IBD:Epidemiology and Risk Factors

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of diseases affecting the bowel, the most common of which are ulcerative colitis and Crohn’s disease.

Whereas UC is characterised by a continuous distri- bution of mucosal/submucosal inflammation within the colon, CD may result in focal areas of disease in any part of the gastrointestinal tract from the mouth to the anus; the inflammation is transmural and almost inevitably progresses over time, often leading to structuring or fistulising complications. Extra- intestinal complications affecting eyes, skin and joints occur in both illnesses. Although inflammatory bowel disease is not common or highly fatal, it is important to public health because its highest incidence is early in life, its therapy involves major surgery including a curative colectomy for ulcerative colitis, and having the disease increases the risk of developing colon cancer.

There are literally hundreds of articles describing the incidence of ulcerative colitis and Crohn’s disease in many regions of the world. In general, the highest incidence rates and prevalence for both diseases have been reported in northern Europe [1–8], the United Kingdom [9–11], and North America [12–15], which

world such as southern or central Europe [16–18], Asia [19–22], Africa [23], and Latin America [24]

underscore the fact that the occurrence of IBD is a dynamic process. Incidence of UC, especially, is rising in several areas previously thought to have low incidence including Japan [21], South Korea [25], Singa- pore [22], northern India [26] and Latin America [24].

In most of these areas, however, CD remains rare.

In North America, incidence rates range from 2.2 to 14.3 cases/100 000 person-years for UC and from 3.1 to 14.6 cases/100 000 person-years for CD. Preva- lence ranges from 37 to 246 cases/100 000 persons for UC and from 26 to 199 cases/100 000 persons for CD [12–14].

The Multicenter European Collaborative Study on Inflammatory Bowel Disease (EC-IBD) reported blended incidence rates between 8.7 and 11.8 cases/100 000 person-years for UC and between 3.9 and 7.0 cases/100 000 person-years for CD [6]. The EC-IBD quantified the north–south gradient of incidence in Europe: the incidence rates for UC and for CD were respectively 40 and 80% higher in northern regions.

Fig. 1.UC incidence rates in Italy ([27]) Fig. 2.CD incidence rates in Italy ([27])

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The last study from northern England [11] suggested that the prevalence of IBD in 1995 was 243/100 000 persons for UC and 144/100 000 persons for CD.

Italy, until some years ago, was considered among the countries with low incidence. In Italy, incidence rates are of 5.2 cases/100 000 person-years for UC and 2.3 cases/100 000 person-years for CD (Figs. 1, 2) [27].

The northern European studies based on population grounds have shown that there is no increase in overall mortality in IBD [28]. Only in CD has there been an increased mortality observed in the first few years after diagnosis in young patients. In some studies, this was observed primarily in the females. The Italian studies data confirm other European studies [29–31].

In general, there is a slight female predominance in Crohn’s disease, especially among women in late adolescence and early adulthood, which suggests that hormonal factors may play a role in disease expression. On the other hand, if there is a slight gender predominance regarding UC, it rests with males [15].

For UC, different patterns of incidence were observed for men and women aged 35 and over, with Fig. 4.Female annual incidence for UC ([32])

Fig. 5.Male annual incidence for UC ([32]

Fig. 6. Ratio of males to females according to smoking habits and age quartiles ([33])

Fig. 3.a Male and female incidence in different age groups for UC. b Male and female incidence in different age groups for CD ([6])

b a

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increase with age. The correlation between the age groups and the M/F ratio could be explained by a greater tendency to smoke in men and therefore by a greater, gradual prevalence among them of giving up the habit in relation to, for example, the occurrence of cardiovascular problems (Fig. 6) [33].

Risk Factors

The etiology and pathogenesis of IBD probably involve an interaction between genetic and environmental factors; the precise mechanism for the begin- ning of the intestinal inflammation remains unclear.

There is increasing evidence that both environmental and host genetic factors are important in determining not only disease susceptibility, but also disease clinical course and response to therapy. Many factors have been suggested including family history of IBD, cigarette smoking, appendectomy, oral contraceptive agents, diet, breastfeeding, perinatal or early childhood infections, hygienic factors and physical activity.

Evidence for genetic factors includes epidemiological data showing differences in IBD among different races and ethnic groups, familial aggregation and high concordance for the IBD type in monozygotic vs. dizygotic twins [34–35]. The incidence is highest among whites, somewhat lower among blacks and lowest among Asians, although it is increasing among the latter [36]. Among Caucasians, the most consistent observation has been that the Ashkenazi Jewish population has been shown to be at higher risk than other ethnic groups (ratio 4:1) and this risk is maintained irrespective of geographical location and time period [37].

A family history is the single greatest known risk factor for the development of IBD. Between 6 and 32% of patients with IBD have an affected first or second-degree relative and the prevalence of family history is highest in Jewish patients and in patients with early onset of disease [38–39]. The risk is greatest among siblings, whereas it is lower among offsprings and second-degree relatives; the relative risk to a sib- ling of a patient with CD is 13–36% and for UC

in CD, but the discordance between monozygotic and dizygotic prevalence rates again argues for a genetic contribution to UC. However, genes alone are not sufficient to cause the disease and complex environmental triggers are required for disease expression [43–45].

In genetic terms, the IBD are “complex” because classical Mendelian inheritance attributable to a single gene locus is not exhibited. The model which appears most pertinent at the present time suggests that CD and UC may be related heterogeneous poly- genic disorders, sharing some but not all susceptibility loci. The disease phenotype is likely to be deter- mined by the interaction between allelic variants at a number of loci and the interaction between genetic and environmental factors [46].

Recently the candidate genes have been selected on the basis of their location within an area of replicated linkage in multiplex IBD pedigrees (Fig. 7). The first susceptibility locus was identified in the pericen- tromeric region of chromosome 16 (IBD1) [47]. The importance of this locus has been confirmed by vari- ous groups, including the GISC [48] and the Interna- tional IBD Genetics Consortium [49]. In 2001, three independent studies reported the identification of the IBD1gene as NOD-2 [50–52]. Three coding region variants of this gene are associated with CD but not with UC. Patients carrying one high-risk allele have a 1.5–3-fold increased risk of developing CD, whereas those carrying two high-risk alleles have a 14–44-fold increased risk of developing CD [53]. The NOD2gene has recently been renamed CARD15(caspase recruit- ment domain gene) and is involved in the regulation of innate immune response and apoptosis; the leucine-rich repeat (LLR) domain of the gene appears to function as a sensor for bacterial products such as lipopolysaccharides (LPS; Fig. 8). Recently several genetic studies have been carried out in order to relate NOD2/CARD15variants to specific clinical fea- tures of patients. The studies have generally correlat- ed NOD2mutations with younger age at onset, ileal localisation and fibrostenotic behaviour of CD [54–57].

It has now been 23 years since the association of

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non-smoking with UC was first identified by Harries et al. in 1982 [58], which was followed within 2 years by the observation that patients with CD were more often smokers [59]. This remarkable finding of

“opposite associations” for smoking with IBD has been the subject of intense scrutiny in the hope that it may help identify important pathogenic mecha- nisms responsible for the two conditions and per- haps provide the key to alternative therapeutic options.

In 1989, Calkins reviewed the available studies on the association with IBD. A meta-analysis showed an increased risk of ulcerative colitis among lifelong non-smokers and ex-smokers compared with current smokers (OR 1.64) [60]. The M/F ratio, at diagnosis of UC, increases progressively with age in relation to the ex-smoker’s habit compared with the M/F ratio that remains constant in non-smoking patients [33]. Moreover, it appears that ex-smokers are 70%

more likely than those who never smoked to develop UC. In contrast to UC, several studies have implicat- ed cigarette smoking as a risk factor for CD and the same meta-analysis suggests that in smokers the risk of having the disease is double in comparison to non- smokers. This association may not apply to all ethnic groups or geographic regions, a recent multicentre study performed in Israel has stressed the lack of association between smoking and CD and a negative association for UC [61]. Passive cigarette smoking has also been linked to IBD risk, but results have been conflicting. For UC the effect of passive smoking in childhood was comparable with that of active smoking in adulthood [62]. However, another study demonstrated that passive smoking exposure and maternal smoking at birth were significantly associated with development of either subtype of IBD; in CD the association had a dose-response relationship [63].

Cigarette smoking may also influence the clinical

course of IBD. Active smokers were half as likely to be hospitalised for UC as non-smokers, whereas ex- smokers had higher hospitalisation and colectomy rates [64]. In another study, approximately 45% of UC patients who resumed smoking noted improve- ment in symptoms [65]. Moreover, significantly fewer smokers developed pouchitis compared with non-smokers among patients who had a restorative proctocolectomy for UC [66], and smoking is associated with decreased risk of primary sclerosing cholangitis (PSC) [67].

Patients with CD who smoke (>10 cigarettes/day,

>150 cigarettes/year) are more likely to have ileal than colonic or ileocolonic involvement and fistulising or stenosing than inflammatory disease [68-70].

Most of the studies show severe symptoms, more frequent relapses, higher recurrence rate after surgery and more frequent treatments with steroids and immunosuppressors in smokers compared with non- smokers [71-73]. Young women with CD who contin- ued to smoke, suffered more bowel and systemic symptoms in addition to more emotional dysfunc- tion than female non-smokers [74].

More recently the role of the appendix in IBD epidemiology has become the subject of increasing interest. Appendectomy appears to be protective for the development of UC; important factors associated with a lower incidence of UC include an appendectomy before the age of 20 and appendectomy for appendicitis or mesenteric lymphadenitis [75–77].

Similar to the effect of cigarette smoking, an appendectomy also influences the clinical course of UC. In fact, patients who developed UC after appendectomy were diagnosed at an older age, showed few recurrent symptoms and were significantly less likely to require colectomy [78–79].

On the other hand, many studies have suggested that appendectomy is associated with future risk of CD even after excluding a diagnosis within 1 year of Fig. 7.Significant areas of replicated linkage Fig. 8.Schematic representation of the NOD2/CARD15[51]

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appendix in CD; it could be hypothesised that an etiopathogenic process may be phenotypically expressed in the form of appendicitis avoiding the expression of CD in the colon, similar to the protective role of appendectomy regarding the development of UC. In addiction, the occurrence of an appendectomy before CD diagnosis seems to show a negative association with articular manifestations [81].

Several case-control and cohort studies have suggested an increased risk of IBD in women who take oral contraceptives. In some studies, a positive association between oral contraceptives use and risk of CD was confined to women who were current smokers (OR 2.64) [62], whereas the opposite finding has been reported in other studies in which the elevated risk was found only among non-smokers (OR 3.1 vs.

0.91) [82]. There was no association between oral contraceptive use and UC (OR 0.70). Therefore, there is no evidence suggesting that women predisposed to the development of UC should be advised to avoid oral contraceptive use [83]. However, a 1995 meta- analysis demonstrated an elevated risk both for UC (OR 1.29) and CD (OR 1.44) [84]. Since this meta- analysis, other studies have been published with the same pattern of results: an overall weak association for both diseases but non-sufficiently compelling to infer a causal association [85-86]. The mechanism for this association is not definitively known, but it is thought that the thrombogenic properties of oral contraceptives, in the setting of a process of multifo- cal, microvascular gastrointestinal infarction, might play a role [87].

Because dietary agents are, next to bacterial anti- gens, 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 significant differences in IBD risk across geographic regions and the increase in IBD incidence in migrant populations. However, numer- ous studies have investigated dietary factors in IBD, and the methodological problems related to studies of this kind (type of population studied, recall bias, measure) have brought contradictive results. The

an inverse association between breastfeeding and IBD [86, 92, 93], in most cases the odds ratios were not statistically significant and other studies have not demonstrated such an association [94-95]. In general, the association has been stronger for CD than for UC.

Perinatal infections, either in the infant or the mother, might influence the expression of IBD. It has been proposed that perinatal or childhood paramyx- oviral infection might result in persistent infection of the vascular endothelium of the mesentery, resulting in a chronic granulomatous vasculitis (CD) [96].

However, other studies have not been able to confirm these findings [97]. The same investigators who ini- tially proposed persistent measles infection as a cause of CD suggested that attenuated live measles virus vaccine might lead to IBD [98], but several case- control studies in different locales have not demonstrated significant differences in vaccination rates among IBD cases and unaffected controls [99]. Based on the available evidence, it would be difficult to con- clude that measles vaccination is a risk factor for IBD. A study of IBD from central Sweden noted that IBD patients with an infection or serious illness, mother or child, had a fourfold increased risk for IBD. In the same study, infants from families of low socioeconomic status were 3 times more likely later to develop IBD [100]. On the other hand, some have suggested that the absence of infections might be a risk for IBD; CD, but not UC, is more common in those who lived in houses with a hot water tap during childhood [101]. In addition, toothpaste has been proposed as a risk factor for CD; it contains such microparticles that could serve as a proxy measure of hygienic conditions or have an impact on the micro- biological intestinal flora [102]. However, no obser- vational studies have shown such an association implicating toothpaste as an independent risk factor.

Finally, Klein et al. have investigated the physical activity levels of patients with IBD and controls for the period prior to onset of the disease: IBD patients were over-represented in the low-activity group vs.

controls [103].

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