 6. ____ 7. ____ 8. ____ 9. ____ 10. ____
Participants will receive a confidential report of their results along with the correct answers to each question.
A certificate of credit will be sent to those who successfully complete the examination with a score of 80% or higher.
EVALUATION FORM
Strongly agree
1
2
3
4
Strongly disagree
5
2. The activity helped increase my knowledge and skills.
1
2
3
4
5
3. The activity content was educational and understandable
1
2
3
4
5
4. The activity content met its objectives.
1
2
3
4
5
5. The amount of information presented was adequate for my needs.
1
2
3
4
5
6. I felt I absorbed a reasonable amount of the presented materials.
1
2
3
4
5
7. The technical quality of the activity was acceptable.
1
2
3
4
5
8. I would recommend this program to my peers.
1
2
3
4
5
Yes
No
Yes
No
1. The activity provided new information I had not yet acquired.
9. Funding for this activity may have come from commercial sponsors.
Do you think you were adequately informed of commercial sponsorship or faculty conflict of interest?
10. Do you think the overall activity was biased toward certain commercial products or services?
LEARNING OBJECTIVES
Novel Anti-Inflammatory Mechanisms of 5-ASAs in
Ulcerative Colitis. Vignal C, Rousseaux C, Peyrin-Biroulet L,
Dubuquoy L, Chavatte P, and Desreumaux P.
Goal: To educate the reader on recent insights into
the molecular mechanisms of action of 5-ASAs
in ulcerative colitis.
Objectives: After reading this article the reader should
be able to discuss:
•
The metabolism of 5-ASA and its consequences
on drug efficacy in the gut.
•
Anti-inflammatory effects mediated by peroxisomeproliferator activated receptor γ (PPARγ).
•
Evidence for a role for PPARγ in the anti-inflammatory
effects of 5-ASA in ulcerative colitis.
Capsule Endoscopy in the Diagnosis of Crohn’s Disease.
Delvaux M and Gay G.
REGISTRATION FORM
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.
•
The current indications for capsule endoscopy.
•
The risks associated with capsule endoscopy.
...............................................................................................................................................................................................................................
City: ..................................................................... State: ................................................... Zip Code: .................................................................
Office Phone: ..................................................................................................................... Home Phone: ............................................................
Date of release: March 2007
Period of validity: Until March 2008
Email: .....................................................................................................................................................................................................................
Last 4 Digits of Social Security Number (optional) ........................................................................................................... (for recordkeeping only)
Signature: .......................................................................................................................... Credit Hours: .............................................................
Vol 7 No 3 2007
✂
By signing this certificate, I attest that I have attended the above named continuing medical education program.
CME
CME
Attn: Distance Education
UKCPMCE [MEN07077-02]
One Quality Street, 6th Floor
Lexington, KY 40517, USA
Fax: (859) 323-2920
NEEDS ASSESSMENT
Inflammatory Bowel Disease Monitor, a CME-accredited
educational program, systematically identifies, evaluates,
and places into clinical context the most important recent
studies into the science and medicine of inflammatory
bowel disease. It provides rapid access for busy specialists
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
management options for clinicians to allow them
to better diagnose and treat patients with IBD.
Editors-in-Chief
Stephen Hanauer
University of Chicago, Chicago, IL, USA
Jack Satsangi
Western General Hospital, Edinburgh, UK
Editors
Ian Arnott
Western General Hospital, Edinburgh, UK
Federico Balzola
Azienda Ospedaliera San Giovanni Battista di Torino,
Turin, Italy
Charles Bernstein
University of Manitoba, Winnipeg, MB, Canada
Contents
Leading Articles
Cécile Vignal, Christel Rousseaux,
Laurent Peyrin-Biroulet, Laurent Dubuquoy,
90
99
Clinical Reviews
Pathogenesis
106
Clinical Observations
111
Editorial Advisory Board
Treatment and Clinical Practice
117
Zane Cohen
Mount Sinai Hospital, Toronto, ON, Canada
Epidemiology
120
Meeting Reports
American College of Gastroenterology
Annual Scientific Meeting 2006
(ACG 2006)
Corey A Siegel and David T Rubin
121
United European Gastroenterology Week
(UEGW) 2006
Séverine Vermeire
125
The First European Symposium on
Pediatric Inflammatory Bowel Disease
Richard K Russell
130
Simon Murch
University of Warwick, Coventry, UK
Jean-Frédéric Colombel
Hôpital Huriez, Lille, France
Anders Ekbom
Karolinska Institute, Stockholm, Sweden
Brian Feagan
University of Western Ontario, London, ON, Canada
Claudio Fiocchi
Cleveland Clinic, Cleveland, OH, USA
John O’Leary
Coombe Women’s Hospital, Dublin, Ireland
Roy E Pounder
Royal Free and University College Medical School,
London, UK
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.
Subscriptions are available at the following rates: Europe €150, USA, Canada and all other
territories US$200 per year. Additional subscription information is available from the publisher.
© Remedica Medical Education and Publishing 2007.
Editorial Policy
Inflammatory Bowel Disease Monitor is an independent journal published by Remedica Medical
Education and Publishing Ltd. The aim is to provide an up-to-date overview of the recent literature
compiled by an international team of practising physicians. Leading articles commissioned by the
Editors-in-Chief review new therapeutic techniques and emerging technologies, and news from
major international meetings is reported. Editorial control is vested entirely in the Editors-in-Chief,
Editors, and Editorial Advisory Board.
Any queries regarding the content of the journal should be addressed to: Remedica Medical
Education and Publishing Ltd, 20 N. Wacker Drive, Suite 1642, Chicago, IL 60606, USA.
Tel: +1 (312) 372 4020, Fax +1 (312) 372 0217. Email: [email protected]
ISSN 1466-7401
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system
or transmitted in any form or by any means, electronic, mechanical, photocopying, recording
or otherwise without the prior permission of the copyright owners. While every effort is made by
the publishers and editorial board to see that no inaccurate or misleading data, opinions,
or statements appear in this journal, they wish to make it clear that the material contained in the
publication represents a summary of the independent evaluations and opinions of the authors
and contributors. As a consequence, the board, publishers and any sponsoring company accept
no responsibility for the consequences of any such inaccurate or misleading data or statements.
Neither do they endorse the content of the publication or the use of any drug or device in a way
that lies outside its current licensed application in any territory.
For detailed information on any drugs or devices discussed in this publication, readers are
advised to consult the Physicians Circular issued by the manufacturer.
Editorial Team: Rhian Phillips, Scott Millar
Editorial Director: Reghu Venkatesan
Design and Artwork: AS&K Skylight Creative Services
Publishers: Ian Ackland-Snow, Simon Kirsch
LEADING ARTICLE
Cécile Vignal, Christel Rousseaux, Laurent Peyrin-Biroulet, Laurent Dubuquoy,
INSERM U795, University of Lille 2, and Digestive Tract Diseases and Nutrition Department,
Huriez Hospital, Lille, France
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-aminosalicylic acid (5-ASA), which is also called mesalamine
or mesalazine, is among the oldest medication prescribed by
gastroenterologists for patients with IBD. The first decisive
phase of 5-ASA development was the discovery of the curative
action of certain sulfonamide-containing azo compounds.
Developing the extensive work of Professor Nanna Svartz,
these compounds were synthesized by the chemists Joseph
Klarer and Fritz Mietzsch, and eventually led to the awarding
of the Nobel Prize for Physiology or Medicine to Gerhard
Domagk in 1939. At that time, the most effective sulfonamide
compounds, known as prontosil rubrum and prontosil solubile,
were used for their curative action against streptococcal
infections of man and also in diverse inflammatory diseases
believed to be of bacterial origin, including rheumatic
polyarthritis, colitis, and regional enteritis. Combined with an
antibiotic, sulfapyridine, in 1942 to form a molecule named
sulfasalazine (sulfapyridine linked to 5-ASA by an azo bond)
(Fig. 1), it was only in 1977 that Azad Khan et al. demonstrated
that the efficacy of sulfasalazine depended on the splitting
of the diazo bond in the molecule by the action of bacteria
in the large bowel, releasing the pharmacologically active
Address for correspondence: Pierre Desreumaux, INSERM U795,
Hôpital Swynghedauw, Rue A. Verhaeghe, F-59037 Lille cedex, France.
90
5-ASA moiety [1]. The recognition that 5-ASA was the
active component and that the side effects were related to
the sulfapyridine carrier molecule explained why many
countries replaced sulfasalazine with 5-ASA as first-line
therapy in the management of active mild-to-moderate
ulcerative colitis (UC) and for the maintenance of remission.
Today, 5-ASA represents the most commonly prescribed
treatment in IBD patients (50–65% of UC patients and
30–75% of Crohn’s disease [CD] patients) for an estimated
market of US$750 million per year (Pierre Desreumaux,
personal communication).
5-ASA metabolism
The therapeutic effect of 5-ASA is obtained through a local
action on colonic epithelial cells, rather than by a systemic
effect, when an effective and clinically relevant luminal
concentration of pure, non-acetylated 5-ASA reaches
5–100 mM [2,3].
Drug concentration
At a pH of 6–8, 5-ASA is present in the colonic lumen
as a zwitterion, sharing an intramolecular hydrogen bond
between its hydroxyl and carboxylate groups (Fig. 1). 5-ASA
concentration is an important determinant of the response
to treatment as the efficacy of 5-ASA is related to its local
concentration in the colon [4]. Therefore, factors such as
INFLAMMATORY BOWEL DISEASE MONITOR VOL 7 NO 3 2007
NOVEL ANTI-INFLAMMATORY MECHANISMS OF 5-ASAS IN UC
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
O
S
H
O
C
O
11
O
NH
O
H
N
O
1
6
N
OH
H
O
5-ASA
12
O
C11
N
N
H
–
OH
Sulfasalazine:
Sulfapyridine + 5-ASA
intestinal metabolism and elimination, which affect tissue
delivery, may be crucial in determining drug efficacy. Previous
studies examining the intestinal absorption of 5-ASA have
indicated that the drug is better absorbed in the upper than
the lower intestine [5], thus motivating the development
of sustained-release drug preparations to minimize systemic
5-ASA absorption in the proximal intestine and to deliver
more drugs to the diseased colon. After oral or rectal
administration, some 5-ASA is absorbed in the colon by
epithelial cells, but most remains within the lumen and is
passed in the stool (Fig. 2) [6]. In IBD patients receiving
standard 5-ASA maintenance treatment, the median mucosal
concentration of 5-ASA is 16 ng/mg, ranging from 3 to
50 ng/mg of wet colonic tissue [2]. More importantly than
the tissue concentration of 5-ASA in the colon, the
therapeutic effect of 5-ASA depends on the direct contact
of the molecule with the epithelium of the colon, implying
that a high perimucosal concentration of 5-ASA is a
prerequisite for its action [7]. It has previously been reported
in conventionally treated patients, that stool concentrations
of 5-ASA are in the median order of 30 mM, ranging from
10 to 100 mM, which correspond to luminal concentrations
of 5-ASA that are 100-times greater than those in the
colonic mucosa [2,3].
Drug acetylation and cell absorption
5-ASA is metabolized by N-acetylation, which is an important
metabolic pathway for the elimination of carcinogenic amines
occurring primarily in the liver through the action of
N-acetyltransferase (NAT), and also along the intestinal
tract [8]. The principal site of acetylation and its relevance to
+
H3N
5
2
5
OH
2
3
4
5-ASA zwitterion
the drug’s mode of action are not clear, but colonic epithelial
cells absorb and acetylate 5-ASA rapidly (Fig. 2) [6,9]. Orally
administered N-acetyl 5-ASA has consistently been shown
to be ineffective, probably due to an absence of absorption
by epithelial cells. From previous work on intestinal and
systemic N-acetylation of 5-ASA, there appear to be some
unresolved questions regarding intestinal metabolic capacity
and the fate of the intestinal metabolite in relation to
systemic 5-ASA elimination. In situ jejunal perfusion studies
of 5-ASA in the rat demonstrate that at a low concentration
in the intestinal lumen, 5-ASA is transported in epithelial
cells via a carrier identified as an intestinal organic anion
transporter [5]. At these low concentrations, the carrier
transports 5-ASA into the epithelial cell cytosol where a
major fraction (60%) is metabolized to N-acetyl 5-ASA,
which is then secreted predominantly into the intestinal
lumen. Absorbed 5-ASA that is not metabolized by epithelial
cells enters the circulation and is subject to hepatic
metabolism and subsequent renal elimination [4]. At higher
concentrations of 5-ASA in the intestinal lumen, carriermediated drug absorption is saturated and paracellular
absorption dominates, leading to an enhancement of 5-ASA
in the systemic circulation. In this case, systemic metabolism
has a greater role in drug elimination through N-acetylation
in the liver. N-acetyl 5-ASA formed in intestinal epithelia is
secreted only in the luminal direction, whereas N-acetyl
5-ASA in the systemic circulation is unlikely to be secreted
from plasma into the intestinal lumen. It should also be
noted that N-acetyl 5-ASA is not absorbed after luminal
administration, and intravenous administration of 5-ASA
results in essentially complete elimination of N-acetyl
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
Lumen
5-ASA
SR-5-ASA
Ac 5-ASA
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
obtained using a computerized medical literature search of
all English language articles selected from the “PubMed”
online database with the keywords “aminosalicylate”,
“mesalamine”, and “mesalazine”, from 1986–2005.
Number of publications
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
chemokine production, signal transduction pathways, reactive
oxygen metabolites, leukocyte chemotaxis, cyclooxygenase-2,
leukotrienes, and prostaglandins, the primary mechanisms
of action of 5-ASA have remained largely unknown (Fig. 3).
Due to functional similarities between 5-ASA and the
peroxisome-proliferator activated receptor γ (PPARγ), as well
as structural analogies between 5-ASA and the known
ligands of this nuclear receptor, it has been hypothesized
that 5-ASA may be a new ligand of PPARγ, driving its
400
300
200
100
0
1986–1990 1991–1995 1996–2000 2001–2005
5-ASA: 5-aminosalicylic acid.
92
5-ASA in the urine. Thus, N-acetyl 5-ASA is unlikely to enter
intestinal cells.
In conclusion, 5-ASA concentration and the route of
administration determine the acetylation and elimination
profiles of the compound, two major determinants of 5-ASA
efficacy that appear not to be impaired during intestinal
inflammation in IBD patients.
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. Liganddependent 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
AF-1
Dimerization
C-terminus
AF-2
B
PPAR
RXR
DNA
PPRE
Regulation of gene expression
C
PPARγγ
5-ASA
5-ASA
PPARγγ
LBD
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,
these observations led to the characterization of the
potential anti-inflammatory effect of 5-ASA through PPARγ
expression and activation.
PPARγ structure and expression
PPARγ belongs to the nuclear receptor family consisting
of a group of approximately 50 transcription factors
characterized by a common structure [10]. The PPARγ
structure is characterized by a central DNA-binding domain
(DBD) and a carboxy-terminal domain that mediates ligand
binding (LBD), dimerization, and transactivation functions.
In order to be functional, PPARγ must form a heterodimer
with another nuclear receptor known as the retinoid
X receptor α (RXRα) (Fig. 4), leading to the binding of
this heterodimer to specific DNA sequence elements,
termed peroxisome proliferator response elements [11].
Ligand-dependent transcription requires a highly conserved
motif, termed activating function-2 (AF-2), located at the
C-terminus of the LBD [12]. PPARγ is an essential nuclear
receptor controlling the expression of a large number of
regulatory genes for lipid metabolism and insulin sensitization,
as well as inflammation and cell proliferation [13,14].
High levels of PPARγ expression have been reported in
both colonic and adipose tissues. It was originally described
as a receptor expressed by adipose tissue – where it plays a
93
Figure 5. Regulation of PPARγ expression in intestinal
epithelial cells. PPARγ expression is induced in epithelial
cells by three major factors: probiotics such as bacteria
and yeast, nutrients (e.g. tocopherol), and PPARγ agonists
(e.g. rosiglitazone). With regard to bacteria, a component of
the Gram-negative wall, LPS, has been shown to increase
PPARγ expression after activation of the TLR4. Butyrate,
which is produced by colonic bacteria, is able to induce
PPARγ expression in colonocytes.
Microorganisms:
Bacteria
LPS
Saccharomyces boulardii
Butyrate
Nutrients:
Tocopherol
TLR4
Apex
Agonists:
Rosiglitazone
5-ASA
PPARγ
Intestinal epithelial cell
Base
5-ASA: 5-aminosalicylic acid; LPS: lipopolysaccharide; PPAR: peroxisome
proliferator activated receptor; TLR4: Toll-like receptor 4.
role in adipocyte differentiation and in the regulation of
insulin responses; in the colon, PPARγ is mainly expressed by
epithelial cells located at the luminal surface and, to a lesser
degree, in lamina propria mononuclear cells [15–19].
Regulation of PPARγ expression remains poorly investigated.
In adipocytes, different in vitro studies have demonstrated
a synergistic effect of insulin and corticosteroids [20,21].
In the colon, where PPARγ is overexpressed compared with
the small bowel, microorganisms such as bacteria and yeast
are able to increase expression and/or activation of this
nuclear receptor (Fig. 5) [17,22–24].
Classical ligands of PPARγ
The LBD of PPARγ is particularly large and can accept a high
variety of natural and synthetic ligands. Many natural
endogenous lipophilic species such as the polyunsaturated
fatty acids (PUFAs) and eicosanoids are classically proposed
as natural PPARγ ligands (Fig. 6) [25,26]. Although many
PUFAs activate PPARγ in micromolar concentrations and
are recorded as functional in human plasma at these
94
concentrations, their in vivo intestinal effects through
PPARγ activation remain hypothetical; this is because the
concentrations of these fatty acids within colonic cells are
unknown [25]. The eicosanoid 15-deoxy-prostaglandin J2
(15d-PGJ2) is also proposed to be a natural ligand of PPARγ
[26]. However, the physiological role of 15d-PGJ2 in PPARγ
activation in the colon remains open for debate as the
minimal concentrations of 15d-PGJ2 required to activate
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),
which is generated via nitric oxide-dependent oxidative
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
500 nM, LNO2 is considered to be one of the most potent
physiological endogenous natural ligands of PPARγ at
present, efficacious at nM concentrations.
Concerning synthetic ligands, two main different groups
of chemical compounds have been developed; these are
glitazones, which bind selectively to PPARγ, and glitazars,
which have the ability to bind both PPARα and PPARγ.
Numerous glitazone molecules have been developed, and
two (rosiglitazone, Avandia® [GlaxoSmithKline, Research
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).
Due to their systemic effects, the most well known adverse
events of glitazones observed in patients with diabetes are
weight gain and, infrequently, hepatotoxicity. Glitazars are a
novel family of dual-acting PPARα/γ agonists developed as
on oral treatment for insulin resistance-related glucose and
lipid abnormalities associated with type 2 diabetes and the
metabolic syndrome [29]. Nonsteroidal anti-inflammatory
drugs are also reported to be PPARγ ligands in vitro, but
their binding affinities of 0.1 mM are 1000-fold higher than
the mean concentrations found in patients conventionally
treated with these drugs [30].
5-ASA: a prototype of a new class of PPARγ agonists
Recently, the current authors published studies showing
functional, biological, pharmacological, and chemical evidence
that aminosalicylates were a new functional synthetic ligand
of PPARγ in colonic epithelial cells [31]. They showed that
chemically induced colitis in mice heterozygous at the PPARγ
locus (PPARγ+/–) was refractory to 5-ASA therapy, arguing for
a major role of PPARγ in mediating the anti-inflammatory
effect of 5-ASA in the gut. In addition, they found that 5-ASA
induced PPARγ expression in the HT-29 human colonic
epithelial cell line. 5-ASA is also able to bind PPARγ to induce
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:
Omega 3
8S-hydroxyeicosapentaenoic ac.
α-linolenic ac.
12-hydroxyeicosatetraenoic ac.
γ-linolenic ac.
15-hydroxyeicosatetraenoic ac.
eicosapentanic ac.
9-hydroxyoctodecadienoic ac.
docohexanoic ac.
15dPGJ2
Omega 6
linoleic ac.
Miscellaneous:
dihomo-γ-linolenic ac.
Swientenia mahagony extract
arachidonic ac.
Lysophosphatidic acid
Omega 9
9-tetrahydrocannabinol
palmitoleic ac.
Soy isoflavavone
oleic ac.
Derivatives
Conjugated linoleic ac. (CLA)
Nitrolinoleic ac. (LNO2)
Nitrooleic ac. (OA-NO2)
Glitazones:
Omega 3
Rosiglitazone
Ciglitazone
Troglitazone
Pioglitazone
Netoglitazone (MCC-555)
Glitazars:
Muraglitazar
Tesaglitazar
Farglitazar
Ragaglitazar
PPAR
NSAIDs:
Indomethacin
Flufenamic acid
Fenoprofen
Ibuprofen
L-Tyrosine
derived
compounds:
FMOC-L-Leu
Miscellaneous:
5-ASA
CDDO
COOH
Triphenyltin
BADGE
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-2propylphenoxy) 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
nucleus, to promote a PPARγ conformational change, and to
recruit a coactivator named vitamin D receptor-interacting
protein (Fig. 7). Docking simulations showed a binding
mode of 5-ASA very similar to the crystal orientation of the
thiazolidinedione head group of rosiglitazone. 5-ASA fitted
tightly with the PPARγ LBD, interacting through hydrogen
bonding with His-323, His-449, Tyr-473, and Ser-289,
which are considered the key molecular determinants
required for ligand recognition and PPARγ activation [31].
Taken together, these data show that PPARγ is an essential
receptor mediating the common 5-ASA activities in IBD.
Anti-inflammatory properties
of PPARγ in the colon
Preclinical data
In vitro studies have shown that PPARγ is able to limit
the production of inflammatory mediators, such as proinflammatory cytokines produced by human activated
monocytes and mouse peritoneal macrophages, through
an inhibition of transcription driven by nuclear factor-κB
(NF-κB) and activator protein-1 transcription factors [32,33].
The first evidence of the involvement of PPARγ in the regulation
of intestinal inflammation came from the use of the PPARγ
synthetic agonist thiazolidinedione in mice with colitis
induced by oral administration of dextran sodium sulfate
[34]. In that study, the two different thiazolidinediones,
troglitazone and rosiglitazone, dramatically reduced the
disease severity in mice by 47–70%. These results were
confirmed and extended several months later in another
mouse model of experimental colitis induced by intrarectal
administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS).
Thiazolidinediones given preventively or in treatment
mode have a therapeutic effect in reducing the mortality
rate, and also reduce the intensity of macroscopic and
histological lesions and levels of biological markers of
colonic inflammation, including the NF-κB and stress kinase
pathways involved in the transduction of inflammation [35].
95
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
p50
Cell
membrane
JNK
p38
calcineurin
5-ASA
CBP
p65 p50
NF-κB
5-ASA
CBP
Jun
CBP
fos
Jun
AP-1
fos
AP-1
NFAT
Cytokines
Chemokines
Cell proliferation
Adhesion molecules
Cytoplasm
PPAR
EC
Adhesion molecules
(VCAM-1 ICAM-1, E- and P-selectins)
DRIP
5ASA
Nucleus
PPAR
RXR
EC activation
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
protection against inflammation of the colon was shown by
the increased susceptibility of PPARγ heterozygous mice
(PPARγ+/–) to TNBS-induced inflammation compared with
their wild-type littermates [35]. At present, >20 published
studies have reported similar prophylactic and therapeutic
effects of PPARγ in animal models. These include acute
colitis induced by chemical compounds, bacteria, or
ischemia-reperfusion in different strains of mice, rats,
or pigs, and also in chronic colitis occurring after the transfer
of immunocompetent T cells to severe combined immunodeficient mice or spontaneously in interleukin-10-deficient
mice and SAMP1/YitFc animals [34–41]. Recently, two
studies have shown the importance of PPARγ expression in
96
both epithelial cells and macrophages for regulation of
intestinal inflammation during experimental colitis [42,43].
PPARγ in patients with UC
Despite in vitro and in vivo evidence of the anti-inflammatory
functions of the PPARγ/RXR heterodimer in the colon,
very few studies have assessed the roles of PPARγ in UC
[17,40,44]. As PPARγ is mainly expressed in the colon by
epithelial cells, the expectation might be that a decreased
expression of this receptor may be found in an inflammatory
disorder confined to superficial layers of the intestine and
limited to the colon, such as UC. A decreased expression
of PPARγ was observed at the mRNA and protein levels in
the colons of UC patients compared with individuals who
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
PPAR:
Anti-inflammatory
Control
TLR4:
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
was found in both healthy and inflamed colons and was
limited to epithelial cells, suggesting that the perturbed
levels of PPARγ in UC is not secondary to the inflammatory
process. The etiology underlying the impaired PPARγ
expression in colonic epithelial cells of UC patients remains
unknown. Comparable levels of PPARγ in the peripheral
mononuclear cells of IBD patients and controls, and the
absence of specific mutations of the PPARγ gene or its
promoter in UC patients, suggest that epigenetic events
may account for the impaired PPARγ expression in UC
patients [17]. Another attractive possibility may be that
the Toll-like receptor 4 (TLR4) signaling to PPARγ is
impaired in UC, and an imbalance between elevated
levels of TLR4 and the impaired expression of PPARγ in
epithelial cells of UC patients may alter mucosal tolerance to
luminal lipopolysaccharide, resulting in superficial colonic
inflammation (Fig. 8) [17]. More generally, it could be
hypothesized that impaired expression of PPARγ in UC may
be secondary to non-functional regulation of PPARγ
expression in epithelial cells due to abnormal signaling
pathways and/or a lack of luminal stimuli induced by natural
ligands or microorganisms. Further study is required to
investigate more precisely the complex regulation of PPARγ
expression by epithelial cells in UC patients. It is possible
that the 5-ASA effect observed in UC patients for the
maintenance of remission is due to PPARγ activation in
epithelial cells; however, during active disease, when the
epithelium is disorganized, 5-ASA might also act through
activation of PPARγ expressed by lamina propria macrophages
and T lymphocytes.
To date, only one open-label, pilot trial has evaluated
the efficacy of the PPARγ ligand rosiglitazone (4 mg orally,
twice daily) in 15 patients with active UC, refractory to
conventional treatment with either corticosteroids or
immunomodulators and 5-ASA [44]. After 12 weeks of
treatment with rosiglitazone, a substantial decrease in
disease activity index score was reported, with clinical and
endoscopic remission (27% and 20%, respectively) or a
partial response (27%) in eight patients. This study in IBD
patients has led to new clinical trials in IBD with these
chemical compounds, and may lead to the development of
safer PPARγ agonists that have topical effects and selectively
targeting the colon.
Conclusion and perspectives
Anti-inflammatory effects of 5-ASA are mainly mediated
through PPARγ, a key receptor expressed by epithelial cells
that regulates bacterial-induced inflammation. Present
knowledge supports the concept that the therapeutic effect
of 5-ASA in UC patients is mainly mediated through a
normalization of PPARγ expression and its activation in
97
colonic epithelial cells. This may also explain why 5-ASA is
less effective in CD, which is a condition characterized by
transmural inflammation affecting predominantly the small
bowel, where the levels of PPARγ expression remain low
(Fig. 8). The description of 5-ASA as a new PPARγ ligand
also opens an avenue for the rational development of novel
molecules that have a local effect and better affinity for
PPARγ in colonic epithelial cells. Together with the
development of new galenic formulations designed to
facilitate prolonged exposure of the active compound into
the colonic mucosa, such as the MMXTM technology, we can
expect new 5-ASA optimized molecules with higher antiinflammatory properties combined with anti-neoplasic
effects to be developed in the near future [45].
17. Dubuquoy L, Jansson EA, Deeb S et al. Impaired expression of peroxisome proliferator
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.
19. Tontonoz P, Nagy L, Alvarez JG et al. PPARgamma promotes monocyte/macrophage
differentiation and uptake of oxidized LDL. Cell 1998;93:241–52.
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
by insulin and glucocorticoids. J Clin Invest 1997;99:2416–22.
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
1999;48:699–705.
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.
23.
Lee SK, Kim HJ, Chi SG et al. [Saccharomyces boulardii activates expression of peroxisome
proliferator-activated receptor-gamma in HT-29 cells]. Korean J Gastroenterol 2005;45:328–34.
24. Konturek PC, Kania J, Kukharsky V et al. Implication of peroxisome proliferator-activated
receptor gamma and proinflammatory cytokines in gastric carcinogenesis: link to
Helicobacter pylori-infection. J Pharmacol Sci 2004;96:134–43.
25. Schoonjans K, Martin G, Staels B et al. Peroxisome proliferator-activated receptors,
orphans with ligands and functions. Curr Opin Lipidol 1997;8:159–66.
Acknowledgments
26. Forman BM, Tontonoz P, Chen J et al. 15-Deoxy-delta 12, 14-prostaglandin J2 is
a ligand for the adipocyte determination factor PPAR gamma. Cell 1995;83:803–12.
The authors would like to thank the Centre Thématique de Recherches
27. FitzGerald GA, Loll P. COX in a crystal ball: current status and future promise of
prostaglandin research. J Clin Invest 2001;107:1335–7.
et de soins (CTRS), the Lions Club, the Association François Aupetit,
the Fondation pour la Recherche Médicale, the Institut Universitaire
de France, IRMAD, UCB Pharma, and Giuliani S.p.A for their support.
Disclosures
Dr Desreumaux has received support for research on 5-ASA from
Giuliani Pharma, Milan, Italy.
1.
Azad Khan AK, Piris J, Truelove SC. An experiment to determine the active therapeutic
moiety of sulphasalazine. Lancet 1977;2:892–5.
2.
Frieri G, Giacomelli R, Pimpo M et al. Mucosal 5-aminosalicylic acid concentration
inversely correlates with severity of colonic inflammation in patients with ulcerative colitis.
Gut 2000;47:410–4.
3.
Christensen LA, Fallingborg J, Abildgaard K et al. Topical and systemic availability
of 5-aminosalicylate: comparisons of three controlled release preparations in man.
Aliment Pharmacol Ther 1990;4:523–33.
4.
Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral
mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative
colitis. Aliment Pharmacol Ther 2003;17:29–42.
5.
Zhou SY, Fleisher D, Pao LH et al. Intestinal metabolism and transport of 5-aminosalicylate.
Drug Metab Dispos 1999;27:479–85.
6.
Bondesen S. Intestinal fate of 5-aminoslicylic acid: regional and systemic kinetic studies
in relation to inflammatory bowel disease. Pharmacol Toxicol 1997;81:1–28.
7.
Naganuma M, Iwao Y, Ogata H et al. Measurement of colonic mucosal concentrations
of 5-aminosalicylic acid is useful for estimating its therapeutic efficacy in distal ulcerative
colitis: comparison of orally administered mesalamine and sulfasalazine.
Inflamm Bowel Dis 2001;7:221–5.
8.
Vree TB, Dammers E, Exler PS et al. Liver and gut mucosa acetylation of mesalazine
in healthy volunteers. Int J Clin Pharmacol Ther 2000;38:514–22.
9.
Allgayer H, Ahnfelt NO, Kruis W et al. Colonic N-acetylation of 5-aminosalicylic acid
in inflammatory bowel disease. Gastroenterology 1989;97:38–41.
10. Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the
nuclear receptor superfamily. Cell 1999;97:161–3.
11. Kliewer SA, Umesono K, Noonan DJ et al. Convergence of 9-cis retinoic acid and
peroxisome proliferator signalling pathways through heterodimer formation of their
receptors. Nature 1992;358:771–4.
Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988;240:889–95.
13. Debril MB, Renaud JP, Fajas L et al. The pleiotropic functions of peroxisome proliferatoractivated receptor gamma. J Mol Med 2001;79:30–47.
14. Fajas L, Debril MB, Auwerx J. Peroxisome proliferator-activated receptor-gamma:
from adipogenesis to carcinogenesis. J Mol Endocrinol 2001;27:1–9.
15. Fajas L, Auboeuf D, Raspe E et al. The organization, promoter analysis, and expression
of the human PPARgamma gene. J Biol Chem 1997;272:18779–89.
16. Lefebvre M, Paulweber B, Fajas L et al. Peroxisome proliferator-activated receptor gamma
is induced during differentiation of colon epithelium cells. J Endocrinol 1999;162:331–40.
98
29. Lohray BB, Lohray VB, Bajji AC et al. (-)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2ethoxypropanoic acid [(-)DRF 2725]: a dual PPAR agonist with potent antihyperglycemic
and lipid modulating activity. J Med Chem 2001;44:2675–8.
30. Lehmann JM, Lenhard JM, Oliver BB et al. Peroxisome proliferator-activated receptors
alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory
drugs. J Biol Chem 1997;272:3406–10.
31. Rousseaux C, Lefebvre B, Dubuquoy L et al. Intestinal antiinflammatory effect of
5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma.
J Exp Med 2005;201:1205–15.
References
12.
28. Schopfer FJ, Lin Y, Baker PR et al. Nitrolinoleic acid: an endogenous peroxisome
proliferator-activated receptor gamma ligand. Proc Natl Acad Sci USA 2005;102:2340–5.
32. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte
inflammatory cytokines. Nature 1998;391:82–6.
33. Ricote M, Li AC, Willson TM et al. The peroxisome proliferator-activated receptor-gamma
is a negative regulator of macrophage activation. Nature 1998;391:79–82.
34. Su CG, Wen X, Bailey ST et al. A novel therapy for colitis utilizing PPAR-gamma ligands
to inhibit the epithelial inflammatory response. J Clin Invest 1999;104:383–9.
35. Desreumaux P, Dubuquoy L, Nutten S et al. Attenuation of colon inflammation through
activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor
gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies.
J Exp Med 2001;193:827–38.
36. Hontecillas R, Wannemeulher MJ, Zimmerman DR et al. Nutritional regulation of porcine
bacterial-induced colitis by conjugated linoleic acid. J Nutr 2002;132:2019–27.
37. Nakajima A, Wada K, Miki H et al. Endogenous PPAR gamma mediates anti-inflammatory
activity in murine ischemia-reperfusion injury. Gastroenterology 2001;120:460–9.
38. Bassaganya-Riera J, Reynolds K, Martino-Catt S et al. Activation of PPAR gamma and
delta by conjugated linoleic acid mediates protection from experimental inflammatory
bowel disease. Gastroenterology 2004;127:777–91.
39. Lytle C, Tod TJ, Vo KT et al. The peroxisome proliferator-activated receptor gamma ligand
rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10
deficiency. Inflamm Bowel Dis 2005;11:231–43.
40. Sugawara K, Olson TS, Moskaluk CA et al. Linkage to peroxisome proliferator-activated
receptor-gamma in SAMP1/YitFc mice and in human Crohn’s disease.
Gastroenterology 2005;128:351–60.
41. Sánchez-Hidalgo M, Martin AR, Villegas I et al. Rosiglitazone, an agonist of peroxisome
proliferator-activated receptor gamma, reduces chronic colonic inflammation in rats.
Biochem Pharmacol 2005;69:1733–44.
42. Shah Y, Morimura K, Gonzalez F. Expression of peroxisome proliferator-activated
receptor-{gamma} in macrophage suppresses experimentally-induced colitis.
Am J Physiol Gastrointest Liver Physiol 2006; [Epub ahead of print].
43. Adachi M, Kurotani R, Morimura K et al. Peroxisome proliferator activated receptor
gamma in colonic epithelial cells protects against experimental inflammatory bowel
disease. Gut 2006;55:1104–13.
44. Lewis JD, Lichtenstein GR, Stein RB et al. An open-label trial of the PPAR-gamma ligand
rosiglitazone for active ulcerative colitis. Am J Gastroenterol 2001;96:3323–8.
45. Baker DE. MMX mesalamine. Rev Gastroenterol Disord 2006;6:146–52.
Department of Internal Medicine and Digestive Pathology, University Hospital of Nancy, Nancy, France
The development of capsule endoscopy over recent years has significantly improved investigations of the small bowel in
Crohn’s disease (CD) patients, and in those suspected of having CD. Although multiple morphological investigations of the
small bowel may be required for a definitive diagnosis of CD, capsule endoscopy has been shown to detect significantly
more lesions than other modalities such as small bowel follow-through, entero-CT scanning, or classical endoscopic
procedures. Capsule endoscopy has a number of important indications, for example, to support a diagnosis of CD in
patients with a clinical and/or biological suspicion of CD and a negative classical endoscopic work-up. Furthermore, the
procedure is well tolerated and can be repeated during follow-up. This review summarizes the studies that have evaluated
capsule endoscopy in patients with CD to date, and discusses the specific clinical issues that are associated with the
procedure, along with its indications. Inflamm Bowel Dis Monit 2007;7(3):99–105.
Crohn’s disease (CD) was initially described as “terminal
ileitis” and endoscopic investigations of patients suffering
from the disease focused mainly on the colon and the
terminal ileum, which are accessible to colonoscopy.
Until recently, lesions in other segments of the small bowel
were poorly investigated in the absence of specific
symptoms, such as obstruction due to an intestinal stenosis.
Elemental lesions found in the small bowel of CD patients
are multiple and can be distributed along the whole small
bowel. Depending on the inflammatory status and duration
of the disease, endoscopic findings will be characterized
by the presence of aphthae, erosions, mucosal fissures,
fibrotic stenoses, or inflammatory pseudo-polyps [1]. The
endoscopic pattern may be highly suggestive of CD, but
in many instances the differential diagnosis between this
and other conditions will be challenging as, individually,
these elemental lesions may not be specific to CD (Table 1).
Biopsies will be required to establish a firm diagnosis [2].
Examples of endoscopic findings in patients with CD and in
those who have diseases with endoscopic patterns similar to
CD are shown in Figures 1 and 2.
Endoscopic investigations of the small bowel must be
considered in several clinical situations including in patients
with known CD or those who are strongly suspected of
having CD, when lesions are limited to the small bowel, in
Address for Correspondence: Michel Delvaux, Department of
Internal Medicine and Digestive Pathology, Hôpitaux de Brabois,
CHU de Nancy, F-54511 Vandoeuvre les Nancy, France.
the presence of extra-intestinal manifestations of the disease
without typical colonic lesions, and in patients with clinical
symptoms not explained by lesions found at colonoscopy.
Morphological investigations of the small bowel, both
radiological and endoscopic, have dramatically improved
over the last two decades. Computed tomography (CT),
magnetic resonance imaging (MRI), and abdominal
ultrasound allow for a more effective examination of the
small bowel compared with that achieved with small bowel
follow-through series [3,4].
Examinations performed with enteroclysis and infusion
of water into the lumen of the gut further increase the
diagnostic yield of CT and MRI. Following on from
the development of push-enteroscopy in the 1980s [5],
the emergence of wireless capsule endoscopy in 2000 [6]
and, more recently, double balloon enteroscopy [7], have
enabled the endoscopic examination of the entire small
bowel. Moreover, biopsies and therapeutic interventions are
possible during double balloon enteroscopy. Radiological
investigations are effective in exploring intestinal stenoses,
large ulcers, and extra-intestinal manifestations such as
abscesses, sclerolipomatosis, or fistulae. In contrast,
endoscopic examinations more frequently detect tiny
mucosal lesions such as aphthae and erosions. Thus, the
combination of these investigations has significantly
increased the capacity to investigate the small bowel in
clinical settings. This has also resulted in a dramatic increase
in the diagnostic yield in patients with suspected intestinal
diseases, and has enabled the diagnostic and therapeutic
approach to several conditions to be modified.
99
LEADING ARTICLE
Capsule Endoscopy in the
Diagnosis of Crohn’s Disease
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
comparative controlled studies, and its success in the
diagnosis of patients with obscure gastrointestinal bleeding
has been demonstrated to be consistently higher than that
of other modalities [8,9]. In these studies, in >85% of
patients the capsule was shown to enter into the cecum by
the end of the 8-h recording period, and thus, had
examined the entire intestinal mucosa. However, the role of
capsule endoscopy in the diagnosis of CD has not yet been
fully elucidated. The clinical situation of patients presenting
with CD are variable and the diagnostic assessment must be
tailored to the current status of the disease (level of activity,
main symptoms, and surgical history). Therefore, it is not
possible to design a simple algorithm to define the role of
capsule endoscopy. Indications must be discussed case by
case, and further studies are clearly needed to validate a
specific strategy.
Consequently, the aim of this review is to summarize the
results of studies that have evaluated capsule endoscopy in
patients with CD, to discuss the specific clinical issues related
100
Table 1. Intestinal diseases showing elemental lesions similar
to those of CD.
Frequency
CD
++++
Drug-related injuries (NSAIDs)
+++
Mesenteric ischemia
++
Celiac disease (jejunitis)
++
Cryptogenetic multifocal ulcerous
stenosing enteritis
+
Radiational enteritis
+
Lymphoma, ulcerated cancer
+
Vasculitus (lupus, polyarthritis, PAN)
+
Behçet’s disease
+/–
Eosinophilic enteritis
+/–
Infections (CMV, yersinia)
+/–
+/–: Indicates the frequency of intestinal lesions in the disease compared with
CD; CD: Crohn’s disease; CMV: cytomegalovirus; NSAID: nonsteroidal antiinflammatory drug; PAN: polyarteritis nodosa.
CAPSULE ENDOSCOPY IN THE DIAGNOSIS OF CROHN’S DISEASE
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
finally, to outline its possible indications.
Elemental lesions of CD at capsule endoscopy
The endoscopic diagnosis of CD is based on the presence of
a spectrum of elemental lesions, which can occur either in
the small bowel or in the colon. During classical endoscopy,
insufflation of air distends the lumen of the organ and allows
the immediate examination of long segments of the gut,
thus allowing the simultaneous identification of multiple
lesions presented in an endoscopic pattern that may be
highly suggestive of CD. Capsule endoscopy examines the
gut wall in a distinct way to classical endoscopy. Due
to the absence of air insufflation during the former
procedure, the mucosa is closely observed and only a short
segment of the gut can be viewed on each frame. Therefore,
most of the time, the lesions will be observed and described
separately. At the end of the analysis, the endoscopist
will consider all of the findings in order to formulate
a diagnosis.
The Minimal Standard Terminology for Digestive
Endoscopy, which is a structured language for the description
of the lesions observed during endoscopic procedures
was proposed and validated in 2000 [10]. More recently,
an adapted version named Capsule Endoscopy Structured
Terminology (CEST), which takes into account the specificity
of capsule endoscopy for the small bowel, was designed
[11]. The CEST is based on the principle of a separate
description of the elemental lesions (e.g. ulcers, stenosis,
aphthae, and erosions) and a diagnosis that is based on the
global understanding of all the findings. Terms describing
the lesions are listed, and each of these be can further
categorized according to specific attributes. Similarly, the
diagnosis can be specified by indicating the confidence level
that it can be assigned. The objective is to promote
standardized descriptions to be used in the reports of
capsule endoscopy. In the setting of CD, this effort is
of considerable importance, as an accurate description of
the lesions observed by the capsule will support a better
outcome of the studies evaluating the diagnostic capability
101
of the technique. Moreover, individual intestinal or colonic
lesions are not pathognomonic of CD and can be observed
in a number of conditions (Table 1). In addition, some
minimal lesions can also be observed in healthy subjects, as
shown by Goldstein et al., who found mucosal breaks and
erosions in 14% of healthy subjects (not taking nonsteroidal
anti-inflammatory drugs [NSAIDs]) [12]. This highlights the
clinical importance of capsule findings.
In summary, the diagnosis of these lesions presents
a real challenge for the endoscopist as they are not specific
to CD, and a firm diagnosis may require the pathological
examination of the biopsies. Clinical relevance can be
ascertained by the severity of the lesions, their number, and
the diffuse involvement of the mucosa. However, isolated,
minute lesions should be more cautiously interpreted to
avoid over-diagnosis of CD.
Diagnostic yield of capsule endoscopy
and comparison with other investigations
Initial studies of capsule endoscopy were predominantly
performed in patients with obscure gastrointestinal
bleeding (reviewed in [13]). However, over the same time
period, several studies involving small series of CD patients
were published. The limitations of these early studies
are the number of patients included, the choice of the
comparator subjects, and often the use of small bowel
follow-through, which should no longer be regarded as the
most effective radiological investigation for the small bowel
in view of advances in abdominal ultrasound, CT, and MRI
with enteroclysis [14,15]. Capsule endoscopy detects more
intestinal lesions of CD compared with any radiological
modality (small bowel follow-through, entero-CT scanning,
entero-MRI) or other classical endoscopic procedures
(oesophago-gastro-duodenoscopy [OGD], ileo-colonoscopy,
push-enteroscopy) [16–22]. The diagnostic yield of capsule
endoscopy in this indication has been reported to be as high
as 40–74% and even 93% in some of these studies.
Furthermore, detection of intestinal lesions of CD by
capsule endoscopy may modify the management of the
patient. Studies by Voderholzer et al. [18] and Chong et al.
[21] showed that capsule endoscopy significantly influences
the therapeutic strategy in at least 25% of patients
undergoing investigations for known CD. Finally, in a recent
report, capsule endoscopy influenced the choice of therapy
in 17 patients who underwent surgery (ileo-cecal resection)
for CD, as the presence of intestinal ulcers at capsule
endoscopy was predictive of disease recurrence [23].
These results were recently summarized in a metaanalysis that considered all published studies [24]. This
analysis found that capsule endoscopy detects more lesions
compared with small-bowel follow through (incremental
102
yield 42%), entero-CT scanner (incremental yield 38%), and
ileo-colonoscopy (incremental yield 15%).
Capsule endoscopy and double
balloon enteroscopy
A diagnosis of CD can be suggested by a typical endoscopic
pattern, the association of endoscopic lesions with positive
serological tests, or the combined findings from biological,
radiological, and endoscopic analyses that are not individually
typical of CD, but together indicate the presence of the
disease. In the latter case, the diagnosis will require
confirmation by biopsies. Intestinal lesions may be accessible
to biopsy during double balloon enteroscopy [25]. By
combining the oral and the anal routes, the whole small
bowel can be examined, and biopsies or therapeutic
interventions performed as easily as during colonoscopy.
However, it is difficult to define the actual number of cases in
which the entire small bowel can be examined by double
balloon enteroscopy. In the study of Yamamoto et al.,
examination of the entire small bowel was reported in
approximately 25% of the patients using a combined
procedure (oral plus anal routes) [25]; however, these authors
did not have access to capsule endoscopy at this time.
In CD, double balloon enteroscopy may be proposed
after capsule endoscopy has identified lesions that require
biopsies, for example, pseudopolyps. In this situation,
capsule endoscopy can direct the choice of route to be used,
and therefore avoid unnecessary double examinations [9].
In patients who are at a risk of capsule blockade – a frequent
issue in patients with CD – double balloon enteroscopy may
be proposed as the initial investigation for detection of
intestinal lesions. In this indication, double balloon
enteroscopy has been shown to detect intestinal lesions in
about one-third of patients who are suspected of having CD
by biological analyses, but have a normal classical endoscopic
assessment (OGD plus colonoscopy) [26]. Moreover, double
balloon enteroscopy may have a therapeutic application in
some patients with symptomatic intestinal strictures that can
be dilated with a hydrostatic balloon [27].
Indications of capsule endoscopy
in patients with CD
To date, indications for capsule endoscopy in patients with CD
have remained under evaluation, and the current literature
needs to be scrutinized before a standard of practice
is defined. The most extensively evaluated application is
for the investigation of the patient with a clinical and/or
biological suspicion of CD and a negative classical endoscopic
work-up, including OGD and ileo-colonoscopy. In such
patients, capsule endoscopy may detect intestinal lesions in up
to 70% of individuals [18,19,22,29]. In the study by
Voderholzer et al. [18], capsule endoscopy was more effective
than CT with enteroclysis for detection of lesions in the small
bowel, but not in the terminal ileum. This result may be
explained by the frequent association of CD lesions in the
terminal ileum with sclerolipomatosis, which is easily
recognized by CT. The studies of Voderholzer et al. and
Chong et al. demonstrated that the detection of intestinal
lesions by capsule endoscopy resulted in adaptation of
treatment in 25% [18] and 70% [21] of patients, respectively.
Patients with indeterminate colitis may benefit from an
investigation with capsule endoscopy. In a study of 21 patients
with unclassified colitis, the detection of intestinal lesions
led to a diagnosis of CD in five subjects [29]. Similar findings
were reported by Whitaker et al. [30].
Another potential indication for capsule endoscopy
is during the follow-up of patients having undergone an ileocecal resection for CD. Two studies have shown that capsule
endoscopy may detect early recurrence of disease after surgery
[23,31]. According to these studies, recurrence occurs within
the first year in two out of three patients. Capsule endoscopy
and colonoscopy are equally effective for diagnosis of lesions
located around the ileo-colonic anastomosis [23]. However,
capsule endoscopy detected jejunal lesions in 60% of the
patients and allowed the diagnosis of recurrence in an
additional two patients compared with those diagnosed by
ileo-colonoscopy. In the study by Biancone et al., capsule
endoscopy appeared equally as effective as colonoscopy or
contrast-enhanced ultrasonography for the diagnosis of
recurrence [31]. The main advantage of capsule endoscopy in
this indication is its excellent tolerance by the patient;
therefore, it can be easily repeated during the follow-up in
these subjects, who undergo frequent investigations. To
summarize, capsule endoscopy may be indicated in four
different clinical situations in patients with CD:
• To add support to a potential diagnosis of CD
in patients with a clinical and/or biological suspicion
of the disease, but who have normal results of
radiological and classical endoscopic procedures.
• The diagnosis of disease recurrence after surgery.
• To evaluate the extent of the lesions in the small
bowel in patients with known CD, although the
influence that this may have on patient management
has not been demonstrated.
• To further diagnose undetermined colitis by detection
of intestinal lesions, thus directing a double balloon
enteroscopy, with biopsies.
In contrast, capsule endoscopy has no indication in
patients in whom the diagnosis of CD can be firmly obtained
by the way of classical investigations. One could envisage
that capsule endoscopy may, in the future, be used to assess
the efficacy of immunosuppressive treatments, which are
increasingly prescribed to patients with CD.
Tolerance of capsule endoscopy:
the risk of capsule retention
Capsule retention is defined by the absence of natural
excretion of the capsule within 7 days following capsule
endoscopy. It must be distinguished from cases in which the
capsule did not reach the cecum during the 8-h recording
period, but was naturally excreted in a normal time. Capsule
retention has been shown to occur in approximately
1.5–1.8% of patients investigated for obscure gastrointestinal bleeding [32,33]. However, the frequency of
capsule retention is dramatically higher in patients with CD,
observed in up to 5% of the patients [19,20,34,35].
The experience from the literature shows that patients may
be contraindicated for capsule endoscopy, due to either an
intestinal stenosis demonstrated by a radiological
investigation, or clinical signs suggesting such a stenosis,
which is subsequently confirmed by radiology. In patients
with CD, the consequence of capsule retention may be
dramatically different from that in patients with an intestinal
tumor. The latter will most likely undergo surgery to treat
the lesion and the capsule removed at the same time,
whereas in patients with CD, surgery would not necessarily
be indicated, but performed only to remove the capsule.
There is no clear indicator of the presence of an intestinal
stenosis in patients undergoing capsule endoscopy.
Radiological assessment of the small bowel by abdominal
ultrasound [36], CT-enteroclysis, or MRI [37] is impaired
by low sensitivity and operator-dependent results. The
correlation between radiological and intra-operative findings
has been shown to be weak [38]. Clinical suspicion is based
mainly on the careful recording of the patient’s medical history,
i.e. history of abdominal surgery, use of NSAIDs, or the
presence of obstructive symptoms. To overcome this problem,
Given Imaging (Yoqneam, Israel) developed a “patency
capsule” to test the patency of the gastrointestinal tract.
However, three studies published in 2005, by Spada et al. in
Italy [39], Boivin et al. in Germany [40], and Delvaux et al. in
France [41], found that this system did not meet the
expectations of clinicians. Indeed, the envelope of the
dissolved capsule was itself responsible for an intestinal
occlusion requiring surgery in three patients who did not have
prior signs of obstruction and who would not otherwise have
required surgery at that time. Although prior radiological
investigations had suggested the presence of a stenosis in the
study by the current authors [41], the patients who underwent
surgery had a long fibrotic stenosis in which the envelope of
the dissolved capsule had become impacted.
103
In view of this experience, a second-generation patency
capsule has been developed: the AGILETM patency capsule
(Given Imaging). This has a timer plug at each end of the
capsule, which allows the dissolution to be more easily
triggered, even if one of the plugs is trapped in a tight
stenosis. Clinical studies are ongoing, but patients with CD
who are considered for an AGILE patency capsule should
always be informed of the risk of retention, as there is no
radiological investigation that allows the detection of these
stenoses with a high sensitivity. Therefore, indications of
capsule endoscopy should be discussed cautiously in patients
with known CD, taking into account a careful evaluation of
the risk/benefit ratio. Contrary to some advice previously
expressed in the literature [42], surgery is frequently not
mandatory in patients with CD, and the retention of the
capsule must be regarded as a serious adverse event when it
requires a surgical procedure that is otherwise not indicated.
1.
Lee SD, Cohen RD. Endoscopy of the small bowel in inflammatory bowel disease.
Gastrointest Endosc Clin N Am 2002;12:485–93.
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:
definitions and diagnosis. Gut 2006;55:i1–15.
3.
Gourtsoyiannis NC, Papanikolaou N, Karantanas A. Magnetic resonance imaging evaluation
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
diseases. Am J Roentgenol 2006;187:522–31.
5.
Gay GJ, Delmotte JS. Enteroscopy in small intestinal inflammatory diseases. Gastrointest
Endosc Clin N Am 1999;9:115–23.
6.
Iddan G, Meron G, Glukhovsky A et al. Wireless capsule endoscopy. Nature 2000;405: 417.
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.
8.
Triester SL, Leighton JA, Leontiadis GI et al. A meta-analysis of the yield of capsule
endoscopy compared to other diagnostic modalities in patients with obscure
gastrointestinal bleeding. Am J Gastroenterol 2005;100:2407–18.
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
strategy based on the patient outcome after 12 months. Endoscopy 2004;36:1067–73.
10. Delvaux M, Crespi M and the Computer Committee of ESGE. Minimal Standard
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):
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
Capsule endoscopy is now assuming a prominent role in the
investigation of patients with CD. Although it should not be
proposed systematically, indications can currently be refined
from data in the literature. Capsule endoscopy can be used in
patients with a clinical and/or biological suspicion of CD and a
negative classical endoscopic work-up, in patients followed
after surgical ileo-cecal resection, or in patients with abnormal
radiological findings requiring further investigations. Capsule
endoscopy may also be useful in patients with undetermined
colitis. However, capsule endoscopy must be integrated in a
graduated and multidisciplinary approach. The combination of
radiological and endoscopic investigations – capsule endoscopy
and/or double balloon enteroscopy – with advanced
immunological and biological tests has significantly improved
the differential diagnosis of intestinal diseases.
Capsule endoscopy and double balloon enteroscopy are
well tolerated by patients and can be repeated during the
follow-up in chronic diseases such as CD. The information
obtained will modify the knowledge about the involvement
of the small bowel, which appears to be more diffuse or
more frequent than previously described [43]. The frequency
of CD cases limited to the small bowel also seem to be more
frequent than previously reported – when investigations
were almost exclusively limited to the colon and terminal
ileum. Future studies need to demonstrate, in homogenous
groups of patients, that this earlier work-up will result in a
better outcome.
prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and
placebo. Clin Gastroenterol Hepatol 2005;3:133–41.
13. Delvaux M, Gay G. Capsule endoscopy in 2005: facts and perspectives. Best Pract Res
Clin Gastroenterol 2006;20:23–39.
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.
15. Schmidt S, Lepori D, Meuwly JY et al. Prospective comparison of MR enteroclysis with
multidetector spiral-CT enteroclysis: interobserver agreement and sensitivity by means of
“sign-by-sign” correlation. Eur Radiol 2003;13:1303–11.
16. Rieber A, Wruk D, Potthast S et al. Diagnostic imaging in Crohn’s disease: comparison of
magnetic resonance imaging and conventional imaging methods.
Int J Colorectal Dis 2000;15:176–81.
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
fluoroscopic enteroclysis. Gut 2005;54:1721–7.
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
enteroclysis. Gut 2005;54:369–73.
19. Fireman Z, Mahajna E, Broide E et al. Diagnosing small bowel Crohn’s disease with wireless
capsule endoscopy. Gut 2003;52:390–2.
20. Buchman AL, Miller FH, Walter A et al. Videocapsule endoscopy versus barium contrast
studies for the diagnosis of Crohn’s disease recurrence involving the small intestine.
Am J Gastroenterol 2004;99:2171–5.
21. Chong AK, Taylor A, Miller A et al. Capsule endoscopy vs push-enteroscopy and enteroclysis
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
established and suspected small-bowel Crohn’s disease: correlation with radiologic,
endoscopic and histologic findings. Gastrointest Endosc 2005;62:538–44.
23. Bourreille A, Jarry M, D’Halluin PN et al. Wireless capsule endoscopy versus
ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn’s disease:
a prospective study. Gut 2006;55:978–83.
24. Triester SL, Leighton JA, Leontiadis GI et al. A meta-analysis of the yield of capsule
endoscopy compared to other diagnostic modalities in patients with non-stricturing small
bowel Crohn’s disease. Am J Gastroenterol 2006;101:954–64.
25. Yamamoto H, Sekine Y, Sato Y et al. Total enteroscopy with a non-surgical steerable
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
double-balloon enteroscopy in Crohn’s disease. Am J Gastroenterol 2006;101:1484–9.
27. Sunada K, Yamamoto H, Kita H et al.Clinical outcomes of enteroscopy using the doubleballoon method for strictures of the small intestine. World J Gastroenterol 2005;11:1087–9.
28. Goldfarb NI, Pizzi LT, Fuhr JP Jr et al. Diagnosing Crohn’s disease: an economic analysis
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
in indeterminate colitis. Gut 2005;54:A73 (abstract).
Disclosures
The authors have no relevant financial interests to disclose.
104
References
30. Whitaker DA, Hume G, Radford-Smith GC. Can capsule endoscopy help differentiate
the aetiology of indeterminate colitis? Gastrointest Endosc 2004;59:117 (abstract).
31. Biancone L, Calabrese E, Bozzi RM et al. Small intestine contrast ultrasonography
versus videocapsule endoscopy for assessing Crohn’s disease post-operative recurrence:
a prospective longitudinal study. Gastroenterology 2006;130:A204 (abstract).
37. Schmidt S, Lepori D, Meuwly JY et al. Prospective comparison of MR enteroclysis with
multidetector spiral-CT enteroclysis: interobserver agreement and sensitivity by means
of “sign-by-sign” correlation. Eur Radiol 2003;13:1303–11.
32. Barkin JS, O’Loughlin C. Capsule endoscopy contraindications: complications and
how to avoid their occurrence. Gastrointest Endosc Clin N Am 2004;14:61–5.
38. Otterson MF, Lundeen SJ, Spinelli KS et al. Radiographic underestimation of small bowel
stricturing Crohn’s disease: a comparison with surgical findings. Surgery 2004;136:854–60.
33. Rosch T, Ell C. [Position paper on capsule endoscopy for the diagnosis of small bowel
disorders]. Z Gastroenterol 2004;42:247–59.
34. Mow WS, Lo SK, Targan SR et al. Initial experience with wireless capsule enteroscopy
in the diagnosis and management of inflammatory bowel disease. Clin Gastroenterol
Hepatol 2004;2:31–40.
35. Herrerias JM, Caunedo A, Rodriguez-Tellez M et al. Capsule endoscopy in patients
with suspected Crohn’s disease and negative endoscopy. Endoscopy 2003;35:564–8.
36. Fraquelli M, Colli A, Casazza G et al. Role of US in detection of Crohn disease:
meta-analysis. Radiology 2005;236:95–101.
39. Spada C, Spera G, Riccioni M et al. A novel diagnostic tool for detecting functional
patency of the small bowel: the Given patency capsule. Endoscopy 2005;37:793–800.
40. Boivin ML, Lochs H, Voderholzer WA. Does passage of a patency capsule indicate
small-bowel patency? A prospective clinical trial? Endoscopy 2005;37:808–15.
41. Delvaux M, Ben Soussan E, Laurent V et al. Clinical evaluation of the use of the M2A
patency capsule system before a capsule endoscopy procedure, in patients with known
or suspected intestinal stenosis. Endoscopy 2005;37:801–7.
42. Swain P. Wireless capsule endoscopy and Crohn’s disease. Gut 2005;54:323–6.
43. Kornbluth A, Colombel JF, Leighton JA et al. ICCE consensus for inflammatory bowel
disease. Endoscopy 2005;37:1051–4.
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
Muc2-deficient mice spontaneously develop colitis,
indicating that MUC2 is critical for colonic protection
Van der Sluis M, De Koning BA, De Bruijn AC et al.
Mucins are produced by goblet cells in the gut, and
are a major component of the protective mucus layer.
The authors of this study generated mice deficient in
MUC2 (the predominant mucin type) and assessed the
development and course of disease in experimentally
induced colitis in the knockout (Muc2–/–) compared with
heterozygous (Muc2+/–), and wild-type (Muc2+/+) mice.
MUC2 deficiency resulted in inflammation of the colon,
which occurred at an earlier time point and was more
severe when an experimental colitis was induced.
An appreciation that defects in mucosal protection may be
critical in the development of IBD is increasing rapidly. This is
of relevance in both ulcerative colitis (UC) and Crohn’s disease
(CD). The association of defensin deficiency in carriers of
NOD2 gene variants is a pertinent example. The defensins, a
family of antimicrobial peptides, are secreted by paneth cells
deep in the epithelial crypt, and are important in mucosal
protection. However, it is clear that the products of goblet
cells are also important, and the major products of these cells
are mucins, which are the building blocks of the protective
mucus layer. The mucus layer is a hydrated polymeric gel of
a thickness of 50–800 μm, and is composed of two layers:
a loosely adherent layer that is removable by suction, and
a layer firmly attached to the mucosa. In humans, mice, and
rats, MUC2 is the predominant mucin type secreted in large
amounts from apical granules within the goblet cell.
Damage to the epithelium, in particular events affecting the
protective properties conferred by the secretory products
of the goblet cells, is a likely cause of inflammation. An
illustration of this is the goblet cell depletion seen in UC.
106
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
of interest that the development of small-bowel adenomas and
carcinomas is a feature of these mice. The mice were challenged
with dextran sodium sulfate (DSS) to induce an experimental
colitis. Wild-type (Muc2+/+), heterozygous (Muc2+/–), and
homozygous deficient (Muc2–/–) mice were studied, and
groups of mice were sacrificed at 5, 8, 12, and 16 weeks.
The authors demonstrated that the Muc2–/– mice showed
clinical signs of colitis from week 5, becoming more severe as
the mice grew older. This was manifest as weight loss, diarrhea,
overt rectal bleeding, and rectal prolapse. Microscopic analysis
of the colon of Muc2–/– mice showed mucosal thickening,
increased proliferation, and superficial erosions. Colonic goblet
cells in the Muc2–/– mice were negative for MUC2, but trefoil
factor 3 (a protein also expressed by goblet cells in the intestine
that plays a role in the maintenance and repair of the mucosa)
was still detectable. In Muc2–/– mice, transient de novo
expression of Muc6 mRNA was observed in the distal colon.
On day 2 of DSS treatment, the histological damage was more
severe in Muc2+/– versus Muc2+/+ mice, but the disease activity
index was not different at this stage. By day 7, the disease
activity index and histological score were significantly elevated
in Muc2+/– compared with Muc2+/+ mice. The disease activity
index of the Muc2–/– mice was higher (versus both Muc2+/+
and Muc2+/– mice) throughout DSS treatment. The histological
damage in the DSS-treated Muc2–/– mice was different
compared with Muc2+/+ and Muc2+/– mice, with many crypt
abscesses seen, rather than mucosal ulcerations.
The authors concluded that MUC2 deficiency is a cause
of inflammation of the colon and, when combined with an
experimental colitis, this occurs earlier and is more severe.
This study is an important demonstration of the significance
of the barrier function of the intestinal mucosa. Further data
are awaited with interest.
Address for reprints: IB Renes, Laboratory Pediatrics, Erasmus MC and
Sophia Children’s Hospital, Room Ee 15.71A, Dr. Molewaterplein 50,
3015 GE Rotterdam, The Netherlands. Email: [email protected]
PATHOGENESIS
Serological and DNA-based evaluation
of Chlamydia pneumoniae infection
in inflammatory bowel disease
Müller S, Arni S, Varga L et al.
Eur J Gastroenterol Hepatol 2006;18:889–94.
It has been suggested that Chlamydia pneumoniae can
trigger autoimmune events. Thus, the authors of this
study assessed the relationship between Chlamydia
infection and IBD. No significant differences in the serum
titers of anti-C pneumoniae immunoglobulin G or the
presence of C pneumoniae DNA were found between
healthy controls and patients with IBD, although
inflamed biopsies from Crohn’s disease patients were
significantly more likely to contain C pneumoniae DNA
compared with biopsies from non-inflamed tissue.
Chlamydia pneumoniae is an obligate intracellular Gramnegative bacterium that has emerged as an important
pathogen in humans over the last decade. It is one of the
most common causes of eye, respiratory tract, genital tract,
joint, and vasculature infections, occurring in millions of
people every year. More recently, it has been suggested that
C pneumoniae triggers autoimmune events. Although the
exact mechanism is still unknown, Chlamydia shares some
epitopes with certain reactive proteins (e.g. myelin basic
protein) and, for this reason, is potentially involved in the
etiology or pathogenesis of autoimmune disorders. As
Chlamydia has also been found in the intestinal mucosa of
IBD patients and healthy controls, a possible role for the
bacteria in the pathogenesis of IBD has been proposed, but
not yet confirmed.
The current authors measured the titers of
immunoglobulin G (IgG) antibodies against C pneumoniae
and tested for C pneumoniae DNA in the sera and mucosal
biopsies, respectively, of 78 patients with Crohn’s disease
(CD) and 24 with ulcerative colitis (UC). Moreover, CD
patients with mutations in NOD2/CARD15 (a gene involved
in the immune reactivity to intracellular bacterial antigens)
were selected in order to assess possible correlations with the
presence or absence of C pneumoniae DNA. The blood of
73 family members and the sera and biopsies of 20 healthy
subjects were also evaluated as control groups. The results
showed that IgG antibodies against C pneumoniae were
present in 41%, 46%, 48%, and 45% of the CD, UC,
unaffected family members, and healthy control groups,
respectively. C pneumoniae DNA was found in 23% and 31%
of the biopsies from patients with CD and UC, respectively.
Surprisingly, even in the 35% of intestinal biopsies from
healthy controls, C pneumoniae DNA was present. In addition,
C pneumoniae DNA was more frequently found in inflamed
biopsies of CD (27%) compared with non-inflamed biopsies
(8%). Among CD patients, the NOD2/CARD15 mutation
was present in 33% of C pneumoniae DNA-positive patients
and in 47% of C pneumoniae DNA-negative patients.
These data demonstrate that there is no direct involvement
of Chlamydia in the etiology of IBD. Nevertheless, the
results suggest that this agent has an important influence on
inflammation in CD patients.
Address for reprints: F Seibold, Division of Gastroenterology,
Inselspital Bern, Freiburgstrasse, 3010 Bern, Switzerland.
Identification of novel virulence determinants
in Mycobacterium paratuberculosis by screening
a library of insertional mutants
Shin SJ, Wu CW, Steinberg H et al.
Infect Immun 2006;74:3825–33.
The Mycobacterium avian subspecies paratuberculosis
(MAP) has been proposed to play a role in the pathogenesis
of Crohn’s disease. The authors of this study identified
several novel virulence determinants of MAP during
screening of a library of mutants. These determinants of
virulence may represent novel targets for drug development.
Mycobacterium avian subspecies paratuberculosis (MAP) is
the cause of Johne’s disease in cattle and other ruminants,
which is a worldwide problem for dairy farming. The role of
this organism in the pathogenesis of Crohn’s disease (CD)
remains controversial. Consistent data have demonstrated a
higher frequency of the MAP insertion sequence IS900 in
patients than in healthy controls but there has been very little
scientific proof that this is a causative organism rather than a
bystander. A randomized control trial of antituberculous
therapy in patients with CD has yielded negative results [1].
The mechanisms of virulence of MAP remain poorly
understood and the key steps for developing paratuberculosis
remain elusive. Characterization of these pathways could
lead to the development of vaccines or other treatments
that, in turn, may have relevance to IBD. In an attempt to
identify virulence factors in MAP organisms, Shin et al.
constructed a library of 5060 transposon mutants using
Tn5367 insertion mutagenesis. They analyzed a total of
1150 mutants, and 970 unique insertion sites were identified.
The authors found that insertion of Tn5367 was more
prevalent in genomic regions with a G+C content that was
lower than the average G+C content of the MAP genome.
Disruptions in genes involved in iron, tryptophan, and mycolic
acid metabolic pathways were demonstrated to confer unique
growth characteristics. Bioinformatic analyses of disrupted
genes identified several potential virulence determinants,
107
CLINICAL REVIEWS
which subsequently underwent further testing in vivo.
Infection studies in mice showed a significant decrease in
tissue colonization by mutants with a disruption of specific
genes. Furthermore, these “attenuation phenotypes” were
tissue-specific, and the time-course of infection progression
varied according to the mutant, suggesting that certain
genes may be involved in distinct virulence mechanisms.
The novel virulence determinants identified in this study
represent new functional classes that may be necessary for
mycobacterial survival during infection; these could provide
suitable targets for new drug development.
1.
Borody TJ, Clancy R, Wettstein A et al. Anti-MAP therapy in the treatment of active
Crohn’s disease. J Gastroenterol Hepatol 2005;20(suppl):A2.
Address for reprints: AM Talaat, Department of Animal Health
and Biomedical Sciences, University of Wisconsin – Madison,
1656 Linden Drive, Madison, WI, USA. Email: [email protected]
Evidence for the association of the SLC22A4
and SLC22A5 genes with type 1 diabetes:
a case control study
Santiago JL, Martinez A, de la Calle H et al.
BMC Med Genet 2006;7:54.
Santiago et al. performed a case–control study in order
to identify polymorphisms in the IBD5 region of
chromosome 5 in a group of patients with type 1
diabetes. They identified one single nucleotide polymorphism that was significantly associated with type 1
diabetes; however, this was different to the recently
identified organic cation transporters 1 and 2 (OCTN1/2)
polymorphisms associated with Crohn’s disease.
The cluster of cytokine genes located on chromosome 5q31
(IBD5) has attracted much interest in recent months with the
description of variants in organic cation transporters 1 and 2
(OCTN1/2) in Crohn’s disease (CD). However, the strong
linkage disequilibrium that occurs across this region has
always been a barrier to the clarification of individual
candidate genes. In a study by Peltekova et al., the CD
susceptibility haplotype (the so-called TC haplotype) was
seen to be independent of other markers in the IBD5 region
[1]. Subsequent studies from different geographical locations
have confirmed the association of OCTN1/2 with CD but
have not been able to substantiate the independence of this
association, and, hence, questions remain regarding the role
of OCTN1/2 as the causative genes.
The OCTN genes encode proteins that function as carnitine
transporters (with the transporter activity of OCTN2 being
much greater than that of OCTN1). Carnitine is important
for lipid and energy metabolism; therefore, Santiago et al.
postulated that OCTN1/2 could be susceptibility genes in
108
type 1 diabetes. They examined six single nucleotide
polymorphisms (SNPs) across OCTN1/2 in 295 subjects with
type 1 diabetes and 508 healthy controls. TaqMan® (Applied
Biosystems, Foster City, CA, USA) was used to genotype the
SNPs slc2F2 (rs3792876), slc2F11 (rs2306772), T306I
(rs272893), L503F (rs1050152) (all OCTN1), OCTN2-intron
(rs274559), and an OCTN2 promoter polymorphism.
The authors demonstrated that, when analyzed
independently, one SNP in the SLC22A4 gene at position
1672 (L503F) showed a significant association with type 1
diabetes. It is of note that this was not the variant associated
with CD or rheumatoid arthritis (although the high linkage
disequilibrium across this region should be kept in mind).
The overall comparison of the inferred haplotypes was
significantly different between patients and control subjects,
with one of the haplotypes showing a protective effect for
type 1 diabetes (odds ratio 0.62; p=0.02).
In summary, this Spanish group presented some
interesting data on the possible role of this cytokine cluster
in type 1 diabetes. It is clear from their data that OCTN1/2
may not be the causative genes and that, in addition to
confirmation in other populations, further genetic, functional,
and expression data are required to address this issue.
However, when complete, this work may have significant
implications for many important diseases.
1.
Peltekova VD, Wintle RF, Rubin LA et al. Functional variants of OCTN cation transporter
genes are associated with Crohn disease. Nat Genet 2004;36:471–5.
Address for reprints: EG de la Concha, Immunology Department,
Hospital Universitario San Carlos, Madrid, Spain.
Patients with inflammatory bowel disease
are at risk for vaccine-preventable illnesses
Melmed GY, Ippoliti AF, Papadakis KA et al.
Although immunization therapies are potentially
important in immunosuppressed patients such as those
with IBD, there is a lack of available data regarding
vaccination in this population. The authors of this study
evaluated the immunization history and exposure to
viral risk factors in a cohort of IBD patients, using a
self-administered questionnaire. They conclude that
there is a low rate of immunization of IBD patients,
probably due to lack of patient awareness and concerns
regarding side effects of immunization therapies.
During the past two decades, medical therapy for Crohn’s
disease (CD) and ulcerative colitis (UC) has expanded to
incorporate a variety of long-term immunosuppressive agents
or biological therapies to control the inflammatory course of
PATHOGENESIS
the disease. Simultaneously, new information regarding the
abnormal mechanism of the mucosal immune response, which
could underlie IBD, has become available. The relationship
between host susceptibility to infection and the safety and
efficacy of immunization for vaccine-preventable diseases has
been explored in other immune-mediated disease, but rarely
in IBD. The paucity of available data highlights how vaccines
are underused in this group of patients, notwithstanding
that these individuals are at risk for acquired infections, which
are potentially preventable using immunization therapies.
Using a self-administered questionnaire, the authors evaluated
the immunization history and exposure to known viral risks
factors (influenza, pneumococcus, viral hepatitis, and varicella)
in a group of IBD patients who attended the Cedars-Sinai
Inflammatory Bowel Disease Center (Los Angeles, CA, USA).
Of the 196 patients enrolled, 169 completed the study,
showing the following results:
• 86% of patients were at risk for infection as
they had been treated with immunosuppressive
medications or had frequent hospitalizations.
• Only 28% of patients received routine influenza
vaccinations and only 9% had been immunized
against pneumococcus (despite the recommendations
for immunosuppressed patients).
• Only 45% of patients recalled receiving tetanus
immunization within the past 10 years.
• 44% of patients showed an increased risk for hepatitis B
infections (having at least one known risk factor), but
only 28% had been vaccinated against hepatitis B.
The most frequent causes cited by patients for not being
vaccinated against influenza were lack of awareness (49%)
and concerns about side effects (18%).
As the efficacy of immunization may be diminished in
some patients in whom the immune status is compromised
by immunosuppression therapy, additional larger studies are
required to assess the protection conferred by immunization.
These are also required to convince patients that, with
the exception of live agent vaccines, the majority of
immunizations may be safely administered and provide
long-term efficacy. Interestingly, the low rate of
immunization of IBD patients demonstrated in this study is
similar to the rate in the general population, which possibly
reflects a deficiency in the communication of information by
clinicians to patients regarding vaccine-preventable illnesses,
rather than patients concerns (lack of awareness of possible
infections or concerns about side effects).
Address for reprints: GY Melmed, Inflammatory Bowel Disease Center,
Cedars-Sinai Medical Center, Thalians Building, 8730 Alden Drive,
Los Angeles, CA 90048, USA.
Comparative study of the intestinal mucous
barrier in normal and inflamed colon
Swidsinski A, Loening-Baucke V, Theissig F et al.
Gut 2006; [Epub ahead of print].
The authors of this study examined the interaction
of the microbial flora with the mucus layer in healthy
and inflamed tissue. In biopsies from healthy subjects
the mucosal surface beneath the mucus layer was free
of bacteria in ≥80% of cases; however, in patients
with colitis or ulcerative colitis there was deep mucosal
infiltration with bacteria and leukocytes, with a thinning
of the mucus layer, and epithelial defects.
A distinct approach to examine the importance of the mucus
layer in IBD was taken by Swidsinski et al. The mucus layer is
the site of interaction between the host and the enteric
bacteria, and these bacteria are essential for the development
and perpetuation of chronic IBD. Although changes in the
mucus layer have been described in inflammation, the
significance of this remains unclear. The authors of this study
used advances in specimen fixation and techniques including
fluorescent in situ hybridization to examine the interaction
of the microbial flora with the mucus layer in healthy and
inflamed tissue. They aimed to minimize the bias that is
often encountered in specimen collection by using enema
preparation of the left colon and by using appendix specimens
from individuals who had not been treated with antibiotics.
Biopsy samples from 20 healthy individuals, 20 patients with
self-limiting colitis, and 20 patients with ulcerative colitis
(UC) were examined. In addition, biopsy samples from
60 randomly selected appendices were examined.
The main findings of the study were that the mucosal
surface beneath the mucus layer was free of bacteria in
≥80% of the non-inflamed appendices and biopsy samples
from healthy subjects. The thickness of the mucus layer,
and its spread, decreased with increasing severity of the
inflammation; the epithelial surface showed bacterial
adherence, and epithelial tissue defects and deep mucosal
infiltration with bacteria and leukocytes were observed.
Bacteria and leukocytes were found within the mucus in all
biopsy samples from patients with UC, self-limiting colitis,
and acute appendicitis. The concentration of bacteria
within the mucus was inversely correlated with the number
of leukocytes.
The authors concluded that the normal mucus layer
provides an effective barrier between the luminal microbial
flora and the mucosa, and prevents contact in all parts of the
colon. They effectively showed that in colonic inflammation
this process is disrupted, with regular mucosal breaks and
contact of microbes with the mucosa. Although the process
109
CLINICAL REVIEWS
of inflammation functions to reduce the number of bacteria
within the mucus, it is unable to prevent bacterial migration,
adherence, and invasion. Considerable interest remains in
identifying the initiating event for these processes.
Address for reprints: A Swidsinski, Humboldt University, Charité,
CCM, 10098 Berlin, Germany. Email: [email protected]
Immunohistochemical study of chymase-positive
mast cells in inflammatory bowel disease
Andoh A, Deguchi Y, Inatomi O et al.
Oncol Rep 2006;16:103–7.
This analysis of mast cells in IBD demonstrates that
differences are observed between Crohn’s disease
and ulcerative colitis with regard to the numbers
of mast cells that are immunoreactive for chymase.
This type of mast cell is implicated in fibrosis.
Much of the early literature on mast cells focuses on their
role in allergic responses. Indeed, the release of mediators
from these cells in response to the cross-linking of
membrane-bound immunoglobulin E remains a central
component of the type I allergic response. However, there is
increasing evidence that mast cells play a broader role in
immunopathogenesis, and that their release of cytokines
such as tumor necrosis factor-α may be critical in nonallergic disease processes. Activated mast cells can release a
number of proteinases, notably tryptase, chymase, and
carboxypeptidase. Two types of mast cells may be identified
on the basis of staining for proteinases – those producing
tryptase but not chymase (MCT cells) and those producing
both tryptase and chymase (MCTC cells). The latter type has
a particular role in fibrogenesis, due to the role that chymase
plays in the generation of angiotensin II, which promotes
fibroblast proliferation and matrix production.
Previous studies have shown an essential role for mast
cells in models of stress-induced colitis in rats [1], and also
that their number is increased within the mucosa in IBD,
particularly at sites of stricturing [2]. Thus, the authors of the
present study aimed to localize chymase-positive MCTC cells
within the mucosa from 10 patients with Crohn’s disease
(CD) and 10 with ulcerative colitis (UC), in view of their
particular role in stricturing.
Clear differences were seen between the tissues of
patients with UC and those with CD. In comparison with
the histologically normal resection margin tissues from
patients with colon carcinoma, patients with UC in relapse
actually showed a reduction in MCTC cell density within
the mucosa, although those in remission showed a normal
density of cells. In contrast, patients with CD (either active
or inactive) showed a substantial increase, with a doubling
110
of cells number in inactive disease and a tripling in
active disease.
This study was undoubtedly limited by the small
numbers of patients included, and it is unclear how many
of the 10 subjects within each group were in relapse or
remission; however, the differences between the CD and UC
groups were apparent. The localization of these MCTC cells
in CD was consistent with a direct role in fibrosis, as
previously suggested [2]. Thus, further characterization in
subgroups of CD patients with different propensities for
stricturing would be interesting in order to determine
whether the mast cells may become a therapeutic target in
patients with a history of stricturing.
1.
Soderholm JD, Yang PC, Ceponis P et al. Chronic stress induces mast cell-dependent
bacterial adherence and initiates mucosal inflammation in rat intestine.
2.
Gelbmann CM, Mestermann S, Gross V et al. Strictures in Crohn’s disease are
characterised by an accumulation of mast cells colocalised with laminin but not
with fibronectin or vitronectin. Gut 1999;45:210–7.
Address for reprints: A Andoh, Department of Internal Medicine,
Shiga University of Medical Science, Seta Tukinowa, Otsu 520-2192,
Japan. Email: [email protected]
Bosentan, an endothelin receptor antagonist,
reduces leucocyte adhesion and inflammation
in a murine model of inflammatory bowel disease
Anthoni C, Mennigen RB, Rijcken EJ et al.
Int J Colorectal Dis 2006;21:409–18.
The authors of this report describe a potentially novel
therapeutic approach to treatment of IBD – through
inhibiting production of endothelin-1. The observed
therapeutic effects may be mediated by inhibiting
leukocyte recruitment.
Endothelins, which are structurally related to the sarafotoxins
of scorpion venom, are the most potent vasoconstrictors
discovered to date, and are thought to play a fundamental
role in vascular biology. Their pressor effects are counteracted
by nitric oxide (NO), and the balance between endothelin
and NO concentrations may determine vascular tone at the
local level. Four endothelins, endothelin-1 (ET-1), ET-2, ET-3,
and ET-4 mediate their effects through two receptors (ETA
and ETB), and may be generated in situ from precursor proendothelins. A role is emerging for endothelins in inflammatory
disorders, and leukocytes such as macrophages may produce
endothelin within tissues.
A possible role for endothelins in the pathogenesis of IBD
was suggested several years ago following identification of
a significant upregulation of ET-1 within the mucosa in both
Crohn’s disease (CD) and ulcerative colitis (UC) patients,
and in Crohn’s submucosa, often associated with perivascular
macrophage aggregates [1]. The plasma levels of ET-1 are
CLINICAL OBSERVATIONS
also increased in active IBD [2], although other studies have
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
of a role for these mediators in leukocyte recruitment to the
intestine, and the observed improvement in colonic damage
in a model of rodent colitis upon administration of the
endothelin receptor blocker bosentan [4]. The current study
develops these earlier observations, with the aim of
assessing the effects of bosentan in greater detail, using the
dextran sodium sulfate (DSS) mouse model of colitis.
Employing a daily disease activity index, the authors
were able to establish that intraperitoneal bosentan
administration rapidly induced clinical improvement of
established disease. Histological examination of tissues
showed some evidence of inflammation, but this was
substantially milder than that observed in tissue from
untreated animals, with an approximate 40% reduction in
severity upon quantitation. The changes that occurred were
found to relate particularly to the vasculature, with increased
venular diameter and measured blood flow in the bosentantreated animals. Leukocyte adhesion, studied by in vivo
microscopy, was significantly lower in the bosentan-treated
group than in animals with untreated DSS-induced colitis,
and indeed was at the level of that observed in animals
without colitis. Leukocyte rolling velocity was significantly
increased in the bosentan-treated mice compared with
untreated mice with DSS-induced colitis.
The key finding of this study is that the blockade of
endothelin activity with bosentan induces a therapeutic
effect in experimental colitis by reducing leukocyte
recruitment to the lesion. Whether this effect is due to
prevention of endothelin-mediated upregulation of cell
adhesion molecules remains to be determined. The
importance of the experimental design is that, for the first
time, bosentan treatment was shown to ameliorate fully
established colitis. Orally administered bosentan has been
used in a variety of human studies, mainly in cardiovascular
disease, and appears to be a well-tolerated medication.
There seems to be sufficient preliminary evidence to suggest
that clinical efficacy in IBD should be assessed in future.
1.
Murch SH, Braegger CP, Sessa WC et al. High endothelin-1 immunoreactivity
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
with Crohn’s disease and ulcerative colitis. Ital J Gastroenterol Hepatol
1998;30:266–9.
3.
McCartney SA, Ballinger AB, Vojnovic I et al. Endothelin in human inflammatory
bowel disease: comparison to rat trinitrobenzenesulphonic acid-induced colitis.
Life Sci 2002;71:1893–904.
4.
Hogaboam CM, Muller MJ, Collins SM et al. An orally active non-selective endothelin
receptor antagonist, bosentan, markedly reduces injury in a rat model of colitis.
Eur J Pharmacol 1996;309:261–9.
Address for reprints: C Anthoni, Department of General Surgery,
Westfalian Wilhelm’s University, Muenster, Germany.
The efficacy of corticosteroid therapy in
inflammatory bowel disease: analysis
of a 5-year UK inception cohort
Ho G-T, Chiam P, Drummond H et al.
Aliment Pharm Ther 2006;24:319–30.
Ho et al. evaluated the outcomes at 1 year of an
inception cohort of newly diagnosed IBD patients.
Of these subjects, 63% of ulcerative colitis patients
and 75% of Crohn’s disease (CD) patients were treated
with corticosteroids. In CD, 60% of those requiring
corticosteroids were either corticosteroid-dependent
by 1 year or had required surgery within the first year.
All new diagnoses of ulcerative colitis (UC) and Crohn’s
disease (CD) that had been made at the Western General
Hospital, Edinburgh, UK between 1998 and 2003, were
analyzed retrospectively. Of 216 newly diagnosed IBD
patients, 63% of those with UC (n=136) and 75% of CD
patients (n=80) required corticosteroid therapy. At 30 days,
there was complete, partial, or no response to corticosteroid
treatment in 51%, 31%, and 18% of UC patients,
respectively. In comparison, there was complete, partial, or
no response to corticosteroid treatment at 30 days in 40%,
35%, and 25% of CD patients, respectively. At 1 year, the
prolonged response was 55% and 38% in the UC and CD
groups, respectively. Furthermore, corticosteroid dependence
was 17% in the UC group and 24% in the CD group, and
surgery was required in 21% of UC and 35% of CD patients
by 1 year. Extensive UC was a predictor of surgery by 1 year
(odds ratio [OR] 15.2, 95% confidence interval [CI]
3.7–62.4), whereas inflammatory activity was negatively
associated with surgery (OR 0.13, 95% CI 0.02–0.7).
In the UC group, 72% did not initially require
corticosteroids or were in a prolonged remission offcorticosteroids at 1 year. Of those who required corticosteroids
early, 55% were in a prolonged remission at 1 year.
However, in the CD group, only 54% of patients did not
initially require corticosteroids or were in a prolonged
remission at 1 year. Of the CD patients who did require
corticosteroids at an early stage, 59% were corticosteroiddependent or required surgery. However, 33% of the UC
group was prescribed azathioprine following diagnosis,
which limited the conclusions that could be drawn regarding
corticosteroid treatment alone. Only 13% of the CD group
was prescribed concomitant azathioprine.
This study serves as a reminder that approximately 55%
of patients with newly diagnosed CD either do not require
111
CLINICAL REVIEWS
corticosteroids or are in a prolonged remission at 1 year
following a course of corticosteroids. This information
should be heeded by those who advocate a “top down”
approach, with an early introduction of biological agents
to all who present with disease.
Address for reprints: G-T Ho, Gastrointestinal Unit, Molecular Medicine
Centre, University of Edinburgh, Western General Hospital, Edinburgh
EH4 2XU, UK. Email: [email protected]
Change of diagnosis during the first five years after
onset of inflammatory bowel disease: results of a
prospective follow-up study (the IBSEN study)
Henriksen M, Jahnsen J, Lygren I et al.
Scand J Gastroenterol 2006;21:1037–43.
The authors of this study evaluated an inception cohort
of 843 newly diagnosed IBD patients from 1990–1994
and found that, by 5 years, only five individuals had a
changed diagnosis. It was more common for patients
to be diagnosed with ulcerative colitis (UC). A switch
of diagnosis to UC from Crohn’s disease (CD) or
indeterminate colitis was also more likely than for initial
UC or indeterminate colitis to evolve into CD.
The authors of this study assessed the accuracy of first
diagnosis of IBD in an inception cohort enrolled during
1990–1993, with a 5-year follow-up. The initial diagnoses
for the 843 enrolled patients were:
•
•
•
•
Ulcerative colitis (UC) in 518.
Crohn’s disease (CD) in 221.
Indeterminate colitis in 40.
Possible IBD in 64.
Address for reprints: M Henriksen, Department of Internal Medicine,
Østfold Central Hospital, 1535 Moss, Norway. Email: [email protected]
Ulcerative colitis and clinical course: results
of a 5-year population-based follow-up study
(the IBSEN Study)
Henriksen M, Jahnsen J, Lygren I et al.
Patients who were diagnosed with IBD, or possible IBD,
in southeastern Norway in the early 1990s were more
likely to be diagnosed with ulcerative colitis than with
Crohn’s disease. When followed-up over a 5-year
period from diagnosis, only 7.5% had colectomies and
≤41% of patients were off-medication. Although
approximately 50% relapsed in any 1 year, few had
disease symptoms that interfered with their daily
living activities.
Patients diagnosed with definite or possible ulcerative colitis
(UC) in southeastern Norway from 1990–1993 were
followed prospectively over 5 years. Definite UC was
diagnosed in 454 patients who were alive and available for
follow-up at 5 years. Of this cohort, 7.5% had a colectomy,
with 71% of these individuals undergoing surgery during
the first 2 years following diagnosis. Within 5 years:
• 43% of patients had used corticosteroids.
• 19% of patients had not used 5-aminosalicylates.
• 28% of patients initially diagnosed with proctitis had
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
changed diagnoses: 6.2% to non-IBD and 2.7% to CD. Of
those initially diagnosed with CD, 8.6% had a changed
diagnosis: 3.2% to UC and 5.4% to non-IBD. Thus, it was
more common to change diagnosis to non-IBD than to UC
or CD. Of the 40 patients initially classified as having
indeterminate colitis, 42.5% were classified at 5 years as
having UC, 12.5% as having CD, and 22.5% as non-IBD.
Of those with possible IBD, 30% proved to have UC,
5% were found to have CD, and 50% were deemed to not
have IBD. Hence, in those diagnosed with UC or CD, only
2.8% of patients switched from one diagnosis to the other
at 5 years. Of those initially diagnosed with UC or CD,
6% proved to have non-IBD. In southeastern Norway in the
mid-1990s more patients had UC than CD, more patients
who were undifferentiated at presentation eventually proved
112
to have UC than CD, and only 9% ultimately changed from
the initial diagnosis.
At the 5-year review, 41% were off-medications, only
7% had symptoms that interfered with their daily activities,
and 22% of patients had a relapse-free course. There was
no correlation between the extent of the disease and the
number of patients reporting symptoms, or the severity of
these symptoms. Furthermore, the relapse rate in the first
year of follow-up was similar to the fifth year, at approximately
50%, and was not correlated with disease extent.
Of interest, only 200 of the 843 patients assessed with
newly diagnosed or possible IBD were ultimately diagnosed
with Crohn’s disease (CD), whereas 454 patients were
diagnosed with UC. Therefore, UC continued to have a
higher incidence rate than CD during the early 1990s in
southeastern Norway.
Address for reprints: M Henriksen, Department of Internal Medicine,
Østfold Central Hospital, 1535 Moss, Norway. Email: [email protected]
Long-term effectiveness of azathioprine
in IBD beyond 4 years: a European multicenter
study in 1176 patients
Holtmann MH, Krummenauer F, Claas C et al.
Dig Dis Sci 2006;51:1516–24.
This was a retrospective assessment of 1176 patients
who used azathioprine for the treatment of IBD. The
intent was to discern if azathioprine could be safely
withdrawn after 4 years of use; however, the study
design did not allow for a proper assessment of
this endpoint.
Charts of 1176 patients with IBD who had been using
azathioprine for ≥6 months were reviewed from 16 different
centers in Germany, Holland, and Belgium. Patients were
divided according to length of azathioprine use into groups
of <3 years, 3–4 years, or >4 years of treatment.
Azathioprine dosing was 2.0–2.5 mg/kg. There was a total
follow-up time following discontinuation of azathioprine
of 462 years for 818 Crohn’s disease (CD) patients and
153 years for 358 ulcerative colitis (UC) patients. This
equates to an average follow-up of approximately 0.5 years
for each patient, which was a short time period to analyze
the effects of drug discontinuation.
In 6% of patients, azathioprine was prescribed for postoperative maintenance of remission. This is a very different
indication than the maintenance of remission following
steroid withdrawal or for treatment of active disease, and
such patients should have been excluded from the analysis.
A flare was defined as an increase in steroid dose. The
median flare incidence in patients with CD prior to
azathioprine therapy in the groups treated for <3 years,
3–4 years, and >4 years was 1.32, 1.2, and 1.44,
respectively. Flare incidence decreased in all groups during
azathioprine therapy to a median of zero flares. Minimal
flares were evident after azathioprine was discontinued. In
179 patients who continued azathioprine for >4 years,
sustained improvement was illustrated by further reduction
in flares and steroid dosing. The authors conclude that
azathioprine treatment for CD could be safely stopped after
4 years in those in remission and off-steroids, but should be
continued in those with active disease and still using
steroids. In UC patients, azathioprine use decreased flare
incidence and steroid requirement. However, when
azathioprine was discontinued after 4 years there was a
trend toward more flares and increased steroid use.
This study has a number of flaws. For example, its
retrospective design led the authors to a fairly simple definition
of disease flare, and some flares might have been successfully
treated without steroids. Furthermore, the duration of
follow-up was too short to determine whether or not patients
can remain in remission after discontinuing azathioprine.
Address for reprints: MF Neurath, 1 Medical Clinic, University
of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Adverse events leading to modification
of therapy in a large cohort of patients
with inflammatory bowel disease
Hindorf U, Lindqvist M, Hildebrand H et al.
The authors of this study assessed adverse events
related to thiopurine methyltransferase (TPMT) levels
and thiopurine metabolite levels in thiopurine users. Low
TPMT levels were associated with a marked leukopenia
in five out of six patients. Intermediate or normal levels
of TPMT did not predict adverse events. Thiopurine
metabolite levels of >400 pmol/8×108 red blood cells
were associated with adverse events, although there
was an overlap of levels in those with and without
adverse events. The high prevalence of thiopurine
therapy-related adverse events led to drug
discontinuation in 31% of patients in this study.
Patients with IBD who were treated with purine analogue
therapy (n=364) were assessed for adverse events related to
thiopurine methyltransferase (TPMT) levels and thiopurine
metabolite levels. Adverse events were more common
in adults than in children (40% vs. 15%, respectively;
p<0.001), although both groups were on similar doses
adjusted for weight, and had similar TPMT levels. Adverse
events were more common in subjects with low-tointermediate TPMT levels (≤9 U/mL red blood cells) and in
those with 6-thioguanine levels >400 pmol/8×108 red blood
cells or methylated thioinosine monophosphate (meTIMP)
levels >11 450 pmol/8×108 red blood cells. Low TPMT activity
was evident in six patients (1.6%) and intermediate activity
was evident in 45 patients (12%). Adverse events occurred
in 83% of patients with low TPMT activity, 42% with
intermediate TPMT activity, and 32% with normal TPMT
activity. On average, patients with adverse events were
older than those without adverse events (mean age 34 years
and 24 years, respectively; p<0.001). Patients who experienced
adverse events were also more likely to be using corticosteroids
than those who did not (60% vs. 34%; p<0.001). Patients
who experienced adverse events were on lower doses of
azathioprine at the time of occurrence than those who did
not experience any adverse events (1.5 mg/kg vs. 1.9 mg/kg;
p<0.001). There was no difference between those with and
without adverse events in terms of age or disease diagnosis.
113
CLINICAL REVIEWS
Of those who experienced adverse events, 71% did so
within the first 3 months of drug therapy. The most common
adverse events were:
•
•
•
•
•
Allergic/systemic reactions (9%).
Myelotoxicity (8%).
Gastrointestinal upset (8%).
Hepatotoxicity (5%).
Pancreatitis (4%).
Allergic/systemic reactions occurred at a median of
40 days (range 20–188 days) while pancreatitis occurred
at a median of 21 days (range 17–28 days). Myelotoxicity
occurred at a median of 104 days (range 54–490 days).
Adverse events led to drug discontinuation in 31% of
patients. A shift to 6-mercaptopurine therapy was successful
in 48% of azathioprine intolerant patients and in all cases of
patients suffering azathioprine-induced myalgias or arthralgias.
One patient was successfully shifted from 6-mercaptopurine
to azathioprine.
The authors conclude that the determination of TPMT
status prior to treatment could help predict the likelihood of
adverse events. However, this is only likely to be true for a
small minority of patients with TPMT deficiency (low levels).
In this study, the prevalence of deficiency was higher than
expected. Furthermore, patients with intermediate levels
were as likely to have an adverse event as those with normal
levels, and the time to the adverse event tended to be
longer in the group with intermediate TPMT levels than in
the group with normal TPMT levels. In patients with
recorded thiopurine metabolite levels (50/124 with adverse
events and 214/240 without adverse events), there was no
difference in thioguanine (TG) or meTIMP levels between
those who experienced adverse events and those who did
not. However, there were higher TG levels in patients with
gastrointestinal side effects than those without adverse
events (332 vs. 170 pmol/8×108 red blood cells; p=0.03). In
addition, higher meTIMP levels were observed in patients
with myelotoxicity than in those who did not experience
adverse events (2650 vs. 1500 pmol/8×108 red blood cells;
p=0.02). However, the ranges of TG and meTIMP levels
overlapped between the adverse event group and no
adverse event group, raising doubts about the usefulness of
individual metabolite measurements in predicting adverse
events. Furthermore, the authors recommend that
6-mercaptopurine therapy should be attempted in patients
with azathioprine intolerance except in cases where
intolerance relates to profound leukopenia.
The results of this study do not support the use of
thiopurine metabolite level measurements to determine the
course of therapy. If a patient were to experience an adverse
114
event that necessitated drug discontinuation, this would
occur regardless of thiopurine metabolite levels, and a
decision to try an alternate thiopurine may be made
regardless of the metabolite levels. However, if there were
uncertainties regarding drug efficacy, the combination of
high metabolite levels (associated with more adverse events)
and a lack of any therapeutic response would encourage
drug discontinuation. In addition, pre-administration TPMT
level measurements seem warranted in a population with a
high prevalence of low TPMT levels, in order to avoid
profound leukopenia.
Address for reprints: U Hindorf, Department of Clinical Sciences,
Division of Gastroenterology, Faculty of Medicine, Lund University,
SE-22185 Lund, Sweden. Email: [email protected]
Determinants of vitamin D status in adult
Crohn’s disease patients, with particular
mphasis on supplemental vitamin D use
Gilman J, Shanahan F, Cashman KD.
Eur J Clin Nutr 2006;60:889–96.
This study evaluated vitamin D intake and serum
levels in 58 patients with Crohn’s disease. Levels were
significantly lower in the winter than in the summer
and, not surprisingly, vitamin D supplement use
correlated with serum levels in both seasons.
Of 58 Crohn’s disease (CD) patients in the Republic of Ireland,
50% were vitamin D deficient in winter and 19% were
vitamin D deficient in summer. Vitamin D deficiency was
defined as serum levels of <50 nmol/L 25-hydroxyvitamin
D. At the first visit, 36% of patients were taking vitamin D
supplements. The mean dietary intake plus supplemental
intake of vitamin D was 7.1 μg/day (standard deviation [SD]
5.2 μg/day) and calcium intake was 1482 mg/day (SD
728 mg/day). These intakes are high compared with other
previously reported western populations, but the large SD
reflects a large variance of intake. Multiple regression analysis
showed that summer vitamin D levels were positively
associated with supplement use (p=0.033), and negatively
associated with smoking (p=0.006). In the summer, serum
levels of vitamin D did not differ between supplement users
versus non-users. However, vitamin D levels were positively
associated with supplement use (p=0.04) and negatively
associated with small intestinal involvement (p=0.005)
during the winter. Age, steroid use, calcium, and vitamin D
dietary intake did not correlate with vitamin D serum levels.
However, when the cut-off for vitamin D deficiency was
increased to 80 nmol/L 25-hydroxyvitamin D, 64% of
patients in late summer and 84% of patients in late winter
were classed as being vitamin D deficient.
This study design suffers from small sample size, and
thus the real effects of some of the variables tested may
have been missed. However, it does suggest that vitamin D
deficiency is common and that vitamin D supplementation is
effective in raising intake levels and serum levels. Therefore,
routine supplementation should be considered in all CD
patients, not just in those using corticosteroids.
Address for reprints: KD Cashman, Department of Food and Nutritional
Sciences, University College, Cork, Ireland. Email: [email protected]
Does pregnancy change the disease course?
A study in a European cohort of patients with
inflammatory bowel disease
Riis L, Vind I, Politi P et al.; European Collaborative
study group on Inflammatory Bowel Disease.
The aim of this study was to describe the effect of
pregnancy on disease outcome in a European cohort of
IBD patients. Pregnancy before or during the course of
IBD did not influence the disease phenotype and disease
locations at time of the diagnosis. Moreover, in women
who conceived ≥3 years after diagnosis, the numbers of
relapses per year were significantly reduced in the 3 years
following pregnancy compared with the 3 years prior
to pregnancy. This suggests that the maternal immune
response to paternal human leukocyte antigens plays
a role in pregnancy-induced remission of disease.
In IBD, the outcome of pregnancy is dependent mostly on the
activity of the disease. An increase in adverse events including
fetal loss, stillbirth, preterm delivery, low birth weight, and
developmental defects have been reported in patients with
active disease at the time of conception or during pregnancy.
Conversely, few data are available on the influence of
pregnancy on disease course and IBD phenotype.
This interesting report describes the prospective
evaluation over a 10-year follow-up period of 206 women
with ulcerative colitis (UC) and 110 women with Crohn’s
disease (CD) using a European IBD database. Of this cohort,
266 women reported a total of 580 pregnancies; 191 (72%)
women were pregnant for the first time prior to diagnosis
whereas the remaining 75 (28%) became pregnant after
the discovery of the disease.
The analysis of patient files confirmed some predictable
information but also disclosed new and unexpected findings.
Women having their first pregnancy after the diagnosis of
IBD were older and had fewer children compared with the
ones who were pregnant before diagnosis. This may reflect a
general trend in the European population (several of the
women who were pregnant before diagnosis were pregnant
during the 1960s and 1970s), but is also likely to be affected
by the greater difficulties experienced with chronic intestinal
diseases during family planning. Spontaneous abortions
occurred in 13% of the pregnancies following IBD diagnosis
(similar to the background population of 10–13%);
however, the frequency of spontaneous abortion was
significantly lower in women not yet diagnosed with IBD
(6.5%). Furthermore, spontaneous abortion was more
frequent in women following diagnosis with CD (4.1%
before diagnosis vs. 19.1% after diagnosis; p<0.001) than
in women diagnosed with UC (7.5% before diagnosis vs.
9.2% after diagnosis; non significant). Prior to IBD
diagnosis, vaginal delivery rates were similar for patients
with CD and UC (87.7% and 93.6%, respectively) but
were dramatically reduced following diagnosis (CD 28.6%
and UC 28.7%) with significantly more cesareans being
performed. This appears to reflect a growing trend in the
general population rather than the recommendation of
cesarean delivery in the subgroup of CD patients with active
perianal disease. Interestingly, half of the patients were
receiving 5-aminosalicylates or corticosteroids at the time of
conception or during pregnancy, but these treatments were
not implicated in any of the four birth defects observed
(in 1.4% of pregnancies prior to IBD diagnosis and 2.7%
of pregnancies after IBD diagnosis), which were similar to
the rate of birth defects in the general population.
Two further points are very interesting. Firstly, pregnancy
before or during the course of IBD did not influence the
disease phenotype and disease locations at time of the
diagnosis. Specifically, terminal ileum involvement was
similar for pregnant following diagnosis (n=38) and never
pregnant following diagnosis (n=63) women (66% and
52%, respectively; p=0.19). In addition, resection rates were
not significantly affected by pregnancy following diagnosis,
compared with non-pregnancy following diagnosis
(53% vs. 43%; p=0.37). Secondly, in women who conceived
≥3 years after diagnosis and for whom there were sufficient
follow-up data (n=40), the numbers of relapses per year
were significantly reduced in the 3 years following
pregnancy compared with the 3 years prior to pregnancy
(0.17 flares/year vs. 0.46 flares/year; p<0.001).
This study appears to confirm mechanisms proposed in
studies of other autoimmune conditions, which suggest that
the maternal immune response to paternal human leukocyte
antigens plays a role in pregnancy-induced remission.
Moreover, it also demonstrates that the improved knowledge
of the disease permits better treatment and quality of life for
pregnant patients, who are no longer advised against
conception by clinicians or parents/family.
Address for reprints: L Riis, Department of Medical Gastroenterology,
Herlev Hospital, Herlev Ringvej 75, 2730 Herlev, Denmark.
115
CLINICAL REVIEWS
Phenotype at diagnosis predicts recurrence
rates in Crohn’s disease
Wolters FL, Russel MG, Sijbrandij J et al.
Gut 2006;55:1124–30.
This study from the European Collaborative Study Group
on IBD (EC-IBD) attempted to identify factors at diagnosis
that would predict more rapid clinical recurrence of Crohn’s
disease and the need for surgery. A total of 358 patients
who were classified for phenotype at diagnosis were
available for analysis of disease recurrence. Interestingly,
the disease documented was relatively mild, with 57%
of patients experiencing just two recurrences during the
10-year period of analysis. Although these phenotypic
data are of interest, they do not provide significant
information regarding the future course of the disease.
The stratification of risk is an important issue in the treatment
of IBD. There has always been a need to give individual patients
the correct treatments; however, as more vigorous initial
treatment regimens become popular, there is an increasing
need for reliable markers to identify individuals who will do
less well with these regimens. The availability of such markers
will enable a reduction of treatment-related morbidity and
mortality rates, particularly in the era of biological therapies.
This study from the European Collaborative Study Group
on IBD (EC-IBD) aimed to identify factors at diagnosis that
would predict more rapid clinical recurrence of Crohn’s
disease (CD) and the need for surgery. Between 1991 and
1993, the group assembled a prospective and uniformly
diagnosed inception cohort consisting of 2201 patients with
IBD from 12 European countries. There were originally
706 patients with CD. In the detailed follow-up, 10 out
of 13 centers were able to achieve the required minimal
response rate of 60%, giving a total of 380 patients.
A total of 358 subjects who were classified for
phenotype at diagnosis were available for analyses of
recurrence; 262 (73.2%) patients had a first recurrence and
113 (31.6%) patients had a first surgical operation during
the first 10 years after diagnosis. The authors demonstrated
that those with upper gastrointestinal disease at diagnosis
had an increased risk of recurrence (hazard ratio 1.54, 95%
confidence interval [CI] 1.13–2.10) and those who had CD
diagnosed at age ≥40 years experienced fewer recurrences
(hazard ratio 0.82, 95% CI 0.70–0.97). Colonic disease
was a protective factor for surgery (hazard ratio 0.38,
95% CI 0.21–0.69). Interestingly, more frequent surgery
was observed in patients from Copenhagen, Denmark
(hazard ratio 3.23, 95% CI 1.32–7.89).
This study provides useful data from a Europe-wide
cohort of patients with IBD. It is clear that the disease
116
documented here is relatively mild, with 57% of patients
experiencing only two recurrences in the 10-year period
of analysis. This may represent anomalies in data collection
or a genuinely milder spectrum of disease. However, the
phenotypic data – although of interest – will not provide
physicians with very much indication of the future course of
the disease. It is possible that further investigation of genetic
and serological data will provide additional details.
Address for reprints: FL Wolters, Department of Gastroenterology and
Hepatology, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
The bacteriology of biopsies differs between
newly diagnosed, untreated, Crohn’s disease
and ulcerative colitis patients
Bibiloni R, Mangold M, Madsen KL et al.
J Med Microbiol 2006;55:1141–9.
Using molecular biology methods, the authors of this
study found that distinct differences in the numbers and
types of mucosa-associated bacteria are seen in Crohn’s
disease and ulcerative colitis.
The advent of techniques allowing molecular analysis of the
intestinal flora has uncovered a hugely complex ecosystem
with much greater diversity than might have been
considered using current bacterial culture techniques.
Indeed, only a minority of species found in the gut lumen
can be cultured by present methods. It appears to be a task
of significant complexity to determine those elements of
the flora that may be driving inflammatory responses of the
mucosal immune system in individual patients. In general,
it is unlikely that a single species will emerge as dominant
inducers of IBD.
The authors of this study used the techniques of
denaturing gradient gel electrophoresis (DGGE) and analysis
of clone libraries prepared using bacterial 16S RNA to detect
specific groups of bacteria within mucosal biopsies in IBD
patients, in comparison with those taken from healthy
subjects. Biopsies were obtained from 20 patients with
newly diagnosed Crohn’s disease (CD), 15 individuals with
ulcerative colitis (UC), and 14 healthy control subjects.
A feature observed in the three groups was that biopsyassociated profiles, as assessed by DGGE, were similar within
an individual, regardless of the site of biopsy. An average of
25 densely stained DNA fragments were obtained from each
patient, showing essentially identical band patterns in biopsies
from the terminal ileum and colon. Even in inflamed IBD tissue,
band appearances were similar to those found in an analysis
of uninflamed biopsies from the same individual. In contrast,
the band patterns differed greatly between individuals.
TREATMENT AND CLINICAL PRACTICE
Using group-specific polymerase chain reaction techniques,
the authors were able to exclude the presence of sulfatereducing bacteria, Helicobacter species, and the Mycobacterium
avium subspecies paratuberculosis in all cases. Patients with
UC had higher numbers of bacteria associated with biopsies
than patients with CD or healthy control subjects. Clone libraries
generated from patients with CD and UC differed from each
other, and those of normal controls. Unclassified species of
Bacteroidetes were notably more prevalent in CD than in
the other groups, and may represent a target for future
studies. In addition, unclassified Verrucomicrobia species
were found only in CD patients, while Porphyromonadaceae
were found only in patients with UC. The authors suggest
that future metagenomic studies will be needed, in order to
study antigens present in such uncultivatable bacteria.
Address for reprints: GW Tannock, Department of Agricultural, Food
and Nutritional Science, University of Otago, PO Box 56, Dunedin,
New Zealand. Email: [email protected]
Guidelines for capsule endoscopy:
diagnoses will be missed
Makins R, Blanshard C.
The authors of this study retrospectively evaluated the
outcome of capsule endoscopy in 100 patients at the
Homerton Hospital, London, UK. Their aim was to identify
possible indications for the use of the procedure, which are
not currently recommended by regulatory bodies. Capsule
endoscopy identified pathologies in >60% of patients with
abdominal pain who were examined for non-conventional
indications, suggesting that this imaging modality may
be useful for an extensive range of indications.
Capsule endoscopy has revolutionized the management of
digestive tract diseases by providing a new, non-invasive,
and well-tolerated method for directly viewing the entire
small bowel mucosa. This method is considered superior to
other standard imaging techniques. Thus far, it has been
performed in >200 000 patients worldwide. At present, the
indications for its use are limited by the UK National Institute
of Health and Clinical Excellence (NICE) and the European
Society of Gastrointestinal Endoscopy (ESGE) guidelines. The
approved indications comprise obscure gastrointestinal
bleeding, iron deficiency anemia, suspected Crohn’s disease,
small-bowel tumors, and, more recently, celiac disease
follow-up and evaluation of pathologies secondary to
nonsteroidal anti-inflammatory drug exposure. However, its
potential ease of utilization for both clinicians and patients
are factors that may lead to an expansion of its use for the
diagnosis of other gastrointestinal diseases or symptoms.
The authors of this report retrospectively evaluated
consecutive unselected capsule endoscopy examinations
(37 children, 63 adults; age range 7–86 years), which were
performed at the Homerton Hospital, London, UK, during
2003–2005 when there were no local referral guidelines
in place. This retrospective assessment for unrestricted
indications allowed the authors to identify diagnoses that may
have been missed by adherence to recommended guidelines.
Of the 100 patients, 30 underwent capsule endoscopy for
non-NICE recommended indications such as abdominal pain,
vomiting, arthritis, poor growth, lymphangiectasia, and
intussusceptions. Interestingly, pathology was found in
>60% of the 16 patients with abdominal pain (seven had
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
with vomiting had widespread lymphangectasia, one with poor
growth showed lymphoid nodular hyperplasia, one with an
indication of lymphangectasia had this confirmed, while one
subject with arthritis and one with intussusception had a
normal intestinal pattern. In five patients who underwent
investigations for celiac disease, two demonstrated persistent
villous atrophy, one had jejunal inflammation, one had delayed
gastric empting, and one had colitis, confirming the role of
this examination for disease follow-up. No complications
(capsule retention or obstructive symptoms) were reported.
In conclusion, this procedure confirmed the supposed
diagnosis in 83 patients who were examined for standard
indications. Nevertheless, in the remaining 17 patients who
underwent capsule endoscopy for non-NICE-recommended
indications, several pathologies were identified by chance
(eight mucosal ulcers, one worm infection, seven delayed
gastric empting, and one biliary bleeding); these may have
been missed using conventional techniques. Moreover,
capsule endoscopy was able to identify pathologies in >60%
of patients with abdominal pain who were examined for
non-conventional indications. These results support the use
of this procedure as a safe and effective diagnostic method
for an extended range of indications. In addition, new
lesions or patterns that are unexpectedly discovered with
this direct vision of the bowel (unseen by other diagnostic
tools), are crucial as they may uncover novel interactions
between gastrointestinal symptoms, signs, or diseases that
were previously not suspected to be related.
Address for reprints: R Makins, Department of Gastroenterology,
Whipps Cross University Hospital, Whipps Cross Road, Leytonstone,
London, E11 1NR, UK. Email: [email protected]
117
CLINICAL REVIEWS
Use of antibiotics in the treatment
of inflammatory bowel disease
Perencevich M, Burakoff R.
There is increasing evidence that the gut flora has an
important role in the pathogenesis of IBD. The authors
of this article review the current literature on the role
of the intestinal flora and the use of antibiotics in the
management of patients with IBD. In addition, they
present a clinical model for the use of antibiotics for the
treatment of IBD.
A growing volume of evidence indicates that the intestinal
flora plays a pathogenic role in IBD; hence, manipulation of
the luminal content of the gut using antibiotics or probiotics
represents a potentially effective therapeutic option.
Notwithstanding the fact that no specific infectious agent
has been found to be behind the etiology of IBD, the altered
composition of the gut microflora (dysbiosis), together
with evidence for an aberrant immune response to this (in
susceptible individuals with genetic variants of the NOD2
gene), has encouraged the use of antimicrobial agents.
Antibiotics are effective for the treatment of the septic
complications of IBD, and their frequent use for perianal and
post-operative Crohn’s disease (CD), and for the treatment
and prevention of pouchitis are common in clinical practice.
However, their optimal use as a primary therapy for active
mild-to-moderate IBD remains controversial.
For these reasons, the authors of this interesting article
reviewed the current antibiotic approaches to the management of patients with IBD, summarizing the efficacy and
side-effects data thus far reported. Whereas the results of
studies with anti-tubercular agents remain inconclusive,
antibiotic treatment, usually with metronidazole (active
against Gram-positive and Gram-negative anaerobes), or
ciprofloxacin (active against enteric Gram-negative and
aerobic bacteria), or both, appears to be more effective in
colonic compared with ileal IBD. Controlled trials are limited
and, although both antibiotics appear to provide clinical
benefit, definitive conclusions cannot be drawn and precise
therapeutic guidelines cannot be decisively recommended.
Moreover, because of the obvious need for lifelong or longterm therapy to maintain disease remission, the tolerability
of antibiotics – which has been shown to be poor due to the
appearance of systemic side effects – remains an important
consideration. For these reasons, the use of non-absorbable
anti-bacterial agents such as rifaximin (which is poorly
absorbed and is an effective antibiotic for most Gram-positive
and Gram-negative bacteria, including aerobes, anaerobes,
and some mycobacterium) or probiotics are encouraging and
118
could represent a preferred tool for manipulating enteric
flora in patients with IBD. Preliminary data suggest their
beneficial effects in the treatment of active ulcerative colitis
(and pouchitis) and mild-to-moderate colonic CD, as well as
for the prevention of post-operative IBD recurrence.
Lastly, these authors present two interesting treatment
algorithms for active CD, which may be useful for
clinical practice.
Address for reprints: R Burakoff, Division of Gastroenterology,
Brigham and Women’s Hospital, Boston, MA 02115, USA.
Therapeutic efficacy of leukocytapheresis in a
pregnant woman with severe active ulcerative colitis
Okada H, Makidono C, Takenaka R et al.
Digestion 2006;74:15–8.
The authors of this report describe the use of weekly
leukocytapheresis for treatment of an exacerbation of
ulcerative colitis (UC) in a pregnant woman. The patient
demonstrated a rapid recovery following the first
treatment, with an almost complete remission within
2 weeks. After the fourth treatment, leukocytapheresis
was discontinued due to the improvement in clinical
activity index. No side effects were observed.
Furthermore, the pregnancy continued normally
and the patient delivered a healthy baby.
Leukocytapheresis has recently been used to induce
remission in patients with ulcerative colitis (UC) who fail to
respond to corticosteroids. Three methods are currently used
to perform leukocytapheresis: centrifugation, filtration, and
passage through a granulocyte and monocyte removal
column. The mechanisms by which these treatments induce
clinical remission are still not well understood; one
hypothesis is that the removal of peripheral activated
leukocytes would interrupt the communication between
those cells and those attacking the colonic mucosa. The
method of selective removal of granulocytes, monocytes,
and macrophages with columns has showed an
immunomodulating effect characterized by the reduction of
pro-inflammatory cytokines, downregulation of L-selectin
(which is responsible for the adhesion of leukocytes to the
endothelial cells), and an increase of anti-inflammatory
cytokines including interleukin-1 receptor antagonist, tumor
necrosis factor soluble receptors I and II, and hepatocyte
growth factors.
The authors of this case study are the first to report
treatment of a pregnant woman with centrifugation
leukocytapheresis for an exacerbation of UC. The patient
was diagnosed as having an exacerbation of UC at the
seventh week of pregnancy. After showing no response to
1.5 g/day of mesalazine, she responded to 60 mg/day of
intravenous prednisolone in combination with mesalazine.
However, a reduction of the prednisolone dose to 40 mg/day
was followed by an exacerbation of UC. The patient refused
any increase beyond 40 mg/day of prednisolone and
additional immunosuppressive agents due to the increased
risk of fetal abnormalities. Her clinical activity index was
12 out of a possible 21. The patient was subsequently
recommended for weekly leukocytapheresis. Such a treatment
has previously been performed in pregnant women, only for
the treatment of chronic myeloid leukemia. Side effects of
these procedures are those connected with an extracorporeal
circulation, with the possibility of a variation in blood volume
of approximately 400–500 mL during the procedures along
with a slight reduction of hemoglobin levels, which could be
critical for these patients. This patient did not experience any
side effects. Furthermore, she demonstrated a rapid and
dramatic recovery following the first treatment (decrease in
mucus-containing bloody stools), with an almost complete
remission within 2 weeks. After the fourth treatment,
leukocytapheresis was discontinued as the clinical activity
index had decreased to 4; 2 weeks later the patient was
discharged from hospital. Pregnancy continued normally and
the patient delivered a healthy baby by uncomplicated
vaginal delivery, while maintaining remission of UC.
Address for reprints: H Okada, Department of Medicine and Medical
Science Okayama University Graduate School of Medicine and
Dentistry 2-5-1, Shikata-cho, Okayama 700-8558, Japan.
Cyclophosphamide pulse therapy followed
by azathioprine or methotrexate induces
long-term remission in patients with
steroid-refractory Crohn’s disease
Schmidt C, Wittig BM, Moser C et al.
The authors of this study report the results of a small
number of patients with steroid-refractory Crohn’s
disease (CD) who received monthly cyclophosphamide
(CPM). At 8 weeks after the first infusion of CPM,
>80% of the patients were in clinical remission, which
was maintained for a median of 19 months. These data
suggest that CPM may be a useful adjunctive treatment
in this subgroup of CD patients, although larger,
controlled trials are required.
The search for an effective immunosuppressive regimen for
the treatment of diseases such as Crohn’s disease (CD)
continues. Schmidt et al. report on an extension of their
2003 study examining the use of intravenous cyclophosphamide (CPM) in patients with acute, severe CD [1].
CPM has been widely used in the treatment of systemic
vasculitides, Wegener’s granulomatosis, and systemic lupus
erythematosus for several years. Its mode of action is a
direct cytotoxic effect of the metabolite, chloroacetaldehyde,
on activated and resting lymphocytes. There has always
been some concern regarding the side effect profile of the
drug. Mesna (2-mercaptoethanesulfonic acid) is given
routinely during the infusion to prevent hemorrhagic cystitis,
but there is a significant frequency of opportunistic
infections, neutropenia, and other side effects.
The authors enrolled 16 patients with steroid-refractory
CD. All had suffered a relapse and were inpatients who had
failed to respond to 7 days of treatment with intravenous
steroids. Their CD activity index (CDAI) values ranged from
228–550. All were treated with 750 mg CPM. Treatments
were given monthly; all patients received two infusions and,
if they responded, received further infusions. The median
number of infusions was four. Some patients received six
infusions. The patients were also started on azathioprine or
methotrexate if they were not already taking them. Seven of
the 16 subjects were described in the current authors’
previous report of short-term CPM efficacy [1]. It is of note
that the authors defined a response as a rather modest
70-point reduction in CDAI.
At 8 weeks following the first treatment, 13 of the
16 patients had achieved clinical remission (CDAI ≤150).
There was a steady reduction in the mean CDAI over this
time period. Once achieved, remission was maintained
for a median of 19 months. There were particularly good
responses in patients who had extra-intestinal manifestations
of CD and it is also noteworthy that there appeared to be
better responses in those who were immunomodulator naïve.
Adverse events occurred in six patients and comprised
opportunistic infections (specifically candidal esophagitis and
a urinary tract infection) and relatively mild neutropenia.
In summary, the authors have demonstrated efficacy of
CPM in a small group of patients with steroid-refractory,
acute CD. This group of subjects represents a highly selected
population of CD patients. Moreover, they were treated by
a study group that has considerable experience with the use
of this drug. Further assessment by randomized controlled
trial is required before definitive conclusions regarding the
drug’s efficacy can be made; nonetheless, it may represent
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
cyclophosphamide in acute steroid refractory inflammatory bowel disease.
Gut 2003;52:377–82.
Address for reprints: A Stallmach, Department of Gastroenterology,
Hepatology and Infectiology, Friedrich Schiller-University, Erlanger Allee
101, 07740 Jena, Germany.Email: [email protected]
119
CLINICAL REVIEWS
EPIDEMIOLOGY
Epidemiology of inflammatory bowel diseases
in childhood
Ravikumara M, Sandhu BK.
Indian J Pediatr 2006;73:717–21.
This review evaluated the current opinion on incidence,
age and gender distribution, geographical variation,
trends over time, presenting features, and disease
distribution, from analysis of the epidemiological
studies of pediatric IBD published to date.
The incidence of pediatric IBD has been increasing in
Western countries in recent decades, and now comprises
almost 30% of the total cases of IBD. In parallel with the
overall population trends, younger people showed a
predominant colonic Crohn’s disease (CD) compared with
ulcerative colitis (UC), with a familial pattern of disease
concordance. An atypical clinical manifestation that differs
from the classical abdominal pain, diarrhea, and weight loss
symptoms of CD has been described in a high proportion of
these patients. Many studies have reported an unexplained
preponderance of males with early onset CD (with an equal
gender distribution in pediatric UC) and an increased
amount of indeterminate colitis, although these findings
are not universal. Understanding the difference between
these forms of disease is crucial as there are significant
implications, including the choice of medical treatment,
timing of surgery, prognosis, and disease course. Further-
120
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
the published epidemiological studies have led to better
understanding of IBD, most of these focused on the
incidence/prevalence of disease, with substantial local and
regional variables including geographical, ethnic, and
demographic influences. In addition, the different inclusion
criteria or design of many studies resulted in data and
conclusions that could not be directly compared between
studies; implications for clinical practice are therefore limited.
For these reasons, the IBD working group of the European
Society of Paediatric Gastroenterology, Hepatology and
Nutrition published the “Porto Criteria”, which detail
consensus diagnostic criteria for the management of
childhood IBD. The aim was to prospectively create a
uniform database to characterize the incidence, prevalence,
disease behavior, genetic characteristics, risk factors, drug
therapy, health outcomes, social and economics aspects of
the disease, in order to better understand the disease.
This review highlighted discrepancies between
epidemiological studies of pediatric IBD, and underlined the
difficulties in obtaining homogeneous and comparable data.
Addressing these differences in order to produce uniform
results that may be validated in other studies is extremely
important as it could lead to improvement in the clinical
management and understanding of a disease, which begins
at a critical period of growth and development in childhood.
Address for reprints: BK Sandhu, Department of Pediatric Gastroenterology,
Bristol Children’s Hospital, Upper Maudlin Street, Bristol, BS2 8BJ, UK.
Las Vegas, NV, USA, 20–25 October, 2006
Corey A Siegel1 and David T Rubin2
1
Section 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
Scientific Meeting for 2006 took place in Las Vegas,
NV, USA, from October 20–25, 2006. The Vegas strip
was an exciting backdrop for gastroenterologists to get
updated on the “state of the art” advances in the care
of patients with IBD. Here, we present the highlights of
the scientific presentations related to the treatment and
diagnosis of IBD, along with the “bottom line” take-home
message from each.
and no new safety concerns were observed. No delayedhypersensitivity reactions occurred over the course of
the study, and the presence or absence of human antichimeric antibodies (HACA) did not influence efficacy.
The authors concluded that adalimumab rapidly and
significantly induced clinical remission and response in this
patient population and that there was no cross-reactivity
to antibodies against infliximab.
Adalimumab appears to be a safe and effective option
in CD patients who have lost response or had a hypersensitivity reaction to infliximab.
Therapeutics
Biological therapy
William Sandborn (Mayo Clinic, Rochester, MN, USA)
commenced the IBD presentations with results of the GAIN
(Gauging Adalimumab Efficacy in Infliximab Non-Responders)
study [1]. GAIN was a randomized, controlled trial of
adalimumab, a self-injectable, fully human anti-tumor
necrosis factor (anti-TNF) monoclonal antibody in patients
with moderate-to-severe Crohn’s disease (CD) who had
previously received infliximab but had either lost the
response to the drug or developed a hypersensitivity
reaction. This was the first trial studying the efficacy and
safety of switching from one anti-TNF agent to another in
CD. A total of 325 patients were randomized to receive
either adalimumab 160 mg subcutaneously at week 0 and
80 mg subcutaneously at week 2, or placebo at both time
points. The primary endpoint was clinical remission at week
4. At this time point, 21% of patients in the adalimumab
arm were in clinical remission compared with 7% of those
who received placebo (p≤0.001). In addition, 38% of
patients responded to treatment (a decrease in CD activity
index [CDAI] of ≥100 points) compared with 25% in the
placebo group (p≤0.01). The medication was well tolerated
Further data on adalimumab from the CHARM (Crohn’s
Trial of the Fully Human Antibody Adalimumab for
Remission Maintenance) study were presented by Stephen
Hanauer (University of Chicago, Chicago, IL, USA). CHARM
was a 56-week study of the maintenance of remission
of CD, which was initially presented in Los Angeles, CA,
USA, in May 2006 at Digestive Disease Week [2]. The
investigators of this post hoc analysis evaluated the benefit
of concomitant immunosuppressant therapy (IMM) while
patients received maintenance injections (every 2 weeks) of
adalimumab for 1 year [3]. Of 778 randomized patients,
58% responded to treatment with adalimumab at 4 weeks.
By 56 weeks, 41% of the responders receiving IMM were in
clinical remission compared with 49% who were not
receiving IMM; 17% of those receiving placebo were in
remission. The conclusion of this post hoc analysis was
that adalimumab is superior to placebo in inducing
remission of moderate-to-severely active CD irrespective of
concomitant IMM.
121
MEETING REPORT
American College of Gastroenterology
Annual Scientific Meeting 2006
(ACG 2006)
COREY A SIEGEL AND DAVID T RUBIN
Adalimumab may be equally effective with or without
concomitant immunosuppression. Additional data
are needed to determine the long-term outcomes
of this approach.
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
Safety and Efficacy Fragment Evaluation) trial found that
certolizumab pegol has a similar efficacy to infliximab and
adalimumab for maintenance of remission of moderate-toseverely active CD [4]. At this year’s ACG, Dr Sandborn and
colleagues presented a unique subgroup analysis from
PRECiSE 2 that evaluated response rates stratified by disease
duration [5]. With a similar trial design to ACCENT 1
(A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New
Long-Term Treatment Regimen) and CHARM, all patients
initially received open-label drug, and then the responders
(68%) were randomized to receive maintenance certolizumab
pegol or placebo every 4 weeks. At 26 weeks, patients who
had had CD for <1 year achieved response and remission
rates of 89% and 68%, respectively. This is in contrast to
response and remission rates of 57% and 44%, respectively,
for patients who had been diagnosed with CD for ≥5 years.
These data suggest benefit of early, rather than late, use of
certolizumab pegol.
These data mirror the higher therapeutic response rates
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
biological therapy earlier in the course of CD.
Natalizumab is a monoclonal antibody designed to bind
α4 integrin, which is a key intestinal adhesion molecule. It
has previously been shown to induce and maintain remission
in patients with moderately-to-severely active CD, but safety
concerns based on the report of three cases of progressive
multifocal leukoencephalopathy (PML) led to a hold on
further clinical trials. At this meeting, Remo Panaccione and
colleagues (University of Calgary, Calgary, AB, Canada)
presented follow-up, open-label extension data from the
previously reported ENACT-2 (Evaluation of Natalizumab as
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
(2 years in total). With continued infusions, 86% of patients
in remission at 1 year successfully maintained this remission
for 2 years. This high percentage of remission maintenance
122
held true for patients who had previously failed infliximab
therapy. There were no cases of PML in this follow-up.
Patients achieving remission with natalizumab are highly
likely to maintain that remission with ongoing treatment
for up to 2 years.
5-aminosalicylates
Information on 5-aminosalicylates (5-ASAs) presented at ACG
included effects of delayed-release mesalamine on mucosal
healing, and safety data for the new Multi Matrix System
(MMX™, Shire Pharmaceuticals, Wayne, PA, USA; licensed
from Giuliani S.p.A., Milan, Italy) delivery of mesalamine.
Pooling data from two previously presented Phase III,
multicenter, randomized, double-blind controlled studies,
David Rubin (University of Chicago, Chicago, IL, USA) and
colleagues reported rates of mucosal healing in moderately
active ulcerative colitis (UC) using delayed-release oral
mesalamine at either 2.4 g/day or 4.8 g/day [8]. They found
that at 6 weeks, 67% of patients who had achieved treatment
success also achieved mucosal healing. This was independent
of dose. Interestingly, there was a poor correlation between
mucosal healing and symptom improvement.
Treatment with mesalamine can induce mucosal healing
in UC as early as 3 and 6 weeks. However, endoscopic
healing and improvement in UC symptoms were not
well-correlated.
Gary Lichtenstein (University of Pennsylvania, Philadelphia,
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 8week studies that included 560 patients with mild-to-moderate
UC who were treated with MMX mesalamine and 179 patients
who were treated with placebo. Rates of serious adverse events
were very low in all groups and similar to placebo. Only
pancreatitis (two cases, one in each mesalamine group) was
seen more commonly in the MMX mesalamine group, but this
is a previously described rare side-effect of mesalamine.
MMX mesalamine appears to be well tolerated in
patients with UC up to 4.8 g/day.
Novel treatments
There was a paucity of data on novel IBD drug therapies
presented at this meeting, but two “procedural” treatments
appear to show promise for patients refractory to standard
ACG 2006
interventions. For the most refractory, end-stage patients
with CD, Kareem Abu-Elmagd and colleagues (University of
Pittsburgh, Pittsburgh, PA, USA) reported their experience with
intestinal transplant (IT) in patients with intestinal failure [10].
Of their series of 196 patients who underwent IT for various
causes of intestinal failure, 38 had a history of complicated
CD. All CD patients were recalcitrant to previous therapy,
had undergone multiple surgeries, and failed total parenteral
nutrition (TPN). The overall survival of CD patients undergoing
IT was 85% at 1 year, and 62% at 3 years. Survival rates
improved to 92% at 1 year and 78% at 3 years with the
addition of induction immunosuppression, which was used in
the more recent IT recipients. All survivors achieved full
nutritional autonomy with an unrestricted oral diet. Disease
recurrence occurred in 7.5% of recipients at 18 months.
Intestinal transplantation is an option for the most
refractory CD patients who have failed medical and
surgical therapy and can no longer be maintained
on TPN, but is not a “cure” for their disease.
Perhaps the most interesting presentation regarding IBD
treatment at the conference was that by Jane Onken (Duke
Clinical Research Institute, Durham, NC, USA). Dr Onken and
colleagues studied the effect of PROCHYMAL™ (Osiris
Therapeutics Inc, Baltimore, MD, USA), ex vivo cultured adult
human mesenchymal stem cells, for patients who had CD that
was refractory to standard therapeutic options [11].
PROCHYMAL has anti-TNF activity, and has previously been
shown to induce colonic mucosal healing in patients with acute
graft-versus-host disease [12]. They reported open-label data on
nine patients who received two infusions of PROCHYMAL,
administered 7 days apart. Three patients (33%) achieved the
primary endpoint of clinical response (a decrease in CDAI of ≥100
points) by day 14. All three of these patients had previously failed
infliximab treatment. All infusions were well tolerated and
there were no treatment-related serious adverse events.
PROCHYMAL may be a promising novel therapy for
patients with CD, but further safety and pharmacokinetic
data are needed before its potential is fully understood.
multicenter, observational study enrolled 323 patients with IBS
and 241 controls (no symptoms of IBS and no history of IBD).
They were tested for the presence of perinuclear antineutrophil
cytoplasmic antibodies, immunoglobulin A (IgA) and IgG antiSaccharomyces cerevisiae antibodies, and anti-Escherichia coli
outer membrane porin C (anti-OmpC). A total of 31% of IBS
patients and 28% of the control population had measurable
titers to at least one marker (p=0.6). The high false-positive
rate (30% overall) and low positive predictive value (0.62%)
results in a low specificity for IBD serological testing in this
patient population. The authors concluded that serological
markers of IBD are frequently present in patients without CD
or UC. Of note, they did not report the test performance of
combinations of markers or how new computer heuristic
algorithmic approaches may impact these results.
These results reinforce the importance of understanding
the population prevalence of IBD when interpreting
serology results, and suggest that in a low-risk patient
population, serological testing may not be an effective
screening tool for IBD.
A group from the Mayo Clinic (Rochester, MN, USA)
examined cumulative radiation exposure from radiological
testing in patients with CD and UC [15]. Their aim was to
quantify the amount of ionizing radiation received by IBD
patients over the course of their disease. The significance is
that higher doses of radiation have been associated with an
increased risk of cancer. They reported on an Olmsted County
inception cohort of 220 patients with IBD (115 with CD and
105 with UC) who were diagnosed between 1990 and 2001.
The mean follow-up time was just over 10 years. The mean
cumulative effective radiation dose received from radiographic
testing over this 10-year period was 36.9 millisieverts (mSv).
As a comparison, the average annual radiation exposure in
the USA is 3.0 mSv. Patients with CD had a significantly
higher mean dose than those who had UC, primarily
resulting from nearly twice the number of abdominopelvic
computed tomography scans. When annualizing their data,
the authors found that the radiation exposure in the IBD
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
IBD patients included data on the utility of serological markers
and radiation exposure associated with radiographic imaging.
A collaborative group studied the diagnostic accuracy of IBD
serological markers in patients meeting Rome II criteria [13]
for irritable bowel syndrome (IBS) [14]. This prospective,
To decrease a possible increased carcinogenic risk,
alternative imaging modalities (e.g. ultrasound or
magnetic resonance imaging) should be considered for
IBD patients destined to undergo multiple radiographic
tests (i.e. younger or sicker patients).
123
COREY A SIEGEL AND DAVID T RUBIN
Conclusion
Presentations at ACG 2006 focused on optimizing available
biological therapies. While we await further data on novel
approaches for the treatment of IBD, we hope that this new
information will translate into more effective and safe use of
the currently available (and hopefully soon to be available)
medications. We look forward to ACG 2007 in Philadelphia,
PA, USA.
3.
Hanauer SB, D’Haens GR, Colombel JF et al. Sustained clinical remission in patients with
moderate to severe Crohn’s disease with adalimumab, regardless of anti-TNF history
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 antiTNF PEGylated Fab’ fragment is safe and effective in the maintenance of response and
remission following induction in active Crohn’s disease: a Phase III study (PRECiSE).
Gut 2005;54(Suppl VII):A82.
5.
Sandborn WJ, Colombel JF, Panes J et al. Higher remission rate and maintenance of
response rates with subcutaneous monthly certolizumab pegol in patients with recentonset 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
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
infliximab exposure: Results from an open-label extension study. Am J Gastroenterol
2006;101(9):1152.
8.
Rubin DT, Yacyshyn BR, Ramsey D et al. Endoscopically measured mucosal healing
correlated with response to therapy in moderately active UC. Am J Gastroenterol
2006;101(9):S442.
9.
Lichtenstein GR, Kamm MA, Sandborn WJ et al. MMX mesalamine is well tolerated in
patient with active mild-to-moderate ulcerative colitis: pooled analysis of adverse events
from three randomized studies. Am J Gastroenterol 2006;101(9):S432.
Disclosures
Dr Siegel has served on advisory boards of Abbott and UCB
Pharmaceuticals and on speakers’ bureaus for Prometheus Labs,
Salix Pharmaceuticals, and Shire, has served as a consultant for Elan
Pharmaceuticals and has received grant support from Procter and
Gamble. Dr Rubin has served as a consultant for Abbott, Given Imaging,
Procter & Gamble, Prometheus Labs, Salix, Shire, and UCB Pharmaceuticals,
and has served on speakers’ bureaus for Abbott, Procter and Gamble,
Prometheus Labs, and Salix Pharmaceuticals. Dr Rubin has received
10. Abu-Elmagd K, Wu T, Bond G et al. Intestinal transplantation for end stage Crohn’s
disease: therapeutic efficacy and risk of recurrence. Am J Gastroenterol 2006;101(9):S468.
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
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.
References
13. Thompson WG, Longstreth GF, Drossman DA et al. Functional bowel disorders and
functional abdominal pain. Gut 1999;45(Suppl 2):II43–7.
1.
Sandborn WJ, Rutgeerts P, Enns RA et al. Adalimumab rapidly induces clinical remission
and response in patients with moderate to severe Crohn’s disease who had a secondary
failure to infliximab: Results of the GAIN study. Am J Gastroenterol 2006;101(9):S448.
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.
Program and abstracts of the Digestive Disease Week; May 20–25, 2006; Los Angeles,
CA, USA.
14. Andrews AH, Cash BD, Lee DH et al. The high false positive rate of inflammatory
bowel disease serologic markers in patients with irritable bowel syndrome.
Am J Gastroenterol 2006;101(9):S475.
124
15. Peloquin JM, Pardi DS, Sandborn WJ et al. Exposure to diagnostic ionizing radiation
in a population-based cohort of patients with inflammatory bowel disease.
Am J Gastroenterol 2006;101(9):S448.
MEETING REPORT
United European Gastroenterology Week
(UEGW) 2006
Berlin, Germany, 21–25 October 2006
Séverine Vermeire
Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
The annual United European Gastroenterology Week (UEGW)
2006 was held in Berlin, Germany from 21–25 October
2006. A total of 9955 people from 103 countries were
registered for the meeting. This report highlights several
abstracts that were presented on some of the most active
areas of IBD research, and also discusses the European
Crohn’s and Colitis Organisation (ECCO) consensus
guidelines for ulcerative colitis (UC), details of which were
presented during the last day of the congress.
ECCO UC consensus guidelines
Clinical guidelines are generated to assist physicians in their
daily care of patients. Although they have no automatic
legal mandate and are not intended to override individual
clinical judgment, evidence-based guidelines will, in general,
assure good medical care.
Recently, ECCO published European evidence-based
consensus guidelines on the diagnosis and management of
Crohn’s disease (CD) [1–3]. ECCO is a forum for specialists
in IBD from 22 European countries. Eduard Stange (Robert
Bosch Hospital, Stuttgart, Germany), the driving force
behind the consensus guidelines on CD, has now repeated
this exercise for UC [4]. The aim of the UC consensus was
to promote a European perspective on the management of
the disease. The main statements and recommendations
were presented during the last day of the congress. The
process was very similar to that of the previously published
consensus on CD [1–3]. Working parties for 13 topics
(including diagnosis, classification, active disease,
maintenance of disease, complementary and alternative
medicine, pediatrics, pathology, and pouchitis) circulated
questionnaires to quantify “expert opinion”. The content
of the questionnaires was based on systematic literature
search on each topic. Finally, statements with an Oxford
evidence level (EL) and guideline recommendations were
drafted [5]. All statements, levels of evidence, and grades
of recommendation (RG) were reviewed during a 2-day
consensus meeting prior to UEGW with 61 European
opinion leaders and experts on IBD present. Consensus was
defined as >80% agreement.
Three examples of ECCO guidelines on the management
of UC are given below. The full publication of these guidelines
is expected early in 2007.
ECCO Statement: “Extent of Disease”. The extent
of UC influences the patient’s management. Disease
extent influences the treatment modality and
determines if oral and/or topical therapy is initiated
(EL1b, RG B). Disease extent influences start and
frequency of surveillance (EL2, RG B). Therefore,
a classification according to extent of disease is
recommended (EL5, RG D). The preferred classification
is an endoscopic classification into ulcerative proctitis
(limited to the rectum), left-sided colitis (up to the
splenic flexure) and extensive colitis, and by maximal
extent upon follow-up (EL5, RG D).
ECCO Statement: Classification of UC based on
disease severity is useful for clinical practice and dictates
the patient’s management (EL1b, RG B). Disease
severity influences the treatment modality and
determines if no, oral, intravenous, or surgical therapy
is initiated. Indices of disease severity have not been
adequately validated. Clinical, laboratory, imaging and
endoscopic parameters, including histopathology assist
physicians in patient management (EL 2; RG B). There
is no fully validated definition of remission. The best
way of defining remission is a combination of clinical
parameters (i.e. stool frequency ≤3 per day with no
bleeding) and a normal mucosa at endoscopy (EL5,
RG D) (majority vote).
125
SÉVERINE VERMEIRE
Figure 1. Induction study design of the GAIN (Gauging
Adalimumab Efficacy in Infliximab Non-Responders) study.
Double-blind,
placebo-controlled period
Week
Week
Week
0
2
4
n=166
325
Patients
n=159
Placebo
Placebo
160 mg
adalimumab
80 mg
adalimumab
Primary endpoint
ECCO Statement: Left-sided active UC of mild-tomoderate severity should initially be treated with topical
aminosalicylates [EL1b, RG B] combined with oral
mesalazine ≥2 g/day [EL1a, RG A]. Topical steroids or
mesalazine alone are also effective, but less effective
than combination therapy [EL1b, RG B]. Topical
mesalazine is more effective than topical steroid [EL1a,
RG A]. Oral aminosalicylates alone are less effective
[EL1a, RG A]. Systemic corticosteroids are appropriate
if symptoms of active colitis do not respond rapidly to
mesalazine [EL1b, RG C]. Severe left-sided colitis is
usually an indication for hospital admission for intensive
treatment with systemic therapy [EL1b, RG B].
IBD therapeutics
Besides new and interesting data on the available and
upcoming anti-tumor necrosis factor (anti-TNF) biological
agents (infliximab, adalimumab, and certolizumab pegol),
and 5-aminosalicylates, this year’s UEGW also reported
some encouraging results for some novel molecules for
treatment of CD and UC. A summary of these is presented
in the following section.
Anti-TNF-agents
Walter Reinisch and colleagues (University of Vienna, Vienna,
Austria) presented the results of the impact of infliximab on
UC-related hospitalizations and UC-related hospitalizations
requiring high-dose corticosteroids (a surrogate measure of
acute, severe flare of UC requiring hospitalization in ACT 1
(Active UC Trial 1) and ACT 2 [6]. A total of 728 patients
were included in the ACT studies, the results of which were
published in 2005 [7]. At week 30 (for both studies
combined), infliximab-treated patients showed significantly
less UC-related hospitalizations (2.7/100 patients) compared
with patients receiving placebo (7.8/100 patients; p=0.025).
At week 54 (ACT 1 patients only), the respective numbers
of UC-related hospitalizations were 4.1/100 and 11.6/100
(p=0.055). Therefore, maintenance therapy with infliximab
is associated with a reduced number of hospitalizations
requiring high-dose corticosteroids.
As a result of its chimeric properties, treatment with
infliximab may be associated with antibody formation and risk
of acute infusion reactions and loss of response. Treatment
with the fully human monoclonal antibody adalimumab may
be effective and safe in these patients. Adalimumab is an
immunoglobulin G1 (IgG1) isotype monoclonal antibody that
is structurally identical to naturally occurring human antibodies,
and is therefore less likely to engender an immune response. Its
half-life is 12–14 days, and the drug is administered every 2
weeks by subcutaneous injection. The GAIN (Gauging
126
Adalimumab Efficacy in Infliximab Non-Responders) study
assessed the efficacy and safety of adalimumab versus placebo
for the induction of clinical remission in patients with
moderate-to-severe CD (CD activity index [CDAI] 220–450)
who had lost the response or had reactions to infliximab. The
results were presented by Paul Rutgeerts on behalf of the
GAIN study investigators [8]. This was a 4-week, double-blind,
placebo-controlled trial with patients randomized to either
adalimumab (160 mg) at week 0 and 80 mg at week 2, or
placebo at weeks 0 and 2 (Fig. 1). The primary endpoint,
defined as the induction of remission (CDAI <150) at week 4,
was reached in 21% of the adalimumab-treated patients
compared with just 7% of patients that received placebo
(p<0.001). Secondary endpoints included a 70 (CR-70)
or 100 (CR-100) point decrease in the CDAI. A CR-70 and
CR-100 response was seen in 52% and 38% of patients
treated with adalimumab, and 34% and 25% of patients
receiving placebo, respectively (p<0.01). The effect was
observed as early as week 1 with response rates of 35% and
21% for adalimumab and placebo, respectively (p<0.005).
Adalimumab was well tolerated with an overall lower incidence
of adverse events compared with placebo.
Despite their extensive use, the precise mechanisms
of action of all anti-TNF agents remain incompletely
understood. Although complement activation, antibodydependent cell mediated cytotoxicity (ADCC), and induction
of apoptosis have been shown to be important in explaining
the mechanisms of action of infliximab and adalimumab,
certolizumab pegol does not induce ADCC or apoptosis but
has shown similar efficacy in recent clinical trials in CD. This
has led to further investigations of the mechanisms of action
of these drugs. It has been suggested that anti-TNF agents
induce signaling via membrane-bound TNF-α, which results
in an inhibitory effect on lipopolysaccharide (LPS)-induced
UEGW 2006
cytokine production. Gianluca Fossati and colleagues (UCB,
Slough, Berkshire, UK) compared certolizumab pegol (an
antibody Fab’ fragment conjugated with polyethylene
glycol) with other anti-TNF agents in terms of their effect
on LPS-stimulated production of TNF-α and interleukin-1β
(IL-1β) [9]. Human monocytes were selected from the
peripheral blood of healthy blood donors and were preincubated with etanercept, certolizumab pegol, adalimumab,
infliximab, or control buffer. After washing, monocytes were
then incubated with LPS or buffer, and supernatants were
collected to measure cytokine levels using an enzyme-linked
immunosorbent assay. Etanercept was much less efficient
than all other anti-TNF agents in inhibiting LPS-stimulated
production of TNF-α and IL-1β, while certolizumab
appeared to be 100-fold more potent than adalimumab
or infliximab at inhibiting the release of TNF-α and IL-1β
by monocytes. The potent inhibition by certolizumab pegol
of cytokine production by monocytes may represent an
important mechanism of action in CD.
Mesalazine
A number of presentations from Michael Kamm (University
College London, London, UK) and colleagues discussed pivotal
data from the multicenter, randomized, placebo-controlled,
Phase III trials (SPD476-301 and SPD476-302) of MMXTM
(Shire Pharmaceuticals, Wayne, PA, USA; licensed from Giuliani
S.p.A., Milan, Italy) mesalazine in which patients with mild-tomoderate UC (UC disease activity index [DAI] 4–10) were
randomized to receive MMX mesalazine 2.4 g/day once daily
(study 302) or twice daily (study 301), MMX mesalazine 4.8
g/day once daily (both studies), or placebo. The MMX formulation of mesalazine utilizes Multi Matrix System technology to
delay and extend delivery of the active drug throughout the
colon. The primary endpoint of these studies was clinical and
endoscopic remission defined according to the criteria described
in the previously published Phase II study of MMX mesalazine
in patients with mild-to-moderate UC (SPD476-202) [10]. In
the two Phase III trials, at week 8, remission was achieved by a
significantly greater number of patients receiving MMX
mesalazine 2.4 g/day (37.2% [64/172]; p<0.001) or MMX
mesalamine 4.8 g/day (35.1% [61/174]; p<0.001) compared
with placebo (17.5% [30/171]) [11]. Similar findings were
obtained from patients with moderate disease, indicating that
MMX mesalazine is effective for the induction of remission of
both mild and moderate UC [12].
A post hoc analysis of pooled data from SPD476-301 and
SPD476-302 found that a significant induction of remission
was achieved in patients with mild-to-moderate UC who
switched from a low-dose formulation of mesalamine (or who
were previously 5-ASA-naïve/had discontinued 5-ASAs) to
subsequent treatment with MMX mesalazine [13]
Stefan Schreiber (Christian Albrechts Universität, Kiel,
Germany) and colleagues presented data on the safety and
tolerability of MMX mesalazine in patients with mild-tomoderate UC, which were pooled from the three studies
(SPD476-202, SPD476-301, and SPD476-302). A total of
560 patients received MMX mesalazine 2.4 g/day (n=191),
4.8 g/day (n=190), or placebo (n=179). Only 10 patients
(<2%) reported 13 serious adverse events (seven with
placebo, four with MMX mesalazine 2.4 g/day [aggravated
UC, pancreatitis, perianal abscess, and urinary retention],
and two with MMX mesalazine 4.8 g/day [viral gastroenteritis
and pancreatitis]) [14].
A poster by Dr Kamm and colleagues described 4-month
interim safety data from an open-label, extension study
(SPD476-303) to evaluate the long-term safety and tolerability
of MMX mesalazine. Patients who were not in remission
following the 8-week SPD476-301 and SPD476-302 studies
received MMX mesalazine 4.8 g/day for 8 weeks (acute
phase). Subjects from the SPD476-301, -302, or -303 studies
who achieved remission were randomized in an extension
study to receive MMX mesalazine 2.4 g/day for 12 months.
At 4 months, 146/458 patients who entered the maintenance
phase reported at least one treatment-emergent adverse
event (TEAE), the majority of which were gastrointestinal and
were mild or moderate. A total of 55 treatment-related adverse
events and 21 serious adverse events were reported [15].
These Phase III studies demonstrate that MMX mesalazine
is well tolerated, with a safety profile similar to other
mesalazine formulations, and is effective for the induction
of remission of mild-to-moderate UC at both doses tested.
It is anticipated that MMX mesalazine may improve patient
compliance and enhance the overall treatment success.
Chyon Yeh (Procter and Gamble Pharmaceuticals, Mason,
OH, USA) and colleagues assessed the effects of mesalamine
on creatinine clearance using 6-week data from the ASCEND I
and II (Assessing the Safety & Clinical Efficacy of a New Dose
of 5-ASA), multicenter, randomized, Phase III clinical trials of
delayed-release oral mesalamine (Asacol®, Procter & Gamble
Pharmaceuticals, Cincinnati, OH, USA) in patients with
moderate UC. In patients with predominantly normal renal
function at baseline, no detrimental effects on creatinine
clearance were observed [16]. A separate presentation by Dr
Yeh and colleagues demonstrated that this modified-release
oral mesalamine induced mucosal healing in >50% of patients
with moderately active UC (a total of 391 patients from
ASCEND I and II were included in this analysis) [17].
Novel molecules and approaches for Crohn’s disease
CCX282-B
Satish Keshav and colleagues (University College London,
London, UK) presented the results of a Phase II study of
127
SÉVERINE VERMEIRE
CCX282-B, an orally active inhibitor of the chemokine
receptor, CCR9, in moderate-to-severe CD [18]. The ligand
for CCR9 is CCL25, which is selectively expressed in the
digestive tract. CCX282-B is an orally bioavailable specific
CCR9 antagonist that was found to be well tolerated in a
previous Phase I study in healthy volunteers [19]. In this
study, the safety and tolerability of CCX282-B in 71 patients
with CD was assessed. Patients were randomized in a 2:1
ratio to either CCX282-B or placebo. CCX282-B was well
tolerated and the only transient side effect seen more
frequently in the group that received CCX282-B was
headache. The investigators found encouraging evidence of
clinical benefit in CD patients, although strictly speaking no
statistical significance was reached. However, there was
an observed decrease of 4.4±3.7 mg/L in the levels of
C-reactive protein in the group that received CCX282-B
after 28 days of therapy, while an increase of 6.7±4.2 mg/L
was seen in the placebo group (p=0.07). This study was not
designed to measure the efficacy of the drug; this should be
evaluated in subsequent studies.
Fibrin glue
Fibrin glue was presented as a new option for treatment of
anal fistulas [20]. It is a simple technique that may be
repeatedly used and will not affect anal sphincter function.
This multicenter, randomized study assessed the efficacy
and safety of fibrin glue injected in the fistula tracts of CD
patients. All patients received a baseline magnetic
resonance imaging scan or endoscopic ultrasound to rule
out the presence of abscess. Stable doses of concomitant
treatment were allowed, but anti-TNF agents were
excluded. Patients were randomized to receive either fibrin
glue injection or no treatment. The primary endpoint was
complete response at week 8, defined as the absence of
perianal pain and absence of draining fistulas. At week 8,
patients randomized to the no treatment group who had no
response could receive active treatment. At this stage, retreatment was possible in the group randomized to fibrin
glue. A total of 77 patients with a mean duration of CD
of 6.7 years were enrolled. At week 8, 38% of the fibrin
glue group had a complete response compared with 16% in
the no treatment group (p<0.05). The significant results
were only observed in the subgroup of patients treated with
a simple fistula (53% of all patients). In those who were
defined as fibrin-glue responders at week 8, 83%
maintained remission at week 16. Therefore, fibrin glue
appears to be an effective therapy for achieving complete
closure of anal fistulas in patients with CD. The procedure
appears safe and should be regarded as a good option in
patients with persisting or relapsing perineal fistulas without
intestinal symptoms.
128
Novel molecules for treatment of UC
Phosphatidylcholine
Phosphatidylcholine was studied in a randomized, doubleblind, placebo-controlled trial of 60 patients with steroiddependent, chronic, active UC [21]. Patients received either
0.5 g of phosphatidylcholine (PC) or placebo daily for
12 weeks. The primary endpoint was steroid withdrawal and
clinical remission (defined as a disease activity index of ≤3),
or a ≥50% clinical activity index improvement. This was
achieved in 15 patients (50%) in the PC group compared
with only three (10%) in the placebo group (p=0.002).
Therefore, retarded-release PC seems effective in steroid
withdrawal of chronic, active, steroid-dependent UC and
promotes a parallel improvement of clinical activity.
Curcumin
Curcumin is a plant-derived natural substance present in
turmeric. Curcumin is known to have tumor suppressing
actions, as well as anti-inflammatory and anti-microbial
activities. These activities are explained in part by inhibition
of nuclear factor-κB. In the double-blind, randomized study
presented by Hiroyuki Hanai and colleagues (Hamamatsu
University School of Medicine, Hamamatsu, Japan), the
clinical efficacy of curcumin in combination with 5-ASA or
sulphasalazine was tested [22]. A total of 89 patients with
UC in remission were randomized to receive curcumin plus
sulphasalazine or 5-ASA, or placebo plus sulphasalazine or
5-ASA for 6 months. The relapse rate during the 6 months
of therapy was significantly lower in the curcumin group
(4.55%) compared with the placebo group (20.51%;
p=0.04). Curcumin treatment improved the clinical activity
index as well as the endoscopic index after 6 months and
may prove to be a promising treatment for maintaining
remission in patients with UC. Further studies of this agent
are essential.
IBD epidemiology
Long-term outcome of infliximab therapy
Data on the long-term outcome of treatment with infliximab
are scarce. A large population-based registry of all patients
treated with infliximab in 22 medical centers between
1998–2005 were included in the Danish Crohn Colitis
Database [23]. A total of 648 patients (615 with CD,
16 with UC, and 17 with indeterminate colitis) were treated
with infliximab. The duration of the disease at the first
infliximab treatment was a median of 5 years (range
0–38 years) and 64 patients were aged <18 years. A median
of three infusions per patient (range 1–30 infusions) were
administered, giving a total of 3320 infusions. Maintenance
therapy was given to 26% of patients and 33% had ondemand therapy. Overall response rates for CD were 84.7%
UEGW 2006
(luminal disease) and 82.6% (fistulizing disease), and, for
UC, the response rate was 69.2%. Five patients were
diagnosed with cancer, but only one was possibly related to
the use of infliximab. In total, 13 patients died; two of these
may have been related to infliximab (0.3%). The authors
concluded that, in this large database, infliximab is an
efficacious treatment for IBD with response rates of >80%.
This was in spite of 33% of patients being treated episodically.
References
Biological therapies and pregnancy
The increased use of biologics such as anti-TNFs in the
treatment of IBD and other immune-mediated diseases
raises the question of safety for developing fetuses. A
question that is frequently asked by young (female) patients
relates to the use of anti-TNF agents during pregnancy. The
preliminary data from the Organization of Teratology
Information Specialists (OTIS) Autoimmune Diseases in
Pregnancy Project were presented [24]. OTIS is a non-profit
organization that was founded in 1988 and has an overall
objective to help prevent birth defects and improve public
health. The organization conducts pregnancy exposure
cohort studies. Specialists provide current information about
the possible effects on pregnancies of patient exposure to
various agents, including prescription and over-the-counter
medications, alcohol and illicit drugs, diseases and infections,
and occupational and paternal exposures. The current target
diseases include rheumatoid arthritis, ankylosing spondylitis,
psoriatic arthritis, and psoriasis. This prospective, observational
cohort study, presented by Christina Chambers and colleagues
(University of California, San Diego, CA, USA) compared
pregnancy outcomes in women with these diseases with a
disease-matched control group and a non-diseased control
group. The current US Food and Drug Administration
pregnancy label category of both infliximab and adalimumab
is B. In this study, 19 women with a target disease were
adalimumab-exposed, while 32 adalimumab-exposed women
did not meet cohort criteria but were enrolled (eight of whom
were using adalimumab for CD). There was one spontaneous
abortion in the adalimumab cohort group and one in the
group of women from the adalimumab registry. No
developmental abnormalities were seen. These preliminary
findings do not suggest an increased risk for adverse
pregnancy outcomes with exposure to adalimumab early in
pregnancy. Of course, definite conclusions await the
accumulation of a sufficient sample size in the cohort study.
1.
Stange EF, Travis SP, Vermeire S et al.; European Crohn’s and Colitis Organisation.
definitions and diagnosis. Gut 2006;55(Suppl 1):i1–15.
2.
Travis SP, Stange EF, Lemann M et al.; European Crohn’s and Colitis Organisation.
current management. Gut 2006;55(Suppl 1):i16–35.
3.
Caprilli R, Gassull MA, Escher JC et al.; European Crohn’s and Colitis Organisation.
special situations. Gut 2006;55(Suppl 1):i36–58.
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
recommendation. Available at: http://www.cebm.net/levels_of_evidence.asp.
6.
Reinisch W, Sandborn WJ, Yan S et al. Infliximab reduces UC-related hospitalizations
requiring high-dose corticosteroids: the ACT trial experience in ambulatory patients with
moderately to severely active UC. Gut 2006;55(Suppl V):A23.
7.
Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance
therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76.
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
failure to infliximab therapy: results of the GAIN study. Gut 2006;55(Suppl V):A20.
9.
Fossati G, Brown D, Nesbitt A. Effects of certolizumab pegol, etanerceprt, adalimumab
and infliximab on lipopolysaccharide-induced cytokine production by human peripheral
blood monocytes. Gut 2006;55(Suppl V):A18.
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
Ther 2006;24:1087–97.
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
formulation given once or twice daily, is effective for the induction of remission of mildto-moderate ulcerative colitis. Gut 2006;55(Suppl V):A126.
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
ulcerative colitis: a prespecified analysis of combined data from two pivotal, randomised,
placebo-controlled, Phase III studies. Gut 2006;55(Suppl V):A132.
13. Kamm MA, Lichtenstein GR, Sandborn WJ et al. MMX mesalazine, a novel, high-strength
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
discontinued: an analysis of pooled data from two Phase III, randomised, placebo
controlled studies. Gut 2006;55(Suppl V):A126.
14. Schreiber S, Kamm MA, Lichtenstein G et al. MMX mesalazine, a novel formulation of
5-ASA given once or twice daily, is well tolerated in patients with active mild-to-moderate
ulcerative colitis: an analysis of adverse events in combined data from three randomised
studies. Gut 2006;55(Suppl V):A132.
15. Kamm MA, Schreiber S, Butler T et al. Safety analysis of MMX mesalazine for the
maintenance of remission of mild-to-moderate ulcerative colitis: results of 4-month
interim data analysis. Gut 2006;55(Suppl V):A126.
16. Sandborn W, Yeh C, Magowan S. Mesalazine 2.4 & 4.8 g/day demonstrates no difference
in creatinine clearance (CrCl) in moderately active ulcerative colitis patients over a 6 week
treatment period. Gut 2006;55(Suppl V):A20.
17. Lichtenstein G, Rubin D, Regalli G et al. Endoscopy measured mucosal healing of
modified-release oral mesalazine 4.8 g/day versus 2.4 g/day. Gut 2006;55(Suppl V):A127.
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
to severe Crohn’s disease. Gut 2006;55(Suppl V):A22.
19. http://chemocentryx.com/product/CCR9.html
20. Grimaud J, Munoz-Bongrand N, Siproudhis L et al. Fibrin glue injection for perianal fistulas
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
dependent ulcerative colitis. Gut 2006;55(Suppl V):A22.
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 doubleblind placebo-controlled clinical trial. Gut 2006;55(Suppl V):A23.
23. Elkjaer M, Caspersen S, Pedersen N et al. Longterm outcome of inflixmab treatment
in the national Danish Crohn and colitis database. Gut 2006;55(Suppl V):A41.
Disclosures
Dr Vermeire has received honoraria from Abbott, Ferring,
Schering-Plough, and UCB Pharmaceuticals.
24. Chambers CD, Johnson DL, Jones KL; OTIS collaborative Research Group. Adalimumab
and pregnancy outcome: preliminary data from the OTIS auto-immune diseases in
pregnancy project. Gut 2006;55(Suppl V):A71.
129
MEETING REPORT
The First European Symposium on
Pediatric Inflammatory Bowel Disease
Rome, Italy, 23–25 November, 2006
Richard K Russell
Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children,
Edinburgh, Scotland, UK.
The First European Symposium on Pediatric IBD was a joint
meeting of the pediatric gastroenterology societies of Europe
and North America (the European Society for Paediatric
Gastroenterology, Hepatology and Nutrition [ESPGHAN] and
the North American Society for Pediatric Gastroenterology,
Hepatology and Nutrition [NASPGHAN]), and was hosted
by Salvatore Cucchiara on behalf of the Italian Society for
Pediatric Gastroenterology, Hepatology and Nutrition. It was
held in Rome, Italy, and attended by >300 delegates. The list
of speakers resembled a “who’s who” of the major
contributors to advances in pediatric IBD from the past
20–30 years.
It is beyond the scope of this review to discuss the whole
meeting in fine detail; therefore, this report will concentrate
on new and emerging information described in lectures and
abstract presentations. The full program of abstracts and
invited lectures has been published as a supplement of the
Journal of Pediatric Gastroenterology and Nutrition [1].
Epidemiology
Jean-Frédéric Colombel (Hôpital Huriez, Lille, France)
eloquently summarized all of the environmental data
published to date on IBD, focusing particularly on studies
involving children. He summarized the current state of
knowledge and highlighted that, in the main, studies have
produced conflicting and inconsistent data. Professor
Colombel deemed that the only truly robust data were those
linking appendicectomy for appendicitis in children and
adolescents aged <20 years with a reduced risk of developing
ulcerative colitis (UC) [2]. As he was providing an overview
of children’s studies, smoking was not discussed. Professor
Colombel outlined that the way forward with regard to
advances in IBD epidemiology was to abandon any further
retrospective studies and focus on prospective studies. These
studies should be population-based, and, if possible, follow
patients from the “pre-IBD state” to the period when IBD
130
develops. Patients should then undergo follow-up over a
protracted period of time, for several decades in the postdiagnosis phase – a challenge indeed.
Animal models of IBD
Simon Murch (University of Warwick, Warwick, UK) and
others discussed the evidence for the pathogenesis and the
evolution of IBD derived from animal models. Professor Murch
highlighted recent data that add to the well-established
Th1/Th2 paradigm, describing the further sub-classification
of T cells into Th17 cells and their important relationship
with interleukin-23 (IL-23). Several key papers in this field
have been published this year [3–5]. IL-23 is a key player in
the intestinal inflammation in IBD and these new experimental
data complement genetic data (see below), offering a novel,
potential therapeutic target in patients with IBD.
Genetics
The pioneer of IBD genetics, Jean-Pierre Hugot (INSERM
U458, Hôpital Robert Debré, Paris, France), who was
responsible for the ground-breaking work describing the first
ever susceptibility gene for IBD (NOD2/CARD15) gave an
up-to-date overview of IBD genetics [6]. He described data
on candidate genes that were, in general, variable, with a
lack of consistency in replication studies. However, two
exceptions were highlighted: the C3435T allele in the
multidrug resistance 1 (MDR1) gene, which demonstrates
susceptibility to UC in a recently published meta-analysis [7],
and the A1011S allele in the myosin IXB (MY09B) gene,
which was initially implicated in increased susceptibility to
celiac disease, but is now also associated with a modest
increase in the risk of UC [8]. As these data on the MY09B
gene are new, replication studies in cohorts outside of the
index populations are still to be undertaken.
Professor Hugot then went on to highlight more recently
used genome-wide association studies which have used
THE FIRST EUROPEAN SYMPOSIUM ON PEDIATRIC IBD
several hundred thousand single nucleotide polymorphisms
to map across the entire genome, in order to identify novel
genes associated with disease susceptibility in patients with
IBD. This has resulted in the identification of an association
between variants in the TNFSF gene and Crohn’s disease
(CD) in the Japanese population [9], and an association
between the IL-23 receptor gene and a protective effect in
patients with ileal CD [10].
Thomas Walters (The Hospital for Sick Children,
University of Toronto, Toronto, ON, Canada) presented new
genetic data from an analysis of 380 children with IBD from
the Canadian population. He produced data from IBD trios
to show that susceptibility to UC is increased in patients
possessing variants of the G2677T allele of the MDR1 gene,
but not for the C3435T allele or for variants in the discs
large homologue 5 (DLG5; G113A and C4136A), Toll-like
receptor 4 (TLR4; D299G and T399I), or NOD1/CARD4
(E266K) genes. Dr Walters also described phenotypic
associations of the G2677T MDR1 allele and D299G TLR4
allele with isolated colonic CD, and of the C3435T MDR1
allele with a more complicated disease course.
Disease assessment scores
Dan Turner (The Hospital for Sick Children, University of
Toronto) gave a very interesting presentation on the
development of a novel pediatric UC activity index (PUCAI).
At the present time there is no UC disease activity index that
can be used for clinical assessment in children with UC. He
developed an initial disease activity index after employing
the Delphi consensus method, taking into account the
opinion of 48 experts, combined with a thorough literature
review that generated an initial list of 41 potential items for
the activity index. The score was reduced to 11 key items
and was subsequently prospectively tested on a cohort of
157 children with UC. After further statistical analysis, the
score was modified, and the resulting eight-item score was
then validated in a further 48 patients with UC. The final
disease assessment activity score that has now been
developed for use in children with UC is based on six items
and requires neither endoscopic assessment nor the
performing of blood tests, making it an excellent and most
needed tool for use in the childhood UC population.
Diagnostic methods
The latest data on wireless capsule endoscopy were
presented by Ernest Seidman (Sainte-Justine Hospital,
University of Montreal, Montreal, QC, Canada). A recent
meta-analysis in adults has identified that a capsule is
superior to all other current imaging modalities of the small
bowel, especially for disease in the small bowel proximal to
the terminal ileum [11]. However, only a limited number of
studies have been performed in children, with several
prospective studies now underway. The difficulties of the
differential diagnosis after identifying small-bowel lesions,
and the issue of retention of capsules in patients with
strictures (around 5% in patients with established CD,
quoted by Dr Seidman) are still being resolved.
In a separate abstract presentation, Dr Seidman
described retrospective data collected over a period of
5 years, on 57 patients who were strongly suspected of
having CD, but in whom imaging (small-bowel radiography)
and endoscopic examination (upper GI endoscopy and ileocolonoscopy) had not confirmed CD. This analysis found
that 37% of the patients had small-bowel lesions in keeping
with CD, and a further 9% were suspected, but not
confirmed, as having CD. Of the 57 patients, two required
the capsule to be placed endoscopically and two had a
retained capsule (these retained capsules resolved upon
treatment with steroids). Therefore, this technique may
be especially useful in children who are strongly suspected
of having CD, but in whom findings from conventional
investigations are negative (as techniques used in adults,
such as push enteroscopy, are not generally available
for children).
Therapeutics
A cohort study of 27 patients with CD who were unresponsive
to azathioprine treatment was presented by Pamela Rogers
(Department of Paediatric Gastroenterology and Nutrition,
Royal Hospital for Sick Children, Edinburgh, Scotland, UK).
All patients were initially treated with subcutaneous
methotrexate (15 mg/m2) for induction of remission, and
responders subsequently received the drug for the
maintenance of remission. In total, 85% of those who were
treated entered clinical remission as defined by a pediatric
CD activity index score of <15. A number of patients
subsequently relapsed and thus the number of patients in
maintained remission for ≥12 months was 30%.
A half-day of the meeting was devoted to discussion on
the use of biological therapy in children with IBD. There
continues to be debate within the pediatric IBD community
regarding the development of hepatosplenic T cell lymphomas
in children with IBD treated with azathioprine, with or
without infliximab. This has been discussed in previous
meeting reports in this journal [12,13]. Jeffrey Hyams
(Connecticut Children’s Medical Center, Hartford, CT, USA)
provided an update on this subject. There have been a
total of 14 reports in the medical literature, describing
predominantly children who have developed this lymphoma
while receiving azathioprine/6-mercaptopurine. There have
been a further four case reports in the literature of this
lymphoma in patients with CD receiving azathioprine/
131
RICHARD K RUSSELL
6-mercaptopurine. In addition, a further eight patients have
been reported through post-marketing surveillance – these
patients were taking immunomodulators in combination
with infliximab, and developed this lymphoma.
The consensus opinion at the meeting was that
treatment with these agents should continue, but
consideration should be given to an early withdrawal of
azathioprine/6-mercaptopurine treatment in patients who
will continue to receive maintenance (but not episodic)
infliximab therapy. Séverine Vermeire (University Hospital
Gasthuisberg, Leuven, Belgium) presented data on 80 adult
patients receiving maintenance treatment with infliximab,
half of whom had immunomodulators withdrawn at
6 months after commencing infliximab. The clinical relapse
rate at 24 months after commencing infliximab was not
significantly different between the group that continued to
receive immunomodulators and patients who did not.
Summary
The overriding theme emerging from the meeting was that
a collaborative, prospective approach to investigating and
treating pediatric patients with IBD is now required if the
questions raised at the symposium are to be answered at
any stage in the future. This entails studying disease from
early childhood over the following several decades, and the
establishment of multicenter treatment trials. This presents
significant challenges for investigators with regard to the
132
organization of lengthy follow-up of patients, and in the
persuasion of funding bodies to support such research. The
next meeting is planned for 2008.
Disclosures
The author has no relevant financial interests to disclose.
References
1.
First European Symposium on Pediatric Inflammatory Bowel Disease, November 23–25,
2006, Rome, Italy. J Pediatr Gastroenterol Nutr 2006;43:S1–55.
2.
Andersson RE, Olaison G, Tysk C et al. Appendectomy and protection against ulcerative
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
2006;116:1218–22.
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.
5.
Hue S, Ahern P, Buonocore S et al. Interleukin-23 drives innate and T cell-mediated
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
with susceptibility to Crohn’s disease. Nature 2001;411:599–603.
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
Associated With Ulcerative Colitis. Gastroenterology 2006;131:1768–74.
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.
10. Duerr RH, Taylor KD, Brant SR et al. A genome-wide association study identifies IL23R
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
endoscopy compared to other diagnostic modalities in patients with non-stricturing small
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
Monit 2006;7:41–8.
13. Russell RK, Van Limbergen J. 39th Annual Meeting of the European Society for Paediatric
Gastroenterology, Hepatology and Nutrition (ESPGHAN). Inflamm Bowel Dis Monit
2006;7:86–8.
Reader Survey – Let Us Know What You Think!
Please take a few moments to complete this survey. We value your opinion.
Please photocopy this page, complete the survey below, and fax it back to Remedica
on +44 (0)20 7759 2951. Or you can visit the INFLAMMATORY BOWEL DISEASE MONITOR
website and complete the survey online: www.ibdmonitor.com
1. We aim to provide practical information for practicing physicians, surgeons, and other healthcare professionals.
How would you rate the information presented in this issue?
Strongly agree
Strongly disagree
a) The technical quality of information included in INFLAMMATORY
BOWEL DISEASE MONITOR was acceptable:
1
2
3
4
5
b) The information was relevant to my practice:
1
2
3
4
5
c) The information was presented clearly:
1
2
3
4
5
d) The Leading Articles provided new information regarding the
understanding and treatment of inflammatory bowel disease:
1
2
3
4
5
e) The Clinical Review section was helpful, and I would like
to see analyses in future issues:
1
2
3
4
5
2. Did you learn anything from the CME activity INFLAMMATORY BOWEL
DISEASE MONITOR that will change the way you practice medicine?
■ Yes
■ No
If so, what?.....................................................................................................................................................................................
3. Is there anything you learned from the CME activity INFLAMMATORY BOWEL
DISEASE MONITOR that prompts you to seek further information that may
influence the way you practice medicine in the future?
■ Yes
■ No
If so, what?.....................................................................................................................................................................................
4. Would you like to recommend INFLAMMATORY BOWEL DISEASE MONITOR
to a colleague?
■ Yes
■ No
My colleague’s email is: .................................................................................................................................................................
5. What specific topics do you think should be covered in future issues?
.......................................................................................................................................................................................................
Name ....... ......................................................................
Job title
..........................................................................................
Institution . .....................................................................................................................................................................................
Address .... .....................................................................................................................................................................................
Country .... ........................................................................ Post/zip code
.................................................................................
Email ........ .....................................................................................................................................................................................

inflammatory bowel disease monitor

Transcription

Similar documents

Strike out the 3C`s Crohns Colitis Cancer Bowling Poster

GET THE GUTSY TRUTH ABOUT INFLAMMATORY BOWEL DISEASE EXPECT MORE

Crohn`s disease and ulcerative colitis

Inflammatory Bowel Disease (IBD)

Understanding Bowel Sounds – QL

Naso-Pharyngoscopes

Crohn`s disease - BMJ Best Practice

THE DIGESTIVE DIGEST - Atlantic Health System

Ulcerative Colitis The A to Z of Treating UC Slides

Non neoplastic lesions of intestine