Journal of Crohn's and Colitis (2013) 7, e178e185 Available online at www.sciencedirect.

com

Ethnicity and the risk of development of Crohn's disease of the ileal pouch,
Saurabh Mukewar a , Xianrui Wu b , Rocio Lopez a , Ravi P. Kiran b , Feza H. Remzi b , Bo Shen a,
a b

Department of Gastroenterology/Hepatology, the Cleveland Clinic Foundation, OH, United States Department of Colorectal Surgery, the Cleveland Clinic Foundation, OH, United States

Received 3 May 2012; received in revised form 2 July 2012; accepted 1 August 2012

KEYWORDS
Ethnicity; Ileal pouch-anal anastomosis; Inflammatory bowel disease; Race; Restorative proctocolectomy

Abstract Background: A system-wide, multi-ethnicity study on Crohn's disease (CD) of the pouch, including Indian American (IA) patients has not been conducted. Aim: To compare the frequency of subsequent development of CD of the pouch for African-American (AA), Hispanic-American (HA), IA and Caucasian patients with ulcerative (UC) undergoing ileal-pouch anal anastomosis (IPAA). Methods: In this historical cohort study from our Pouch Registry, patients with restorative proctocolectomy and IPAA for IBD with identifiable, self-declared racial background (i.e. AA, HA, IA or Caucasian) were included. Univariable and multivariable analyses were performed to identify risk factors for CD of the pouch. Results: The study included 235 patients: AA (N = 26), HA (N = 37), IA (N = 22) and randomly selected Caucasian (N = 150) controls. Greater number of HA and Caucasians had a history of smoking than IA (27.3% and 27.0% vs. 0; p = 0.007). Caucasians and HA were also more likely to have a family history of IBD than IA or AA (25% vs. 27% vs. 5% vs. 4%; p = 0.016.) IA less frequently had extensive colitis before colectomy than Caucasians (71.4% vs. 94.0%; p = 0.004) and more frequently required anti-TNF biologics than HA (22.7% vs. 0; p = 0.016). On multivariable logistic regression analysis, AA (odds ratio [OR] = 10.1, 95% confidence interval [CI]: 1.03, 1365.8, p = 0.004) and Caucasians (OR = 11.1, 95% CI: 1.4, 1427.2, p = 0.015) had a higher risk of developing

Abbreviations: AA, African-American; CA, Caucasian American; CD, Crohn's disease; EIM, Extra-intestinal manifestations; HA, Hispanic American; HMO, Health Maintenance Organizations; IA, Indian-American; NSAID, Non-steroidal anti-inflammatory drugs; IPAA, Ileal pouch anal anastomosis; mPDAI, modified Pouch Disease Activity Index; PPO, Preferred Provider Organizations; PSC, primary sclerosing cholangitis; UC, Ulcerative colitis. Conference presentation: The results from this study will be presented in Digestive Disease Week, San Diego, CA May 2012. Grant Support: The project was partially supported by a research grant from the Crohn's and Colitis Foundation of America (to B.S.). Corresponding author at: Department of Gastroenterology/Hepatology-A31, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, United States. Tel.: + 1 216 444 9252; fax: + 1 216 444 6305. E-mail address: shenb@ccf.org (B. Shen). 1873-9946/$ - see front matter 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.crohns.2012.08.002

Ethnicity and Crohn's Pouch

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CD of the pouch than IA. However, the event-free survival was not significantly different between the groups on Cox regression analysis, presumably due to the sample size. Conclusion: Racial background may be associated with different risk for the development of CD of the pouch for patients with IBD undergoing IPAA. 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

1. Introduction
The incidence, prevalence, and phenotype of inflammatory bowel disease (IBD) vary depending on the ethnic background. 1,2 Caucasians residing in the North Europe and North America have a higher incidence and prevalence of IBD than the rest of the world. 1,3 Recent data suggest that the incidence of both ulcerative colitis (UC) and Crohn's disease (CD) is rising in developing countries, 4,5 with UC being more common than CD. 4 In addition, studies from migrant populations suggest that the incidence and prevalence of IBD in South-Asians (Indians, Pakistanis and Bangladeshis) may in fact be higher than the indigenous Caucasian European population. 6 UC is more common than CD in these populations as well, a pattern similar to their native countries. 7 Furthermore, the phenotype of IBD differs according to the racial background. For example, Asian patients with UC have been found to less frequently have extensive colitis (21% to 45%) than other ethnicities. 2 Few studies have compared the outcomes of ileal pouchanal anastomosis (IPAA) surgery for UC between patients of different ethnic groups. A recent study from our group compared the outcome of IPAA for Hispanic non-White patients and Caucasian-Americans and showed different pre-operative characteristics of UC, but similar pouch outcomes in terms of pouchitis and pouch failure. 8 A separate study from our group described similar outcomes after IPAA for African-American (AA) and Caucasian patients. 9 A study comparing outcomes of IPAA between South Asians residing in UK and their Caucasian counterparts, however, showed a higher frequency of pouchitis in the former group. 10 There are no published studies on direct comparison of outcomes after IPAA with regards to the development of CD for multiple ethnicities. It has been estimated that 2.7% to 13.0% of IPAA patients would develop CD or CD-like condition of the pouch. 1114 Reported risk factors for CD of the pouch include the presence of family history of CD, 15,16 smoking, 17 longer duration of pouch, 18 pre-operative diagnosis of indeterminate colitis (IC), 18 and seropositivity for anti-Saccharomyces cerevisiae-IgA antibody. 18 A recent study showed that Ashkenazi Jewish ethnicity was associated with a greater risk for inflammatory complications of the pouch (including CD of the pouch), 19 suggesting a role of genetic predisposition. However, the risk for CD of the pouch in other ethnic groups has not been directly compared. We hypothesized that ethnicity is associated with a varying risk for development of CD the pouch. The aim of the study was to compare the risk for CD of pouch and other adverse outcomes of the pouch, between different ethnic groups.

2. Materials and methods

2.1. Patients
The patients for this historical cohort study were identified from our Institutional Review Board (IRB)- approved Pouchitis Registry from 2002 to 2011. Ethnicity was based on self-declared racial background. We expanded sample sizes of the HA and AA groups from our previous studies 8,9 by adding 14 AA patients and 1 HA patient, respectively. Caucasian controls were randomly selected from the Registry with an approximate ratio of 1:4. In addition, we included an additional group consisting of 22 Indian-American (IA) patients. Demographics, clinical characteristics, details of surgery and course of disease were obtained from the registry and by chart review.

2.2. Inclusion and exclusion criteria

All eligible AA, HA, IA and Caucasian IBD patients with IPAA, above age of 18 years, were included. Pouch patients with familial adenomatous polyposis, and those with an unknown or mixed racial background were excluded.

2.3. Study variables

Demographics, clinical characteristics of UC (duration of UC, disease extent, history of anti-TNF biologic use (before and after colectomy) and non-steroid anti-inflammatory drugs [NSAIDs], family history of IBD, extra-intestinal manifestations [EIM], and indication for colectomy), and data pertaining to pouch surgery (stage of pouch surgery and pouch configuration) were compared among the ethnic groups. Details of country of birth were recorded from the charts. When not available, patients were contacted and the necessary information was obtained for Indian patients. To assess socio-economic status we compared insurance status and type as a substitute marker. Preferred Provider Organizations (PPO) offers coverage and ability for patients to choose the physician they request. Health Maintenance Organizations (HMO) is the next best with limited ability to choose a physician. Government sponsored insurances had limited coverage and limited ability to choose physicians. All patients had routine follow-up at the Pouchitis Clinic staffed by an IBD specialist (B.S.). Typically, we routinely followed patients with chronic pouchitis, CD of the pouch, and refractory cuffitis every 36 months, acute pouchitis or cuffitis every 612 months, and yearly for those with normal pouches.

e180 The anatomical distribution of UC at the time of colectomy was determined by endoscopic, radiographic, macroscopic and histopathological data as proctitis, leftsided colitis, or extensive colitis. History of smoking and details with time of beginning and stopping cigarette smoking with respect to diagnosis of UC, colectomy and final diagnosis was recorded when available. Concurrent autoimmune disorders detected before or after surgery were also studied, which included autoimmune thyroid diseases, rheumatoid arthritis, pernicious anemia, celiac disease, systemic lupus erythematosus, adult-onset asthma, psoriasis, type 1 diabetes, autoimmune hemolytic anemia, vitiligo, idiopathic thrombocytopenic purpura, and multiple sclerosis. Duration of UC was defined as the interval between the time of UC diagnosis and the time of colectomy. We also evaluated significant comorbidities including congestive heart failure, coronary artery bypass graft, chronic obstructive pulmonary disease, renal insufficiency, liver failure, non-pouch-related cancer and stroke.

S. Mukewar et al.

2.5. Outcome measurement

Primary outcome was the development of CD of the pouch at the most recent follow-up and to identify its risk factors associated. Secondary outcome was to compare pouchrelated hospitalization and pouch failure and number of Pouchitis Clinic visits between the different ethnicities.

2.6. Statistical analysis

Data were presented as mean standard deviation (SD), median with interquartile interval (IQR) or N (%). A univariable analysis was performed to assess differences between the four ethnic groups. Analysis of variance (ANOVA) or the non-parametric KruskalWallis tests were used to compare continuous factors and Pearson's chi-square tests were used for categorical variables. Ad-hoc pair-wise comparisons were done using a significance criterion of 0.008 (0.05/6) in order to account for multiple comparisons. In addition, a multivariable logistic regression analysis was used to assess the impact of ethnicity on the development of CD of the pouch. None of the IA patients developed CD of the pouch; hence a penalized maximum likelihood and the likelihood ratio tests were used for the regression model. The final model was chosen using an automated stepwise variable selection method performed on 1000 bootstrap samples. Ethnicity was included in the model and all other factors were considered for inclusion; variables with inclusion rates of at least 40% were kept in the model. P b 0.05 was considered statistically significant. All analyses were performed using SAS (version 9.2, The SAS Institute, Cary, NC).

2.4. Diagnostic criteria for pouch disorders

Patients were considered to have a normal pouch if they were asymptomatic, without any endoscopic and histological inflammation and fewer than three episodes of antibioticresponsive pouchitis (symptoms responding to a 2-week, single-agent antibiotic) per year with the last episode occurring at least 6 months. 17 Pouchitis was defined as a condition with the modified Pouchitis Disease Activity Index (mPDAI) scores N 5. 20 Acute pouchitis was defined as pouchitis that responded to a short course of a single antibiotic, which included antibioticresponsive (b 4 episodes per year) and antibiotic-dependent (N 4 episodes per year, and requires long-term, continuous antibiotic or probiotic therapy to maintain remission). Refractory pouchitis was defined as a condition where a patient failed to respond to a 4-week course of a single antibiotic (metronidazole or ciprofloxacin), requiring prolonged therapy of N 4 weeks consisting of N 2 antibiotics, oral or topical 5-aminosalicylate, corticosteroid therapy, immunomodulator therapy, or therapy with anti-TNF biologics. CD of the pouch was diagnosed if there were nonsurgery-related perianal fistulae, granulomas on histology, or inflammation and ulcerations in the afferent limb or in the small bowel on endoscopy in the absence of NSAID use. All patients with CD of the pouch underwent clinical, endoscopic, radiographic, and histologic evaluations. 21 The presence of serum or fecal anti-Saccharomyces cerevisiae antibodies (ASCA) was recorded when available. Irritable pouch syndrome (IPS) was defined as the presence of abdominal pain, pelvic discomfort, and diarrhea with no inflammation of the afferent limb, pouch, or cuff on endoscopy. These symptoms had persisted for at least 12 weeks in 12 months prior to the data entry. Duration of pouch was defined as the interval between the time of pouch creation and the time of pouch failure or the most recent follow-up. Pouch failure was defined as pouch excision, revision or a permanent diversion.

3. Results
3.1. Demographics and IBD-related features
Twenty-six AA, 37 HA, 22 IA and 150 Caucasian patients were included in the study. Out of twenty-two Indian patients, we were able to get further information from 18 patients. Eight patients were born in the US and ten were born in India. The average age since migration was 30.6 8.9 years. Table 1 shows clinical characteristics between different ethnic groups. There were no differences in gender distribution, age at diagnosis, age at pouch surgery, duration of pouch, and current age of patients between the study groups. A greater number of Caucasians and HA were current or past smokers than IA (27.3% and 27.0% vs. 0%; p = 0.007). Caucasians and HA were also more likely to have a family history of IBD than IA or AA. (Caucasian vs. IA p = 0.034; Caucasian vs. AA p = 0.017; HA vs. AA p = 0.017; HA vs. IA; 0.032). There was significant difference in beginning and ending or continuation of smoking between patients with chronic pouchitis, CD of pouch and other pouch diagnosis (Table 2). Fewer IA patients had extensive colitis at the time of colectomy than Caucasians (71.4% vs. 94.0%; p = 0.004). A greater number of IA received anti-TNF biologics than HA (22.7% vs. 0%; p = 0.016). However, there were no differences in pre-operative diagnosis (CD, IC or UC), indication

Ethnicity and Crohn's Pouch

Table 1 Variable Clinical characteristics between different ethnic groups. Caucasian (N = 150) Male 79(52.7) Current age, yrs. 44.3 13.5 Age at UC diagnosis, yrs. 27.2 11.7 Age at colectomy, yrs. 34.8 13.1 Duration from UC diagnosis to colectomy, yrs. 5.0[2.0,11.0] Insurance Preferred Provider Organizations 47(31.5) 2,4 Health Maintenance Organizations 20(13.4) Self pay 8(5.4) Government 24(16.1) Other 50(33.6) Active or ex-smoker 41(27.3) 3 Chronic NSAID use 11(7.3) Family history of IBD 37(24.7) Family history of CD 6(4.0) Family history of UC 31(20.7) Pre-IPAA diagnosis CD 3(2.0) Indeterminate colitis 12(8.0) UC 135(90.0) Extent of UC Extensive colitis 141(94.0) 3 Left sided colitis or Proctitis 9(6.0) Pre-colectomy use of biologics 12(8.0) Indication for colectomy Refractory UC 130(86.7) Neoplasia 20(13.3) Fulminant colitis 17(11.3) Other extra-intestinal manifestations 57(38.0) Primary sclerosing cholangitis 10(6.7) Liver transplant 2(1.3) Concurrent autoimmune disorders 19(12.7) Significant comorbidities 11(7.3) African-American Indian-American Hispanic-American (N = 26) 13(50.0) 39.5 9.3 28.0 11.1 33.3 11.6 5.0[2.0,7.0] 13(50.0) 1 3(11.5) 1(3.8) 5(19.2) 4(15.4) 2(7.7) 5(19.2) 1(3.8) 0 1(3.8) 0 0 26(100.0) 22(84.6) 4(15.4) 4(15.4) 26(100.0) 0 0 7(26.9) 1(3.8) 1(3.8) 4(15.4) 3(11.5) (N = 22) 10(45.5) 43.7 13.5 28.7 10.3 36.7 11.9 5.5[4.0,12.0] 9(42.9) 2(9.5) 0 4(19.0) 6(28.6) 0 14 1(4.5) 1(4.5) 0 1(4.5) 0 1(4.5) 21(95.5) 15(71.4) 1 6(28.6) 5(22.7) 4 20(90.9) 2(9.1) 3(13.6) 6(27.3) 1(4.5) 0 0 0 (N = 37) 23(62.2) 41.9 15.0 24.4 13.2 32.9 13.5 8.0[2.0,11.0] 10(30.3) 1 1(3.0) 11(33.3) 6(18.2) 5(15.2) 10(27.0) 3 2(5.4) 10(27.0) 1(2.7) 9(24.3) 1(2.7) 1(2.7) 35(94.6)

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p-value 0.6 0.33 0.48 0.68 0.48 b 0.001

0.007 0.16 0.016 0.57 0.046 0.58

0.004 35(94.6) 2(5.4) 03 29(78.4) 8(21.6) 4(10.8) 9(24.3) 1(2.7) 1(2.7) 3(8.1) 2(5.4)

0.016 0.081

0.33 0.3 0.77 0.7 0.27 0.44

Values presented as Mean SD with ANOVA; Median [P25, P75] with KruskalWallis test, or N (%) with Pearson's chi-square test. Data not available for all subjects. Missing values: Extent of UC = 1; Insurance = 6. Significantly different from Caucasian. 2 Significantly different from African-American. 3 Significantly different from Indian-American. 4 Significantly different from Hispanic-American. A significance level of 0.008 was used for pairwise ad-hoc comparisons.
1

for colectomy (refractory or dysplasia), history of fulminant colitis, the presence of EIM, the presence of primary sclerosing cholangitis (PSC), liver transplantation, significant co-morbidities and other autoimmune conditions, among the study groups.

immunomodulators or anti-TNF biologics for pouch diseases, pouch-related hospitalization, and the frequency of pouch failure were similar among the study groups.

3.3. Crohn's disease of the pouch

Table 4 presents the results of multivariable logistic regression analysis for the risk for CD of the pouch. After adjusting for age at time of pouch, duration of pouch, pre-op diagnosis, family history of CD and smoking, Caucasians were found to be nearly 11 times more likely to develop CD of the pouch than IA (p = 0.015). Similarly, AA patients had 10 times higher odds (p = 0.004) of developing CD of the pouch than IA. On the other hand, there was no difference in the frequency of CD of the pouch between HA and IA patients (p = 0.072). ASCA test positivity was significantly greater in

3.2. Pouch surgery and outcomes

Table 3 shows comparison of characteristics of pouch surgery and outcome. Final diagnosis was significantly different for the ethnicity groups with Caucasians being less likely to have a normal pouch than IA or HA (p = 0.017). Caucasians had greater number of visits to the pouch clinic than IA or HA (2.0; IQR:1.00, 3.0 in Caucasians vs. 1.0; IQR:1.00, 2.0 in HA vs. 1.0; IQR:1.0, 2.0 in IA; p b 0.001). The type and stage of pouch construction, post-operative use of

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Table 2 Factor Relationship between smoking and diagnosis of pouch disorders. N Chronic Pouchitis (N = 75) Current/Past smoking Smoking Never Ex-smoker Current smoker If ex-smoker, they stopped smoking before UC diagnosis after UC diagnosis but before final pouch diagnosis after final pouch diagnosis If ex or active smoker, started smoking before UC diagnosis after UC diagnosis Pack years
1 2 3

S. Mukewar et al.

CD of the Pouch (N = 41) 13(31.7) 28(68.3) 8(19.5) 5(12.2) 2(40.0) 1(20.0) 2(40.0) 3(33.3) 1,3 6(66.7) 7.3[5.0,12.0]

Other diagnosis (N = 118) 20(16.9) 98(83.1) 16(13.6) 4(3.4) 0.006 5(35.7) 9(64.3) 0 0.009 13(81.3) 2 3(18.8) 3.5[0.55,17.5] p-value 0.12 0.17

234 234

14(18.7) 61(81.3) 11(14.7) 3(4.0)

28 7(77.8) 2(22.2) 0 36 10(90.9) 2 1(9.1) 20.0[2.3,28.5]

22

0.52

Significantly different from chronic pouchitis. Significantly different from CD of the pouch. Significantly different from other diagnosis.

Table 3 Variable

Comparison of characteristics of pouch surgery and outcome. Caucasian (N = 150) African-American Indian-American Hispanic-American p-value (N = 26) 26(100.0) 0 0 0 22(84.6) 3(11.5) 1(3.8) 2(7.7) 2(7.7) 5(19.2) 4(15.4) 5(19.2) 1(3.8) 5(19.2) 2(7.7) 4(15.4) 1.00[1.00,2.0] 4(15.4) 3(11.5) 4.5[2.0,10.0] 1 (N = 22) 21(95.5) 0 1(4.5) 0 16(84.2) 3(15.8) 0 1(4.5) 1(4.5) 7(31.8) 1 1(4.5) 7(31.8) 3(13.6) 0 1(4.5) 3(13.6) 1.00[1.00,2.0] 1 6(27.3) 4(18.2) 4.0[2.0,10.0] (N = 37) 0.73 139(92.7) 3(2.0) 8(5.3) 4(2.7) 117(78.0) 20(13.3) 9(6.0) 15(10.0) 14(9.3) 12(8.0) 3,4 29(19.3) 33(22.0) 14(9.3) 32(21.3) 11(7.3) 19(12.7) 2.0[1.00,3.0] 3,4 25(16.7) 15(10.0) 8.0[5.0,13.0] 2 36(97.3) 0 1(2.7) 0.92 0 30(81.1) 5(13.5) 2(5.4) 2(5.4) 1(2.7) 13(35.1) 1 5(13.5) 6(16.2) 5(13.5) 4(10.8) 2(5.4) 2(5.4) 1.00[0.00,2.0] 1 8(21.6) 2(5.4) 9.0[4.0,13.0]

Pouch type J S Other Stage of pouch surgery 1 2 3 4 or pouch redo Post-IPAA use of immunomodulators Post-IPAA use of biologics Final Diagnosis Normal pouch Irritable pouch syndrome Active pouchitis Refractory pouchitis Crohn's disease of pouch Cuffitis Surgical complications Number of visits to Pouchitis Clinic Pouch-related hospitalization Pouch failure Duration from pouch creation to failure or last visit, yrs.

0.72 0.54 0.017

b 0.001 0.6 0.47 0.011

Values presented as mean standard deviation with ANOVA; median (interquartile range) with KruskalWallis test, or N (%) with Pearson's chi-square test. Data not available for all subjects. Missing values: Stage of Pouch Surgery = 3; Follow-up Pouch Failure (yrs.) = 1. Significantly different from Caucasian. 2 Significantly different from African-American. 3 Significantly different from Indian-American. 4 Significantly different from Hispanic-American. A significance level of 0.008 was used for pairwise ad-hoc comparisons.
1

Ethnicity and Crohn's Pouch

Table 4 Variable African-American vs. Indian-American Caucasian vs. Indian-American Hispanic-American vs. Indian-American Current smoker Family history of CD Age at the time of pouch construction (5 year increase) Association between ethnicity and Crohn's disease of the pouch: Multivariable logistic regression analysis. Odds ratio (95% Confidence Interval) 10.1 (1.03, 1365.8) 11.1 (1.4, 1427.2) 4.9 (0.48, 671.8) 1.5 (0.68, 3.3) 0.21 (0.002, 1.9) 0.82 (0.71, 0.95)

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p-value 0.004 0.015 0.072 0.32 0.058 0.005

CD of pouch than in those without [10/14 (71.4%) vs. 7/22 (31.8%); p = 0.02] (Table 5). Table 6 shows multivariate Cox regression analysis for CD of pouch between different groups and Fig. 1 shows Kaplan-Meier curve with log rank test. The event-free survival for CD of pouch was not significantly between the different groups.

4. Discussion
This is the first study comparing CD of the pouch among multiethnic groups of patients. The current study confirmed our previous findings that the disease course of UC before colectomy was different among various ethnic study groups. Furthermore, this study also showed that the disease course of the pouch, reflected by the development of CD of the pouch, was different among the ethnic groups. AA had 10 times and Caucasians 11 times higher risk of developing CD of the pouch compared to IA, suggesting a role for genetic susceptibility to the disease. CD of the pouch is being increasingly recognized in IPAA patients with an estimated prevalence rate varying from 2.7% to 13.0% of IPAA patients. 1114 The exact etiopathogenesis of CD of the pouch remains to be determined. However, genetic and environmental factors may contribute. The presence of family history of CD was found to be associated with 3 to 8 times greater risk for the development of CD of the pouch, 15,16 suggesting the role for a genetic predisposition. The notion is supported by a recent study in which Ashkenazi Jewish ethnicity was found to have a greater risk for inflammatory complications of pouch, including CD of the pouch. 19 In our study, none of the IA patients developed CD of the pouch, while AA and Caucasian patients had a much higher risk. These Indian-American patients were either born in the US or had migrated to the US in 1970s80s. However, in Cox regression analysis the event-free survival for CD of pouch was

not significantly between the groups. This could be due to two reasons small sample size with type II error or absence of CD of pouch in the IA group. As seen in the Kaplan Meier plot, the curves diverged and followed paths distinct from that of IA. Other reported risk factors for CD of the pouch included smoking, 17 longer duration of pouch, 18 pre-operative diagnosis of indeterminate colitis 18 and seropositivity for antiSaccharomyces cerevisiae-IgA antibody. 15 In addition, our study showed that patients with CD of pouch had significantly more ASCA positivity than those without. Environmental and genetic factors have extensively been studied in IBD. In this study we found that a greater number of Caucasians and HA were current or past smokers than IA. Few studies have assessed smoking habits in Indian UC patients 2224 and none of the previous studies discussed smoking habits of Hispanics. Walker et al. 22 noted that there was no difference between South-Asians and North-Europeans, while Carr et al. 23 showed that South-Asians were significantly less likely to be smokers. In our study, none of IA patients living in the North America ever smoked. Even after adjusting for smoking as a risk factor, IA patients were still found to have a lower risk for CD of the pouch. Interestingly, smoking history was different between patients with chronic pouchitis and CD of pouch. Those with chronic pouchitis were mostly ex-smokers and a majority of these had started and stopped smoking before the diagnosis of UC. On the other hand, a greater number of CD of pouch patients were current smokers or had started smoking after UC diagnosis. Studies from Asian countries suggest that, although the incidence of CD in Asia is lower than that in the West, it is gradually rising over the last few decades. 25 For example, a study by Leong et al. 26 showed a 3-fold increased incidence of CD during the past decade. Although there are no actual reports of incidence and prevalence of CD in India, 25 anecdotal evidence suggests that it is rare in India. It is considered to be less prevalent than UC. A study by Pai et al. 27 reported 71 UC and 25 CD patients in the hospital over a

Table 5 Anti- Saccharomyces cerevisiae antibodies positivity rates between patients with CD of pouch and other pouch diagnosis. Factor Number of patients CD of the Pouch (N = 41) Stool ASCA Serum ASCA ASCA (stool or serum) 18 31 36 5/7 (71.4%) 10/14 (71.4%) 10/14 (71.4%) Other pouch diagnoses (N = 193) 2/11 (18.2%) 6/17 (35.3%) 7/22 (31.8%) p-value 0.024 0.045 0.02

ASCA: Anti- Saccharomyces cerevisiae antibodies.

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Table 6 Factor

S. Mukewar et al.
Association between ethnicity and Crohn's disease of the pouch: Multivariable Cox regression analysis. a Hazard Ratio (95% Confidence Interval ) p-value 0.086 0.21 0.067 0.5

Ever smoked Indian vs. rest Pre-op use of biologics Pre-op diagnosis of ulcerative colitis
a

1.8 (0.92, 3.6) 0.16 (0.01, 2.7) 3.7 (0.91, 14.7) 0.63 (0.16, 2.4)

Cox regression using Firth's penalized maximum likelihood estimation.

5-year period. Another study by Prakash et al. 28 reported 13 patients over an 18-year period. In addition, this pattern in more patients having UC rather than CD is seen in the migrant Indian population as well. 7 The role of genetic predisposition for IBD in Indian patients may be different from their Western counterparts. The NOD2 mutations commonly seen in the West are rarely seen in Indian patients with CD. 29 A recent study revealed limited replication of genome wide studies and reported susceptibility loci for UC in patients living in Northern India, suggesting a distinct genomic architecture in those patients. 30 On the basis of these results, we speculate that genetic differences could possibly contribute to the absence of CD of pouch in IA patients with IBD who have migrated to the US. However, given westernization and rise in the incidence of CD in Asia-Pacific, this may be explained by variable exposure to environmental factors between patients with different ethnic backgrounds. There was significant difference between the groups with regards to insurance coverage. More AA had PPO coverage than HA and Caucasians, which may reflect the referral pattern of our institution, as a privately owned medical facility. HA had more self-pay patients than other groups. The proportion of patients with government-sponsored insurances was similar between the groups.

The findings of our study have several implications. Differences in the use of biologics, history of smoking, number of visits to the pouch clinic and insurance status likely represent socio-economic and cultural factors affecting the course of UC in patients of various backgrounds. Thus ethnicity may be a surrogate marker for cultural factors influencing the disease. The difference in the frequency of CD of the pouch among ethnic groups suggests the possible contribution of genetic make-up in development of the disease. Alternatively, patients with various ethnic backgrounds may be differentially exposed to unmeasured environmental factors and thus affecting the diagnosis of CD of pouch. The information from this study may help guide clinicians in making a diagnosis of CD of the pouch, with different pretest probability among ethnic groups in mind. Furthermore, the findings suggests that patients who are considered to be at a higher risk for CD of the pouch to be monitored closely. Our study has several limitations. First, our study was limited by small sample size, despite being one of the largest in the literature. It might have been underpowered to detect a difference in event free survival for development of CD of pouch between the different ethnicities. In addition, it was underpowered to identify differences in other adverse pouch outcomes. However, a study of this kind can only be performed in such a specialized tertiary care center like ours. Second, although the cohort had a range of healthy and diseased pouch conditions, there might have been a referral bias, as a majority of patients in our Pouchitis Clinic had diseased pouches. Thirdly, the ethnicity was determined by self-reported ethnic background. There may have been patients with mixed racial background and first generation immigrants in the cohort. Fourth, due to retrospective nature of our study limited information was available regarding socio-economic status of the patients. Finally, although we did not perform genotyping on our patients, a sample size calculation suggested that a genetic study would involve thousands of patients. The results are certainly interesting and will likely benefit clinicians assessing prognosis while managing patients with IPAA. In conclusion, we found that racial background may be associated with different risk for the development of CD of pouch.

Acknowledgement
Figure 1 Occurrence of Crohn's disease of the pouch between different ethnic groups. Figure shows KaplanMeier curve with log rank test. The event-free survival for CD of pouch was not significantly between the different groups.
SM contributed to study concept and design, acquisition, analysis and interpretation of data, drafting of the manuscript. XW, RP, FR and BS contributed to study concept and design, analysis and interpretation of data and critically revised the manuscript. RL conducted statistical analysis. All authors read and approved the final manuscript.

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