Accepted Manuscript Epidemiology of Inflammatory Bowel Disease: Focus on Asia Siew C. Ng, MRCP, PhD

PII:

S1521-6918(14)00047-X

DOI:

10.1016/j.bpg.2014.04.003

Reference:

YBEGA 1248

To appear in:

Best Practice & Research Clinical Gastroenterology

Received Date: 25 January 2014 Revised Date:

6 February 2014

Accepted Date: 14 April 2014

Please cite this article as: Ng SC, Epidemiology of Inflammatory Bowel Disease: Focus on Asia, Best Practice & Research Clinical Gastroenterology (2014), doi: 10.1016/j.bpg.2014.04.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Epidemiology of Inflammatory Bowel Disease: Focus on Asia

Siew C Ng, MRCP, PhD

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Institute of Digestive Disease, Department of Medicine and Therapeutics, Chinese University Hong Kong, Hong Kong

Correspondence to: Siew C Ng

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Institute of Digestive Disease

Chinese University Hong Kong Tel: +852 2632 3845 Fax: +852 2637 3852

Conflicts of interest: nil

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Short title: IBD in Asia

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E-mail: [email protected]

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Department of Medicine and Therapeutics

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Abstract word count: 150 words Total word count: 6,668

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ACCEPTED MANUSCRIPT Abstract

The epidemiology of inflammatory bowel disease (IBD) is changing globally. Incidence and prevalence may have stabilized in high-incidence areas such as North America and Europe

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but they continue to rise in previously low-incidence areas such as Eastern Europe, Asia, and much of the developing world. This epidemiological shift likely relates to westernization of lifestyle, changes in diet, and improved hygiene as part of socioeconomic development in

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developing countries. In Asia, UC is more prevalent than CD, although the UC:CD ratio is narrowing in certain areas. Clinical manifestations of IBD in Asia resemble the Western

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population, but with some differences, including higher prevalence of males and ileo-colonic CD, less familial clustering, lower surgical rates and extra-intestinal manifestations. These differences may relate to time, genetics and environmental factors. Studying the epidemiology of IBD in an area of rapidly increasing incidence may lead to discovery of

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important etiologic factors associated with disease development.

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Keywords: inflammatory bowel disease, epidemiology, incidence, genetics, ethnic, Asia

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ACCEPTED MANUSCRIPT Background Crohn's disease (CD) and Ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) of unknown aetiology. The pathogenesis of inflammatory bowel disease (IBD) relates to a dysregulated immune response to antigenic stimulation from intestinal microbiota on a

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background of genetic susceptibility (1). Traditionally, the highest occurrence of both UC and CD has been reported in Western countries including North America, Europe, United Kingdom and Scandinavia, whilst the disease remains less common in Eastern Europe or

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much of the developing world (2). However, during the past two decades the epidemiology of IBD has changed in many ways. Incidence rates of traditionally high incidence areas such as

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Western Europe has remained relatively stable or even decreasing (2), while diseases have become more prevalent in previously low incidence areas, such as Asia and Eastern Europe (3-6). In these “new” IBD countries, UC has emerged first followed by CD after a variable period of time. Such phenomenon mirrored what took place in the West decades ago when

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the disease first appeared. The cause for this epidemiologic shift remains unclear. Although increased disease awareness and improved diagnostic tools may play a role, this change is most likely secondary to the influence of lifestyle, environmental and genetic factors (7).

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Genetic susceptibility has been reported to be different in Asian compared with Western IBD patients (8). Overall the burden of IBD varies in different countries and populations and

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variations in disease incidence may reflect differences in distribution or magnitude of the impact of environmental etiologic factors within specific populations. The changing epidemiology IBD worldwide provides an opportunity to study disease etiology.

Incidence The incidence rates of CD and UC vary worldwide between 0.1 to 16 per 100,000 inhabitants and 0.5 to 24.5 per 100,000 inhabitants, respectively (2;9). IBD is more common in the 3

ACCEPTED MANUSCRIPT Northern than the Southern part of the world, and it is more common among Caucasian compared with non-caucasian populations. The incidence of IBD is highest in westernized nations, with the highest reported incidence rates in North America (2;9-12), Northern

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Europe (13), the United Kingdom (14) and Australia (15).

In countries that are becoming more westernized, including Eastern Europe, Asia, French West Indies, and North Africa, IBD is emerging. A recent population-based inception cohort

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across 31 European centres reported a West–East gradient in disease incidence. The highest incidence in the world was reported in the Faroe Islands (81.5 per 100 000). Overall annual

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incidence rates for CD and UC in all Western European centres were approximately twice as high as those in Eastern European centres (4). The east-west gradient in Europe may be either a real phenomenon or the result of evolving health care systems and case ascertainment in eastern European countries although the reasons behind these regional differences are not

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completely clear.

Traditionally considered an area of low incidence, Asia is also witnessing a rise in incidence

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in parallel with rapid socioeconomic development (16-19). Previous challenges of

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conducting epidemiologic studies in Asia include difficulty in defining catchment areas and the lack of uniform criteria for case ascertainment. In a recent large scale population-based study across eight countries in Asia, it has been shown that the incidence rate of IBD ranged from 0.54 to 3.44 per 100,000 individuals. Within Asia, the incidence of IBD was highest in Guangzhou (mainland China), followed by Hong Kong, and Macau (5). One may speculate that these countries are highly urbanized. In Hong Kong, data from a hospital cohort demonstrated an increased incidence of CD and UC from 0.4 to 1.0, and from 0.8 to 1.2, respectively, between 1990 and 2001(20). In India, a community-based study reported a 4

ACCEPTED MANUSCRIPT relatively high incidence of UC of 6.0 per 100,000 people (21). Japan is the only country in Asia with a nationwide IBD registry run by the Ministry of Health and Welfare. The incidence of UC in Japan has increased from 0.02 to 1.95 per 100,000 person-years between 1961 and 1991(22;23), whereas the incidence of CD has increased from 0.60 to 1.20 between

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1986 and 1998 (24). Currently it has been estimated that over 100, 000 patients are suffering from UC in Japan (24). In Korea, two population-based studies have demonstrated a rise in incidence for both CD (0.05 to 5.1) and UC (0.34 to 5.4) from 1986 to 2008 (25;26). Even

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within Asia incidence rates of IBD vary according to geography and ethnic groups. The highest rates have been reported in India particularly for UC, Japan and the Middle East,

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whereas overall rising trends of IBD are seen in East Asia. Rates of IBD also appear to be higher in urban than in rural communities. Apart from geographic differences, ethnic differences have been described in multi-racial countries including Malaysia and Singapore whereby Indians appeared to be more susceptible to IBD than Chinese and native Malays

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within the same country (27-29). These differences may reflect differences in genetic susceptibility, living conditions and/or dietary habits (30). In Africa and Central and South

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America, epidemiologic data remain scarce or are not available.

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In summary, incidence rates of IBD in Asia are still low compared to recent figures from Western countries such as North America, Canada, New Zealand and Australia. Nonetheless these figures represent a clinically important disease burden given that two decades ago IBD was rare or almost non-existent in Asia. There appears to be a time lag phenomenon compared to time trends in the West. Marked differences in incidence have been reported in various geographic areas and ethnic differences have been observed in multi-racial Asian countries. As development and industrialization in developing countries continue the

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ACCEPTED MANUSCRIPT incidence of IBD is likely to increase further. Table 1 shows the incidence rates of IBD in Asia compared with Western countries.

Prevalence

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Similarly, the prevalence of IBD is highest in Europe, Canada and the United States (2). In Canada the prevalence rates were reported to be 248 per 100,000 for UC and 319 per 100,000 for CD (10). In the USA, prevalence rates were 238 and 201 per 100,000 for UC and CD,

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per 100,000, respectively, in New Zealand (31).

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respectively (12). Age-standardized point prevalence rates for CD and UC were 155 and 145

There are few population-based prevalence data of IBD from developing countries and most data were derived from hospital-based cohorts. In Turkey, the prevalence of UC was significantly lower in rural (2.2 per 100,000) than urban areas (5.9 per 100,000)(32).

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In Hong Kong, the prevalence of UC almost tripled from 2.3 to 6.3 per 100,000 over a 9-year period (33). In China, the number of cases of UC has increased by 4-fold between 1981-90 and 1991-2000 (34). One review from China which extrapolated the crude prevalence rate

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based on 55 years of research in China calculated the prevalence of CD to be 2.29 (35) and

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showed that this figure has increased from the estimate of 1.3 since 1994 (36). A rise in the prevalence of UC in Japan from 7.85 to 63.6 per 100,000 population has been reported across three different studies between 1984 to 2005 (23;37;38) whilst the prevalence of CD has risen rapidly from 2.9 in 1986 to 13.5 per 100,000 in 1998 (24). In South Korea the prevalence of UC has quadrupled from 7.6 per 100,000 in 1997 to 30.9 per 100,000 in 2005 (39), whereas CD prevalence rise from 2.9 to 13.5 between 1986 and 1998 (24). In studies from Singapore, UC and CD prevalence has risen from 6 to 8.6, and from, 1.3 to 7.2 respectively (29;40). Studies from South Asia have documented the UC prevalence in Northern India and Sri 6

ACCEPTED MANUSCRIPT Lanka to be 44.3(21) and 5.3(41), respectively. Overall, literature from Asia has confirmed that the prevalence of both UC and CD are also increasing, although the reported rates are still lower than in Westernized countries. Table 2 shows the prevalence rates of IBD in Asia

Patterns in the Ratio of Ulcerative Colitis to Crohn’s disease

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compared with Western countries.

In addition to variations between countries and regions in the incidence and prevalence of

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IBD, the ratio between UC and CD also shows geographic variations. In Canada, the U.S and Australia, CD appears to be the predominant disease, although in some North American

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studies the prevalence of UC remains greater than CD (2;15). In Europe, the incidence of NOD2-mutations seems to be highest in the middle part of Europe which corresponds with areas where there is a higher CD to UC ratio (42). In some of the Eastern European countries with high IBD incidence, the CD to UC ratio approximates 1:1 and in some of the countries

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such as Croatia, CD was even surpassing UC (43;44). Compared to the rest of Europe (13;45;46), a higher incidence rate for UC than for CD has been reported in Nordic countries

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(47-49) although the reason for this is not completely clear.

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Traditionally in low incidence areas UC emerges first followed by CD, but over time the incidence of CD ultimately matches, and may eventually overtake, the incidence of UC. In a comparative study between Asia and Australia, the ratio of UC to CD was approximately 2.0 in Asia and 0.5 in Australia (5). Population-based studies have confirmed that the ratio of UC to CD varies within Asia and ranged from 1.2 to 6.0 (2). This variation between countries and regions might reflect differences in environmental risk factors, but genetic predispositions may also play a role. Reports from Asia have described a decrease in the ratio of UC to CD over time (3). In China the ratio of UC to CD has dropped from 41 to 15, 7

ACCEPTED MANUSCRIPT whereas in Korea this has dropped from 6.8 to 2.3 in the last 20 years (50). This temporal trend suggests that CD and UC have both common and distinct risk factors. The former might explain the rise in both diseases with socioeconomic growth whereas the latter might

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explain the time lag between the increased incidence in UC followed by CD.

Pediatric Inflammatory bowel disease

Although recent studies have demonstrated that the incidence of CD in adults in Europe has

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stabilized, temporal trends showed that the incidence of CD in Europe continued to rise due to pediatric CD (51). For example, in Northern France, the CD incidence rate has increased

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by 71% in the 10 to 19-year-old age group between 1988 and 2007 (52). A study from Stockholm reported that the standardised incidence rate was 9.2 for CD and 2.8 for UC (53). In Asia, pediatric IBD data are lacking. One larger study from the Japanese nationwide registry reported that between 2003 and 2006, patients newly registered who were aged 16

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years or less included 311 CD (10.6% of all ages newly registered) and 880 UC (5.9% of all ages newly registered) (54). In Singapore, the incidence of children with IBD rose from an initial rate of 2.2 per 100,000 patients in the year 2000 to a peak of 11.4 patients per 100,000

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patients by 2008 (55). More population-based pediatric IBD data with longitudinal follow-up

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are warranted from Asia and other developing countries to determine if pediatric IBD is indeed on the rise.

Epidemiology of Inflammatory Bowel Disease in Migrant Populations Several studies have shown that individuals emigrating from low prevalent regions (eg, Asia) to higher prevalent countries (eg, England, Canada) are at increased risk for developing IBD, particularly among the first-generation children (56-58). These migration studies indicate that the children take on the risk factors of the new environment whereas the parents maintain 8

ACCEPTED MANUSCRIPT their original risk pattern, suggesting that environmental influence during childhood is crucial (57). Earlier studies have reported that the incidence rate of UC among South Asians, particularly Indian migrants to Leicestershire, United Kingdom was about twice that of the indigenous Caucasians in that region and the incidence was one of the highest in the world.

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Incidence and prevalence data from Leicestershire have reported a higher incidence of UC, but an equal or lower incidence of CD, in individuals of South Asian compared to European ethnicity (58-60) again supporting the observation that Hindus and Sikhs had a particularly

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higher incidence of UC than other ethnic groups while Hindus had a lower incidence of CD than Europeans (58). Altogether these data support genetic and racial heterogeneity for the

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development of IBD. A more recent study has shown an increase in CD incidence in Bangladeshi migrants from 2.3 to 7.3, and an increase in UC incidence from 2.4 to 8.2 over a ten year period (61). Epidemiologic data from migrant populations indicate that environmental factors contribute to the risk of IBD and that first and second generation

Clinical Characteristics

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migrants were at similar, if not increased risk (57).

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The clinical phenotypes and complication rates of IBD in Asians generally resemble those of the Caucasian population, but with some heterogeneity observed in different regions of Asia.

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Table 3 shows the differences in clinical characteristics of IBD in Asia compared with Western countries. The majority of studies from the West have shown an equal gender distribution for UC and a slight female predominance for CD (10;47;62). In contrast, in lowincidence areas, CD has been reported more frequently in men (9;63). This male predominance in Asian patients with CD is in sharp contrast to the female predominance in studies in developed societies and may be the result of differences in genetic susceptibility although this remains to be proven. 9

ACCEPTED MANUSCRIPT In the West, the median age of onset of CD is 20 to 30 years and for UC is 30 to 40 years (9). Consistent with these findings, CD in Asia is diagnosed at a younger age than UC (3;5;63). The median age of diagnosis of UC in Asia is similar, or slightly older than in the West, ranging from 35 to 44 years (64;65). Studies in Asia have reported a lower rate of family

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history of IBD (0 to 3%) compared with studies from the West (10 to 25%) (64). In Korea, an increase in the incidence of a positive family history from 1.3% in 2001 to 2.7% in 2005 (25) paralleled the increased incidence of IBD. Low rates of family history in Asians are likely to

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relate to the short duration that these diseases have been present in the population; this is likely to increase as the incidence and prevalence of disease rise over time. In the West, the

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prevalence of extra-intestinal manifestations (EIM) in IBD is approximately 25-40% (66-68) whilst lower rates of EIM has been reported in Asian countries (69). Joint manifestations are the most commonly reported EIM in Asian populations whilst primary sclerosing cholangitis

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is uncommon (64;70).

The disease location for CD and UC in Asia were broadly similar to those reported in other Western studies (63;71;72). In the West, CD has been found to occur in the ileum, colon, and

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both ileum and colon in equal proportions of patients (9), whereas ileocolonic disease

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appeared to be the most common in East Asia. In South and West Asia, distribution of disease site is more variable. CD behavior varied across Asia and complex disease behavior including stricturing, penetrating, or perianal disease was not uncommon in Asia (52). Perianal disease is present at diagnosis in about one third of patients in Hong Kong (73) and Korea (74). These figures are higher than that reported in large Caucasian CD studies (75). For UC, disease location was similar between Asia and the West (proctitis, 37% vs 32%; leftsided colitis, 32% vs 27%; extensive/total colitis, 31% vs 41%) (5). The clinical course of Asian UC and CD patients in terms of relapse rates are generally similar to patients in the 10

ACCEPTED MANUSCRIPT developed world, but detailed comparisons are limited by the differences in the duration of follow up, the higher likelihood of acute infectious colitis in Asian cohorts and variable definitions of clinical relapse and disease activity. Colectomy rates are generally lower in Asian countries for both UC and CD. The exact cause is not unknown but may be due to

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cultural differences, a higher threshold for surgery in Asia or a milder disease course for UC subjects.

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In summary, some differences in the clinical phenotypes and complications of IBD in Asia are noted compared with the West, including a male predominance for CD, a higher

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prevalence of ileocolonic involvement, lower surgical rates, less familial clustering and lower frequency of EIM (3;63). These differences in disease, severity and complications is likely to be multifactorial secondary to differences in genetic background, environmental

Environmental Factors

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exposure such as diet and intestinal flora, and the duration of disease.

Geographical differences, population migration and changing epidemiology suggest an

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environmental role in the prevalence and phenotypic expression of IBD. Changes in lifestyle in Asia during the last two decades have resulted in a more “westernized” standard way of

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living, with increased consumption of refined sugar, fatty acids, fast food, and reduced consumption of fruit, vegetables and fibres (7). With all of these aspects of westernization previously being associated with IBD, westernization of lifestyle could explain the observed increases of the incidence of UC and CD. In a recent systematic review, a high dietary intake of fats, fatty acids, sugars and meat increased the risk for developing CD and UC, while increased intake of fiber, fruit and vegetables decreased the risk for development of CD and UC (79). In Japan, the increased intake of dairy products and meat has paralleled the rising 11

ACCEPTED MANUSCRIPT trend of UC in Japan (80). A higher consumption of sweets and high fat diet has been associated with UC and CD (81). In a prospective cohort study from the United Kingdom, a high meat diet or alcoholic consumption are associated with an increased likelihood of relapse for UC patients (82). A more recent case-control Japanese study showed that a higher

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consumption of sweets, sweeteners, fats, fatty acids and oils were associated with an increased risk of CD and UC (83).

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The epidemiological change appears to parallel the rapid socioeconomic development in Asia and exposure to environmental factors during childhood appears to be critical. The precise

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environmental factors that account for changing IBD prevalence have not been defined, downstream effect on the intestinal microbial milieu from dietary changes probably play an important pathogenic role in CD and UC. Other putative factors such as tonsillectomy, oral contraceptives use, breastfeeding and vaccinations and recently additional novel factors such

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as vitamin D levels, psychological stress and amount of physical exercise have been proposed to be associated with IBD (76). To date, the only factors that have been proven to be important environmental factors in both UC and CD are smoking and appendectomy. Studies

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in the West have shown that smoking is a risk factor for the development of CD but is

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protective for the development of UC (7) (77). However smoking rates in IBD subjects appeared to be lower in Asia than the West. At a population level countries with high CD incidence, (eg. Canada and Sweden) have a low prevalence (65% of adult males) but a low incidence of CD. This observation suggests that smoking influences CD course but may not influence population trends of IBD. (78). Smoking in CD may not play the same role in different ethnic groups as it does in Western populations; more studies are needed in

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ACCEPTED MANUSCRIPT Asia to determine the impact of smoking on the development and progression of CD and its association with disease phenotype

Overall, Asian populations probably has genetic susceptibility, that when exposed to putative

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environmental factors will develop IBD. This predisposition appears to be stronger in certain racial groups. Other factors with possible links to IBD such as breastfeeding, altered hygiene, vaccinations, use of antibiotics and gastrointestinal infections have not been studied in Asian

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countries.

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Summary

The incidence of IBD is increasing with time and in different regions around the world. The incidence rate of UC first increased then stabilized or even decreased whilst that of CD has continued to increase. The rising incidence of IBD in Asia in the last two decades is a real

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phenomenon. There appears to be variation in the incidence, prevalence and disease characterisitics between Asians of different nationalities and geography. Increased disease awareness, better health care and improved diagnostic methods can only contributed partly to

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the significant increase in cases. The increased incidence when there is a transition from

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"developing" to developed nation status strongly supports the link between changing epidemiology with changing lifestyle and environmental factors, particularly modernisation and Western lifestyle. More likely than not, the incidence of IBD will continue to surge in Asia in the next decade. So far all of the proposed environmental factors have been hypothesized and not yet proven as causal. Well conducted epidemiological studies of IBD with longitudinal follow-up will not only inform health care policy of the true scale of the disease in Asia but also offer the opportunity to help clinicians and researchers elucidate the

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ACCEPTED MANUSCRIPT role of enviromental factors and identify new aetiological factors responsible for this “IBD epidemic” in Asia, and most developing countries.

Conflicts of interest: None

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Funding source: none

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ACCEPTED MANUSCRIPT Practice Points •

The incidence and prevalence of IBD are increasing with time and in different regions around the world

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Disease emergence in Asia suggests that epidemiologic evolution relates to westernization of lifestyle and industrialization Changes in diet, antibiotic use, improved hygiene status and microbial exposures

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have been implicated as potential environmental risk factors for IBD •

A higher prevalence of males, ileo-colonic Crohn’s disease, less familial clustering, lower rates of surgery and extra-intestinal manifestations have been reported

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Research Agenda

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amongst Asians with IBD

Large prospective cohorts examining the role of established and novel environmental factors is needed to further elucidate disease aetiology

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Unique populations to assess disease development should include immigrants, pediatrics and populations of increasing rates of disease incidence Studies of gene–environment interactions in the development of IBD are needed

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Longitudinal data on clinical outcomes of IBD in Asia are necessary to study the

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•

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natural history of disease in different populations

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ACCEPTED MANUSCRIPT Table 1. Incidence rates for ulcerative colitis and Crohn’s disease in developed countries and the Asia

Ulcerative colitis

Crohn’s disease

(per 100,000)

(per 100,000)

1993 (87)

8.3

6.9

1998- 2000 (10;11)

19.2

20.2

2004 (12)

14.3

North Europe

1993 (13)

11.8

South Europe

1993 (13)

8.7

East Europe

2010-2011(4)

4.1

West Europe

2010-2011 (4)

10.8

6.5

United Kingdom

1994 (88)

13.9

8.3

Australia

2007-2008 (15)

17.4

29.3

New Zealand

2004 (31)

16.5

7.6

Japan

1965 (89)

0.08

0.01

1.95

0.51

-

1.2

1986-1990 (90)

0.34

0.05

2001-2005(39)

3.08

1.34

1999-2001(20)

1.20

1.00

2011-2012 (5)

1.66

1.31

2011-2012 (5)

2.22

1.22

2011-2012 (5)

0.36

0.30

2011-2012 (5)

0.55

0.33

2011-2012 (5)

0.59

0.24

Singapore

2011-2012 (5)

0.61

0.40

North India

1999-2000 (21)

6.02

-

Sri Lanka

2007-2008 (41)

0.69

0.09

2011-2012 (5)

0.95

0.59

North America

1991 (23)

Hong Kong

Thailand Indonesia Malaysia

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China (Guangzhou)

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South Korea

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1998 (24)

14.6 7.0 3.9

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Year

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Incidence

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Country

3.1

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ACCEPTED MANUSCRIPT Table 2. . Prevalence for ulcerative colitis and Crohn’s disease in developed countries and the Asia

Ulcerative colitis

Crohn’s disease

(per 100,000)

(per 100,000)

2001 (87)

246

162

2004 (12)

238

1998-2000 (10)

248

North Europe

1987 (91)

161

South Europe

1992 (92)

121

United Kingdom

1996 (93)

122

New Zealand

2004 (31)

155

Japan

1965 (89)

North America

1984-1985 (37) 1991 (23)

319 54 40

214 145

5.5

5.85

7.9

1.9

18.1

5.9

63.6

21.2

30.9

11.22

2001-2005 (25)

Hong Kong

1994 (36)

-

1.3

1997 (33)

2.3

-

2001 (33)

4.9

-

2006 (33)

5.3

-

1950-2000 (35)

7.0

-

1980-1990 (29)

8.6

1.3

1999 (40)

6.0

3.6

2004 (94)

-

7.2

Singapore

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China

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South Korea

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2005 (38)

201

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Year

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Prevalence

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Country

North India

1999-2000 (21)

44.3

-

Sri Lanka

2007-2008 (41)

5.3

1.2

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ACCEPTED MANUSCRIPT Table 3: Clinical characteristics of IBD in Asia compared with the West Asia Male predominance for CD Equal gender distribution for UC

West Female predominance for CD Equal gender distribution for UC

Peak age of diagnosis

Similar to the West but smaller second peak for CD and UC

20-30 years old for CD and 30-40 years old for UC

CD phenotype

Ileo-colonic disease predominant Perianal disease more common (33-40%)

Equal disease distribution with isolated colonic disease predominance in some studies

UC phenotype

Disease distribution similar to the West Milder disease course

Approximately 30% for proctitis, distal colitis and extensive colitis

Extra-intestinal manifestation

Overall lower frequency (6% -14%) Primary sclerosing cholangitis (0-1%)

21% - 41% Primary sclerosing cholangitis (2-7%)

Colorectal cancer

Lower rates (0% to 1.8%)

3% to 5%

Colectomy rates

Variable in Asia but lower than the West especially for UC Lower rates of familial aggregation (0%-3%)

-

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10%-25%

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Family history of IBD

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Gender

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ACCEPTED MANUSCRIPT

Reference List

(1) Danese S, Fiocchi C. Etiopathogenesis of inflammatory bowel diseases. World J Gastroenterol 2006;12(30):4807-12.

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(2) Molodecky NA, Soon IS, Rabi DM et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142(1):46-54.

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(3) Thia KT, Loftus EV, Jr., Sandborn WJ et al. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol 2008;103(12):3167-82. (4) Burisch J, Pedersen N, Cukovic-Cavka S et al. East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort. Gut 2013.

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(5) Ng SC, Tang W, Ching JY et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study. Gastroenterology 2013;145(1):158-65. (6) Lakatos L, Mester G, Erdelyi Z et al. Striking elevation in incidence and prevalence of inflammatory bowel disease in a province of western Hungary between 1977-2001. World J Gastroenterol 2004;10(3):404-9.

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(7) Ng SC, Bernstein CN, Vatn MH et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut 2013;62(4):630-49. (8) Ng SC, Tsoi KK, Kamm MA et al. Genetics of inflammatory bowel disease in Asia: Systematic review and meta-analysis. Inflamm Bowel Dis 2011.

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(9) Cosnes J, Gower-Rousseau C, Seksik P et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011;140(6):1785-94.

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(10) 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(7):1559-68. (11) Lowe AM, Roy PO, Poulin M et al. Epidemiology of Crohn's disease in Quebec, Canada. Inflamm Bowel Dis 2009;15(3):429-35. (12) Kappelman MD, Rifas-Shiman SL, Kleinman K et al. The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007;5(12):1424-9. (13) Shivananda S, Lennard-Jones J, Logan R et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996;39(5):690-7. (14) Thompson NP, Fleming DM, Charlton J et al. Patients consulting with Crohn's disease in primary care in England and Wales. Eur J Gastroenterol Hepatol 1998;10(12):1007-12. 19

ACCEPTED MANUSCRIPT (15) Wilson J, Hair C, Knight R et al. High incidence of inflammatory bowel disease in Australia: a prospective population-based Australian incidence study. Inflamm Bowel Dis 2010;16(9):1550-6. (16) Zheng JJ, Shi XH, Zhu XS et al. [A comparative study of incidence and prevalence of Crohn's disease in mainland China in different periods]. Zhonghua Nei Ke Za Zhi 2011;50(7):597-600.

RI PT

(17) Zheng JJ, Zhu XS, Huangfu Z et al. Crohn's disease in mainland China: a systematic analysis of 50 years of research. Chin J Dig Dis 2005;6(4):175-81. (18) Zheng JJ, Zhu XS, Huangfu Z et al. Prevalence and incidence rates of Crohn's disease in mainland China: a meta-analysis of 55 years of research. J Dig Dis 2010;11(3):161-6.

SC

(19) Desai HG, Gupte PA. Increasing incidence of Crohn's disease in India: is it related to improved sanitation? Indian J Gastroenterol 2005;24(1):23-4.

(20) Leong RW, Lau JY, Sung JJ. The epidemiology and phenotype of Crohn's disease in the Chinese population. Inflamm Bowel Dis 2004;10(5):646-51.

M AN U

(21) Sood A, Midha V, Sood N et al. Incidence and prevalence of ulcerative colitis in Punjab, North India. Gut 2003;52(11):1587-90. (22) Kitahora T, Utsunomiya T, Yokota A. Epidemiological study of ulcerative colitis in Japan: incidence and familial occurrence. The Epidemiology Group of the Research Committee of Inflammatory Bowel Disease in Japan. J Gastroenterol 1995;30 Suppl 8:5-8.

TE D

(23) Morita N, Toki S, Hirohashi T et al. Incidence and prevalence of inflammatory bowel disease in Japan: nationwide epidemiological survey during the year 1991. J Gastroenterol 1995;30 Suppl 8:1-4. (24) Yao T, Matsui T, Hiwatashi N. Crohn's disease in Japan: diagnostic criteria and epidemiology. Dis Colon Rectum 2000;43(10 Suppl):S85-S93.

EP

(25) Yang SK, Yun S, Kim JH et al. Epidemiology of inflammatory bowel disease in the SongpaKangdong district, Seoul, Korea, 1986-2005: a KASID study. Inflamm Bowel Dis 2008;14(4):542-9.

AC C

(26) Shin DH, Sinn DH, Kim YH et al. Increasing incidence of inflammatory bowel disease among young men in Korea between 2003 and 2008. Dig Dis Sci 2011;56(4):1154-9. (27) Goh K, Xiao SD. Inflammatory bowel disease: a survey of the epidemiology in Asia. J Dig Dis 2009;10(1):1-6. (28) Hilmi I, Singh R, Ganesananthan S et al. Demography and clinical course of ulcerative colitis in a multiracial Asian population: a nationwide study from Malaysia. J Dig Dis 2009;10(1):1520. (29) Tan YM, Goh KL. Ulcerative colitis in a multiracial Asian country: racial differences and clinical presentation among Malaysian patients. World J Gastroenterol 2005;11(37):5859-62.

20

ACCEPTED MANUSCRIPT (30) Juyal G, Prasad P, Senapati S et al. An investigation of genome-wide studies reported susceptibility loci for ulcerative colitis shows limited replication in north Indians. PLoS One 2011;6(1):e16565. (31) Gearry RB, Richardson A, Frampton CM et al. High incidence of Crohn's disease in Canterbury, New Zealand: results of an epidemiologic study. Inflamm Bowel Dis 2006;12(10):936-43.

RI PT

(32) Tezel A, Dokmeci G, Eskiocak M et al. Epidemiological features of ulcerative colitis in Trakya, Turkey. J Int Med Res 2003;31(2):141-8. (33) Lok KH, Hung HG, Ng CH et al. Epidemiology and clinical characteristics of ulcerative colitis in Chinese population: experience from a single center in Hong Kong. J Gastroenterol Hepatol 2008;23(3):406-10.

SC

(34) Jiang L, Xia B, Li J et al. Risk factors for ulcerative colitis in a Chinese population: an agematched and sex-matched case-control study. J Clin Gastroenterol 2007;41(3):280-4.

M AN U

(35) Zheng JJ, Zhu XS, Huangfu Z et al. Crohn's disease in mainland China: a systematic analysis of 50 years of research. Chin J Dig Dis 2005;6(4):175-81. (36) Sung JJ, Hsu RK, Chan FK et al. Crohn's disease in the Chinese population. An experience from Hong Kong. Dis Colon Rectum 1994;37(12):1307-9. (37) Higashi A, Watanabe Y, Ozasa K et al. Prevalence and mortality of ulcerative colitis and Crohn's disease in Japan. Gastroenterol Jpn 1988;23(5):521-6.

TE D

(38) Asakura K, Nishiwaki Y, Inoue N et al. Prevalence of ulcerative colitis and Crohn's disease in Japan. J Gastroenterol 2009;44(7):659-65. (39) Yang SK, Yun S, Kim JH et al. Epidemiology of inflammatory bowel disease in the SongpaKangdong district, Seoul, Korea, 1986-2005: a KASID study. Inflamm Bowel Dis 2008;14(4):542-9.

EP

(40) Lee YM, Fock K, See SJ et al. Racial differences in the prevalence of ulcerative colitis and Crohn's disease in Singapore. J Gastroenterol Hepatol 2000;15(6):622-5.

AC C

(41) Niriella MA, De Silva AP, Dayaratne AH et al. Prevalence of inflammatory bowel disease in two districts of Sri Lanka: a hospital based survey. BMC Gastroenterol 2010;10:32. (42) Lakatos PL, Lakatos L, Szalay F et al. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: phenotype-genotype correlations. World J Gastroenterol 2005;11(10):1489-95. (43) Lakatos L, Kiss LS, David G et al. Incidence, disease phenotype at diagnosis, and early disease course in inflammatory bowel diseases in Western Hungary, 2002-2006. Inflamm Bowel Dis 2011;17(12):2558-65. (44) Sincic BM, Vucelic B, Persic M et al. Incidence of inflammatory bowel disease in Primorskogoranska County, Croatia, 2000-2004: A prospective population-based study. Scand J Gastroenterol 2006;41(4):437-44. 21

ACCEPTED MANUSCRIPT (45) Ott C, Obermeier F, Thieler S et al. The incidence of inflammatory bowel disease in a rural region of Southern Germany: a prospective population-based study. Eur J Gastroenterol Hepatol 2008;20(9):917-23. (46) Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J Gastroenterol 2006;12(38):6102-8.

RI PT

(47) 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 Danish Crohn colitis database. Am J Gastroenterol 2006;101(6):1274-82. (48) Lehtinen P, Ashorn M, Iltanen S et al. Incidence trends of pediatric inflammatory bowel disease in Finland, 1987-2003, a nationwide study. Inflamm Bowel Dis 2011;17(8):1778-83.

SC

(49) Moum B, Vatn MH, Ekbom A et al. Incidence of ulcerative colitis and indeterminate colitis in four counties of southeastern Norway, 1990-93. A prospective population-based study. The Inflammatory Bowel South-Eastern Norway (IBSEN) Study Group of Gastroenterologists. Scand J Gastroenterol 1996;31(4):362-6.

M AN U

(50) Wang YF, Ouyang Q, Hu RW. Progression of inflammatory bowel disease in China. J Dig Dis 2010;11(2):76-82. (51) Martin-de-Carpi J, Rodriguez A, Ramos E et al. Increasing incidence of pediatric inflammatory bowel disease in Spain (1996-2009): The SPIRIT registry. Inflamm Bowel Dis 2012.

TE D

(52) Chouraki V, Savoye G, Dauchet L et al. The changing pattern of Crohn's disease incidence in northern France: a continuing increase in the 10- to 19-year-old age bracket (1988-2007). Aliment Pharmacol Ther 2011;33(10):1133-42. (53) Malmborg P, Grahnquist L, Lindholm J et al. Increasing incidence of paediatric inflammatory bowel disease in northern Stockholm County, 2002-2007. J Pediatr Gastroenterol Nutr 2013;57(1):29-34.

EP

(54) Ishige T, Tomomasa T, Takebayashi T et al. Inflammatory bowel disease in children: epidemiological analysis of the nationwide IBD registry in Japan. J Gastroenterol 2010;45(9):911-7.

AC C

(55) Chu HP, Logarajah V, Tan N et al. Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J 2013;54(4):201-5. (56) Carr I, Mayberry JF. The effects of migration on ulcerative colitis: a three-year prospective study among Europeans and first- and second- generation South Asians in Leicester (19911994). Am J Gastroenterol 1999;94(10):2918-22. (57) 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(5):687-93. (58) Jayanthi V, Probert CS, Pinder D et al. Epidemiology of Crohn's disease in Indian migrants and the indigenous population in Leicestershire 3. Q J Med 1992;82(298):125-38.

22

ACCEPTED MANUSCRIPT (59) Probert CS, Jayanthi V, Hughes AO et al. Prevalence and family risk of ulcerative colitis and Crohn's disease: an epidemiological study among Europeans and south Asians in Leicestershire. Gut 1993;34(11):1547-51. (60) 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(5):687-93.

RI PT

(61) Tsironi E, Feakins RM, Probert CS et al. Incidence of inflammatory bowel disease is rising and abdominal tuberculosis is falling in Bangladeshis in East London, United Kingdom. Am J Gastroenterol 2004;99(9):1749-55. (62) Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004;126(6):1504-17.

SC

(63) Hou JK, El-Serag H, Thirumurthi S. Distribution and manifestations of inflammatory bowel disease in Asians, Hispanics, and African Americans: a systematic review. Am J Gastroenterol 2009;104(8):2100-9.

M AN U

(64) Prideaux L, Kamm MA, De Cruz PP et al. Inflammatory bowel disease in Asia: a systematic review. J Gastroenterol Hepatol 2012;27(8):1266-80. (65) Prideaux L, Kamm MA, De CP et al. Comparison of clinical characteristics and management of inflammatory bowel disease in Hong Kong versus Melbourne. J Gastroenterol Hepatol 2012;27(5):919-27. (66) Williams H, Walker D, Orchard TR. Extraintestinal manifestations of inflammatory bowel disease. Curr Gastroenterol Rep 2008;10(6):597-605.

TE D

(67) Bernstein CN, Blanchard JF, Rawsthorne P et al. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 2001;96(4):1116-22.

EP

(68) Lakatos L, Pandur T, David G et al. Association of extraintestinal manifestations of inflammatory bowel disease in a province of western Hungary with disease phenotype: results of a 25-year follow-up study. World J Gastroenterol 2003;9(10):2300-7.

AC C

(69) Wang YF, Zhang H, Ouyang Q. Clinical manifestations of inflammatory bowel disease: East and West differences. J Dig Dis 2007;8(3):121-7. (70) Kochhar R, Mehta SK, Nagi B et al. Extraintestinal manifestations of idiopathic ulcerative colitis. Indian J Gastroenterol 1991;10(3):88-9. (71) Henriksen M, Jahnsen J, Lygren I et al. Ulcerative colitis and clinical course: results of a 5year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis 2006;12(7):543-50. (72) Jess T, Riis L, Vind I et al. Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark. Inflamm Bowel Dis 2007;13(4):481-9.

23

ACCEPTED MANUSCRIPT (73) Chow DK, Leong RW, Lai LH et al. Changes in Crohn's disease phenotype over time in the Chinese population: validation of the Montreal classification system. Inflamm Bowel Dis 2008;14(4):536-41. (74) Ye BD, Yang SK, Cho YK et al. Clinical features and long-term prognosis of Crohn's disease in Korea. Scand J Gastroenterol 2010;45(10):1178-85.

RI PT

(75) Beaugerie L, Seksik P, Nion-Larmurier I et al. Predictors of Crohn's disease. Gastroenterology 2006;130(3):650-6. (76) Ananthakrishnan AN. Environmental triggers for inflammatory bowel disease. Curr Gastroenterol Rep 2013;15(1):302.

SC

(77) Lakatos PL, Szamosi T, Lakatos L. Smoking in inflammatory bowel diseases: good, bad or ugly? World J Gastroenterol 2007;13(46):6134-9.

M AN U

(78) Prideaux L, Kamm MA, De CP et al. Comparison of clinical characteristics and management of inflammatory bowel disease in Hong Kong versus Melbourne. J Gastroenterol Hepatol 2012;27(5):919-27. (79) Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol 2011;106(4):563-73. (80) Kitahora T, Utsunomiya T, Yokota A. Epidemiological study of ulcerative colitis in Japan: incidence and familial occurrence. The Epidemiology Group of the Research Committee of Inflammatory Bowel Disease in Japan. J Gastroenterol 1995;30 Suppl 8:5-8.

TE D

(81) Sakamoto N, Kono S, Wakai K et al. Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. Inflamm Bowel Dis 2005;11(2):154-63. (82) Jowett SL, Seal CJ, Pearce MS et al. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut 2004;53(10):1479-84.

EP

(83) Sakamoto N, Kono S, Wakai K et al. Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. Inflamm Bowel Dis 2005;11(2):154-63.

AC C

(84) Bernstein CN, Shanahan F. Disorders of a modern lifestyle: reconciling the epidemiology of inflammatory bowel diseases. Gut 2008;57(9):1185-91. (85) Smith, L. A., Rameshanker, R., and Healy, J. An unusual prevalence of inflammatory bowel disease in a multiethnic population-single centre UK data. Gut 59 (supl III): A181. 2010.

(86) Barreiro-de AM, Alvarez CA, Souto R et al. Emigration to western industrialized countries: A risk factor for developing inflammatory bowel disease. J Crohns Colitis 2011;5(6):566-9. (87) Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004;126(6):1504-17. (88) 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(12):1553-9. 24

ACCEPTED MANUSCRIPT (89) Yoshida Y, Murata Y. Inflammatory bowel disease in Japan: studies of epidemiology and etiopathogenesis. Med Clin North Am 1990;74(1):67-90. (90) Yang SK, Hong WS, Min YI et al. Incidence and prevalence of ulcerative colitis in the SongpaKangdong District, Seoul, Korea, 1986-1997. J Gastroenterol Hepatol 2000;15(9):1037-42. (91) Langholz E, Munkholm P, Nielsen OH et al. Incidence and prevalence of ulcerative colitis in Copenhagen county from 1962 to 1987. Scand J Gastroenterol 1991;26(12):1247-56.

RI PT

(92) Trallori G, Palli D, Saieva C et al. A population-based study of inflammatory bowel disease in Florence over 15 years (1978-92). Scand J Gastroenterol 1996;31(9):892-9. (93) Montgomery SM, Morris DL, Thompson NP et al. Prevalence of inflammatory bowel disease in British 26 year olds: national longitudinal birth cohort. BMJ 1998;316(7137):1058-9.

AC C

EP

TE D

M AN U

SC

(94) Thia KT, Luman W, Jin OC. Crohn's disease runs a more aggressive course in young Asian patients. Inflamm Bowel Dis 2006;12(1):57-61.

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