ok biblio: epidemiology and natural history of inﬂammatory bowel diseases

8/3/2019 OK biblio: Epidemiology and Natural History of Inflammatory Bowel Diseases

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Epidemiology and Natural History of Inflammatory Bowel Diseases

Jacques Cosnes* Corinne

GowerRousseauPhilippe Seksik* Antoine Cortot

Service de Gastroentrologie et Nutrition, Hpital St-Antoine and Pierre-et-Marie Curie University (Paris VI), Paris; andUniversity Lille Nord de France, CHU Lille and

Lille-2 University, Clinique des Maladies de lAppareil Digestif, and Registre EPIMAD, Lille, France

In the West, the incidence and prevalence of inflam-matory bowel diseases has increased in the past 50years, up to 814/100,000 and 120200/100,000 per-sons, respectively, for ulcerative colitis (UC) and6 15/100,000 and 50200/100,000 persons, respec-tively, for Crohns disease (CD). Studies of migrantpopulations and populations of developing countriesdemonstrated a recent, slow increase in the incidenceof UC, whereas that of CD remained low, but CDincidence eventually increased to the level of UC. CDand UC are incurable; they begin in young adulthoodand continue throughout life. The anatomic evolu-tion of CD has been determined from studies of

postoperative recurrence; CD begins with aphtousulcers that develop into strictures or fistulas. Lesionsusually arise in a single digestive segment; this sitetends to be stable over time. Strictures and fistulas aremore frequent in patients with ileal disease, whereasCrohns colitis remains uncomplicated for manyyears. Among patients with CD, intestinal surgery isrequired for as many as 80% and a permanent stomarequired in more than 10%. In patients with UC, thelesions usually remain superficial and extend proxi-mally; colectomy is required for 10%30% of patients.Prognosis is difficult to determine. The mortality of

patients with UC is not greater than that of the pop-ulation, but patients with CD have greater mortalitythan the population. It has been proposed that onlyaggressive therapeutic approaches, based on treat-ment of early recurrent lesions in asymptomatic in-dividuals, have a significant impact on progression ofthese chronic diseases.

Keywords: Colon; Intestine; Gastrointestinal Disorder; In-flammatory Response.

Inflammatory bowel disease (IBD) includes Crohns

disease (CD) and ulcerative colitis (UC), chronic dis-eases that generally begin in young adulthood and last

throughout life. Although progress has been made inunderstanding these diseases, their etiology is unknown.Their incidence is increasing worldwide, and the diseasesremain incurable. IBD places a heavy burden on popula-tions because it reduces quality of life and capacity forwork and increases disability. The prevalence of IBD ismore than 200 cases per 100,000 inhabitants in the West,and IBD has a major impact on health care resources.

Most data on epidemiology and the natural history ofIBD have been taken from population-based studies per-formed in Scandinavia and in Olmsted County, Minne-sota, during the years 19501970; data have been col-lected and maintained using remarkable systems. Disease

progression and prognosis greatly changed radically withthe discoveries of steroid therapies in the 1950s, immu-nosuppressants in the 1970s, and more recently, biolog-ics. Although these treatments do not have severe com-plications and improve quality of life, it is not clearwhether they are able to modify the long-term course ofthe diseases.

Epidemiology of IBD

Incidence

The highest incidences of CD and UC have beenreported in northern Europe,1 the United Kingdom,2,3

and North America.4,5 In those regions, such highincidences may indicate common etiologic factors. Theincidence of UC is greater than that of CD, except inCanada57 and several areas of Europe,811 althoughthis has been changing over the past 20 years. Canter-bury County, New Zealand, has among the highestincidence of CD (16.5/100,000 people)12; IBD hasemerged in countries in which it had rarely been pre-

Abbreviations used in this paper: CD, Crohns disease; IBD, inflam-

matory bowel diseases; UC, ulcerative colitis.

2011 by the AGA Institute

0016-5085/$36.00doi:10.1053/j.gastro.2011.01.055

GASTROENTEROLOGY 2011;140:17851794


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viously reported, including South Korea, China, India,Iran, Lebanon, Thailand, the French West Indies, andNorth Africa.1315 In these countries, the occurrence ofUC preceded that of CD by about 10 years. In somecountries, such as Japan, the incidence of IBD was

initially low but has recently increased.16

The overallincidence of IBD can be broken down into severalgeographic zones: those with a high incidence, thosewith a moderate incidence, those with low incidence 15years ago but where incidence has constantly in-creased, and those with unknown incidence (Figure 1)(Tables 1 and 2).

Prevalence

Data on IBD prevalence are scarce but important.Simultaneous measurement of the prevalence/incidenceratio is available from only a few studies; the ratio varies

from 6.6 to 23.3,17

The prevalence of CD in North Amer-ica varies from 44 to 201/100,000, and that for UC from37.5 to 238/100,0002,18; in Europe, CD prevalence variesfrom 8 to 214/100,000 and that of CD from 21 to294/100,000.19 When values are extrapolated to the Eu-ropean Community, they are estimated to be 1 millionpersons with CD and 1.4 million with UC in Europe. It isa challenge to extrapolate incidence data to 490 millionEuropeans because of spatial heterogeneity. One study inthe United States, based on health insurance data from 9million persons, calculated the CD prevalence to be 201and the UC prevalence to be 238, leading to an estimate

that there are more than 1.3 million patients with IBD inthe United States19 (Tables 1 and 2).

Age

The peak age for CD occurrence is 2030 years; forUC, it is 3040 years. Some studies have reported that asecond peak occurs at 6070 years, but this observation hasnot been confirmed. Pediatric IBD accounts for 7% to 20%

of all IBD cases, based on varying results from population-based studies.2022 Recent data indicate higher rates of pe-diatric CD than UC; in France, pediatric CD incidenceincreased from 3.5/100,000 in 1990 to 5.2/100,000 in 2005,whereas pediatric UC remained at around 0.8/100,000.23 Asimilar trend has been reported in many areas of Europeand North America, except in Finland and northern Cali-fornia where the incidence of pediatric UC is higher thanthat of pediatric CD.24,25 These observations indicate thatenvironmental factors affect incidence of IBD (mainly CD)in children, leading to many research investigations ofpediatric cohorts. Among migrant populations, age at

time of migration affects IBD risk; the risk of devel-oping an IBD is highest among children that migratebefore the age of 15 years, illustrated by findings froma study performed in British Columbia.26 Interestingly,appendectomies were reported to reduce risk for UC ifperformed before the age of 20 years. This indicatesthat environmental factors may remain active in trig-gering IBD (mainly CD) in children, focusing researchinvestigations on pediatric cohorts.

Sex

UC occurs slightly more frequently in men

(60%), whereas CD occurs 20%30% more frequently inwomen, particularly in high-incidence areas,5,9,12 al-

Figure1. Theglobal mapof inflammatory bowel disease:redrefers to annualincidencegreater than 10/105, orange to incidenceof 510/105,green

to incidence less than 4/105, yellow to low incidence that is continuously increasing. Absence of color indicates absence of data.

1786 COSNES ET AL GASTROENTEROLOGY Vol. 140, No. 6


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though CD was reported to occur more frequentlyamong men in some low-incidence areas.17 The higher

incidence of CD in women is not observed worldwide;in high-rate areas in Europe and North America and, in

some developing countries, the incidence of CD amongmen has increased, becoming equivalent to or even

higher than that of women.1,4,27,28

The distribution ofCD and UC among pediatric patients is opposite to

Table 1. Incidence and Prevalence of CD

Country

Dates of studies

(references)

Incidence

(/105)

Prevalence

(/105)

Japan 197499 0.08 5.8

1991100 0.5 21.2

2005101

South Korea 19861990102 0.5 11.2

20012005102 1.3

Romania 2002200327 0.5 8.3

Croatia 19801989103 0.7

Zagreb 20002004104 7.0

Primorsko-Goranska

Czech Republic 1999105 1.5

South Africa 19801984106 2.6 (White)

1.8 (Colored)

0.3 (Black)

Spain 19811988107 1.6 19.8

Navarra 20012003108 5.9

Northern Spain 2000200233 7.5

French West Indies 1997199915 1.9

Hungary 1977109 0.4 52.9

2001109 4.7

Italy (8 cities) 19891992110 2.3 40.0

Italy (Florence) 1978111 1.9

1992111 3.4

Finland (Helsinki) 1985112 3.0

Greece (Crete) 19901994113 3.3

Northern Greece 19832005114 0.9

12 Southern European

citiesa1991199331 3.6

Olmsted County,

Minnesota

19401993115 5.8 133

199020004 7.9 174

Denmark 19791987116 4.1 54

Copenhagen County 200320051 8.6 151

North Jutland 1978198218 4.1b; 3.21

1998200218 10.7b; 8.5Sweden

Orebro 19831987117 6.7 146

Stockholm 19551989118 4.6

Stockholm 19902001119 8.3

South Norway 19901993120 5.8

Wales (Cardiff ) 198619902 5.6

199620058 6.6

8 North European

citiesa1991199331 6.3

Northern France 1988200523 6.3

Germany 2004200611 6.6

Canada

Alberta 197719816 10 44.4

Manitoba 198919947 14.6 198.5

British Colombia 199820005

8.8 161Nova Scotia 199820005 20.2 319

United Kingdom (Derby) 1951121 0.7

1985121 6.7

New Zealand

(Canterbury)

2004200512 16.5 155.2

NOTE. Colored refers to persons of a mixed origin.aMulticenter European study that included 8 northern and 12 south-

ern areas.bWomen; men.

Table 2. Incidence and Prevalence of UC

Country

Study dates

(references)

Incidence

(/105)

Prevalence

(/105)

Japan 197499 0.5

1991100 1.9 18.1

2005101

South Korea 19861990102 0.3 7.6

20012005102 3.1 31

Oman 19871994122 1.4

Olmsted County,

Minnesota

19401993115 7.6 229

1991115 8.8 214

199020004

Isral 19651994123 3.5 44.6

Isral (Galilee) 19671976124 0.9

Beer Sheva 19711986 3.8

1986 5.8

19611985125

Germany 19801984126 2.4

19911995126 3.0

2004200611 3.9

Hungary 1977109 1.7 142.6

2001109 11.0

2000109

South Africa 19801984106 5.0 (White)

1.9 (Colored)

0.6 (Black)

Croatia 20002004104 4.3 21.4 (1989)

Primorsko-Goranska 19801989103 1.5

Zagreb 1989103

Northern France 1988200523 4.1

Italy (8 cities) 19891992110 5.2 121.0

Italy (Florence) 1990111 3.8

1992111 9.6

Canada 197719816 6.0 37.5

Alberta 19816 19.5 169.7

Nova Scotia 199820005 14.3 249Manitoba 198919947

Sweden 1958127 4.2

Malm 1982127 9.4

The Netherlands 19911995128 10.0

12 South European

citiesa1991199331 8.0

Spain 19811988107 3.2 43.4

Navarra 1988107 9.6

Northern Spain 20012003108 9.1

2000200233

8 North European

citiesa1991199331 11.4

Norway 19901993129 13.6

Denmark 200320051 13.4 294

Copenhagen 19781982

18

8.3

b

; 7.2North Jutland 1998200218 17.0b; 16.7

200218

New Zealand

(Canterbury)

2004200512 7.6 145.0

200512

NOTE. Colored refers to persons of a mixed origin.aMulticenter European study that included 8 northern and 12 south-

ern areas.bWomen; men.

May 2011 INFLAMMATORY BOWEL DISEASES 1787


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that of adults: there is a predominance of CD amongboys and of UC among girls. The change in the balanceof IBDs among male and female patients occurs be-tween 14 and 17 years.20

EvolutionIn the past 50 years, the incidence of UC first

increased then stabilized or even decreased; during thestabilization phase, the incidence of CD has continuallyincreased. Studies of populations in Olmsted County,Minnesota, found that the prevalence of UC increasedfrom 117/100,000 to 268/100,000 from 1965 to 1991and then decreased to 214/100,000 in 2001; the preva-lence of CD increased from 91/100,000 to 144/100,000from 1983 to 1991 and then increased to 174/100,000 in2001.2 Similar trends have been observed in regions ofEurope.1,18 In northern France, the incidence of CD

increased from 5.3/100,00 in 1988 to 7/100,000 in1999 and then stabilized at 6.4/100,000 in 2005,23

whereas the incidence of UC remained stable at around4/100,000. However, the incidence of UC remainedstable or even continued to increase in other regions,including northeastern Scotland, Sweden, Germany,Italy (it doubled in Florence between 1978 and 1992),and Denmark (it increased 2-fold between 1978 and2002).18

In countries that are becoming Westernized, the inci-dence of UC increases first, followed later by CD; Asiahad a high ratio of UC/CD incidence in the 1980s and1990s, but, then in 2000, the incidence of CD increased(Table 2). In Japan, Singapore, and South Korea, IBDfrequency was initially low but rapidly increased.29 InSouth Korea, between 19861990 and 20012005, theincidence of UC increased from 0.3/100,000 to 3.1/100,000 and that of CD increased from 0.5/100,000 to1.3/100,000, respectively. In China, a systematic review ofpublished hospital-based cohorts from 1950 to 2002 es-timated a CD incidence and prevalence of 0.3/105 and1.4, respectively. In India, the prevalence of UC in thePunjabi population has been reported to be 44/100,000,and its incidence is 6.0/100,000.14 In Africa and Centraland South America, data are not available or scarce.

Overall, a pattern can be drawn for IBD frequency in thedeveloping world: an initially low UC incidence, followedby an increase in UC while the CD incidence remains low,and eventually a CD incidence that approaches UC levels.

Geographic Heterogeneity

In North America, the highest incidences of CDoccur in Canada and the northern United States, com-pared with the southern part of the continent. A studyusing insurance data confirmed a higher rate of hospi-talization in the northern United States.30 A North-South gradient was also reported for IBD in Europe.

Mean incidence rates of UC were 11.8/100,000 in theNorth and 8.7/100,000 in the South; mean incidence

rates of CD were 6.3/100,000 and 3.6/100,000 for Northand South, respectively.31 However, this pattern cannotbe generalized. The incidence rates of UC in centralGreece32 and northern Spain33 were reported to be 11/100,000 and 9/100,000, respectively. One of the highest

incidence rates of CD in the United States was reportedin Georgia,34 and northern Canada has low rates com-pared with southern Canada, possibly from differentpopulations (aboriginals).35 In France, the incidence ofCD (nationwide, calculated using insurance data) washigher in the North, whereas the incidence of UC wasevenly distributed throughout the country.36 However,each area may have specific local environmental factors. Accordingly, a CD relative risk1.5 was found in 96 of273 cantons (the smallest geographic administrativelevel) in northern France.37 There are no clear explana-tions for regional variations in IBD risk.

Ethnic Differences and Migrant Populations

IBD was initially believed to occur less frequentlyamong non-white populations, particularly AfricanAmericans, compared with whites. However, IBD is ob-served with equal frequency among these populations:the seemingly lower incidence might be related to limi-tations in access to care. A study performed in southernCalifornia revealed that, although hospitalization ratesfor CD were the same between whites and African Amer-icans, the prevalence of CD in African Americans wastwo-thirds that of whites.38 In the state of Georgia, in theUnited States, Ogunbi et al reported that the highestincidence of CD occurs in African American children.34

Adult Hispanic Americans and Asian Americans seemto have a lower prevalence of CD than non-Hispanicwhites. However, in a systematic review of IBD and eth-nicity, worldwide, the incidence of IBD increased between1996 and 2000 in Hispanics (Puerto Rico) from 2.6/100,000 to 7.5/100,000 and, in Asians (South Korea),from 0.3/100,000 to 5.3/100,000 (1986 to 2005).39 Arecent study showed more UC cases in Hispanic andAsian children but a trend toward more CD in African American children.24 There have also been reports ofincreased risk of UC among southern Asians who mi-

grated to the United Kingdom26 compared with the Eu-ropean UK population (17/100,000 vs 7/100,000). Epide-miologic data from migrant populations indicate thatgenetic and environmental factors each contribute toIBD risk.

There is a high prevalence of IBD among Jewish pop-ulations; among the Jewish population living outside ofIsrael, the prevalence of IBD remains higher than amongthe non-Jewish population and is similar to the preva-lence of local populations; when the prevalence is high inthe overall population (as in Malmo, Sweden), it is higherin the Jewish population living in that area than in the

Jewish population living in areas with low prevalence ofIBD.40,41 From 1960 to 1970, a lower incidence of IBD



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was reported among Jewish individuals born in Asia,Africa, and Israel than among Jewish individuals born inEurope and North America.41,42 Ten years later, the prev-alence of IBD in Israel had increased among all ethnicgroups, reducing previously reported differences.43,44

These data support the combination of genetic and en-vironmental factors in the pathogenesis of IBD.

Environmental Factors

Epidemiologic studies of IBD susceptibility indi-cate an interaction between genetic and environmentalfactors. An analysis of putative environmental factorsinvolved in IBD is beyond the scope of this review. Onlysmoking and appendectomy have been clearly shown toaffect IBD risk; appendectomy and smoking reduce riskfor UC, whereas active smoking increases risk for CD.However, these parameters cannot account for all varia-

tions in IBD incidence and prevalence; rates of appendec-tomies have decreased in developed countries, whereasthe incidence of UC has remained constant or even de-creased. Smoking cannot explain worldwide increases inCD; the incidence of CD is low in several populations ofheavy smokers (Asia, Africa) and high in some popula-tions of mild smokers (Sweden, Canada).

Natural History of CD

Anatomic Evolution

Our understanding of the anatomic evolution ofCD improved with the description of the postoperativerecurrence model.45,46 In this model, within 8 days aftersurgery for CD, a primary lesion of focal inflammatoryinfiltrate forms in the ileum, above the anastomosis47;aphtous ulcers then appear and are visible in as many as66% of patients by 3 months after surgery, followed bysuperficial extensive ulcers and deep ulcers that precedethe development of a stricture.45 A stricture can be asso-ciated with a fistula that develops above it, or a fistula candevelop within the most severe inflammatory area.48

Postoperative recurrence is almost guaranteed; fewerthan 5% of patients have normal results in endoscopyexaminations 10 years after surgery. Symptoms occur on

average 23 years after the anatomic lesions are found.46The progression of CD that is not treated by surgery does

not necessarily differ from postoperative disease progres-sion, from aphtous ulcers to development of complications.The progression of tissue damage ranges from weeks todecades but can be stopped or reversed, spontaneously orthrough therapy. Superficial lesions, particularly aphtousulcers, are most prone to regression; deep ulcers and evenfistulas can heal, whereas a stricture, when associated withprestenotic dilatation, is usual definitive.

During progression of CD, the inflammatory processcan involve any part of the digestive tract, from the

mouth to the anus, but mainly affects the distal ileumand the colon. The Montreal classification of CD distin-

guishes disease of the ileum, colon, and both ileum andcolon49; CD occurs in these regions in equal proportionsof patients.50 Approximately 10%15% of patients haveassociated upper gastrointestinal lesions. The disease sitetends to be stable over time.51 In patients with ileal

disease, subsequent colonic lesions develop in 20% ofpatients after 10 years52; disease extends to the smallbowel in 20% of patients with colitis.53

About 20%30% of patients present with perianal lesionsand 15%20% have or have had a fistula.16,54,55 During thedisease course, the cumulative risk for perianal involvementis about 50%.56,57 In patients with CD in Olmsted County,Minnesota, the cumulative risk of perianal fistula was 45%at 20 years58; risk in patients with colonic disease was 2-foldthat of patients with ileal disease.59 Perianal lesions causemany penetrating complications that require surgical drain-age, with risk of incontinence.

Patients who received surgery for an abscess, fistula,or peritonitis, have an increased risk for developingfurther penetrating complications.60 Conversely, pa-tients with strictures tend to have recurrence of stric-tures. This distinction led to the definition of 3 typesof CD behaviors: penetrating, stricturing, and nonpen-etrating/nonstricturing (or inflammatory). CD pheno-type changes with longer follow-up periods.51,61 Duringthe first few years of disease, inflammatory forms pre-dominate, whereas, after 40 years, most patients haveexperienced complications and are classified as having apenetrating, or less often, a stricturing disease. Comparedwith cohorts from referral centers, complications are less

frequent among population-based cohorts62: the 20-yearcumulative rate of all complications is more than 60% inthe Olmsted County, Minnesota, population63 and 52% ifperianal disease is excluded.63 CD evolution relates todisease location. Small bowel involvement might be com-plicated at diagnosis or during the first years after diag-nosis by an abscess or fistula, or by a stricture followed byformation of a fistula,48 whereas colonic disease can re-main uncomplicated or inflammatory for many years(Figure 2). Stricturing and penetrating lesions can coexistin the same individual or even within the same intestinalsegment.

Disease Progression

CD becomes symptomatic when lesions are ex-tensive or distal, associated with a systemic inflamma-tory reaction, or when they are complicated by stric-tures or abscesses and fistulas. The disease course isgenerally distinguished by a sequence of flare-up epi-sodes and remissions of varying durations, whereas10%15% of patients undergo a chronic, continuousdisease course.64 Colonic disease usually has manysymptoms, with frequent extraintestinal manifesta-tions, whereas ileal disease can remain latent for sev-

eral years. Extraintestinal manifestations vary; arthri-tis, erythema nodosum, iritis and uveitis, aphtous



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stomatitis, and pyoderma gangrenosum are the mostprevalent.65,66 There is no relationship between symp-toms and progression of anatomic damage. Stricturesand fistulas can develop for years without any symp-tom, whereas short, uncomplicated ileitis can causerefractory abdominal pain and fatigue. Mucosal heal-

ing, in contrast, is associated with sustained clinicalremission, less need for steroid therapy, and reducedrates of hospitalization and surgical resection.67

A CD cohort studied in Copenhagen county (Den-mark) is unique in the homogeneity of management,before use of immunosuppressants, and in the qualityof surveillance (only 0.3% patients were not followedfor the entire study).59 During the first 3 years, diseasewas active in most patients then the proportion ofpatients with active disease, each year, reached a pla-teau of about 45%. Patients who had active disease inthe first 3 years after diagnosis more frequently hadcontinuous disease activity during the 5 following

years.64 In the Inflammatory Bowel South-Eastern Nor-way study, although 50% of patients thought that theirdisease had improved during the first 5 years afterdiagnosis, there was no further clear-cut ameliorationduring the subsequent 5 years.68 There is therefore noevidence to support spontaneous reduction in disease.Although disease progression in any one individual isunpredictable, some factors are associated with a worseprognosis in the few first years of the disease (Table 3).

Surgery

Progression of anatomic damage leads to devel-

opment of complications that are inaccessible to med-ical therapy and require surgery. Based on several stud-

ies, 70%80% of patients with CD require intestinalsurgery at 20 years.64,6870 The study in OlmstedCounty, Minnesota, reported that 64% required sur-gery by 30 years.71 Many patients experience diseaserecurrence and require a second operation (about 30%)by 10 years later.64 Every year, about 3%5% of patients

with CD require surgery; a patient with CD undergoessurgery within a mean time frame of every 1520years.72 These percentages have not changed from 1950to 2000.73 Immunosuppressant74 and biologic thera-pies75,76 might reduce the need for surgery but need tobe given early in disease progression, before the devel-opment of irreversible anatomic lesions, and indefi-nitely.77

Patients with CD are also at risk for permanentstoma. Proctocolectomies for refractory colitis are per-formed less frequently now than in the past but do notprotect patients from disease recurrence in the smallbowel.78 Segmental colonic resection adequately treats

strictures or fistulas.79 However, permanent fecal diver-sion might be required in patients with disablingchronic active perianal disease80; 10% of CD patientseventually require permanent fecal diversion,57,81 andthose with colorectal CD and anal stenosis are atgreatest risk. Although antitumor necrosis factoragents might be effective for early- to midstage disease,it has not been determined whether they reduce therequirements for permanent stoma.

Mortality From CD

Patients with CD have slightly greater mortality

than the general population. A meta-analysis using arandom effects model showed that the pooled estimate

Figure 2. Cumulative rate of remaining free of intestinal penetrating or stricturing complications in ileal (left ) and colonic (right ) CD. Perianalcomplications were not taken into account. Data were obtained from the studies at St-Antoine hospital that included 1448 patients with ileal disease

(L1) and 1129 patients with colonic disease (L2). Acta Gastro-Enterologica Belgica (Cosnes J, Acta Gastroenterol Belg 2008;71:303307),

reproduced with permission.



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for the standardized mortality ratio in CD was 1.52.Mortality has decreased slightly over the past 30 years,although this decrease is not statistically significant.82

In a study of Danish patients with CD who werefollowed for more than 20 years after diagnosis,women diagnosed before the age of 50 years had thegreatest mortality.83 Most deaths were connected toCD (malnutrition, postoperative complications, intes-tinal cancer), whereas smoking, more prevalent in CD,could account for other deaths (from respiratory dis-eases, infections, and diseases of the urinary organs83).

Natural History of UC

Anatomic Evolution

UC involves the rectum and colon and extends in acontinuous retrograde mode. Lesions are generally diffuseand superficial. Deep ulcerations are observed only in pa-

tients with severe disease. According to a prospective, Nor-wegian study,84 at the time of presentation, colitis is limited

to the rectum in one-third of patients, the colorectum distalto the splenic flexure in another one-third, and proximal to

the splenic flexure in the remaining third. Pancolitis isobserved in 25% of the patients. Some patients have simul-

taneous distal disease and periappendicular or cecal inflam-

mation; this observation is of no particular clinical signifi-cance.85,86 The rectum is always involved in adults, althoughsometimes only based on histologic analysis87; children do

not always have rectal lesions.88 During the disease course,the proximal extent of inflammation progresses, and, after

20 years,89 about 50% of patients have cumulative pancoli-tis. In patients with pancolitis, the last few centimeters of

the ileum can be inflamed. Such a backwash ileitis remainssuperficial and does not share deep ulcerations, stricture, or

fistula. Colonic lesions can also regress84 and may localize tothe distal colon.

The development of penetrating perianal lesions and

small bowel involvement mimicking CD does not occursimply in cases difficult to classify (unclassified colonic

Table 3. Main Clinical Factors Associated With a Poor Prognosis in Patients With IBD

CD UC

At presentation At first surgery At presentation At IPAA

Younger age

130132133, 134

135137

138, 139

(CD)

140

Perianal disease 69, 130, 133, 135, 141

135

142

* *

Need for steroids 70, 133, 143

137

138

*

Current smoking 70, 131, 144, 145

146148

149

* (CD)150

Not smoking * * 138

143, 151

152

(pouchitis)153, 154

155, 156

Extensive disease

157

142, 158

131, 132, 159, 160

(pouchitis)161, 162

Penetrating complication 68, 131, 144, 163

133

60, 137, 142

164, 165

* *

Extraintestinal manifestations 166

137

166, 167

(pouchitis)153, 154, 168, 169

170

Short disease duration * 171, 172

* 150, 153

No appendectomy in childhood 173

* 174, 175

*

Crohns disease family history 176, 177

149

138, 177

(CD)178, 179

NOTE. Main clinical factors associated with a poor prognosis: disabling disease, occurrence of complications, early need for surgery,

postoperative recurrence.

IPAA, ileal pouch-anal anastomosis.

, Concordant data in favor of an aggravating effect; , concordant data in favor of the absence of effect; , contradictory or inconclusive data;

*, no data or irrelevant.



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IBD). It may be observed even in typical forms of UC withdiagnosis confirmed by examination of the colectomy spec-imen. Diagnosis is changed from UC to CD in 5%10% ofpatients after 25 years of disease.90 This might occur morefrequently in patients with childhood-onset UC, active

smokers, and those with a family history of CD (Table 3).

Disease Progression

The course of UC is characterized by flares thatalternate with periods of remission; a minority of pa-tients have continuous activity. Severity of flares andtheir response to treatment vary and are hard to pre-dict, from minor symptoms without systemic manifes-tations to life-threatening fulminant colitis that doesnot respond to treatment and requires colectomy.Some patients present with severe UC, with extensivedisease or deep ulcerations. Remission is usually asso-

ciated with mucosal healing. One year after the onsetof UC, about 50% of patients undergo clinical andendoscopic remission; in these patients, the risk ofsubsequent colectomy significantly decreased, com-pared with patients without mucosal healing.67 Duringthe disease course, extraintestinal manifestations areobserved in as many as 31% of the patients.66 UC seemsto be particularly severe in young children, with fre-quent occurrence of flares that do not respond tomedical treatment.91

Disease activity tends to decrease over time. In a studyof a Danish cohort that did not receive immunosuppres-

sants,90

40%50% of subjects were in prolonged remissionafter a few years, and the proportion with active diseaseeach year gradually decreased to about 30%. About one-third of patients had no recurrence within the 10 yearsfollowing the first attack of UC, although the severity ofthe first attack does not indicate prognosis; patients witha severe presentation but who avoided colectomy tendedto have a more benign disease course during the follow-ing years.

Surgery

The reported cumulative probabilities of colec-

tomy vary among studies but are most often about 20%30% after 25 years; probabilities are found to be higher instudies from referral centers and lower in population-based studies, particularly in southern Europe.90,92,93

Probability of colectomy is highest during the first yearafter diagnosis, up to 10% in some studies.90 The extentand severity of symptoms at diagnosis are the best pre-dictors of colectomy.90 Cyclosporine94 and infliximab,95

respectively, are effective treatments for some severeforms that do not respond to steroids and can delay orprevent colectomy in most patients, particularly thosewithout severe endoscopic lesions. However, in the ab-

sence of active maintenance treatment (thiopurines orbiologics), disease returns and requires colectomy.

It is more difficult to determine prognosis of patientswith UC than with CD (Table 3) because the diseasecourse of UC is so variable. Moreover, surgery cannot beregarded as a definitive treatment. Patients who receivedcolectomies and have ileal pouch-anal anastomoses are at

risk for pouchitis; acute episodes occur in 50% of thesepatients within 5 years after surgery. In up to 10% ofpatients, pouchitis has a chronic or short-relapsingcourse that is refractory to antibiotics. This can be re-garded as the recurrence of the inflammatory diseasewithin the pouch that requires immunosuppressant andbiologic therapies and eventually pouch excision.96

Mortality From UC

The overall mortality from UC overall is notgreater than that of the population.97 However, mortalityis increased among newly diagnosed patients and in pa-tients with extensive disease.97,98 Most of these deaths areobserved in the perioperative period in patients withsevere disease. Over the long-term, there is an increasedrisk of dying from UC-related causes (liver disease, colo-rectal cancer) and a decreased risk of dying from pulmo-nary cancer and other tobacco-related diseases, whichoccur in the low numbers of smokers with UC.

Conclusion

The increases in incidence and prevalence of IBDover the last 15 years and its emergence in developingcountries indicate a role of the environment in patho-genesis. Epidemiologic studies of migrant populations

indicate that genetic and environmental factors interactto determine risk for IBD early in life. Research shouldfocus on pediatric IBD, comparing areas of high and lowincidence and prevalence to identify environmental fac-tor(s). Factors for study should be those from the mod-ern lifestyle: improved home amenities, widespread use ofvaccine and antibiotics, consumption of fat- and protein-rich diets, refrigeration, and industrial pollution.

There is no cure for IBD; even patients with longperiods of quiescent disease can experience a devastatingflare or a complication that requires surgery. However,the postoperative model indicates that lesions usually

precede symptoms. It might therefore be possible tomonitor patients for intestinal ulcerations or thickeningusing noninvasive techniques (assays for C-reactive pro-tein, ferritin, and fecal calprotectin; videocapsule andmagnetic resonance imaging) and treat them as early aspossible to prevent disease progression.

Supplementary Material

Note: The first 50 references associated with thisarticle are available below in print. The remaining refer-ences accompanying this article are available online onlywith the electronic version of the article. Visit the online

version ofGastroenterology at www.gastrojournal.org, andat doi:10.1053/j.gastro.2011.01.055.

http://www.gastrojournal.org/http://www.gastrojournal.org/http://dx.doi.org/10.1053/j.gastro.2011.01.055http://dx.doi.org/10.1053/j.gastro.2011.01.055http://www.gastrojournal.org/


9/14

References

1. Vind I, Riis L, Jess T, et al. Increasing incidences of inflammatory

bowel disease and decreasing surgery rates in Copenhagen City

and County, 2003-2005: a population-based study from the Dan-

ish Crohn colitis database. Am J Gastroenterol 2006;101:1274

1282.

2. Yapp TR, Stenson R, Thomas GA, et al. Crohns disease inci-dence in Cardiff from 1930: an update for 1991-1995. Eur J

Gastroenterol Hepatol 2000;12:907911.

3. Rubin GP, Hungin AP, Kelly PJ, et al. Inflammatory bowel disease:

epidemiology and management in an English general practice

population. Aliment Pharmacol Ther 2000;14:15531559.

4. Loftus CG, Loftus EV Jr, Harmsen WS, et al. Update on the

incidence and prevalence of Crohns disease and ulcerative coli-

tis in Olmsted County, Minnesota, 1940-2000. Inflamm Bowel

Dis 2007;13:254261.

5. Bernstein CN, Wajda A, Svenson LW, et al. The epidemiology of

inflammatory bowel disease in Canada: a population-based

study. Am J Gastroenterol 2006;101:15591568.

6. Pinchbeck BR, Kirdeikis J, Thomson AB. Inflammatory bowel dis-

ease in northern Alberta. An epidemiologic study. J Clin Gastro-

enterol 1988;10:505515.

7. Bernstein CN, Blanchard JF, Rawsthorne P, et al. Epidemiology of

Crohns disease and ulcerative colitis in a central Canadian

province: a population-based study. Am J Epidemiol 1999;149:

916924.

8. Gunesh S, Thomas GA, Williams GT, et al. The incidence of

Crohns disease in Cardiff over the last 75 years: an update for

19962005. Aliment Pharmacol Ther 2008;27:211219.

9. Molinie F, Gower-Rousseau C, Yzet T, et al. Opposite evolution in

incidence of Crohns disease and ulcerative colitis in Northern

France (1988-1999). Gut 2004;53:843848.

10. Latour P, Louis E, Belaiche J. Incidence of inflammatory bowel

disease in the area of Liege: a 3 years prospective study (1993-

1996). Acta Gastroenterol Belg 1998;61:410413.

11. Ott C, Obermeier F, Thieler S, et al. The incidence of inflammatory

bowel disease in a rural region of Southern Germany: a prospec-

tive population-based study. Eur J Gastroenterol Hepatol 2008;

20:917923.

12. Gearry RB, Richardson A, Frampton CM, et al. High incidence of

Crohns disease in Canterbury, New Zealand: results of an epi-

demiologic study. Inflamm Bowel Dis 2006;12:936943.

13. Yang SK, Hong WS, Min YI, et al. Incidence and prevalence of

ulcerative colitis in the Songpa-Kangdong District, Seoul, Korea,

1986-1997. J Gastroenterol Hepatol 2000;15:10371042.

14. Sood A, Midha V, Sood N, et al. Incidence and prevalence of

ulcerative colitis in Punjab, North India. Gut 2003;52:1587

1590.

15. Edouard A, Paillaud M, Merle S, et al. Incidence of inflammatory

bowel disease in the French West Indies (1997-1999). Gastro-

enterol Clin Biol 2005;29:779783.16. Thia KT, Loftus EV Jr, Sandborn WJ, et al. An update on the

epidemiology of inflammatory bowel disease in Asia. Am J Gas-

troenterol 2008;103:31673182.

17. Devlin HB, Datta D, Dellipiani AW. The incidence and prevalence

of inflammatory bowel disease in North Tees Health District.

World J Surg 1980;4:183193.

18. Jacobsen BA, Fallingborg J, Rasmussen HH, et al. Increase in

incidence and prevalence of inflammatory bowel disease in north-

ern Denmark: a population-based study, 1978-2002. Eur J Gas-

troenterol Hepatol 2006;18:601606.

19. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The preva-

lence and geographic distribution of Crohns disease and ulcer-

ative colitis in the United States. Clin Gastroenterol Hepatol

2007;5:14241429.

20. Auvin S, Molinie F, Gower-Rousseau C, et al. Incidence, clinicalpresentation and location at diagnosis of pediatric inflamma-

tory bowel disease: a prospective population-based study in

northern France (19881999). J Pediatr Gastroenterol Nutr

2005;41:4955.

21. Kelsen J, Baldassano RN. Inflammatory bowel disease: the dif-

ference between children and adults. Inflamm Bowel Dis 2008;

14(Suppl 2):S9S11.

22. Langholz E, Munkholm P, Krasilnikoff PA, et al. Inflammatorybowel diseases with onset in childhood. Clinical features, mor-

bidity, and mortality in a regional cohort. Scand J Gastroenterol

1997;32:139147.

23. Chouraki V, Savoye G, Dauchet L, et al. The changing pattern of

Crohns disease incidence in northern France: a continuing in-

crease in the 10- to 19-year-old age bracket (19882005). Ali-

ment Pharmacol Ther 2010. [Epub ahead of print]

24. Abramson O, Durant M, Mow W, et al. Incidence, prevalence, and

time trends of pediatric inflammatory bowel disease in Northern

California, 1996 to 2006. J Pediatr 2010;157:233239.

25. Turunen P, Kolho KL, Auvinen A, et al. Incidence of inflammatory

bowel disease in Finnish children, 19872003. Inflamm Bowel

Dis 2006;12:677683.

26. Probert CS, Jayanthi V, Pinder D, et al. Epidemiological study of

ulcerative proctocolitis in Indian migrants and the indigenous

population of Leicestershire. Gut 1992;33:687693.

27. Gheorghe C, Pascu O, Gheorghe L, et al. Epidemiology of inflam-

matory bowel disease in adults who refer to gastroenterology

care in Romania: a multicentre study. Eur J Gastroenterol Hepatol

2004;16:11531159.

28. Abdul-Baki H, ElHajj I, El-Zahabi LM, et al. Clinical epidemiology of

inflammatory bowel disease in Lebanon. Inflamm Bowel Dis

2007;13:475480.

29. Ahuja V, Tandon RK. Inflammatory bowel disease in the Asia-

Pacific area: a comparison with developed countries and regional

differences. J Dig Dis 2010;11:134147.

30. Sonnenberg A. Demographic characteristics of hospitalized IBD

patients. Dig Dis Sci 2009;54:24492455.

31. Shivananda S, Lennard-Jones J, Logan R, et al. Incidence ofinflammatory 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;

39:690697.

32. Ladas SD, Mallas E, Giorgiotis K, et al. Incidence of ulcerative

colitis in Central Greece: a prospective study. World J Gastroen-

terol 2005;11:17851787.

33. Rodrigo L, Riestra S, Nino P, et al. A population-based study on

the incidence of inflammatory bowel disease in Oviedo (Northern

Spain). Rev Esp Enferm Dig 2004;96:296305.

34. Ogunbi SO, Ransom JA, Sullivan K, et al. Inflammatory bowel

disease in African-American children living in Georgia. J Pediatr

1998;133:103107.

35. Blanchard JF, Bernstein CN, Wajda A, et al. Small-area variations

and sociodemographic correlates for the incidence of Crohns

disease and ulcerative colitis. Am J Epidemiol 2001;154:328

335.

36. Nerich V, Monnet E, Etienne A, et al. Geographical variations of

inflammatory bowel disease in France: a study based on na-

tional health insurance data. Inflamm Bowel Dis 2006;12:

218226.

37. Declercq C, Gower-Rousseau C, Vernier-Massouille G, et al. Map-

ping of inflammatory bowel disease in northern France: spatial

variations and relation to affluence. Inflamm Bowel Dis;16:807

812.

38. Kurata JH, Kantor-Fish S, Frankl H, et al. Crohns disease among

ethnic groups in a large health maintenance organization. Gas-

troenterology 1992;102:19401948.

39. Hou JK, El-Serag H, Thirumurthi S. Distribution and manifesta-tions of inflammatory bowel disease in Asians, Hispanics, and



10/14

African Americans: a systematic review. Am J Gastroenterol

2009;104:21002109.

40. Gilat T, Hacohen D, Lilos P, et al. Childhood factors in ulcerative

colitis and Crohns disease. An international cooperative study.

Scand J Gastroenterol 1987;22:10091024.

41. Fireman Z, Grossman A, Lilos P, et al. Epidemiology of Crohns

disease in the Jewish population of central Israel, 1970-1980.Am J Gastroenterol 1989;84:255258.

42. Shapira M, Tamir A. Crohns disease and the Jews. J Clin Gas-

troenterol 1992;15:278280.

43. Birkenfeld S, Zvidi I, Hazazi R, et al. The prevalence of ulcerative

colitis in Israel: a twenty-year survey. J Clin Gastroenterol 2009;

43:743746.

44. Zvidi I, Hazazi R, Birkenfeld S, et al. The prevalence of Crohns

disease in Israel: a 20-year survey. Dig Dis Sci 2009;54:848

852.

45. Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the

postoperative course of Crohns disease. Gastroenterology

1990;99:956963.

46. Olaison G, Smedh K, Sjodahl R. Natural course of Crohns dis-

ease after ileocolic resection: endoscopically visualised ileal ul-cers preceding symptoms. Gut 1992;33:331335.

47. DHaens GR, Geboes K, Peeters M, et al. Early lesions of recur-

rent Crohns disease caused by infusion of intestinal contents in

excluded ileum. Gastroenterology 1998;114:262267.

48. Oberhuber G, Stangl PC, Vogelsang H, et al. Significant associa-

tion of strictures and internal fistula formation in Crohns dis-

ease. Virchows Arch 2000;437:293297.

49. Silverberg M, Satsangi J, Ahmad T, et al. Toward an integrated

clinical, molecular and serological classification of inflammatory

bowel disease: report of a working party of the 2005 Montreal

World Congress of Gastroenterology. Can J Gastroenterol

2005;19:1A32A.

50. Gasche C, Scholmerich J, Brynskov J, et al. A simple classifica-

tion of Crohns disease: report of the Working Party for the World

Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel

Dis 2000;6:815.

Received October 16, 2010. Accepted January 11, 2011.

Reprint requests

Address requests for reprints to: Jacques Cosnes, MD, Service de

Gastroentrologie et Nutrition, Hpital St-Antoine, 184 rue du

Faubourg St-Antoine, 75571 Paris. e-mail: [email protected].

fr; fax: (33) 1 49 28 31 88.

Acknowledgments

The authors thank Christophe Declercq, who realized the map

(Figure 1).

Conflicts of interest

The authors disclose the following: Dr Cosnes received

research support from Abbott. The remaining authors disclose noconflicts.

Funding

EPIMAD is organized under an agreement between the Institut

National de la Sant et de la Recherche Mdicale (INSERM) and the

Institut National de Veille Sanitaire (InVS) and also received

financial support from the Franois Aupetit Association, Lions Club

of Northern France, Ferring Laboratories, Astra-Zeneca Company

(IRMAD), the Socit Nationale Franaise de Gastroentrologie, and

Lille University Hospital.

mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


11/14

References (Online Only)

51. Louis E, Collard A, Oger AF, et al. Behaviour of Crohns disease

according to the Vienna classification: changing pattern over the

course of the disease. Gut 2001;49:777782.

52. Peschard S, Carbonnel F, Beaugerie L, et al. Colonic involve-

ment in ileal Crohns disease. Gastroenterol Clin Biol 1998;22:

594600.53. Hamon JF, Cosnes J, Carbonnel F, et al. The risk of extra-colonic

extension in Crohns colitis. Ann Gastroenterol Hepatol (Paris)

1993;29:110.

54. Vermeire S, Van Assche G, Rutgeerts P. Perianal Crohns dis-

ease: classification and clinical evaluation. Dig Liver Dis 2007;

39:959962.

55. Vermeire S, van Assche G, Rutgeerts P. Review article: altering

the natural history of Crohns diseaseevidence for and

against current therapies. Aliment Pharmacol Ther 2007;25:3

12.

56. Schwartz DA, Pemberton JH, Sandborn WJ. Diagnosis and treat-

ment of perianal fistulas in Crohn disease. Ann Intern Med

2001;135:906918.

57. Cosnes J. Crohns disease phenotype, prognosis, and long-term

complications: what to expect? Acta Gastroenterol Belg 2008;

71:303307.

58. Schwartz DA, Loftus EV Jr, Tremaine WJ, et al. The natural

history of fistulizing Crohns disease in Olmsted County, Minne-

sota. Gastroenterology 2002;122:875880.

59. Sachar DB, Bodian CA, Goldstein ES, et al. Is perianal Crohns

disease associated with intestinal fistulization? Am J Gastroen-

terol 2005;100:15471549.

60. Greenstein AJ, Lachman P, Sachar DB, et al. Perforating and

non-perforating indications for repeated operations in Crohns

disease: evidence for two clinical forms. Gut 1988;29:588

592.

61. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of dis-

ease behavior of Crohns disease. Inflamm Bowel Dis 2002;8:

244250.

62. Oussalah A, Chevaux JB, Fay R, et al. Predictors of infliximab

failure after azathioprine withdrawal in Crohns disease treated

with combination therapy. Am J Gastroenterol 2010;105:1142

1149.

63. Thia KT, Sandborn WJ, Harmsen WS, et al. Risk factors associ-

ated with progression to intestinal complications of Crohns

disease in a population-based cohort. Gastroenterology 2010;

139:11471155.

64. Munkholm P, Langholz E, Davidsen M, et al. Disease activity

courses in a regional cohort of Crohns disease patients. Scand

J Gastroenterol 1995;30:699706.

65. Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, et al. Long-term

complications, extraintestinal manifestations, and mortality in

adult Crohns disease in population-based cohorts. Inflamm

Bowel Dis 2011;17:471478.66. Vavricka SR, Brun L, Ballabeni P, et al. Frequency and risk

factors for extraintestinal manifestations in the Swiss Inflam-

matory Bowel Disease Cohort. Am J Gastroenterol 2011;106:

110119.

67. Froslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in

inflammatory bowel disease: results from a Norwegian popula-

tion-based cohort. Gastroenterology 2007;133:412422.

68. Solberg IC, Vatn MH, Hoie O, et al. Clinical course in Crohns

disease: results of a Norwegian population-based ten-year fol-

low-up study. Clin Gastroenterol Hepatol 2007;5:14301438.

69. Mekhjian HS, Switz DM, Melnyk CS, et al. Clinical features and

natural history of Crohns disease. Gastroenterology 1979;77:

898906.

70. Sands BE, Arsenault JE, Rosen MJ, et al. Risk of early surgery

for Crohns disease: implications for early treatment strategies.Am J Gastroenterol 2003;98:27122718.

71. Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, et al. The natural

history of adult Crohns disease in population-based cohorts.

Am J Gastroenterol 2010;105:289297.

72. Cosnes J, Nion-Larmurier I, Beaugerie L, et al. Impact of the

increasing use of immunosuppressants in Crohns disease on

the need for intestinal surgery. Gut 2005;54:237241.

73. Wolters FL, Russel MG, Stockbrugger RW. Systematic review:has disease outcome in Crohns disease changed during the

last four decades? Aliment Pharmacol Ther 2004;20:483496.

74. Picco MF, Zubiaurre I, Adluni M, et al. Immunomodulators are

associated with a lower risk of first surgery among patients with

non-penetrating non-stricturing Crohns disease. Am J Gastro-

enterol 2009;104:27542759.

75. Lichtenstein GR. Infliximab: lifetime use for maintenance is

appropriate in Crohns disease. PRO: maintenance therapy is

superior to episodic therapy. Am J Gastroenterol 2005;100:

14331435.

76. Feagan BG, Panaccione R, Sandborn WJ, et al. Effects of ada-

limumab therapy on incidence of hospitalization and surgery in

Crohns disease: results from the CHARM study. Gastroenter-

ology 2008;135:14931499.

77. Lemann M, Mary JY, Colombel JF, et al. A randomized, double-blind, controlled withdrawal trial in Crohns disease patients in

long-term remission on azathioprine. Gastroenterology 2005;

128:18121818.

78. Bernell O, Lapidus A, Hellers G. Recurrence after colectomy in

Crohns colitis. Dis Colon Rectum 2001;44:647654.

79. Andersson P, Olaison G, Bodemar G, et al. Surgery for Crohn

colitis over a twenty-eight-year period: fewer stomas and the

replacement of total colectomy by segmental resection. Scand J

Gastroenterol 2002;37:6873.

80. Hurst RD, Molinari M, Chung TP, et al. Prospective study of the

features, indications, and surgical treatment in 513 consecu-

tive patients affected by Crohns disease. Surgery 1997;122:

661668.

81. Galandiuk S, Kimberling J, Al-Mishlab TG, et al. Perianal Crohn

disease: predictors of need for permanent diversion. Ann Surg

2005;241:796802.

82. Canavan C, Abrams KR, Mayberry JF. Meta-analysis: mortality in

Crohns disease. Aliment Pharmacol Ther 2007;25:861870.

83. Jess T, Winther KV, Munkholm P, et al. Mortality and causes of

death in Crohns disease: follow-up of a population-based co-

hort in Copenhagen County, Denmark. Gastroenterology 2002;

122:18081814.

84. Moum B, Ekbom A, Vatn MH, et al. Change in the extent of

colonoscopic and histological involvement in ulcerative colitis

over time. Am J Gastroenterol 1999;94:15641569.

85. Byeon JS, Yang SK, Myung SJ, et al. Clinical course of distal

ulcerative colitis in relation to appendiceal orifice inflammation

status. Inflamm Bowel Dis 2005;11:366371.

86. Mutinga ML, Odze RD, Wang HH, et al. The clinical significanceof right-sided colonic inflammation in patients with left-sided

chronic ulcerative colitis. Inflamm Bowel Dis 2004;10:215

219.

87. Joo M, Odze RD. Rectal sparing and skip lesions in ulcerative

colitis: a comparative study of endoscopic and histologic find-

ings in patients who underwent proctocolectomy. Am J Surg

Pathol 2010;34:689 696.

88. Bousvaros A, Antonioli DA, Colletti RB, et al. Differentiating

ulcerative colitis from Crohn disease in children and young

adults: report of a working group of the North American Society

for Pediatric Gastroenterology, Hepatology, and Nutrition and

the Crohns and Colitis Foundation of America. J Pediatr Gas-

troenterol Nutr 2007;44:653674.

89. Langholz E, Munkholm P, Davidsen M, et al. Changes in extent

of ulcerative colitis: a study on the course and prognostic fac-tors. Scand J Gastroenterol 1996;31:260266.

May 2011 INFLAMMATORY BOWEL DISEASES 1794.e1


12/14

90. Langholz E, Munkholm P, Davidsen M, et al. Course of ulcerative

colitis: analysis of changes in disease activity over years. Gas-

troenterology 1994;107:311.

91. Turner D, Walsh CM, Benchimol EI, et al. Severe paediatric

ulcerative colitis: incidence, outcomes and optimal timing for

second-line therapy. Gut 2008;57:331338.

92. Henriksen M, Jahnsen J, Lygren I, et al. Ulcerative colitis andclinical course: results of a 5-year population-based follow-up

study (the IBSEN study). Inflamm Bowel Dis 2006;12:543550.

93. Hoie O, Wolters FL, Riis L, et al. Low colectomy rates in ulcer-

ative colitis in an unselected European cohort followed for 10

years. Gastroenterology 2007;132:507515.

94. Campbell S, Travis S, Jewell D. Ciclosporin use in acute ulcer-

ative colitis: a long-term experience. Eur J Gastroenterol Hepatol

2005;17:7984.

95. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue

therapy in severe to moderately severe ulcerative colitis: a

randomized, placebo-controlled study. Gastroenterology 2005;

128:18051811.

96. Shen B, Fazio VW, Remzi FH, et al. Comprehensive evaluation of

inflammatory and noninflammatory sequelae of ileal pouch-anal

anastomoses. Am J Gastroenterol 2005;100:93101.97. Palli D, Trallori G, Saieva C, et al. General and cancer specific

mortality of a population based cohort of patients with inflam-

matory bowel disease: the Florence Study. Gut 1998;42:175

179.

98. Winther KV, Jess T, Langholz E, et al. Survival and cause-

specific mortality in ulcerative colitis: follow-up of a population-

based cohort in Copenhagen County. Gastroenterology 2003;

125:15761582.

99. Ishikawa M, Watanabe H, Yamagishi G, et al. Crohns disease,

non-specific ulcers of the small intestine, and idiopathic proc-

tocolitis in a Japanese university hospital from 1954 to 1974.

Tohoku J Exp Med 1976;118(Suppl):97109.

100. Morita N, Toki S, Hirohashi T, et al. Incidence and prevalence of

inflammatory bowel disease in Japan: nationwide epidemiolog-

ical survey during the year 1991. J Gastroenterol 1995;

30(Suppl 8):14.

101. Asakura K, Nishiwaki Y, Inoue N, et al. Prevalence of ulcerative

colitis and Crohns disease in Japan. J Gastroenterol 2009;44:

659665.

102. Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory

bowel disease in the Songpa-Kangdong district, Seoul, Korea,

1986-2005: a KASID study. Inflamm Bowel Dis 2008;14:542

549.

103. Vucelic B, Korac B, Sentic M, et al. Epidemiology of Crohns

disease in Zagreb, Yugoslavia: a ten-year prospective study. Int

J Epidemiol 1991;20:216220.

104. Sincic BM, Vucelic B, Persic M, et al. Incidence of inflammatory

bowel disease in Primorsko-goranska County, Croatia, 2000-

2004: a prospective population-based study. Scand J Gastro-enterol 2006;41:437444.

105. Bitter J, Dyrhonov V, Komrkov O. Nespecifick stevn znty

vesk republice. Cesk Gastroenterol Viliva 1992;46:313321.

106. Wright JP, Froggatt J, OKeefe EA, et al. The epidemiology of

inflammatory bowel disease in Cape Town 1980-1984. S Afr

Med J 1986;70:1015.

107. Mate-Jimenez J, Munoz S, Vicent D, et al. Incidence and prev-

alence of ulcerative colitis and Crohns disease in urban and

rural areas of Spain from 1981 to 1988. J Clin Gastroenterol

1994;18:2731.

108. Arin Letamendia A, Borda Celaya F, Burusco Paternain MJ, et al.

High incidence rates of inflammatory bowel disease in Navarra

(Spain). Results of a prospective, population-based study. Gas-

troenterol Hepatol 2008;31:111116.

109. Lakatos L, Mester G, Erdelyi Z, et al. Striking elevation inincidence and prevalence of inflammatory bowel disease in a

province of western Hungary between 19772001. World J

Gastroenterol 2004;10:404 409.

110. Tragnone A, Corrao G, Miglio F, et al. Incidence of inflammatory

bowel disease in Italy: a nationwide population-based study.

Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Int J

Epidemiol 1996;25:10441052.

111. Trallori G, Palli D, Saieva C, et al. A population-based study ofinflammatory bowel disease in Florence over 15 years (1978-

92). Scand J Gastroenterol 1996;31:892899.

112. Halme L, Paavola-Sakki P, Turunen U, et al. Family and twin

studies in inflammatory bowel disease. World J Gastroenterol

2006;12:36683672.

113. Manousos ON, Koutroubakis I, Potamianos S, et al. A prospec-

tive epidemiologic study of Crohns disease in Heraklion, Crete.

Incidence over a 5-year period. Scand J Gastroenterol 1996;31:

599603.

114. Economou M, Filis G, Tsianou Z, et al. Crohns disease inci-

dence evolution in North-western Greece is not associated with

alteration of NOD2/CARD15 variants. World J Gastroenterol

2007;13:51165120.

115. Loftus EV Jr, Silverstein MD, Sandborn WJ, et al. Crohns dis-

ease in Olmsted County, Minnesota, 1940-1993: incidence,

prevalence, and survival. Gastroenterology 1998;114:1161

1168.

116. Munkholm P, Langholz E, Nielsen OH, et al. Incidence and

prevalence of Crohns disease in the county of Copenhagen,

1962-87: a sixfold increase in incidence. Scand J Gastroenterol

1992;27:609614.

117. Lindberg E, Jornerot G. The incidence of Crohns disease is not

decreasing in Sweden. Scand J Gastroenterol 1991;26:495

500.

118. Lapidus A, Bernell O, Hellers G, et al. Incidence of Crohns

disease in Stockholm County 1955-1989. Gut 1997;41:480

486.

119. Lapidus A. Crohns disease in Stockholm County during 1990-

2001: an epidemiological update. World J Gastroenterol 2006;12:7581.

120. Moum B, Vatn MH, Ekbom A, et al. Incidence of Crohns disease

in four counties in southeastern Norway, 1990-93. A prospec-

tive population-based study. The Inflammatory Bowel South-

Eastern Norway (IBSEN) Study Group of Gastroenterologists.


121. Fellows IW, Freeman JG, Holmes GK. Crohns disease in the city

of Derby, 1951-1985. Gut 1990;31:12621265.

122. Radhakrishnan S, Zubaidi G, Daniel M, et al. Ulcerative colitis in

Oman. A prospective study of the incidence and disease pattern

from 1987 to 1994. Digestion 1997;58:266270.

123. Shapira M, Tamir A. Ulcerative colitis in the Kinneret sub dis-

trict, Israel 1965-1994: incidence and prevalence in different

subgroups. J Clin Gastroenterol 1998;27:134137.

124. Niv Y, Torten D, Tamir A, et al. Incidence and prevalence of

ulcerative colitis in the upper Galilee, Northern Israel, 1967-

1986. Am J Gastroenterol 1990;85:15801583.

125. Odes HS, Fraser D, Krawiec J. Incidence of idiopathic ulcerative

colitis in Jewish population subgroups in the Beer Sheva region

of Israel. Am J Gastroenterol 1987;82:854 858.

126. Timmer A, Goebell H. Incidence of ulcerative colitis, 1980-

1995: a prospective study in an urban population in Germany.

Z Gastroenterol 1999;37:10791084.

127. Stewenius J, Adnerhill I, Ekelund G, et al. Ulcerative colitis and

indeterminate colitis in the city of Malmo, Sweden. A 25-year

incidence study. Scand J Gastroenterol 1995;30:3843.

128. Russel MG, Dorant E, Volovics A, et al. High incidence of

inflammatory bowel disease in The Netherlands: results of a

prospective study. The South Limburg IBD Study Group. DisColon Rectum 1998;41:3340.

1794.e2 COSNES ET AL GASTROENTEROLOGY Vol. 140, No. 6


13/14

129. 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;40:328332.

130. Beaugerie L, Seksik P, Nion-Larmurier I, et al. Predictors of

Crohns disease. Gastroenterology 2006;130:650656.

131. Romberg-Camps MJ, Dagnelie PC, Kester AD, et al. Influence of

phenotype at diagnosis and of other potential prognostic fac-tors on the course of inflammatory bowel disease. Am J Gas-

troenterol 2009;104:371383.

132. Solberg IC, Lygren I, Jahnsen J, et al. Clinical course during the

first 10 years of ulcerative colitis: results from a population-

based inception cohort (IBSEN Study). Scand J Gastroenterol

2009;44:431440.

133. Loly C, Belaiche J, Louis E. Predictors of severe Crohns dis-

ease. Scand J Gastroenterol 2008;43:948954.

134. Tremaine WJ, Timmons LJ, Loftus EV Jr, et al. Age at onset of

inflammatory bowel disease and the risk of surgery for non-

neoplastic bowel disease. Aliment Pharmacol Ther 2007;25:

14351441.

135. Bernell O, Lapidus A, Hellers G. Risk factors for surgery and

postoperative recurrence in Crohns disease. Ann Surg 2000;

231:3845.

136. Scarpa M, Ruffolo C, Bertin E, et al. Surgical predictors of

recurrence of Crohns disease after ileocolonic resection. Int J

Colorectal Dis 2007;22:10611069.

137. Hofer B, Bottger T, Hernandez-Richter T, et al. The impact of

clinical types of disease manifestation on the risk of early

postoperative recurrence in Crohns disease. Hepatogastroen-

terology 2001;48:152155.

138. Roth LS, Chande N, Ponich T, et al. Predictors of disease

severity in ulcerative colitis patients from Southwestern On-

tario. World J Gastroenterol 2010;16:232236.

139. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The

natural history of pediatric ulcerative colitis: a population-based

cohort study. Am J Gastroenterol 2009;104:20802088.

140. Melton GB, Kiran RP, Fazio VW, et al. Do preoperative factorspredict subsequent diagnosis of Crohns disease after ileal

pouch-anal anastomosis for ulcerative or indeterminate colitis?

Colorectal Dis 2010;12:10261032.

141. Veloso FT, Ferreira JT, Barros L, et al. Clinical outcome of

Crohns disease: analysis according to the Vienna classification

and clinical activity. Inflamm Bowel Dis 2001;7:306313.

142. Bernell O, Lapidus A, Hellers G. Risk factors for surgery and

recurrence in 907 patients with primary ileocaecal Crohns

disease. Br J Surg 2000;87:16971701.

143. Beaugerie L, Massot N, Carbonnel F, et al. Impact of cessation

of smoking on the course of ulcerative colitis. Am J Gastroen-

terol 2001;96:21132116.

144. Wolters FL, Russel MG, Sijbrandij J, et al. Phenotype at diagno-

sis predicts recurrence rates in Crohns disease. Gut 2006;55:

11241130.

145. Cosnes J, Carbonnel F, Beaugerie L, et al. Effects of cigarette

smoking on the long-term course of Crohns disease. Gastroen-

terology 1996;110:424431.

146. Yamamoto Y, Nishida N, Tanaka M, et al. Association between

passive and active smoking evaluated by salivary cotinine and

periodontitis. J Clin Periodontol 2005;32:10411046.

147. Ryan WR, Allan RN, Yamamoto T, et al. Crohns disease pa-

tients who quit smoking have a reduced risk of reoperation for

recurrence. Am J Surg 2004;187:219225.

148. Cottone M, Rosselli M, Orlando A, et al. Smoking habits and

recurrence in Crohns disease. Gastroenterology 1994;106:

643648.

149. Unkart JT, Anderson L, Li E, et al. Risk factors for surgical

recurrence after ileocolic resection of Crohns disease. DisColon Rectum 2008;51:12111216.

150. Shen B, Fazio VW, Remzi FH, et al. Risk factors for clinical

phenotypes of Crohns disease of the ileal pouch. Am J Gastro-

enterol 2006;101:27602768.

151. Boyko EJ, Perera DR, Koepsell TD, et al. Effects of cigarette

smoking on the clinical course of ulcerative colitis. Scand J


152. Szamosi T, Banai J, Lakatos L, et al. Early azathioprine/biolog-ical therapy is associated with decreased risk for first surgery

and delays time to surgery but not reoperation in both smokers

and nonsmokers with Crohns disease, while smoking de-

creases the risk of colectomy in ulcerative colitis. Eur J Gastro-

enterol Hepatol 2009;22:872879.

153. Fleshner P, Ippoliti A, Dubinsky M, et al. A prospective multivar-

iate analysis of clinical factors associated with pouchitis after

ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol

2007;5:952958; quiz 887.

154. Kuisma J, Jarvinen H, Kahri A, et al. Factors associated with

disease activity of pouchitis after surgery for ulcerative colitis.


155. Joelsson M, Benoni C, Oresland T. Does smoking influence the

risk of pouchitis following ileal pouch anal anastomosis for

ulcerative colitis? Scand J Gastroenterol 2006;41:929933.

156. Merrett MN, Mortensen N, Kettlewell M, et al. Smoking may

prevent pouchitis in patients with restorative proctocolectomy

for ulcerative colitis. Gut 1996;38:362364.

157. Freeman HJ. Long-term clinical behavior of jejunoileal involvement

in Crohns disease. Can J Gastroenterol 2005;19:575578.

158. Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohns

disease: risk factors for postoperative recurrence. Am J Gastro-

enterol 2001;96:21692176.

159. Langholz E, Munkholm P, Davidsen M, et al. Colorectal cancer

risk and mortality in patients with ulcerative colitis. Gastroen-

terology 1992;103:14441451.

160. Ekbom A, Helmick CG, Zack M, et al. Survival and causes of

death in patients with inflammatory bowel disease: a popula-

tion-based study. Gastroenterology 1992;103:954960.161. Achkar JP, Al-Haddad M, Lashner B, et al. Differentiating risk

factors for acute and chronic pouchitis. Clin Gastroenterol

Hepatol 2005;3:60 66.

162. Schmidt CM, Lazenby AJ, Hendrickson RJ, et al. Preoperative

terminal ileal and colonic resection histopathology predicts risk

of pouchitis in patients after ileoanal pull-through procedure.

Ann Surg 1998;227:654 665.

163. Henckaerts L, Van Steen K, Verstreken I, et al. Genetic risk

profiling and prediction of disease course in Crohns disease

patients. Clin Gastroenterol Hepatol 2009;7:972980.

164. Avidan B, Sakhnini E, Lahat A, et al. Risk factors regarding the

need for a second operation in patients with Crohns disease.

Digestion 2005;72:248253.

165. Yamamoto T, Allan RN, Keighley MR. Perforating ileocecal

Crohns disease does not carry a high risk of recurrence but

usually re-presents as perforating disease. Dis Colon Rectum

1999;42:519524.

166. Farhi D, Cosnes J, Zizi N, et al. Significance of erythema nodo-

sum and pyoderma gangrenosum in inflammatory bowel dis-

eases: a cohort study of 2402 patients. Medicine (Baltimore)

2008;87:281293.

167. Bardazzi G, Mannoni A, dAlbasio G, et al. Spondyloarthritis in

patients with ulcerative colitis. Ital J Gastroenterol Hepatol

1997;29:520524.

168. Shen B, Remzi FH, Brzezinski A, et al. Risk factors for pouch

failure in patients with different phenotypes of Crohns disease

of the pouch. Inflamm Bowel Dis 2008;14:942948.

169. Hoda KM, Collins JF, Knigge KL, et al. Predictors of pouchitis

after ileal pouch-anal anastomosis: a retrospective review. DisColon Rectum 2008;51:554560.

May 2011 INFLAMMATORY BOWEL DISEASES 1794.e3


14/14

170. Hata K, Watanabe T, Shinozaki M, et al. Patients with extraint-

estinal manifestations have a higher risk of developing pouchi-

tis in ulcerative colitis: multivariate analysis. Scand J Gastroen-

terol 2003;38:10551058.

171. Lautenbach E, Berlin JA, Lichtenstein GR. Risk factors for early

postoperative recurrence of Crohns disease. Gastroenterology

1998;115:259267.172. Cristaldi M, Sampietro GM, Danelli PG, et al. Long-term results

and multivariate analysis of prognostic factors in 138 consec-

utive patients operated on for Crohns disease using bowel-

sparing techniques. Am J Surg 2000;179:266270.

173. Cosnes J, Seksik P, Nion-Larmurier I, et al. Prior appendectomy

and the phenotype and course of Crohns disease. World J


174. Cosnes J, Carbonnel F, Beaugerie L, et al. Effects of appen-

dicectomy on the course of ulcerative colitis. Gut 2002;51:

803807.

175. Radford-Smith GL, Edwards JE, Purdie DM, et al. Protective role

of appendicectomy on onset and severity of ulcerative colitis

and Crohns disease. Gut 2002;51:808 813.

176. Carbonnel F, Macaigne G, Beaugerie L, et al. Crohns disease

severity in familial and sporadic cases. Gut 1999;44:9195.

177. Henriksen M, Jahnsen J, Lygren I, et al. Are there any differ-

ences in phenotype or disease course between familial andsporadic cases of inflammatory bowel disease? Results of a

population-based follow-up study. Am J Gastroenterol 2007;

102:19551963.

178. Shen B, Remzi FH, Hammel JP, et al. Family history of Crohns

disease is associated with an increased risk for Crohns dis-

ease of the pouch. Inflamm Bowel Dis 2009;15:163170.

179. Melmed GY, Fleshner PR, Bardakcioglu O, et al. Family history

and serology predict Crohns disease after ileal pouch-anal

anastomosis for ulcerative colitis. Dis Colon Rectum 2008;

51:100108.

1794.e4 COSNES ET AL GASTROENTEROLOGY Vol. 140, No. 6

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