inflammatory bowel disease monitor

Transcription

VOLUME 8 NUMBER 1 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
Classification of Inflammatory
Bowel Disease: A Work in Progress
Rupert Abdalian, MD and Mark S Silverberg,
MD, PhD
Antineoplastic Effects of 5-Aminosalicylic
Acid in the Intestine: From Bench to Bedside
Christel Rousseaux, PhD, Olivier Romano, MD,
and Pierre Desreumaux, MD, PhD
Orofacial Granulomatosis
and Oral Crohn’s Disease
Carlo Nunes, MD, Miranda Lomer, PhD, Michael
Escudier, FDS, RCS, Stephen Challacombe,
FMedSci, and Jeremy Sanderson, MD
CLINICAL REVIEWS
MEETING REPORTS
ESPGHAN 2007
DDW 2007
www.ibdmonitor.com
Jointly sponsored by the University of Kentucky Colleges of Pharmacy
and Medicine and Remedica Medical Education and Publishing.
The University of Kentucky is an equal opportunity university.
This journal is supported by an
educational grant from Shire
Faculty Disclosures
The following are relevant financial relationships declared by the journal’s Editors-in-Chief.
Stephen Hanauer: Abbott, Amgen, Asahi, Bristol Myers Squibb, Centocor, Chemocentryx, Elan,
Ferring, Genentech, GSK, Novartis, Otsuka, Protein Design Labs, Procter & Gamble,
Prometheus, Salix, Shire, Targacept, Teva, Therakos, Millennium Pharmaceuticals, and UCB
Pharma (Celltech). Jack Satsangi: Abbott, Elan, Schering-Plough, and UCB.
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Pharma, Bristol Myers Squibb, Pfizer, Procter & Gamble, Shire Canada, and UCB Canada. Simon
Murch: Not yet received.
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The following are relevant financial relationships declared by the journal’s Editorial Advisory
Board: Zane Cohen: Not yet received. Jean-Frédéric Colombel: Abbott, Centocor, ScheringPlough, and UCB Pharma. Anders Ekbom: AstraZeneca, Centocor, and Schering-Plough. Brian
Feagan: Abbott, AstraZeneca, Berlex, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene,
Centocor, CombinatoRx, Elan/Biogen, ISIS, Janssen-Ortho, Millennium, Napo Pharma, Novartis,
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Plough, Serono, Synta, Teva Pharmaceuticals, Tillotts, and UCB Pharma. Claudio Fiocchi: None
to declare. John O’leary: Not yet received. Paul C Rutgeerts: Not yet received. Ernest G Seidman:
Not yet received. Stephan Targan: Berlex, Bristol Myers Squibb, Elan, Gilead Science, Procter &
Gamble, Prometheus, Salix, Santarus, and UCB Pharma. William J Tremaine: AstraZeneca,
Procter & Gamble, and NPS Pharmaceuticals.
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.
Publisher’s Statement
© Remedica Medical Education and Publishing 2007.
Editorial Team: Rhian Phillips, Amy Loader
Editorial Manager: Scott Millar
Design and Artwork: AS&K Skylight Creative Services
Publishers: Ian Ackland-Snow, Simon Kirsch
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Email: [email protected]
ISSN 1466-7401
RT292_1_REM_IBD_8.1_07.qxd
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Page 1
Editors-in-Chief
Stephen Hanauer, MD
University of Chicago, Chicago, IL, USA
Jack Satsangi, MBBS, DPhil
Western General Hospital, Edinburgh, UK
Editors
Ian Arnott, MD
Western General Hospital, Edinburgh, UK
Federico Balzola, MD
Azienda Ospedaliera San Giovanni Battista di Torino,
Turin, Italy
Charles Bernstein, MD
University of Manitoba, Winnipeg, MB, Canada
Simon Murch, MD
University of Warwick, Coventry, UK
Editorial Advisory Board
Zane Cohen, PhD
Mount Sinai Hospital, Toronto, ON, Canada
Jean-Frédéric Colombel, MD
Hôpital Huriez, Lille, France
Anders Ekbom, PhD
Karolinska Institute, Stockholm, Sweden
Brian Feagan, MD
University of Western Ontario, London, ON, Canada
Claudio Fiocchi, MD
Case Western Reserve University, Cleveland, OH, USA
John O’Leary, MD
Coombe Women’s Hospital, Dublin, Ireland
Paul C Rutgeerts, MD
Universitaire Ziekenhuizen Leuven, UZ Gasthuisberg,
Leuven, Belgium
Ernest G Seidman, MD
Hôpital Sainte-Justine, Université de Montréal, Montreal,
QC, Canada
Stephan Targan, MD
Cedars-Sinai Medical Center, Los Angeles, CA, USA
William J Tremaine, MD
Mayo Clinic, Rochester, MN, USA
Contents
Leading Articles
Classification of Inflammatory Bowel Disease:
A Work in Progress
Rupert Abdalian and Mark S Silverberg
Antineoplastic Effects of 5-Aminosalicylic Acid
in the Intestine: From Bench to Bedside
Christel Rousseaux, Olivier Romano, and
Pierre Desreumaux
Orofacial Granulomatosis and Oral Crohn’s Disease
Carlo Nunes, Miranda Lomer, Michael Escudier,
Stephen Challacombe, and Jeremy Sanderson
2
8
18
Clinical Reviews
Clinical Observations
23
Genetics
29
Epidemiology
31
Pathogenesis
32
Meeting Reports
40th Annual Meeting of the European Society
for Paediatric Gastroenterology Hepatology
and Nutrition (ESPGHAN)
Barcelona, Spain, 9–12 May, 2007
35
Digestive Diseases Week 2007 (DDW 2007)
Washington, DC, USA, 20–23 May, 2007
38
LEADING ARTICLE
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Classification of Inflammatory Bowel
Disease: A Work in Progress
Rupert Abdalian, MD1 and Mark S Silverberg, MD, PhD2
1
Department of Medicine, Division of Gastroenterology, University of Toronto, and 2Mount Sinai Hospital
Inflammatory Bowel Disease Centre, Division of Gastroenterology, Toronto, ON, Canada
Crohn’s disease and ulcerative colitis (UC) represent idiopathic forms of IBD with significant clinical heterogeneity. A
major need in their investigation is the ability to identify patient subgroups with distinctive and, perhaps, unique
characteristics. Definition of patient subtypes with specific prognoses and disease behavior could add power to research in
therapeutics and genetics. It may also offer the clinician an invaluable tool to better assess disease prognosis, optimize
patient counseling, and select the most optimal therapeutic strategy. The recent and ongoing discovery of serological
biomarkers and genetic associations may soon revolutionize our approach and understanding of IBD. The current article is
a comprehensive review of recently proposed classification systems for Crohn’s disease and UC, and aims to highlight their
relevance to clinical practice and research endeavors. Inflamm Bowel Dis Monit 2007;8(1):2–7.
Over the past few decades, investigators and clinicians
have attempted to classify IBD using recognizable clinical,
epidemiological, and endoscopic features. The recent
discovery of novel genetic determinants and serological
markers associated with IBD susceptibility and phenotype has
made the prospect of developing a more integrated and
useful classification system achievable. Evaluation of these
markers is the subject of intense investigation, although their
relative importance to the diagnosis, natural history, and
phenotypic differentiation of IBD remains largely speculative.
Several classification schemes have been proposed since
1991. Most recently, a Working Party with an interest in IBD
classification was formed with the aim of summarizing recent
developments in disease classification and establishing an
integrated classification of IBD [1]. Their recommendations
were presented at the 2005 World Congress of
Gastroenterology in Montreal, QC, Canada. The following is
a comprehensive review of existing and recently proposed
classification systems for IBD, and highlights their relevance
to clinical practice and research endeavors.
Clinical classification of Crohn’s disease
Greenstein et al. first distinguished patients with Crohn’s
disease who require surgery into those with an aggressive,
perforating phenotype from those with a more indolent, nonperforating disease [2]. Patients with perforation were found
Address for correspondence: Mark S Silverberg, Mount Sinai Hospital
Inflammatory Bowel Disease Centre, Division of Gastroenterology,
Toronto, ON, Canada. Email: [email protected]
2
to have earlier disease recurrence following surgery, regardless
of disease location. Indications for subsequent surgery were
found to be generally the same as those for the first or
previous operation. This categorization of Crohn’s disease into
perforating and non-perforating subtypes was later integrated
in the International Working Party’s report issued in Rome,
Italy, in 1991, which proposed a classification based on
anatomical distribution, operative history, and clinical behavior
(inflammatory, fistulizing, or stenotic disease). However,
this classification was felt to be impractical in the clinical
setting, and was later revised at the World Congress of
Gastroenterology in Vienna, Austria, in 1998 [3]. The ensuing
classification scheme integrated age of onset (below or above
40 years), disease location (ileal, colonic, ileocolonic, or upper
GI), and disease behavior (non-stricturing, non-penetrating,
stricturing, or penetrating) as the key phenotypic
determinants. Although the Vienna classification has not been
widely applied to the clinical setting, its utility in this
environment has been scrutinized for its potential applicability
[4]. Difficulties with the Vienna classification included a failure
to evaluate particular aspects of disease course and prognosis.
For instance, severity of disease and rate of progression of
disease behavior were difficult to reliably and objectively
define, although they are important clinical parameters that
have a probable impact on natural history, outcome of
therapeutic trials, and the need for surgery. Additional
features such as presence of extraintestinal manifestations,
ethnicity, country of birth, smoking history, and family history
are omitted as well. All of these are related to factors that may
affect Crohn’s disease phenotype, course, and behavior.
INFLAMMATORY BOWEL DISEASE MONITOR VOL 8 NO 1 2007
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CLASSIFICATION OF IBD
Recently, the Vienna classification has been employed as
a categorization tool allowing the study of correlates
between specific Crohn’s disease phenotypes and other
aspects of disease presentation, course, and genetic
susceptibility. An association between certain subtypes and
perinuclear antineutrophil cytoplasmic antibody (pANCA) or
anti-Saccharomyces cerevisiae antibody (ASCA) profiles has
been described [5]. Additionally, the carriage of at least one
nucleotide-binding oligomerization domain 2/caspase
recruitment domain-containing protein 15 (NOD2/CARD15)
gene mutation was significantly associated with ileal
involvement, stricturing evolution, and presence of
granulomas [6,7]. The Vienna classification also helped
predict the need for immunosuppressant therapy and
surgery in a retrospective review of 480 patients [8].
The Montreal revision of the original Vienna classification
has not altered the three predominant parameters of age
at diagnosis, location, and behavior of disease, but
modifications within each of these categories have been
made in light of evidence highlighting intriguing new
correlates (Table 1). With regard to age at Crohn’s disease
diagnosis, the Montreal classification allows for an earlier
onset of disease (i.e. aged 16 years or younger) to be
categorized separately as a novel A1 category, whereas A2
and A3 account for age of diagnosis between 17 and
40 years and >40 years, respectively. There is indeed
evidence that disease phenotype varies according to age
at Crohn’s disease diagnosis [9,10]. For instance, disease
distribution seems to vary based on age at diagnosis, with
small intestinal and upper GI involvement (L4) observed
more commonly in individuals diagnosed before the age of
20 years and colonic disease seen more frequently in patients
aged >60 years [11]. The male-to-female ratio decreases
with increasing age of onset of Crohn’s disease, and a family
history of IBD is more likely to be noted in patients with an
earlier age at diagnosis [12]. Given the differing clinical
characteristics of early-onset disease, the introduction of a
separate age category was timely. This modification will allow
the categorization of pediatric-onset disease as a clinically
distinct entity both in practice and in the research setting.
The major anatomical sites of Crohn’s disease distribution
that are agreed upon by most experts are the ileum (L1), the
colon (L2), and the ileocolonic region (L3). These were
recognized and featured within the Vienna classification;
however, upper GI involvement (L4) in this scheme implied
an absence of disease activity distal to the jejunum. As
modalities to investigate the upper GI tract have become
more refined and accessible, especially with the widespread
introduction of wireless capsule endoscopy, it is now
apparent that foregut involvement in Crohn’s disease is not
uncommon, and in fact may coexist with ileal (L1) and/or
Table 1. Montreal classification of Crohn’s disease.
Age at Diagnosis
A1
≤16 years
A2
17–40 years
A3
>40 years
Location
Upper GI
Modifier (L4)
L1
Terminal
ileum
L1 + L4
Terminal ileum +
upper GI
L2
Colon
L2 + L4
Colon + upper GI
L3
Ileocolon
L3 + L4
Ileocolon + upper
GI
L4
Upper GI
–
–
Behavior
Perianal
disease
modifier (p)
B1*
Non-stricturing B1p
non-penetrating
Non-stricuring
non-penetrating
+ perianal
B2
Stricturing
B2p
Stricturing
+ perianal
B3
Penetrating
B3p
Penetrating
+ perianal
*B1 category should be considered “definitive” only after a pre-specified time
period has elapsed (≥5 years of follow-up recommended). Otherwise, the
identified disease behavior should be considered only “interim”.
GI: gastrointestinal. Table redrawn with permission from [1].
colonic disease (L2 and/or L3). Therefore, in the revised
Montreal classification, these parameters of disease
distribution are no longer mutually exclusive.
As for disease behavior, the Montreal revision of the
Vienna classification denotes perianal disease alone as a
separate subclassification (p), and no longer includes it in the
penetrating disease category. It also recognizes that disease
behavior is dynamic over time and that classifying it should
incorporate some aspect of time course or at least a
minimum elapsed period of follow-up before assigning a
definite disease behavior designation. The arbitrary period of
5 years was selected, based on evidence from several studies
that documented progression of disease during follow-up
periods ranging from 5 to 10 years [13,14]. It is noteworthy
to mention that this 5-year observation period is only the
minimum, and that the preferred assessment point should
be the latest observation preceding any surgery.
In contrast, disease localization in Crohn’s seems
surprisingly stable. This observation may stem from the role
of defensins in the pathogenesis of chronic IBD. Defensins
are endogenous antimicrobial peptides that mediate innate
immunity. Expressed within the intestinal epithelium, they
contribute to the maintenance of mucosal barrier integrity
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RUPERT ABDALIAN AND MARK S SILVERBERG
[15]. In fact, Crohn’s disease of the terminal ileum, especially
if associated with a NOD2 mutation, is characterized by a
diminished α-defensin (human defensin 5 and 6) expression,
and in Crohn’s colitis, the β-defensin (human β-defensins
2 and 3) response is reduced [16]. NOD2 and defensin
deficiency at the level of the epithelial barrier and gutassociated lymphoid tissue may favor Crohn’s disease by
disrupting the barrier of protection from enteropathogens
and interrupting adaptive immune responses in the gut
micro-environment.
Table 2. Montreal classification of UC.
Clinical classification of ulcerative colitis
S0
Clinical remission
Asymptomatic
Unlike Crohn’s disease, neither the Rome nor the Vienna
working parties formally addressed a classification system for
ulcerative colitis (UC). A systematic classification scheme for
UC would be invaluable as it could help unravel intricacies of
pathogenesis if certain subtypes are found to correlate with
specific genetic or serological biomarkers. It may facilitate
the implementation of optimal treatment strategies and help
the challenging task of prognostication (e.g. predicting risk
of surgery, colorectal cancer risk, or response to therapy).
Expert opinion suggests that an adequate classification
system for UC should take into account extent of colonic
activity and overall disease severity. The Montreal
classification of UC defines three subgroups of disease
extent (E1: ulcerative proctitis, E2: left-sided UC, E3:
extensive UC; Table 2). This three-tiered classification system
is biologically plausible as it serves several clinical purposes.
Firstly, it dictates choice of medical therapy, and helps
differentiate those who are more likely to respond
to topical therapy. Hydrocortisone and mesalamine
suppositories are mostly useful as primary therapy in
patients with ulcerative proctitis (E1), although alone they
are probably insufficient for the management of extensive
UC (E3) [17]. Secondly, classification by extent of disease
helps predict subsequent course and severity of disease.
Higher rates of medication usage and hospitalizations, as
well as an increased and earlier need for colectomy, have
been correlated with increased disease burden [18]. In
addition, the differential risk of colorectal malignancy further
strengthens this subclassification [19].
The predominant flaw in an extent-based classification
system for UC is that it assumes that disease characteristics
remain constant over time. However, the dynamic nature of
IBD as demonstrated by disease progression or regression
imposes a challenging dilemma. The actual risk of proximal
extension of proctitis over a cumulative 10-year period is
estimated to range between 41% and 54%, whereas the
rate of progression of left-sided colitis may be even higher
[1]. Regression of disease has also been well-described, from
a crude rate of 1.6% to an age- and sex-adjusted rate of
S1
Mild UC
Passage of four or fewer stools
per day
No systemic illness
Normal inflammatory markers
(ESR)
S2
Moderate UC
Passage of more than
four stools per day
Signs of systemic toxicity
S3
Severe UC
Passage of at least six bloody
stools per day
Heart rate ≥90 beats/min
Temperature >37.5°C
Hemoglobin level <105 g/L
ESR >30 mm/h
4
Disease extent
E1
Ulcerative proctitis
Involvement limited
to rectum
E2
Left-sided UC
(distal UC)
Inflammation limited to
colorectum distal to the
splenic flexure
E3
Extensive UC
Involvement proximal
to splenic flexure
Disease severity
ESR: erythrocyte sedimentation rate; UC: ulcerative colitis.
71% after 10 years [20]. The Montreal classification thus
proposes the maximal extent of involvement as the most
useful and prognostic parameter. However, it fails to
recognize a minimum disease extent within a given time
period. Since extensive UC may present with a “prodrome”
of up to 4–6 months of proctitis, it is probably premature
to classify a UC case as proctitis prior to 4–6 months
of observation.
The Montreal classification also addressed UC disease
severity with a categorization into four groups (S0: clinical
remission, S1: mild UC, S2: moderate UC, S3: severe UC;
Table 2). One of the limitations of such a subclassification
attempt is that it predicts clinical course only in the short
term and does not necessarily reflect a longitudinal outlook.
The classification also proposes to omit the term “fulminant
colitis”, a designation with debatable clinical utility or
prognostic significance. As for the need for a separate
classification system for patients with UC and primary
sclerosing cholangitis (PSC) overlap, demonstrable
differences in clinicopathological features (rectal sparing and
backwash ileitis), and prognosis (increased incidence of
pouchitis and colorectal neoplasia), suggest that PSC-IBD
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may indeed be an IBD phenotype distinct from both UC and
Crohn’s disease, warranting its own recognition as a
separate subclass [21].
Indeterminate colitis: a distinct entity?
In 1978, Price first introduced the term “indeterminate
colitis” (IC) to describe patients following colectomy in
whom specific clinicopathological features were not
sufficient to diagnose either Crohn’s disease or UC but were
sufficient to allow a diagnosis of IBD affecting the colon
[22]. Today, there is marked confusion about the appropriate
use of this term. This diagnosis is now routinely made in
patients with obvious clinical and endoscopic features of
colonic inflammation, but in whom the histological and all
other clinical parameters do not permit a clear diagnosis of
either Crohn’s disease or UC. The Montreal Working Party
recommended that the term IC be reserved only for cases
where colectomy has been performed and pathologists are
unable to certifiably confirm one diagnosis after full
examination of the gross specimen. An alternative
designation of “inflammatory bowel disease, type
unclassified” (IBDU) was suggested for patients with colonic
disease and sparing of the terminal ileum, without definitive
histological corollary to favor either Crohn’s disease or UC.
Specific serological and genetic markers may help refine
the classification of IC and IBDU further. Both established
serological markers, ASCA and pANCA, in conjunction with
novel markers currently under study (anti-OmpC, antiCBir1/flagellin, and anti-I2) have the potential to further the
understanding of the classification of these entities. There is a
need for more studies investigating which combination of
serological and genetic markers provides the best specificity
and positive predictive value for different forms of IBD,
including IBDU. Recognition of IBDU as a distinct disease
subgroup may be important, as its clinical course and
prognosis seem worse than that of UC [23]. Post-surgical
outcomes and pouchitis risk seem unfavorable as well [24,25].
An integrated molecular diagnosis of IBD:
a way of the future?
Various serological and genetic marker tests integrating
clinical data are currently under investigation and may, in the
future, have an impact on classification schemes in IBD.
Thus far, the two most widely recognized serological
markers have been pANCA and ASCA. The utility of routine
testing of these in the diagnosis of IBD or in patients with illdefined GI symptoms is limited because of their lack of
specificity and low sensitivity. For instance, pANCA positivity
has been observed in other inflammatory diseases of the
colon, such as eosinophilic and collagenous colitis [26].
Several independent studies found that a combination of
both had positive predictive values ranging from 77–96%
for differentiating Crohn’s disease from UC [27]. These
markers may also have a role in disease stratification. In
Crohn’s disease, pANCA has been linked to a UC-like
phenotype, late-onset disease, and inflammatory diseasetype according to the Vienna classification [28]. ASCApositive status on the other hand is associated with more
proximal (gastroduodenal and small bowel) involvement
rather than purely colonic disease and with a more severe
disease phenotype and requirement for surgery [29]. As for
a role in disease monitoring and predicting treatment
responsiveness, thus far the published data are more
disparate. The presence of ASCA in Crohn’s disease is
generally stable over time and is independent of Crohn’s
disease activity or duration [30]. Studies assessing the power
of these markers to predict the response to infliximab in
Crohn’s disease or the risk of pouchitis in UC have yielded
contradictory results and have been plagued with
methodological flaws [31–33]. In light of the uncertainties
and lack of diagnostic acumen of both pANCA and ASCA,
there is a need to widen the autoantibody panel with
serological markers of higher sensitivity and specificity.
Studies of immune responsiveness to several specific
microbial antigens in patients with Crohn’s disease and UC
have yielded potential candidates. Most of the progress thus
far has been recorded in the stratification of Crohn’s disease,
with the identification of novel antibodies (anti-OmpC and
anti-I2, and most recently anti-CBir1/flagellin) [34]. These
have been associated with more complicated and severe
Crohn’s disease behavior, including the need for surgery
[35]. However, relying exclusively on serum indicators for
diagnosis and classification of IBD is not yet justified. The
available serological markers are not sensitive enough to be
used for IBD screening in the general population. The
addition of novel markers may improve overall sensitivity;
however, more studies are needed to further delineate their
role in clinical decision-making.
Similar to serological indicators, integration of genetic
markers in the proposed classification system cannot yet be
justified. The most definite and well-replicated gene found
to be associated with Crohn’s disease is NOD2/CARD15
[36]. The odds ratio for developing Crohn’s disease in simple
heterozygotes in a meta-analysis was 2.4, and odds ratio for
persons with two mutant chromosomes was estimated to be
17.1 [37]. The differences in risks associated with individual
alleles were relatively minor. Despite widespread replication
of the NOD2/CARD15 associations, a marked ethnic and
geographical heterogeneity was noted in epidemiological
surveys [38–40]. These mutations are scarce in Asians
(Japanese, Chinese, Koreans), Arabs, Africans, and AfricanAmericans. However, even in Europe, the degree of disease
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RUPERT ABDALIAN AND MARK S SILVERBERG
susceptibility conveyed by different NOD2/CARD15 allelic
variants differs in specific regions. The importance of these
variants in Northern Europe (Scandinavia, Ireland, and
Scotland) is less than in the index studies from central
Europe, perhaps reflecting significant genetic founder effects
[38]. This complexity between populations is further
challenged by heterogeneity within populations and
genotype–phenotype relationships.
From a phenotypic perspective, NOD2/CARD15
mutations are associated with ileal rather than colonic
Crohn’s disease with some studies supporting a correlation
with more complicated internal fistulizing or stenosing
disease [37]. NOD2/CARD15 variations have also been
correlated with more severe disease, lower weight and
earlier age at diagnosis, acute intestinal obstruction, and
increased risk for surgery [41,42]. Conversely, they are
uncommon in patients with perianal complications of
Crohn’s disease [42]. No consistent association between
NOD2/CARD15 variations and the presence of granulomas
or extraintestinal manifestations of IBD has been found.
Also, genetic variants have not been shown to predict
treatment responsiveness, although only infliximab has been
evaluated thus far [43].
The identification of the NOD2/CARD15 gene has been
a significant discovery, shedding light on the complex
pathogenesis of IBD. Moreover, the contribution of
numerous additional genetic markers identified in genomewide association studies (autophagy-related 16-like 1
[ATG16L1], IL-23 receptor [IL23R], organic cation
transporter [OCTN], disc, large homologue gene 5 [DLG5],
multi-drug resistance 1 [MDR1], Toll-like receptors [TLRs],
and pregnane X receptor [PXR] genes) [44–48], as well as
other replicated candidate regions such as those within the
major histocompatibility complex or the IBD5 locus, will
eventually be integrated into a complex model of markers
that aid in classifying IBD. However, to successfully achieve
this, very large studies with well-phenotyped patients will be
required and, ultimately, prospective validation studies
conducted over many years will be needed.
Disclosures
Dr Silverberg has received funding for research from Prometheus
Laboratories. Dr Abdalian has no relevant financial interests to disclose.
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Klebl FH, Bataille F, Bertea CR et al. Association of perinuclear antineutrophil cytoplasmic
antibodies and anti-Saccharomyces cerevisiae antibodies with Vienna classification
subtypes of Crohn’s disease. Inflamm Bowel Dis 2003;9:302–7.
6.
Newman B, Silverberg MS, Gu X et al. CARD15 and HLA DRB1 alleles influence
susceptibility and disease localization in Crohn’s disease. Am J Gastroenterol
2004;99:306–15.
7.
Heresbach D, Gicquel-Douabin V, Birebent B et al. NOD2/CARD15 gene polymorphisms
in Crohn’s disease: a genotype-phenotype analysis. Eur J Gastroenterol Hepatol
2004;16:55–62.
8.
Veloso FT, Ferreira JT, Barros L et al. Clinical outcome of Crohn’s disease: analysis according
to the Vienna classification and clinical activity. Inflamm Bowel Dis 2001;7:306–13.
9.
Levine A, Karban A, Eliakim R et al. A polymorphism in the TNF-alpha promoter gene is
associated with pediatric onset and colonic location of Crohn’s disease. Am J Gastroenterol
2005;100:407–13.
10. Idestrom M, Rubio C, Granath F et al. CARD15 mutations are rare in Swedish pediatric
Crohn disease. J Pediatr Gastroenterol Nutr 2005;40:456–60.
11. Heyman MB, Kirschner BS, Gold BD et al. Children with early-onset inflammatory bowel
disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 2005;146:35–40.
12. Polito JM 2nd, Childs B, Mellits ED et al. Crohn’s disease: influence of age at diagnosis on
site and clinical type of disease. Gastroenterology 1996;111:580–6.
13. Louis E, Collard A, Oger AF et al. Behaviour of Crohn’s disease according to the Vienna
classification: changing pattern over the course of the disease. Gut 2001;49:777–82.
14. Schwartz DA, Loftus EV Jr, Tremaine WJ et al. The natural history of fistulizing Crohn’s
disease in Olmsted County, Minnesota. Gastroenterology 2002;122:875–80.
15. Peyrin-Biroulet L, Chamaillard M. NOD2 and defensins: translating innate to adaptive
immunity in Crohn’s disease. J Endotoxin Res 2007;13:135–9.
Conclusion
The classification of IBD is a formidable task in light of the
significant heterogeneity of clinical presentation and disease
course. An adequate classification scheme should be
practical, easily remembered, and simple enough for clinical
applicability, yet comprehensive enough to serve as
categorization tool for research studies. Such a classification
system for Crohn’s disease, UC, or both will be further
strengthened by the identification and integration of novel
genetic, serological, and future biomarkers with strong
pathophysiological links to various disease phenotypes.
6
However, data available to date do not support their use in
clinical practice and decision making at this time. The
adoption of a standardized minimal dataset for research
protocols may serve as an invaluable tool for the rigorous
exploration of genotype–phenotype relationships and better
delineate the sensitivity and specificity of potential
biomarkers. The Montreal classification system aims to
initiate that process. Hopefully, in 5–10 years from now, an
integrated classification system for IBD will be more than
simply a dream.
16. Wehkamp J, Harder J, Weichenthal M et al. NOD2 (CARD15) mutations in Crohn’s disease
are associated with diminished mucosal alpha-defensin expression. Gut 2004:53:1658–64.
17. Cohen RD, Woseth DM, Thisted RA et al. A meta-analysis and overview of the literature
on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J
Gastroenterol 2000;95:1263–76.
18. Ritchie JK, Powell-Tuck J, Lennard-Jones JE. Clinical outcome of the first ten years of
ulcerative colitis and proctitis. Lancet 1978;1:1140–3.
19. Langholz E, Munkholm P, Davidsen M et al. Colorectal cancer risk and mortality in patients
with ulcerative colitis. Gastroenterology 1992;103:1444–51.
20. Langholz E, Munkholm P, Davidsen M et al. Changes in extent of ulcerative colitis: a study
on the course and prognostic factors. Scand J Gastroenterol 1996;31:260–6.
21. Loftus EV Jr, Harewood GC, Loftus CG et al. PSC-IBD: a unique form of inflammatory
bowel disease associated with primary sclerosing cholangitis. Gut 2005;54:91–6.
22. Price AB. Overlap in the spectrum of non-specific inflammatory bowel disease. J Clin
Pathol 1978;31:567–77.
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23. Brown CJ, Maclean AR, Cohen Z et al. Crohn’s disease and indeterminate colitis and the
ileal pouch-anal anastomosis: outcomes and patterns of failure. Dis Colon Rectum
2005;48:1542–9.
24. Stewénius J, Adnerhill I, Ekelund GR et al. Operations in unselected patients with
ulcerative colitis and indeterminate colitis. A long-term follow-up study. Eur J Surg
1996;162:131–7.
25. Koltun WA, Schoetz DJ Jr, Roberts PL et al. Indeterminate colitis predisposes to perineal
complications after ileal pouch-anal anastomosis. Dis Colon Rectum 1991;34:857–60.
26. Holstein A, Burmeister J, Plaschke A et al. Autoantibody profiles in microscopic colitis.
J Gastroenterol Hepatol 2006;21:1016–20.
27. Reumaux D, Sendid B, Poulain D et al. Serological markers in inflammatory bowel diseases.
Best Pract Res Clin Gastroenterol 2003;17:19–35.
28. Klebl FH, Bataille F, Bertea CR et al. Association of perinuclear antineutrophil cytoplasmic
antibodies and anti-Saccharomyces cerevisiae antibodies with Vienna classification
subtypes of Crohn’s disease. Inflamm Bowel Dis 2003;9:302–7.
29. Walker LJ, Aldhous MC, Drummond HE et al. Anti-Saccharomyces cerevisiae antibodies
(ASCA) in Crohn’s disease are associated with disease severity but not NOD2/CARD15
mutations. Clin Exp Immunol 2004;135:490–6.
30. Teml A, Kratzer V, Schneider B et al. Anti-Saccharomyces cerevisiae antibodies: a stable
marker for Crohn’s disease during steroid and 5-aminosalicylic acid treatment. Am J
31. Esters N, Vermeire S, Joossens S et al. Serological markers for prediction of response
to anti-tumor necrosis factor treatment in Crohn’s disease. Am J Gastroenterol
2002;97:1458–62.
32. Papp M, Altorjay I, Norman GL et al. Seroreactivity to microbial components in Crohn’s
disease is associated with ileal involvement, noninflammatory disease behavior and
NOD2/CARD15 genotype, but not with risk for surgery in a Hungarian cohort of IBD
patients. Inflamm Bowel Dis 2007;13:984–92.
33. Aisenberg J, Legnani PE, Nilubol N et al. Are pANCA, ASCA, or cytokine gene
polymorphisms associated with pouchitis? Long-term follow-up in 102 ulcerative colitis
patients. Am J Gastroenterol 2004;99:432–41.
34. Targan SR, Landers CJ, Yang H et al. Antibodies to CBir1 flagellin define a unique response
that is associated independently with complicated Crohn’s disease. Gastroenterology
2005;128:2020–8.
35. Mow WS, Vasiliauskas EA, Lin YC et al. Association of antibody responses to microbial
antigens and complications of small bowel Crohn’s disease. Gastroenterology
2004;126:414–24.
36. Brant SR, Okazaki T. Inflammatory bowel disease genetics. In: Bernstein CM, ed.
Inflammatory Bowel Disease Yearbook. London, UK; Remedica Publishing, 2004:79–128.
37. Economou M, Trikalinos TA, Loizou KT et al. Differential effects of NOD2 variants on
Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J
38. Arnott ID, Nimmo ER, Drummond HE et al. NOD2/CARD15, TLR4 and CD14 mutations in
Scottish and Irish Crohn’s disease patients: evidence for genetic heterogeneity within
Europe? Genes Immun 2004;5:417–25.
39. Guo QS, Xia B, Jiang Yet al. NOD2 3020insC frameshift mutation is not associated with
inflammatory bowel disease in Chinese patients of Han nationality. World J Gastroenterol
2004;10:1069–71.
40. Sugimura K, Taylor KD, Lin YC et al. A novel NOD2/CARD15 haplotype conferring risk for
Crohn disease in Ashkenazi Jews. Am J Hum Genet 2003;72:509–18.
41. Brant SR, Picco MF, Achkar JP et al. Defining complex contributions of NOD2/CARD15
gene mutations, age at onset, and tobacco use on Crohn’s disease phenotypes. Inflamm
Bowel Dis 2003;9:281–9.
42. Cukovic-Cavka S, Vermeire S, Hrstic I et al. NOD2/CARD15 mutations in Croatian patients
with Crohn’s disease: prevalence and genotype-phenotype relationship. Eur J
Gastroenterol Hepatol 2006;18:895–9.
43. Vermeire S, Louis E, Rutgeerts P et al.; Belgian Group of Infliximab Expanded Access
Program and Fondation Jean Dausset CEPH, Paris, France. NOD2/CARD15 does not
influence response to infliximab in Crohn’s disease. Gastroenterology 2002;123:106–11.
44. Hampe J, Franke A, Rosenstiel P et al. A genome-wide association scan of nonsynonymous
SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet
2007;39:207–11.
45. 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.
46. Yamazaki K, Onouchi Y, Takazoe M et al. Association analysis of genetic variants in IL23R,
ATG16L1 and 5p13.1 loci with Crohn’s disease in Japanese patients. J Hum Genet
2007;52:575–83.
47. Martinez A, Marquez A, Mendoza J et al. Role of the PXR gene locus in inflammatory
bowel diseases. Inflamm Bowel Dis 2007; [Epub ahead of print].
48. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease.
Nature 2007;448:427–34.
7
LEADING ARTICLE
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Antineoplastic Effects of 5-Aminosalicylic
Acid in the Intestine: From Bench to Bedside
Christel Rousseaux, PhD, Olivier Romano, MD, Pierre Desreumaux, MD, PhD
Institut National de la Santé et de la Recherche Médicale (INSERM) U795, Physiopathologie des Maladies
Inflammatoires Intestinales, CHU Lille, Lille, France
Colorectal cancer is a serious complication of IBD, affecting a significantly greater number of IBD sufferers compared with
the general population. In patients with ulcerative colitis (UC), the risk of colorectal cancer is reported to increase from 2%
at 10 years after diagnosis to 18% at 30 years. Thus, colorectal cancer represents a major challenge in the ongoing
surveillance and therapeutic strategy in IBD patients. 5-Aminosalicylic acid (5-ASA) is a long-standing anti-inflammatory
agent used in the treatment of IBD, which, in addition to its anti-inflammatory activity, has demonstrated antineoplastic
effects in the gut. Recent studies have begun to elucidate the molecular mechanisms of these 5-ASA-mediated effects, and
κB, Wnt/β
β-catenin
a variety of important pathways including arachidonic acid metabolism, inhibition of nuclear factor-κ
signaling, epidermal growth factor receptor signaling, control of DNA replication, and peroxisome proliferator-activated
receptor γ activation have been implicated. The present authors review the current evidence demonstrating 5-ASA-mediated
modulation of colorectal cancer mechanisms. Inflamm Bowel Dis Monit 2007;8(1):8–17.
The most serious complication of IBD affecting the colon is
colorectal cancer (CRC). Globally, a diagnosis of IBD is
associated with a six- to seven-fold increased risk of CRC
[1], and for patients with ulcerative colitis (UC), the risk
increases from 2% at 10 years after diagnosis to 18% at 30
years [2]. The duration of colitis, extent of the disease in the
colon, personal history of primary sclerosing cholangitis, and
familial history of colon cancer are well-established risk
factors for the development of CRC in IBD patients [3]. The
prevention strategy usually relies upon regular surveillance
colonoscopy with random biopsies [4]. However, several
disadvantages of this costly strategy exist, such as the
difficulty in identification of high-risk patients and the
performance and interpretation of mucosal biopsies. A
promising option in the primary prevention of CRC among
IBD patients is mesalazine (also known as mesalamine or
5-aminosalicylic acid [5-ASA]) therapy.
5-ASA is among the oldest anti-inflammatory agents
in use today for IBD treatment [5]. New evidence, discussed
herein, has emerged related to its potential therapeutic
effect in the prevention of CRC occurrence. The
mechanisms sustaining the putative antineoplastic effects of
5-ASA are multiple and not fully understood. Owing to its
structural similarities to aspirin, it is assumed that 5-ASA has
Address for correspondence: Pierre Desreumaux, Service de
Gastroentérologie, Hôpital Huriez, CHU Lille, Lille 59037, France.
8
similar molecular targets to nonsteroidal anti-inflammatory
drugs (NSAIDs). In fact, the therapeutic effect of 5-ASA is
obtained through a local effect on colonic epithelial cells
rather than via a systemic effect. In this review, the authors
detail the preclinical data demonstrating – in vitro, in vivo,
and ex vivo in humans – the antineoplastic effect of 5-ASA
mediated through “inflammatory”-dependent
and
“non-inflammatory”-dependent mechanisms.
References were selected from the “PubMed” database
using combinations of the search words “IBD”, “Crohn”,
“ulcerative colitis”, “cancer”, “mesalamine”, “5aminosalicylic acid” and “sulphasalazine”. Only in vitro
studies reporting a specific role of 5-ASA (or sulfasalazine),
used at clinically relevant concentrations (between 5 and
100 mM), in the modulation of CRC mechanisms are
discussed in this review.
In vitro studies
Inflammatory-dependent antineoplastic
mechanisms of 5-ASA
Chronic inflammation and cancer are closely associated
in the intestine. NSAIDs reduce intestinal neoplasia, while
CRC incidence is increased in patients with UC. The
main inflammatory-dependent antineoplastic mechanisms
of 5-ASA involve inhibition of the nuclear factor-κB
(NF-κB)
pathway,
cyclooxygenase
(COX),
and
prostaglandin (PG) expression, and regulation of cell
proliferation/apoptosis.
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ANTINEOPLASTIC EFFECTS OF 5-ASA IN THE INTESTINE
Inhibition of the NF-κB pathway by 5-ASA
Although the molecular mechanisms linking UC with CRC
are not well understood, recent results obtained in
preclinical models point to the transcription factor NF-κB as
a central player. On the one hand, NF-κB regulates the
expression of various cytokines and modulates the
inflammatory processes in IBD. On the other, NF-κB
stimulates the proliferation of tumor cells and enhances
their survival through the regulation of anti-apoptotic
genes. Furthermore, it has been clearly established that
most carcinogens and tumor promoters activate NF-κB,
while chemopreventive agents generally suppress this
transcription factor. In fact, several lines of evidence
suggest that activation of NF-κB may cause cancer [6].
These include the finding that NF-κB genes can act as
oncogenes, and that this transcription factor controls
apoptosis, cell-cycle progression and cell proliferation, and
possibly also cell differentiation.
To date, many in vitro studies have been published in
the literature showing an inhibition of the NF-κB pathway
by 5-ASA or sulphasalazine [7–10]. These studies,
performed using rodent and human colonic epithelial cells,
demonstrate that 5-ASA or sulphasalazine may inhibit NF-κB
via distinct mechanisms:
Inhibition of COX and PGs by 5-ASA
In inflamed tissue, much of the mucosal PG seems to be
generated by the action of inducible COX2 on its substrate,
arachidonic acid. COX2 activity is associated with diverse
antineoplastic effects such as inhibition of apoptosis [15],
regulation of epidermal growth factor receptor (EGFR) and βcatenin signaling, and enhancement of angiogenesis [16–18],
effects that are favorable to cancer development. Specific
inhibitors of this enzyme, such as celecoxib, have been
shown to reduce polyp numbers in individuals with familial
adenomatous polyposis [19]. The mechanism underlying this
effect still requires clarification. It is not clear which cell type
is the predominant source of PGs in the diseased colon, but it
is apparent that cancerous epithelial cells demonstrate a
marked overexpression of COX2 [20]. There has been
remarkably little study of mucosal PG metabolism in colitisassociated dysplasia and cancer, although there is evidence
for increased COX2 expression [21]. 5-ASA inhibits
lipoxygenase [22], and can be predicted to cause reduced
mucosal metabolism of unesterified arachidonic acid. Thus, it
is possible that 5-ASA may have a therapeutic effect in the
prevention of dysplasia and CRC occurrence in IBD patients
through, at least in part, inhibition of COX2 and PGE2
production in colitis-associated colon cancer.
• Inhibition of inducible interleukin-1 (IL-1)-stimulated
RelA phosphorylation without prevention of inhibitor of
NF-κB-α (IκBα) degradation [10].
• Inhibition of NF-κB nuclear translocation and inhibition
of the degradation of IκBα [9].
• Inhibition of tumor necrosis factor-α (TNF-α)-induced
NF-κB and mitogen-activated protein kinase (MAPK)
activation (Fig. 1) [7].
Regulation of cell proliferation and apoptosis by 5-ASA
Inflammation mediated through NF-κB activation,
production of cytokines or growth factors, and inhibition of
anti-apoptotic genes has been shown to induce epithelial
cell proliferation and decrease physiological apoptosis, two
main abnormalities sustaining CRC formation. The putative
chemopreventive actions of 5-ASA include effects on
components involved in cell growth and proliferation, for
example COX1 and COX2, which regulate cell proliferation
through the formation of PGs, lipoxygenase, NF-κB,
MAPKs, and the Bcl-2 protein, as well as the activation of
apoptotic processes [23].
Many in vitro studies have demonstrated the antiproliferative effect of 5-ASA in colonic adenocarcinoma
Caco-2 cells [24]. Reinacher-Schick et al. showed that 5ASA caused a dose- and time-dependent inhibition of the
proliferation of colon cancer cells through a mitotic arrest.
5-ASA also induced apoptosis through partial activation of
the caspase cascade, probably acting on caspase-3 [25].
These results were confirmed in animal models of
carcinogenesis induced by chemical compounds such as
azoxymethane (AOM) [26] and 1,2-dimethylhydrazine
(DMH) [27], and in a genetically induced tumor model (B6Min/+ mice: B6 mice heterozygous for the multiple
intestinal neoplasia nonsense mutation) [26]. Indeed, in
these different models, 5-ASA reduced tumor load and
The inhibitory roles of 5-ASA on the NF-κB pathway were
not detected in lymphocytic leukemia and hepatic stellate
cells, suggesting that the 5-ASA-induced NF-κB inhibition
may be specific to intestinal epithelial cells [11]. These in
vitro data were confirmed in vivo in animals and in humans,
thus demonstrating that 5-ASA administration inhibits
intestinal expression or activation of NF-κB. In an animal
model of colitis induced by trinitrobenzene sulfate (TNBS) in
rats, 5-ASA was effective for relieving and repairing colonic
inflammation, and the effects were related – at least in part –
to a downregulation of IL-1β production and NF-κB
expression [12]. In 2006, Kim et al. also demonstrated that
5-ASA inhibited TNF-α-mediated NF-κB activation in a
TNBS-induced experimental model of colitis [13]. Similar data
were obtained by Bantel and colleagues, providing further
evidence that 5-ASA downregulates the activation of NF-κB
in actively inflamed mucosa of UC patients [14].
9
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CHRISTEL ROUSSEAUX, OLIVIER ROMANO, AND PIERRE DESREUMAUX
Figure 1. 5-ASA may inhibit the NF-κB pathway through (i) inhibition of inducible IL-1 stimulated RelA phosphorylation, (ii)
inhibition of NF-κB nuclear translocation and degradation of IκBα, and (iii) inhibition of TNF-α induced NF-κB and MAPK activation.
TNF
IL-1
5-ASA
5-ASA
IL-1R
TNFR
MyD88
MAPKKKs
IRAK
TRAF6
NEMO
TRADD
MAPKKs MEK
P
IKK1
IKK2
P
TRAF2
MAPKs
(p38, JNKs, ERKs)
P
Ub
P
IκB
AP1
5-ASA
p50
p50
p65
p65
Jun
Jun
Fos
Fos
AP1
5-ASA: 5-aminosalicylic acid; AP1: activator protein 1; ERK: extracellular-signal regulated kinase; IκBα: inhibitor of NF-κB subunit α; IL-1: interleukin-1; IL-1R: IL-1
receptor; IKK: IκB kinase; IRAK: IL-1 receptor-associated kinase; JNK: Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MAPKK: MAPK kinase;
MAPKKK: MAPK kinase kinase; MEK: MAP/ERK kinase; NEMO: NF-κB essential modulator; NF-κB: nuclear factor-κB; P: phosphate; RelA: p65 subunit of NF-κB;
TNF-α: tumor necrosis factor-α; TNFR: TNF receptor; TRADD: TNF-receptor 1-associated death domain; TRAF: TNF-receptor associated factor; Ub: ubiquitination.
number, increased the rate of tumor apoptosis, and reduced
the rate of tumor cell proliferation. Similarly, ex vivo studies
using biopsies from patients with CRC or sporadic polyps of
the large bowel showed an induction of apoptosis and a
decrease of cell proliferation after treatment with 5-ASA
(1 g/day for 14 days) [25,28].
Non-inflammatory dependent antineoplastic
mechanisms of 5-ASA
Modulation of the Wnt/β-catenin pathway
An important role for β-catenin in colorectal carcinogenesis
was implied by its association with the tumor suppressor
protein, adenomatous polyposis coli (APC) [29], and by
10
evidence of dysregulation of β-catenin protein expression
at all stages of the adenocarcinoma progression. Indeed,
APC mutation leads to nuclear accumulation of β-catenin
[30]. The degradation of β-catenin involves binding of the
protein to a complex involving APC protein, axin, and
glycogen synthase kinase-3β (GSK-3β), which serves to
phosphorylate serine and threonine residues on β-catenin,
a crucial step that is required to target the protein
for ubiquitination and proteosomal degradation.
An important regulator of GSK-3β activity is the Wnt
pathway (for review, see [31]). Free pools of β-catenin
must be regulated via a second pathway involving
p53-inducible Siah-1.
2/10/07
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A direct effect of 5-ASA on the Wnt/β-catenin pathway is
described in one recent study using CRC cell lines [32]. These
data demonstrated that mesalazine affects the Wnt/βcatenin pathway in APC-mutated cells with intact β-catenin,
as assessed by luciferase reporter gene assays. Furthermore,
5-ASA treatment reduced the expression of nuclear β-catenin
and Wnt/β-catenin target genes, and increased β-catenin
phosphorylation. This effect on the Wnt/β-catenin pathway
is mediated via protein phosphatase 2A (PP2A): increased
phosphorylation of PP2A is observed after 5-ASA treatment,
which coincides with decreased PP2A enzymatic activity. The
inhibition of PP2A enzymatic activity by 5-ASA is essential for
its effect on the Wnt/β-catenin pathway, as shown by
transient transfection with small interfering PP2A RNA and
mutant PP2A. This study suggests that by using
concentrations of 5-ASA identical to those that are clinically
relevant in patients with IBD, the drug inhibits the Wnt/βcatenin pathway via inhibition of PP2A (Fig. 2) [32]. Other
studies are needed to confirm this interesting finding.
Figure 2. 5-ASA decreases the nuclear translocation of
β-catenin through an activation of PPARγ and
phosphorylation of PP2A.
5-ASA
Conductin/Axin
P
P
PP2A
P
APC
Degradation
Disruption of EGFR signaling
The EGFR is thought to play a key role in the pathogenesis
or maintenance of a number of human cancers of epithelial
origin, including CRC. This supposition is based on the
demonstration that EGFR itself is overexpressed in CRC
cells [33], and that within the neoplastic microenvironment,
there is secretion of factors that activate EGFR in an
autocrine/paracrine manner [34,35]. Evidence also indicates
that the aberrant activation of EGFR contributes to sustain
the growth of CRC cells [36]. Indeed, EGFR expression
seems to represent an independent predictor of decreased
survival in CRC patients. Consistent with this, the EGFR has
become a biochemical target for chemoprevention and
chemotherapeutic agents against CRC [37,38].
Data from a study by Monteleone et al., who used four
different CRC cell lines (HT-29, HT-115, T84, and Caco-2)
and ex vivo organ cultures of CRC explants, indicate that
clinically relevant concentrations of 5-ASA (from 10 to
50 mM) inhibit EGFR activation by specifically enhancing a
phosphorylated EGFR-targeting phosphatase (PTP), namely
SH-PTP2 (Fig. 3) [39].
Together, these data suggest that, in vitro, 5-ASA
inhibits the activation of EGFR, a transmembrane tyrosine
kinase involved in the mitogenic signaling of CRC cells.
Control of activating checkpoint responses
Another possible target for 5-ASA is the improvement of
accuracy of DNA replication. The fidelity of DNA replication
is a product of polymerase accuracy, its proofreading activity,
and the proficiency of the postreplicational mismatch repair
system [40]. Inefficiency of one of these processes can be a
Nuclear
importation
Nucleus
APC: adenomatous polyposis coli; GSK-3β: glycogen synthase kinase-3β;
PPARγ: peroxisome proliferator-activated receptor γ; PP2A: protein
phosphatase 2A.
key to the development of human cancer, best illustrated by
the familial cancer syndrome, hereditary nonpolyposis CRC
(also called Lynch syndrome).
Data from Gasche et al. suggest an effect of 5-ASA on
the occurrence of frameshift mutations at a (CA)13
microsatellite, which is quite different from the
chemopreventive effects of aspirin, despite their structural
similarities [41]. The observed effects of 5-ASA on replication
fidelity were seen at concentrations >1.25 mmol/L
(HCT116-A1.3 cells) or 2.5 mmol/L (HCT116-A2.1 cells) and
were greatest at the highest dose tested (5.0 mmol/L). At the
5.0 mmol/L level, a 19% reduction of the mutation rate was
observed in mismatch repair-deficient HCT116 colon cancer
cells. Keeping in mind that the rate of the emergence of
mutations defines the speed of tumor progression (as
predicted in the mutator phenotype hypothesis),
11
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Figure 3. 5-ASA inhibits the activation of EGFR by enhancing SH-PTP2.
5-ASA
Ligands
of EGFR
PGE2
EGFR
dephosphorylation
SH-PTP2
EGFR
EP
Amphiregulin
PI3K
Ras
TyrP
TyrP
TyrP
TyrP
cAMP
Src
PKA
CREB
AKT
MAPK
Cyclin D1
TCF
5-ASA: 5-aminosalicylic acid; cAMP: cyclic adenosine monophosphate; CREB: cAMP response element-binding protein; EGFR: epidermal growth factor receptor; EP:
PGE2 receptor 1; GSK-3β: glycogen synthase kinase-3β; MAPK: mitogen-activated protein kinase; PGE2: prostaglandin E2; PI3K: phosphatidyl inositol 3-kinase; PKA:
protein kinase A; SH-PTP2: protein-tyrosine phosphatase containing two Src homology domains; TCF: tumor complement factor; TyrP: phosphorylated tyrosine.
5-ASA therapy could introduce a significantly delay in the
clinical manifestation of a tumor. Thus, the authors of the
study rightly state that if 5-ASA increases the number of
years required for cells to accumulate the requisite number of
mutations necessary for invasiveness or metastases by 19%,
the drug would significantly reduce the life-threatening
manifestations of cancer and diminish cancer deaths even in
the absence of reducing cancer incidence. In this respect, 5ASA is potentially useful for prevention of CRC independent
of its anti-inflammatory properties.
Induction of peroxisome proliferator-activated receptor γ
(PPARγ) expression and activation
PPARγ is a nuclear receptor mainly expressed by colonic
epithelial cells and involved in the regulation of gut
homeostasis. Using a computerized medical literature search
12
of all English language articles in the PubMed online
database, >100 articles were found that reported a role for
PPARγ in the prevention of colon cancer and intestinal
inflammation by distinct mechanisms [42,43]. Several
molecular mechanisms that could explain the anticarcinogenic functions of PPARγ have been described. The
data obtained in studies using various cancer cells that
express PPARγ indicate that activation of this receptor by an
agonist can:
• Inhibit cell proliferation and S phase entry through
increased degradation of cyclin D1.
• Promote cell death by induction of the anti-apoptotic
protein Bcl-2 and inhibition of the survival gene NF-κB.
• Stimulate cell differentiation.
• Activate the degradation of β-catenin.
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Figure 4. 5-ASA is a specific ligand of PPARγ. Binding of
5-ASA to PPARγ induces a coordinated cascade of reactions
leading to the translocation of PPARγ to the cell nucleus, a
modification of its conformation permitting the recruitment
of coactivators (e.g. DRIP) and expression or repression of
PPARγ target genes via the activation of the PPRE.
Figure 5. In vivo in SCID mice, treatment with 5-ASA
(50 mM) for 21 days reduces by 80% the human colonic
tumor weight and volume compared with untreated animals.
Anti-inflammatory effects
Antineoplasic effects
5-ASA
Cell
membrane
5-ASA: 5-aminosalicylic acid; SCID: severe combined immunodeficient.
5-ASA
PPARγ
Cytoplasm
DRIP
5-ASA
RXR
PPARγ
Nucleus
nucleus, to promote a PPARγ conformational change, and to
recruit a coactivator named vitamin D receptor-interacting
protein (DRIP). Docking simulations showed a binding mode
of 5-ASA very similar to the crystal orientation of the known
ligand of PPARγ. 5-ASA fitted tightly with the PPARγ ligandbinding domain, interacting with key determinants required
for molecular recognition and PPARγ activation (Fig. 4). In
the HT-29 colonic epithelial cell line, 5-ASA induces PPARγ
expression, inhibits colonic epithelial cell proliferation,
and induces epithelial cell apoptosis through binding to
PPARγ [42]. In an in vivo model of severe combined
immunodeficient (SCID) mice engrafted with human colon
cancer, treatment with 5-ASA decreased the volume and
weight of a human colonic tumor by 80%, in a PPARγdependent manner (Fig. 5).
PPRE
5-ASA: 5-aminosalicylic acid; DRIP: vitamin D receptor-interacting protein;
PPARγ: peroxisome proliferator-activated receptor γ, PPRE: PPARγ response
element; RXR: retinoid X receptor.
Redrawn from [49] with permission.
• Induce expression of the transcriptional repressor
transforming growth factor β-stimulated protein TSC22
and of the tumor-suppressor gene phosphatase and
tensin homologue (PTEN).
• Inhibit angiogenesis.
Taken together, PPARγ acts as a tumor-suppressor gene
at an early step in the development of colonic tumors before
damage of the APC/β-catenin pathway.
Recently, 5-ASA was described – at clinically relevant
concentrations – to be a new synthetic ligand of PPARγ, able
to induce its expression and activation in colonic epithelial
cells (Fig. 2). 5-ASA is also able to bind PPARγ inducing its
translocation from the cytosol of epithelial cells to the
Summary
5-ASA regulates several mechanisms, related and unrelated
to inflammation, associated with the enhanced risk of CRC
occurrence in patients with IBD located in the colon.
Regarding the role of 5-ASA during inflammation, it is only
recently that an integrated understanding of the
mechanisms of action of aminosalicylates has been proposed
involving the nuclear receptor PPARγ, as previously
described in this journal [44]. 5-ASA interacts with PPARγ,
inducing its activation in epithelial cells, explaining, at least
in part, the reduction of many key elements of inflammation
such as the NF-κB signaling pathway, the production of
cytokines and chemokines, the synthesis of COX enzymes
and PGs, and the expression of adhesion molecules. The
antineoplastic effect of 5-ASA is not solely due to PPARγ
binding but involves also a reduced expression of nuclear
β-catenin and Wnt/β-catenin target genes, increased
β-catenin phosphorylation, disruption of EGFR signaling,
and an enhanced fidelity of epithelial cell replication.
13
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Figure 6. Antineoplastic effects of 5-ASA can be divided into (i) inflammatory dependent mechanisms including an inhibition of
the NF-κB pathway and COX2/PGE2 production, and (ii) non-inflammatory dependent mechanisms involving the Wnt/β-catenin
pathway, disruption of EGFR signaling, and control of DNA replication.
Inflammatory dependent mechanisms
Non-inflammatory dependent mechanisms
Wnt
Wnt
IKKγ
P
P
P
P
P
Axin
IKKγ
Axin
APC
Aspirin
Salicylate
Sulindac
P
RelA
p50
RelA
p50
P
P
APC
P
P
RelA
p50
P
Ub P
Ub
Ub
Ub
Proteasomal
Ub
degradation
Ub
P
26S proteasome
Groucho
TCF
RelA
p50
Inflammation
(cytokines, COX)
Cell proliferation
Cell growth
Cell differentiation
Apoptosis
PGI2 TXA2 PGE2 PGF1α PGD2
Apoptosis
PGH2
COX2
Arachidonic acid
sPLA2
cPLA2
Repression
15d-PGJ2
CBP
PYG
Activation
BCL9 TCF
LBD
Activation of signaltransduction cascades
Apoptosis
Invasion and metastasis
Cell proliferation
Angiogenesis
5-ASA
Control of activating
checkpoint response
DNA replication
P
TK
TK
P
TK
TK
EGFR
COX/PGE2
5-ASA: 5-aminosalicylic acid; APC: adenomatous polyposis coli; β-cat: β-catenin; β-TRCP: β-transducin repeat containing protein; BCL9: B-cell lymphoma protein
9; CBP: cyclic adenosine monophosphate response element-binding protein; CK1α: casein kinase 1α; COX2: cyclooxygenase 2; cPLA2: cytosolic phospholipase A2;
EGFR: epidermal growth factor receptor; GSK-3β: glycogen synthase kinase-3β; IκB: inhibitor of NF-κB; IKKα: IκB kinase α subunit; IKKβ: IκB kinase β subunit; LBD:
ligand-binding domain; NF-κB: nuclear factor-κB; P: phosphate; PGD2: prostaglandin D2; PGE2: prostaglandin E2; PGF1α: prostaglandin F1α; PGH2: prostaglandin H2;
PGI2: prostaglandin I2; PGJ2: prostaglandin J2; 15d-PGJ2: 15-deoxy-prostaglandin J2; PYG: pygopus; sPLA2: secretory phospholipase A2; TCF: tumor complement factor;
TK: tyrosine kinase; TXA2: thromboxane A2; Ub: ubiquitination.
14
2/10/07
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Page 15
Taken together, these in vitro data suggest that the
antineoplastic effects of 5-ASA are multistep processes
(summarized in Fig. 6). 5-ASA acts as a tumor-suppressor at
an early stage in the development of colonic tumors, before
damage of the APC/β-catenin pathway, but also at a later
stage, delaying tumor progression.
In vivo studies in mice
This latter section of the review will focus on studies
investigating the roles of 5-ASA in different experimental
models of CRC in rodents including mice and rats. Briefly,
there are two main groups of validated experimental models
of CRC. The first are chemical-induced CRC models in mice
and rats, using:
• AOM, leading to aberrant crypt foci followed by
invasive cancer.
• DMH, resulting in Ras mutation and leading to
invasive carcinomas.
• N-methyl-N-nitrosurea (NMNU), leading to colon
cancer within 10 days.
To better mimic IBD-associated colon cancer, some
studies have associated the administration of chemical
carcinogen with inflammatory compounds, for example,
AOM and dextran sodium sulphate (DSS).
The second group of validated experimental models of
CRC is characterized by the spontaneous occurrence of small
bowel and colon cancer in mice carrying a nonsense mutation
in the murine homologue of the APC gene, named APCMin
mice. In all of these experimental models, 5-ASA has been
demonstrated to prevent or reduce colon cancer occurrence.
Presentation of studies in animals
The antineoplastic effect of 5-ASA has been well characterized
in chemically induced CRC in mice and rats. In 1992, Davies et
al. evaluated the effect of therapeutic drugs used for the
treatment of IBD in a model of colonic cancer induced by
DMH (40 mg/kg) in Wistar rats [45]. They found that 5-ASA
(60 mg/kg/day) inhibited tumor size by >60% compared with
untreated animals. In the study by MacGregor et al.,
balsalazide reduced aberrant crypt foci induced by AOM in a
dose-dependent manner, by 60% [26]. Similarly, 5-ASA
treatment in rats receiving DMH reduced tumor number and
load through an increased rate of tumor apoptosis and a
reduced tumor cell proliferation rate [27]. The preventive
anticarcinogenic effect of 5-ASA was also confirmed by
Narisawa et al. in 2003, using a model of colon cancer induced
by NMNU in F344 rats. They demonstrated that intrarectal
administration of 5-ASA strongly suppressed the initial stage of
chemically induced colon carcinogenesis (by 70%) [46].
In Min mice, which develop intestinal neoplasia, two
studies report controversial results depending on the genetic
strain of animals. Ritland et al. failed to observe the effect of
several formulations of 5-ASA (free acid, sulfasalazine, and
Pentasa® [Shire, Wayne, PA, USA]) at multiple dosage levels
on tumor number in APCMin mice [47]. In contrast,
MacGregor et al. treated another strain: B6-Min/+ mice, and
found a dose-dependent reduction of intestinal tumor
number, reaching 80% inhibition in the distal small intestine
and colon [26].
Summary
Most preclinical studies performed in experimental models of
CRC in mice and rats demonstrated that 5-ASA, at clinically
relevant concentrations, prevented and inhibited the
progression of colonic tumors by 60–70%. These results
confirm and extend data obtained in vitro using intestinal
epithelial cell lines. Controversial results are only observed in
one experimental model of CRC occurring in Min mice [47]. If
we consider that 5-ASA acts at an early stage in the
development of colonic tumors, before damage of the APC/βcatenin pathway, it is not surprising that the antineoplastic
effect of 5-ASA was reduced in this model, which is
characterized by mutation of the APC/β-catenin pathway.
Ex vivo studies in human
Endoscopic studies in IBD patients
Inflammation-related antineoplastic mechanisms of 5-ASA
involving an inhibition of the NF-κB pathway were
investigated in inflammatory colonic endoscopic biopsies of
20 UC patients treated with 5-ASA [14]. In this study, Bantel
and colleagues showed that 8 weeks of treatment with
5-ASA resulted in a strong abrogation of NF-κB activation in
situ, evaluated by immunostaining using a specific antibody
directed against activated NF-κB.
Regarding the therapeutic properties of 5-ASA on cell
apoptosis and proliferation, Reinacher-Schick and colleagues
investigated the effects of 5-ASA ex vivo in 21 patients with
sporadic colorectal polyps (≥5 mm) [48]. Among these
patients, 17 underwent polypectomy and biopsy of
uninvolved mucosa before and after treatment with 5-ASA
1 g/day (for 1, 3, 7, or 14 days); four patients served as
untreated controls. Apoptotic and proliferation rates were
measured by terminal transferase dUTP nick end labeling
(TUNEL) assay and immunostaining using an anti-Ki67
antibody, respectively. The authors found that apoptosis was
significantly increased 1 and 3 days after initiation of
treatment with 5-ASA compared with control subjects
(p=0.0107 for the 1-day treatment group and p=0.0142 for
the 3-day treatment group), and inversely that proliferation
appeared to be decreased by mesalazine in all treatment
15
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Page 16
groups, while proliferation in controls did not change.
Similarly, in 10 patients with CRC, mesalazine enemas for 14
days were associated with an increased apoptotic score and
a decreased cell proliferation in malignant tissue, according
to the Ki67 antibody staining [28].
Disclosures
Drs Rousseaux and Romano have no relevant financial interests to
disclose. Dr Desreumaux has received consulting fees from, or served on
advisory boards for, Biofortis, Danisco France SAS, Danone France,
Ferring, Giuliani S.p.A., Roquette, TxCell, and UCB Pharma. Dr
Desreumaux has also received lecture fees from CME events indirectly
Short-term culture of intestinal biopsies with 5-ASA
supported by commercial sponsors (Ferring, Procter & Gamble,
As mentioned earlier, an inhibitory role of 5-ASA on EGFR
signaling was demonstrated in ex vivo organ cultures of CRC
explants in which clinically relevant concentrations of 5-ASA
(10–50 mM) inhibit EGFR activation by specifically enhancing
a phosphorylated EGFR-targeting phosphatase (PTP), namely
SH-PTP2 [39]. These data suggest that, in vivo, 5-ASA
inhibits the activation of EGFR, a transmembrane tyrosine
kinase involved in the mitogenic signaling of CRC cells.
Confirmation of functional binding of 5-ASA to PPARγ, a
nuclear receptor with antineoplastic effects was obtained ex
vivo in colonic biopsies of control subjects and patients with
IBD (both Crohn’s disease and UC patients). In this study, 5ASA at clinically relevant concentrations (30 and 50 mM)
induced PPARγ expression and activation, inducing
particularly the expression of the PPARγ-activation related
gene NGal [43].
Schering Plough, Shire, and UCB Pharma), and grant support from Astra
Summary
These ex vivo studies performed using colon specimens of
different patients with UC, Crohn’s disease, sporadic polyps,
and CRC confirm the preclinical results demonstrating that
5-ASA in human colon decreases NF-κB activation, epithelial
cell proliferation, and EGFR signaling, increases epithelial cell
apoptosis and induces PPARγ expression and activation.
Conclusion
5-ASA has been a cornerstone in the treatment of UC
patients for many years to control disease activity and, in the
last decade, to reduce the risk of development of CRC.
Large epidemiological studies have shown that between
48% and 65% of patients with UC receive continuous
5-ASA treatment. As ethical considerations mean that it will
never be possible to carry out a randomized, placebocontrolled clinical trial to assess the efficacy of 5-ASA in
reducing the risk of CRC in patients with UC, a better
understanding of the mechanisms sustaining the putative
antineoplastic effects of 5-ASA is crucial. The present in vitro
data, in vivo studies in mice and rats, and the ex vivo
experiments performed in patients provide a mechanistic
foundation for the possibility that long-term treatment with
5-ASA can reduce the risk of CRC in patients with IBD
located in the colon. This statement would imply that these
patients should be put on continuous 5-ASA treatment to
reduce the risk of neoplasia development.
16
Zeneca, Danisco France SAS, Danone France, Ferring, Giuliani S.p.A.,
Lesaffre, Ocera Therapeutics, Roquette, Sanofi-Synthelabo, UCB
Pharma, and Yoplait.
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17
LEADING ARTICLE
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Orofacial Granulomatosis and Oral
Crohn’s Disease
Carlo Nunes, MD1, Miranda Lomer, PhD1, Michael Escudier, FDS, RCS2, Stephen
Challacombe, FMedSci2, and Jeremy Sanderson, MD1
1
Department of Gastroenterology, Guy’s & St Thomas’s NHS Foundation Trust, and 2Department of Oral
Medicine, Kings College London Dental Institute, London, UK
Orofacial granulomatosis (OFG) is a rare, chronic inflammatory disease of unknown etiology affecting the orofacial tissue,
with no apparent systemic involvement. Lip swelling is the most common clinical presentation but several intra-oral sites
may also be affected. OFG is used as an umbrella term and includes the Melkersson–Rosenthal syndrome, cheilitis
granulomatosa, and systemic granulomatous diseases, of which, Crohn’s disease is the most common. Histological
characteristics consist of epithelioid granulomas and lymphedema of the corium. No definitive etiological cause has been
identified, but dietary antigens appear to play an important role in the pathogenesis of the disease. Dietary manipulation,
in particular a cinnamon- and benzoate-free diet, is used with success as a first-line treatment. Failing dietary therapy,
disease management largely follows a Crohn’s disease-like treatment regimen involving immunosuppressants, whilst lipreduction surgery is reserved for treatment-resistant, severe cases. Inflamm Bowel Dis Monit 2007;8(1):18–22.
Orofacial granulomatosis (OFG) is an uncommon chronic
inflammatory condition affecting the mouth presenting most
often with lip swelling but also affecting multiple sites
throughout the oral cavity. The term “OFG” is used as an
umbrella to cover a range of conditions in which
granulomatous inflammation may involve the oral cavity,
with the commonest of these being Crohn’s disease [1].
More rarely, sarcoidosis and tuberculosis present in this way
[2,3]. Importantly, however, it is clear that OFG can exist as
a separate entity [4]. The Melkersson–Rosenthal syndrome
(MRS) and cheilitis granulomatosa, which is regarded as an
oligosymptomatic form of MRS, are also included under the
umbrella term OFG.
The true prevalence is unknown as no reliable
epidemiological data exist [5]. In known Crohn’s disease, true
OFG occurs in <1% of cases [6]. Conversely, the incidence of
the various other oral manifestations of Crohn’s disease may
be as high as 20% [7]. OFG is more common in the pediatric
and young adult population and, anecdotally, a long-held
view has been that cases of pediatric OFG would frequently
evolve into classical gut Crohn’s disease in adolescence or
adulthood. Certainly, a small number of cases with OFG may
Address for correspondence: Jeremy Sanderson, Department of
Gastroenterology, 1st Floor, College House, Guy’s & St Thomas’
NHS Foundation Trust, Lambeth Palace Road, London, SE1 7EH, UK.
18
precede gut Crohn’s disease by a number of years, but
specialist experience suggests this is the exception rather than
the rule [8–11]. Geographical variation in the prevalence of
OFG has been observed but not documented in any formal
study. The condition is reported most frequently in the UK
literature and there is a remarkable Celtic predominance. The
greatest numbers of cases are seen in Scotland (in particular,
Glasgow) and in Ireland [5,12].
Importantly, the psychosocial impact of OFG is
disproportionately high, particularly in teenagers and young
adults where avoidance behavior and anxiety/depression
scores match those of individuals with major facial burns
(Sanderson J, unpublished data).
Clinical features
The onset of OFG is often with acute or subacute lip
swelling, either upper or lower, or both, and whilst the first
episode may subside completely in hours to days,
subsequent attacks may not fully resolve leaving the lip
chronically swollen [13]. Spontaneous resolution is rare but
has been reported [14]. The majority follow a chronic
relapsing course, not infrequently with chronic swelling and
intervening bouts of acute swelling.
The features of true OFG should not be confused with
the more common oral manifestations of Crohn’s disease,
which include aphthous-like ulceration, angular cheilitis,
glossitis, and intra-oral candidiasis. These are often related to
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OFG AND ORAL CROHN’S DISEASE
active intestinal disease, to hematinic deficiency, or to drug
treatment (corticosteroids in particular). The characteristic
features of OFG consist of lip swelling (Fig. 1), often with
fissuring, and erythema, edema, and nodularity affecting a
variety of intra-oral sites. Buccal cobblestoning, mucosal
tags, and deep, painful, linear sulcal ulceration are features
that are very reminiscent of gut Crohn’s disease [1,15].
Gingival enlargement and erythema is also commonly seen
and may be the presenting feature [16]. Involvement of the
salivary duct orifices in the floor of the mouth with firm
swelling and erythema is unique and often referred to as a
“staghorn appearance” [17]. Fissuring of the dorsum of the
tongue is less common, but when seen in association with
lip swelling and a lower motor neurone VIIth nerve palsy, is
referred to as MRS [18,19]. Facial swelling and erythema,
most commonly spreading peri-orally, may also occur.
Rarely, cervical lymphadenopathy may be present [20].
Etiology
The etiology of OFG remains unknown. The association with
Crohn’s disease inevitably suggests that the pathogenesis
involves an interaction between genetic susceptibility and
environmental trigger factors. However, unlike most forms of
Crohn’s disease, OFG has clinical features in keeping with an
allergic mechanism, and an increased prevalence of atopy (up
to 60%) is well described [16,21–24]. Whilst earlier reports
of cutaneous patch testing to agents such as cobalt, dental
materials, and food additives revealed no consistent pattern,
more recent evidence suggests that dietary cinnamon and
benzoate may play an important role in the disease [17,25].
Cutaneous patch test studies at the Glasgow Dental School
(Glasgow, UK) related cinnamaldehyde and benzoate strongly
to OFG and a favorable response was reported when these
substances were excluded from the diet [26]. Benzoates are a
preservative in many foods, especially fizzy drinks, whilst
cinnamaldehyde is used as flavoring in soft drinks, chewing
gum, ice cream, cakes, toothpaste, and mouthwashes. Whilst
anecdotal, the remarkable incidence of OFG in Glasgow may
relate to the well-known high rates of fizzy drink
consumption (The Independent [London], August 17, 1998).
Immunologically, the inflammatory infiltrate is T cell driven,
with the formation of non-caseating epithelioid granulomas
that frequently are deep seated in the corium [27,28]. There
are few studies that have addressed the pathogenesis and
immunology of OFG. Gibson and Wray demonstrated
specific human leukocyte antigen genotypes, A2/3, B7, and
DR2/3/4, in 16 patients with OFG [29], whilst Lim et al.
identified a restricted T cell receptor (TCR) V-β gene
expression by lesional lymphocytes compared with normal
peripheral blood lymphocytes in patients with OFG. In the
latter study, there was also an identical, unique V-D-J
Figure 1. Predominant lower lip swelling and erythema in a
patient with OFG.
OFG: orofacial granulomatosis.
Available in color at www.ibdmonitor.com
junctional sequence seen in >20% of the V-β 6 TCR
transcripts, suggesting a local antigen-driven V-β 6 T cell
clonal expansion within the lesional lymphocytes only [28].
Moreover, immunohistochemical studies suggest an
inflammatory process driven by a type 1 helper T cell
environment similar to that seen in gut Crohn’s disease [30].
Recent evidence also implicates B cells in the pathogenesis
of OFG [31].
Diagnosis
The diagnosis of OFG may be delayed, not least because the
disease is uncommon and presentation may be limited to
intra-oral disease. Moreover, patients often present to a
variety of specialists, most frequently general dental
practitioners and maxillofacial surgeons [32]. The diagnosis of
OFG is confirmed by typical histological changes observed in
biopsies of affected sites, most commonly lip or buccal
mucosa. The characteristic findings are the presence of noncaseating epithelioid granulomas on the background of a
chronic inflammatory cell infiltrate (Fig. 2). Lymphedema of
the corium and dilated lymphatics are also seen and are a
major contributor to the persistence of lip swelling [1,13].
Granulomas are frequently deepseated and deeper sections
may be required for a definitive diagnosis [27].
The current authors’ group has demonstrated, using
ileocolonoscopy, that minor macroscopic intestinal
abnormalities with microscopic granulomatosis are common
and present in up to 60% of patients with OFG who have
no gastrointestinal symptoms [33]. These findings were
more common in those aged <30 years and, importantly,
most patients have not progressed to gut Crohn’s disease
with up to 15 years of follow-up. The true significance of
these findings is not clear but they suggest that, in most
cases, OFG represents an individual disease entity.
19
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CARLO NUNES ET AL.
Figure 2. H/E-stained lip histology from a patient with
OFG showing a sub-epithelial epithelioid granuloma,
with surrounding chronic inflammatory cell infiltrate. The
inflammatory infiltrate has focally infiltrated the epithelium.
Magnification: x20.
H/E: hematoxylin/eosin; OFG: orofacial granulomatosis.
Available in color at www.ibdmonitor.com
Approximately one in five patients with OFG from the
present authors’ institute have concurrent gut Crohn’s
disease and, although a large number present with gut
involvement at the time of diagnosis, only a small number
subsequently progress to true gut Crohn’s disease.
The ability to predict which patients are at risk of developing
Crohn’s disease is important as early therapeutic intervention
may improve the natural history of the disease. Clinically, buccal
cobblestoning and mucosal tags are predictive of Crohn’s
disease compared to lip swelling [32]. Likewise, those with
elevated inflammatory markers and hematinic deficiencies are
significantly more likely to suffer from concurrent gut Crohn’s
disease [32]. A recent investigation measuring a specific
Saccharomyces cerevisiae 200-kDa glycoprotein antigen in
serum and saliva in patients with OFG suggested that raised
serum immunoglobulin A (IgA) antibodies to the S cerevisiae
200-kDa antigen are predictive of gut inflammation, while
elevated salivary IgA antibody levels were not [34]. Thus, high
titers of serum IgA antibodies to the S cerevisiae 200-kDa
antigen might identify a subgroup of patients with OFG who
may benefit from early gastrointestinal investigation.
Management of OFG
The initial analysis of patients with suspected OFG should
include a detailed oral examination, and referral to a specialist
20
oral medicine clinic is advisable. Hematological assessment
should include standard inflammatory parameters as these
may reflect systemic involvement. A chest X-ray and serum
angiotensin-converting enzyme level should be considered
during preliminary analysis, for exclusion of sarcoidosis.
Swabs of lip fissures and angular cheilitis are important
as secondary infection is common, and aggravates
inflammation. Likewise, salivary Candida culture may identify
a group benefiting from antifungal medication. As with
dermatology, clinical photography is an important element of
recording clinical signs at any visit and an oral activity score
can also be used to quantify disease activity.
The treatment of OFG remains a challenge and strategies
used are largely based on small, non-randomized trials and
anecdotal case reports. In general, the management of OFG
follows a similar approach to that used in gut Crohn’s
disease. Initial aims are to induce remission followed by
maintenance therapy and can be largely divided into
general, topical, systemic, and surgical therapy. Also relevant
is whether patients have concurrent Crohn’s disease as
therapy aimed at active gut disease may result in
improvement of oral disease. In those with minor symptoms
only or disease that remits spontaneously, it is possible that
no therapy will be required. A multidisciplinary approach to
management is ideal with a team consisting primarily of an
oral/dental surgeon, gastroenterologist, and dietitian.
General
Non-specific lesions such as glossitis, aphthous-like ulcers,
and oral candidiasis may often indicate concurrent hematinic
and/or nutritional deficiencies [35]. Particular attention
should be paid to correcting vitamin B12, folate, and iron
deficiencies. Patients with malnutrition may benefit from
calorie supplementation. Topical antibiotics, such as Fucidin®
(Leo Pharma, Princes Risborough, Buckinghamshire, UK),
should be used in cases of infected lip fissures and/or
angular cheilitis. Moreover, oral hygiene and regular dental
inspection should be encouraged as poor dentition and
periodontitis may be present at the time of diagnosis, or be
a consequence of treatment such as corticosteroids. It is also
important to exclude and treat any underlying infective foci
such as a dental abscess prior to considering immunosuppressive therapy, in particular biologics, as infective/
septic complications have been described [36].
Dietary
The role of dietary manipulation in the form of exclusion
diets has shown some promise in the last few years and
supports the view that dietary antigens play a substantial
role in the pathogenesis of OFG. At the authors’ institution,
a cinnamon- and benzoate-free diet is used as first-line
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OFG AND ORAL CROHN’S DISEASE
treatment in patients with confirmed OFG. Moreover, using
an oral activity score, the authors have demonstrated a 68%
(39/57 patients) response rate in both lip and intra-oral
disease following a cinnamon- and benzoate-free diet for a
period of 12 weeks [17]. The use of enteral nutrition (either
polymeric or elemental) for a period of 6 weeks as secondline therapy may also be effective, particularly in those with
intra-oral compared with lip disease [37]. As with gut
Crohn’s disease, compliance may be a particular problem in
younger patients with OFG. However, overall, a dietary
approach to the management of OFG is an effective
treatment strategy and may avoid the use of corticosteroids
and immunosuppression in many cases.
Topical
The use of topical preparations is perhaps of particular
benefit in those with mild disease and without evidence of
gut involvement. Remission of oral symptoms has been
reported to be as high as 58% in a small cohort of patients
using topical steroids [15]. Intra-lesional injections using
delayed-release triamcinolone may be of benefit for lip
swelling, and disease-free periods of up to 19 months have
been reported [38]. Response is likely to be less optimal in
those who already have histological evidence of fibrotic lip
disease. Overall, the long-term use of steroids should be
discouraged as the improvement is, at best, short lived and
not without the risk of unacceptable side effects. Topical
mesalazine (Topasa™, Tillotts Pharma AG, Basel,
Switzerland) and tacrolimus have also been used with some
success for both lip swelling and intra-oral disease [39–41].
Topical steroid mouthwashes, such as betamethasone
(Betnesol®, GSK, Middlesex, UK), may be useful for intraoral disease but the response is usually short-lived. If pain
is a particular feature, adjunctive antiseptic/analgesic
mouthwashes can be helpful.
limited use due to adverse effects intra-orally. Some
institutions regularly use thalidomide, at doses ranging from
50–300 mg, with anecdotal success, but toxicity and
restrictions limit its use [42,43]. Infliximab has demonstrated
some success in severe cases where conventional
immunosuppressive agents have failed [44,45]. The authors’
own experience suggests that response is greater for intraoral disease, supporting the concept of this pattern being
more reflective of gut Crohn’s disease.
Surgery
Lip reduction procedures should be considered in severe
cases with chronically enlarged, deformed fibrotic lip
swelling [46]. These patients may frequently suffer
unrecognized psychosocial morbidity and social isolation.
Moreover, it may interfere with the ability to eat and speak.
Any residual active inflammation should be excluded prior to
recommending surgery and the best outcome is likely to
result from a carefully planned first surgical procedure.
Conclusion
OFG is a rare, chronic inflammatory disease with links to
Crohn’s disease, but which mainly exists as a separate entity.
The presence of an associated intestinal granulomatosis
should be interpreted with caution as the majority of cases
do not appear to develop gut Crohn’s disease. Dietary
exclusion using a cinnamon- and benzoate-free diet is
effective in the majority of cases, but failing this, an
immunosuppressant regimen mirroring that for the
treatment of Crohn’s disease is used. Experience outside
specialist centers is limited, and the best outcomes are likely
to be achieved using a multi-disciplinary approach.
Disclosures
The authors have no relevant financial interests to disclose.
Systemic
References
The systemic therapeutic regimen employed in OFG closely
resembles that used in Crohn’s disease and includes
corticosteroids, thiopurines, methotrexate, and biological
therapy with infliximab. In general, systemic therapy should
be considered in patients who have concomitant gut
involvement and/or those who have failed dietary or topical
therapy. Systemic corticosteroids are effective for more
severe disease and in acute exacerbations. A dose-tapering
regimen, similar to that in Crohn’s disease, is used. Steroid
dependence or refractory disease should prompt the
use of steroid-sparing agents, with azathioprine and
6-mercaptopurine the first choice, as in Crohn’s disease.
Those intolerant to or failing on thiopurine therapy should
receive methotrexate, but experience suggests a more
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CLINICAL REVIEWS
Commentary and Analysis on Recent Key Papers
Clinical reviews were prepared by Ian Arnott, MD, Federico Balzola, MD, and
Charles Bernstein, MD
CLINICAL OBSERVATIONS
Systematic review: the potential influence
of mesalazine formulation on maintenance
of remission in Crohn’s disease
Steinhart AH, Forbes A, Mills EC et al.
Aliment Pharmacol Ther 2007;25:1389–99.
The current authors performed a systematic analysis of
studies of pH 6- and pH 7-dependent, and controlledrelease mesalazine formulations in the maintenance of
surgically or medically induced remission of Crohn’s disease.
The risk of disease relapse was found to be significantly
reduced in those treated with pH 7-dependent mesalazine
compared with placebo, whereas the pH 6-dependent and
controlled-release formulations showed no significant
reduction in the risk of relapse. Large-scale, randomized
controlled trials of pH 7-dependent mesalazine in
maintenance of remission are warranted.
Several studies and meta-analyses have suggested that
mesalazine is effective for the maintenance of surgically
induced remission in Crohn’s disease, while the evidence is
less clear regarding its use in maintaining medically induced
remission. Thus, current guidelines recommend mesalazine,
as a class, for the maintenance of disease remission postsurgery. However, there are a number of formulations of
mesalazine that allow timed delivery of the active drug to
specific regions of the gut. The current authors undertook a
Medline/Embase literature review from January 1986 to
January 2006 to identify studies of mesalazine in
maintenance of medically or surgically induced remission of
Crohn’s disease, with the aim of comparing effectiveness of
formulations that release the drug at >pH 7 (Asacol®; Procter
& Gamble Pharmaceuticals UK Ltd, Egham, UK), >pH 6
(Salofalk®; Dr Falk Pharma UK Ltd, Bourne End, UK; Mesasal®;
GlaxoSmithKline, Brentford, UK), and a controlled-release
form (Pentasa®; Ferring Pharmaceuticals Ltd, Langley, UK). A
total of 13 randomized controlled trials were included in the
analysis. Outcome measures included the pooled odds ratio
(OR) of maintenance of remission, the number needed to
treat (NNT) to prevent one relapse, and the percentage
overall therapeutic benefit.
Analysis of maintenance of surgically induced remission
showed that the risk of relapse was significantly reduced in
patients who were treated with pH 7-dependent
mesalamine compared with placebo (OR 0.28, 95%
confidence interval [CI] 0.12–0.65; p=0.0032), while there
was no significant improvement in those treated with pH 6dependent formulation (OR 0.65, 95% CI 0.34–1.24;
p=0.1954), or those who received controlled-release
mesalazine (OR 0.72, 95% CI 0.47–1.08; p=0.1109).
Similarly, treatment with pH 7-dependent mesalamine
significantly reduced the risk of relapse in patients with
medically induced remission (OR 0.38, 95% CI 0.17–0.85;
p=0.0113), while controlled-release and pH 6-dependent
formulations again demonstrated no improvement over
placebo (p=0.0802 and p=0.3176, respectively).
The NNT to prevent relapse of surgically or medically
induced remission of Crohn’s disease were 4 and 5,
respectively, for pH 7-dependent mesalamine; 11 and 23,
respectively, for pH 6-dependent mesalamine; and 15 and
16, respectively, for the controlled-release formulation.
Again, this demonstrated greater therapeutic advantage of
the pH 7-dependent formulation, although the authors
caution that the placebo relapse rates across the studies
were heterogeneous. The calculated therapeutic benefit
(absolute risk reduction) was also highest for pH 7dependent mesalazine (surgical 30.6%, medical 22.8%),
compared with pH 6-dependent mesalazine (9.8% and
4.4%, respectively) and controlled-release mesalazine (6.9%
and 6.4%, respectively).
The authors discuss limitations of this type of metaanalysis, such as publication or selection bias, and also the
interpretation of data when outcomes are based on single
studies, as is the case with the maintenance of remission
with pH 7-dependent mesalazine. However, they highlight
that data are consistent for both medically and surgically
induced remission in their analysis. The authors also describe
23
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CLINICAL REVIEWS
the differences between their analysis and the meta-analysis
of Akobeng and Gardener [1], which included studies of
azo-bonded mesalazine. Importantly, they discuss the
potential suitability of pH- and azo-bonded formulations for
subgroups of patients with specific disease location. Lastly,
they encourage further large-scale studies of the efficacy of
mesalazine formulations in CD, in order to confirm their
current findings.
1.
Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced
remission in Crohn’s Disease. Cochrane Database Syst Rev 2005;(1):CD003715.
Address for reprints: SPL Travis, Gastroenterology Unit, John Radcliffe
Hospital, Oxford, OX3 9DU, UK. Email: [email protected]
Abnormal hepatic biochemistries in patients with
inflammatory bowel disease
Mendes FD, Levy C, Enders FB et al.
Am J Gastroenterol 2007;102:344–50.
The prevalence of abnormal hepatic biochemistries and
chronic liver disease in patients with IBD were examined
in this study. The authors found that abnormal hepatic
biochemistries were present in nearly 30% of patients,
but that these were unrelated to IBD activity.
While primary sclerosing cholangitis (PSC) is the most widely
discussed and investigated hepatobiliary abnormality in
patients with IBD, it is likely not to be the most common.
Although it may be the most serious chronic liver disease in
IBD patients, autopsy series have also reported high rates of
fatty liver in IBD patients.
Patients presenting at the Mayo Clinic (Rochester, MN,
USA) with IBD in 2000 were included in this study. Hepatic
biochemistry analyses included blood testing for aspartate
aminotransferase, alanine aminotransferase, and alkaline
phosphatase. Of 621 IBD patients, 544 had hepatic
biochemistry assessed; of those, 29% had abnormal test
results. Chronic liver disease was diagnosed in 5.8% of
patients, including 4.6% with PSC. There was no significant
difference in the likelihood of having abnormal hepatic
biochemistry test outcomes, whether patients had active
disease or disease in remission (27% vs. 36%, respectively;
p=0.06). Patients with Crohn’s disease were as likely to
have abnormal hepatic biochemistries as patients with
ulcerative colitis; however, they were less likely to have a
diagnosis of liver disease (2% vs. 9%; p=0.0002). Patients
with abnormal hepatic biochemistries were less likely to be
using 5-aminosalicylate drugs (35% vs. 51%; p<0.001) and
were also more likely to be dead at follow-up (proportion
alive at last follow-up: 90.4% vs. 98.5%; p<0.0001, risk
ratio 4.8). Of IBD patients with chronic liver disease, fewer
had active disease (61% vs. 80%; p=0.006), and excessive
24
alcohol use was more common (6% vs. 1.3%; p=0.04), in
comparison with IBD patients who did not have chronic
liver disease.
One drawback of this study was that only 75% of
subjects had at least one follow-up, some of which may
simply have been by telephone with further laboratory
investigations not being performed. Only 226 (42%) patients
had subsequent hepatic biochemistry testing. Furthermore,
there was a paucity of imaging studies reported and this
might have contributed to the minimal rates of fatty liver
reported in this study. The most important take-home
message was that hepatic biochemistry abnormalities
occurred at some time in nearly 30% of patients and were
unrelated to disease activity.
Address for reprints: KD Lindor, Mayo Clinic, 200 First Street SW,
Rochester, MN 55905, USA.
Chromoscopy-guided endomicroscopy increases
the diagnostic yield of intraepithelial neoplasia
in ulcerative colitis
Kiesslich R, Goetz M, Lammersdorf K et al.
Gastroenterology 2007;132:874–82.
Patients with ulcerative colitis (UC) have an increased risk
of developing colorectal cancer in the long term. These
authors evaluated the use of combined chromoendoscopy
and endomicroscopy in neoplasia surveillance in patients
with UC. They concluded that chromoendoscopy-guided
endomicroscopy may lead to significant improvements in
the management of neoplasia surveillance in UC.
The authors of this study evaluated the utility of combined
chromoendoscopy and endomicroscopy in dysplasia
surveillance in ulcerative colitis (UC). To facilitate this, a
miniature confocal microscope was integrated into the distal tip
of a conventional colonoscope and fluorescein dye was injected
intravenously. This enabled histological evaluation of the
mucosal layer during colonoscopy. Owing to the large surface
area of the colon it would not be practical to use
endomicroscopy in the entire colon of a patient with UC as this
would be excessively time-consuming. For this reason, the
investigators combined the endomicroscopy with chromoendoscopy such that the endomicroscopy would only be
applied to lesions of interest that were identified with dye
spraying. All lesions identified by endomicroscopy were digitally
stored and evaluated at a later time by an investigator who was
blinded to the recordings of the endoscopist. Images were
graded as being good, average, or poor. For conventional
colonoscopy, four biopsies were taken every 10 cm; biopsies of
targeted lesions were also taken. A total of 161 subjects with
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UC in clinical remission were randomized in a 1:1 ratio to
undergo either conventional colonoscopy with multiple
surveillance biopsies, or chromoendoscopy with endomicroscopy. Eight patients were excluded due to insufficient
bowel preparation that precluded satisfactory examination.
Notably, 62 (39%) subjects had only histological proctitis,
a condition not thought to be predispose to neoplasia and
hence not included in dysplasia surveillance programs. In the
conventional colonoscopy group (n=73), four were found to
have dysplasia. In the endomicroscopy group (n=80), 19
dysplastic lesions were identified in 11 subjects. Fourteen of
these 19 were not identified by conventional endoscopy. In
the endomicroscopy group, 16 flat dysplasias were identified
compared with only two in the conventional endoscopy
group (p=0.002). In this latter group, 4.75-fold more neoplasia
was found, despite utilizing 50% fewer biopsy specimens
(there were an average of 21.2 biopsies per case in the endomicroscopy group compared with 42.2 biopsies per case in
the conventional colonoscopy group). A total of 5580 confocal
endomicroscopic images from 134 circumscribed lesions were
compared with the histology results. Endomicroscopy was
found to predict neoplasia with a sensitivity of 94.7%,specificity
of 98.3%, and accuracy of 97.4%. Endomicroscopically normal
tissue revealed, with 99% accuracy, non-neoplastic tissue by
histological analysis. This could also reduce the need for biopsies
to simply stage the extent of histological inflammation.
In summary, the authors report that chromoendoscopy
with endomicroscopy could increase diagnostic yield while
reducing biopsy burden and enhancing neoplasia detection
in the setting of UC.
Address for reprints: R Kiesslich, I. Medical Clinic, University of
Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Clinical usefulness of EUS for active
ulcerative colitis
Yoshizawa S, Kobayashi K, Katsumata T et al.
Gastrointest Endosc 2007;65:253–60.
The authors of this study assessed the utility of endoscopic
ultrasound for predicting the response to medical treatment
and the need for surgery in ulcerative colitis patients.
This study assessed whether endoscopic ultrasound (EUS)
could identify the depth of intestinal inflammation, predicting
the response to medical treatment, and determining the
necessity for surgery in active ulcerative colitis (UC). Initially,
EUS was tested in vitro in 13 surgically resected specimens.
In vivo, the severest lesions on colonoscopic examination
were evaluated by EUS in 42 patients with active UC with
the aim of potentially identifying ultrasound characteristics
that predict the need for surgery. In vitro, the spread of UC
identified by EUS was consistent with histological findings in
45/50 (90%) cases. The concordance for transmural
inflammation between EUS and histology extending to the
submucosa was 95%, to the muscularis propria was 83%,
and to the subserosa was 100%. In the in vivo studies,
inflammation was evaluated to extend at least as deep as the
muscularis propria on EUS in 10 of the 15 cases who failed
medical therapy and who ultimately underwent surgery. In
five of the 27 subjects who achieved medical remission
it extended to at least muscularis propria (p=0.002 for
predicting surgery, based on the depth of inflammation).
The authors argue that EUS in active UC can be used to
help predict those likely to require surgical therapy and,
therefore, might help reduce the hospitalization time,
perhaps by encouraging either earlier surgery or more
aggressive medical therapy.
Address for reprints: S Yoshizawa, Department of Gastroenterology,
Kitasato University East Hospital, 2-1-1 Asamizodai, Sagamihara-city,
Kanagawa 228-8520, Japan.
Incidence of minor complications and time lost
from normal activities after screening
or surveillance colonoscopy
Ko CW, Riffle S, Shapiro JA et al.
Gastrointest Endosc 2007;65:648–56.
The authors of this article investigated the incidence of
minor complications in patients undergoing surveillance
colonoscopy during screening for colorectal cancer.
Approximately one-third of patients reported minor
adverse events during the first week post-procedure, and
5.9% reported complications between day 7 and day 30
after colonoscopy. The duration of the procedure was the
only factor identified to be correlated with the risk of
minor adverse events.
Although the risk of bowel perforation and hemorrhage during
colonoscopy represent the major complications of the
procedure, which lead to surgery or death, the reasons for
post-procedural minor complications (such as fever, light
gastrointestinal bleeding, self-limited abdominal pain, shoulder
pain, bloating, nausea, rash, diarrhea, or constipation) remain
poorly understood and have not yet been quantified. The aims
of this prospective study was to determine whether there were
short-term (within 1 week) or long-term (within 1 month)
procedure-related minor complications among asymptomatic
patients undergoing complete colonoscopy for colorectal
cancer screening or surveillance.
From a total of 502 patients, 470 completed 7- and
30-day telephone interviews. The colonoscopic examination
25
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CLINICAL REVIEWS
was concluded to the cecum in 99% of subjects. In 36%
of patients, a gastroenterology trainee participated in
the procedure. Minor complications were reported in
33.8% during the first week (25.0% bloating, 10.5%
abdominal pain, 6.3% diarrhea, 4.0% nausea, 3.8% light
gastrointestinal bleeding, 1.9% shoulder pain, 1.9%
constipation, and 0.8% rash), and in 5.9% during the first
month (1.6% nausea, 1.6% light gastrointestinal bleeding,
1.4% constipation, 1.2% diarrhea, 1.2% abdominal pain,
0.8% fever, 0.6% bloating, 0.2% shoulder pain, and 0.2%
rash). Surprisingly, the presence of minor complications was
higher in women than in men, but was not influenced by
age, procedure indications, or colonoscopy findings. The
duration of the endoscopic procedure was the only factor
directly correlated with the development of mild adverse
events. This could be related to the large quantity of air
insufflations or increased external abdominal pressure
required to perform a difficult examination, for example as a
result of a complex colonic anatomy, poor colon preparation,
or presence of polyps or other abnormalities requiring
biopsies or polypectomy.
In conclusion, the results of this simple study on the
perception of an invasive examination from the patient point
of view show that screening or surveillance colonoscopy is
safe and well tolerated, although one-third of patients report
minor side effects. Moreover, a prior, extensive knowledge
of the possible presence of immediate or delayed minor
events should lead to a better acceptance and satisfaction by
patients who may undergo a recurring procedure as routine
surveillance screening. The colon preparation (and not the
colonoscopy itself) remains the greatest concern, in terms of
minor adverse events.
Address for reprints: CW Ko, Division of Gastroenterology, Box 356424,
University of Washington, Seattle, WA 98195, USA.
Respiratory symptoms in patients with
inflammatory bowel disease and the impact
of dietary salicylates
Sivagnanam P, Koutsoumpas A, Forbes A et al.
Dig Liver Dis 2007;39:232–9.
Respiratory complaints are a common extraintestinal
manifestation of IBD. In this study of a cohort of 69
ulcerative colitis (UC) and 73 Crohn’s disease patients,
respiratory symptoms were reported in >60% of subjects.
Asthma or possible undiagnosed asthma was the most
prevalent respiratory diagnosis in both UC and Crohn’s
disease (43%). Thus, it is suggested that clinicians closely
monitor respiratory symptoms in IBD patients.
26
Respiratory symptoms are a frequent extraintestinal
manifestation of IBD. They have been described in >50% of
IBD patients, although they are frequently underestimated
by clinicians. This may be because their onset is reported
before the manifestation of the intestinal disease (and thus
may not be correlated with the presymptomatic underlying
bowel disease), or because their presence can be subclinical
and frequently not described by patients. The increased
prevalence of both respiratory conditions and IBD reported
in the past half century shows a fascinatingly similar
epidemiological trend. The respiratory involvement in IBD
(which includes pleuritis, airway disease, interstitial lung
disease, necrobiotic nodules, pulmonary eosinophilia,
thromboembolic disease, vasculitis, or granulomatous lung
disease) has been postulated to be related to environmental
trigger factors such as smoking and pollution, or a leaky gut
in subjects with a genetically predisposed background. This
altered permeability, together with an altered gut flora,
can increase the passage of food antigens or bacteria into
the venous blood circulation, causing direct damage to
the lungs, which act as the primary filter. In addition,
5-aminosalicylates, a group of drugs used in the treatment
of IBD, have been implicated in interstitial lung disease and
eosinophilic pneumonia [1,2]. Salicylates are also present in
certain natural food (fruits and vegetables). A salicylateexclusion diet has been suggested to be therapeutic in IBD
patients with concurrent respiratory symptoms. For these
reasons, the authors of this study aimed to quantify the
prevalence of respiratory symptoms, pulmonary disease, and
salicylate intake in a cohort of 69 ulcerative colitis (UC) and
73 Crohn’s disease patients referred to their hospital.
Respiratory symptoms were reported in the 62% and 65%
of Crohn’s disease and UC patients, respectively. Asthma or
possible undiagnosed asthma was the prevalent respiratory
diagnosis in both UC and Crohn’s disease (43%), whereas
chronic bronchitis, emphysema, bronchiectasis, asbestosis, or
nasal symptoms were equally distributed in 12 of the overall
142 patients. Eleven of 14 Crohn’s disease patients (79%)
with extraintestinal manifestations reported defined
respiratory conditions, as did three of five UC patients
(60%). This study underlines the linkage between
respiratory phenomena and intestinal/extraintestinal features
of IBD. The weekly dietary salicylate intake was modest,
ranging from 1 mg to 120 mg in both Crohn’s disease and
UC patients, and did not correlate with the respiratory
status. Interestingly, a significant inverse correlation between
dietary salicylate intake and disease activity was found in UC
but not in Crohn’s disease, where the low number of
patients indicated only a slight numerical trend.
In conclusion, this study confirmed the frequent
association between respiratory symptoms and extraintestinal
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manifestations of IBD (the lung and the gastrointestinal system
originate from the primitive gut); therefore, it is suggested that
clinicians improve on the investigation of the respiratory status
of such patients. No concomitant respiratory symptom or
disease activity was reduced with a low intake of 5-ASAcontaining food, thus the salicylate-exclusion diet should not
be considered as a therapeutic tool. However, an improved
knowledge of the content of 5-ASA in food, together with its
active absorbable action is considered important, not only to
protect from potential allergies in these or other frequently
atopic patients, but also to introduce specific diets with the aim
of preventing IBD, colorectal cancer, or cardiovascular disease
in the normal or at-risk population.
1.
Moseley RH, Barwick KW, Dobuler Ket al. Sulfasalazine induced pulmonary disease.
Dig Dis Sci 1985;30:901–4.
2.
Tanigawa K, Sugiyama K, Matsuyama H et al. Mesalazine-induced eosinophilic
pneumonia. Respiration 1999;66:69–72.
Address for reprints: A Forbes, University College Hospital, 235 Euston
Road, London NW1 2BU, UK. Email: [email protected]
Effect of allopurinol on clinical outcomes in
inflammatory bowel disease nonresponders to
azathioprine or 6-mercaptopurine
Sparrow MP, Hande SA, Friedman S et al.
Clin Gastroenterol Hepatol 2007;5:209–14.
The 6-thioguanine (6-TGN) metabolite of the prodrugs
azathioprine (AZA) and 6-mercaptopurine (6-MP)
appears to be the active metabolite responsible for
efficacy in maintaining disease remission in IBD. Levels
of another metabolite, 6-methylmercaptopurine
(6-MMP), correlate with those of hepatotoxic enzymes.
Allopurinol has previously been shown to optimize
6-TGN production and minimize that of 6-MMP. In this
study, IBD patients classed as AZA/6-MP nonresponders
who received allopurinol were demonstrated to have
a significant increase in mean 6-TGN levels, a decrease
in 6-MMP levels, and significant reductions of disease
activity indices scores.
Azathioprine (AZA) and 6-mercaptopurine (6-MP) are both
inactive prodrugs that are metabolized via three main
enzymatic pathways to produce the nucleotide metabolites:
6-thioguanine (6-TGN), 6-methylmercaptopurine (6-MMP),
and 6-thiouracil (6-TU). 6-TGN appears to be the active
metabolite responsible for therapeutic efficacy in IBD. In
Crohn’s disease and in ulcerative colitis (UC), there is
evidence to support the use of AZA or 6-MP for maintaining
remission and as steroid-sparing agents; moreover, in
Crohn’s disease patients, these drugs have been
demonstrated to be effective for treatment of perianal
fistulas. It has previously been assumed that the
immunosuppressive actions of thiopurines are achieved by
incorporation of the metabolite 6-TGN into lymphocytic
DNA, thereby inhibiting cellular proliferation [1]. However,
an alternative mechanism of action has recently been
proposed [2]. This suggests that the 6-TGN triphosphate
(6-TGTP) – a metabolite of 6-TGN – actively stimulates
apoptosis of lamina propria T lymphocytes. The 6-MMP
metabolite of the 6-MP does not demonstrate therapeutic
efficacy, but its levels correlate with the risk of hepatotoxicity
in the form of elevation of hepatic transaminase enzyme
(aspartate transaminase and alanine transaminase) levels. For
these reasons, a desirable metabolic profile of thiopurine drug
metabolism would be one in which 6-TGN levels were
maximized, and 6-MMP production was minimal. It has been
shown that 6-TGN concentrations are inversely correlated
with functional activity of the thiopurine methyltransferase
(TPMT) enzyme, whereas elevations in 6-MMP are associated
with high functional TPMT activity.
The authors of this article recently demonstrated that in
IBD patients displaying a high TPMT activity metabolite
profile (6-MMP>6-TGN) the addition of low doses of
allopurinol, a xanthine oxidase inhibitor, can safely and
effectively optimize 6-TGN production and minimize that of
6-MMP [3]. In the present study, the clinical efficacy of the
addition of allopurinol in AZA/6-MP nonresponders (in
whom the metabolism of these drugs is preferentially
directed towards 6-MMP) was investigated. Twenty AZA/6MP nonresponders with high 6-MMP metabolite levels were
started on allopurinol 100 mg/day and the dose of AZA/6MP reduced to 25–50% of the original dose. A significant
increase in mean 6-TGN levels, a decrease in mean 6-MMP
levels, and statistically significant reductions of Harvey
Bradshaw Index scores in Crohn’s disease patients and of
Mayo index scores in UC patients, were observed.
Furthermore, addition of allopurinol enabled a reduction in
mean daily dosage of prednisone, from 18±4 mg to 2±1 mg,
and led to normalization of transaminase levels in all cases.
As 6-TGN levels are responsible for myelotoxicity, the
addition of allopurinol, enhancing 6-TGN levels, could cause
the development of leukopenia, which could be resolved
with thiopurine dose reduction. This side effect could also
be easily prevented by a close monitoring of white blood
cell counts.
1.
Lepage GA. Basic biochemical effects and mechanism of action of 6-thioguanine. Cancer
Res 1963;23:1202–6.
2.
Tiede I, Fritz G, Strand S et al. CD28-dependent Rac1 activation is the molecular target of
azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003;111:1133–45.
3.
Sparrow MP, Hande SA, Friedman S et al. Allopurinol safely and effectively optimizes
tioguanine metabolites in inflammatory bowel disease patients not responding to
azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005;22:441–6.
Address for reprints: M Sparrow, Section of Gastroenterology and
Nutrition, University of Chicago Medical Center, Chicago, IL, USA.
27
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CLINICAL REVIEWS
Narrow-band imaging compared with conventional
colonoscopy for the detection of dysplasia in
patients with longstanding ulcerative colitis
Dekker E, van den Broek FJ, Reitsma JB et al.
Endoscopy 2007;39:216–21.
These investigators compared the use of standard
colonoscopy with a narrow-band imaging (NBI) technique,
which enables better visualization of the intestinal mucosa,
for detection of dysplasia in patients with longstanding
ulcerative colitis. No difference in sensitivity was observed
between these techniques. Furthermore, targeted biopsies
using both NBI and standard colonoscopy failed to detect
one-third of patients with cancer, as identified during
random biopsies using standard colonoscopy.
Longstanding ulcerative colitis (UC) has been correlated with a
higher risk of colorectal cancer, compared with that observed in
the general population, with a cumulative incidence estimated
by Rutter et al. of 2.5% at 20 years, 8% at 30 years, and 11%
at 40 years [1]. Colonoscopic surveillance is recommended but
is difficult for several reasons, including issues of patient
compliance, the risk of missing lesions, and the presence of
macroscopically invisible lesions. Narrow-band imaging (NBI) is
a novel endoscopic procedure that facilitates an improved
investigation of mucosal characteristics. The application of an
optical filter to the light used for illumination enhances the
appearance of the surface of the intestinal mucosa; specifically,
the blue excitation light view has a minimal penetration depth
in the mucosa, which better highlights the intestinal surface and
vascular pattern. Moreover, NBI has been shown to be more
practical than chromoendoscopy, a labor-intensive technique
that involves staining the whole colon with dye spraying, which
inexorably prolongs endoscopic examination, thus reducing its
use in clinical practice.
The authors prospectively investigated 42 patients with
longstanding UC, with both standard white-light colonoscopy
and NBI randomly performed by different endoscopists (who
were blinded to the results of the first procedure) at an interval
of 3 weeks. Targeted biopsies on suspicious lesions were
collected using both procedures, whereas random biopsies to
exclude dysplasia were taken with standard colonoscopy only.
Targeted biopsies using NBI identified 52 suspicious lesions in
17 patients, while standard colonoscopy detected 28 suspicious
lesions in 13 of the same patients. Histological evaluation of
the biopsies identified a cancer in 11 patients; four of these
cancers were detected using both NBI and standard
colonoscopy, four with NBI only, and three with standard
colonoscopy alone. As a comparison with the targeted
biopsies, 1522 random biopsies using standard colonoscopy
revealed neoplasia in six patients. In one additional patient, the
28
random biopsy identified severe dysplasia in a suspicious area,
which has not been detected by targeted biopsy.
In conclusion, this first, prospective, randomized study
comparing NBI with standard colonoscopy did not identify a
difference in sensitivity between the two techniques.
Notwithstanding that NBI detected more false-positive lesions,
probably because of the use of a first-generation prototype
(the new NBI system is likely to have improved brightness and
resolution), targeted biopsies with both procedures failed to
detect approximately one-third of patients with cancer. For
this reason, the importance of random biopsies, even in
presence of more sensitive, novel techniques, was confirmed.
1.
Rutter MD, Saunders BP, Wilkinson KH et al. Thirty-year analysis of a colonoscopic
surveillance program for neoplasia in ulcerative colitis. Gastroenterology
2006;130:1030–8.
Address for reprints: E Dekker, Department of Gastroenterology and
Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Fecal calprotectin in first-degree relatives
of patients with ulcerative colitis
Montalto M, Curigliano V, Santoro L et al.
Fecal calprotectin (FC) has been proposed as a non-invasive
marker of disease activity in IBD, with a close correlation
between FC levels and disease activity reported in
ulcerative colitis (UC). The current authors determined that
FC levels were higher in first-degree relatives of UC patients
than in healthy control subjects or patients’ spouses. They
conclude that some first-degree relatives of patients with
UC may have subclinical mucosal inflammation, which
suggests a possible genetic component in UC.
Calprotectin is a neutrophil-derived protein that is an objective,
but non-specific, marker of intestinal inflammation. It is stable
in feces and fecal levels of the protein correlate with the
histological degree of inflammation as well as with the fecal
excretion of 111-indium-labeled leukocytes in IBD. Fecal
calprotectin (FC) has been proposed as a non-invasive marker
of disease activity in IBD. However, it should be noted that
there is closer correlation between FC levels and clinical disease
activity indices in ulcerative colitis (UC) than in Crohn’s disease.
FC is elevated in first-degree relatives of patients with
Crohn’s disease. This elevation is greater that that seen in
spouses, giving further support to the genetic predisposition of
the disease. In this investigation, Montalto et al. assessed
whether FC is elevated in first-degree relatives of patients with
UC – a condition in which the genetic contribution is thought
to be less than that found in Crohn’s disease. They examined
55 patients with UC, 167 first-degree relatives, 38 spouses,
and 150 healthy control subjects. FC was assessed by enzyme-
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GENETICS
linked immunosorbent assay and, in patients with UC, disease
activity was assessed according to the disease activity index.
FC levels were found to be higher in UC patients than in
all other groups. However, FC was also significantly higher in
first-degree relatives of patients than in healthy controls or
spouses (p=0.01), although there was no correction for
multiple comparisons. In addition, spouses had higher
concentrations than control subjects (p=0.01).
These results suggest that some first-degree relatives of
patients with UC may have subclinical mucosal
inflammation; however, the nature of this inflammation was
not defined in this study. These data suggest that genetic,
environmental, and gene–environment interactions are all
important in the pathogenesis of UC as well as Crohn’s
disease; results that raise more questions than answers.
Address for reprints: M Montalto, Istituto di Medicina Interna, Università
Cattolica del Sacro Cuore, Largo Gemelli, 8-00168 Rome, Italy.
Cytomegalovirus is frequently reactivated and
disappears without antiviral agents in ulcerative
colitis patients
Matsuoka K, Iwao Y, Mori T et al.
In order to determine the incidence of cytomegalovirus
(CMV) reactivation in patients with active ulcerative colitis
(UC), CMV-antigen and CMV-real-time quantitative
polymerase chain reaction (PCR) tests were undertaken by
the current investigators. CMV was found to be reactivated
in 25 of 48 CMV-immunoglobulin G-positive patients
during the study period. However, antigen levels and PCR
test values were low and none of the patients showed any
evidence of CMV infection on biopsy specimens.
In immunocompetent individuals, primary cytomegalovirus
(CMV) infections are generally mild; however, they are
frequently more serious in the immunocompromised patient.
CMV inclusion bodies are often identified, in varying numbers,
in patients admitted to hospital with flares of ulcerative colitis
(UC). This has led to considerable conjecture and debate
regarding the role of the virus in perpetuating the inflammatory
activity. It has been proposed that in patients with acute, severe
UC, CMV may contribute to worsening of disease, steroid
resistance, and even toxic megacolon. The natural history of
CMV infection in patients with active UC is not known.
Previously, assessing this issue has been problematic due to
methodological difficulties detecting the virus in biopsy, stool,
and blood specimens. The CMV antigen test and CMV
quantitative real-time polymerase chain reaction (PCR) test in
blood have emerged as sensitive assays of virus presence and
activity. The authors of this report used these two tests to assess
CMV at sequential timepoints in patients admitted with UC.
A total of 69 patients who were admitted to hospital with
moderately or severely active UC were enrolled in the study.
Those who were CMV-immunoglobulin G (IgG)- or CMVIgM-positive had CMV antigen and PCR test levels measured
every 2 weeks for 8 weeks. CMV-IgG was detected in
48 of the 69 (69.6%) patients. CMV was reactivated in 25 of
the 48 (52.1%) seropositive patients during the study period.
The CMV antigen and PCR values were low and none of the
patients displayed any evidence of CMV infection on biopsy
specimens. Gancyclovir was used in two patients but the
authors felt that rates of remission and colectomy did not
differ between CMV-positive and -negative patients. It is of
note that CMV disappeared without therapy in most of the
patients who had evidence of reactivation. CMV reactivation
was more frequent in patients treated with cyclosporine but
not significantly with other treatments.
The authors concluded that CMV is frequently reactivated
in patients with active UC. In many, it disappears without
antiviral therapy; thus, such therapies should not be necessary
for most UC patients with CMV reactivation provided that
CMV antigen values are low. Although these data offer
reassurance to the treating physician for most patients, there
are individuals in whom antiviral therapy does lead to clinical
improvement and careful consideration should be given to this
therapeutic option if viral antigen or PCR test values are high,
or if multiple inclusion bodies are seen in biopsy specimens.
Address for reprints: T Hibi, Division of Gastroenterology, Department
of Internal Medicine, School of Medicine, Keio University, 35 Shinamomachi, Shinjuku, Tokyo 160-8585, Japan.
GENETICS
Genetic variation in myosin IXB is associated with
ulcerative colitis
van Bodegraven AA, Curley CR, Hunt KA et al.
Genetic variation in the 3' region of the myosin IXB
(MYO9B) gene has been reported to be associated with
celiac disease. The current authors examined variations
of the MYO9B gene in three IBD patient cohorts. An
association was observed between five of eight tested
MYO9B single nucleotide polymorphisms and IBD (and
celiac disease) in all three cohorts. Thus, MYO9B genetic
variants appear to predispose to IBD.
Many of the recent advances in the genetics of IBD have
related to Crohn’s disease, and twin studies would indicate
29
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CLINICAL REVIEWS
that the genetic contribution to this condition is stronger than
that seen with ulcerative colitis (UC). The authors of this study
report a genetic variant that is strongly associated with UC.
Recently, genetic variation in the 3' region of the myosin
IXB (MYO9B) gene was reported to be associated with
celiac disease [1]. In a Dutch population with celiac disease,
this gene was identified by screening an area of linkage
on chromosome 19p13 with 291 single nucleotide
polymorphisms (SNPs). The area in 19p13 has also been
associated with IBD in two genome wide scans of 2000 and
2003, and has been termed IBD6 [2,3].
Overexpression of rat myosin IXB leads to actin-related
morphological changes in epithelial cells. MYO9B is most
strongly expressed in human leukocytes but is also detected in
intestinal epithelial cells. The mechanism by which this may
predispose to celiac disease (or perhaps to IBD) is unknown, but
variations in intestinal permeability have been hypothesized.
The authors examined variations of the MYO9B gene in a large
cohort of IBD patients from three distinct geographical areas.
Eight SNPs were typed across the region of interest in
1197 patients with Crohn’s disease, 1520 with UC, and
4440 controls from the UK, Canada, and Italy. These SNPs
were selected from those associated with celiac disease and
from a tagging approach, to effectively cover the region.
Genotyping was performed independently by each
institution using a combination of Taqman (Applied
Biosystems, Foster City, CA, USA) and Sequenom
(Sequenom, San Diego, CA, USA) sequencing techniques.
Association was observed between five of the tested
MYO9B SNPs and IBD in all three cohorts. From a
meta-analysis of the data, the most strongly associated
SNP was found to be rs1545620, with an odds ratio of
1.2 (p=1.9×10–6). The alleles demonstrating association with
IBD also showed association with celiac disease.
The authors concluded that MYO9B genetic variants
predispose to IBD. They note that the associated SNP,
rs1545620, is a non-synonymous variant leading to an amino
acid change (Ala1011Ser) in the third calmodulin-binding IQ
domain of MYO9B. It is also of note that this association is
considerably stronger with UC, although a weaker association
with Crohn’s disease is also observed. These data imply shared
causal mechanisms underlying intestinal inflammatory diseases.
1.
Monsuur AJ, de Bakker PI, Alizadeh BZ et al. Myosin IXB variant increases the risk of celiac
disease and points toward a primary intestinal barrier defect. Nat Genet 2005;37:1341–4.
2.
Rioux JD, Silverberg MS, Daly MJ et al. Genomewide search in Canadian families with
inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet
2000;66:1863–70.
3.
van Heel DA, Dechairo BM, Dawson G et al. The IBD6 Crohn’s disease locus demonstrates
complex interactions with CARD15 and IBD5 disease-associated variants. Hum Mol Genet
2003;12:2569–75.
Address for reprints: DA van Heel, Centre for Gastroenterology, Institute
of Cell and Molecular Science, Barts & The London, Queen Mary’s
School of Medicine & Dentistry, Turner Street, London, E1 2AD, UK.
30
TUCAN (CARD8) genetic variants
and inflammatory bowel disease
McGovern DP, Butler H, Ahmad T et al.
The current authors examined the role of tumor-upregulated CARD-containing antagonist of caspase nine
(TUCAN; CARD8) gene variants in IBD pathogenesis.
Analysis of 10 single nucleotide polymorphisms (SNPs)
across the gene in control subjects, Crohn’s disease
patients, and ulcerative colitis (UC) patients identified
one SNP associated with Crohn’s disease. Further
analyses are needed to confirm this finding.
The discovery of NOD2/CARD15, a landmark in complex
disease genetics, has catalyzed a surge in the efforts to find
new genetic determinants in IBD. McGovern and colleagues
examined the role of tumor-up-regulated CARD-containing
antagonist of caspase nine (TUCAN) in the Oxford
IBD cohort (Oxford, UK). TUCAN (also know as
CARD8/CARDINAL) is expressed in gut epithelium, may be
a negative regulator of nuclear factor-κB, and has a
regulatory role in apoptosis. The gene encoding TUCAN is
located beneath a peak of linkage identified on a genomewide scan performed in 2003, which showed peak logarithm
of odds scores in NOD2-negative, IBD5-positive patients
[1]. This suggests that TUCAN is an attractive positional and
functional candidate gene for IBD.
The current authors examined 10 single nucleotide
polymorphisms (SNPs) across the area of linkage in
365 control subjects, 372 patients with Crohn’s disease, and
373 patients with ulcerative colitis. They subsequently
constructed a predictive model using smoking status and
TUCAN, NOD2, IBD5, NOD1, and TNFSF15 genotypes.
A significant association between a single SNP in TUCAN
and Crohn’s disease was identified. This SNP changes a
cysteine residue to a stop codon at codon 10 (rs2043211).
The odds ratio (OR) for the association was 1.35 (p=0.0083)
with no correction for multiple comparisons. The association
was stronger in patients with non-colonic disease (OR 1.52)
and in Crohn’s disease patients who were negative for
NOD2 variants (OR 1.50). The prognostic model showed an
association between Crohn’s disease and an increasing
number of positive variables. Depending on the number
of variables selected, the model could provide either
good sensitivity or specificity, but not both together. The
provided data would make it difficult to extrapolate into
clinical practice.
The authors concluded that there was an association
between TUCAN and Crohn’s disease. It is of note that more
recent, larger studies have questioned this association [2,3].
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EPIDEMIOLOGY
1.
van Heel DA, Dechairo BM, Dawson G et al. The IBD6 Crohn’s disease locus demonstrates
complex interactions with CARD15 and IBD5 disease-associated variants. Hum Mol Genet
2003;12:2569–75.
2.
Franke A, Rosenstiel P, Balschun T et al.; IBSEN Study Group, Solberg C. No association
between the TUCAN (CARD8) Cys10Stop mutation and inflammatory bowel disease in a
large retrospective German and a clinically well-characterized Norwegian sample.
3.
Fisher SA, Mirza MM, Onnie CM et al. Combined evidence from three large British
Association studies rejects TUCAN/CARD8 as an IBD susceptibility gene. Gastroenterology
2007;132:2078–80.
Address for reprints: DPB McGovern, Wellcome Trust Centre for Human
Genetics, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
EPIDEMIOLOGY
Meta-analysis: cancer risk of low-grade dysplasia
in chronic ulcerative colitis
Thomas T, Abrams KA, Robinson RJ et al.
The aim of the current meta-analysis was to determine
the incidence of cancer and the relative risk of developing
cancer in patients with ulcerative colitis who had lowgrade dysplasia identified on surveillance. A significant,
nine-fold risk of developing cancer after a diagnosis of
low-grade dysplasia was derived from this analysis.
The authors of this report performed a meta-analysis of
20 studies of dysplasia surveillance in patients with ulcerative
colitis (UC). This analysis included 508 lesions identified as
having low-grade dysplasia in flat mucosa (n=477) or in a
dysplasia-associated lesion or mass (DALM; n=31). Most of
the subjects underwent continued surveillance with a mean of
4.3 colonoscopies per patient and an average 18 biopsies per
colonoscopy. Some studies did not include the total number of
UC patients involved and some did not include the average
number of colonoscopies performed on follow-up. There were
73 (14%) advanced lesions (cancer or high-grade dysplasia)
detected pre-operatively, which translates into 30 per 1000
patient-years duration and a nine-fold increased risk of
developing cancer (odds ratio 9.0, 95% confidence interval
4.0–20.5) and a 12-fold increase in the risk of developing any
advanced lesion if low-grade dysplasia is detected during
surveillance. Of the 31 cancers detected, 45% were Dukes
stages C or D. In an additional 98 cases, colectomy was
performed within 6 months of the initial diagnosis of lowgrade dysplasia. In 25 (26%) cases, cancer was found at
surgery, suggesting that this is the rate of having coexisting
cancer when low-grade dysplasia is found. For flat, low-grade
dysplasia only (excluding DALMs), the rate of concurrent
cancer was 22% and the progression to cancer was not
identified, whereas progression to an advanced lesion was
found in 15%. The number needed to colonoscope in order
to detect one cancer was eight over an average of
5.2 years. Using a meta-analysis regression, only the number
of biopsies taken per colonoscopy had a significant influence
on the incidence rates of advanced lesions (p=0.002) whereas
the duration of colitis prior to low-grade dysplasia diagnosis,
the number of pathologists reviewing histology, and the
number of surveillance colonoscopies performed per patient
did not influence the cancer incidence obtained. One problem
with meta-analyses of this type is the inclusion of studies
where modern reviews of past diagnoses of low-grade
dysplasia are not undertaken; hence, it is possible that these
data include case series in which many so-called low-grade
dysplasias may not have been low-grade dysplasia at all. In
other words, the nine-fold risk of developing cancer after a
diagnosis of low-grade dysplasia derived here may even be an
underestimate. In fact, there was a significant trend towards
an increased incidence of cancer and advanced lesions from
1987 to the present date (p=0.05), with cancer incidence
increasing by 13% per year of study.
Address for reprints: R Robinson, Digestive Diseases Centre, Leicester
General Hospital, Gwendolen Road, Leicester, LE4 5PW, UK.
Meta-analysis: mortality in Crohn’s disease
Canavan C, Abrams KR, Mayberry JF.
The aim of the authors of this meta-analysis was to
identify the standardized mortality ratio (SMR) for
Crohn’s disease. A total of 13 articles identified on the
Medline database were included. From these, the
estimate for standardized mortality ratio (SMR) was 1.52
(95% confidence interval 1.32–1.74). Thus, patients with
Crohn’s disease have an increased mortality risk,
compared with the general population.
Thirteen studies addressing mortality rates in Crohn’s disease
were combined in a meta-analysis. Eight of these showed an
increased mortality rate for Crohn’s disease compared with the
general population. The pooled estimate for standardized
mortality ratio (SMR) was 1.52 (95% confidence interval [CI]
1.32–1.74). Meta-regression analysis showed that the SMR has
decreased slightly over the past 30 years (p=0.08). Subanalysis
by country showed that a consistently higher SMR for Crohn’s
disease was reported from the UK and Scandinavia, compared
with other countries. Seven studies were community-based
(some of which were population-based), three were hospitalbased, two were from referral centers, and one was from the
population-based UK General Practice Research Database. Not
surprisingly, hospital-based and referral center-based studies
that would likely bias the analysis toward an increased SMR for
31
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CLINICAL REVIEWS
Crohn’s disease did in fact show a higher SMR (1.73, 95% CI
1.45–2.47). Nonetheless, community-based studies also had a
significantly increased SMR (1.48, 95% CI 1.28–1.7). Overall,
there was a 2.3% decrease in SMR per median year of
diagnosis (p=0.002). There was also a significant difference in
SMR for those diagnosed prior to 1970 compared with those
diagnosed after 1970, but both eras were associated with a
significantly increased SMR over that of the general population.
Furthermore, there was no significant difference in terms of
year of diagnosis when assessing just the studies where
diagnoses were made after 1970. A sensitivity analysis showed
that no single study changed the SMR to such an extent that
omitting it would change the combined SMR significantly.
While no conclusions on life expectancy can be drawn from this
study, the data are fairly consistent that patients with Crohn’s
disease have an increased mortality risk over the general
population. Whether this relates to smoking, disease-specific
factors, or treatment-related factors is unknown.
Address for reprints: C Canavan, Digestive Diseases Centre, Leicester
General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK.
PATHOGENESIS
Crohn’s disease, fatigue, and infliximab: is there a
role for cytokines in the pathogenesis of fatigue?
Minderhoud IM, Samsom M, Oldenburg B.
World J Gastroenterol 2007;13:2089–93.
The aim of this pilot study was to determine the role of
cytokines in fatigue in patients with Crohn’s disease. The
effects of infliximab infusion on fatigue and cytokine levels
were assessed. No correlation between the level of fatigue
and level of measured cytokines was found; however, both
the infliximab and placebo infusions reduced fatigue.
The cause of fatigue in Crohn’s disease may be multifactorial,
but there is a paucity of studies that explore this issue. Fourteen
patients with Crohn’s disease underwent infusion of placebo at
baseline and received infliximab at 2 weeks; subjects were
reassessed at 4 weeks from baseline. The Multidimensional
Fatigue Inventory was used to assess fatigue. Scores of this
Inventory range from 4–20, with higher scores reflecting
increased fatigue. With a score >13 reflecting fatigue, 86% of
subjects were classed as fatigued at baseline. After placebo
infusion, fatigue scores decreased by 3.5±1.1 points, which was
predominantly accounted for by the 33% of subjects who
responded to placebo. Placebo responders with reduced fatigue
had fatigue scores that returned to baseline 2 weeks later. After
infliximab infusion, fatigue scores decreased by 3.8±1.4 points,
32
and remained reduced for 14 days after the infusion. Fatigue
scores correlated with depression scores. There was no
correlation between the level of fatigue and level of measured
cytokines, including interleukin-6 (IL-6), IL-10, IL-18, and
tumor necrosis factor-α (TNF-α). IL-18 levels did decrease after
infliximab infusion, but there was no change in the circulating
levels of the other cytokines. The reduction of fatigue after
infliximab infusion is subject to a placebo effect; however,
infliximab’s effect is more sustained than that achieved by
placebo. It is not known why placebo can acutely reduce
fatigue, or what aspect of infliximab therapy reduces fatigue.
Address for reprints: B Oldenburg, Department of Gastroenterology,
F02.618, PO Box 85500, 3508 GA Utrecht, The Netherlands.
Increase in substance P precursor mRNA in
noninflamed small-bowel sections in patients
with Crohn’s disease
Michalski CW, Autschbach F, Selvaggi F et al.
Am J Surg 2007;193:476–81.
There is significant evidence to demonstrate the
involvement of the enteric nervous system in intestinal
inflammation; therefore, the authors of this study
investigated the role of the substance P (SP) pathway
in IBD. Analysis of transmural intestinal tissue samples
demonstrated upregulation of protein levels of the receptor
for SP (the neurokinin-1 receptor) in IBD samples – primarily
in ileal Crohn’s disease. Expression of preprotachykinin-A,
which encodes for SP, was significantly upregulated in
non-inflamed Crohn’s disease samples. This may indicate
an influence of inflamed tissue on healthy parts of
the intestine.
There is increasing evidence that the nervous system plays an
active role in the modulation of intestinal inflammation in IBD.
Tachykinins, which include the neuropeptide substance P (SP),
mediate their effects on target cells by activation of three
distinct G-protein-coupled receptors: the neurokinin-1, -2, and
-3 receptors (NK-1R, NK-2R, and NK-3R). Of these, the NK1R has been demonstrated to be crucial in the transmission of
the biological effects of SP. The activity of SP is limited by its
degradation and inactivation by neutral endopeptidase (NEP)
– an enzyme that is widely distributed in mammalian tissues.
There are conflicting data in the literature regarding the
neuro-inflammatory role of SP and its receptors in IBD, with
some reports demonstrating an increase, and others showing
a decrease in the SP immunoreactivity index in samples from
Crohn’s disease patients. Both a marked upregulation of NK1R mRNA levels and decreased SP receptor expression have
also been reported in ulcerative colitis (UC).
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PATHOGENESIS
The present authors analyzed 112 IBD and control
transmural intestinal tissue samples for concomitant
expression of NEP, SP, and NK-1R isoforms (NK-1R-L and
NK-1R-S), in addition to the expression of the
preprotachykinin-A (PPT-A) gene, which encodes for SP.
Analysis of different intestinal segments from Crohn’s disease
and UC samples (inflamed and non-inflamed small and large
bowel) revealed no significant differences in NK-1R-L and
NK-1R-S mRNA expression, although there was a tendency
towards overall lower NK-1R-S mRNA copy numbers.
Immunoblot analysis showed that NK-1R protein levels were
upregulated in the IBD samples, with a more pronounced
enhancement in cases of Crohn’s disease compared with UC.
NEP protein levels were similar in normal, Crohn’s disease,
and UC intestinal tissue. Interestingly, a significant
upregulation of PPT-A mRNA expression and a tendency
towards slightly increased NK-1R-L isoform expression was
found in non-inflamed Crohn’s disease tissue samples.
In conclusion, the authors suggest a contribution of SP
and its NK-1R isoforms, in the local inflammatory reaction in
IBD, predominantly in ileal Crohn’s disease. They also
speculate that the significant upregulation of PPT-A mRNA
in the non-inflamed ileum suggests that inflamed intestine
has an influence on healthy tissue.
Address for reprints: H Friess, Department of General Surgery,
University of Heidelberg, Im Neuenheimer Feld 110, D-69120
Heidelberg, Germany. Email: [email protected]
Regulation of oxidant-induced intestinal
permeability by metalloprotease-dependent
epidermal growth factor receptor signaling
Forsyth CB, Banan A, Farhadi A et al.
J Pharmacol Exp Ther 2007;321:84–97.
The aim of the present authors was to address the role of
oxidant stress in hyperpermeability of intestinal epithelium,
as observed in IBD. Specifically, they aimed to characterize
in vitro the putative role of the epidermal growth factor
receptor (EGFR) in mediating oxidant-induced gut
epithelium hyperpermeability. Using specific inhibitors,
oxidant-induced epithelial barrier hyperpermeability was
demonstrated to be partly dependent on tumor necrosis
factor-converting enzyme-mediated transactivation of
EGFR signaling. The authors conclude that their study
highlights potential novel therapeutic targets in IBD.
Two key determinants of IBD pathogenesis are the
hyperpermeability of the gut epithelial barrier, which allows
penetration of luminal bacterial products into the mucosa,
and an abnormal immune response to these products. The
major permeability pathway in IBD is considered to be the
paracellular route, which is regulated by tight junctions
between the intestinal epithelial cells. Oxidant-induced
stress and pro-inflammatory cytokines such as tumor
necrosis factor-α (TNF-α) and interferon-γ are considered to
be critical mediators of intestinal hyperpermeability in IBD.
The goal of this well-designed study was to identify the
mechanisms of oxidant-induced intestinal hyperpermeability,
and to characterize the specific role of oxidant stressmediated transactivation of the epidermal growth factor
receptor (EGFR). The authors used in vitro models of
intestinal epithelium (Caco-2 human colonic epithelial cells)
for their analysis. Cells were grown to confluence on tissue
culture plate inserts for permeability and signaling studies
and on glass coverslips for microscopy studies. Permeability
was measured as apical-to-basolateral flux of a fluorescent
marker; Western blotting and reverse transcriptasepolymerase chain reaction techniques were employed for
analyses of receptor signaling.
Using specific pharmacological inhibitors and blocking
antibodies, the authors found oxidant-induced epithelial
barrier hyperpermeability to be partly dependent on TNFconverting enzyme (TACE)-mediated transactivation of
EGFR signaling, which is convincing evidence to support an
association between oxidants and TNF-α in mediating
intestinal barrier disruption.
The authors propose a novel intestinal hyperpermeability model: the process starts with the presence of
oxidant stress, which has previously been demonstrated
(and confirmed here) to activate the metalloprotease TACE.
Activation of TACE results in its translocation to cell–cell
contact zones where it cleaves the precursor form of
transforming growth factor-α (TGF-α) to a soluble form.
This soluble form of TGF-α is a ligand for the EGFR.
Subsequent to ligand binding, the receptor becomes
phosphorylated and activates downstream mitogenactivated protein kinases (specifically, extracellular signalregulated kinases 1/2 [ERK1/2]). Activated ERK1/2
then phosphorylates cellular targets, increasing intestinal
permeability through pathways that have yet to
be characterized.
These data may have a significant impact on the
understanding of IBD pathogenesis, and could help to identify
potential targets for the development of new therapies.
Address for reprints: CB Forsyth, Rush University Medical Center,
Department of Internal Medicine, Section of Gastroenterology,
1725 West Harrison Street, Suite 206, Chicago, IL 60612, USA.
33
MEETING REPORT
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40th Annual Meeting of the European
Society for Paediatric Gastroenterology
Hepatology and Nutrition (ESPGHAN)
Barcelona, Spain, 9–12 May, 2007
Johan Van Limbergen and Richard K Russell
Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children,
Edinburgh, UK
The European Society for Paediatric Gastroenterology
Hepatology and Nutrition (ESPGHAN) meeting is the annual
meeting of European pediatric gastroenterologists but
continues to attract a global audience. This year’s meeting
was held in Barcelona, Spain, which was hosting the Spanish
Grand prix concurrently with ESPGHAN. IBD was, as always,
well represented throughout the meeting.
IBD registries
Data demonstrating increasing IBD incidence rates have
led many groups to establish databases/registries in their own
populations [1]. Jakobsen and colleagues (Hvidovre Hospital,
Copenhagen, Denmark) presented data from a population of
98 children diagnosed with IBD at age <15 years during
1998–2004 in the east of Denmark. This area represents
approximately 60% of the total Danish population. The
median age at diagnosis was 9.8 years. The investigators
noted that the incidence of childhood Crohn’s disease
increased throughout the study. The incidence of ulcerative
colitis (UC), which has stabilized in most populations, also
continued to rise. The incidence of IBD during the last 2 years
of the study was 6.2 cases per 100 000 population.
Katarzyna Karolewska-Bochenek (University of Warsaw,
Warsaw, Poland) presented data on pediatric IBD patients
from Poland, which were collected from 2002–2004.
Notably, this was a national, prospective study. The median
age at diagnosis was 11.7 years. In contrast to most other
pediatric IBD study populations, a much lower incidence of
IBD – 2.7 cases per 100 000 – was found; furthermore,
there was a predominance of UC with an incidence rate
double that of Crohn’s disease.
Data from an analysis of the CEDATA registry (a combined
IBD population in Austria and Germany) were presented. This
study collected data on 2289 pediatric patients, 648 of whom
represented new diagnoses of IBD during the study period of
2004–2006. Patients with UC had a shorter time to diagnosis
34
(approximately 4 months compared with 8 months in Crohn’s
disease patients), and had significantly lower C-reactive
protein levels than patients with Crohn’s disease. The most
remarkable fact about this study was the extremely low
number of Crohn’s disease patients in whom enteral feeding
was used, at just 4%.
Dominique Turck (Lille University Children’s Hospital, Lille,
France) presented data from the well-established EPIMAD
registry, collected from the North of France (1988–2002) on
the natural history of UC diagnosed in childhood. A total
of 151 cases of childhood-onset UC were identified, and
follow-up data were available on 113 subjects. The study
demonstrated the usual high rates of pancolitis in childhood
UC (60% at follow-up). Interesting clinical data were
presented demonstrating that 68% of patients required
steroids within the first year after diagnosis, 26% needed
immunosuppression during the first 2 years, and cumulative
colectomy rates were 9%, 15%, and 20% at 1, 3, and 5 years
post-diagnosis, respectively. In a sister presentation from the
same registry, Gwenola Vernier-Massouille (Hôpital Huriez,
Lille, France) demonstrated in 477 pediatric Crohn’s disease
patients that more than one-third would require surgery at
5 years post-diagnosis. This risk was reduced in patients
treated with 5-aminosalicylates, azathioprine, or infliximab.
Data from the current authors’ own registry, based on
the comparative analysis of 1234 adults and 353 children
with IBD, demonstrated that children with Crohn’s disease
were more likely to be male, have less isolated ileal and
colonic disease, have more upper tract disease, and less
complicated disease at diagnosis using the Montreal
classification [2]. Children with UC were more likely to have
extensive disease at diagnosis.
Genetics
The genome-wide association study reported by Duerr et al.
in 2006, which implicated variants of the IL23R gene in
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ESPGHAN 2007
conferring protection against Crohn’s disease, has led
to several pediatric replication studies [3]. At this meeting,
the present authors presented data from the Scottish
pediatric population that analyzed the contribution of the
Arg381Gln allele in 358 patients with IBD who were
diagnosed at <17 years of age. The results demonstrated
that the prevalence of this mutation in children with IBD
differed significantly from healthy controls (5.9% vs.
11.1%; p=0.01).
Arie Levine (Tel Aviv University, Tel Aviv, Israel) presented
data on the same allele in children and adults from Israel (a
total of 381 patients, of whom, 143 were pediatric). These
data replicated the Scottish data, with a lower carriage rate
in Crohn’s disease patients compared with healthy controls
(4.3% vs. 13.6%; p=0.003). However, no differences were
noted in carriage rates when comparing the adult and
pediatric Crohn’s disease populations.
In a second presentation, Dr Levine presented data on
721 pediatric Crohn’s disease patients from three different
populations (USA, Israel, and Italy) demonstrating that the
isolated, colonic form of Crohn’s disease is found in patients
who carry normal (wild-type) copies of the NOD2/CARD15
Crohn’s disease susceptibility gene. This suggests that the
“colonic” phenotype, which has been so well described in
young children [4], may be genetically determined.
However, this study did not identify the gene or genes that
may be involved.
Treatment
Enteral nutrition
A 10-year, single-center experience with enteral nutrition to
induce remission in moderate-to-severe Crohn’s disease was
described by Kjaergaard Nielsen and colleagues (Hvidovre
Hospital). By 30 days of treatment, 63% of Crohn’s disease
patients (22/35) achieved clinical remission. Following
completion of 4 weeks of enteral nutrition, 50% remained in
remission at 3 months.
Rita Shergill-Bonner and colleagues (Royal Free
Hospital, London, UK) presented their experience with
food reintroduction after exclusive enteral nutrition in
children presenting with newly diagnosed Crohn’s disease.
Although 10 of 102 children had a documented reaction
to a specific food item, only two children remained
intolerant to these items after food reintroduction. The
investigators concluded that gradual reintroduction over
4 weeks in order to identify specific food intolerances is
not necessary, and that specific foods are only rarely
responsible for symptoms in children with Crohn’s disease.
Thus, they suggested that a shorter period of food-group
reintroduction over 1–2 weeks after exclusive enteral
nutrition may be adequate.
Victor Manuel Navas (Materno-Infantil Hospital, Malaga,
Spain) presented pilot data on fecal calprotectin levels after
successfully inducing disease remission in children with
Crohn’s disease using enteral nutrition (Modulen®, Nestle
Clinical Nutrition, Glendale, CA, USA). Although 12 of
14 children had a significant reduction in Pediatric
Crohn’s disease Activity Index (PCDAI) score by week 4 and
week 8 (PCDAI ≤15), fecal calprotectin remained elevated
(>125 μg/g) in all children.
Infliximab
Frank Ruemmele (Necker Enfants Malades, Paris, France)
presented data on sustained remission after stopping
infliximab in a cohort of 42 children with Crohn’s disease,
using a combined retrospective/prospective analysis. After
three infliximab infusions, 35 of 42 children (83%) were in
full remission. Twenty-three of 35 responders (66%)
developed infliximab dependency, as defined by the need to
continue or repeat (n=13), or increase infliximab doses
(n=10). Mucosal healing or marked improvement was seen
in 10 of 13 children at follow-up endoscopy. Nevertheless,
relapses occurred within 6 months after stopping infliximab
in most of these patients.
Lissy De Ridder (VU Medical Center, Amsterdam, The
Netherlands) reported a similar experience with infliximab
dependency in The Netherlands, in a retrospective study
describing the clinical experience with infliximab in nine
Dutch pediatric centers from 1992–2006. A clinical response
to infliximab was observed in 75% of patients that received
the agent (n=62). However, 60% of this cohort was
dependent on repeat infliximab infusions. There was no
difference in response between early (within 1–2 years of
diagnosis) and late starting of infliximab therapy, in contrast
with earlier reports from Kugathasan et al. [5].
In the Question & Answer sessions of both these
studies, concerns regarding the long-term safety of
infliximab maintenance therapy were raised. Over the
last year, the reports of hepatosplenic γδ-T cell
lymphoma in children treated with infliximab and
6-mercaptopurine/azathioprine have led to much debate at
international meetings regarding the concomitant use
of immunomodulators and infliximab [6]. During this
ESPGHAN meeting, a symposium entitled “Young patients,
Big considerations: REACHing new heights in pediatric
Crohn’s disease” was held in order to discuss the latest
evidence on this issue. In spite of its early morning slot, this
session was one of the best attended of the whole meeting.
Firstly, Gigi Veereman-Wauters (Queen Paola Children’s
Hospital, Antwerp, Belgium) discussed the findings of the
REACH (A Randomized, Multicenter, Open-label Study to
Evaluate the Safety and Efficacy of Anti-TNF Monoclonal
35
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JOHAN VAN LIMBERGEN AND RICHARD K RUSSELL
Antibody Infliximab in Pediatric Subjects with Moderate to
Severe Crohn’s Disease) study, which was published recently
in the Gastroenterology journal [7]. This trial evaluated the
efficacy of infliximab in inducing remission of moderate-tosevere pediatric Crohn’s disease, and maintaining remission in
infliximab responders. Concomitant therapy with an
immunomodulator was required for inclusion in the trial. The
main conclusions of REACH were that pediatric patients
responding to an induction regimen of infliximab were more
likely to achieve a clinical response and be in remission at
week 54 without dose adjustment when their maintenance
therapy was given every 8 weeks, rather than every 12
weeks. Allowing for dose intensification in the case of relapse,
remission rates but not response rates at week 54 were
superior with every 8-week dosing compared with every 12week dosing.
Following this overview, Anne Griffiths (Sick Kids
Hospital, Toronto, ON, Canada) provided a comprehensive
overview of the different strategies to optimize infliximab
treatment, taking into account the latest safety data and
recent reports from our colleagues that work with adult
patients on infliximab efficacy relative to concomitant use of
an immunomodulator. Salvatore Cucchiara (University of
Rome, Rome, Italy) then summarized the available evidence
and hypotheses on how early infliximab treatment could
change the course of disease. During the panel discussion,
both the management of loss of response to infliximab and
long-term safety concerns were addressed. Differences in
practice between Europe and North America regarding the
withdrawal of immunomodulator therapy while continuing
infliximab were debated.
36
The complexity of the question of prolonged
immunosuppressive therapy was further illustrated by a case
report presented at the meeting. Klaus-Michael Keller
(Deutsche Klinik für Diagnostik, Wiesbaden, Germany)
described the first case of a 15-year-old boy, diagnosed at
26 months with indeterminate colitis (later changed to UC),
who died from a disseminated T cell lymphoma following
9 years of azathioprine therapy. The development of this
lymphoma has been described in post-transplant patients
receiving azathioprine, but this is the first reported case in
a pediatric IBD patient.
Acknowledgements
Johan Van Limbergen is funded by a Research Training Fellowship from
Action Medical Research, The Gay-Ramsay-Steel-Maitland or Stafford
Trust, and the Hazel M Wood Charitable Trust.
Disclosures
The authors have no relevant financial interests to disclose.
References
1.
Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence,
and environmental influences. Gastroenterology 2004;126:1504–17.
2.
Silverberg MS, Satsangi J, Ahmad T et al. Toward an integrated clinical, molecular and
serological classification of inflammatory bowel disease: report of a Working Party of the
2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005;19:5–36A.
3.
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.
4.
Heyman MB, Kirschner BS, Gold BD et al. Children with early-onset inflammatory bowel
disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 2005;146:35–40.
5.
Kugathasan S, Werlin SL, Martinez A et al. Prolonged duration of response to infliximab in
early but not late pediatric Crohn’s disease. Am J Gastroenterol 2000;95:3189–94.
6.
Mackey AC, Green L, Liang LC et al. Hepatosplenic T cell lymphoma associated with
infliximab use in young patients treated for inflammatory bowel disease. J Pediatr
Gastroenterol Nutr 2007;44:265–7.
7.
Hyams J, Crandall W, Kugathasan S et al. Induction and maintenance infliximab therapy
for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology
2007;132:863–73.
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Washington, DC, USA, 20–23 May 2007
Fernando Velayos, MD
University of California San Francisco, San Francisco, CA, USA
The annual Digestive Diseases Week (DDW) meeting for
2007 was held in Washington, DC, USA, from May 20–23.
A record number were present this year, with close to
17 000 attendees. Over 1500 abstracts related to IBD were
presented. Any attempt to condense within a brief summary
the wide variety of research presented over the 4-day
meeting would be challenging. Therefore, this report seeks
to provide a representative overview of some of the most
important IBD-related clinical research presented this year in
the areas of IBD therapeutics, novel therapies, and finally
genetic, serological, and clinical predictors of disease.
IBD therapeutics
Biologics
Biological agents are antibodies engineered to attack specific
components of the inflammatory cascade. Pivotal
randomized controlled trials presented at previous DDW
meetings have demonstrated efficacy for four biologics:
infliximab, adalimumab, certolizumab, and natalizumab. The
first three compounds are monoclonal antibodies that inhibit
the potent inflammatory cytokine, tumor necrosis factor-α
(TNF-α), while natalizumab is a monoclonal antibody that
targets the leukocyte adhesion molecule, α4 integrin.
Infliximab and adalimumab have been approved by the US
Food and Drug Administration (FDA) for the treatment of
mild-to-moderate Crohn’s disease, while certolizumab and
natalizumab are undergoing regulatory review. Infliximab
has also been approved for the treatment of ulcerative
colitis (UC).
At this year’s meeting, several important post hoc analyses
of these pivotal trials, as well as investigator-initiated clinical
trials, sought to address as yet unanswered questions, such as
whether introduction of biologics earlier in the disease course
of IBD improves outcomes and whether concomitant
immunomodulators are necessary for maintaining remission in
patients receiving biologics. With regard to the first question,
Stefan Schreiber (Christian Albrechts University, Kiel,
Germany) and colleagues presented several post hoc analyses
of pivotal randomized trials showing that in all but one,
treatment with biologics earlier in the disease course of
Crohn’s disease improved response. In the CHARM (Crohn’s
Trial of the Fully Human Antibody Adalimumab for Remission
Maintenance) study, 52% of patients who had disease of <2
years were in remission at week 56, compared with 35% who
had 2–5 years of disease, and 33% who had >5 years of
disease. In the PRECISE 2 (Pegylated Antibody Fragment
Evaluation in Crohn’s Disease: Safety and Efficacy) study,
61.5% of patients treated with certolizumab who had <2
years of disease were in remission at week 26, compared with
47.9% in all treated patients. In the ENCORE (Efficacy of
Natalizumab in Crohn’s Disease Response and Remission)
study, 52% of patients treated with natalizumab who had <3
years of disease were in remission at week 12 compared with
38% in the entire treated population. In contrast to these
positive studies, 57% of patients who had <3 years of disease
and received natalizumab in the ENACT-2 (Evaluation of
Natalizumab As Continuous Therapy-2) study were in
remission at 12 months compared with 55% in the overall
treated population. Taken together, these data are consistent
with the hypothesis that earlier introduction of biologics may
improve patient outcomes, although clearly this hypothesis
needs to be more rigorously and formally tested in dedicated
clinical trials.
With regard to the second question, several studies
presented this year examined whether concomitant
immunomodulators improve clinical outcomes in patients
receiving biological agents. This question has become
particularly pertinent in light of recently reported rare but
fatal cases of hepatosplenic T cell lymphoma in patients
receiving both medications. Gary Lichtenstein (University of
Pennsylvania, Philadelphia, PA, USA) and colleagues
analyzed four clinical trials for infliximab, ACCENT I (A
Crohn’s Disease Clinical Trial Evaluating Infliximab in a New
Long-term Treatment Regimen I), ACCENT II, ACT I (Active
Ulcerative Colitis Trial I) and ACT II, and found concomitant
immunomodulators use did not appreciably influence
clinical outcomes. As examples, 34% of patients receiving
concomitant immunomodulators in ACT I were in remission
37
MEETING REPORT
Digestive Diseases Week 2007
(DDW 2007)
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FERNANDO VELAYOS
at week 54 compared with 36% of patients who were not
on immunomodulators. In ACCENT I, 37% of patients
receiving concomitant immunomodulators were in remission
compared with 32% without. These post hoc results are
similar to those found in a prospective trial, the IMID
(Infliximab Maintenance Immunosuppressive Discontinuation)
trial, presented by Gert Van Assche (University of Leuven
Hospitals, Leuven, Belgium) and colleagues. In this trial, 80
Crohn’s patients who were in clinical remission on both
infliximab and an immunomodulator were randomized to
either continue or interrupt their immunomodulator after 6
months of infliximab therapy. In the 41 patients undergoing
ileocolonoscopy at 2 years, 61% of patients who continued
immunomodulator therapy were in remission compared with
67% of control subjects. While both studies support the
notion that concomitant immunosuppression does not
impact the 1–2 year outcome of maintenance infliximab in
Crohn’s disease, the longer term outcome remains unknown.
Immunomodulators
Patients with Crohn’s disease who undergo ileocolic resection
are known to be at a significantly elevated risk of disease
recurrence. This year, several presentations addressed whether
immunomodulators, particularly azathioprine, could prevent
endoscopic recurrence and a second surgery. In a retrospective
study, Pavol Papay and colleagues (Medical University of
Vienna, Vienna, Austria) identified 377 patients with Crohn’s
disease who underwent a first operation; 40% of these patients
(n=123) underwent a second surgery within 10 years. In a
multivariate model, use of azathioprine or 6-mercaptopurine
therapy for ≥3 months after the initial surgery reduced the odds
of a second surgery by one-third, suggesting that azathioprine
is effective for preventing a second surgery. In a prospective
clinical trial, Geert D’Haens (University of Leuven) and
colleagues treated all patients with Crohn’s disease who were at
high risk of developing postoperative recurrence (age <40
years, more than one intestinal surgery, use of steroids at
surgery) with metronidazole (750 mg/day) for 3 months
immediately after surgery and randomized patients to receive
azathioprine or placebo. They found that at 12 months, severe
endoscopic recurrence was lower in the azathioprine-treated
group than in the placebo group (44% vs. 69%; p<0.05), again
suggesting that azathioprine is beneficial in maintaining
surgically induced remission.
5-Aminosalicylates
5-Aminosalicylates (5-ASAs) are the cornerstone of therapy
for mild-to-moderate UC. Several studies presented at DDW
evaluated whether less frequent dosing was as effective as
more frequent dosing for the induction and maintenance of
remission in UC. Using Salofalk® (Axcan Pharma, Mont-
38
Saint-Hilaire, QC, Canada), an oral mesalamine formulation
coated with a Eudagrit-L polymer, Wolfgang Kruis
(University of Cologne, Cologne, Germany) and colleagues
randomized 381 patients with active UC to receive either
once daily 3 g mesalamine (Salofalk) or 1 g mesalamine
granules three times daily for 8 weeks. After 8 weeks, both
groups were equivalent with regard to the primary endpoint
of clinical remission (79.1% daily mesalamine vs. 75.7%
three times per day mesalamine). Using a different
formulation, MMX® (Multi-Matrix System)-mesalamine
(Shire Pharmaceuticals, Wayne, PA, USA), which contains a
gastro-resistant, pH-dependent coating with hydrophilic and
lipophilic matrices, Michael Kamm (St Mark’s Hospital,
London, UK) and colleagues randomized 362 UC patients
in remission to receive 12 months of MMX-mesalamine at
either 2.4 g daily or 1.2 g twice daily. In this open-label
study, both groups were equivalent with regard to rates of
endoscopic and clinical remission (67.8% once-daily vs.
72.3% twice daily).
Both of these studies highlight the efficacy of 5-ASA as a
cornerstone therapy in UC and reflect current attempts to
ensure efficacy while improving patient adherence through
less frequent dosing.
Investigational therapies
This year, several promising investigational and novel
therapies for Crohn’s disease and UC were presented at
DDW that expand not only on the molecular targets being
tested, but also the mode of delivery.
Crohn’s disease
CNTO 1275
CNTO 1275 is a fully human monoclonal antibody targeting
the common p40 subunit of interleukin-12 (IL-12) and
IL-23. In a 54-week, randomized Phase IIa trial, William
Sandborn (Mayo Clinic, Rochester, MN, USA) and
colleagues assessed the safety and efficacy of a single
intravenous infusion of CNTO 1275 compared with four
subcutaneous injections. At week 8, 49% of patients
receiving CNTO 1275 were in clinical response compared
with 39.6% of those who received placebo (p=0.34).
Among patients with prior infliximab experience, 59.1%
receiving CNTO 1275 were in response compared with
25.9% receiving placebo (p=0.02). The authors concluded
that short-term treatment with CNTO 1275 was well
tolerated and showed a beneficial effect in the infliximabexperienced patients.
CCX282-B
Unlike other investigational therapies for Crohn’s disease,
which are administered intravenously or subcutaneously,
2/10/07
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DDW 2007
CCX282-B is an orally administered antagonist of the
chemokine receptor, CCR9, which is expressed by mucosahoming intestinal leukocytes. Satish Keshav (Royal Free
and University College London Medical School, London, UK)
and colleagues tested the safety and efficacy of CCX282-B
in 71 patients with mild-to-moderate Crohn’s disease.
Patients were randomized to receive a daily capsule of
CCX282-B for 28 days or placebo. A total of 49% of
patients treated with CCX282-B had a 70-point reduction in
their Crohn’s disease activity index, which was similar to
that seen in patients who received placebo (45%; p=not
significant). In a subgroup analysis consisting of patients
with more active disease, there was a trend toward a greater
improvement (58% vs. 31% in patients receiving placebo).
Although a trend for benefit was observed only on subgroup
analysis, this study provides encouraging data to suggest
that there may be benefit to this oral biologic for the
treatment of Crohn’s disease.
Visilizumab
Visilizumab, a humanized anti-CD3 monoclonal antibody,
has been investigated in Phase II/III clinical trials for severe
UC that is resistant to intravenous steroids. This year, Daan
Hommes (University of Leiden, Leiden, The Netherlands)
and colleagues presented open-label, Phase I data
describing its use in patients with moderate-to-severe nonfistulizing Crohn’s disease. Patients were administered an
intravenous bolus of visilizumab (10 μg/kg) on two
consecutive days. At day 59, a response was observed
in 72% of patients, and remission in 33%. As expected,
most patients experienced mild-to-moderate cytokine
release. This study adds to a growing list of important
inflammatory targets currently under evaluation for
Crohn’s disease.
It should be noted, however, that since this year’s DDW,
visilizumab has been withdrawn from a trial in steriodresistant, severe UC, due to complications.
Extracorporeal photoimmune therapy
Data for another unique approach to Crohn’s disease
therapy, extracorporeal photoimmune therapy (ECP), was
presented at DDW. ECP involves treatment of peripheral
blood leukocytes with 8-methoxypsoralen and ultraviolet
A light to induce apoptosis. After this process, these
autologous apoptotic leukocytes are re-infused back into the
patient. Maria Abreu (Mount Sinai School of Medicine, New
York, NY, USA) and colleagues evaluated the safety and
efficacy of ECP in a multicenter, open-label study of 28
patients with moderate Crohn’s disease. Patients received
twice weekly ECP treatments for 4 weeks, followed by twice
weekly treatment every other week for the subsequent 6
weeks. At week 6, 50% of patients responded to ECP and
25% were in remission. Half of the patients who were
refractory or intolerant to anti-TNF agents responded to this
therapy. Two adverse events – health deterioration and
anemia – were observed. Again, these preliminary data
appear promising, leading the authors to recommend a
randomized trial of ECP.
Ulcerative colitis
Rosiglitazone
Thiazolidinedione ligands for the gamma subtype of
peroxisome proliferator-activated receptors (PPARγ), which
are widely used to treat type 2 diabetes mellitus, have
been proposed to have anti-inflammatory properties in the
colon. However, their efficacy in humans with active UC
has not previously been tested. To this end, James Lewis
(University of Pennsylvania, Philadelphia, PA, USA) and
colleagues randomized 105 patients with mild-to-moderate
UC refractory or intolerant to 5-ASAs to receive 12 weeks
of either 4 mg twice daily rosigliatzone or placebo. At
12 weeks, 44% of patients treated with rosiglitazone and
23% who received placebo had achieved a clinical response
(p=0.03). The main adverse effect of rosiglitazone was
lower extremity swelling, which is a known side effect of this
class of medications. Unfortunately, concurrent with the
presentation of these data at DDW, a meta-analysis
was published in the New England Journal of Medicine
that linked rosiglitazone with a 43% increased risk of
myocardial infarction in diabetes patients [1], prompting
a review of this drug by the US FDA. Should short- and
long-term safety concerns be adequately addressed, this
study is important as rosiglitazone could provide a novel
second line therapy for patients refractory to or intolerant
of 5-ASAs.
MMX budesonide
Ileal-release budesonide is currently approved for treatment
of mild, ileocolic Crohn’s disease, as it has preferential
release in the right-sided colon. Using MMX technology,
Geert D’Haens (University Hospitals Leuven) and colleagues
reported the efficacy and safety of MMX-budesonide
(Cosmo Technologies Ltd., Ireland) in patients with UC
limited to the left colon. A total of 36 patients with
moderately active, left-sided UC were treated with either
9 mg of MMX-budesonide for 8 weeks, or placebo for
4 weeks followed by MMX-budesonide for 4 weeks.
Though not significant, there were trends toward clinical
improvement in the MMX-budesonide group compared
with the “placebo” group (47% vs. 33%). Based on these
encouraging findings, the authors recommended a larger,
controlled trial for this novel formulation of budesonide.
39
2/10/07
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FERNANDO VELAYOS
Genetic, serological, and clinical predictors
of disease severity
The diverse clinical phenotypes of IBD appear to be
influenced by a variety of genetic, immune, and clinical
factors. There is interest in having the ability to predict
which patients are at risk for developing complicated IBD, as
these patients are most likely to benefit from early and
aggressive medical therapy. Several studies presented this
year reflect the genetic, serological, and clinical approaches
for determining those who are at high risk for developing
complicated IBD phenotype. A few of the important studies
are presented here.
Liesbet Henckaerts (University Hospital Gasthuisberg,
Leuven, Belgium) and colleagues genotyped a cohort of
505 patients with Crohn’s disease for NOD2/CARD15
variants, which act as an intracellular receptor for bacterial
components in monocytes, and, in turn, lead to activation of
the inflammatory response. Using the Kaplan–Meier
method, the authors observed a stepwise shortening of the
surgery-free interval with increasing number of CARD15
variants. Based on these results, the authors suggested that
genotyping for CARD15 at the time of diagnosis might be
useful for identifying those patients who might benefit from
early introduction of aggressive treatment.
Marla Dubinsky (Cedars-Sinai Medical Center, Los Angeles,
CA, USA) and colleagues tested the sera of 797 prospectively
followed pediatric Crohn’s disease patients with the aim of
examining the associations between the serological immune
responses to microbial antigens (anti-Cbir1 [flagellin], antiouter membrane protein C [OmpC], and anti-Saccharomyces
cerevisiae antibodies [ASCA]) and clinical phenotypes. The
authors found that increasing immune reactivity predicted
aggressive complicating disease in children, as the highest odds
of developing internal penetrating or fibrostenosing disease
occurred in patients positive for all three immune responses.
They also tested three CARD15 variants, which were found to
be associated with small bowel disease, but not with disease
behavior. Based on the these results, the authors
recommended that baseline serological assessment may
identify children at highest risk for a complicated phenotype
and might be useful in identifying those patients who may
benefit from early introduction of aggressive treatment.
Besides genetic and serological factors, clinical factors
have also been shown to predict disabling Crohn’s disease
within the first 5 years of diagnosis [2]. Recently, three clinical
factors (diagnosis age <40 years, early steroids, and early
perianal disease) that predicted disabling Crohn’s disease
40
within the first 5 years of diagnosis were recently determined
in a large cohort of patients from France. These factors had
not previously been validated in other populations. To this
end, two studies attempted to validate these criteria. In a
Belgian population, Edouard Louis and colleagues (University
of Liège, Liège, Belgium) applied these criteria to 361 Crohn’s
diease patients, distinguishing between very severe and
moderately severe Crohn’s disease. They found that two to
three risk factors had a positive predictive value of 67.8% for
moderately disabling Crohn’s disease and 78.3% for severe
disabling Crohn’s disease. In a North American population,
Philippe Seksik (Hôpital Saint-Antoine, Paris, France) and
colleagues reported that the positive predictive value of
disabling Crohn’s disease with two and three predictors was
62% and 75%, respectively. Due to variations in definitions
for disabling Crohn’s disease, the authors differed in their
estimate of the percentage of patients that may benefit from
a top-down, more aggressive therapeutic approach (20% in
the Belgian population study, and 74% in the study of North
American patients).
Routine use of genetic, serological, and clinical factors to
identify patients at risk of complicated disease is not
currently standard care. Nevertheless, identification of such
factors and refinement of relevant criteria should be
encouraged in order to help create a risk profile that can aid
the clinician in identifying which patients are likely to have
the more aggressive clinical course, and therefore could
benefit from a more aggressive medical approach.
Summary
Presentations at DDW 2007 examined ways of improving
current therapy and tested novel targets of delivery systems
that will expand the clinical options available to treat IBD.
Refining which genetic, serological, and clinical predictors
are associated with particular phenotypes will help to match
current and emerging therapies with those patients most
likely to benefit from a more aggressive medical approach.
Disclosures
Dr Velayos has served on speaker’s bureau for Centocor, Procter and
Gamble, Prometheus, and Shire, and has received grant support from
Procter and Gamble.
References
1.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death
from cardiovascular causes. N Engl J Med 2007;356:2457–71.
2.
Beaugerie L, Seksik P, Nion-Larmurier I et al. Predictors of Crohn’s disease.
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