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Clinical Epidemiology of Inammatory Bowel Disease: Incidence, Prevalence, and Environmental Inuences
EDWARD V. LOFTUS, JR.
Inammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota

Although the incidence and prevalence of ulcerative colitis and Crohns disease are beginning to stabilize in high-incidence areas such as northern Europe and North America, they continue to rise in low-incidence areas such as southern Europe, Asia, and much of the developing world. As many as 1.4 million persons in the United States and 2.2 million persons in Europe suffer from these diseases. Previously noted racial and ethnic differences seem to be narrowing. Differences in incidence across age, time, and geographic region suggest that environmental factors signicantly modify the expression of Crohns disease and ulcerative colitis. The strongest environmental factors identied are cigarette smoking and appendectomy. Whether other factors such as diet, oral contraceptives, perinatal/childhood infections, or atypical mycobacterial infections play a role in expression of inammatory bowel disease remains unclear. Additional epidemiologic studies to dene better the burden of illness, explore the mechanism of association with environmental factors, and identify new risk factors are needed.

light environmental factors thought to predispose to these conditions.

Descriptive Epidemiology
Descriptive epidemiology is the study of disease incidence, prevalence, and demographic factors such as age, gender, and race or ethnic group. Variations of incidence and prevalence of disease across age, gender, race, geographic region, or time may yield clues to the etiology of disease or at least identify areas that deserve further scrutiny. Moreover, studies of incidence and prevalence provide valuable information about the burden of illness to policy makers, funding agencies, resource planners, health care insurers, and pharmaceutic companies. Such epidemiologic studies can be particularly difcult to perform for IBD because the onset of illness may be gradual, there is no single gold standard for diagnosis, and the differential diagnosis is broad. Furthermore, availability of diagnostic techniques, criteria for what constitutes an IBD case, methods of case ascertainment, and awareness of the diagnosis among physicians in a particular region may vary considerably across studies, making comparison of studies difcult. Incidence and Prevalence Incidence is the frequency of new cases over a certain time interval and is expressed as an incidence rate (the convention in the IBD literature is cases per 100,000 person-years). There are literally hundreds of articles describing the incidence of Crohns disease and ulcerative colitis in many regions of the world,4 and a full enumeration of these articles is beyond the scope of this review. Incidence rates of IBD from selected geographic regions around the world are shown in Table 1, and prevalence gures are shown in Table 2. In general, the highest incidence rates and prevalence for both Crohns disease and ulcerative colitis have been reported from northern Europe,518 the United Kingdom,19 22 and
2004 by the American Gastroenterological Association

n the broadest sense of the term, epidemiology is the study of occurrence of illness. Although many of us associate the discipline with the study of acute outbreaks of illness (usually infectious), epidemiology still remains vitally important in seeking clues to the etiology and/or pathogenesis of chronic idiopathic diseases, including Crohns disease and ulcerative colitis. The current leading hypotheses for the etiology of the inammatory bowel diseases (IBD) emphasize genetic predispositions to dysregulation of the gastrointestinal immune system.1 Many authors have pointed to the 50% 60% concordance of Crohns disease in identical twins2,3 to illustrate the importance of genetic inuences in IBD. However, one must remember the ip side of the coinapproximately 40%50% of individuals with identical genetic makeup are discordant for Crohns disease, pointing to the inescapable conclusion that environmental inuences play an equally important role in the development of IBD. This article will review the descriptive epidemiology of Crohns disease and ulcerative colitis and high-

0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.01.063

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Table 1. Incidence Rates of Ulcerative Colitis and Crohns Disease From Selected Registries
Author(s) (reference) North America Pinchbeck et al.23 Hiatt et al.24 Stowe et al.25 Kurata et al.26 Loftus et al.27,29 Bernstein et al.28 Blanchard et al.30 Europe Shivananda et al.14 Shivananda et al.14 Scandinavia Bjornsson et al.18 Munkholm et al.9 Langholz et al.8 Moum et al.12,13 Roin et al.6 Lapidus et al.15 United Kingdom Rubin et al.22 Yapp et al.21 Kyle19 Northern Europe Russel et al.16 Gower-Rousseau et al.10 Southern/Central Europe Mate-Jiminez et al.34 Manousos et al.35,36 Vucelic et al.32,33 Trallori et al.37 Tragnone et al.38 Asia Odes et al.42 Sood et al.46 Yang et al.44 Morita et al.43 Africa Wright et al.47 Setting Northern Alberta Northern California Monroe County, NY Southern California Olmsted County, MN Manitoba Manitoba 8 N. European cities 12 S. European cities Iceland Copenhagen County S.E. Norway Faroe Isles, Denmark Stockholm County North Tees Cardiff, Wales N.E. Scotland S. Limburg, The Netherlands N.W. France 2 Spanish regions Heraklion, Crete Zagreb, Croatia Florence, Italy 8 Italian cities Southern Israel Punjab, India Seoul, Korea Japan Cape Town, South Africa Case ascertainment Population HMO Hospital HMO, outpatient HMO, hospital Population Population Population Population Population Population Population Population Population Population Population Population Population Population Population Hospital Population Population Population Population Population Survey Population Survey Population, white Population, colored Population, black Hospital Hospital Incidence dates 1981 19801981 19801989 19871988 1988 19841993 19891994 19871996 19911993 19911993 19901994 19801987 19901993 19811999 19851989 19851994 19911995 19851987 19911994 19881990 19811988 19901994 19801989 19901992 19891992 19871992 19992000 19921994 1991 19801984 19801984 19801984 19871993 19871993 Incidence of UCa 6 10.9 2.3 NA NA 8.3 14.3 15.6 11.8 8.7 16.5 9.2 13.6 20.3 NA 13.9 NA NA 10.0 3.2 3.2 9.4 1.5 9.6 5.2 NA 6.0 1.2 1.9 5.0 1.9 0.6 1.2 2.2 Incidence of CDa 10 7.0 3.9 3.6 5.4 6.9 14.6 15.6 7.0 3.9 5.5 4.1 5.8 3.6 4.9 8.3 5.6 9.8 6.9 4.9 1.6 3.3 0.7 3.4 2.3 4.2 NA NA 0.5 2.6 1.8 0.3 0 0.03

Latin America Linares de la Cal et al.48 Linares de la Cal et al.48

Colon, Panama Partido General de Pueyrredon, Argentina

Adapted and reprinted with permission from Sandler RS, Loftus EV. Epidemiology of inammatory bowel diseases. In: Sartor RB, Sandborn WJ, eds. Kirsners inammatory bowel diseases. 6th ed. Philadelphia: Saunders, 2004;245262. NA, not available. aCases per 100,000 person-years.

North America,2331 which are the geographic regions that have been historically associated with IBD. However, reports of increasing incidence and prevalence from other areas of the world such as southern or central Europe,3238 Asia,39 46 Africa,47 and Latin America48 underscore that the fact that the occurrence of IBD is a dynamic process. In North America, incidence rates for IBD range from 2.2 to 14.3 cases per 100,000 person-years for ulcerative

colitis and from 3.1 to 14.6 cases per 100,000 personyears for Crohns disease (Table 1). Prevalence ranges from 37 to 246 cases per 100,000 persons for ulcerative colitis and from 26 to 199 cases per 100,000 persons for Crohns disease (Table 2). When extrapolated to an estimated combined population of 320 million persons in the United States and Canada in 2003, this implies that between 7000 and 46,000 persons are newly diagnosed with ulcerative colitis each year and that as many as

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Table 2. Prevalence of Ulcerative Colitis and Crohns Disease From Selected Registries
Author(s) (reference) North America Pinchbeck et al.23 Kurata et al.26 Loftus et al.27,29 Loftus et al.31 Bernstein et al.28 Europe Langholz et al.8 Munkholm et al.9 Kyle et al.19 Mate-Jiminez et al.34 Vucelic et al.32,33 Trallori et al.37 Rubin et al.22 Daiss et al.5 Montgomery et al.20 Asia Fireman et al.40 Grossman et al.41 Odes et al.39 Odes et al.42 Sood et al.46 Morita et al.43 Lee et al.45 Yang et al.44 Setting Northern Alberta Southern California Olmsted County, MN Olmsted County, MN Manitoba Copenhagen N.E. Scotland, United Kingdom 2 Spanish regions Zagreb, Croatia Florence, Italy North Tees, United Kingdom Tubingen, Germany United Kingdom Central Israel Southern Israel Southern Israel Punjab, India Japan Singapore Seoul, Korea Case ascertainment Population HMO Population Population Population Population Population Hospital Population Population Population Population Survey Population Population Population Survey Survey Hospital Population Prevalence date 12/31/1981 1988 1/1/1991 1/1/2001 12/31/1994 12/31/1987 12/31/1988 12/31/1988 12/31/1989 12/31/1992 1/1/1995 12/31/1984 1996 1980 12/31/1985 12/31/1992 1999 1991 19851996 12/31/1997 Prevalence of UCa 37.5 NA 229 246 169.7 161.2 NA 43.4 21.4 121 243 24.8 122 55.2 70.6 NA 44.3 18.1 6.0 7.6 Prevalence of CDa 44.4 26.0 144.1 162 198.5 54 147 19.8 8.3 40 144 54.6 214 19.5 NA 50.6 NA 5.8 3.6 NA

Adapted and reprinted with permission from Sandler RS, Loftus EV. Epidemiology of inammatory bowel diseases. In: Sartor RB, Sandborn WJ, eds. Kirsners inammatory bowel diseases. 6th ed. Philadelphia: Saunders, 2004;245262. NA, not available. aCases per 100,000 persons.

780,000 persons may have ulcerative colitis. Likewise, between 10,000 and 47,000 residents of the United States and Canada are diagnosed with Crohns disease annually, and as many as 630,000 persons suffer from Crohns disease. Rates seem to be highest in northern locales (the so-called north-south gradient).23,2730 Studies of hospitalization rates for IBD among Medicare recipients and U. S. military veterans also suggest a north-south gradient,49,50 although exceptions to this concept exist.51 In Europe, incidence rates range from 1.5 to 20.3 cases per 100,000 person-years for ulcerative colitis and from 0.7 to 9.8 cases per 100,000 person-years for Crohns disease (Table 1). The entire European population (including non-European Union countries) has been estimated to be approximately 580 million as of 2002. The multicenter European Collaborative Study on Inammatory Bowel Disease (EC-IBD) reported blended incidence rates between 8.7 and 11.8 cases per 100,000 personyears for ulcerative colitis and between 3.9 and 7.0 cases per 100,000 person-years for Crohns disease.14 Using these gures produces estimates of between 50,000 and 68,000 new cases of ulcerative colitis diagnosed annually throughout Europe and between 23,000 and 41,000 new

cases of Crohns disease. The EC-IBD quantied the degree of north-south gradient of incidence in Europe (in general, incidence rates of IBD were 40% to 80% higher in northern locales), but this gradient was narrower than previously believed.14 A study from northern England suggested that the prevalence of IBD in 1995 was as high as 387 cases per 100,000 persons (243 per 100,000 for ulcerative colitis and 144 per 100,000 for Crohns disease).22 Extrapolating these gures across the European population yields a maximal estimate of 2.2 million persons aficted with IBD. Historically, IBD was rare on other continents, with the exceptions of Israel, Australia, and South Africa. However, the incidence of IBD, especially ulcerative colitis, is rising in several areas previously thought to have low incidence, including Japan,43 South Korea,44 Singapore,45 northern India,46 and Latin America.48 In most of these areas, however, Crohns disease remains rare. The incidence of Crohns disease is rising in many areas (Figure 1), but the incidence has stabilized in many high-incidence areas, such as Scandinavia and Minnesota. In Olmsted County, the prevalence of Crohns disease has continued to rise despite a stable incidence rate, presum-

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Figure 1. Temporal trends in incidence rates (cases per 100,000 person-years) of Crohns disease in selected areas (Olmsted County, Minnesota27; Cardiff, Wales, United Kingdom21; Rochester, New York25; Iceland17,18; Aberdeen, Scotland, United Kingdom19; Helsinki, Finland7; and Florence, Italy37).

ably because of longer life expectancies of Crohns disease patients and possibly in-migration of patients. Similarly, the incidence of ulcerative colitis for the most part has stabilized in high-incidence areas but has continued to rise in areas with formerly low incidence rates (Figure 2). Several themes emerge after examining temporal and geographic trends in IBD incidence. First of all, IBD incidence seems low in developing countries (whether this is due to low diagnostic awareness, confusion with infectious causes of diarrhea, or a truly low incidence rate remains unclear). As societies become more Westernized or industrialized, with attendant changes in lifestyle and diet and perhaps other environmental exposures, ulcerative colitis emerges, but the incidence of Crohns disease remains low. Over time, Crohns disease emerges, and its incidence ultimately matches that of ulcerative colitis. Demographic Features There appear to be slight gender-related differences in IBD incidence. In general, there is a slight female predominance in Crohns disease, although in certain low-incidence areas a male predominance exists. The female predominance, especially among women in late adolescence and early adulthood, suggests that hormonal factors may play a role in disease expression. On the other hand, if there is a slight gender predominance in ulcerative colitis, it rests with males. Indeed, some studies of ulcerative colitis incidence suggest that, although overall incidence has stabilized, it continues to rise in males (with a corresponding decrease in females).29 Crohns disease and ulcerative colitis are most commonly diagnosed in late adolescence and early adulthood, but the diagnosis may occur at all ages. In a systematic review of population-based cohorts of Crohns disease

from North America, the mean age at diagnosis ranged from 33.4 years to 45 years,52 whereas the median age at diagnosis, available in only 1 paper,27 was 29.5 years. Mean and median ages at diagnosis of ulcerative colitis are, in general, 5 to 10 years later than those associated with Crohns disease.18,29 Although some studies focusing on IBD incidence among children have noted increasing incidence rates, these increases have generally mirrored increases in the overall population, and the percentage of patients who are diagnosed in the pediatric age range does not appear to have risen in recent years. IBD has classically been thought to demonstrate a bimodal age distribution (i.e., incidence peak in the second or third decades in life followed by a second, smaller peak in later decades), but, in several recent epidemiologic studies, this has not been uniformly found. It is not known whether these differences in age distribution are real or represent variations in diagnostic criteria and/or classication. In some studies of ulcerative colitis, there are gender-related differences in late onset disease. Men are signicantly more likely than women to be diagnosed in the fth and sixth decades of life. Racial/Ethnic Differences in Incidence and Prevalence Several studies suggest that the incidence of IBD among African Americans is approaching that of whites. Hospitalization rates for Crohns disease were similar among whites and blacks in a southern California HMO, and the prevalence of Crohns disease among blacks was approximately two thirds that of whites.26 The incidence of IBD among African-American children from Georgia was estimated to be, at a minimum, 7 to 12 cases per 100,000 person-years for Crohns disease and 5 to 7 cases per 100,000 person-years for ulcerative colitis.51 African Americans composed 28% of the pediatric IBD cohort,

Figure 2. Temporal trends in incidence rates (cases per 100,000 person-years) of ulcerative colitis in selected geographic regions (Olmsted County, Minnesota29; Rochester, New York25; Iceland17,18; Florence, Italy37; Malmo, Sweden11; Heraklion, Crete, Greece36; and Seoul, South Korea44).

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approaching the overall percentage of African Americans in the Atlanta metropolitan area (41%) or the state of Georgia (36%).51 In a prospective survey from the United Kingdom, the risk of IBD among African-Caribbean children was similar to that of white children,53 whereas a retrospective study of IBD incidence in Derby, United Kingdom, showed that the risk of Crohns disease among whites and African-Caribbean adults was similar.54 Although data are limited, it appears that Asian Americans, Americans of Hispanic background, and aboriginal North Americans are less likely to develop IBD, especially Crohns disease. A study of Medicare recipients from the 1980s showed that hospitalizations for IBD among Hispanics and Asian Americans were uncommon,49 and similar ndings were seen for Crohns disease hospitalizations among members of a southern California HMO.26 Aboriginal Canadians residing in Manitoba, Canada, were less likely to develop IBD.30 Studies of migrant populations suggest that ethnic and racial differences may be more related to lifestyle and environmental inuences than true genetic differences. For example, until recently, IBD was thought to be rare in the Indian subcontinent. However, South Asians who have moved to the United Kingdom, and their offspring, are at increased risk of ulcerative colitis relative to whites,5557 and those who have moved to Singapore are at increased risk relative to ethnic Chinese.45 Israeli studies suggest a higher prevalence of IBD among Jews from Europe and America compared with those from Asia and Africa, but those differences may be narrowing over time.40,42

Table 3. Putative Risk Factors for Inammatory Bowel Disease

Family history of inammatory bowel disease Cigarette smoking (risk factor for Crohns, protective factor for ulcerative colitis) Appendectomy (protective factor for ulcerative colitis, risk factor for Crohns?) Oral contraceptives? High sugar diet? High fat diet? Breastfeeding? (protective factor?) Perinatal or early childhood infections? Wild-type measles infection? Attenuated live measles virus vaccine? (unlikely) Mycobacterium paratuberculosis infection?

Risk Factors for IBD

Cigarette Smoking Since the rst widely publicized report of an inverse association between ulcerative colitis and cigarette smoking,58 many studies have conrmed this unusual nding59 74 (Table 3). The odds ratio for developing ulcerative colitis among current smokers is consistently less than 1; stated another way, current smokers seem to have a signicantly decreased risk of ulcerative colitis. A 1989 meta-analysis noted that current smokers are 40% as likely as those who have never smoked to develop ulcerative colitis.75 The mechanism of action for this unusual association remains unclear potentially important effects of nicotine on rectal blood ow, colonic mucus, cytokines, and eicosanoids have been reviewed elsewhere.76,77 Interestingly, a similar inverse association with cigarette smoking and illness has been noted for related conditions such as primary scle-

rosing cholangitis (PSC), with or without associated IBD,78 80 and pouchitis.81 The protective effect against PSC suggests a systemic protective effect rather than a local effect in the colon. In many of the above studies, former cigarette smokers were noted to have an increased risk of ulcerative colitis relative to those who never smoked.60,62,65 68,73,74 When these results are pooled, it appears that exsmokers are 70% more likely than those who never smoked to develop ulcerative colitis.75 Why this should be the case remains unclear. Some have suggested that early gastrointestinal symptoms might lead to smoking cessation, explaining the increased risk among exsmokers. However, even remote smoking cessation is associated with increased risk of ulcerative colitis.66 Cigarette smoking may inuence the course of ulcerative colitis. In one study, active smokers were half as likely to be hospitalized for ulcerative colitis as nonsmokers, whereas exsmokers were 50% more likely to be hospitalized and twice as likely as current smokers or those who never smoked to undergo colectomy.82 In another study, approximately 45% of ulcerative colitis patients who resumed smoking noted improvement in symptoms, and those who improved smoked, on average, twice as many cigarettes daily as those who did not.83 French smokers with ulcerative colitis who quit smoking had more active disease, more hospitalizations, and greater need for corticosteroids or azathioprine compared with those continued to smoke.84 Two randomized, placebo-controlled trials of transdermal nicotine for active ulcerative colitis demonstrated clinical improvement in 40%50% of patients receiving nicotine (as compared with 9%24% in the placebo groups); however, neither study demonstrated signicantly higher remission rates with nicotine.85,86 A randomized trial of nicotine vs. placebo patches for maintenance of remission showed no benet of nicotine over placebo.87 Another randomized clinical trial compared

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transdermal nicotine with moderate-dose oral prednisolone for active disease.88 The nicotine group had fewer remissions and more side effects than the prednisolone group. Only 1 in 5 patients in the nicotine group reached full sigmoidoscopic remission in the 6-week trial.88 It is possible that the benet of smoking on ulcerative colitis depends on levels of nicotine higher than can be provided with patches, or it may be that other components of cigarette smoke contribute to the protective effect of smoking. In contrast to ulcerative colitis, several studies have implicated cigarette smoking as a risk factor for Crohns disease,64,67,68,89 91 and meta-analytic techniques suggest that smokers are more than twice as likely to develop Crohns disease.75 Former smokers are also at risk, but the magnitude is less than that for current smokers. The association between smoking and Crohns disease may not apply to all ethnic groups or geographic regions several Israeli studies have failed to demonstrate that smoking is a risk factor for Crohns disease.74,92,93 Smoking can inuence the clinical course of Crohns disease. Patients with Crohns disease who smoke are more likely to have ileal than colonic or ileocolonic involvement,94,95 and smokers are much less likely to have pure inammatory Crohns disease (as opposed to stulizing or stenosing disease).96 Continued cigarette smoking following surgical resection increases the risk of recurrent disease.97100 In a Canadian study, women who smoked were more than 4 times more likely to require another surgery for recurrent Crohns disease than nonsmokers,97 and a dose-response effect was noted. Crohns disease patients who smoke are more likely to require immunosuppressive agents,100 and women who smoke are more likely to have a poor health-related quality of life.101 On a hopeful note, Crohns disease patients who quit smoking note fewer exacerbations and require less corticosteroids or immunosuppressive therapy to control symptoms compared with patients who continue to smoke.102 Passive cigarette smoking has also been linked to IBD risk, but results have been conicting. One study found that adult subjects exposed as children to environmental tobacco smoke in the home were half as likely to develop ulcerative colitis.71 The effect of passive smoking in childhood was comparable with that of active smoking in adulthood. However, another study found that passive smoking exposure at birth was signicantly associated with the development of either subtype of IBD.103 The association for Crohns disease demonstrated a dose-response relationship. Secondhand exposure to cigarette smoke in childhood increased the risk of Crohns, but not

ulcerative colitis, in a Swedish study.94 An Israeli study of passive smoking among adults with IBD showed no overall differences in exposure among IBD patients or controls, although ulcerative colitis patients may have had less exposure to secondhand smoke when a quantitative index was employed.104 Appendectomy Appendectomy appears to be protective for the development of ulcerative colitis. The inverse association was rst noted in a multicenter study of pediatric IBD,105 and it has been conrmed in over a score of studies.106,107 A metaanalysis of 17 case-control studies involving almost 3600 cases and over 4600 controls showed that appendectomy was associated with a 69% reduction in the subsequent risk of ulcerative colitis.108 Even in studies that employ multivariate analysis to control for other important factors such as cigarette smoking, the apparent protective effect of appendectomy remains signicant. Cohort studies of the relationship between appendectomy and subsequent risk of ulcerative colitis have yielded conicting results.109,110 A Swedish national inpatient register was utilized to assemble a cohort of over 212,000 patients who had undergone appendectomy and a cohort of age-, gender-, and location-matched controls.109 These cohorts were followed for over 5 million person-years for a subsequent hospital diagnosis of ulcerative colitis. Those undergoing appendectomy had an incidence of ulcerative colitis approximately three quarters that of controls.109 Important factors associated with a lower incidence of ulcerative colitis included appendectomy before the age of 20 years and appendectomy for appendicitis or mesenteric lymphadenitis (vs. abdominal pain or other reasons).109 A Danish cohort of over 154,000 patients who had undergone appendectomy was followed for over 1 million person-years for a subsequent hospital diagnosis of IBD.110 Expected numbers of hospitalizations for IBD were derived from previously published national rates.111 The appendectomy cohort was 13% less likely than expected to be diagnosed with ulcerative colitis, but this was not statistically signicant.110 Why these 2 large cohort studies yielded conicting results remains unclear. The Swedish study excluded UC diagnosed within 1 year of appendectomy, whereas the Danish study did not; however, even if these UC diagnoses are included, the results are little changed.109,110 Most of the evidence from the case-control and cohort studies suggests that appendectomy is a protective factor for ulcerative colitis. Similar to the effect of cigarette smoking, appendectomy may inuence not only the occurrence of ulcerative

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colitis but also its clinical course. In a Japanese multicenter study, ulcerative colitis patients who developed ulcerative colitis after appendectomy were diagnosed at older age and were less likely to develop recurrent symptoms than colitis patients with an intact appendix.112 In studies from France and Australia, ulcerative colitis patients who had undergone appendectomy prior to diagnosis were signicantly less likely to require colectomy,113,114 and, in the case of the Australian study, signicantly less likely to require immunosuppressive therapy for control of disease.113 Another Australian study conrmed the older age at diagnosis among colitis patients who had undergone previous appendectomy but could not demonstrate greater need for immunosuppressive therapy or colectomy.115 The effect of appendectomy on the clinical course of patients with known ulcerative colitis is limited to case reports and small case series, and results are conicting. The effect of appendectomy on the future risk of Crohns disease has also been examined in at least 16 studies.107 Most studies have suggested that appendectomy is associated with future risk of Crohns disease, but, in many of these studies, statistically signicant differences were not noted, whereas, in other studies, appendectomies performed at the time of diagnosis of Crohns disease were not excluded107 (some patients with Crohns disease will initially present with a syndrome mimicking appendicitis, and appendectomies performed just prior to Crohns diagnosis may have been because of undiagnosed Crohns disease). Andersson et al. followed the large Swedish cohorts for the development of Crohns disease and noted an increased risk of Crohns disease following appendectomy even after excluding a diagnosis within 1 year of the procedure.116 However, children who underwent appendectomy before the age of 10 years were less likely to develop Crohns disease.116 Those who developed Crohns disease following a surgery for perforated appendicitis had a more aggressive form, requiring intestinal resection at least twice as frequently as others, whereas patients who underwent appendectomy for other reasons had a less aggressive form of Crohns disease.116 The mechanisms whereby appendectomy protects against ulcerative colitis but increases risk of Crohns disease are unknown, but hypotheses abound.107 The development of appendiceal inammation or mesenteric adenitis might protect against ulcerative colitis and/or predispose to Crohns disease. Alternatively, removal of the appendix might inuence the mucosal immune system of the gut in such a way as to reduce the risk of ulcerative colitis but increase the risk of Crohns disease.

Oral Contraceptives Several case-control and cohort studies have suggested an increased risk of IBD in women who take oral contraceptives. Cohort studies from the United States117 and the United Kingdom,63,118 involving over 80,000 women, pointed to a 40% to 3-fold increase in IBD risk, but, in most instances, these results were not statistically signicant, especially after adjusting for cigarette smoking. Case-control studies have also yielded somewhat conicting results.119 123 However, a 1995 metaanalysis that pooled the results of 2 cohort studies and 7 casecontrol studies derived an odds ratio for Crohns disease among users of oral contraceptives, after adjusting for smoking, of 1.4 (95% CI: 1.11.9).124 Women who used oral contraceptives, after adjusting for smoking, were 29% more likely to develop ulcerative colitis, but this did not reach statistical signicance (95% CI: 0.9 1.8).124 Other case-control studies not included in the metaanalysis, from western Washington state and Italy, also suggest an association between oral contraceptive use and IBD, especially Crohns disease.125,126 Some of the studies have suggested a dose response, with higher risks for IBD seen among longtime users of oral contraceptives119,123,125 or among users of high estrogen dose preparations.125 Whether oral contraceptive use modies the course of existing IBD remains unclear. Although one study of women enrolled in the placebo arm of a Crohns disease trial pointed to oral contraceptive use as a predictor of relapse,99 a prospective French study examining risk factors for Crohns relapse did not nd that oral contraceptives were associated with recurrence.127 The bulk of evidence does suggest a weak association between oral contraceptive use and IBD. The mechanism for this association is not denitively known, but it is thought that the thrombogenic properties of oral contraceptives, in the setting of a process of multifocal, microvascular gastrointestinal infarction, might play a role.128 Diet Because dietary antigens are, next to bacterial antigens, the most common type of luminal antigen, it is logical to surmise that diet might play a role in the expression of IBD. Furthermore, differences in diet might explain the signicant differences in IBD risk across geographic regions and the increases in IBD incidence in migrant populations. However, despite numerous studies of dietary factors in IBD, no consensus has emerged. Studies examining the association between diet and disease are difcult to perform because of poor recall of diet and the possibility that diet was subconsciously

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altered even before formal diagnosis because of gastrointestinal symptoms. The most consistent association noted in dietary studies has been the link between increased sugar intake and IBD, especially Crohns disease, rst identied over 25 years ago.129 Numerous case-control studies have conrmed the association between sugar intake and Crohns disease, and these have been reviewed elsewhere.130 Studies that have minimized difculties with dietary recall by studying patients diagnosed within 1 year have yielded conicting results, with some studies showing an association131133 but others not.134 A population-based, case-control study from The Netherlands implicated chocolate and cola drink consumption as possible risk factors for IBD.135 The role of fat intake in the expression of IBD has not been studied extensively, but some epidemiologic studies have implicated monounsaturated and polyunsaturated fats in both Crohns disease and ulcerative colitis.136,137 High intake of dietary ber, fruit, or vegetables may be protective against the development of IBD, but results vary from study to study.133,135,138 This could very well be a spurious nding in that patients with Crohnsrelated bowel strictures may restrict intake of bercontaining foods to prevent symptoms. The studies on dietary factors in IBD remain difcult to interpret. Studies of dietary interventions (other than elemental diets), such as low sugar diets, have been disappointing,130 and certain restrictive diets advocated on the Internet for treatment of IBD have not been subjected to enough rigorous scientic analysis to recommend them. Perinatal and Childhood Factors It has been proposed that the expression of IBD may be inuenced by events in early childhood, such as mode of feeding, domestic hygiene, or perinatal infections. Whether breastfeeding protects against the development of IBD remains unclear. Although several studies have suggested an inverse association between breastfeeding and IBD,139 143 in most cases, the odds ratios were not statistically signicant, and other studies have not demonstrated such an association.105,144 146 In general, the association has been stronger for Crohns disease than for ulcerative colitis. Like studies of dietary factors in IBD, these studies often suffer from long recall intervals and potential for recall bias. Perinatal infections, either in the infant or the mother, might inuence the expression of IBD. It was noted in a study of IBD from central Sweden that incidence rates were higher in the rst half of the year.147 In the same population, it was determined that IBD patients, espe-

cially Crohns disease, were signicantly more likely than controls to have a birth date within 6 days of another case.148 The medical records of over 250 IBD patients born in 1 of these hospitals were compared with those of over 500 controls, and those with a recorded perinatal health event (i.e., infection or serious illness in mother or child) had a 4-fold increased risk for IBD.144 In the same study, infants from families of low socioeconomic status were 3 times more likely later to develop IBD.144 Several studies have noted a higher frequency of gastroenteritis or diarrheal illness during infancy among future IBD patients, but, in most of these studies, recall bias is a concern.140,145,149 A history of frequent childhood infections or exposure to antibiotics has also been proposed as a risk factor for IBD.150 On the other hand, some have suggested that absence of infections might be a risk factor for IBD (similar to the sheltered child hypothesis in asthma). Crohns disease (but not ulcerative colitis) is more common in those who lived in houses with a hot water tap during childhood,151,152 and others have noted an inverse correlation between infant mortality rates and IBD incidence rates in various countries.153 Measles Infection or Vaccination It has been proposed that perinatal or childhood paromyxoviral infection might result in persistent infection of the vascular endothelium of the mesentery, resulting in a chronic granulomatous vasculitis (Crohns disease).154 In the decade following World War II, several measles epidemics occurred in central Sweden, and it was noted that the number of people born in the 3 months following the epidemic peaks, subsequently diagnosed with Crohns disease, was 46% higher than expected.155 The same group identied 4 women who had developed measles infection during pregnancy in the 1940s and found that 3 of the 4 children born had developed Crohns disease; moreover, immunohistochemistry identied measles virus antigen in the intestinal tissue of the 3 patients.156 However, other studies of the association between perinatal and/or in utero measles infection have not been able to conrm these ndings,146,157,158 and the bulk of evidence does not support the hypothesis that wild-type measles infection leads to IBD.159 The same investigators who initially proposed persistent measles infection as a cause for Crohns disease suggested that attenuated live measles virus vaccine might lead to IBD.160 The prevalence of IBD in a group of 3500 people who had received live measles vaccine in 1964 was compared with that of a cohort of over 11,000 subjects who were born in the same week in 1958 who

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had not received vaccine. Those receiving vaccine were 2 to 3 times more likely to develop IBD160; however, concerns have been raised about this studys methodology because the means by which IBD cases were identied in these 2 cohorts differed considerably. Moreover, several case-control studies in different locales have not demonstrated signicant differences in vaccination rates (with either measles-mumps-rubella vaccine or other forms of measles vaccine) among IBD cases and unaffected controls.161163 Indeed, one of these studies, a population-based report from 4 health maintenance organizations on the West Coast of the United States, suggested that measles vaccination after the age of 18 months was associated with a decreased risk of IBD.163 Based on the available evidence, it would be difcult to conclude that measles vaccination is a risk factor for IBD. Mycobacterial Infection Years ago, the similarities between tuberculosis and Crohns disease were rst noted.164 Johnes disease, a chronic wasting diarrheal illness in ruminants and other species characterized by granulomatous inammation of the intestine, is caused by Mycobacterium avium subspecies paratuberculosis (MAP). This organism was rst cultured from the intestinal tissue of patients with Crohns disease in the early 1980s,165 and this nding has generated 2 decades worth of controversy.166 169 Subsequent attempts at recovery of atypical mycobacteria from cultures have had variable success.166 The specicity of a positive mycobacterial culture has been questioned because atypical mycobacteria can also be recovered from the intestinal tissue of unaffected individuals.170 Initial studies of MAP seroprevalence suggested higher rates of MAP antibody formation in Crohns disease, but subsequent studies have not been able to reproduce these ndings.166 A similar theme has been seen in studies utilizing polymerase chain reaction technology to recover MAP DNA from patients with Crohns diseasethe rate of detection varies considerably, both among Crohns cases and unaffected controls.166 However, several recent studies highlight that a mycobacterial hypothesis for Crohns disease cannot be completely discounted at the present time. MAP DNA could be recovered in 40% of subepithelial Crohns-related granulomas and 0% of granulomas from other conditions such as foreign body granulomas and sarcoidosis.171 In another study utilizing fresh ileocolonic mucosal biopsy specimens, MAP DNA was recovered from 92% of Crohns disease patients and 26% of controls.172 After tissue was cultured in conditions favorable to mycobacteria, MAP DNA was recovered in 42% of cases and only 9% of controls.172

It stands to reason that, if MAP were a signicant pathogen in Crohns disease, antimycobacterial therapy should be of benet. On the other hand, some of these antimycobacterial agents are broad-spectrum antibiotics and would be active against many normal gut ora. Although several open-label studies of antibiotic regimens with antimycobacterial activity have suggested clinical improvement,173175 the results from randomized clinical trials are less compelling. A meta-analysis of 8 trials of antimycobacterial therapy for Crohns disease yielded somewhat conicting results.176,177 In the 2 trials (total of 89 patients) in which both treatment arms (antimycobacterial drugs vs. standard therapy) received a tapering course of corticosteroids, the pooled odds ratio favored antimycobacterial therapy.177 In the other 4 trials (n 226), the pooled odds ratio favored standard therapy.177 The authors concluded that antimycobacterial therapy could not be recommended on the basis of this evidence.176 Although the MAP hypothesis is an intriguing one, the burden of proof remains on the proponents of the hypothesis to demonstrate unequivocally the link between MAP and Crohns disease.

Conclusion
Despite years of investigation, the root causes of IBD are yet to be identied. Descriptive epidemiologic studies not only provide valuable information about the burden of illness, they highlight differences in incidence of IBD across age, time, and geographic region, suggesting that environmental factors can signicantly modify the expression of these conditions. The strongest modifying factors identied thus far include family history of IBD, cigarette smoking, and appendectomy. Continued efforts at understanding how these factors inuence the expression of IBD, and identifying new risk factors, are needed.

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Received January 5, 2004. Accepted January 22, 2004. Address requests for reprints to: Edward V. Loftus, Jr., M.D., Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. e-mail: loftus.edward@mayo.edu; fax: (507) 266 0335. Dr. Loftus has served as a consultant for AstraZeneca and Novartis and has received research support from AstraZeneca, Procter and Gamble, and GlaxoSmithKline.