Pierre Paré

An epidemiological survey of constipation in canada: definitions, rates, demographics, and predictors of health care seeking.

OBJECTIVES:The prevalence of functional constipation is highly variable among epidemiological surveys and may relate to the definitions applied. We estimated the population prevalence of self-reported, Rome I–defined, and Rome II–defined constipation in Canada and determined the variables that best predicted health care seeking.METHODS:A research firm was employed to conduct a random digit dial national survey, inviting household members at least 18 yr of age to participate in a study assessing personal health issues. The sample was stratified to ensure that each region of Canada was represented. Data collection involved three stages: 1) recruitment of participants by phone, 2) mailing of the questionnaire, and 3) data retrieval through a follow-up phone call. The Rome II questionnaire was used to derive the prevalence of functional constipation using both Rome I and Rome II criteria.RESULTS:Of the 1149 participants, 27.2% self-reported constipation within the past 3 months, and 16.7% and 14.9% had functional constipation according to Rome I and II, criteria, respectively. For all three definitions, the rate for women was close to twice that for men. Approximately 34% of those with self-reported constipation had visited a physician for it, versus 26.3% of Rome II subjects. In a regression model, subjects self-reporting in the past 3 months were more likely to have seen a doctor for their constipation (odds ratio 2.47, p < 0.01) and significantly more women than men (35.6% vs 19.5%, p < 0.05).CONCLUSIONS:Functional constipation and related health care seeking are common in the Canadian population and are strongly determined by the definition used. The Rome II criteria for this disorder seem to be satisfactory, but modifications may be considered to allow for constipated subjects taking laxatives and to increase the number of qualifying symptoms.

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 × 10−13, combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 × 10−12, combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 × 10−16, combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 × 10−8, combined OR = 0.56; rs10889677, combined P = 1.3 × 10−8, combined OR = 1.29).

FUNCTIONAL GASTROINTESTINAL DISORDERS IN CANADA: FIRST POPULATION-BASED SURVEY USING ROME II CRITERIA WITH SUGGESTIONS FOR IMPROVING THE QUESTIONNAIRE

The Rome II criteria and questionnaires developed to identify functional gastrointestinal disorders have not been evaluated. Our objectives were to determine the prevalence of functional gastrointestinal disorders in Canada, compare our results with data from other published studies, assess concordance of Rome I and Rome II criteria for irritable bowel syndrome, and suggest improvements in the Rome II questionnaire. An independent research firm was employed to conduct a random digit dial national survey, inviting household members ≥18 years of age to participate in a study examining personal health issues. Subjects recruited by telephone, who agreed to participate, were mailed a questionnaire, and the data were retrieved by a follow-up phone call. The Rome II questionnaire and algorithms were used and where possible Rome I algorithms were also applied. At least one functional gastrointestinal disorder occurred in 61.7% of 1149 respondents (65.6% female versus 57.6% male; P < 0.05). The most prevalent were the functional bowel disorders at 41.6% followed by esophageal disorders at 28.9%. Irritable bowel syndrome prevalence by Rome II and I criteria were 12.1% and 13.5%, respectively (kappa = 0.76). Because the Rome II criteria have added exclusion items that are not present in the Rome I criteria, the prevalence of esophageal, gastroduodenal, and anorectal disorders is lower than the figures from a US market survey. In conclusion, functional gastrointestinal disorders are highly prevalent in Canada, with a significantly higher rate in women. There is substantial agreement between Rome I and Rome II criteria for irritable bowel syndrome. Rome criteria and questionnaire remain works in progress.

CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.

The caspase recruitment domain gene (CARD15) was recently identified as the underlying gene associated with the IBD1 locus that confers susceptibility to Crohn disease (CD). CARD15 is related to the NOD1/Apaf-1 family of apoptosis regulators, and three sequence variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) in the gene were demonstrated to be associated with CD. We collected a cohort of 231 patients with CD and 71 healthy control individuals from the Canadian province of Quebec, to determine the prevalence of these sequence variants in an independent population. Clinical records of all patients were systematically reviewed, and detailed phenotypic information was obtained. All patient DNA samples were genotyped for the three variants, thus enabling an analysis of genotype-phenotype correlations. In this cohort, 45.0% of patients with CD carried at least one variant in the CARD15 gene, compared with 9.0% of control individuals (P<10-7). Allele frequencies of Arg702Trp, Gly908Arg, and Leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with CD, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Importantly, CARD15 mutants were seen with equal frequency in patients with familial and sporadic CD. Analysis of the relationship between genotype and phenotype convincingly demonstrates that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P<.001). Moreover, we were able to determine the haplotype structure surrounding this disease gene by genotyping 45 single-nucleotide polymorphisms (SNPs) in a 177-kb region that contained the CARD15 gene. This structure helps clarify the history of these causal mutations. Finally, this analysis shows that CARD15 involvement with CD is detectable by use of publicly available SNPs alone.

Treatment of Active Crohn's Disease With MLN0002, a Humanized Antibody to the α4β7 Integrin

BACKGROUND & AIMS Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohns disease. METHODS Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohns Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score <or=150) and with an enhanced clinical response (>or=100-point decrement in CDAI). Human anti-human antibody levels were measured. RESULTS Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohns disease. CONCLUSIONS This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohns disease.

Health-related quality of life in functional GI disorders: focus on constipation and resource utilization.

OBJECTIVE:Functional GI disorders are common in the general population. However, their impact on health status and health resource use in Canada has not been well examined. We describe 1) health-related quality of life in Canadians with functional constipation or other functional GI disorders versus Canadian normative data or those without a functional GI disorder and 2) health resource utilization in subjects self-reporting of constipation.METHODS:An independent research firm was employed to conduct a randomly selected national survey examining GI symptoms and personal health. Household members 18 yr or older were recruited by a random-digit dial technique. Participants were then mailed a questionnaire and data were retrieved by a follow-up phone call. All functional GI disorders were defined using Rome II criteria, and constipation was further defined using self-report. Health-related quality of life was assessed using the Short Form 36.RESULTS:One thousand one hundred forty-nine subjects (49.3% male) with a mean age of 42.2 yr completed the survey. The prevalence of any Rome II functional GI disorder was 61.7%. The rate of functional constipation was 14.9%, whereas that of self-reported constipation was 27.2%. The mean physical and mental component summary and eight subscores of the Short Form 36 were significantly lower (p < 0.05) than Canadian norms for both self-reported constipation and Rome II functional constipation. Subjects with no GI disorder had significantly better Short Form 36 scores than the Canadian norms. The rate of physician visits for constipation was strongly predicted by the physical component of the Short Form 36. Most subjects (66.2%) were satisfied with their current constipation treatment.CONCLUSIONS:Constipation is common in the Canadian population and significantly impairs health-related quality of life. Poor quality of life is an important predictor of health care utilization in these subjects.

Omega-3 Free Fatty Acids for the Maintenance of Remission in Crohn Disease: The EPIC Randomized Controlled Trials

CONTEXT Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. OBJECTIVE To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. DESIGN, SETTING, AND PATIENTS Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohns Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. INTERVENTIONS Patients with a Crohns Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. MAIN OUTCOME MEASURE Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. RESULTS For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. CONCLUSION In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. TRIAL REGISTRATION clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542.

Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort.

OBJECTIVES:Inflammatory bowel disease (IBD), comprising primarily of Crohns disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population.METHODS:Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions.RESULTS:African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4–5.5), colorectal disease (OR = 1.9; 95% CI: 1.1–3.4), perianal disease (OR = 1.7; 95% CI: 1.03–2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32–0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3–13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55–10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8–4.6) and erythema nodosum (3.3; 95% CI: 1.7–6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts.CONCLUSIONS:There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.

Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone.

The symptoms of functional dyspepsia are still unexplained. To evaluate the possible role of abnormal visceral perception, we studied the symptomatic responses and the pressure variations during progressive gastric distension in 10 female healthy control subjects (mean age 33.6 years) and in 10 female patients with functional dyspepsia (mean age 35.2 years). A rubber balloon was positioned 4 cm below the lower esophageal sphincter (LES) and inflated with progressively larger volumes of air by steps of 50 ml; pressures at the gastric fundus and at the LES were continuously recorded by perfused manometric catheters. Each subject was studied on two separate occasions after randomized double-blind administration of either placebo or 20 mg of domperidone. Symptomatic responses and the manometric data were analyzed at the time of the initial recognition of distension (bloating step) and at the time of reporting pain or up to a maximum of 700 ml of balloon inflation (pain or 700-ml step). On placebo, the volumes of gastric distension were more than two times lower in patients than in control subjects at the bloating step (185±32 ml vs 470±40 ml,P=0.001) and at the pain or 700-ml step (265±54 ml vs 600±34 ml,P<0.005), while the pressure gradients (pressure at inflation steps minus baseline pressure before beginning inflation) were not statistically different between the two groups. On domperidone, the volumes at each of the two steps did not change in comparison to results on placebo except in healthy controls at the bloating step (470±40 ml on placebo vs 355±35 ml on domperidone,P<0.001); however, there was a trend for pressure gradients to increase on domperidone in comparison to results on placebo. We conclude that patients with functional dyspepsia have a lower threshold both to the initial symptomatic recognition and to perception of pain during gastric distension and that domperidone might have an effect on the threshold of these conscious visceral sensations. This increased visceral perception may alone or with other abnormalities of the gastroduodenal tract explain the symptoms of functional dyspepsia.

Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial

BACKGROUND Conventional management of Crohns disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohns disease. METHODS In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohns Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohns disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohns disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. FINDINGS This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. INTERPRETATION Although ECI was not more effective than conventional management for controlling Crohns disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. FUNDING AbbVie Pharmaceuticals.