Publications // 2020

Banerjee R, Pal P, Nugent Z, Ganesh G, Adigopula B, Pendyala S, Bernstein CN.  IBD in India: Similar phenotype but different demographics than the West. Journal of Clinical Gastroenterology 2020; 54:725-732.


Inflammatory bowel disease (IBD) is emerging in the developing world but phenotypic data are limited. In this study we aimed to describe the phenotype, clinical presentation, disease behavior and treatments of IBD in a large cohort in India. All persons presenting to the Asian Institute of Gastroenterology in Hyderabad, India since 2004 with a confirmed diagnosis of IBD were enrolled. The demographic profile at the first visit, family history of IBD, smoking history, time from first symptom onset to diagnosis, use of anti-tuberculous treatment before IBD-specific treatment, disease phenotype, and medication history were collected by interview and chart review. Disease and family history and treatments used were updated at each follow-up visit. Of 4006 persons enrolled, 59.9% had ulcerative colitis and the majority were male (60.3%). The median diagnostic delay in both ulcerative colitis and Crohn’s disease was at least two years. At the time of diagnosis only 4.5% of Crohn’s disease were smokers and only 3.8% of ulcerative colitis were ex-smokers. Positive family history was uncommon (2.1%). The phenotype of persons with Crohn’s disease included 22.9% with stricturing disease and 9.4% with fistulizing disease. The most common site of disease was ileo-colonic (40.9%) and only 2.5% had perineal fistulas. Among those with ulcerative colitis 18.7% had proctitis and 30.3% had pan-colitis.


This is the largest cohort of persons with IBD reported from Asia. While there are several demographic differences between persons with IBD from India compared with the West, the phenotypes of the disease are not highly different. We hope to ultimately undertake a study comparing Indians with IBD from India and Indians with IBD from Canada to contrast the differences in diet, gut microbiome and clinical presentation. This might lead us to understand causes of IBD.

Targownik LE, Kaplan GG, Witt J, Bernstein CN, Singh H, Tennakoon A, Aviña Zubieta A, Coward S, Jones J, Kuenzig ME, Murthy SK, Nguyen GC, Peña-Sánchez JN, Benchimol EI. Longitudinal trends in the direct costs and health care utilization ascribable to inflammatory bowel disease in the biologic era: Results from a Canadian population based analysis. American Journal of Gastroenterology 2020; 115(1):128-137.

We aimed to assess the total direct costs of IBD on a population-wide level in the era of biologic therapy. We identified all persons with IBD in Manitoba between 2005 and 2015, with each matched to 10 controls on age, sex, and area of residence. We enumerated all hospitalizations, outpatient visits and prescription medications including biologics, and their associated direct costs. Total and per capita annual IBD-attributable costs and health care utilization were determined by taking the difference between the costs/ health care utilization accrued by an IBD case and their controls. Generalized linear modeling was used to evaluate trends in direct costs and Poisson regression for trends in health care utilization. The number of people with IBD in Manitoba increased from 6,323 to 7,603 between 2005 and 2015. The total per capita annual costs attributable to IBD rose from $3,354 in 2005 to $7,801 in 2015, primarily driven by an increase in per capita annual anti-tumor necrosis factor costs, which rose from $181 in 2005 to $5,270 in 2015. There was a significant decline in inpatient costs for Crohn’s disease ($99 ± 25/yr. P < 0.0001), but not for ulcerative colitis ($8 increase ±$18/yr, P = 0.63).

We concluded that the direct health care costs attributable to IBD have more than doubled over the 10 years between 2005 and 2015, driven mostly by increasing expenditures on biological medications. IBD-attributable hospitalization costs have declined modestly over time for persons with Crohn’s disease, although no change was seen for patients with ulcerative colitis.​

El-Matary W, Leung S, Tennakoon A, Benchimol EI, Bernstein CN, Targownik LE. Trends of utilization of tumor necrosis factor antagonists in children with inflammatory bowel disease: A Canadian population-based study. Inflammatory Bowel Diseases 2020; 26:134-8.


Population-based studies examining the prevalence of anti-tumor necrosis factor (anti-TNF) antagonist utilization in children and young adults with IBD are lacking. We aimed to describe the trend of anti-TNF utilization in pediatric IBD over time. Survival analyses were performed for all patients diagnosed with IBD before age 18 years in the province of Manitoba to determine the time from diagnosis to first anti-TNF prescription in different time eras (2005-2008, 2008-2012, 2012-2016). There were 291 persons diagnosed with IBD (157 with Crohn's disease and 134 with UC over the study period. The likelihood of being initiated on an anti-TNF by 1, 2, and 5 years postdiagnosis was 18.4%, 30.5%, and 42.6%, respectively. The proportion of persons aged <18 years utilizing anti-TNFs rose over time; in 2010, 13.0% of Crohn's disease and 4.9% of UC; by 2016, 60.0% of Crohn's disease and 25.5% of UC. For those diagnosed after 2012, 42.5% of Crohn's disease and 28.4% of UC patients had been prescribed an anti-TNF antagonist within 12 months of IBD diagnosis. Initiating an anti-TNF without prior exposure to an immunosuppressive agent increased over time (before 2008: 0%; 2008-2012: 18.2%; 2012-2016: 42.8%; P < 0.001). There was a significant reduction in median cumulative dose of corticosteroids in the year before anti-TNF initiation (2005-2008: 4360 mg; 2008-2012: 2010 mg; 2012-2016: 1395 mg prednisone equivalents; P < 0.001).

Over a period of 11 years, anti-TNFs are being used earlier in the course of pediatric IBD, with a parallel reduction in the cumulative corticosteroid dose.​

Siegel C, Bernstein CN. Risk Stratifying Patients with IBD – Identifying Patients at High- vs. Low-risk of Complications. Clinical Gastroenterology and Hepatology 2020, 18(6):1261-1267.


This editorial reviewed the available evidence to classify patients with IBD at either high risk or low risk for progressing to more aggressive disease or complicated outcomes.


Bernstein CN. Is antibiotic use a cause of IBD worldwide? Inflammatory Bowel Diseases 2020; 26: 448-449.


This editorial reviewed the evidence for antibiotics as a possible culprit in triggering IBD onset.


Stone J, Grover K, Bernstein CN. The use of capsule endoscopy for diagnosis of iron deficiency anemia: A retrospective analysis. Journal of Clinical Gastroenterology 2020; 54(5):452-458.


There was some ambiguity in the recent guidelines on the use of capsule endoscopy in cases of iron deficiency anemia (IDA). We aimed to examine the yield of capsule endoscopy in diagnosing the cause of IDA and to define clinical parameters that predict higher diagnostic yields. A total of 1351 individuals underwent capsule endoscopy in Winnipeg between 2005 and 2016. All studies were reported by 1 reading physician. Data included demographics and requested information on medication use, prior imaging studies, and hemoglobin and ferritin levels. In a total of 620 (46%) patients, capsule endoscopy was indicated for occult gastrointestinal bleeding or IDA. Positive findings on capsule endoscopy were separated into "definite" and "possible." Multinomial regression analysis was used to determine the variables correlated with definite capsule endoscopy findings. A survey analysis was then used to assess how the study results impacted further management. With regard to the 620 patients, the mean age was 62.9 years, mean hemoglobin level was 89 g/L, and median ferritin level was 9 μg/L. A total of 210 (33.9%) patients had positive findings (definite: 23%, possible: 10.8%). Vascular ectasias were the majority of definite findings (47.5%). Predictors of definite findings were age (relative risk ratio: 1.04; 95% confidence interval: 1.02-1.06) and male sex (relative risk ratio: 1.88; 95% confidence interval: 1.25-2.83). An overall 12.7% of positive studies required therapeutic intervention, with 65.8% undergoing further workup. We report a 33.9% positive yield, with 65.8% of patients undergoing further workup as a result of capsule endoscopy and 12.7% requiring therapeutic intervention. We conclude that capsule endoscopy plays an important role in the investigation of IDA and occult gastrointestinal bleeding and has important implications on further management.

Vagianos K, Shafer LA, Witges K, Targownik LE, Haviva C, Graff LA, Lix LM, Sexton KA, Sargent M, Bernstein CN.  Association between Change in Inflammatory Aspects of Diet and Change in IBD-related Inflammation and Symptoms over 1 Year: The Manitoba Living with IBD Study. Inflammatory Bowel Diseases 2020; in press.


We aimed to investigate: (1) the stability of inflammatory aspects of diet over one year among persons with Inflammatory Bowel Disease (IBD) and (2) the impact of change in diet on changes in inflammation and IBD symptoms over one year. Participants were recruited into the Manitoba Living with IBD Study and completed the Harvard Food Frequency Questionnaire (FFQ). The Dietary Inflammatory Index (DII) and the Empirical Dietary Inflammatory Index (EDII) were used to calculate the inflammatory potential of the diet. Inflammation was measured by fecal calprotectin (> 250 ug/g). Symptoms were measured by the IBD Symptom Inventory (IBDSI). All measures were obtained at baseline and one year. DII and EDII scores > 0 and < 0 reflect pro- and anti-inflammatory diet, respectively. Variance components analyses were used to describe diet stability. Associations between changes in diet and changes in active inflammation and symptoms were assessed using ordinal logistic regression and multilevel linear regression modelling. 135 participants (66% Crohn’s disease) were included. Approximately one-third of the variance in EDII (36%) and DII (33%) scores was explained by changes in diet over time. Each unit increase in the change in EDII (baseline to follow-up) was associated with a greater odds of fecal calprotectin indicating active inflammation (>250 ug/g; OR=3.1, 95% C.I. 1.02-9.93, p=0.04) and with a rise in IBDSI of 6.7 (95% C.I. 1.0-12.4, p=0.022) (theoretical IBDSI range: 0-81). There was no association between changes in DII and changes in fecal calprotectin or IBDSI.

We concluded that the EDII, but not the DII, may have utility to identify the inflammatory potential of diet. This inflammatory potential can contribute to inflammation and/or disease symptoms in persons with IBD.



Silvester JA, Comino I, Kelly CP, Sousa C, Duerksen DR on behalf of the DOGGIE BAG Study Group (CN Bernstein Study Group member). Most patients with celiac disease on gluten-free diets consume measurable amounts of gluten. Gastroenterology 2020; 158: 1497–1499.


Many patients with celiac disease trying to follow a gluten free diet have persistent villous atrophy and/or symptoms; however, it has not been proven whether this is related to gluten exposure. Our aim was to measure directly the frequency of gluten exposure in patients on a gluten free diet utilizing recently developed tests for gluten immunogenic peptides in food, urine and stool. The relationship among gluten immunogenic peptides detection, symptoms and persistent villous atrophy was also examined. Adults with biopsy-confirmed Crohn’s disease on a gluten free diet were recruited from a population-based inception cohort, prior to follow-up intestinal biopsy 24 months after Crohn’s disease diagnosis. During the 10 days immediately prior to biopsy, subjects collected multiple urine and stool samples. During the first 7 days, subjects also saved “doggie bags” containing ¼ portions of any cooked or processed food consumed. All 18 enrolled participants (12 female, age 21-70 years) completed the study. Gluten was detected in ≥1 sample from 12/18 (66%) participants despite all being on a “gluten free diet” [10 food (56%), 8 urine (44%), 4 stool (22%)]. Overall, gluten was detected in 25/318 (8%) of food, 30/519 (6%) of urine and 8/72 (11%) of stool samples. Nearly 50% of positive food samples contained >20 ppm gluten; 20% contained >100 ppm gluten. Median estimated gluten ingestion per exposure was 5.4 mg (range 0.2 mg to >80 mg). Although histology improved in all participants after 24 months of gluten free diet, only 6 (33%) had normal histology. There was no clear association between 10 day gluten exposure and current symptoms or villous atrophy. Direct measurements in food, urine and stool indicate that most participants (66%) with Crohn’s disease trying to follow a strictly gluten free diet consumed measurable gluten during the study period.

These novel data confirm the general concern that a completely gluten free diet is difficult to achieve even by highly motivated and well-informed patients. Less challenging and more feasible treatments are needed for this common condition.

Bernstein CN, Crocker E, Nugent Z, Virdi P, Singh H, Targownik LE. Gastroenterologist Consultation is Uncommon but Associated with Improved Care among IBD Patients Presenting to Emergency Departments in Winnipeg Hospitals. Journal of the Canadian Association of Gastroenterology 2020; in press.


We aimed to describe the patterns of care when persons with IBD present to the Emergency Department and post Emergency Department follow-up. We linked the University of Manitoba IBD Epidemiology Database with the Emergency Department Information System of the Winnipeg Regional Health Authority from 01/01/10 to 12/31/12. We then generated a list of all Emergency Department attendances by persons with IBD at 4 of 6 hospitals within the City of Winnipeg (2 academic and 2 community hospitals). The charts were reviewed by 2 investigators extracting data on testing, consulting and treatment undertaken in the Emergency Department as well as post discharge follow up. We focused on outcomes among those attending the Emergency Department but not admitted to hospital.  Of 1275 IBD patients with a first visit to the Emergency Department, 523 (41%) were for IBD-specific complaints. 327 (62.5%) were discharged from the Emergency Department without an in-hospital admission.  Nearly 80% had an identified gastrointestinal (GI) specialist (either gastroenterologist or GI surgeon) involved in their care. A gastroenterologist was consulted in the Emergency Department 20% of the time. Follow-up post Emergency Department with a gastroenterologist was only documented in 36%. For those who saw a gastroenterologist in the Emergency Department there was more likely to be a change in medications and follow-up arranged with a gastroenterologist. Emergency Department consultation with a gastroenterologist was the only predictor of seeing a gastroenterologist in follow-up post Emergency Department.


We concluded that ED gastroenterology consultation is more likely to effect IBD management change. When discharged from the Emergency Department gastroenterology follow-up should be arranged and documented.

Shen B, Kochhar G, Navaneethan U, Farraye FA, Schwartz DA, Iacucci M, Bernstein CN, Dryden G, Cross R, Bruining DH, Kobayashi T, Lukas M, Shergill A, Bortlik M, Nan L, Lukas M, Tang S-J, Kotze P, Kiran RP, Dulai PS, El-Hachem S, Coelho-Prabhu N, Thakkar S, Mao R, Chen G,González Suárez B, Gonzalez Lam, Silverberg MS, Sandborn WJ. Consensus statement on endoscopic therapy for Crohn's disease strictures: practical guidelines from the Global Interventional Inflammatory Bowel Disease Group. Lancet Gastroenterology and Hepatology 2020; 5(4):393-405.


Stricture formation is a common complication of Crohn’s disease. Stretching open the stricture by balloon dilation through an endoscope is widely used in the management of strictures. However, there are new techniques being used as well including endoscopic electroincision and stenting. This refers to using a heated knife through the endoscope and cutting open the stricture and then placing a stent or bridge across it to keep it open. There is an important need for the standardisation of endoscopic procedures and management strategies around the time of the endoscopy. A consensus group of experts from around the world was convened who reviewed the medical literature and combined with expert opinion based on clinical experience of the consensus group, this report provides guidance on all aspects of the principles and techniques for endoscopic procedures in the treatment  inflammatory bowel disease-associated strictures.


Schoenfeld R, Nguyen G, Bernstein CN. Integrated Care Models:  Optimizing adult ambulatory care in inflammatory bowel disease. Journal of Canadian Association of Gastroenterology 2020; 3: 44-53.


In this article we reviewed the literature on outpatient care models used to treat adults with IBD, and proposed approaches to improve quality of care and reduce costs. A comprehensive review of recent literature on PubMed, Scopus, and Google Scholar databases about care models used to treat IBD was performed. Key terms included “inflammatory bowel disease”, “organizational models”, “patient care team”, and “quality improvement”. Studies showed that an integrated care model decreases hospital admissions, IBD-related surgeries, and comorbidities of IBD, ultimately decreasing direct and indirect costs of IBD compared to a more traditional patient-physician model.  A gastroenterologist-led multidisciplinary team, involving comprehensive care by IBD nurses, a surgeon, psychologist, dietician, pharmacist, and other members as needed is recommended.


We concluded that a holistic approach to IBD care delivered by a multidisciplinary team with structured monitoring, active follow-up, patient education, and prompt access to care improves outcomes for IBD patients. More research is needed on the cost-effectiveness of integrated care models to demonstrate long-term value and secure funding for implementation. Future research should compare integrated models of care and assess patient and physician satisfaction in these models of delivering IBD care.


Murthy SK, Begum J, Benchimol EI, Kaplan GG, Targownik LE, Singh H, Bernstein CN, McCurdy JD, Taljaard. Introduction of anti-TNF therapy has not yielded expected declines in hospitalization and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study. Gut 2020; 69: 274-282.


We evaluated the effect of introduction of infliximab in Ontario on the population rates of major health events and direct costs in persons with IBD. We studied all adult patients with Crohn’s disease (CD) and ulcerative colitis (UC) living in Ontario, Canada between July 1, 1995 and March 31, 2012 using population-level health administrative data. Marketplace introduction of infliximab in CD did not have a significant immediate  or gradual impact on the rate of IBD-related hospitalizations, nor an immediate or gradual impact on the rate of intestinal resections. Marketplace introduction of infliximab in UC was not associated with an immediate effect but was associated with a gradual decrease in IBD-related hospitalization rates. There were no significant persistent effects of infliximab availability on colectomy rates among UC patients nor on the rates of non-IBD hospitalizations or other major abdomino-thoracic surgeries (control outcomes) among CD or UC patients. We concluded that robust market penetration of infliximab among CD patients has not resulted in a meaningful reduction in the population rates of IBD-related hospitalizations or intestinal resections. Despite the absence of UC-related colectomies there was a reduction in UC-related hospitalization rates. Since we know these drugs can have dramatic effects in a substantial number of patients we believe that the absence of an impact of infliximab on key outcomes likely relates to underuse of this agent in the target populations.​

Elias E, Targownik LE, Singh H, Bernstein CN. A population-based study of combination versus monotherapy of anti-TNF in persons with IBD. Inflammatory Bowel Diseases 2020; 26: 150-57.


Few data exist about the utilization of combination therapy (anti-tumor necrosis factor [anti-TNF] plus immunosuppressives) in clinical practice. We assessed the prevalence and predictors of combination therapy use vs anti-TNF monotherapy in IBD in the Canadian province of Manitoba. All 23 prescribers of anti-TNF medications for IBD in Manitoba facilitated chart review of their comprehensive lists of adult anti-TNF patients from 2005 to 2015. Subjects were stratified by year of first anti-TNF exposure. Patient, disease, and prescriber factors influencing combination therapy use were explored. A total of 774 patients met inclusion criteria. 71% had Crohn's disease, 28.3% had ulcerative colitis, and 0.6% had IBD unclassified; 45.3% received combination therapy, with no difference between Crohn's disease and ulcerative colitis. Crohn's disease subjects receiving combination therapy were more likely to have penetrating or perianal disease (56.9% vs 42.8%; P = 0.001) and less likely to have had previous IBD-related surgeries (36.2% vs 46.2%; P = 0.02). The median age at diagnosis and at anti-TNF initiation was lower among combination therapy users. Adalimumab (Humira) users were as likely as infliximab (Remicade or Inflectra) users to receive combination therapy but persisted with treatment for a shorter time. The proportion of new anti-TNF users receiving combination therapy did not change over time (P = 0.43). There was substantial variation in combination therapy use between prescribers (P = 0.002). The most frequently encountered reasons for avoiding combination therapy were previous intolerance or ineffectiveness of immunosuppressive monotherapy.

We concluded that use of combination therapy has remained unchanged over time despite the publication of high-quality data supporting its efficacy over anti-TNF monotherapy.

Jain A, Marrie RA, Shafer LA, Graff LA, Patten S, El-Gabalawy3R, Sareen J, Bolton J, Fisk J, Bernstein CN. Incidence of adverse psychiatric events during treatment of inflammatory bowel disease with biologic therapies: A systematic review. Crohn’s and Colitis 360 2020; Jan; 2(1).1-7


We conducted a systematic review and a fixed effects meta-analysis to determine if incident adverse psychiatric events including depression, anxiety, psychosis or suicide, were associated with biologic therapy in IBD. Six randomized controlled trials and a cohort study met criteria, reporting an incidence of adverse psychiatric events in 4,882 patients. The risk difference per 100 person-months of any adverse psychiatric events with a biologic medication was 0.01 (95% confidence interval = 0.00-0.02). There was insufficient evidence available in randomized controlled trials to conclude that biologic therapy in IBD is associated with an increased incidence of adverse psychiatric events. In conducting this analysis it is clear that researchers are not documenting adverse psychiatric events in clinical trials of biologicals. However, there is not signal that biological therapy in IBD causes adverse psychiatric events.


Hansen TM, Sabourin BC, Oketola B, Bernstein CN, Singh H, Targownik LE. Cannabis use in persons with inflammatory bowel disease and vulnerability to substance misuse. Inflammatory Bowel Diseases 2020; 26:1401-1406.

It is unknown whether cannabis users self-medicating their IBD symptoms are more likely to have comorbid mental health or personality risk factors associated with an increased potential for substance misuse compared with recreational cannabis users.

We surveyed individuals with IBD about their cannabis use, their mental health symptoms, and personality risk factors associated with substance misuse. We compared risk factors for substance misuse between individuals using cannabis to manage IBD symptoms and those using cannabis recreationally. Of 201 persons with IBD who completed the questionnaire, 108 reported lifetime cannabis use. Of those, a larger proportion of Crohn's disease patients used cannabis to manage IBD symptoms (53% [34/64] vs 28% [12/43]; P = 0.01). Individuals self-medicating with cannabis were more likely to use cannabis for coping reasons (P = 0.016) and demonstrated higher levels of impulsivity (P = 0.004) and depressive symptoms (P = 0.012) when compared with individuals using cannabis recreationally. Logistic regression revealed that cannabis was 4.1 times (P = 0.05) and 3.7 times (P = 0.05) more likely to be used for IBD symptoms by smokers and individuals with moderate-severe depressive symptoms, respectively. Individuals high in impulsivity were 4.1 times more likely to use cannabis for their IBD symptoms than those low in impulsivity (P = 0.005).

We concluded that persons with IBD self-medicating with cannabis have characteristics associated with increased vulnerability to substance misuse when compared with those using cannabis recreationally. Screening for mental health comorbidities and vulnerability to substance misuse should be undertaken if cannabis is to be used to treat IBD symptoms.

Reinhorn I, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM, Hitchon C, Marrie RA. Social Phobia in Immune-Mediated Inflammatory Diseases. Journal of Psychosomatic Research 2020; Jan;128:109890.

Immune-mediated inflammatory diseases such as multiple sclerosis (MS), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are associated with a high prevalence of psychiatric comorbidity but little is known about the prevalence of social phobia in Immune-mediated inflammatory diseases, or the factors associated with social phobia. We aimed to determine the prevalence of social phobia in MS, IBD and RA, and the factors associated with social phobia in these immune-mediated inflammatory diseases. We obtained data from the enrollment visit of a cohort study in immune-mediated inflammatory diseases of whom 654 participants were eligible for this analysis (MS: 254, IBD: 247, RA: 153). Each participant underwent a semi-structured psychiatric interview which identified depression and anxiety disorders including social phobia (lifetime and current), an assessment of disease activity, and reported sociodemographic information. Overall, 12.8% of participants had a lifetime diagnosis of social phobia (MS: 10.2%, IBD: 13.0%, RA: 17.0%). Social phobia was associated with younger age (OR 0.98; 0.97-1.00), having a high school education or less (OR 1.78; 1.08-2.91), comorbid major depressive disorder (OR 2.79; 1.63-4.78) and comorbid generalized anxiety disorder (OR 2.56; 1.30-5.05). Persons with RA had increased odds of having social phobia as compared to persons with MS (OR 2.26; 1.14-4.48) but not IBD.

We concluded that persons with immune-mediated inflammatory diseases have a relatively high lifetime prevalence of social phobia, exceeding that reported for the Canadian general population. Strategies aimed at early detection, and effective clinical management of social phobia in immune-mediated inflammatory diseases are warranted.


Blaney C, Sommer J, El Gabalawy R, Bernstein CN, Walld R, Hitchon CA, Bolton J, Sareen J, Patten SB, Singer A, Lix LM, Katz A, Fisk JD, Marrie RA.  Incidence and Temporal Trends of Co-Occurring Personality Disorder Diagnoses in Immune-Mediated Inflammatory Diseases. Epidemiology and Psychiatric Sciences 2020; in press.

Although immune-mediated inflammatory diseases are associated with multiple mental health conditions, there is a paucity of literature assessing personality disorders in these populations. We aimed to estimate and compare the incidence of any personality disorders in IMID and matched cohorts over time, and identify sociodemographic characteristics associated with the incidence of personality disorders. We used population-based administrative data from Manitoba, Canada to identify persons with incident inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) using validated case definitions. Unaffected controls were matched 5:1 on sex, age and region of residence. personality disorders were identified using hospitalization or physician claims. We used unadjusted and covariate-adjusted negative binomial regression to compare the incidence of personality disorders between the immune-mediated inflammatory diseases and matched cohorts. We identified 19 572 incident cases of immune-mediated inflammatory diseases (IBD n = 6,119, MS n = 3,514, RA n = 10 206) and 97 727 matches overall. After covariate adjustment, the immune-mediated inflammatory diseases cohort had an increased incidence of personality disorders (incidence rate ratio [IRR] 1.72; 95%CI: 1.47-2.01) as compared to the matched cohort, which remained consistent over time. The incidence of personality disorders was similarly elevated in IBD (IRR 2.19; 95%CI: 1.69-2.84), MS (IRR 1.79; 95%CI: 1.29-2.50) and RA (IRR 1.61; 95%CI: 1.29-1.99). Lower socioeconomic status and urban residence were associated with an increased incidence of personality disorders, whereas mid to older adulthood (age 45-64) was associated with overall decreased incidence. In a restricted sample with 5 years of data before and after immune-mediated inflammatory diseases diagnosis, the incidence of personality disorders was also elevated before immune-mediated inflammatory diseases diagnosis among all immune-mediated inflammatory diseases groups relative to matched controls.

We concluded that immune-mediated inflammatory diseases are associated with an increased incidence of personality disorders both before and after an immune-mediated inflammatory diseases diagnosis. These results support the relevance of shared risk factors in the co-occurrence of personality disorders and immune-mediated inflammatory disease conditions.


Kornelsen J, Wilson A, Witges K, Labus J, Mayer EA, Bernstein CN. Brain resting state network alterations associated with Crohn’s disease. Frontiers in Neurology 2020; Feb 18;11:48.


IBD is a chronic disease that is associated with aspects of brain anatomy and activity. In this preliminary MRI study, we investigated differences in brain structure and in functional connectivity of brain regions in 35 participants with Crohn's disease and 21 healthy controls. Voxel-based morphometry analysis was performed to contrast Crohn’s disease and healthy controls structural images. Region of interest analyses were run to assess functional connectivity for resting-state network nodes. Independent component analysis identified whole brain differences in functional connectivity associated with resting-state networks. Though no structural differences were found, region of interest analyses showed increased functional connectivity between the frontoparietal network and salience network, and decreased functional connectivity between nodes of the default mode network. Independent component analysis results revealed changes involving cerebellar, visual, and salience network components. Differences in functional connectivity associated with sex were observed for both region of interest analysis and Independent component analysis.

Taken together, these changes are consistent with an influence of Crohn's disease on the brain and serve to direct future research hypotheses.


Levis B, Benedetti A, Ioannidis J, Sun Y, Negeri Z, He C, Wu Y, Krishnan A, Bhandari PM, Neupane D, Imran M, Rice D, Riehm KE, Saadat N, Azar M, Boruff J, Cuijpers P, Gilbody P, Kloda LA, McMillan D, Patten S, Shrier I, Ziegelstein I, Alamri S, Amtmann D, Ayalon L, Baradaran HR, Beraldi A, Bernstein CN, Bhana A, Bombardier CH, Carter G, Chagas M, Chibanda D, Clover K, Conwell Y, Diez-Quevedo C, Fann JR, Dr. Felix Fischer, Gholizadeh L, Gibson L, Green E, Greeno C, Hall B, Haroz E, Ismail K, Jette N, Khamseh ME, Kwan Y, Lara MA, Liu SI, Loureiro S, Löwe B, Marrie RA, Marsh L, McGuire A, Muramatsu K, Navarrete L, Osório FL, Petersen I, Picardi A, Pugh S, Quinn T, Rooney AG, Shinn E, Sidebottom A, Spangenberg L, Tan PL, Taylor-Rowan M, Turner A, van weert H, Vöhringer P, Wagner LI, White J, Winkley K, Thombs B. Patient Health Questionnaire-9 scores do not accurately estimate depression prevalence: individual participant data meta-analysis. Journal of Clinical Epidemiology 2020; in press.


Depression symptom questionnaires are not for diagnostic classification. Patient Health Questionnaire-9 (PHQ-9) scores greater than or equal to 10 are nonetheless often used to estimate depression prevalence. We compared PHQ-9 greater than or equal to 10 prevalence to Structured Clinical Interview for DSM (SCID) major depression prevalence and assessed whether an alternative PHQ-9 cutoff could more accurately estimate prevalence. This study was a meta-analysis of datasets comparing PHQ-9 scores to SCID major depression status. 9,242 participants (1,389 SCID major depression cases) from 44 primary studies were included. Pooled PHQ-9 ≥ 10 prevalence was 24.6% (95% CI: 20.8%, 28.9%); pooled SCID major depression prevalence was 12.1% (95% CI: 9.6%, 15.2%); pooled difference was 11.9% (95% CI: 9.3%, 14.6%). Mean study-level PHQ-9 greater than or equal to 10 to SCID-based prevalence ratio was 2.5 times. PHQ-9 greater than or equal to 14 and the PHQ-9 diagnostic algorithm provided prevalence closest to SCID major depression prevalence, but study-level prevalence differed from SCID-based prevalence by an average absolute difference of 4.8% for PHQ-9 greater than or equal to 14 (95% prediction interval: -13.6%, 14.5%) and 5.6 % for the PHQ-9 diagnostic algorithm (95% prediction interval: -16.4%, 15.0%).


We concluded that PHQ-9 greater than or equal to 10 substantially overestimates depression prevalence. There was too much heterogeneity to correct statistically in individual studies.


Stone J, Shafer LA, Graff LA, Lix L, Witges K, Targownik LE, Haviva C, Sexton K, Bernstein CN. Utility of the MARS-5 in assessing medication adherence in IBD. Inflammatory Bowel Diseases 2020; in press.

We aimed to validate the Medication Adherence Report Scale-5 (MARS-5) as a tool for assessing medication adherence in inflammatory bowel disease (IBD), and determine predictors of medication adherence.  One-hundred and twelve (n=112) adults with confirmed IBD, participating in the longitudinal Manitoba Living with IBD Study were eligible. Demographics, IBD type, surgeries, disease activity (using Inflammatory Bowel Disease Symptom Inventory and fecal calprotectin levels), perceived stress and medication use were collected biweekly through online surveys. MARS-5 scores were obtained at baseline and at 1 year. Correlation between medication monitoring data and MARS-5 scores was performed and the optimal MAR-5 cut-off point for adherence assessment determined. Predictors of medication adherence were assessed at both ≥90% and ≥80%.  Participants were predominantly female (71.4%); mean age was 42.9 years (SD 12.8), and the majority (67.9%) had Crohn’s disease.  Almost half (46.4%) were taking more than one IBD medication, with thiopurines (41.9%) and biologics (36.6%) the most common. Only 17.9% (n=20) were non-adherent at <90% level; of those, 90% (n=18) were using oral medications.  The MARS-5 was significantly associated with adherence based on medication monitoring data at baseline (r=0.48) and week 52 (r=0.57). Sensitivity and specificity for adherence ≥80% and ≥90% was maximized at MARS-5 scores of  greater than 22 and greater than 23, respectively. Having Crohn’s disease (Odds ratio 4.62; 95% CI 1.36-15.7) was the only significant predictor of adherence.


We concluded that MARS-5 is a useful measure to evaluate adherence in an IBD population. In this highly adherent sample, disease type (Crohn’s disease) was the only predictor of medication adherence.

Publications // from the Manitoba IBD Epidemiology Database

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