Publications

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Yuan Y, Vanden Kerchove K, Ma C, Verstockt B, Nardone O, Bernstein CN, Munch A, Jairath V. Heterogeneity in Histological Evaluation of Microscopic Colitis in Randomized Clinical Trials- an Umbrella Review. Inflammatory Bowel Diseases 2025; in press.

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Background: The diagnosis of microscopic colitis is based on endoscopic[CB1]  biopsy with histological assessment. Histological outcomes (remission, response or improvement) are important treatment targets in clinical trials. Although a substantial body of research on microscopic colitis has been published in recent years, no standardized criteria currently exist for its histological outcomes. We sought to review and summarize the histological evaluation of microscopic colitis in published systematic reviews assessing the efficacy of interventions and to examine the heterogeneity in histological evaluation among the randomized controlled trials included in those systematic reviews.

Methods: We conducted an umbrella review (ie, an overview of systematic reviews) of published systematic reviews. A literature search of the Cochrane Database of Systematic Reviews, MEDLINE, and Embase was performed up to May 2025. Definitions of histological evaluation and monitoring following interventions were extracted and summarized from the published systematic reviews and the randomized controlled trials included within them.

Results: Fourteen systematic reviews with meta-analyses that focused on interventions were included. Nineteen randomized controlled trials were included in these systematic reviews. Of them, 12 fully published randomized controlled trials reported histological outcome data and met our inclusion criteria. The definitions for histological outcomes varied between randomized controlled trials but were generally based on reduction in lamina propria cellularity, intraepithelial lymphocytes, or collagen band thickness.

Conclusions: This umbrella review highlights the heterogeneity in the definitions of histological outcomes in microscopic colitis randomized controlled trials. The summarized evidence will support ongoing efforts to develop consensus definitions for histological outcomes in order to facilitate clinical trials of medical therapies for microscopic colitis.

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Narous M, Nugent Z, Rabinovitch-Nikitin I, Kirshenbaum L, Bernstein CN. Cardiac arrhythmia in patients with inflammatory bowel disease: a retrospective, population-based cohort study in Manitoba, Canada. BMJ Open 2025; Mar 21;15(3): e097687. 1-9.

 

Objective: We aimed to characterise the association between inflammatory bowel disease (IBD) and IBD medications and risk of cardiac arrhythmia.

Design, setting and participants: In a retrospective population-based study using the University of Manitoba IBD Epidemiology Database (Manitoba, Canada) from 1984 to 2018, we identified 10,992 IBD cases and 102,875 matched controls.

Analysis: Arrhythmia risk in IBD was adjusted for the presence of comorbidities of the Charlson Comorbidity Index. The effect of IBD medications on the development of arrhythmia was assessed in a nested cohort study of individuals with IBD. Cases were censored at the date of first database identification of a diagnosis of heart failure or myocardial infarction.

Results: The cohort was 48.5% Crohn's disease and 51.5% ulcerative colitis, and 80.5% were incident cases. The median age of incident cases at IBD diagnosis was 35 (interquartile range, IQR, 25 to 49). The median age at arrhythmia diagnosis for persons with IBD was 69 years (IQR, 59 to 77) and for controls 69 years (IQR, 59 to 78). Persons diagnosed with IBD were more likely than controls (HR 1.51; 95% CI, 1.30 to 1.76) to develop arrhythmia. Persons within their sixth decade or younger had increased risk of arrhythmia. When controlling for comorbidities, the significant association between IBD and arrhythmia remains. Medications including 5-aminosalicylates, thiopurines and tumour necrosis factor-α inhibitors were not associated with arrhythmia.

Conclusions: Persons with IBD have a higher risk of arrhythmia prior to a diagnosis with heart disease. Use of IBD medications was not associated with risk of arrhythmia.

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Bernstein CN, Kuenzig E, Coward SE, Nugent Z, Nasr A, El Matary W, Singh H, Kaplan GG, Benchimol EI. Increased Incidence of Inflammatory Bowel Disease after Hirschsprung Disease: A Population-based Cohort Study. Journal of Pediatrics 2021; 233: 98-104. 

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To determine the frequency with which IBD is diagnosed in persons with Hirschsprung disease in population-based datasets from 3 Canadian provinces. In study I, Ontario data were used to assess the incidence of IBD in a birth cohort of children with Hirschsprung disease relative to children without Hirschsprung disease. In study II, a case-control design was used in Alberta and Manitoba to determine the frequency of previously diagnosed Hirschsprung disease in persons with IBD, compared with the frequency of Hirschsprung disease in matched controls. Validated algorithms for Hirschsprung disease and IBD were applied to each provincial health registry.

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In study I, of the 716 children diagnosed with Hirschsprung disease in Ontario since 1991, 18 (2.5%) ultimately developed IBD (168.8 per 100 000 person-years), compared with 7109 of 3 377 394 children without Hirschsprung disease (0.2%, 14.2 per 100 000 person-years). The percentage of males with post-Hirschsprung disease IBD was 77.8%. The incidence rate ratio was 11.9 (95% CI, 7.5-18.8). In study II, the OR of having had Hirschsprung disease before a diagnosis of IBD compared with controls was 74.9 (95% CI, 17.1-328.7) in Alberta and 23.8 (95% CI, 4.6-123) in Manitoba. Crohn's disease was more common after Hirschsprung disease than ulcerative colitis.

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We concluded that IBD can emerge in more than 2% of patients with Hirschsprung disease and, like Hirschsprung disease itself, is more common in males. IBD is much more common after a diagnosis of Hirschsprung disease than in the general population.

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Witges K, Shafer LA, Zarychanski R, Abou-Setta AM, Rabbani R, Dingwall O, Bernstein CN. Ipilimumab induced enterocolitis: A systematic review and meta-analysis. Drug Safety 2020; 43, 1255–1266. 

 

Checkpoint inhibitor drugs including ipilimumab have been reported to induce intestinal injury. There are several aspects of checkpoint inhibitor induced colitis that are unknown. We aimed to evaluate the risk of chronic (> 6 weeks) enterocolitis following ipilimumab administration, and the likelihood that an enteritis vs colitis or enterocolitis is seen. We searched MEDLINE, EMBASE, CENTRAL, the World Health Organization International Clinical Trials Registry, and conference proceedings. We included: (1) randomized controlled trials comparing ipilimumab administration with placebo/standard care/other active chemotherapy regimens and (2) prospective observational studies. Separate meta-analyses were performed for randomized controlled trials and observational studies. Of 4760 records, we included 10 unique randomized controlled trials (n = 5814 subjects) and 34 unique prospective observational studies (n = 3699 subjects). In randomized controlled trials, the pooled relative risk of ≥ grade 3 enterocolitis or ≥ grade 3 diarrhea associated with ipilimumab was 13.31 (95% confidence interval 6.01-29.48, I2 = 0%, ten trials) and 6.72 (95% confidence interval 3.30-13.65, I2 = 63%, ten trials), respectively. In observational studies, the 3-monthly risk of developing grade 3 or higher enteritis, colitis, or enterocolitis was 4% (95% confidence interval 3-7, I2 = 77.40%, 25 studies). Randomized controlled trials and observational studies did not distinguish between acute and chronic enterocolitis. Of the included observational studies, the pooled risk of incurring small bowel involvement associated with ipilimumab was 1% (95% CI 0-4, I2 = 0%, four studies) per every 3-month time period.

 

Insufficient data exist to quantify or distinguish the risk of acute vs chronic enterocolitis following ipilmumab use. Because of the serious impact of chronic enterocolitis on quality of life and further cancer treatment, future trials evaluating the safety of immunotherapy should report gastrointestinal events in greater detail.