Can J Gastroenterol Vol 19 Suppl A September 20055A
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
Mark S Silverberg MD PhD FRCPC1*, Jack Satsangi DPhil FRCP FRCPE2*, Tariq Ahmad MRCP , DPhil3,
Ian DR Arnott BSc MBChB MRCP MD2, Charles N Bernstein MD4, Steven R Brant MD5, Renzo Caprilli MD6,
Jean-Frédéric Colombel MD7, Christoph Gasche MD8, Karel Geboes MD PhD9, Derek P Jewell DPhil FRCP10,
Amir Karban MD11, Edward V Loftus Jr MD12, A Salvador Peña MD PhD FRCP13, Robert H Riddell MD FRCPC FRCPath14,
David B Sachar MD FACP MACG15, Stefan Schreiber MD16, A Hillary Steinhart MD1, Stephan R Targan MD17,
Severine Vermeire MD PhD18, Bryan F Warren MB ChB FRCPath19
*These authors contributed equally to this work. 1Department of Medicine, Mount Sinai Hospital IBD Centre, University of Toronto, Toronto,
Ontario; 2Department of Gastroenterology, Western General Hospital, University of Edinburgh, Edinburgh; 3Gastroenterology Unit,
University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Oxford, United Kingdom; 4Department of Medicine, Section of
Gastroenterology, University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba; 5The Harvey M and Lyn P Meyerhoff
Inflammatory Bowel Disease Center, Department of Medicine, John Hopkins University School of Medicine, and Department of Epidemiology,
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; 6Department of Clinical Sciences, University of Rome
“La Sapienza”, Rome, Italy; 7Department of Hepatogastroenterology and Registre EPIMAD, Hôpital HURIEZ, CH et U Lille, France;
8Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 9Department of Pathology, University Hospital,
Leuven, Belgium; 10Department of Gastroenterology, University of Oxford, Oxford, United Kingdom; 11Department of Gastroenterology,
Rambam Medical Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; 12Division of Gastroenterology and Hepatology,
Mayo Clinic College of Medicine, Rochester, Minnesota, USA; 13Department of Pathology, VU University Medical Centre, Amsterdam, The
Netherlands; 14Department of Pathology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario; 15Mount Sinai School of Medicine,
New York, New York, USA; 16Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; 17Cedars-Sinai
Division of Gastroenterology, Inflammatory Bowel Disease Center and Immunobiology Institute, UCLA School of Medicine, Los Angeles,
California, USA; 18Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium; 19Department of Cellular Pathology,
John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Correspondence and reprints: Dr Mark S Silverberg, Mount Sinai Hospital, 441-600 University Avenue, Toronto, Ontario M5G 1X5.
Telephone 416-586-8236, fax 416-586-4878, e-mail firstname.lastname@example.org
MS Silverberg, J Satsangi, T Ahmad, et al. Toward an
integrated clinical, molecular and serological classifcation of
inflammatory bowel disease: Report of a Working Party of the
2005 Montreal World Congress of Gastroenterology. Can J
Gastroenterol 2005;19(Suppl A):5A-36A.
The discovery of a series of genetic and serological markers associated
with disease susceptibility and phenotype in inflammatory bowel dis-
ease has led to the prospect of an integrated classification system
involving clinical, serological and genetic parameters. The Working
Party has reviewed current clinical classification systems in Crohn’s
disease, ulcerative colitis and indeterminate colitis, and provided rec-
ommendations for clinical classification in practice. Progress with
respect to integrating serological and genetic markers has been exam-
ined in detail, and the implications are discussed. While an integrated
system is not proposed for clinical use at present, the introduction of a
widely acceptable clinical subclassification is strongly advocated,
which would allow detailed correlations among serotype, genotype and
clinical phenotype to be examined and confirmed in independent
cohorts of patients and, thereby, provide a vital foundation for future
Key Words: Anti-Saccharomyces cerevisiae antibodies; Crohn’s
disease; HLA complex; Indeterminate colitis; NOD2/CARD15;
Vers une classification clinique, moléculaire et
sérologique intégrée des maladies inflamma-
toires de l’intestin : Rapport d’un groupe de
travail du World Congress of Gastroenterology
de 2005 à Montréal
La découverte d’une série de marqueurs génétiques sérologiques associés à
la susceptibilité à la maladie et au phénotype dans les maladies inflamma-
toires de l’intestin a donné lieu à la perspective d’un système de classifica-
tion intégré mettant en cause des paramètres cliniques, sérologiques et
génétiques. Le groupe de travail a analysé les systèmes de classification
clinique courants de la maladie de Crohn, de la colite ulcéreuse et de la
colite indéterminée et a fourni des recommandations de classification
clinique dans la pratique. Les progrès réalisés dans l’intégration des mar-
queurs sérologiques et génétiques ont été examinés à fond, et les con-
séquences sont exposées. Aucun système intégré n’est proposé en vue d’un
usage clinique pour l’instant, mais l’adoption d’une sous-classification
clinique acceptable est fortement recommandée, ce qui permettrait d’exa-
miner et de confirmer les corrélations détaillées entre le sérotype, le géno-
type et le phénotype clinique dans des cohortes indépendantes de patients
et, par conséquent, de fournir les fondements essentiels à de futurs
WORKING PARTY REPORT
©2005 Pulsus Group Inc. All rights reserved
rohn’s disease (CD) and ulcerative colitis (UC) afflict
individuals in many parts of the world and have long been
accepted as heterogeneous disorders with a wide variety of
clinical presentations and manifestations. Falling under the
general term idiopathic inflammatory bowel disease (IBD),
these disorders clearly represent a constellation of diseases
with both common and unique characteristics.
As a result of this significant clinical heterogeneity, efforts
have been made to classify IBD using recognizable clinical and
epidemiological features. Most recent attention has focused
on CD. An international working team that issued its report
in Rome in 1991 proposed a classification scheme in which
CD is divided into numerous subgroups based upon anatomi-
cal distribution, operative history and predominant clinical
‘behaviour’, that is, inflammatory, fistulizing or stenotic.
Subsequently, the international working group, commissioned
for the 1998 World Congress of Gastroenterology in Vienna,
Austria, refined the clinical classification of CD. The Vienna
group classified CD according to three critical phenotypic
characteristics (age at diagnosis, location and clinical behav-
iour), thereby developing a system that is more practicable for
clinical use. These classification systems have since been
applied to numerous clinical trials and studies of the patho-
genesis and natural history of CD.
Since 1998, significant advances have been made in the
discovery of molecular and serological markers related to IBD.
Evaluation of these markers and of their importance to IBD
diagnosis and phenotypic categorization is the subject of
intense investigation. Moreover, limitations in the existing
clinical CD classification scheme have become evident, as
described by the original authors. It is also noteworthy that
there remains a need for a similar reassessment of the classifi-
cation of UC. The appropriate use of the term indeterminate
colitis (IC) is another thorny issue in clinical and research
settings. This Working Party has taken on the ambitious task
of addressing these individual issues.
Individual teams have taken on the tasks of developing an
updated CD classification system, proposing a clinical classi-
fication for UC and clarifying the clinical context in which
the term IC should be used. The role of geography and eth-
nicity is discussed, but not of specific environmental influ-
ences. At the present time, the classification of IBD is based
on predominantly clinical parameters, whereas molecular and
serological markers largely remain in the research arena. The
Working Party has evaluated currently available data with
the goal of integrating clinical features of IBD with genetic
and serological markers. Our findings are presented, together
with recommendations for clinical classification systems. We
hope that these data will catalyze progress over the next
decade, with benefits for both clinicians and research investi-
Crohn’s disease clinical classification
Modification of the Vienna classification as follows:
• Introduction of an early age of onset category (diagnosis at
16 years or younger);
• Allow for the co-classification of location L4 (upper gastro-
intestinal [GI] involvement) with L1 to L3 (Table 1); and
• Inclusion of a modifier for perianal disease.
Cosnes J, Cattan S, Blain A, et al. Long-term evolution of dis-
ease behavior of Crohn’s disease. Inflamm Bowel Dis
Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El Yafi FA,
Belaiche J. Behaviour of Crohn’s disease according to the
Vienna classification: Changing pattern over the course of the
disease. Gut 2001;49:777-82.
Sachar DB, Bodian CS, Goldstein ES, et al. Is perianal Crohn’s
disease associated with intestinal fistulization? Am J
CD is a clinically heterogeneous disorder with a variety of
demographic, clinical and phenotypic features. There have
been attempts to use these characteristics to identify subgroups
of CD patients who differ in their natural history, complica-
tions or response to therapy.
Existing classification systems
Greenstein et al (1) proposed classifying patients who require
surgery for CD into those with perforating and nonperforat-
ing disease. They found that the indications for subsequent
surgery tended to be the same as those for the first or previous
operation. Moreover, patients with perforation tended to
have earlier recurrence of CD following surgery, regardless of
disease location. This categorization of CD into perforating
and nonperforating subtypes has since been adapted to
include patients managed with or without surgery and has
been incorporated in the Vienna classification (2).
The Vienna classification of CD considers age of onset (A),
disease location (L) and disease behaviour (B), resulting in
24 possible subgroups (2). However, because disease location
and disease behaviour have been found to be highly correlated
(3,4), the majority of patients fall into a much smaller number
of categories. Furthermore, the distribution of patients within
the subcategories is not even. In a review of 877 patients from
a single practice, it was found that less than 1% had only upper
GI involvement and only 15.6% were diagnosed after 40 years
of age (5). In another series, 21.1% of patients were diagnosed
after 40 years of age (6). This uneven distribution may be an
accurate reflection of the relative rarity of some subtypes, but it
can produce some practical problems when applying statistical
analysis to patient datasets.
Despite some of these concerns, a number of studies have
demonstrated correlations between the Vienna classification
system and other aspects of disease presentation, genetic sus-
ceptibility and natural history. It has been shown that certain
disease location and behaviour variables in the Vienna classifi-
cation system are associated with anti-Saccharomyces cerevisiae
antibody (ASCA) profiles (7,8), and with the presence of one of
the nucleotide-binding oligomerization domain 2/caspase
recruitment domain-containing protein 15 (NOD2/CARD15)
gene mutations (8-10). The Vienna classification also appears
to predict the need for immunosuppressants and surgery (11).
It has been well recognized that disease behaviour, however,
has a tendency to progress from one category to another during
prolonged follow-up (12-14). It has also been suggested that
perianal disease should not be regarded as a manifestation of
penetrating disease behaviour (B3) because its occurrence
has been found to be independent of intestinal penetrating
disease (15,16). In addition, the upper GI disease location
Silverberg et al
Can J Gastroenterol Vol 19 Suppl A September 20056A
(L4) variable is said to be present when there is any disease
proximal to the terminal ileum, even if the ileum and/or colon
are involved. This potentially creates an artificial distinction
that, although useful for its relative ease of use and simplicity,
may obscure the importance of the occurrence of disease at two
or more sites.
There are certain aspects of disease course and prognosis
that are not included in existing classification systems. The
severity and aggressiveness of the disease are features that are
difficult to reliably define and evaluate, even though they are
potentially relevant to studies of natural history and as prog-
nostic variables for therapeutic trials. Potential corollaries of
the severity and aggressiveness of disease are the responsive-
ness to different classes of medical therapies and the need for
Age of onset
Age of onset is a variable that is likely to predict a greater
genetic predisposition to disease or, alternatively, an earlier or
heavier exposure to some, as of yet undetermined, environ-
mental causative or permissive factor. There is evidence that
the phenotype of disease at diagnosis varies according to the
age of onset and may relate to some extent to genotype
(17,18). Small intestinal and upper GI disease is more com-
mon in individuals diagnosed with CD before 20 years of age,
whereas colonic disease is diagnosed more frequently in
patients older than 60 years of age (19-24). Heyman et al (25)
analyzed data from 1370 pediatric-onset IBD cases, with some
striking findings. Colonic disease was present in almost all
children diagnosed before the age of eight years, including
those with CD, but in only 46% of those diagnosed thereafter.
The older children were more likely to have small intestinal or
upper GI disease (25-27). The male to female ratio also
decreases with increasing age of onset of CD (25). Family his-
tory of IBD is also more likely to be elicited in patients with an
earlier age of onset (22). Given the fact that children have dif-
ferent presentations and genotypes from those seen in adults,
we propose the introduction of a new early-onset category. The
revised age breakdown would now be A1, with age at diagnosis
of 16 or younger; A2, with age of diagnosis 17 to 40 years; and
A3, with age of diagnosis older than 40 years (Table 1).
The major divisions of disease site that are agreed upon by
most experts are ileum (distal small intestine), colon and ileo-
colonic. These are recognized and well-defined within the
context of the Vienna classification system. As already dis-
cussed, however, the application of the definition of upper GI
involvement essentially disregards any disease involvement
distal to the jejunum. When the Vienna classification system
was developed and existing databases were examined it
appeared that the presence of disease distal to the jejunum was
unusual in patients with upper GI involvement. Because these
data were derived before the availability of sensitive tech-
niques, such as wireless video capsule endoscopy, subtle disease
in the small intestine might have been missed. We suggest that
the issue of distal disease in patients with upper GI involve-
ment should be re-examined using more sensitive techniques
and, if necessary, modifications of the Vienna classification
should be considered. To resolve this issue, we propose that, if
proximal disease is found in conjunction with distal disease
(categories L1 to L3), a category of L4 be added and not be
considered a mutually exclusive category. For example, a
patient with both distal ileal and jejunal disease would be given
the designation L1 as well as L4. This would enable the analy-
sis of patients with ileal and/or colonic involvement with con-
comitant proximal involvement (Table 1).
Although disease site tends to be relatively stable over time
(16), there are patients in whom new sites of disease appear
only years after the original diagnosis of CD. Regression of dis-
ease can also occur, so that previously affected areas can be
completely healed by treatment. In some cases, surgical resec-
tion appears to have precipitated the extension of disease loca-
tion. Although it would be virtually impossible to arbitrarily
define a specific point in the disease course at which time dis-
ease location can be determined with reasonable validity, it
would seem reasonable to continue to regard the maximum
extent of disease before the first resection as the ‘true’ disease
location for the purposes of the classification scheme.
The classification of disease behaviour, as based on the defini-
tions provided in the Vienna classification system, may be prob-
lematic for a number of reasons. First, disease categories are not
necessarily independent. It has been shown, for example, that
the relatively well-defined category of disease site tends to be
correlated with disease behaviour (eg, ileal with fibrostenotic
disease). Second, a number of factors might lead to interob-
server disagreement in the assignment of a behaviour (28,29).
Various disease behaviours can coexist, making it difficult to
determine which feature is ‘primary’. For example, internal fistu-
las almost always coexist with some degree of stenosis or obstruc-
tion distal to the origin of the fistula (30). Additionally, disease
behaviour has been shown to change or progress over the course
of the disease in some patients, typically from nonpenetrating,
nonstricturing disease (B1) to stricturing (B2) or penetrating
(B3) (5,16). Therefore, any future attempts at classifying disease
behaviour should incorporate some aspect of time course or, at a
Integrated classification of IBD
Can J Gastroenterol Vol 19 Suppl A September 20057A
Summary of revised ‘Montreal classification’ of Crohn’s
Age at diagnosis (A)
A1 16 years or younger
A2 17–40 years
A3 Over 40 years
Location (L) modifier (L4)
L1 Terminal ileumL1 + L4 Terminal ileum + Upper GI
L2 ColonL2 + L4Colon + Upper GI
L3 IleocolonL3 + L4 Ileocolon + Upper GI
L4 Upper GI––
Behaviour (B)modifier (p)
B1* Nonstricturing, B1p Nonstricturing,
B2 StricturingB2p Stricturing + perianal
B3Penetrating B3p Penetrating + perianal
*B1 category should be considered ‘interim’ until a prespecified time has
elapsed from the time of diagnosis. Such a time period may vary from study
to study (eg, 5-10 years is suggested) but should be defined in order for B1
behaviour to be considered ‘definitive’. GI Gastrointestinal
minimum, require a certain amount of time to have elapsed
before assigning a disease behaviour designation. Data from
several studies suggest five years as a reasonable interval because
many, but not all, patients that are destined to develop stricturing
or penetrating disease will have done so by that time (Table 1).
Although a five-year time period following diagnosis might
seem somewhat arbitrary, it is based in part on the rate and
incidence of disease progression reported by Louis et al (14). In
that study, 26.3% of patients had stricturing or penetrating dis-
ease behaviour at diagnosis and, by five years after diagnosis,
the percentage had increased to 48% and, by 10 years, to
almost 70%. These individuals would be considered to have
varying degrees of more progressive or active disease. In a
population-based study from Olmsted County, development of
a fistula (perianal or enteroenteric) was observed in 26% of
patients by five years (31). Approximately one-half of these
patients had one or more fistulas before, or within 30 days
after, diagnosis. In that study, the initial disease behaviour at
diagnosis for the remaining patients and the rates of progres-
sion to stricturing disease were not reported. Based upon the
Louis data (14), if one were to use the 10-year point to deter-
mine the presence of progressive or aggressive disease, fully
70% of patients would fall into this category. This is probably
an overestimate; therefore, the five-year cut-off was suggested
as a reasonable compromise. It should be remembered that a
requirement for a minimum five-year follow-up would mean
that a significant proportion of patients could not be classified
early in the course of their disease. This has important impli-
cations depending on the way in which the behaviour classifi-
cation is used. For clinical trials, the disease behaviour at the
time of intervention is probably more important than the pos-
sible disease behaviour at 10 or 20 years. In such cases, it might
be reasonable to classify disease behaviour before the five-year
point. On the other hand, for studies of genotype-phenotype
correlations, it is important to have a well-defined and stable
phenotype that does not change over time; thus, a minimum of
10 years or more follow-up might be more appropriate. It is sug-
gested that investigators using the disease behaviour classifica-
tion determine what is appropriate for their purposes, because
it will almost certainly vary from study to study.
Another concern with the existing Vienna classification
definition of penetrating disease behaviour (B3) is the inclu-
sion of patients with only perianal fistula. Smith et al (14)
studied the Vienna classification, disease progression and out-
come, serology and genetic markers in 231 well-characterized
CD patients and found that patients with perianal fistulas or
abscesses differed from those with intestinal penetrating dis-
ease. The International Organization for Inflammatory Bowel
Diseases Task Force on Disease Classification (16) examined
the database records of 5491 CD patients from six centres and
found that, in patients with colonic disease but not in those
with ileal disease, there was an association between intestinal
fistulas and perianal fistulas. In addition, data from a population-
based research registry have shown that almost 80% of patients
with perianal fistula have no enteric fistula (32). These obser-
vations suggest that the presence of perianal and enteric fistula
describes two different phenotypes.
We suggest that the Vienna classification be modified so
that perianal fistulas are no longer included in the penetrating
disease category. The wording of the definition of this category
would be changed to “the occurrence of intra-abdominal fistu-
las, inflammatory masses and/or abscesses at any time in the
course of disease”. We suggest the inclusion of perianal fistulas
and abscesses as modifiers of the disease behaviour variable.
This would be indicated by a ‘p’ (for perianal) appended to B1,
B2 or B3, resulting in B1p, B2p or B3p (Table 1).
The recommendations outlined above are based, as much as
possible, on existing clinical and natural history data, as well as
expert opinions. The additions to the Vienna classification
require further validation studies in the ongoing process of
developing a robust scheme that incorporates the most recent
clinical, serological and genetic information.
1. Greenstein AJ, Lachman P, Sachar DB, et al. Perforating and non-
perforating indications for repeated operations in Crohn’s disease:
Evidence for two clinical forms. Gut 1988;29:588-92.
2. Gasche C, Scholmerich J, Brynskov J, et al. A simple classification
of Crohn’s disease: Report of the Working Party for the World
Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis
3. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease
behavior of Crohn’s disease. Inflamm Bowel Dis 2002;8:244-50.
4. Marion JF, Lachman P, Greenstein AJ, Sachar DB. Rarity of fistulas
in Crohn’s disease of the jejunum. Inflamm Bowel Dis 1995;1:34-6.
5. Freeman HJ. Application of the Vienna Classification for Crohn’s
disease to a single clinician database of 877 patients. Can J
6. Dorn SD, Abad JF, Panagopoulos G, Korelitz BI. Clinical
characteristics of familial versus sporadic Crohn’s disease using the
Vienna Classification. Inflamm Bowel Dis 2004;10:201-6.
7. 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.
8. Linskens RK, Mallant-Hent RC, Murillo LS, von Blomberg BM,
Alizadeh BZ, Pena AS. Genetic and serological markers to identify
phenotypic subgroups in a Dutch Crohn’ s disease population.
Dig Liver Dis 2004;36:29-34.
9. 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
10. 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.
11. Veloso FT, Ferreira JT, Barros L, Almeida S. Clinical outcome of
Crohn’s disease: Analysis according to the vienna classification and
clinical activity. Inflamm Bowel Dis 2001;7:306-13.
12. Cosnes J, de Parades V, Carbonnel F, et al. Classification of the
sequelae of bowel resection for Crohn’s disease. Br J Surg
13. Freeman HJ. Natural history and clinical behavior of Crohn’s disease
extending beyond two decades. J Clin Gastroenterol 2003;37:216-9.
14. Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El Yafi FA,
Belaiche J. Behaviour of Crohn’s disease according to the Vienna
classification: Changing pattern over the course of the disease. Gut
15. Smith BR, Arnott ID, Drummond HE, Nimmo ER, Satsangi J.
Disease location, anti-Saccharomyces cerevisiae antibody, and
NOD2/CARD15 genotype influence the progression of disease
behavior in Crohn’s disease. Inflamm Bowel Dis 2004;10:521-8.
16. Sachar DB, Bodian CS, Goldstein ES, et al. Is perianal Crohn’s
disease associated with intestinal fistulization? Am J Gastroenterol
17. 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
18. Idestrom M, Rubio C, Granath F, Finkel Y, Hugot JP. CARD15
mutations are rare in Swedish pediatric Crohn disease. J Pediatr
Gastroenterol Nutr 2005;40:456-60.
Silverberg et al
Can J Gastroenterol Vol 19 Suppl A September 2005 8A
19. 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.
20. Fellows IW, Freeman JG, Holmes GK. Crohn’s disease in the city of
Derby, 1951-85. Gut 1990;31:1262-5.
21 Lee FI, Nguyen-Van-Tam JS. Prospective study of incidence of
Crohn’s Disease in Northwest England: No increase since the late
1970’s. Eur J Gastroenterol Hepatol 1994;6:27-31.
22. Polito JM, Childs B, Mellits ED, Tokayer AZ, Harris ML, Bayless TM.
Crohn’s disease: Influence of age at diagnosis on site and clinical
type of disease. Gastroenterology 1996;111:580-6.
23. Meinzer U, Idestrom M, Alberti C, et al. Ileal involvement is age
dependent in pediatric Crohn’s disease. Inflamm Bowel Dis
24. Cuffari C, Bayless TM. Crohn’s disease: Age of onset determines
clinical phenotype. Gastroenterol Int 1997;10:89.
25. 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.
26. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and
clinical characteristics of children with newly diagnosed
inflammatory bowel disease in Wisconsin:A statewide population-
based study. J Pediatr 2003;143:525-31.
27. Sawczenko A, Sandhu BK. Presenting features of inflammatory
bowel disease in Great Britain and Ireland. Arch Dis Child
28. Steinhart AH, Girgrah N, McLeod RS. Reliability of a Crohn’s
disease clinical classification scheme based on disease behavior.
Inflamm Bowel Dis 1998;4:228-34.
29. Riis L, Munkholm P, Binder V, Skovgaard LT, Candstat LT, Langholz E.
Intra- and interobserver variation in the use of the Vienna
Classification of Crohn’s disease. Inflamm Bowel Dis 2005;11:657-61.
30. Oberhuber G, Stangl PC, Vogelsang H, Schober E, Herbst F,
Gasche C. Significant association of strictures and internal fistula
formation in Crohn’s disease. Virchows Arch 2000;437:293-7.
31. Schwartz DA, Loftus EV Jr, Tremaine WJ, et al. The natural history
of fistulizing Crohn’s disease in Olmsted County, Minnesota.
32. Tang LY, Rawsthorne P, Bernstein CN. In Crohn’s disease is there an
association between perineal fistulizing disease and luminal
fistulizing disease? A population-based study. Gastroenterology
Ulcerative colitis clinical classification
A classification system for UC is proposed that incorporates:
• Disease extent; and
• Disease severity of individual acute relapses.
Langholz E, Munkholm P, Davidsen M, Binder V. Course of
ulcerative colitis: Analysis of changes in disease activity over
years. Gastroenterology 1994;107:3-11.
Langholz E, Munkholm P, Davidsen M, Nielsen OH, Binder V.
Changes in extent of ulcerative colitis: A study on the course
and prognostic factors. Scand J Gastroenterol 1996;31:260-6.
Ritchie JK, Powell-Tuck J, Lennard-Jones JE. Clinical outcome
of the first ten years of ulcerative colitis and proctitis. Lancet
With an increasing understanding of the epidemiology and
genetics of IBD, it has become evident that UC, like CD, may
actually represent several forms of IBD. A formal clinical clas-
sification of UC similar to the Vienna classification of CD (1)
does not exist. We sought to review the evidence that justifies
the existence for a clinical classification of UC.
Theoretically, a clinical classification system for UC would
be useful if it had implications for pathogenesis (ie, if it corre-
lated with subclinical or genetic markers), therapy (eg, topical
or oral therapy) or prognosis (eg, severity of disease, require-
ment for colectomy, colorectal cancer risk or mortality). The
most commonly used classification systems in UC stratify
patients by the extent of colonic involvement or by disease
activity. This section reviews the rationale for these classifica-
Classification by extent
UC can be defined by the extent of colorectal inflammation at
a radiographic, endoscopic or histological level. For the pur-
poses of simplification, we propose that the extent of UC be
defined by endoscopic appearance and by maximal extent dur-
ing follow-up. The three subgroups of UC defined by extent
1. Ulcerative proctitis (E1): involvement limited to the
rectum (ie, proximal extent of inflammation is distal to
the rectosigmoid junction).
2. Left-sided UC (E2) (also known as distal UC):
involvement limited to the portion of the colorectum
distal to the splenic flexure.
3. Extensive UC (E3) (also known as pancolitis):
involvement extends proximal to the splenic flexure.
This three-tiered classification system appears to be useful
in distinguishing patients by medical therapy and by progno-
sis. For example, hydrocortisone or mesalamine suppositories
appear to be most useful as primary therapy for patients with
ulcerative proctitis (2,3), while these same medications in
foam or enema form are most useful as primary therapy in
patients with left-sided UC (2,4,5). Oral delivery of sul-
fasalazine and the 5-aminosalicylate agents is, of course, possible
in patients with proctitis and left-sided disease, but may not be
necessary. On the other hand, use of topical therapy alone is
usually insufficient for the primary therapy of extensive UC.
The extent of colitis has implications for the activity or
severity of the condition, whether measured by rates of med-
ication usage, hospitalization or colectomy. A population-based
study from southeastern Norway (6) found that patients with
extensive colitis were more likely to require 5-aminosalicylate
agents or corticosteroids than patients with left-sided disease
or proctitis. In a study of 269 recently diagnosed UC patients
evaluated at St Mark’s Hospital, United Kingdom, between
1966 and 1975 (7,8), crude hospitalization rates were signifi-
cantly higher among those with extensive colitis (70%) than
proctosigmoiditis (25%) or proctitis (13%). A review of select-
ed referral centre-based (7,9) and population-based (6,10)
cohorts shows that the actuarial risk of colectomy is influenced
by the extent of UC (Table 2). The risk of colectomy among
proctitis patients ranged from 2% to 9% after five years, while
patients with extensive colitis had five-year colectomy rates of
30% to 44%.
It has been recognized for years that, in UC, the risk of
colorectal cancer is correlated with disease extent. This cor-
relation has been established in studies from referral centres
(11,12) or population surveys (13-16) (Table 3). The cumu-
lative risk of colorectal cancer in patients with ulcerative
proctitis ranges from 0% to 12% after 30 years of disease,
compared with a cumulative risk of 4% to 47% after 30 years in
those with extensive or pancolonic disease.
Integrated classification of IBD
Can J Gastroenterol Vol 19 Suppl A September 20059A
Population-based studies suggest that mortality in UC
patients may also correlate with increasing extent of colitis
(10,17,18) (Table 4). In the updated examination of mortality
in the Copenhagen County, Denmark, cohort (18), extensive
colonic involvement at diagnosis remained a significant pre-
dictor of mortality after adjusting for age, sex and calendar
period of diagnosis. Other studies, however, have not shown a
consistent relationship (19,20).
It is important to note that most of the aforementioned stud-
ies based the extent of colitis on radiographic or endoscopic,
not histological, criteria. With the advent of total colonoscopy
in the 1970s, it became evident the previous methods of evalu-
ation for UC (ie, proctoscopy or sigmoidoscopy plus double
contrast barium enema) were relatively insensitive and could
frequently underestimate the extent of involvement or even
miss a diagnosis (21). The significance of histological evidence
of chronic colitis in an endoscopically normal proximal colon
remains unclear in terms of the risk of colectomy, cancer, prox-
imal progression of the disease, or mortality.
One drawback of the extent-based classification system is its
instability over time, especially in the proctitis and left-sided
colitis subgroups. Most longitudinal studies of UC cohorts that
have specifically examined the problem report both progres-
sion and regression of the proximal extent of inflammation
(9,22-25) (Table 5). The actuarial risk of proximal extension of
proctitis after 10 years of disease is between 41% and 54%. For
left-sided colitis, the likelihood of later progression to extensive
colitis may be even higher. Although not as extensively studied,
a diagnosis of extensive colitis may not necessarily be stable
(9,23,26) (Table 5). The regression rate ranges from a crude rate
of 1.6% (9) to an actuarial rate of 71% after 10 years (23). We
therefore propose that the maximum extent of involvement be
used in the clinical classification system.
It is not clear that additional terms that are occasionally
used to classify UC by extent actually identify clinically impor-
tant subgroups. For example, the term ‘proctosigmoiditis’ is
sometimes used to describe patients with rectal and sigmoid
colonic inflammation without descending colonic involve-
ment. The clinical course and prognosis of these patients is
quite similar to those deemed to have left-sided colitis.
Another strategy occasionally used is to separate ‘extensive
UC’ (involving the transverse colon but not the ascending
Silverberg et al
Can J Gastroenterol Vol 19 Suppl A September 200510A
Risk of colectomy stratified by disease extent in selected cohorts of ulcerative colitis patients*
Setting (reference)Proctitis Proctosigmoiditis Left-sided colitis Extensive colitisPancolitis
St Mark’s Hospital, UK (7,8) 2% at five years6% at five years 21% at five years30% at five years
Copenhagen County, Denmark (10)9% at five years 19% at five years 35% at five years
Cleveland Clinic, USA (9)14%†; 7% at five years52%†
61%†; 44% at five years
Southeastern Norway (IBSEN) (6)2% at one year2% at one year 9% at one year
*Rates are actuarial unless otherwise specified; †Crude rate, mean follow-up of 12.7 years (minimum five-year follow-up in 100%). IBSEN Inflammatory Bowel
South-Eastern Norway Study Group; UK United Kingdom; USA United States of America
Risk of colorectal cancer stratified by disease extent in selected cohorts of ulcerative colitis patients*
Setting (reference)Proctitis Left-sided colitisExtensive colitisPancolitis
Mayo Clinic, USA (11) 12% at 30 years30% at 30 years47% at 30 years
Cleveland Clinic, USA (12)4% at 30 years 25% at 30 years
Stockholm County, Sweden (13)<5% at 25 years 13% at 25 years
Central Israel (14)0% at 20 years4% at 20 years 14% at 20 years
Uppsala, Sweden (15)<5% at 30 years 12–32% at 30 years
Malmo, Sweden (16)1.1%†
*Rates are actuarial unless otherwise specified; †Crude rate, mean follow-up of 13.9 years. USA United States of America
Standardized mortality ratio (SMR; observed deaths/expected deaths) and 95% CIs stratified by disease extent in selected
cohorts of ulcerative colitis patients
ProctitisProctosigmoiditis Left-sided colitisExtensive colitisPancolitis SMR
Setting (reference) SMR (95% CI)SMR (95% CI) SMR (95% CI)SMR (95% CI)(95% CI)
Uppsala, Sweden (17) 1.4 (1.2–1.5)1.2 (1.0–1.4)1.9 (1.7–2.2)
Copenhagen County, Denmark (10)1.68 (P<0.02)
Leicestershire, UK (19)0.8 (0.52–1.17) 0.93 (0.55–1.47) 0.84 (0.42–1.49)0.85 (0.54–1.27)
Wolverhampton, Salisbury and Swindon, UK (20)0.64 (0.23–1.40) 0.9 (0.46–1.57)1.56 (0.89–2.52)1.01 (0.40–2.08)
Copenhagen County, Denmark (1997 update) (18)0.87 (0.72–1.07)1.23 (1.04–1.44)
UK United Kingdom
colon or cecum) from ‘pancolitis’. Again, the clinical courses
and prognoses of these two groups are quite similar. There is
little or no evidence that these terms enable us to differentiate
UC patients by pathogenesis, therapy or prognosis any more
precisely than is possible with the three-tiered classification
system described above.
Classification by severity
UC can be classified broadly into four disease activity/severity
1. UC in clinical remission (S0): No symptoms of UC.
2. Mild UC (S1): in the classic description of disease activity
by Truelove and Witts (27), this was defined as four or
fewer bloody stools daily, lack of fever, pulse of less than
90 beats/min, hemoglobin of 105 g/L or greater and
erythrocyte sedimentation rate (ESR) of less than
30 mm/h. A similar definition was given in the practice
guidelines for management of UC recently published by
the American College of Gastroenterology (ACG) (28):
four or fewer stools daily (with or without blood), no
systemic signs of toxicity and a normal ESR.
3. Moderate UC (S2): Truelove and Witts (27) defined this
as the state between mild and severe. The ACG guidelines
defined moderate disease as more than four stools daily but
with minimal signs of systemic toxicity (28).
4. Severe UC (S3): This was defined as the passage of at
least six bloody stools daily, pulse of at least 90 beats/min,
temperature of at least 37.5°C, hemoglobin of less than
105 g/L and ESR of at least 30 mm/h (27). The ACG
guidelines defined severe colitis as at least six bloody
stools daily and evidence of toxicity (fever, tachycardia,
anemia or elevated ESR) (28). The latter guidelines
separated ‘fulminant colitis’ from ‘severe’. Fulminant
patients were those with at least 10 stools daily,
continuous bleeding, toxicity, abdominal tenderness and
distension, requirement for blood transfusion and colonic
dilation on plain abdominal films (28).
One of the limitations of the present disease activity classi-
fication systems is that they are useful only for predicting clin-
ical course in the short term. As in CD, there are no
longitudinal disease severity indices (ie, incorporating disease
severity over time). One of the few studies to address this
comes from Copenhagen County, where UC patients could be
classified into those with prolonged remission, those with
intermittent symptoms and those with continuous activity
(29). Disease activity over the first three years of diagnosis pre-
dicted the clinical course over the next five years (29).
Another issue that needs to be addressed is whether the term
‘fulminant colitis’ adds any additional value to a three-tiered
activity classification system. In most series, fulminant colitis
has typically been defined retrospectively to describe patients
who failed medical therapy and required colectomy. A small
subset of patients with fulminant colitis develop multiple
organ dysfunction (30).
Should age at diagnosis be used to classify UC?
The possible existence of a bimodal distribution in age at onset
of UC continues to be debated. Some studies found a unimodal
distribution, with a peak incidence in the third or fourth
decade of life (31,32), while others demonstrated a large peak
in the third decade of life and a smaller peak in the elderly
(33). Regardless of the pattern, age-related differences in inci-
dence suggest that UC is a heterogeneous entity that varies by
the age at diagnosis.
Early studies indicate that, compared with those diagnosed
after 16 years of age, patients who are diagnosed in childhood
present more often with sudden onset of severe symptoms
rather than an insidious onset, experience more complications,
are more likely to develop colorectal cancer and are more
likely to die of disease-related complications (11,34). In the
population-based Copenhagen County cohort, children diag-
nosed with UC before the age of 15 years had higher rates of
extensive colitis, proximal progression of disease and mortality
rates than those diagnosed in adulthood (35). On the other
hand, that study found no difference in colectomy rates
between the two groups. There are conflicting data about
whether younger age at onset of UC is a risk factor for IBD-
related colorectal cancer, independent of increased duration
At the other end of the age spectrum, some investigators
have reported that elderly patients with UC have a milder
form of the disease. In a 1935 paper from the Mayo Clinic (37)
describing 25 patients diagnosed with UC after the age of
60 years, most patients had mild, even intermittent, symptoms
and responded promptly to treatment. Later reports (38,39)
stated that the prognosis of UC in the elderly was significantly
worse than that of the average patient, but were based on very
small numbers of patients. Finally, other studies (40-42) sug-
gest that elderly patients with IBD do no worse than expected
for the average patient. Therefore, at this juncture, there is
Integrated classification of IBD
Can J Gastroenterol Vol 19 Suppl A September 200511A
Rate of disease extent progression and regression in selected cohorts of ulcerative colitis patients*
Proctitis toProctitis to Proctitis to Left-sided toLeft-sided to Extensive colitis Pancolitis to
Setting (reference) left-sidedextensive any progressionextensive proctitis to any regressionany regression
St Mark’s Hospital, UK (22) 12% at 10 years7% at 10 years
Cleveland Clinic, USA (9) 11.9%†
Copenhagen County, Denmark (23)41% at 10 years56% at 10 years 71% at 10 years
Birmingham, UK (24)49% at 10 years31% at 10 years
Southeastern Norway (IBSEN) (26) 22% at 1 year16% to 24% 23% to 25% 70% at 1 year 39% at 1 year
at 1 yearat 1 year
Northern Italy (25)54% at 10 years 10% at 10 years
*Rates are actuarial unless otherwise specified; †Crude rate, mean follow-up of 12.7 years (minimum of five years in 100%). IBSEN Inflammatory Bowel South-
Eastern Norway Study Group; UK United Kingdom; USA United States of America
insufficient information to warrant using age at diagnosis of
UC in a clinical classification system for the disease.
Nevertheless, it should be recorded as part of a minimal data
Primary sclerosing cholangitis-associated IBD
The characteristics of IBD associated with primary sclerosing
cholangitis (PSC) deserve additional comment. While only
5% of UC patients have evidence of sclerosing cholangitis,
approximately 70% to 80% of sclerosing cholangitis patients
have IBD, with predominantly colonic involvement (43). The
bowel disease is often quite mild and insidious in onset. A high
proportion of newly diagnosed PSC patients, even those with-
out GI complaints, prove to have chronic colitis when they
undergo colonoscopy with biopsy (44). One such patient was
even found to have colorectal dysplasia at the time of UC diag-
nosis, suggesting that some PSC patients may have had undi-
agnosed IBD for years. Several Mayo Clinic studies (45-47)
found that PSC-IBD patients were more likely than patients
with UC alone to have extensive colitis with rectal sparing
and ‘backwash ileitis’ without other typical findings of CD,
such as granulomas, skip areas, fistulas or strictures. PSC-IBD
patients are less likely than matched UC controls to require
colectomy (47). If they undergo proctocolectomy with ileal
pouch-anal anastomosis (IPAA), however, PSC-IBD patients
are more likely than UC patients without PSC to develop pou-
chitis (48). Furthermore, the risk of colorectal dysplasia and
cancer seems to be higher in PSC-IBD patients than UC
patients without PSC, even after accounting for differences in
disease extent and duration (47,49,50). Because of this
increased risk of neoplasia, some authorities have advocated
initiating annual surveillance colonoscopy immediately after
the diagnosis of PSC-IBD. The differences in clinicopatholog-
ical features (rectal sparing and backwash ileitis) and prognosis
(pouchitis and increased risk of colorectal neoplasia) suggest
that PSC-IBD may be an IBD phenotype distinct from both
UC and CD (47).
Right-sided colonic or periappendiceal inflammation in
Several studies (51-55) in the past 15 years have revealed endo-
scopic evidence of right-sided colonic and/or periappendiceal
inflammation in patients with left-sided UC. The prevalence of
this finding ranges from 19% to 75%, but its clinical significance
is debatable. There is no indication that these patients are more
likely to later be diagnosed with CD. One recent pathological
study of colon resection specimens suggested that patients with
appendiceal inflammation were more likely to develop pouchitis
(56), but this finding needs to be confirmed. At this time, there
is insufficient evidence to incorporate periappendiceal inflam-
mation into a clinical classification scheme.
UC can be classified by extent of disease into proctitis (E1), left-
sided disease (E2) or extensive disease (E3), and can be classified
by disease severity into mild (S1), moderate (S2) or severe (S3).
We suggest avoidance of the terms ‘proctosigmoiditis’ and ‘ful-
minant colitis’ in classification systems, because they do not
appear to further differentiate patients into clinically useful cat-
egories. PSC-IBD may represent a unique phenotype of bowel
inflammation. Periappendiceal inflammation in the setting of
left-sided colitis is not uncommon, but the clinical significance
of this finding remains unclear.
1. Gasche C, Scholmerich J, Brynskov J, et al. A simple classification
of Crohn’s disease: Report of the Working Party for the World
Congress of Gastroenterology, Vienna 1998. Inflamm Bowel Dis
2. Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis
and overview of the literature on treatment options for left-sided
ulcerative colitis and ulcerative proctitis. Am J Gastroenterol
3. Regueiro MD. Diagnosis and treatment of ulcerative proctitis. J Clin
4. Marshall JK, Irvine EJ. Putting rectal 5-aminosalicylic acid in its
place: The role in distal ulcerative colitis. Am J Gastroenterol
5. Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative
treatments in ulcerative colitis: A meta-analysis. Gut
6. Moum B, Ekbom A, Vatn MH, et al. Clinical course during the 1st
year after diagnosis in ulcerative colitis and Crohn’s disease – results
of a large, prospective population-based study in southeastern
Norway, 1990-93. Scand J Gastroenterol 1997;32:1005-12.
7. Ritchie JK, Powell-Tuck J, Lennard-Jones JE. Clinical outcome of
the first ten years of ulcerative colitis and proctitis. Lancet
8. Lennard-Jones JE. The clinical outcome of ulcerative colitis depends
on how much of the colonic mucosa is involved. Scand J
Gastroenterol Suppl 1983;88:48-53.
9. Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural
history, and progression of ulcerative colitis. A long-term follow-up
of 1116 patients. Dig Dis Sci 1993;38:1137-46.
10. Langholz E, Munkholm P, Davidsen M, Binder V. Colorectal cancer
risk and mortality in patients with ulcerative colitis.
11. Devroede GJ, Taylor WF, Sauer WG, Jackman RJ, Stickler GB.
Cancer risk and life expectancy of children with ulcerative colitis.
N Engl J Med 1971;285:17-21.
12. Mir-Madjlessi SH, Farmer RG, Easley KA, Beck GJ. Colorectal and
extracolonic malignancy in ulcerative colitis. Cancer 1986;58:1569-74.
13. Brostrom O, Monsen U, Nordenwall B, Sorstad J, Hellers G.
Prognosis and mortality of ulcerative colitis in Stockholm County,
1955-1979. Scand J Gastroenterol 1987;22:907-13.
14. Gilat T, Fireman Z, Grossman A, et al. Colorectal cancer in patients
with ulcerative colitis. A population study in central Israel.
15. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and
colorectal cancer. A population-based study. N Engl J Med
16. Stewenius J, Adnerhill I, Anderson H, et al. Incidence of colorectal
cancer and all cause mortality in non-selected patients with
ulcerative colitis and indeterminate colitis in Malmo, Sweden.
Int J Colorectal Dis 1995;10:117-22.
17. Ekbom A, Helmick CG, Zack M, Holmberg L, Adami HO. Survival
and causes of death in patients with inflammatory bowel disease:
A population-based study. Gastroenterology 1992;103:954-60.
18. Winther KV, Jess T, Langholz E, Munkholm P, Binder V. Survival
and cause-specific mortality in ulcerative colitis: Follow-up of a
population-based cohort in Copenhagen County. Gastroenterology
19. Probert CS, Jayanthi V, Wicks AC, Mayberry JF. Mortality in
patients with ulcerative colitis in Leicestershire, 1972-1989.
An epidemiological study. Dig Dis Sci 1993;38:538-41.
20. Farrokhyar F, Swarbrick ET, Grace RH, Hellier MD, Gent AE,
Irvine EJ. Low mortality in ulcerative colitis and Crohn’s disease in
three regional centers in England. Am J Gastroenterol 2001;96:501-7.
21. Elliott PR, Williams CB, Lennard-Jones JE, et al. Colonoscopic
diagnosis of minimal change colitis in patients with a normal
sigmoidoscopy and normal air-contrast barium enema. Lancet
22. Powell-Tuck J, Ritchie JK, Lennard-Jones JE. The prognosis of
idiopathic proctitis. Scand J Gastroenterol 1977;12:727-32.
Silverberg et al
Can J Gastroenterol Vol 19 Suppl A September 200512A
23. Langholz E, Munkholm P, Davidsen M, Nielsen OH, Binder V.
Changes in extent of ulcerative colitis: A study on the course and
prognostic factors. Scand J Gastroenterol 1996;31:260-6.
24. Ayres RC, Gillen CD, Walmsley RS, Allan RN. Progression of
ulcerative proctosigmoiditis: Incidence and factors influencing
progression. Eur J Gastroenterol Hepatol 1996;8:555-8.
25. Meucci G, Vecchi M, Astegiano M, et al. The natural history of
ulcerative proctitis: A multicenter, retrospective study. Am J
26. Moum B, Ekbom A, Vatn MH, Elgjo K. Change in the extent of
colonoscopic and histological involvement in ulcerative colitis over
time. Am J Gastroenterol 1999;94:1564-9.
27. Truelove SC, Witts LJ. Cortisone in ulcerative colitis: Final report
on a therapeutic trial. Br Med J 1955;2:1041-8.
28. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in
adults (update): American College of Gastroenterology, Practice
Parameters Committee. Am J Gastroenterol 2004;99:1371-85.
29. Langholz E, Munkholm P, Davidsen M, Binder V. Course of
ulcerative colitis: Analysis of changes in disease activity over years.
30. Caprilli R, Latella G, Vernia P, Frieri G. Multiple organ dysfunction
in ulcerative colitis. Am J Gastroenterol 2000;95:1258-62.
31. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ,
Harmsen WS, Zinsmeister AR. Ulcerative colitis in Olmsted
County, Minnesota, 1940-1993: Incidence, prevalence, and survival.
32. Shivananda S, Lennard-Jones J, Logan R, et al. Incidence of
inflammatory bowel disease across Europe: Is there a difference
between north and south? Results of the European Collaborative
Study on Inflammatory Bowel Disease (EC-IBD). Gut
33. Langholz E, Munkholm P, Nielsen OH, Kreiner S, Binder V.
Incidence and prevalence of ulcerative colitis in Copenhagen county
from 1962 to 1987. Scand J Gastroenterol 1991;26:1247-56.
34. Jackman RJ, Bargen JA, Heimholz HF. Life histories of 95 children
with chronic ulcerative colitis, a statistical study based on
comparison with a whole group of 871 patients. Am J Dis Child
35. Langholz E, Munkholm P, Krasilnikoff PA, Binder V. Inflammatory
bowel diseases with onset in childhood. Clinical features, morbidity,
and mortality in a regional cohort. Scand J Gastroenterol
36. Lashner BA, Silverstein MD, Hanauer SB. Hazard rates for dysplasia
and cancer in ulcerative colitis. Results from a surveillance program.
Dig Dis Sci 1989;34:1536-41.
37. Brust JC, Bargen JA. Chronic ulcerative colitis among elderly
persons. Minnesota Med 1935;18:583-5.
38. Brandt L, Boley S, Goldberg L, Mitsudo S, Berman A. Colitis in the
elderly. A reappraisal. Am J Gastroenterol 1981;76:239-45.
39. Brandt LJ, Boley SJ, Mitsudo S. Clinical characteristics and natural
history of colitis in the elderly. Am J Gastroenterol
40. Jones HW, Hoare AM. Does ulcerative colitis behave differently in
the elderly? Age Ageing 1988;17:410-4.
41. Softley A, Myren J, Clamp SE, Bouchier IA, Watkinson G,
de Dombal FT. Inflammatory bowel disease in the elderly patient.
Scand J Gastroenterol Suppl 1988;144:27-30.
42. Triantafillidis JK, Emmanouilidis A, Pomonis E, et al. Ulcerative
colitis in the elderly: Clinical patterns and outcome in 51 Greek
patients. J Gastroenterol 2001;36:312-6.
43. LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL. Current
concepts. Primary sclerosing cholangitis. N Engl J Med
44. Broome U, Lofberg R, Lundqvist K, Veress B. Subclinical time span
of inflammatory bowel disease in patients with primary sclerosing
cholangitis. Dis Colon Rectum 1995;38:1301-5.
45. Perdigoto R, Wiesner RH, LaRusso NF, Dozois R. Inflammatory
bowel disease associated with primary sclerosing cholangitis:
Incidence, severity and relationship to liver disease.
Gastroenterology 1991;100:A238. (Abst)
46. Faubion WA, Loftus EV, Sandborn WJ, Freese DK, Perrault J.
Pediatric “PSC-IBD”: A descriptive report of associated
inflammatory bowel disease among pediatric patients with PSC.
J Pediatr Gastroenterol Nutr 2001;33:296-300.
47. 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.
48. Penna C, Dozois R, Tremaine W, et al. Pouchitis after ileal pouch-
anal anastomosis for ulcerative colitis occurs with increased
frequency in patients with associated primary sclerosing cholangitis.
49. Broome U, Lindberg G, Lofberg R. Primary sclerosing cholangitis in
ulcerative colitis – a risk factor for the development of dysplasia and
DNA aneuploidy? Gastroenterology 1992;102:1877-80.
50. Jayaram H, Satsangi J, Chapman RW. Increased colorectal neoplasia
in chronic ulcerative colitis complicated by primary sclerosing
cholangitis: Fact or fiction? Gut 2001;48:430-4.
51. D’Haens G, Geboes K, Peeters M, Baert F, Ectors N, Rutgeerts P.
Patchy cecal inflammation associated with distal ulcerative
colitis: A prospective endoscopic study. Am J Gastroenterol
52. Okawa K, Aoki T, Sano K, Harihara S, Kitano A, Kuroki T.
Ulcerative colitis with skip lesions at the mouth of the appendix:
A clinical study. Am J Gastroenterol 1998;93:2405-10.
53. Yang SK, Jung HY, Kang GH, et al. Appendiceal orifice
inflammation as a skip lesion in ulcerative colitis: An analysis in
relation to medical therapy and disease extent. Gastrointest Endosc
54. Matsumoto T, Nakamura S, Shimizu M, Iida M. Significance of
appendiceal involvement in patients with ulcerative colitis.
Gastrointest Endosc 2002;55:180-5.
55. Yamagishi N, Iizuka B, Nakamura T, Suzuki S, Hayashi N. Clinical
and colonoscopic investigation of skipped periappendiceal lesions in
ulcerative colitis. Scand J Gastroenterol 2002;37:177-82.
56. Yantiss RK, Sapp HL, Farraye FA, et al. Histologic predictors of
pouchitis in patients with chronic ulcerative colitis. Am J Surg
• The diagnosis of IC should be made only after colectomy.
• The term colonic IBD type unclassified (IBDU) should be
used in all other cases where definitive features of CD and
UC are absent.
Joossens S, Reinisch W, Vermeire S, et al. The value of anti-
Saccharomyces cerevisiae (ASCA) and perinuclear anti-
neutrophil cytoplasmic antibodies (pANCA) in indeterminate
colitis (IC): A prospective follow-up study. Gastroenterology
Price AB. Overlap in the spectrum of non-specific inflamma-
tory bowel disease – ‘colitis indeterminate’. J Clin Pathol
Moum B, Ekbom A, Vatn H, et al. Inflammatory bowel disease:
Re-evaluation of the diagnosis in a prospective population
based study in southeastern Norway. Gut 1997;40:328-32.
IC is a well-recognized term but there is a great deal of confu-
sion about its exact meaning. In this section, we will discuss
this problem and propose a new classification system for chron-
ic inflammatory colitis. Population-based studies from
Scandinavia (1-9) have shown that 5% to 20% of IBD patients
with colonic inflammation only cannot be definitively diag-
nosed with CD or UC using available diagnostic tools, includ-
ing clinical examination, radiology, endoscopy and histology.
These patients have been placed in the category of IC, accord-
ing to the original publication by Price (10). The incidence of
Integrated classification of IBD
Can J Gastroenterol Vol 19 Suppl A September 2005 13A
IC is estimated to be 1.6/100,000 to 2.4/100,000 in adults and
at 0.2/100.000 in children (8,9).
Definition of IC: Evolution of diagnostic criteria
The term ‘indeterminate colitis’ was first introduced at
St Mark’s Hospital, United Kingdom, in 1978 by the pathol-
ogist Ashley Price and was based on examination of surgical
specimens that displayed overlapping features of both CD
and UC (10). Originally, IC was considered to be a tempo-
rary diagnosis because it was believed that the majority of
patients would eventually prove to have either CD or UC
during follow-up (2,3,11).
In the following years, the introduction of colonoscopy led
to the development of an integrated diagnosis based on clinical
features and endoscopy with biopsies. The disease is chronic and
restricted to the colon. Typically, endoscopy is inconclusive
and microscopic features of crypt architectural distortion
(more than 10% of crypts) and patchy acute and chronic
inflammation are described, with no particular diagnostic fea-
tures of either CD or UC. Infectious colitis and other causes of
colitis have to be excluded by stool cultures and histological
examination (12-16). This change in definition supports the
concept that IC is really a distinct disease instead of merely a
CD, UC or IC: Does it matter?
One could argue that it does not really matter if chronic colitis
is further classified as IC, CD or UC, because most treatments
(5-aminosalicylic acid, corticosteroids, azathioprine and inflix-
imab) are effective for all. But this is not entirely true. It has
been shown that the clinical course and the prognosis of
patients with IC is worse than that of UC, and several studies
(17-22) have documented a worse outcome of surgery and
greater risk of chronic pouchitis. However, these findings have
not been confirmed by all investigators (22-24). A recent study
from Toronto (22) found that patients with IC have a greater
risk of pouchitis than those with UC (43% versus 22%;
P<0.05), but the risk of pouch failure with excision was not
significantly different (10% versus 6%). In the series of IC
patients who underwent surgery at St Mark’s Hospital in
London between 1960 and 1983, patients who continued to
have a diagnosis of IC after careful preoperative and postoper-
ative assessment did well and were unlikely to later develop
CD (23). So far, it is still unclear whether a total colectomy
with IPAA should be recommended in these patients, and
prospective studies will be required to answer this clinically
• There is a need for prospective studies investigating the
outcome of surgery and of IPAA in patients with IC.
Toward a molecular classification of IC – A role for
A multicentre prospective study (25) from Leuven, Belgium,
Vienna, Austria and Lille, France identified 97 patients who
could not be classified as having either CD or UC.
Serological markers ASCA and atypical antineutrophil cyto-
plasmic antibody with a perinuclear staining pattern at indi-
rect immunofluoresence (pANCA) were determined in all
patients. A definitive diagnosis of CD was made when there
were characteristic small bowel lesions, fistulas or granulomas.
A definitive diagnosis of UC was based on the finding in surgi-
cal specimens of diffuse involvement, starting distally, with a
lack of transmural inflammation and, if applicable, more severe
lesions distally. For the cases where only endoscopic samples
were available, the diagnosis was based on examination of mul-
tiple biopsies, obtained during repeated endoscopies, that veri-
fied that the ileum was uninvolved and that colonic
inflammation was more severe in the distal than the proximal
colon. Further microscopic features included the presence of
widespread and diffuse mucosal distortion, diffuse transmu-
cosal lymphocytic inflammation, cryptitis and crypt abscess-
es. After a mean follow-up of six years, 31 of 97 patients
(32%) acquired a definitive diagnosis of CD (17 cases) or UC
(14 cases). Interestingly, almost one-half of the patients
(48.5%) had neither ASCA nor pANCA, and the majority of
these patients (85%) remained with the diagnosis of IC. In
contrast, 61% of patients who eventually were given a definitive
diagnosis of either CD or UC had one or both antibodies
(P<0.001) (25). A follow-up study in 90 of the 97 patients in the
original cohort (mean duration of follow-up 14.5 years, mini-
mum of 2.5 years) confirmed that these seronegative patients
more often continued to have a diagnosis of IC even after other
antimicrobial antibodies (anti-OmpC and anti-I2) were sought
(26). Using this panel of four antibodies, approximately one-
quarter (26.4%) of the patients were seronegative and, in 74% of
these patients, the exact diagnosis remained indeterminate, in
contrast to only 50% of patients with positive antibodies
It has been hypothesized that the higher incidence of chron-
ic pouchitis in patients with IC and IPAA represent persistent
immune reactivity to microbial antigens (27). In a prospective
study, preoperative serological responses to ASCA, I2 and
OmpC were assessed in 28 IC patients undergoing IPAA. With
a median follow-up of 38 months (range three to 75 months),
61% of patients developed pouchitis, of whom 25% were acute
and 75% chronic. Chronic pouchitis developed in 10 of
16 patients (63%) who had a positive antibody reactivity profile
compared with only two of 12 patients (17%) with a negative
profile (P=0.015). Therefore, IC patients who have a positive
antibody reactivity profile before IPAA are at significantly
higher risk of developing continuous pouch inflammation after
surgery than are those with a negative profile.
• There is a need for studies on the value of novel (eg, Cbir)
antimicrobial antibodies in patients with IC.
• There is a need for studies investigating which
combination of serological markers provide the best
specificity and positive predictive value for specific forms
of IBD, including IC.
Toward a molecular classification of IC – A role for genetic
At present, no full papers have been published examining the
role of genetic markers in the further classification of patients
with IC. DNA was available from a subgroup of the patients
studied by Joossens et al (25) (68 of 97) and was genotyped for
the three main CD-associated NOD2/CARD15 variants (28).
Overall, 14 (20.6%) carried at least one NOD2/CARD15 vari-
ant and 15 patients were given a definitive diagnosis (10 CD
Silverberg et al
Can J Gastroenterol Vol 19 Suppl A September 200514A
and five UC). Only one of the 10 patients with CD carried
NOD2 mutations, compared with none of those with a final
diagnosis of UC and 13 of the remaining 53 IC patients. There
was one compound heterozygous patient, who is still currently
categorized as having IC. These data do not suggest a role for
NOD2 testing in the further classification of IC patients, but
more studies of genetic markers are required.
• There is a need for genetic markers to help in the
classification of IC patients.
Toward a novel classification of IC?
Advances in medical diagnostics as well as results from recent
studies suggest that the concept of IC as a temporary diagnosis
should be reconsidered. We believe that IC, as currently
defined, is an ambiguous term that is applied to a heteroge-
neous group of patients with chronic inflammatory colitis. We
therefore propose a revision of the concept, based on how the
initial diagnosis is made (Figure 1).
In the cases in which the diagnosis is based on findings at
surgical resection, in which features of both CD and UC are
detected, we propose that the term ‘IC’ be retained, because
this was also the setting in which the term was originally
described by Price (10). Follow-up studies (24) have shown
that, unless transmural lymphoid hyperplasia or granulomas
are found, these patients usually prove not to have CD. The
transmural polymorphous inflammation that is seen in these
patients is a feature of severe colitis per se, and is not indicative
of either CD or UC. On the other hand, we believe that stud-
ies investigating the serological markers ASCA, pANCA,
antiflagellin, anti-OmpC and I2 might be helpful in further
differentiating these conditions, especially when IPAA is
The situation is different when the diagnosis is based on
clinical features and endoscopy with biopsies. The clinical fea-
tures consist of chronic IBD with inflammation restricted to
the colon and without small bowel involvement. The
endoscopy is inconclusive and histology reveals chronic
inflammation with absence of diagnostic features of either CD
or UC. In such cases, we propose that the term colonic IBDU
be applied. A careful upper GI evaluation including gastroscopy
and, if normal, novel endoscopic methods (such as video capsule
endoscopy or double-balloon enteroscopy) may be useful. In
general, we believe that more research, including the study of
novel antimicrobial and genetic markers, is needed to further
characterize this subgroup of patients. It is likely that interna-
tional collaborations will be required to achieve this goal.
1. Lee KS, Medline A, Shockey Q. Indeterminate colitis in the spectrum of
inflammatory bowel disease. Arch Path Lab Med 1979;103:173-6.
2. Hildebrand H, Fredrickzon B, Homlquist L, Kristiansson B, Lindquist B.
Chronic inflammatory bowel disease in children and adolescents in
Sweden. J Pediatr Gastroenterol Nutr 1991;13:293-7.
3. Moum B, Ekbom A, Vatn HN, et al. Inflammatory bowel disease:
Re-evaluation of the diagnosis in a prospective population based
study in southeastern Norway. Gut 1997;40:328-32.
4. Ekbom A. Indeterminate IBD: The magnitude of the problem.
Inflamm Bowel Dis 2000;6:S14-S15.
5. Geboes K, De Hertogh G. Indeterminate colitis. Inflamm Bowel Dis
6. Guindi M, Riddell RH. Indeterminate colitis. J Clin Pathol
7. Hale W, Floch M, Burakoff R, Itzkowitz S, Warren B, Plevy S.
Indeterminate colitis. J Clin Gastroenterol 2004;38:S57.
8. Hildebrand H, Finkel Y, Grahnquist L, Lindholm J, Ekbom A,
Askling J. Changing pattern of paediatric inflammatory bowel
disease in northern Stockholm 1990-2001. Gut 2003;52:1432-4.
9. Stewenius J, Adnerhill I, Anderson H, et al. Incidence of colorectal
cancer and all cause mortality in non-selected patients with
ulcerative colitis and indeterminate colitis in Malmo, Sweden.
Int J Colorect Dis 1995;10:117-20.
10. Price AB. Overlap in the spectrum of non-specific inflammatory bowel
disease – ‘colitis indeterminate’. J Clin Pathol 1978;31:567-77.
11. Meucci G, Bortoli A, Albini Riccioli F, et al; on behalf of the GMII
(Gruppo di Studio per le Malattie Infiammatorie Intestinali).
Frequency and clinical evolution of indeterminate colitis:
A retrospective multi-center study in northern Italy. Eur J
Gastroenterol Hepatol 1999;11:909-13.
12. Le Berre N, Heresbach D, Kerbaol M, et al. Histological
discrimination of idiopathic inflammatory bowel disease from other
types of colitis. J Clin Pathol 1995;48:749-53.
13. Riddell RH. Pathology of idiopathic inflammatory bowel disease.
In: Kirsner JB, ed. Inflammatory Bowel Disease, 5th edn.
Philadelphia: WB Saunders Company, 2000:427-50.
14. Tsang P, Rotterdam H. Biopsy diagnosis of ulcerative colitis.
Possibilities and pitfalls. Am J Surg Pathol 1999;23:423-30.
15. Nostrant TT, Kumar NB, Appelmann HD. Histopathology
differentiates acute self-limited colitis from ulcerative colitis.
16. Mottet NK. Intestinal histopathology of ulcerative colitis.
In: Mottet NK, ed. Histopathologic Spectrum of Regional Enteritis
and Ulcerative Colitis, Vol 2. Philadelphia: WB Saunders Company,
17. Koltun WA, Schoetz DJ Jr, Roberts PL, Murray JJ, Coller JA,
Veidenheimer MC. Indeterminate colitis predisposes to perineal
complications after ileal pouch-anal anastomosis. Dis Colon Rectum
18. Stewenius J, Adnerhill I, Ekelund G, 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.
19. McIntyre BP, Pemberton JH, Wolff BG, Dozois RR, Beart RW.
Indeterminate colitis: Long-term outcome in patients after ileal
pouch-anal anastomosis. Dis Colon Rectum 1995;38:51-4.
20. Atkinson KG, Owen DA, Wankling G. Restorative proctocolectomy
and indeterminate colitis. Am J Surg 1994;167:516-8.
21. Stewenius J, Adnerhill I, Ekelund G, et al. Risk of relapse in new cases
of ulcerative colitis and indeterminate colitis. Dis Colon Rectum
22. Brown CJ, Maclean AR, Cohen Z, MacRae HM, O’Connor BI,
McLeod RS. Crohn’s disease and indeterminate colitis and the ileal
pouch-anal anastomosis: Outcomes and patterns of failure. Dis
Colon Rectum 2005 May 23; [Epub ahead of print]
23. Dayton MT, Larsen KR, Christiansen DD. Similar functional results
and complications after ileal pouch-anal anastomosis in patients
with indeterminate vs. ulcerative colitis. Arch Surg 2002;137:690-5.
Integrated classification of IBD
Can J Gastroenterol Vol 19 Suppl A September 200515A
Diagnosis based on
Diagnosis based on
endoscopy with biopsies
overlapping features of both CD
chronic IBD with inflammation restricted to the colon and without
small bowel involvement.
• microscopy: active patchy chronic inflammation with minimal or
moderate architectural distortion and no diagnostic features for CD
or UC. No infectious colitis
Upper GI evaluation (G-scope, enteroclysis and/or
colonic IBD type unclassified (IBDU)
Figure 1) Flow chart illustrating proposed classification for patients
with chronic inflammatory colitis. CD Crohn’s disease; GI
Gastrointestinal; G-scope Gastroscope; IBD Inflammatory bowel
disease; UC Ulcerative colitis
24. Wells AD, McMillan I, Price AB, Ritchie JK, Nicholls RJ. Natural
history of indeterminate colitis. Br J Surg 1991;78:179-81.
25. Joossens S, Reinisch W, Vermeire S, et al. The value of anti-
Saccharomyces cerevisiae (ASCA) and perinuclear anti-neutrophil
cytoplasmic antibodies (pANCA) in indeterminate colitis (IC):
A prospective follow-up study. Gastroenterology 2002;122:1242-7.
26. Joossens S, Colombel JF, Vermeire S, et al. Panel of serologic
antibodies in patients with indeterminate colitis. Gastroenterology
27. Hui T, Landers C, Vasiliauskas E, et al. Serologic responses in
indeterminate colitis patients before ileal pouch-anal anastomosis
may determine those at risk for continuous pouch inflammation. Dis
Colon Rectum 2005;48:1254-62.
28. Vermeire S, Reinisch W, Joossens S, et al. NOD2/CARD15
genotyping in patients with indeterminate colitis (IC): Helpful
towards definitive diagnosis? Gastroenterology 2002;122:AM1416.
29. 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
30. Ahmad T, Armuzzi A, Bunce M, et al. The molecular classification
of the clinical manifestations of Crohn’s disease. Gastroenterology
31. Peeters M, Joossens S, Vermeire S, Vlietinck R, Bossuyt X, Rutgeerts P.
Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil
cytoplasmic autoantibodies in inflammatory bowel disease. Am J
Geographic and ethnic factors associated
• Wide variations exist in the incidence and prevalence of
• A minimal dataset to be used in genetic and
environmental research must involve details of ethnicity
Ekbom A, Helmick C, Zack M, Adami HO. The epidemiology
of inflammatory bowel disease: A large, population-based study
in Sweden. Gastroenterology 1991;100:350-8.
Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A.
Epidemiology of Crohn’s disease and ulcerative colitis in a
central Canadian province: A population-based study. Am J
Roth MP, Petersen GM, McElree C, Feldman E, Rotter JI.
Geographic origins of Jewish patients with inflammatory bowel
disease. Gastroenterology 1989;97:900-4.
Current knowledge suggests that both genetic and environ-
mental influences are important in the etiopathogenesis of
IBD. In this section of the Working Party report, we assess the
geographical and ethnic contributions to the patterns of IBD
and make suggestions about how the disease should be classi-
fied to aid further research. Incidence rates are quoted as num-
ber of cases per 100,000 population.
Geographical variations in the incidence and prevalence of
CD and UC
A global north-south variation in the incidence of IBD has
been documented. Standardized incidence rates of 10.9 to 12.8
for UC and 6.0 to 7.0 for CD have been reported from north-
ern California (1) and Scandinavia (2). Rates of 2.0 to 6.3 for
UC and 0.9 to 3.1 for CD have been observed in the southern
hemisphere (3). Direct comparisons can be misleading,
because IBD is less prevalent in the developing world. For
example, the incidence of UC and CD are 1.9 and 0.5, respec-
tively, in Asia (4), 2.3 and 1.6, respectively in Africa (5), and
2.2 and 0.03, respectively, in Latin America (6). Studies from
within Europe also suggest a north-south incidence gradient
but, again, direct comparison of studies is confounded by dif-
ferences in case ascertainment and data analysis. Raw data sug-
gest that the incidence in northern areas is four to five times
greater than those in southern areas (7-17).
Data from North America confirmed this observation in a
single study (18) with higher hospitalization and mortality
rates from IBD observed in the northern United States com-
pared with southern states. This pattern was seen for African-
Americans and Caucasians, males and females, and UC and
CD. A prospective collaborative European study (EC-IBD)
(19) found that UC was 40% more common in northern cen-
tres, and that CD was 80% more common. Differences were
not as large as expected, which might be due to a rising inci-
dence in southern Europe (14,19). More recent data examin-
ing the incidence of juvenile-onset CD in Scotland (20)
found age-specific incidence rates for CD in northern
Scotland (3.1) to be higher that those in the south (2.1). The
absolute difference was relatively modest, with CD detected
47% more frequently in the north. This difference was not
seen for UC.
There are a number of ‘hot spots’ for the incidence of IBD.
The highest reported incidence and prevalence rates are from
Manitoba, Canada (21,22); Scandinavia (2,13); Iceland (12);
and the United Kingdom, especially Scotland (20,23,24).
High incidence rates from other provinces in Canada, similar
to that of Manitoba, support the notion of northern geographi-
cal areas having the highest incidence rates (25).
Variations according to ethnic background
Historical data suggest that African-Americans have a lower
incidence of IBD than Caucasians. This pattern was seen in
data from South Africa, but the blacks that did develop IBD
were urbanized and had at least a partially Westernized diet
(5). More recent data suggest that incidence rates in blacks
may actually be closer to those in Caucasians. Kurata et al
(26) found that hospitalization rates for CD were similar in
African-Americans and Caucasians, and a tertiary referral
centre study from Georgia, United States, identified a crude
incidence rate of 5.3 for UC and 8.8 for CD in black chil-
dren (27). A prospective United Kingdom survey of child-
hood IBD found that the incidence of both CD and UC in
black children was similar to that in white populations (23).
Furthermore, retrospective data from the United Kingdom
found a nonsignificant difference in the incidence of CD in
Afro-Caribbean and white populations in Derby (4.5 to 5.6
versus 7.0) (28). Southern Asian populations have been
thought to have a low incidence of IBD but United
Kingdom studies have found that Asians born in the United
Kingdom have a higher incidence of UC and proctitis than
white populations (29,30). A three-year prospective study
from Leicester, United Kingdom found the incidence of UC to
be higher in second-generation than first-generation Asians.
Moreover, the incidence of UC in second-generation Asians
exceeds that in Caucasians (31). Available data suggest that
IBD remains uncommon in Hispanics, Asian Americans
Silverberg et al
Can J Gastroenterol Vol 19 Suppl A September 2005 16A
and aboriginal North Americans (32). Aboriginal
Canadians and First Nations persons from Manitoba are
also less likely to develop IBD, especially CD (22).
Epidemiological data have consistently documented a
higher incidence of IBD in Ashkenazi Jewish than in non-
Jewish populations (33). One study suggested that the inci-
dence of IBD within Jewish populations might be related to
the country of origin (34), but more recent data from Israel
found that the incidence (4.2) and prevalence (50.6) of CD
were independent of country of origin, and comparable with
those in many Caucasian populations (35,36) (Table 6). The
incidence and prevalence of CD among non-Ashkenazi Jews
approach those of Ashkenazi Jews in North America and
Europe, and prevalence rates in Israel are lower than those
reported from Manitoba and Rochester, Minnesota (21,37).
Variations in the incidence of IBD between rural and urban
Higher incidences of both CD and UC have been identified in
urban than rural populations in the United States (18),
Manitoba (22), Uppsala, Sweden (16), the Faroe Islands (38),
Scotland (9) and Rochester, Minnesota (37,39). Data from
Alberta, Canada identified an urban predominance for CD but
not UC (40). Few studies have found no difference (41). The
availability of health care resources is frequently cited as a con-
founding factor. Canada and Sweden (16,22) provide universal
health care, thereby minimizing the ascertainment bias, and
the observed differences for both CD and UC between urban
and rural populations were confirmed.
Association between the incidence of IBD with
Blanchard et al (22) found that a higher average household
income was associated with a higher incidence of CD but
not UC. This finding has been confirmed by recent data
from Scotland, which showed an inverse association
between the deprivation score and incidence of juvenile-
onset CD (20).
There are a number of geographical and ethnic influences on
the incidence of IBD. The most prominent are Ashkenazi
Jewish ethnicity and living within an urban, high prevalence
area (North America and western Europe, especially). Many of
the other identified variables suggest a prominent environmen-
tal influence. Although many of these factors are too variable
to be incorporated into a classification of IBD, it would be
appropriate to collect data to enable population stratification
for research purposes. We therefore suggest that a minimal data
set include parameters shown in Table 7.
1. Hiatt RA, Kaufman L. Epidemiology of inflammatory bowel disease
in a defined northern California population. West J Med
2. Moum B, Ekbom A, Vatn MH, et al. Inflammatory bowel disease:
Re-evaluation of the diagnosis in a prospective population based
study in south eastern Norway. Gut 1997;40:328-32.
3. Andres PG, Friedman LS. Epidemiology and the natural course of
inflammatory bowel disease. Gastroenterol Clin North Am
4. Morita N, Toki S, Hirohashi T, et al. Incidence and prevalence of
inflammatory bowel disease in Japan: Nationwide epidemiological
survey during the year 1991. J Gastroenterol 1995;30 (Suppl 8):1-4.
5. Wright JP, Froggatt J, O’Keefe EA, et al. The epidemiology of
inflammatory bowel disease in Cape Town 1980-1984. S Afr Med J
6. Linares de la Cal JA, Canton C, Pajares JM, Mate-Jimenez J.
Inflammatory bowel disease in Argentina and Panama (1987-1993).
Eur J Gastroenterol Hepatol 1997;9:1129.
7. Orholm M, Munkholm P, Langholz E, Nielsen OH, Sorensen IA,
Binder V. Familial occurrence of inflammatory bowel disease. N Engl
J Med 1991;324:84-8.
8. Binder V, Both H, Hansen PK, Hendriksen C, Kreiner S,
Torp-Pedersen K. Incidence and prevalence of ulcerative colitis and
Crohn’s disease in the County of Copenhagen, 1962 to 1978.
9. Sinclair TS, Brunt PW, Mowat NA. Nonspecific proctocolitis in
northeastern Scotland: A community study. Gastroenterology
10. Shivananda S, Pena AS, Nap M, Weterman IT, Mayberry JF,
Ruitenberg EJ, Hoedemaeker PJ. Epidemiology of Crohn’s disease in
Regio Leiden, The Netherlands. A population study from 1979 to
1983. Gastroenterology 1987;93:966-74.
11. Shivananda S, Pena AS, Mayberry JF, Ruitenberg EJ, Hoedemaeker PJ.
Epidemiology of proctocolitis in the region of Leiden, The
Netherlands. A population study from 1979 to 1983. Scand J
12. Bjornsson S, Johannsson JH. Inflammatory bowel disease in Iceland,
1990-1994: A prospective, nationwide, epidemiological study. Eur J
Gastroenterol Hepatol 2000;12:31-8.
13. Roin F, Roin J. Inflammatory bowel disease of the Faroe Islands,
1981-1988. A prospective epidemiologic study: Primary report.
Scand J Gastroenterol Suppl 1989;170:44-6.
14. Trallori G, Palli D, Saieva C, et al. A population-based study of
inflammatory bowel disease in Florence over 15 years (1978-92).
Scand J Gastroenterol 1996;31:892-9.
Integrated classification of IBD
Can J Gastroenterol Vol 19 Suppl A September 200517A
The prevalence of Crohn’s disease in the Jewish Israeli
population – stratification by birthplace of patients
Reference PopulationYearsTotalN Am Africa Israel
42 Beer-Sheva 1961–198014.024.619.46.9
43Central Israel1970–198019.430.012.2 12.6
44 Kibbutz1987 25.5 17.441.838.9
45 Kinneret 1960–199045.980.141.841.1
36 Beer-Sheva1968–1992 50.658.755.046.3
46 Kibbutz1997 65.179.2 11.978.3
*Figures are quoted per 100,000 population. N Am North America
Recommendations for geographical and ethnic data to be
collected in a research minimal data set
Country of birth Proband/parents/grandparents
Family history of IBDFirst-degree relative (specify)
Multiple affected family members/other
Place of residencePostal codes
IBD Inflammatory bowel disease
15. Cottone M, Cipolla C, Orlando A, Oliva L, Aiala R, Puleo A.
Epidemiology of Crohn’s disease in Sicily: A hospital incidence study
from 1987 to 1989. “The Sicilian Study Group of Inflammatory
Bowel Disease”. Eur J Epidemiol 1991;7:636-40.
16. Ekbom A, Helmick C, Zack M, Adami HO. The epidemiology of
inflammatory bowel disease: A large, population-based study in
Sweden. Gastroenterology 1991;100:350-8.
17. Kyle J. Crohn’s disease in the northeastern and northern Isles of
Scotland: An epidemiological review. Gastroenterology
18. Sonnenberg A, McCarty DJ, Jacobsen SJ. Geographic variation of
inflammatory bowel disease within the United States.
19. Shivananda S, Lennard-Jones J, Logan R, et al. Incidence of
inflammatory bowel disease across Europe: Is there a difference
between north and south? Results of the European Collaborative
Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996;39:690-7.
20. Armitage EL, Aldhous MC, Anderson N, et al. Incidence of
juvenile-onset Crohn’s disease in Scotland: Association with
northern latitude and affluence. Gastroenterology 2004;127:1051-7.
21. Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A. Epidemiology
of Crohn’s disease and ulcerative colitis in a central Canadian
province: A population-based study. Am J Epidemiol
22. Blanchard JF, Bernstein CN, Wajda A, Rawsthorne P. Small-area
variations and sociodemographic correlates for the incidence of Crohn’s
disease and ulcerative colitis. Am J Epidemiol 2001;154:328-35.
23. Sawczenko A, Sandhu BK, Logan RF, et al. Prospective survey of
childhood inflammatory bowel disease in the British Isles. Lancet
24. Rubin GP, Hungin AP, Kelly PJ, Ling J. Inflammatory bowel disease:
Epidemiology and management in an English general practice
population. Aliment Pharmacol Ther 2000;14:1553-9.
25. Bernstein CN, Wajda A, Blanchard JF, et al. The Burden Of IBD in
Canada: A Population-Based Study. Gastroenterology 2005; DDW.
26. Kurata JH, Kantor-Fish S, Frankl H, Godby P, Vadheim CM. Crohn’s
disease among ethnic groups in a large health maintenance
organization. Gastroenterology 1992;102:1940-8.
27. Ogunbi SO, Ransom JA, Sullivan K, Schoen BT, Gold BD.
Inflammatory bowel disease in African-American children living in
Georgia. J Pediatr 1998;133:103-7.
28. Fellows IW, Mayberry JF, Holmes GK. Crohn’s disease in West
Indians. Am J Gastroenterol 1988;83:752-5.
29 Probert CS, Jayanthi V, Pinder D, Wicks AC, Mayberry JF.
Epidemiological study of ulcerative proctocolitis in Indian migrants
and the indigenous population of Leicestershire. Gut 1992;33:687-93.
30. Montgomery SM, Morris DL, Pounder RE, Wakefield AJ. Asian
ethnic origin and the risk of inflammatory bowel disease. Eur J
Gastroenterol Hepatol 1999;11:543-6.
31. Carr I, Mayberry JF. The effects of migration on ulcerative colitis:
A three-year prospective study among Europeans and first- and
second- generation South Asians in Leicester (1991-1994). Am J
32. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease:
Incidence, prevalence, and environmental influences.
33. Yang H, Taylor KD, Rotter JI. Inflammatory bowel disease. I.
Genetic epidemiology. Mol Genet Metab 2001;74:1-21.
34. Roth MP, Petersen GM, McElree C, Feldman E, Rotter JI.
Geographic origins of Jewish patients with inflammatory bowel
disease. Gastroenterology 1989;97:900-4.
35. Ekbom A. The epidemiology of IBD: A lot of data but little
knowledge. How shall we proceed? Inflamm Bowel Dis
36. Odes HS, Locker C, Neumann L, et al. Epidemiology of Crohn’s
disease in southern Israel. Am J Gastroenterol 1994;89:1859-62.
37. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ,
Harmsen WS, Zinsmeister AR. Ulcerative colitis in Olmsted
County, Minnesota, 1940-1993: Incidence, prevalence, and survival.
38. Berner J, Kiaer T. Ulcerative colitis and Crohn’s disease on the Faroe
Islands 1964-83. A retrospective epidemiological survey. Scand J
39. Gollop JH, Phillips SF, Melton LJ, III, Zinsmeister AR.
Epidemiologic aspects of Crohn’s disease: a population based study in
Olmsted County, Minnesota, 1943-1982. Gut 1988;29:49-56.
40. Pinchbeck BR, Kirdeikis J, Thomson AB. Inflammatory bowel
disease in northern Alberta. An epidemiologic study. J Clin
41. Evans JG, Acheson ED. An epidemiological study of ulcerative colitis
and regional enteritis in the Oxford area. Gut 1965;6:311-24.
42. Krawiec J, Odes HS, Lasry Y, Krugliak P, Weitzman S. Aspects of the
epidemiology of Crohn’s disease in the Jewish population in Beer
Sheva, Israel. Isr J Med Sci 1984;20:16-21.
43. Fireman Z, Grossman A, Lilos P, Eshchar Y, Theodor E, Gilat T.
Epidemiology of Crohn’s disease in the Jewish population of central
Israel, 1970-1980. Am J Gastroenterol 1989;84:255-8.
44. Niv Y. The prevalence of Crohn’s disease in the Israeli Kibbutz
population. Can J Gastroenterol 1991;5:91-3.
45. Shapira M, Tamir A. Crohn’s disease in the Kinneret sub-district,
Israel, 1960-1990. Incidence and prevalence in different ethnic
subgroups. Eur J Epidemiol 1994;10:231-3.
46. Niv Y, Abuksis G, Fraser GM. Epidemiology of Crohn’s disease in
Israel: a survey of Israeli kibbutz settlements. Am J Gastroenterol
Serological studies in IBD –
Implications for classification
• Serological markers should not be the only determinant
for clinical decision making.
• Novel markers show promise and panels of markers may
prove useful in differential diagnosis and prognosis.
• The IBD serological panel (Table 8).
Joossens S, Reinisch W, Vermeire S, et al. The value of sero-
logic markers in indeterminate colitis: A prospective follow-up
study. Gastroenterology 2002;122:1242-7.
Mow WS, Vasiliauskas EA, Lin YC, et al. Association of anti-
body responses to microbial antigens and complications of small
bowel Crohn’s disease. Gastroenterology 2004;126:414-24.
Targan S, Landers CJ, Yang H, et al. Antibodies to CBir1
flagellin define a unique response that is associated
independently with complicated Crohn’s disease.
The two most widely studied serological tests are for the pres-
ence of pANCA (reviewed in [1,2]) and ASCA. The sero-
prevalence of these markers among different studies has been
quite variable, likely in part due to the lack of standardization
of the techniques used for these assays (3).
Immune responsiveness to several specific microbial anti-
gens in patients with CD and UC has been described by
Targan et al (4). OmpC is the outer membrane porin C of
Escherichia coli. I2 is a fragment of bacterial DNA that has been
cloned from lamina propria mononuclear cells in patients with
active CD. This sequence has been shown to be associated with
Pseudomonas fluorescens. In patients with CD, reported sero-
prevalence is 55% for anti-OmpC and 50% for anti-I2 (5).
Linskens et al (6) used several strains of Gram-positive anaer-
obic coccoid rods in an agglutination test. The agglutinating
antibodies to coccoid rods were mostly of immunoglobulin G
isotype. A sensitivity of 52% for CD was reported. More
recently, Lodes et al (7) used serological expression cloning
in colitic C3H/HeJBir mice to identify commensal bacterial
Silverberg et al
Can J Gastroenterol Vol 19 Suppl A September 200518A
proteins that could contribute to the pathogenesis of IBD. The Download full-text
dominant antigens identified were flagellins. A T cell line spe-
cific for one of those flagellins (CBir1) induced colitis when
transferred into naive mice with severe combined immunode-
ficiency. A serum response to flagellin CBir1 was detected in
50% of CD patients, 6% of UC patients and 8% of controls
Serological markers and IBD diagnosis
The clinical value of pANCA or ASCA testing in patients
presenting with nonspecific GI symptoms is limited because of
inadequate sensitivity. ANCA positivity has been observed in
other inflammatory disorders of the colon, such as eosinophilic
and collagenous colitis. The specificity of ASCA seems to be
higher for CD, but ASCA positivity has been observed in
patients with Behcet’s disease, primary biliary cirrhosis,
autoimmune hepatitis and celiac disease, in which positive
results have been reported in up to 43% of patients (9).
Although the use of serological markers in routine screening is
not recommended in adults (10), the situation may be differ-
ent in children (11). Two recent studies (12,13) in children
came to the conclusion that, as in adults, the low sensitivity of
serological markers limits their value in screening and evalua-
tion of patients with suspected IBD.
The most specific serological test to distinguish CD from UC is
the combination of ASCA and pANCA. The CD-associated
serological pattern is ASCA+/pANCA–; conversely, the UC-
associated pattern is pANCA+/ASCA–. Several independent
studies have found that these combinations had positive pre-
dictive values of 77% to 96% for differentiating CD from UC
(1,2). Using likelihood ratios, patients who are pANCA+ and
ASCA– are 19 times more likely to have UC, whereas patients
who are ASCA+ and pANCA– are 16 times more likely to
have CD (14). It should be remembered, however, that these
estimates are based on retrospective studies performed mostly
in referral centre populations.
The results of the only prospective study that assessed the
usefulness of serological markers in IC provided further evi-
dence for the theory that IC, rather than being merely undiag-
nosed UC or CD, is rather a distinct clinical entity (15).
ASCA and pANCA tests were performed for 97 patients with
an initial diagnosis of IC. After a mean of one-year follow-up,
a definitive diagnosis was reached in 31 of 97 patients (32%)
(Table 9). ASCA+/ANCA– results predicted CD in 80% of IC
patients, whereas ASCA–/ANCA+ results were predictive of
UC in 64% (Table 10). Nevertheless, 48.5% of IC patients did
not have antibodies against either ASCA or ANCA, perhaps
limiting the clinical utility of serological testing. In summary,
the serological tests may serve as an adjunct to the clinical
workup in IC. Although it may be too early to suggest they be
used alone to determine the appropriateness of restorative
proctocolectomy in patients needing surgery (16), the addition
of new markers may improve overall diagnostic accuracy.
In a study incorporating additional serological markers,
the addition of anti-OmpC and anti-I2 to ASCA and
pANCA was of no value in the diagnosis of IC (17); whereas
the ASCA2 test allowed the reclassification of three CD
patients (18). The new anti-CBir1 flagellin antibodies could
be relevant in IC because they are associated with colonic CD,
independent of ASCA, and may allow differentiation of CD
from UC in patients who are positive for pANCA (4).
Serological markers and IBD stratification
Serological markers have been further used to categorize sub-
groups of patients with IBD. In patients with CD, pANCA
positivity has been associated with a UC-like phenotype
(19,20), and a recent analysis found that it is associated with
late-onset disease and inflammatory disease type according to
the Vienna classification (21). In general, these types of stud-
ies are very difficult to compare, and seemingly contradictory
results could depend on the specific technique employed. For
example, the use of indirect immunofluorescence alone allows
only the detection of the antibody, but the ELISA technique
provides an assessment of the amount of antibody present.
The strongest phenotypic association of ASCA is with
CD involving the small bowel rather than the colon. The
group from Edinburgh (22) described a strong association
between ASCA positivity and progression type from purely
Integrated classification of IBD
Can J Gastroenterol Vol 19 Suppl A September 200519A
Prevalence of antibodies in inflammatory bowel disease
pANCAASCAPAB OmpC Anti-I2flagellin
CD2–2848–6927–39 5550 50
Healthy controls2.550 1.3 108
Data from references 1,2,4,7,23 and 41. ASCAAnti-Saccharomyces cerevisiae
antibody; CD Crohn’s disease; OmpC Outer membrane porin C of
Escherichia coli; PAB Antipancreatic antibody; pANCA Antineutrophil cyto-
plasmic antibody with a perinuclear staining pattern at indirect immunofluo-
resence; UC Ulcerative colitis
Results of anti-Saccharomyces cerevisiae antibody
(ASCA) and antineutrophil cytoplasmic antibody (ANCA)
in a prospective study of patients with indeterminate
Ulcerative Crohn’s Indeterminate
n (%) colitis n (%)disease n (%)colitis n (%)
ASCA+/ANCA– 26 (26.8)8 (30.8) 2 (7.7) 16 (61.5)
ASCA–/ANCA+ 20 (20.6)4 (20) 7 (35)9 (45)
ASCA+/ANCA+ 4 (4.1) 2 (50) 1 (25)1 (25)
ASCA–/ANCA– 47 (48.5)3 (6.4)4 (8.5) 40 (85.1)
Total97 (100) 17 (17.5) 14 (14.4) 66 (68.1)
Data from reference 15
Sensitivity, specificity, positive predictive value (PPV) and
negative predictive value (NPV) of the combination of anti-
Saccharomyces cerevisiae antibody (ASCA) and
antineutrophil cytoplasmic antibody (ANCA) in a
prospective study of patients with indeterminate colitis
ASCA+/ANCA– CD8/12 (66.7) 7/9 (77.8)8/10 (80) 7/11 (63.6)
ASCA–/ANCA+ UC7/9 (77.8) 8/12 (66.7)7/11 (63.6)8/10 (80)
Data from reference 15. CD Crohn’s disease; UC Ulcerative colitis