Epidemiology Publications // 2021

Kapoor K, Eissa N, Tshikudi D, Bernstein CN, Ghia JE. Impact of intrarectal chromofungin treatment on dendritic cells-related markers in different immune compartments in colonic inflammatory conditions. World Journal of Gastroenterology 2021; in press.


Chromofungin (chromogranin-A 47-66) is a chromogranin-A derived peptide with anti-inflammatory and anti-microbial properties. Ulcerative colitis (UC) is characterized by a colonic decrease of chromogranin-A 47-66 and a dysregulation of dendritic CD11c+cells. We aimed to investigate the association between CHR treatment and dendritic cells (DCs)-related markers in different immune compartments in colitis. A model of acute UC-like colitis using dextran sulphate sodium (DSS) was used in addition to biopsies collected from UC patients. Intrarectal chromogranin-A 47-66 treatment reduced the severity of DSS-induced colitis and was associated with a significant decrease in the expression of CD11c, CD40, CD80, CD86 and interleukin (IL)-12p40 in the inflamed colonic mucosa and CD11c, CD80, CD86 IL-6 and IL-12p40 within the mesenteric lymph nodes and the spleen. Furthermore, chromogranin-A 47-66 treatment decreased CD80 and CD86 expression markers of splenic CD11c+cells and decreased NF-κB expression in the colon and of splenic CD11c+cells. In vitro, chromogranin-A 47-66 decreased CD40, CD80, CD86 IL-6 and IL-12p40 expression in naïve bone marrow-derived CD11c+DCs stimulated with lipopolysaccharide. Pharmacological studies demonstrated an impact of chromogranin-A 47-66 on the NF-κB pathway. In patients with active UC, chromogranin-A 47-66 level was reduced and showed a negative linear relationship with CD11c and CD86.

We concluded chromogranin-A 47-66 has protective properties against intestinal inflammation via the regulation of DC-related markers and CD11c+cells. Chromogranin-A 47-66 could be a potential therapy of UC.

Kornelsen J, Witges K, Labus J, Mayer EA, Bernstein CN. Brain structure and function changes in ulcerative colitis. Neuroimage Reports 2021: in press.

As the importance of the brain-gut axis in the pathobiology of inflammatory bowel disease continues to evolve, a greater understanding of brain structure and functional connectivity in diseases such as ulcerative colitis are necessary. In this magnetic resonance imaging (MRI) study, we investigated differences in brain structure and in functional connectivity of brain regions in 76 participants with ulcerative colitis and 74 healthy controls. Voxel based morphometry analysis indicate greater grey matter volume in multiple brain regions in ulcerative colitis as compared to healthy controls. Differences in functional connectivity between groups were identified in the cerebellar, default mode, visual, and dorsal attention networks. functional connectivity differed by sex for the visual and dorsal attention networks. These differences warrant further investigation to determine if they help direct the evolution of ulcerative colitis or if they evolve in response to the presence of ulcerative colitis. These differences provide further evidence that the brain-gut axis is altered in ulcerative colitis.

Coward S, Windsor JW, Kuenzig ME, Bitton A, Bernstein CN, Jones JL, Khanna R, Lee K, Murthy SK, Targownik L, Benchimol E, Huang JG, Mukhtar MS, Tandon P, Kaplan GG. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Epidemiology-The Trends of Disease Over Time. Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S20-S26.


At the beginning of the COVID-19 pandemic, there were many unknowns: transmission vectors of the virus, appropriate intervention strategies and if being immunocompromised due to IBD, for example, or medications put a person at increased risk for severe COVID-19. Imposing and relaxing of public health restrictions at different times and in different regions in Canada led to different epidemiologies of the virus in different provinces and territories. In order to understand the waxing and waning of waves of the COVID-19 pandemic, it is necessary to understand the effective reproductive number (  ) and the countervailing forces that exert upward or downward pressure on the spread of the virus at a given point in time. As many regions in Canada deal with a third wave, the primary forces affecting the   of severe acute respiratory syndrome coronavirus 2 are variants of concern and the increasing vaccinations of Canadians leading to increased population-level immunity. Fortunately, for the IBD population, current research suggests that those with IBD are not at increased risk of contracting COVID-19, nor of having a more severe disease course when compared to the general population.

Benchimol EI, Carroll MW, Geist R, Griffiths AM, Huang JG, Mack DR, Bernstein CN, Bitton A, Jones JL, Kaplan GG, Kuenzig ME, Lee K, Mukhtar MS, Murthy SK, Tandon P, Targownik LE, Windsor JW, Seow CH.  Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Children and Expectant Mothers With Inflammatory Bowel Disease.  Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S27-S33.

Canada has among the highest rates of IBD in the world, and the number of people living with these disorders is growing rapidly. This has placed a high burden on the health care system and on the Canadian economy-a burden that is only expected to grow in the future. It is important to understand IBD and its impact on Canadian society in order to appropriately plan for health care expenditures, reduce the burden on patients and their families, and improve the quality of life for those afflicted with IBD. In Canada, there is a lack of public awareness of the impact of Crohn's disease and ulcerative colitis. Raising awareness is crucial to reducing the social stigma that is common with these diseases and to help individuals maximize their overall quality of life. A better public understanding of IBD can also help to raise and direct funds for research, which could lead to improved treatments and, ultimately, to a cure. This report from Canadian clinicians and researchers to Crohn's and Colitis Canada makes recommendations aimed at the public, policy-makers, scientific funding agencies, charitable foundations and patients regarding future directions for advocacy efforts and areas to emphasize for research spending. The report also identifies gaps in knowledge in the fields of clinical, health systems and epidemiological research.

Bernstein CN, Singh H, Murthy SK, Nguyen GC, Benchimol EI, Bitton A, Kuenzig ME, Huang JG, Jones JL, Lee K, Targownik LE, Windsor JW, Mukhtar MS, Tandon P, Kaplan GG. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Seniors With IBD.  Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S34-S39.

The risk of hospitalization and death from COVID-19 increases with age. The extreme elderly have been particularly vulnerable, with those above the age of 80 having a case-fatality rate as high as 15%. Aging of the immune system can lead to impaired inflammatory responses where eradication of an organism such as SARS-CoV2 is inadequate but is exaggerated in such a way as to enhance pneumonia and acute respiratory distress syndrome. Frailty and comorbidity are both more common in the elderly, and these can enhance the morbidity and mortality from COVID-19. Studies from Northern California and Italy suggest that elderly persons with IBD were more likely to acquire SARS-CoV-2 infection than youths with IBD. While the specific impact of age-related comorbidity is less well established among people with IBD who acquire COVID-19, data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) database reported that having two or more chronic illnesses was independently associated with developing severe COVID-19 among people with IBD. Despite having exaggerated auto-inflammatory responses, people with IBD do not appear to have an overall increased risk of developing severe COVID-19 than the general population. However, whether seniors with IBD do worse once they acquire COVID-19 compared with seniors without IBD is not known. The advent of telehealth care has posed an information technology challenge for many seniors with and without IBD. Most persons with IBD have expressed satisfaction with virtual IBD health care (phone or video-based visits). While the elderly may have less robust immune responses to vaccinations, learning from experiences with other vaccination programs, especially influenza, have shown that vaccinating seniors decreases both morbidity and mortality and, in turn, healthcare resources.

Targownik LE, Bernstein CN, Lakatos PL, Murthy SK, Benchimol EI, Bitton A, Huang JG, Kuenzig ME, Jones JL, Kaplan GG, Lee K, Mukhtar MS, Tandon P, Windsor JW, Panaccione R. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Risk Factors and Medications. Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S40-S45.


IBD is a disease that results from dysregulation of the immune system and frequently requires medications that can affect the immune response to infections; therefore, it was imperative to quickly understand the risk of COVID-19 infection on persons living with IBD and how that risk may be increased by commonly used IBD medications. The IBD research community in Canada and beyond quickly established collaborative efforts to better understand the specific risk posed by COVID-19 on persons with IBD. We learned that IBD itself was not a risk factor for death or serious complications of COVID-19, and that most commonly used drug classes (with the notable exception of corticosteroids) do not increase the risk of COVID-19-related adverse outcomes. The risk factors for serious complications and death from COVID-19 appear to be similar to those identified in the wider population; those being advanced age, having pre-existing heart or lung disease, and smoking. We recommend that persons with IBD do not alter their course of therapy to avoid complications of COVID-19, though the indiscriminate use of corticosteroids should be avoided. Persons with IBD should follow the same public health recommendations as the general population to reduce their personal risk of acquiring COVID-19.

Graff LA, Fowler S, Jones JL, Benchimol EI, Bitton A, Huang JG, Kuenzig ME, Kaplan GG, Lee K, Mukhtar MS, Tandon P, Targownik LE, Windsor JW, Bernstein CN. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Mental Health and Quality of Life.  Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S46-S53.


There has been a dramatic rise in mental health difficulties during the coronavirus COVID-19 pandemic. While young adults have the lowest risk of hospitalization and mortality due to COVID-19, they have been identified as being at highest risk of detrimental mental health outcomes during the pandemic, along with women, those with lower socioeconomic status and those with pre-existing mental health conditions. Somewhat of a crisis in mental health has emerged across the general population through the evolution of the pandemic. A national Canadian survey identified a quadrupling of those experiencing pervasive elevated anxiety symptoms early in the pandemic compared to pre-pandemic levels, and a doubling of those with pervasive elevated depressive symptoms. Independent of the pandemic, persons with IBD can face multiple challenges related to their disease, which can result in a significant psychosocial burden and psychologic distress. Anxiety and depression have been found to be more prevalent in persons with IBD. Many potential factors contribute to the increased psychologic distress and negative impacts on mental health of the COVID-19 pandemic on persons with IBD. These include the fears of contracting COVID-19 or infecting other people. Many believe that IBD or its treatments predispose them to an increased risk of COVID-19 or a worse outcome if acquired. Concerns about access to health care add to mental distress. People with IBD generally report lower quality of life compared to community controls. Psychologic interventions, in addition to adequate disease control, have been shown to improve health-related quality of life. Uncertainty is another factor associated with reduced health-related quality of life. Most studies suggest that persons with IBD have suffered quality of life impairment during the pandemic in comparison to the pre-pandemic period. Uncertainties brought on by the pandemic are important contributors for some of the reduction in quality of life.

Kaplan GG, Windsor JW, Crain J, Barrett L, Bernstein CN, Bitton A, Chauhan U, Coward S, Fowler S, Ghia JE, Gibson DL, Griffiths AM, Jones JL, Khanna R, Kuenzig ME, Lakatos PL, Lee K, Mack DR, Marshall JK, Mawani M, Murthy SK, Panaccione R, Seow CH, Targownik LE, Zelinsky S, Benchimol EI. Crohn's and Colitis Canada's 2021 Impact of COVID-19 & Inflammatory Bowel Disease in Canada: A Knowledge Translation Strategy.  Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S10-S19.


The prevalence of IBD, Crohn's disease and ulcerative colitis, in Canada, is over 0.75% in 2021. Many individuals with IBD are immunocompromised. Consequently, the World Health Organization's declaration of a global pandemic uniquely impacted those with IBD. Crohn's and Colitis Canada (CCC) formed the COVID-19 and IBD Taskforce to provide evidence-based guidance during the pandemic to individuals with IBD and their families. The Taskforce met regularly through the course of the pandemic, synthesizing available information on the impact of COVID-19 on IBD. At first, the information was extrapolated from expert consensus guidelines, but eventually, recommendations were adapted for an international registry of worldwide cases of COVID-19 in people with IBD. The task force launched a knowledge translation initiative consisting of a webinar series and online resources to communicate information directly to the IBD community. Taskforce recommendations were posted to CCC's website and included guidance such as risk stratification, management of immunosuppressant medications, physical distancing, and mental health. A weekly webinar series communicated critical information directly to the IBD community. During the pandemic, traffic to CCC's website increased with 484,755 unique views of the COVID-19 webpages and 126,187 views of the 23 webinars, including their video clips. CCC's COVID-19 and IBD Taskforce provided critical guidance to the IBD community as the pandemic emerged, the nation underwent a lockdown, the economy reopened, and the second wave ensued. By integrating public health guidance through the unique prism of a vulnerable population, CCC's knowledge translation platform informed and protected the IBD community.

Murthy SK, Kuenzig ME, Windsor JW, Ghia JE, Griffiths AM, Panaccione R, Seow CH, Benchimol EI, Bernstein CN, Bitton A, Huang JG, Jones JL, Lee K, Kaplan GG, Mukhtar MS, Tandon P, Targownik LE Gibson D. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: COVID-19 Vaccines-Biology, Current Evidence and Recommendations. Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S54-S60.


The COVID-19 pandemic has ushered a globally focused vaccine development program that produced multiple successful vaccines within a year. Four SARS-CoV-2 vaccines have been approved for use in Canada, using two different technologies, all of which have shown excellent efficacy in reducing the rate of symptomatic COVID-19 infection and 100% efficacy in preventing death from COVID-19. People with IBD, like many others with immune-mediated chronic diseases, were excluded from the pivotal trials of these vaccines, leading to early hesitancy by regulatory bodies to endorse administering the vaccines to these groups. However, recent data has shown that the adverse event rate to SARS-CoV-2 vaccine among people with IBD is similar to the general population. Early data have further shown that people with IBD are capable of mounting a robust immune response to SARS-CoV-2 vaccines, particularly following a second dose, whereas the response to the first dose is blunted in those receiving anti-TNF therapy or conventional immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate). Based on these data and evidence from previous vaccine programs among people with IBD, multiple national and international expert panels have recommended that individuals with IBD receive complete vaccination against SARS-CoV-2 as soon as possible.

Jones JL, Benchimol EI, Bernstein CN, Huang JG, Marshall JK, Mukhtar MS, Murthy SK, Nguyen GC, Kaplan GG, Kuenzig ME, Tandon P, Targownik LE, Windsor JW, Bitton A. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Health Care Delivery During the Pandemic and the Future Model of Inflammatory Bowel Disease Care. Journal of the Canadian Association of Gastroenterology 2021 Oct 26;4(Suppl 2): S61-S67.


The SARS-CoV-2 pandemic has had a profound impact on IBD health care delivery. The implementation of necessary public health restrictions has restricted access to medications, procedures and surgeries throughout the pandemic, catalyzing widespread change in how IBD care is delivered. Rapid large-scale implementation of virtual care modalities has been shown to be feasible and acceptable for the majority of individuals with IBD and health care providers. The SARS-CoV-2 pandemic has exacerbated pre-existing barriers to accessing high-quality, multidisciplinary IBD care that addresses health care needs holistically. Continued implementation and evaluation of both synchronous and asynchronous eHealthcare modalities are required now and in the future in order to determine how best to incorporate these modalities into patient-centred, collaborative care models. Resources must be dedicated to studies that evaluate the feasibility, acceptability and effectiveness of eHealth-enhanced models of IBD care to improve efficiency and cost-effectiveness, while increasing quality of life for persons living with IBD. Crohn's and Colitis Canada will continue to play a major leadership role in advocating for the health care delivery models that improve the quality of life for persons living with IBD.

Tremlett H, Zhu F, Arnold D, Bar-Or A, Bernstein CN, Forbes JD, Graham M, Hart J, Knox NC, Marrie RA, Mirza A, O’Mahony J, Van Domselaar G, Yeh EA, Zhao Y, Banwell B, Waubant E, and the US Network of Pediatric MS Centers and the Canadian Paediatric Demyelinating Disease Network. The gut microbiota in pediatric multiple sclerosis and demyelinating syndromes. Annals of Clinical and Translational Neurology 2021; 8(12):2252-2269.


This study examined the gut microbiota in individuals with and without pediatric-onset multiple sclerosis (MS). Stool samples were collected across the Canadian Pediatric Demyelinating Disease Network and banked at the University of Manitoba IBD Clinical and Research Centre Biobank. Microbiome analysis was undertaken at the National Microbiology Laboratory, Winnipeg, Canada. Study participants were 21 years old or younger, with MS (disease-modifying drug [DMD] exposed and naïve) or monophasic acquired demyelinating syndrome [monoADS] (symptom onset prior to age 18 years), and unaffected controls. All were at least 30 days without antibiotics or corticosteroids. V4 region 16S RNA gene-derived amplicon sequence variants (Illumina MiSeq) were assessed using negative binomial regression and network analyses; rate ratios were age- and sex-adjusted (aRR). There were 32 MS, and 41 monoADS and 36 control participants Although microbiota diversity (alpha, beta) did not differ between participants (p > 0.1), taxa-level and gut community networks did. MS (vs. monoADS) exhibited > fourfold higher relative abundance of the superphylum Patescibacteria (aRR = 4.2;95%CI:1.6-11.2, p = 0.004, Q = 0.01), and lower abundances of short-chain fatty acid (SCFA)-producing Lachnospiraceae (Anaerosporobacter) and Ruminococcaceae (p, Q < 0.05). DMD-naïve MS cases were depleted for Clostridiales vadin-BB60 (unnamed species) versus either DMD-exposed, controls (p, Q < 0.01), or monoADS (p = 0.001, Q = 0.06) and exhibited altered community connectedness (p < 10-9 Kruskal-Wallis), with SCFA-producing taxa underrepresented. Consistent taxa-level findings from an independent US Network of Pediatric MS Centers case/control (n = 51/42) cohort included >eightfold higher abundance for Candidatus Stoquefichus and Tyzzerella (aRR = 8.8-12.8, p < 0.05) in MS cases and 72%-80% lower abundance of SCFA-producing Ruminococcaceae-NK4A214 (aRR = 0.38-0.2, p ≤ 0.01). 

We concluded that the gut microbiota community structure, function and connectivity, and not just individual taxa, are of likely importance in MS.

Harel D, Levis B, Sun Y, Fischer F, Ioannidis JPA, Cuijpers P, Patten SB, Ziegelstein RC, Markham S, Benedetti A, Thombs BD, and the DEPRESsion Screening Data DEPRESSD) PHQ Collaboration (member of group authorship). External Validation of a Shortened Screening Tool Using Individual Participant Data Meta-Analysis: a Case Study of the Patient Health Questionnaire-Dep-4. Methods 2021; Nov 12:S1046-2023(21)00262-0.


Shortened versions of self-reported questionnaires may be used to reduce respondent burden. When shortened screening tools are used, it is desirable to maintain equivalent diagnostic accuracy to full-length forms. This manuscript presents a case study that illustrates how external data and individual participant data meta-analysis can be used to assess the equivalence in diagnostic accuracy between a shortened and full-length form. This case study compares the Patient Health Questionnaire-9 (PHQ-9) and a 4-item shortened version (PHQ-Dep-4) that was previously developed using optimal test assembly methods. Using a large database of 75 primary studies (34,698 participants, 3,392 major depression cases), we evaluated whether the PHQ-Dep-4 cutoff of ≥ 4 maintained equivalent diagnostic accuracy to a PHQ-9 cutoff of ≥ 10. Using this external validation dataset, a PHQ-Dep-4 cutoff of ≥ 4 maximized the sum of sensitivity and specificity. While equivalence with a PHQ-9 cutoff of ≥ 10 was not established, we found the sensitivity of the PHQ-Dep-4 to be non-inferior to that of the PHQ-9, and the specificity of the PHQ-Dep-4 to be marginally smaller than the PHQ-9.

Pratt M, Forbes JD, Knox NC, Bernstein CN, Van Domselaar G. Microbiome-mediated immune signaling in inflammatory bowel disease and colorectal cancer: support from meta-omics data. Frontiers in Cell and Developmental Biology 2021; Nov 16;9:716604.


Chronic intestinal inflammation and microbial dysbiosis are hallmarks of colorectal cancer and IBD. However, the mechanistic relationship between gut dysbiosis and disease has not yet been fully characterized. Although the "trigger" of intestinal inflammation remains unknown, a wealth of evidence supports the role of the gut microbiome as a mutualistic pseudo-organ that significantly influences intestinal homeostasis and is capable of regulating host immunity. In recent years, culture-independent methods for assessing microbial communities as a whole (termed meta-omics) have grown beyond taxonomic identification and genome characterization (metagenomics) into new fields of research that collectively expand our knowledge of microbiomes. Metatranscriptomics, metaproteomics, and metabolomics are meta-omics techniques that aim to describe and quantify the functional activity of the gut microbiome. Uncovering microbial metabolic contributions in the context of IBD and colorectal cancer using these approaches provides insight into how the metabolic microenvironment of the GI tract shapes microbial community structure and how the microbiome, in turn, influences the surrounding ecosystem. Immunological studies in germ-free and wild-type mice have described several host-microbiome interactions that may play a role in autoinflammation. Chronic colitis is a precursor to colorectal cancer, and changes in the gut microbiome may be an important link triggering the neoplastic process in chronic colitis. In this review, we describe several microbiome-mediated mechanisms of host immune signaling, such as short-chain fatty acid (SCFA) and bile acid metabolism, inflammasome activation, and cytokine regulation in the context of IBD and colorectal cancer, and discuss the supporting role for these mechanisms by meta-omics data.

Negeri ZF, Levis BF, Sun Y, Chen HE, Krishnan A, Wu Y, Bandhari PM, Neupane D, Brehaut E, Benedett A, Thombs BD, and the  Depression Screening Data (DEPRESSD) PHQ Group (member of group authorship). Accuracy of the Patient Health Questionnaire-9 for screening to detect major depression: updated systematic review and individual participant data meta-analysis. BMJ 2021 Oct 5;375:n2183.

The objective of this study was to determine the accuracy of the Patient Health Questionnaire-9 (PHQ-9), the most commonly used depression screening tool in general practice, for detecting major depression overall and by study or participant subgroups. The study design was a systematic review and individual participant data meta-analysis. Data was available from 44 503 total participants (27 146 additional from the original update) were obtained from 100 of 127 eligible studies (42 additional studies; 79% eligible studies; 86% eligible participants). Among studies with a semistructured interview reference standard, pooled PHQ-9 sensitivity and specificity (95% confidence interval) at the standard cut-off value of ≥10, which maximized combined sensitivity and specificity, were 0.85 (0.79 to 0.89) and 0.85 (0.82 to 0.87), respectively.  We concluded that researchers and clinicians could use results to determine outcomes, such as total number of positive screens and false positive screens, at different PHQ-9 cut-off values for different clinical settings using the knowledge translation tool at www.depressionscreening100.com/phq.

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 2021; 4: 57-64.


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.



Carney H, Marrie RA, Bolton JM, Patten SB, Graff LA, Bernstein CN, Kowalec K. Prevalence and Risk Factors of Substance Use Disorder in Inflammatory Bowel Disease. Inflammatory Bowel Diseases 2021; 27: 58–64.

Substance use disorders impose a substantial individual and societal burden; however, the prevalence and associated factors in persons with inflammatory bowel disease (IBD) are largely unknown. We evaluated the prevalence and risk factors of substance use disorders in an IBD cohort. Inflammatory bowel disease participants (n = 247) were recruited via hospital- and community-based gastroenterology clinics, a population-based IBD research registry, and primary care providers as part of a larger cohort study of psychiatric comorbidity in immune-mediated inflammatory diseases. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV was administered to participants to identify lifetime substance use disorders, anxiety disorders, and major depressive disorders. Additional questionnaires regarding participants' sociodemographic and clinical characteristics were also completed. We examined demographic and clinical factors associated with lifetime substance use disorders using unadjusted and adjusted logistic regression modeling. Forty-one (16.6%) IBD participants met the criteria for a lifetime diagnosis of a substance use disorder. Factors associated with elevated odds of substance use disorders were ever smoking (adjusted odds ratio [aOR], 2.96; 95% confidence interval [CI], 1.17-7.50), male sex (aOR, 2.44; 95% CI, 1.11-5.36), lifetime anxiety disorder (aOR, 2.41; 95% CI, 1.08-5.37), and higher pain impact (aOR, 1.08; 95% CI, 1.01-1.16).

We concluded that one in six persons with IBD experienced a substance use disorder, suggesting that clinicians should maintain high index of suspicion regarding possible substance use disorders, and inquiries about substance use should be a part of care for IBD patients, particularly for men, smokers, and patients with anxiety disorders


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 2021; 27:190-202.


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.


Marrie RA, Graff LA, Fisk JD, Patten S, Bernstein CN for the CIHR Team in Defining the Burden and Mitigating the Impact of Psychiatric Comorbidity in Immuno-inflammatory Disease. The relationship between symptoms of depression and anxiety and disease activity in IBD over time. Inflammatory Bowel Diseases 2021;27(8):1285-1293.

We aimed to examine associations between elevated symptoms of depression and anxiety and disease activity in inflammatory bowel disease (IBD). Previous findings have been inconsistent and have not accounted for variability in the courses of these conditions over time. We followed 247 participants with IBD (153 Crohn's disease, 94 ulcerative colitis) for 3 years. Annually, participants underwent an abdominal examination, reported therapies used for IBD, and completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. We evaluated associations of elevated symptoms (scores ≥11) of anxiety (HADS-A) and depression (HADS-D) with the presence of active IBD as measured using the Powell Tuck Index for ulcerative colitis and the Harvey-Bradshaw Disease Activity Index for Crohn's disease. Of 247 participants, 15 (6.1%) had elevated symptoms of depression (HADS-D ≥11) at enrollment, 41 (16.6%) had elevated symptoms of anxiety (HADS-A ≥11), and 101 (40.9%) had active IBD. On average, individuals with elevated symptoms of depression (odds ratio [OR], 6.27; 95% CI, 1.39-28.2) and anxiety (OR, 2.17; 95% CI, 1.01-4.66) had increased odds of active IBD. Within individuals, elevations in symptoms of depression over time were associated with increased odds of active IBD (OR, 2.70; 95% CI, 1.15-6.34), but elevated symptoms of anxiety were not. After adjustment for covariates (including disease activity), elevated symptoms of depression were also associated with increased odds of biologic therapy use (OR, 2.02; 95% CI, 1.02-4.00).

We concluded that symptoms of depression and anxiety are associated with disease activity in IBD over time. Reducing these mental health symptoms should be incorporated into the management of IBD.

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 2021; 27: 317-324.

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.



Clooney AG, Eckenberger J, Laserna-Mendieta EJ, Sexton KA, Bernstein MT, Vagianos K, Sargent M, Moran C, Sheehan D, Sleator RD, Targownik LE, Bernstein CN, Shanahan F, Claesson MJ. Ranking microbiome variance in inflammatory bowel disease: A large longitudinal intercontinental study. Gut 2021; Mar;70(3):499-510.

The microbiome contributes to the pathogenesis of IBD but the relative contribution of different lifestyle and environmental factors to the compositional variability of the gut microbiota is unclear. In this study we rank the size effect of disease activity, medications, diet and geographic location of the faecal microbiota composition (16S rRNA gene sequencing) in patients with Crohn's disease (CD; n=303), ulcerative colitis (UC; n = 228) and controls (n=161), followed longitudinally (at three time points with 16 week intervals). This study was conducted in persons from Ireland and persons from Manitoba. Reduced microbiota diversity but increased variability was confirmed in CD and UC compared with controls. Significant compositional differences between diseases, particularly CD, and controls were evident. Longitudinal analyses revealed reduced temporal microbiota stability in IBD, particularly in patients with changes in disease activity. Machine learning separated disease from controls, and active from inactive disease, when consecutive time points were modelled. Geographic location accounted for most of the microbiota variance, second to the presence or absence of CD, followed by history of surgical resection, alcohol consumption and UC diagnosis, medications and diet with most (90.3%) of the compositional variance stochastic or unexplained.

We concluded that the popular concept of precision medicine and rational design of any therapeutic manipulation of the microbiota will have to contend not only with the heterogeneity of the host response, but also with widely differing lifestyles and with much variance still unaccounted for.



Bernstein CN, Ng, SC, Banerjee R, Steinwurz F, Shen B, Carbonnel F, Hamid S, Sood A, Yamamoto-Furusho JK, Griffiths A, Benchimol E, Travis S, Lopes S, Rubin DT, Kaplan GG, Armstrong D, Gearry R, and the IBD-Emerging Nations Consortium and the WGO IBD Task Force on COVID-19. Worldwide management of inflammatory bowel disease during the COVID-19 pandemic: An international survey. Inflammatory Bowel Diseases 2021; 27: 836-847. 

Persons with inflammatory bowel disease (IBD) may be particularly vulnerable to COVID-19 either because of their underlying disease or its management. Guidance has been presented on the management of persons with IBD in the time of this pandemic by different groups. We aimed to determine how gastroenterologists around the world were approaching the management of IBD. Members of the World Gastroenterology Organization (WGO) IBD Task Force contacted colleagues in countries largely beyond North America and Europe, inviting them to review the WGO website for IBD and COVID-19 introduction, with links to guideline documents, and then to respond to 9 ancillary open-ended management questions. 52 gastroenterologists from 33 countries across 6 continents completed the survey (April 14 to May 16, 2020). They were all adhering for the most part to published guidelines on IBD management in the COVID-19 era. Some differences and reductions in services related to access, and some related to approach within their communities in terms of limiting virus spread. In particular, most gastroenterologists reduced in-person clinics (43 of 52), limited steroid use (47 of 51), limited elective endoscopy (45 of 52), and limited elective surgeries (48 of 51). If a patient was diagnosed with COVID-19, immunomodulatory therapy was mostly held.

In most countries, the COVID-19 pandemic significantly altered the approach to persons with IBD. The few exceptions were mostly based on low burden of COVID-19 in individual communities. Regardless of resources or health care systems, gastroenterologists around the world took a similar approach to the management of IBD.

Dolovich C, Bernstein CN, Singh H, Nugent Z, Tennakoon A, Shafer LA, Marrie RA, Sareen J, Targownik L. Anxiety and Depression Leads to Anti-Tumor Necrosis Factor Discontinuation in Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology. 2021;19(6):1200-1208.

Anxiety and mood disorders are common among persons with inflammatory bowel diseases (IBD) and are associated with increased health care use and lower quality of life. We assessed the effects of anxiety and mood disorders on persistence on anti-tumor necrosis factor (anti-TNF) therapy in patients with IBD, and risk of IBD-related adverse outcomes after therapy initiation. We identified all persons with IBD in Manitoba who were dispensed an anti-TNF agent from 2001 through 2016 and then identified those with a validated administrative definition of anxiety and mood disorders in the 2 years before initiation of therapy. Survival analysis was used to assess the association between active anxiety and mood disorders and anti-TNF discontinuation and the first occurrence of an IBD-related adverse outcome (defined as IBD-related hospitalization or surgery, new or recurrent corticosteroid use, switching to an alternative anti-TNF, or death). We identified 1135 persons with IBD who began anti-TNF therapy; 178 of these patients (15.7%) met the diagnostic criteria for an anxiety and mood disorder. Anxiety and mood disorders significantly increased risk of discontinuation of anti-TNF therapy (adjusted hazard ratio, 1.28; 95% CI, 1.03-1.59) and discontinuation in the 1 year following anti-TNF initiation (hazard ratio, 1.50; 95% CI, 1.15-1.94). There was no association between AMDs and subsequent risk of IBD-related adverse events.

We concluded that patients with IBD and an AMD within 2 years before starting anti-TNF therapy are at increased risk of discontinuing therapy, compared to patients with IBD without anxiety and mood disorders. Studies are needed to determine if treatment of anxiety and mood disorders increases compliance with treatment.


Hitchon CA, Peschken CA, Walld R, Bernstein CN, Bolton JM, El-Gabalawy R, Fisk JD, Katz A, Lix LM, Marriott JM, Patten SB, Sareen J, Singer A, Marrie RA. The Impact of Psychiatric Comorbidity on Health Care Use in Rheumatoid Arthritis: A Population-Based Study. Arthritis Care and Research 2021; 73(1):90-99. 

Psychiatric comorbidity is frequent in rheumatoid arthritis and complicates treatment. The present study was undertaken to describe the impact of psychiatric comorbidity on health care use (utilization) in rheumatoid arthritis. We accessed administrative health data (1984-2016) and identified a prevalent cohort with diagnosed rheumatoid arthritis. Cases of rheumatoid arthritis (n = 12,984) were matched for age, sex, and region of residence with 5 controls (CNT) per case (n = 64,510). Within each cohort, we identified psychiatric morbidities (depression, anxiety, bipolar disorder, and schizophrenia [PSYC]), with active PSYC defined as ≥2 visits per year. For the years 2006-2016, annual rates of ambulatory care visits (mean ± SD per person) categorized by provider (family physician [FP], rheumatologist, psychiatrist, other specialist), hospitalization (% of cohort), days of hospitalization (mean ± SD), and dispensed drug types (mean ± SD per person) were compared among 4 groups (CNT, CNT plus PSYC, RA, and RA plus PSYC) using generalized linear models adjusted for age, sex, rural versus urban residence, income quintile, and total comorbidities. Estimated rates are reported with 95% confidence intervals (95% CIs). We tested within-person and RA-PSYC interaction effects. Subjects with RA were mainly female (72%) and urban residents (59%), with a mean ± SD age of 54 ± 16 years. Compared to RA without PSYC, RA with PSYC had more than additive (synergistic) visits (standardized mean difference [SMD] 10.92 [95% CI 10.25, 11.58]), hospitalizations (SMD 13% [95% CI 0.11, 0.14]), and hospital days (SMD 3.63 [95% CI 3.06, 4.19]) and were dispensed 6.85 more medication types (95% CI 6.43, 7.27). Cases of RA plus PSYC had increased visits to FPs (an additional SMD 8.92 [95% CI 8.35, 9.46] visits). PSYC increased utilization in within-person models.

We concluded that managing psychiatric comorbidity effectively may reduce utilization in RA.

Marrie RA, Patel R, Bernstein CN, Bolton J, Graff LA, Marriott J, Hitchon CA, Figley C, Kornelsen J, Fisk J. Anxiety and Depression Affect Performance on the Symbol Digit Modalities Test Over Time in MS and Other Immune Disorders. Multiple Sclerosis 2021 Jul; 27(8): 1284-1292. 

Longitudinal studies assessing depression and anxiety effects on cognition in multiple sclerosis (MS) are limited. We tested whether within-person fluctuations in symptoms of depression or anxiety over time affect cognition in persons with MS, IBD, rheumatoid arthritis, and a lifetime history of depression/anxiety disorders (DEP/ANX) but without an immune-mediated inflammatory diseases. We followed participants (MS: 255, IBD: 247, rheumatoid arthritis: 154, and DEP/ANX: 306) for 3 years. Annually, they completed the hospital anxiety and depression scale (HADS) and cognitive tests including the symbol digit modalities test (SDMT). We evaluated associations of elevated symptoms (scores ⩾ 11) of anxiety (HADS-A) and depression (HADS-D) with SDMT z-scores using multivariable linear models-estimating between-person and within-person effects. Participants with MS performed worse on the SDMT than participants in the DEP/ANX cohort (β = -0.68; 95% CI: -0.88, -0.48). Participants with elevated HADS-A scores performed worse on the SDMT than those without elevated scores (β = -0.43; 95% CI: -0.65, -0.21), particularly those with rheumatoid arthritis. Time-varying within-person elevations in depressive symptoms were associated with worse SDMT performance (β = -0.12; 95% CI: -0.21, -0.021).

We concluded that across persons, elevated symptoms of anxiety adversely affected information processing. Elevated symptoms of depression within-persons over time were associated with declines in information processing speed. This was true in all of these immune-mediated inflammatory diseases including IBD.

Bernstein CN, Nugent Z, Singh H. The persistently high rate of venous thromboembolic disease in IBD: A population-based study. American Journal of Gastroenterology 2021; 116(7):1476-1484.

Venous thromboembolism (blood clots in veins in the legs and lungs) is known to be increased in IBD. We aimed to determine whether rates of venous thromboembolism in IBD have reduced over the past 30 years. We used the population-based University of Manitoba IBD Epidemiology Database (1984-2018) to determine the incidence of venous thromboembolism in IBD and the incidence rate ratio vs matched controls. In persons with IBD with and without VTE, we assessed for variables that were associated with an increased risk of venous thromboembolism on multivariate logistic regression. The incidence of venous thromboembolism in the IBD cohort was 7.6% which was significantly greater than in controls (3.3%, P < 0.0001). The overall age-standardized incidence rate of venous thromboembolism was 433 per 100,000 in IBD and 184 per 100,000 in controls. The incidence of venous thromboembolism was higher in Crohn's disease (8.4%) than in ulcerative colitis (6.9%, P = 0.0028). The incidence rate ratio in IBD vs controls was 2.36 (95% confidence interval 2.16-2.58). The 2-3 times increased risk was similar in males and females and in Crohn's disease compared with ulcerative colitis. The incidence rate among persons with IBD from 1985 to 2018 decreased very slowly, with annual percent change of -0.7% (P = 0.0003). Hospital admission, high comorbidity, use of antibodies to tumor necrosis factor for less than 3 years up until the time of the venous thromboembolism, and the combination of steroid and antibodies to tumor necrosis factor increased the risk of venous thromboembolism.

We concluded that despite advancements in IBD management in the past 30 years, the rates of venous thromboembolism have only been slowly decreasing and remain significantly increased compared with controls.

Turkiewicz J, Bhatt RR, Wang H, Vora P, Krause B, Sauk JS, Jacobs JP, Bernstein CN, Kornelsen J, Labus JS, Gupta A, Mayer EA. Altered brain structural connectivity in patients with longstanding gut inflammation is correlated with psychological symptoms and disease duration.  NeuroImage Clinical 2021; 30:102613. 


We aimed to identify differences in network properties of white matter microstructure between asymptomatic ulcerative colitis participants who had a history of chronic gut inflammation, healthy controls and a disease control group without gut inflammation (irritable bowel syndrome; IBS). Diffusion weighted imaging was conducted in age and sex-matched participants with ulcerative colitis, IBS, and healthy controls (N = 74 each), together with measures of gastrointestinal and psychological symptom severity. Using streamline connectivity matrices and graph theory, we aimed to quantify group differences in brain network connectivity. Regions showing group connectivity differences were correlated with measures showing group behavioral and clinical differences. Ulcerative colitis participants exhibited greater centrality in regions of the somatosensory network and default mode network, but lower centrality in the posterior insula and globus pallidus compared to healthy controls s (q < 0.05). Hub analyses revealed compromised hubness of the pallidus in ulcerative colitis and IBS compared to healthy controls which was replaced by increased hubness of the postcentral sulcus. Surprisingly, few differences in network matrices between ulcerative colitis and IBS were identified. In ulcerative colitis, centrality measures in the secondary somatosensory cortex were associated with depression (q < 0.03), symptom related anxiety (q < 0.04), trait anxiety (q < 0.03), and symptom duration (q < 0.05).

A history of ulcerative colitis is associated with neuroplastic changes in several brain networks, which are associated with symptoms of depression, trait and symptom-related anxiety, as well as symptom duration. When viewed together with the results from IBS subjects, these findings suggest that chronic gut inflammation as well as abdominal pain have a lasting impact on brain network organization, which may play a role in symptoms reported by ulcerative colitis patients, even when gut inflammation has subsided.


Marrie RA, Walld R, Bolton J, Sareen J, Patten SB, Singer A, Lix L, Hitchon C Marriott JJ, El-Gabalawy R, Katz A, Fisk JD, Bernstein CN. Effect of comorbid mood and anxiety disorders on breast and cervical cancer screening in immune-mediated inflammatory disease. PLOS One 2021; Aug 5;16(8):e0249809.


We aimed to examine rates of breast and cervical cancer screening in women with immune-mediated inflammatory diseases, IBD, multiple sclerosis (MS) and rheumatoid arthritis versus a matched cohort with immune-mediated inflammatory diseases; and examine the association of psychiatric comorbidity with screening in these populations. We conducted a retrospective cohort study in Manitoba, Canada using administrative data. We identified women with IBD, MS and rheumatoid arthritis, and controls without these immune-mediated inflammatory diseases matched on age and region. Annually, we identified individuals with any active mood/anxiety disorder. Using physician claims, we determined the proportion of each cohort who had cervical cancer screening within three-year intervals, and mammography screening within two-year intervals. We modeled the difference in the proportion of the immune-mediated inflammatory diseases and matched cohorts who underwent mammography; and pap tests using log-binomial regression with generalized estimating equations, adjusting for sociodemographics, comorbidity and immune therapy use. We tested for additive interactions between cohort and mood/anxiety disorder status. During 2006-2016, we identified 17,230 women with immune-mediated inflammatory diseases (4,623 with IBD, 3,399 with MS, and 9,458 with rheumatoid arthritis) and 85,349 matched controls. Having an IMID was associated with lower (-1%) use of mammography; however, this reflected a mixture of more mammography in the IBD cohort (+2.9%) and less mammography in the MS (-4.8 to -5.2%) and RA (-1.5%) cohorts. Within the IBD, MS and rheumatoid arthritis cohorts, having an active mood/anxiety disorder was associated with more mammography use than having an inactive mood/anxiety disorder. The MS and rheumatoid arthritis cohorts were less likely to undergo Pap testing than their matched cohorts. In the absence of an active mood/anxiety disorder, the IBD cohort was more likely to undergo Pap testing than its matched cohort; the opposite was true when an active mood/anxiety disorder was present. Among women with an immune-mediated inflammatory diseases, mood/anxiety disorder influence participation in cancer screening.


MacDonald TM, Fisk JD, Bernstein CN, El-Gabalawy R, Hitchon CA, Kornelsen J, Patten SB, Tisseverasinghe A, Marrie RA. The association between childhood maltreatment and pain catastrophizing in individuals with immune-mediated inflammatory diseases. Journal of Psychosomatic Research 2021;145:110479. 

Childhood maltreatment is associated with pain catastrophizing. Both childhood maltreatment and pain catastrophizing are prevalent in certain immune-mediated inflammatory disease populations. However, it is unknown whether childhood maltreatment contributes to the high rates of pain catastrophizing in immune-mediated inflammatory diseases cohorts. We assessed the relationship between childhood maltreatment and pain catastrophizing in individuals with immune-mediated inflammatory diseases, and whether this differed across immune-mediated inflammatory diseases. Between November 2014 and July 2016 we recruited individuals with multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatoid arthritis. Participants completed the Childhood Trauma Questionnaire-Short Form, the Pain Catastrophizing Scale, and Hospital Anxiety and Depression Scale. We tested the association between childhood maltreatment and pain catastrophizing using multivariable logistic regression.  We included 577 individuals with immune-mediated inflammatory (MS: 232, IBD: 215, rheumatoid arthritis: 130). Overall, 265 (46%) participants with immune-mediated inflammatory diseases reported any childhood maltreatment, with the most common type of maltreatment being emotional neglect. Childhood maltreatment was associated with pain catastrophizing (OR 3.32; 95% CI 1.89-5.85) independent of other risk factors, including sociodemographics and symptoms of anxiety and depression.

We concluded pain that catastrophizing is highly prevalent in our immune-mediated inflammatory diseases population, and strongly associated with childhood maltreatment in this population. Interventions that consider childhood maltreatment and pain catastrophizing should be incorporated into the clinical management of immune-mediated inflammatory diseases patients.

El-Matary W, Nugent Z, Witt J, Bernstein CN. Trends in paediatric inflammatory bowel disease-attributable direct costs: a population-based analysis. Alimentary Pharmacology and Therapeutics 2021; 53(11):1201-1208. 

In addition to its morbidities, inflammatory bowel disease (IBD) has a major financial burden on patients and healthcare systems. However, there is a paucity of evidence on IBD-attributable costs in children. We aimed to determine the trends of IBD-attributable direct costs over time using a population-based analysis. Data were extracted from Manitoba Health administrative health database and other population registry datasets from 1995 to 2017. Children with IBD were matched by age, sex and location with children without IBD. IBD-attributable direct costs were calculated using utilization counts from the administrative data and cost estimates from different sources. Inpatient hospitalisation and outpatient procedure costs were estimated using the resource intensity weight that is attached to each record in the data. Costs were expressed in Canadian dollars. We included 733 (428 with Crohn's disease) prevalent cases who were diagnosed with IBD before the age of 18 years and were followed for 2450 person-years. A matched control group of 6763 persons who were followed for 21 558 person-years was included. The median annual costs of physician services billed per patient increased from $381 (IQR 215-1064) in 1995 to $936 (IQR 579-1932) in 2017 (P < 0.001). The annual medication costs per patient increased from a median of $270 in 1995 to $7944 in 2017 (P < 0.0001). The median annual direct cost per patient was $1810 in 2004 as compared to $14 791 (P < 0.0001) in 2017.

Over two decades, there was a significant increase in the paediatric IBD-attributable direct costs mainly driven by medication costs.


Gearry RB, McCombie AM, Vatn M, Rubin DT, Steinwurz F, Loftus EV, Kruis W, Tysk C, Colombel JF, Ng SC, Van Assche G, Bernstein CN. What are the most challenging aspects of inflammatory bowel disease? An international survey of gastroenterologists comparing developed and developing countries. Inflammatory Intestinal Diseases 2021 May;6(2):78-86. 


As IBD becomes more prevalent, the challenges that gastroenterologists face in managing these patients evolve. We aimed to describe the most important challenges facing gastroenterologists from around the world and compare these between those working in developed and developing countries. An online questionnaire was developed, and a link distributed to gastroenterologists. Data were analyzed descriptively using Friedman and Wilcoxon matched-pair signed rank tests to compare rankings for responses. Mann-Whitney U tests were used to compare rankings between responses from gastroenterologists from developed and developing countries. Lower scores reflected greater challenges. Of 872 who started, 397 gastroenterologists (45.5%) completed the survey. Respondents represented 65 countries (226 [56.9%] from developed countries). Overall, the challenge ranked most important (smallest number) was increasing IBD prevalence (13.6%). There were significant differences in mean ranking scores for many simple aspects of care for those from developing countries compared to providers from developed countries, such as access to simple IBD treatments (5.52 vs. 6.02, p = 0.01), access to anti-TNF drugs including dose escalation (3.33 vs. 3.93, p < 0.01), access to good stoma care (2.57 vs. 3.03, p < 0.001), access to therapeutic drug monitoring (1.47 vs. 1.84, p < 0.001), and access to care for people from low socioeconomic status (2.77 vs. 3.37, p < 0.001).

Increasing IBD prevalence is seen by gastroenterologists as the greatest challenge facing them. There are significant differences between the IBD challenges facing gastroenterologists from developed and developing countries that reflect inequities in access to health care.


Bernstein CN, Nugent Z, Shaffer S, Singh H, Marrie RA. Comorbidity Before and After a Diagnosis of Inflammatory Bowel Disease. Alimentary Pharmacology and Therapeutics 2021; 54:637–651.

Comorbidity is an important predictor of how disease course in IBD evolves. We aimed to determine pre-diagnosis relative rates and post-diagnosis hazard ratios (HR) of component diseases of the Charlson Comorbidity Index in a cohort study of persons with IBD. The University of Manitoba IBD Epidemiology Database includes all Manitobans with IBD from 1 April 1984 through 31 March 2018 and matched controls. All outpatient physician claims and hospital discharge abstracts were searched for diagnostic codes for Charlson Comorbidity Index component diseases. Some diseases were collapsed into one group such that we assessed 12 conditions. We report the relative rates of these conditions prior to IBD and the incidence of these diagnoses after IBD. Using Cox proportional hazards regression we report post-diagnosis HR. Confidence intervals were adjusted for Bonferroni correction. The relative rates of cardiovascular diseases, peripheral vascular diseases, chronic pulmonary diseases, connective tissue disease/rheumatic diseases, renal disease, liver diseases, peptic ulcer disease, and cancer were all increased prior to diagnoses of IBD compared to controls. All comorbidities were increased post IBD diagnosis. The increased hazard ratio for dementia in persons with Crohn's disease was a concerning novel finding. The increased association with paraplegia/hemiplegia was unexpected. For all comorbidities, except diabetes, the age at diagnosis was younger in IBD than controls.

We concluded that persons with IBD have a higher comorbidity burden than persons without IBD. Optimal care plans for persons with IBD should include an assessment for other comorbidities that include just about every other organ system.



Marrie RA, Walld R, Bolton JM, Sareen J, Patten SB, Singer A, Lix L, Hitchon CA, Marriott JJ, El-Gabalawy R, Katz A, Fisk JD, Bernstein CN; for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Uptake of influenza vaccination among persons with inflammatory bowel disease, multiple sclerosis or rheumatoid arthritis: a population-based matched cohort study. CMAJ Open 2021; 9: E510-E521.

Individuals with immune-mediated inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, are at increased risk for influenza and related complications. We examined and compared the uptake of influenza vaccination among people with and without these diseases, as well as the influence of psychiatric comorbidity on vaccine uptake. Using administrative data from Apr. 1, 1984, to Mar. 31, 2016, we conducted a retrospective matched cohort study in Manitoba, Canada. We matched persons 18 years of age or older who had a diagnosis of inflammatory bowel disease, multiple sclerosis or rheumatoid arthritis (the immune-mediated inflammatory disease cohorts) with persons who did not have these diagnoses (the control cohorts) on age, sex and region. We then identified cohort members with any mood or anxiety disorder (depression, anxiety disorders, bipolar disorder). We identified influenza vaccinations through billing codes. Using binomial regression, we modelled the difference in the proportion of the immune-mediated inflammatory disease and matched cohorts vaccinated annually, with adjustment for sociodemographic characteristics, comorbidity and immune therapy. We tested additive interaction effects between a person's cohort and presence of a mood or anxiety disorder. We identified 32 880 individuals with 1 or more immune-mediated inflammatory diseases (10 148 with inflammatory bowel disease, 6158 with multiple sclerosis and 16 975 with rheumatoid arthritis) and a total of 164 152 controls. In fiscal year 2015, 8668 (41.3%, 95% confidence interval [CI] 40.6% to 42.0%) of the 20 982 persons with an immune-mediated inflammatory disease received an influenza vaccination, a rate higher than among controls (35 238 of 104 634; 33.7%, 95% CI 33.4% to 34.0%). After adjustment, participants with an immune-mediated inflammatory disease but no mood or anxiety disorder had 6.44% (95% CI 5.79% to 7.10%) greater uptake of vaccination than participants without such a disease. Among participants without an immune-mediated inflammatory disease, having a mood or anxiety disorder was associated with 4.54% (95% CI 4.20% to 4.89%) greater uptake of vaccination. However, we observed a subadditive interaction between immune-mediated inflammatory disease and psychiatric status (-1.38%, 95% CI -2.26% to -0.50%).

Uptake of influenza vaccination was consistently low in populations with immune-mediated inflammatory disease, and although psychiatric morbidity is associated with greater vaccine uptake by Manitobans, it negatively interacts with these diseases to reduce uptake. Changes in care delivery are needed to mitigate this gap in care.

Siegel CA, Melmed GY, McGovern DP, Rai V, Krammer F, Rubin DT, Abreu MT, Dubinsky MC; International Organization for the Study of Inflammatory Bowel Disease (IOIBD); International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) (Dr  Bernstein is a member of group authorship). SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting. Gut 2021; 70(4): 635-640. 


Members of the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) used the modified Delphi method to develop consensus statements regarding SARS-CoV-2 vaccination for patients with IBD. The main characteristics of this technique include expert opinion with anonymous voting on statements, iteration with controlled feedback of group opinion and statistical aggregation of the group response.


Highlighted themes of accepted statements related to SARS-CoV-2 vaccination for patients with IBD by the IOIBD

  • Patients with IBD should be vaccinated against SARS-CoV-2.

  • The best time to administer SARS-CoV-2 vaccination in patients with IBD is at the earliest opportunity to do so.

  • SARS-CoV-2 vaccines including messenger RNA vaccines, replication-incompetent vector vaccines, inactivated vaccines and recombinant vaccines are safe to administer to patients with IBD.

  • SARS-CoV-2 vaccination should not be deferred because a patient with IBD is receiving immune-modifying therapies.

  • Patients with IBD vaccinated with SARS-CoV-2 should be counselled that vaccine efficacy may be decreased when receiving systemic corticosteroids.


Mikocka-Walus A, Skvarc D, van Tilburg MAL, Barreiro-de Acosta M, Bennebroek Evertsz F, Bernstein CN, Burisch J, Ferreira N, Gearry RB, Graff LA, Jedel S, Mokrowiecka A, Stengel A, Knowles S. COVID-19-related personal product shortages are associated with psychological distress in people living with gastrointestinal disorders: A cross-sectional survey. Neurogastrointestinal Motility 2021; in press. 


The mental health response to the coronavirus (COVID-19) pandemic-related product shortages in those living with chronic gastrointestinal (GI) disorders has received little attention. We aimed to explore the association between the pandemic-related product shortages and psychological distress in people with GI disorders. This online cross-sectional survey was nested within an ongoing, international, prospective study of well-being in people with GI disorders. The study was advertised in multiple countries in May-September 2020 via patient organizations and social media. The primary outcome measure was distress, evaluated by the Depression Anxiety Stress Scale. We utilized linear regressions, adjusting for covariates and testing individual moderation effects. Overall, 831 people completed the survey from 27 countries, of whom 82% were female (mean age = 49 years). The most common disorders included inflammatory bowel disease (n = 322), celiac disease (n = 273), and irritable bowel syndrome (n = 260). Significant problems accessing food were reported by 19.8%, non-medical therapies by 16%, toilet paper by 10.8%, and essential medication by 8.9% of the sample (>5% pain medication). There was a positive association between toilet paper and pain medication shortages and distress, and a negative association between food shortages and distress. Significant moderation effects were identified for COVID-19 prevalence and toilet paper and food shortages, and between COVID-19 fear and pain medication shortages.

In summary this study documented a significant relationship between product shortages and psychological distress, which were associated with COVID-19 prevalence and fear. Strategies addressing COVID-19 fear could potentially modify the relationship between shortages and distress.


Elias ED, Silvester JA, Graff LA, Bernstein CN, Rigaux LN, Duerksen DR. Patient Perspectives on the Long-Term Management of Celiac Disease. Journal of Clinical Gastroenterology 2021; in press. 


The aim of this study was to survey adults with celiac disease on the utility of specific aspects of follow-up and on information needs. Currently, the treatment for celiac disease is strict gluten avoidance. Although this places the onus on the patient for disease management, patient perspectives on celiac disease care have not been formally assessed. The Manitoba Celiac Disease Cohort prospectively enrolled adults newly diagnosed with celiac disease using serology and histology. At the 24-month study visits, participants rated the utility of aspects of CD care on a 5-point scale anchored by "not at all useful" and "very useful" and the helpfulness of information on celiac disease -related topics on a 6-point scale anchored by "not at all helpful" and "very helpful." The online survey was completed by 149 of 211 cohort members [median age 40 (interquartile range 30 to 56) y; 68% female]. Adherence to a gluten-free diet was good. Most participants (87%) responded that they should be seen regularly for medical follow-up of celiac disease, preferably every 6 (26%) or 12 months (48%). Blood tests were the most highly rated care component (rated scored ≥4/5 by 78% of respondents), followed by the opportunity to ask about vitamins and supplements (50%), symptom review (47%), and information on celiac disease research (44%). Diet review was not considered helpful.


Bernstein CN, Tenakoon A, Singh H, Targownik LE. Continued 5ASA use after initiation of anti-TNF or immunomodulator confers no benefit in IBD: A population based study. Alimentary Pharmacology and Therapeutics 2021; 54: 814-832. 

With the advent of biological therapy in IBD, it is uncertain to what extent 5aminosalicylates (5ASA) are used. We aimed to explore whether or not 5ASA is continued once biological or immunomodulator therapy is initiated, and the outcomes in those who continued the 5ASAs. We conducted a retrospective cohort study using the population-based University of Manitoba IBD Epidemiologic Database which includes prescription drug dispensation from 1996 through 2018. We assessed outcomes among 5ASA users who continued versus discontinued 5ASA after initiation of anti-TNF therapy or immunomodulators. In all, 8379 (77%) of persons with IBD received at least one 5ASA dispensation (85% of ulcerative colitis, and 68% of Crohn's disease. There was a reduction in later years, particularly for Crohn's disease. The most common pattern of 5ASA use was intermittent at 65.1% (stopping and restarting use) versus one-time (4.1%), previous continuous (13.8%) and persistent (17%). Among the total IBD population use was 59% oral, 3% rectal and 14% combination. Of all 5ASA starts, only 25% were continued longer than 20 months. After immunomodulator or anti-TNF initiation, there was no difference in either ulcerative colitis or Crohn's disease for negative outcomes (hospitalisation, surgery, corticosteroid starts, colorectal cancers or drug-related adverse events) between those who continued 5ASA versus those who discontinued.

We concluded that 5ASA remains commonly prescribed in ulcerative colitis and Crohn's disease. Rates of persistent use in ulcerative colitis are low. Once an anti-TNF or immunomodulator is initiated, continuation of 5ASA seems to add no benefit.


Ferreira N, Mikocka-Walus A, van Tilburg MAL, Graff LA, Apputhurai P, Barreiro-de Acosta M,Bennebroek Evertsz F, Burisch J, Lo B, Petrik M, Trindade IA, Jedel S, Moser G Mokrowiecka A, Bernstein CN, Dan Dumitrascu D, Ford AC, Stengel A, Richard Gearry R, Knowles SR. The impact of the coronavirus (Covid-19) pandemic on individuals with gastrointestinal disorders: a protocol of an international collaborative study. Journal of Psychosomaic Research 2021; 148: 110561.

The COVID-19 pandemic has had a significant impact on mental health across the globe. People living with a chronic gastrointestinal (GI) disorder might be particularly at risk of mental health complications given higher rates of comorbid anxiety and depression compared to the healthy population. As GI disorders affect up to 40% of the population worldwide, this international collaborative study seeks to evaluate the extent of the impact of the COVID-19 pandemic on GI symptoms specifically and more generally on the well-being of those living with chronic GI conditions. A longitudinal survey with three time points (baseline, 6-month, and 12-month) will be conducted online. Adult participants with GI disorders from multiple countries will be recruited via patient associations, social media advertising, utilizing snowball sampling. Participants will be invited to complete a battery of questionnaires including demographic and health parameters, and measures of gastrointestinal symptoms, fear of COVID-19, perceived impact of COVID-19, illness perceptions, coping, depression, anxiety, stress, catastrophizing, and quality of life, using validated measures where available. Statistical analyses will include univariate descriptive models, multivariate models utilizing regression, mediation, and moderation, and latent growth models.

This project may present novel information to the field of psychogastroenterology and may provide crucial information regarding the areas of impact for individuals with GI disorders during and following the pandemic. Further, this information can guide healthcare providers and patient associations on how to target support related to the pandemic mental health sequelae for these patients.

Su S, Marrie RA, Bernstein CN. Factors associated with social participation in persons living with inflammatory bowel disease. Journal of Canadian Association of Gastroenterology 2021; in press.


IBD imposes a significant burden on health-related quality of life, particularly in social domains. We sought to investigate the factors that limit social participation in patients with IBD. We assessed a cohort of 239 Manitobans with IBD. We collected sociodemographic information, medical comorbidities, disease phenotype, symptom activity and psychiatric comorbidity (using the Structured Clinical Interview for DSM-IV). Participants completed the 8-item Ability to Participate in Social Roles and Activities (APSRA) questionnaire, which assesses participation restriction, including problems experienced in social interaction, employment, transportation, community, social, and civic life. Poorer social participation scores were associated with earning less than $50, 000 CAD income annually (p<0.001), actively smoking (p=0.006), higher symptom scores (p<0.001 for Crohn’s disease, p=0.004 for ulcerative colitis), and having an increasing number of chronic medical conditions (R= -0.30). History of depression (p<0.001) and anxiety (p=0.001) and having active depression (p<0.001) and anxiety (p=0.001) all predicted poor social participation scores. IBD phenotype or disease duration was not predictive. Based on multivariable linear regression analysis, significant predictors of variability in social participation were medical comorbidity, psychiatric comorbidity, psychiatric symptoms, and IBD-related symptoms. 

In conclusion, the factors that predict social participation by IBD patients include income, smoking, medical comorbidities, IBD symptom burden, and psychiatric comorbidities. Multivariable linear regression suggests that the most relevant factors are medical comorbidity, psychiatric comorbidity, psychiatric symptoms, and IBD symptoms.


Kuenzig ME, Bitton A, Carroll MW, Kaplan GG, Otley AR, Singh H, Nguyen GC, Griffiths AM, Stukel TA, Targownik LE, Jones JL, Murthy SK, McCurdy JD, Bernstein CN, Lix LM, Peña-Sánchez JN, Mack DR, Jacobson K, El-Matary W, Dummer TJB, Fung SG, Spruin S, Nugent Z, Tanyingoh D, Cui Y, Filliter C, Coward S, Siddiq S, Benchimol EI; Canadian Gastro-Intestinal Epidemiology Consortium. Inflammatory bowel disease increases the risk of venous thromboembolism in children: a population-based matched cohort study. Journal of Crohns and Colitis 2021; 2031-2040.

Although venous thromboembolism (clot in veins in legs or lungs) is a well-known complication of IBD in adults, limited data exist on the risk in children. We report the incidence of venous thromboembolism among children with and without IBD. We conducted a matched cohort study within a distributed network of population-based Canadian provincial health administrative databases. Children diagnosed with IBD <16 years were identified using validated algorithms from administrative data in Alberta, Manitoba, Nova Scotia, Ontario, and Québec and compared to age- and sex-matched children without IBD. Hospitalizations for venous thromboembolism within five years of IBD diagnosis were identified. The five-year incidence of venous thromboembolism among 3593 children with IBD was 31.2 (95%CI 23.7-41.0) per 10,000 person-years compared to 0.8 (95%CI 0.4-1.7) per 10,000 person-years among 16,289 children without IBD (unadjusted IRR 38.84, 95%CI 16.59-90.83; adjusted HR 22.91, 95%CI 11.50-45.63). venous thromboembolism was less common in Crohn's disease than ulcerative colitis (unadjusted IRR 0.47, 95%CI 0.27-0.83; adjusted HR 0.52, 95%CI 0.29-0.94). Findings were similar for deep vein thrombosis and pulmonary embolism when comparing children with and without IBD.

We concluded that the risk of VTE is much higher in children with IBD than controls without IBD. While the absolute risk is low, we found a higher incidence rate than previously described in the pediatric literature.



Witges K, Sexton K, Graff LA, Targownik LE, Lix LM, Haviva C, Stone J, Shafer LA, Vagianos K, Bernstein CN. What is a flare? The Manitoba Living with IBD study. Inflammatory Bowel Diseases 2021; in press.

Flare is a poorly defined term used by patients and clinicians to indicate IBD status. This study aimed to evaluate the validity of a single-item 7-point flare indicator relative to other measures of disease flare. The longitudinal Manitoba Living with IBD Study followed persons with IBD for 1 year; they completed biweekly online surveys and provided 3 stool samples. Disease flare on a single-item flare indicator with 7 possible responses developed for the study was defined by report of symptoms as "moderately" or "much" worse. The flare indicator was evaluated against 5 measures of disease activity: fecal calprotectin score, a 2-point disease status indicator, a 4-point flare certainty indicator, the IBD Symptom Index short form (SIBDSI), and the short form IBD Questionnaire (SIBDQ). Participants in a flare, based on the 7-point measure, were matched to a nonflaring participant, and a stool sample was collected. Of the 155 IBD participants, almost half (n = 74) experienced a flare. Of those who flared, 97.0% endorsed active IBD on the 2-point indicator (controls 42.5%; P < .001); 91.9% endorsed active IBD on the 4-point certainty indicator (controls 32.9%; P < .001); 90.5% endorsed active disease on the SIBDSI (controls 34.2%; P < .001); and 48.5% had an elevated fecal calprotectin (controls 34.3%; P < .05). The mean SIBDQ was lower for the flare group compared with controls (43.9 [SD 11.1] vs 58.3 [SD 8.5]; P < .001), indicating worse disease.

We concluded that the 7-point flare indicator robustly identified symptomatic flares. This patient self-report indicator reflected meaningful changes in more complex clinical indices and had only weak concordance with the presence of inflammation.

Wan A, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM, Hitchon C, Marriott JJ, Marrie RA. Childhood maltreatment and psychiatric comorbidity in immune-mediated inflammatory disorders. Psychosomatic Medicine 2021; in press. 


To determine whether childhood maltreatment is associated with immune-mediated inflammatory disorders (multiple sclerosis [MS], IBD and rheumatoid arthritis). We further aimed to determine the relationship between maltreatment and psychiatric comorbidity in immune-mediated inflammatory and whether these relationships differed across immune-mediated inflammatory. 925 participants (MS: 232, IBD: 216, rheumatoid arthritis: 130, healthy controls: 103) completed a structured psychiatric interview to identify psychiatric disorders, and the Childhood Trauma Questionnaire to evaluate five types of maltreatment: emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. We evaluated associations between maltreatment, immune-mediated inflammatory and psychiatric comorbidity using multivariable logistic regression models. The prevalence of having ≥1 maltreatment was similar across immune-mediated inflammatory, but higher than in controls (MS: 63.8%, IBD: 61.6%, rheumatoid arthritis: 62.3%, healthy controls: 45.6%). Emotional abuse was associated with having an immune-mediated inflammatory (adjusted odds ratio [aOR] 2.37; 1.15-4.89). In the sex-specific analysis, this association was only present in women. History of childhood maltreatment was associated with a lifetime diagnosis of a psychiatric disorder in the immune-mediated inflammatory cohort (OR 2.24; 1.58-3.16), but this association did not differ across diseases. In those with immune-mediated inflammatory, total types of maltreatments (aOR 1.36; 1.17-1.59) and emotional abuse (aOR 2.64; 1.66-4.21) were associated with psychiatric comorbidity. 

We concluded that childhood maltreatment is more common in immune-mediated inflammatory than in a healthy population, and is associated with psychiatric comorbidity. Given the high burden of psychiatric disorders in the immune-mediated inflammatory population, clinicians should be aware of the contribution of maltreatment and the potential need for trauma-informed care strategies. 


Olafson K, Marrie RA, Bolton JM, Bernstein CN, Bienvenu OJ, Kredentser MS, Logsetty S,  Chateau D,  Nie Y, Blouw M, Afifi TO, Stein MB, Leslie WD, Katz LY, Mota N, El-Gabalawy R, Enns MW, Leong C, Sweatman S, Sareen J. The Five-Year Pre- and Post-Hospitalization Treated Prevalence of Mental Disorders and Psychotrophic Medication Use in Critically Ill Patients:  A Canadian Population-Based Study. Intensive Care Medicine. 2021; in press.


The interplay between critical illness and mental disorders is poorly understood. The purpose of this study is to measure both the treated prevalence of mental disorders and psychotropic medication use before and after hospitalization and the impact of intensive care unit admission on these outcomes. Using a population-based administrative database in Manitoba, Canada, 49,439 intensive care unit patients admitted between 2000 and 2012 were compared to two matched comparison groups (hospitalized; n = 146,968 and general population; n = 141,937). Treated prevalence of mental disorders and psychotropic medication prescriptions were measured in the 5-year periods before and after the hospitalization. The 5-year treated mental disorder prevalence in the intensive care unit population increased from 41.5% pre-hospitalization to 55.6% post-hospitalization. Compared to non- intensive care unit hospitalized patients, the adjusted treated mental disorder prevalence in intensive care unit patients was lower prior to hospitalization (1-year adjusted prevalence rate, APR 0.94, 95% CI 0.92-0.97, p < 0.0001; 5-year APR 0.99, 95% CI 0.98-1.00, p = 0.1), but higher following discharge (1-year APR 1.08, 95% CI 1.05-1.11, p < 0.0001, 5-year APR 1.03, 95% CI 1.01-1.05, p < 0.0001). A high proportion of ICU patients received antidepressant, anxiolytic and sedative-hypnotic prescriptions before and after their hospitalization. In multivariable analyses, intensive care unit exposure was associated with an increase in mood, anxiety and psychotic disorders, and sedative-hypnotics use (p < 0.0001 for all Time × Group interactions).


We concluded that during the 5 years after admission to ICU, there is a significant increase in treated prevalence of mental disorders and psychotropic medication use compared to the 5 years prior to ICU and compared to general population and hospital cohorts. Prevention and intervention programs that identify and treat mental disorders among survivors of critical illness warrant further study

Mikocka-Walus A, Bennebroek Evertsz F, Jedel S, Graff LA, van Tilburg MAL, Ferreira N, Skvarc D, Knowles S, Mokrowiecka A, Stengel A, Gearry R, Bernstein CN, Burisch JM, Barreiro Acosta M, Trindade I. Exploring the relationship between self-isolation and distress among people with gastrointestinal disorders during the COVID-19 pandemic. Journal of Clinical Psychology in Medical Settings 2021; Sept 7:1-12.


This study aimed to explore the association between perceived isolation and symptoms of distress in people with GI disorders at the time of the pandemic; and to examine factors which moderate this relationship. This online cross-sectional survey was advertised in May-September 2020 via patient organisations and associated social media. Overall, 831 people (82% female, mean age 49 years) from 27 countries participated. A significant relationship between social isolation and psychological distress was noted (r = .525, p < .001). GI symptoms moderated the association between isolation and distress (B = .047, t = 2.47, p = .015). Interventions targeting these factors may help to reduce distress in people with GI disorders at the time of major stressors such as the COVID-19 pandemic.



Dolovich C, Shafer LA, Vagianos K, Witges K, Targownik LE, Bernstein CN. The complex relationship between diet, symptoms and intestinal inflammation in persons with IBD: The Manitoba Living with IBD Study. Journal of Parenteral and Enteral Nutrition 2021; in press.

We aimed to examine whether an association exists between diet quality, based on the Prospective Urban and Rural Epidemiologic Study (PURE) Healthy Diet Score, and active IBD. Participants were drawn from the Manitoba Living with IBD Study cohort. The Harvard Food Frequency Questionnaire was used to calculate the Healthy Diet Score at two time points; baseline and 1-year follow-up. Using generalized estimating equations logistic regression, we assessed the association between the Healthy Diet Score and: 1. the IBD Symptom Inventory (IBDSI), 2. intestinal inflammation, measured by fecal calprotectin, and 3. self-reported IBD flares. There were 294 completed Food Frequency Questionnaires among 153 people. Of these, 100% had completed data about an IBD flare, 98% had fecal calprotectin measurements and 96% had completed IBDSI scores. On a Healthy Diet Score scoring method of 0-8, the odds of fecal calprotectin >250 were lower for participants with a Healthy Diet Score of 4 versus 0-3 [adjusted OR 0.38, 95% CI, 0.19-0.77]. When applying a second Healthy Diet Score scoring method (8-40), the odds of having an IBD flare were 3.6 times greater for participants with a Healthy Diet Score between 21 and 24 compared to a Healthy Diet Score ≤20, [adjusted OR 3.63, 95% CI, 1.03-12.78].

We found that active inflammation was less likely among those with a moderate Healthy Diet Score, while symptomatic IBD flares were more likely. People may choose to consume a moderate amount of healthy foods such as fruits and vegetables, even if known that those foods may cause a symptomatic flare.



Shafer LA, Shaffer S, Witt J, Nugent Z, Bernstein CN. IBD Disability Index (IBDDI) is associated with both direct and indirect costs of inflammatory bowel disease. Inflammatory Bowel Diseases 2021; in press.

We aimed to determine both direct (medical) and indirect (lost wages) costs of IBD, and the association between the degree of IBD-related disability and extent of IBD-related costs. Persons aged 18-65 from the population-based University of Manitoba IBD Research Registry completed a survey including the IBD Disability Index (IBDDI) and questions related to employment, missed work (absenteeism), and reduced productivity at work (presenteeism). Administrative health data including surgeries, hospitalizations, physician claims, and prescriptions were linked to the survey and assessed. To calculate annual wage loss, number of days of missed work was multiplied by the average wage in Manitoba for the given occupation per Statistics Canada. Costs were adjusted to 2016-17 Canadian dollars. Using descriptive and regression analysis, we explored the association between IBDDI and annual direct and indirect costs associated with IBD. Average annual medical costs rose from $1,918 among those with IBDDI 0-4 to $9,993 among those with IBDDI 80-86. Average annual cost of lost work rose from $0 among those with IBDDI 0-4 to $30,101 among those with IBDDI 80-86. Using linear regression, each additional unit of IBDDI was associated with an increase of $77 in annual medical cost (95% C.I. $52-102; p<0.001) and an increase of $341 in annual cost of lost wages (95% C.I. $288-395; p<0.001).


We concluded that IBD-related costs are significantly associated with the degree of IBD-related disability. Among the approximate 30% of the IBD population with IBDDI scores greater than 40, the indirect costs of absenteeism and presenteeism accounts for ~75% of the total IBD-related costs.

Thomann AK, Knödler LL, Karthikeyan S, Atanasova K, Bernstein  CN, Ebert MP , Lis S, Reindl W. The interplay of biopsychosocial factors and quality of life in inflammatory bowel diseases – a network analysis. Journal of Clinical Gastroentrology 2021; in press.

Hayes B, Apputhurai P, Mikocka-Walus A, Barreiro-de Acosta M, Bernstein CN, Burgell R, Burisch J, Bennebroek Evertsz F, Ferreira N, Graff LA, Trindade IA, Gearry R, Lo B, Mokrowiecka A, Moser G, Petrik M, Stengel A, Knowles SR. Extending the common sense model to explore the impact of the fear of COVID-19 on quality of life in an international inflammatory bowel disease cohort. Journal of Clinical Psychology in Medical Settings 2021; Sept 24: 1-11.

The aim of this cross-sectional study was to use an extended common sense model (CSM) to evaluate the impact of fear of COVID-19 on quality of life (QoL) in an international inflammatory bowel disease cohort. An online study involving 319 adults (75% female, mean (SD) 14.06 (15.57) years of symptoms) completed the Gastrointestinal Symptom Rating Scale, Brief Illness Perceptions Questionnaire, Fear of Contracting COVID-19 Scale, Brief-COPE, Depression, Anxiety and Stress Scale, and the EUROHIS-QOL. The extended CSM had an excellent fit (χ2 (9) = 17.06, p =.05, χ2/N = 1.90, RMSEA = 0.05, SRMR = 0.04, CFI =.99, TLI =.97, GFI = 0.99), indicating the influence of gastrointestinal symptoms on QoL was mediated by illness perceptions, fear of COVID-19, adaptive and maladaptive coping, and psychological distress. Interventions targeting the fear of COVID-19 in the context of an individual’s perceptions will likely enhance QoL during the pandemic.

Ananthakrishnan A, Nguyen G, Bernstein CN. AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in the Elderly: Expert Review. Gastroenterology 2021; 160: 445-451. 


It is becoming apparent that treatment of IBD in elderly patients requires special consideration while accounting for the effectiveness of immunosuppressive therapies in this subpopulation and less favorable safety profiles. In this review, we present best practice advice statements on the diagnosis and management of IBD in elderly patients. It should be noted that most clinical data to inform these practices are based on observational data or indirect evidence because elderly patients with IBD comprise a very small proportion of participants enrolled in IBD clinical trials or long-term pharmacovigilance initiatives. This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and it underwent internal peer review by the Clinical Practice Updates Committee and external peer review through the standard procedures of the Gastroenterology journal.



1. A diagnosis of IBD (CD, UC) should be considered in older patients who present with diarrhea, rectal bleeding, urgency, abdominal pain, or weight loss because up to 15% of new diagnoses of IBD occur in individuals older than 60 years.

2. Fecal calprotectin or lactoferrin may help prioritize patients with a low probability of IBD for endoscopic evaluation. Individuals presenting with hematochezia or chronic diarrhea with intermediate to high suspicion for underlying IBD, microscopic colitis, or colorectal neoplasia should undergo colonoscopy.

3. In elderly patients with segmental left-sided colitis in the setting of diverticulosis, consider a diagnosis of segmental colitis associated with diverticulosis in addition to the possibility of CD or IBD–unclassified.


Treatment: general principles

1.A comprehensive initial assessment of the older patient is important to collaboratively establish short- and long-term treatment goals and priorities.

2. Clinicians should risk-stratify patients based on the likelihood of severe clinical course, including assessment of perianal or penetrating phenotype, long-segment small bowel involvement (CD), extensive colitis (UC), anemia, hypoalbuminemia, elevated inflammatory markers, and weight loss, to determine an appropriate therapeutic strategy.

3. Systemic corticosteroids are not indicated for maintenance therapy. When used for induction therapy, when possible, clinicians should prefer nonsystemic corticosteroids (like budesonide) or even early biological therapy initiation if budesonide is not appropriate for the phenotype of the disease being treated.

4. Candidacy for immunosuppression should be based on chronologic age, as well as consideration for the patient’s functional status, comorbidities including prior neoplasia and potential for infectious complications, and frailty.

5. When possible, immunomodulatory treatments with lower overall infection or malignancy risk (vedolizumab, ustekinumab) may be preferred in older patients. However, choice of treatment must also include assessment of clinical context, efficacy of treatments for specific phenotypes, rapidity of onset of action, and ability to achieve corticosteroid-free remission.

6.Consideration of thiopurine monotherapy for maintenance of remission in older patients should balance the convenience of its oral route of administration and lower cost with relatively lower efficacy, slow onset of action, and an increase in risk of nonmelanoma skin cancers and lymphoma in this population.

7. Older patients with IBD have a greater burden of comorbidity than younger patients. Optimization of comorbidity is important to minimize the risks associated with IBD and its treatment and guide selection of the appropriate agent.

8. The decision about the timing and type of surgery in older patients with IBD should incorporate disease severity, impact on functional status and independence, risks and effectiveness of medical therapy, candidacy for surgery, and risk of postoperative complications.

9. The increased risk of fracture, venous thromboembolism, infections including pneumonia, opportunistic infections, and herpes zoster and risk of skin and nonskin cancers (including lymphoma) should be incorporated in therapeutic decisions.

10. Care for the older patient with IBD should be multidisciplinary, actively engaging gastrointestinal specialists, primary care providers (including geriatricians), other medical subspecialists (eg, cardiologists) mental health professionals, general or colorectal surgeons, nutritionists, and pharmacists. Engaging with family and caregivers may also be appropriate in formulating a plan.


Health maintenance

1. Clinicians should facilitate adherence to vaccination schedules, including influenza, pneumococcal, and herpes zoster vaccines, in older patients with IBD. If possible, vaccination should be scheduled before starting immunosuppression.

2. The decision to continue or stop colorectal cancer surveillance in older patients with long-standing UC or Crohn’s colitis should be made incorporating age, comorbidity, overall life expectancy, likelihood of endoscopic resectability of the lesion, and candidacy for colon resection surgery.

Kredentser M, Graff LA, Bernstein CN. Psychological Comorbidity and Interventions in Inflammatory Bowel Disease. Journal of Clinical Gastroenterology 2021; 55: 30-35. 


IBD is associated with significant psychological comorbidities, with associated impacts on patient quality of life, disease course, and health care costs. The present article reviews the latest evidence on the etiology of psychological comorbidities in IBD, with a focus on shared inflammatory pathways. The current state of practice in managing and understanding psychological comorbidities from the perspective of both gastroenterology practice and psychological treatment is reviewed, with a focus on evidence-based treatments shown to be effective in managing depression, anxiety, stress, and improving IBD-related health outcomes.


Marrie RA, Bernstein CN. Psychiatric comorbidity in immune-mediated inflammatory diseases. World Psychiatry 2021; 20: 298-299. 


Chronic immune‐mediated inflammatory diseases are a group of conditions characterized by immune dysregulation and aberrant organ system inflammation. Common examples of these conditions include rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and multiple sclerosis. Although these conditions affect different organ systems, they are all characterized by recurrent relapses and potentially debilitating disease progression. Collectively, immune‐mediated inflammatory diseases affect more than 1 in 20 people worldwide, and substantially burden affected persons, their families and societies. The adverse impacts of immune‐mediated inflammatory diseases include symptoms such as pain and fatigue, impairments in relationships and social participation, loss of employment, increased health care utilization, and reduced life expectancy. Comorbid conditions are common in people with immune‐mediated inflammatory diseases and also contribute substantially to their burden.

Comorbid psychiatric disorders, including depression, anxiety disorders and bipolar disorder, are of particular interest. A growing body of evidence indicates that the incidence and prevalence of psychiatric disorders are elevated in persons with immune‐mediated inflammatory diseases as compared to the general population. For example, a population‐based cohort of persons with rheumatoid arthritis, inflammatory bowel disease or multiple sclerosis had an elevated incidence of depression (incidence rate ratio, IRR=1.71; 95% CI: 1.64‐1.79), anxiety (IRR=1.34; 95% CI: 1.29‐1.40), bipolar disorder (IRR=1.68; 95% CI: 1.52‐1.85) and schizophrenia (IRR=1.32; 95% CI: 1.03‐1.69) compared to age‐, sex‐ and geographically‐matched controls.

The association between immune‐mediated inflammatory diseases and psychiatric disorders appears to be bidirectional, and the increased incidence of psychiatric disorders is not simply due to the challenges of living with a chronic disease. In a population‐based study from Denmark involving 1,016,519 individuals, those with depression had a significantly higher risk of developing any immune‐mediated inflammatory diseases in the subsequent 11 years than individuals without depression. In a population‐based study from Canada, individuals with rheumatoid arthritis, inflammatory bowel disease or multiple sclerosis had an increased incidence of any psychiatric disorder, including depression, anxiety, bipolar disorder and schizophrenia, for 8‐10 years prior to the diagnosis of their immune‐mediated inflammatory diseases, even after accounting for sociodemographic factors and number of physician visits.

Broadly, two health conditions may co‐occur for several reasons. Chance alone may account for comorbidity. Surveillance bias may also occur, wherein a person affected by one chronic health condition uses more health care services and consequently is more likely to get diagnosed with a second condition. Furthermore, conditions may co‐occur due to “true etiologic mechanisms”. These mechanisms may include common genetic or environmental factors, or direct causation of the second condition by the first one. Finally, both conditions could be caused by an unrecognized third condition.

Epidemiological and biological evidence suggests that immune‐mediated inflammatory diseases and psychiatric disorders are comorbid due to “true etiologic mechanisms”. In a cohort of 5,727,655 individuals, incident depression was associated with an increased risk of incident Crohn's disease (hazard ratio, HR=2.11; 95% CI: 1.65‐2.70) and ulcerative colitis (HR=2.23; 95% CI: 1.92‐2.60) after adjusting for age, sex, socioeconomic status, comorbid conditions, smoking status and use of antidepressants. Notably, treatment with antidepressants was protective of developing Crohn's disease or ulcerative colitis among individuals with depression.

The role of inflammation and immune dysregulation in immune‐mediated inflammatory diseases is well‐recognized. Emerging evidence is highlighting the importance of immune dysfunction in psychiatric disorders as well, including depression, bipolar disorder, schizophrenia and anxiety disorders. These latter disorders are associated with dysregulation of T cell function and pro‐inflammatory cytokines, including interleukin‐6 (IL‐6), IL‐2 receptor, IL‐1β, IL‐17A, and C‐reactive protein; altered microglial activation; and disruption of the blood‐brain barrier. Pharmacological and non‐pharmacological therapies for depression are associated with reductions in peripheral inflammatory markers. Relatedly, the role of immunomodulatory therapies in the treatment of psychiatric disorders is also being explored. A randomized placebo‐controlled trial in persons with major depression suggested that infliximab, a tumor necrosis factor antagonist, might improve depressive symptoms in persons who had elevated levels of C‐reactive protein at enrollment.

With respect to common etiologic factors, several pleiotropic genetic loci are jointly associated with the risk of psychiatric disorders and immune‐mediated inflammatory diseases, as shown by an analysis of genome‐wide association studies of five psychiatric disorders (major depressive disorder, bipolar disorder, schizophrenia, autism spectrum disorder and attention‐deficit/hyperactivity disorder) and seven immune‐mediated disorders (Crohn's disease, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes, systemic lupus erythematosus and psoriasis). Notably, shared genetic loci related to immune function were prominent.


In addition to genetic factors, psychosocial factors also influence immune system function and inflammation. Acute stress leads to activation of the autonomic nervous system and hypothalamic‐pituitary‐adrenal axis, and upregulates inflammation. Chronic stress, such as childhood maltreatment, increases inflammation and suppresses cellular and humoral immunity. In turn, these changes increase the risk of chronic diseases such as immune‐mediated inflammatory diseases and psychiatric disorders. Social support can mitigate the adverse effects of psychosocial stressors on the risk of chronic diseases. Concordant with these observations, psychosocial interventions, in particular cognitive behavioral therapy and multi‐modality therapies, are associated with sustained improvements in immune system function as measured by pro‐inflammatory cytokines and immune cell counts.

Thus, epidemiological data support bidirectional relationships between psychiatric disorders and immune‐mediated inflammatory diseases, and inflammation and immune dysregulation are common to these conditions. Increasingly, treatment approaches applied to immune‐mediated inflammatory diseases are being tested for psychiatric disorders. However, much remains to be understood about the interface between psychiatric disorders and immune‐mediated inflammatory diseases.



Eissa N, Elgazzar O, Hussein H, Hendy GN, Bernstein CN, Ghia JE. Pancreastatin reduces alternatively activated macrophages, disrupts the epithelial homeostasis and aggravates colonic inflammation. A descriptive analysis. Biomedicines 2021; 9:134.

Ulcerative colitis (UC) is characterized by modifying alternatively activated macrophages and epithelial homeostasis. Chromogranin-A released by enterochromaffin cells, is elevated in UC and is implicated in inflammation progression. CHGA can be cleaved into several derived peptides, including pancreastatin, which is involved in proinflammatory mechanisms. Previously, we showed that the deletion of Chga decreased the onset and severity of colitis correlated with an increase in alternatively activated macrophages and epithelial cells' functions. Here, we investigated pancreastatin activity in colonic biopsies of participants with active UC and investigated pancreastatin treatment in dextran sulfate sodium (DSS)-induced colitis using Chga-/- mice, macrophages, and a human colonic epithelial cells line. We found that the colonic protein expression of pancreastatin correlated negatively with mRNA expression of alternatively activated macrophages markers and tight junction proteins and positively with mRNA expression of interleukin (IL)-8, IL18, and collagen in human. In a preclinical setting, intra-rectal administration of pancreastatin aggravated DSS-induced colitis by decreasing alternatively activated macrophages' functions, enhancing colonic collagen deposition and disrupting epithelial homeostasis in Chga+/+ and Chga-/- mice. This effect was associated with a significant reduction in AAM markers, increased colonic IL-18 release, and decreased tight junction proteins' gene expression. In vitro, pancreastatin reduced Chga+/+ and Chga-/- alternatively activated macrophages polarization and decreased anti-inflammatory mediators' production. Conditioned medium harvested from PST-treated Chga+/+ and Chga-/- alternatively activated macrophages reduced Caco-2 cell migration, viability, proliferation, and mRNA levels of tight junction proteins and increased oxidative stress-induced apoptosis and proinflammatory cytokines release. In conclusion, pancreastatin is a Chromogranin-A proinflammatory peptide that enhances the severity of colitis and the inflammatory process via decreasing alternatively activated macrophages functions and disrupting epithelial homeostasis.


Shen B, Kochar G, Kariv R, Liu X, Navaneethan U, Rubin DT, Cross R, Sugita A, D’Hoore A, Schairer J, Farraye FA, Kiran RP, Fleshner P, Rosh J, Shah S, Chang S, Scherl E, Pardi D, Schwartz DA, Kotze PG, Bruining DH, Kane S, Philpott J, Abraham B, Segal J, Sedano R, Kayal M, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sehgal P, McCormck JT, Picoraro JA, Silverberg MS, Bernstein CN, Sandborn WJ, Vermeire S. Diagnosis and Classification of Ileal Pouch Disorders: Consensus Guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterology and Hepatology 2021; 6: 826-849.


Restorative proctocolectomy with ileal pouch-anal anastomosis is an option for most patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the construction of an ileal pouch substantially improves patients' health-related quality of life, the surgery is, directly or indirectly, associated with various structural, inflammatory, and functional adverse sequelae. Furthermore, the surgical procedure does not completely abolish the risk for neoplasia. Patients with ileal pouches often present with extraintestinal, systemic inflammatory conditions. The International Ileal Pouch Consortium was established to create this consensus document on the diagnosis and classification of ileal pouch disorders using available evidence and the panellists' expertise. In a given individual, the condition of the pouch can change over time. Therefore, close monitoring of the activity and progression of the disease is essential to make accurate modifications in the diagnosis and classification in a timely manner.


Shen B, Kochhar GS, Navaneethan U, Cross RK, Farraye FA, Iacucci M, Schwartz DA, Gonzalez-Lama Y, Schairer J, Kiran RP, Kotze PG, Kobayashi T, Bortlik M, Liu X, Levy AN, González Suárez B, Tang SJ, Coelho-Prabhu N, Lukas M, Bruining DH, El-Hachem S, Charles RJ, Chen Y, Sood A, Mao R, Loras C, Dulai PS, Picoraro JA, Chiorean M, Lukas M, Shergill A, Silverberg MS, Sandborn WJ, Bernstein CN. Endoscopic evaluation of surgically altered bowel in inflammatory bowel disease: a consensus guideline from the Global Interventional Inflammatory Bowel Disease Group.  Lancet Gastroenterology and Hepatology 2021; 6: 482-487.

The majority of patients with Crohn's disease and a proportion of patients with ulcerative colitis will ultimately require surgical treatment despite advances in diagnosis, therapy, and endoscopic interventions. The surgical procedures that are most commonly done include bowel resection with anastomosis, strictureplasty, faecal diversion, and ileal pouch. These surgical treatment modalities result in substantial alterations in bowel anatomy. In patients with inflammatory bowel disease, endoscopy plays a key role in the assessment of disease activity, disease recurrence, treatment response, dysplasia surveillance, and delivery of endoscopic therapy. Endoscopic evaluation and management of surgically altered bowel can be challenging. This consensus guideline delineates anatomical landmarks and endoscopic assessment of these landmarks in diseased and surgically altered bowel.


Singh A, Mahajan R, Kedia S, Dutta AK, Anand A, Bernstein CN, Desai D, Pai CG, Makharia G, Tevethia HV, Mak JW, Kaur K, Peddi K, Ranjan MK, Arkkila P, Kochhar R, Banerjee R, Sinha SK, Ng SC, Hanauer S, Verma S, Dutta U, Midha V, Mehta V, Ahuja V, Sood A. Use of thiopurines in inflammatory bowel disease: an update. Intestinal Research 2021; in press. 


This is a review of thiopurine use to treat IBD in India. IBD, once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.


Herman SM, MD, Zaborniak K, Bernstein CN. Insight into IBD pathogenesis: Is the answer blowing in the wind? Inflammatory Bowel Diseases 2021; in press.


Inflammatory bowel diseases (IBD) including Crohn's disease and ulcerative colitis are conditions characterized by immune dysregulation to a trigger in those with a genetic predisposition. Environmental factors are thought to contribute to IBD, but no definite trigger has been identified. Aeroallergens have not been thoroughly investigated in their potential contribution to the pathogenesis to IBD. The geographic distribution of aeroallergens and IBD, the association of atopic disease with IBD, seasonality and IBD, and cross-reactive food allergens require further study with implications for targeted dietary and immunomodulatory therapies.



Carney H, Marrie RA, Bolton JM, Patten SB, Graff LA, Bernstein CN, Kowalec K. Prevalence and Risk Factors of Substance Use Disorder in Inflammatory Bowel Disease. Inflammatory Bowel Diseases 2021; 27: 58–64.​

Substance use disorders impose a substantial individual and societal burden; however, the prevalence and associated factors in persons with inflammatory bowel disease (IBD) are largely unknown. We evaluated the prevalence and risk factors of substance use disorders in an IBD cohort. Inflammatory bowel disease participants (n = 247) were recruited via hospital- and community-based gastroenterology clinics, a population-based IBD research registry, and primary care providers as part of a larger cohort study of psychiatric comorbidity in immune-mediated inflammatory diseases. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV was administered to participants to identify lifetime substance use disorders, anxiety disorders, and major depressive disorders. Additional questionnaires regarding participants' sociodemographic and clinical characteristics were also completed. We examined demographic and clinical factors associated with lifetime substance use disorders using unadjusted and adjusted logistic regression modeling. Forty-one (16.6%) IBD participants met the criteria for a lifetime diagnosis of a substance use disorder. Factors associated with elevated odds of substance use disorders were ever smoking (adjusted odds ratio [aOR], 2.96; 95% confidence interval [CI], 1.17-7.50), male sex (aOR, 2.44; 95% CI, 1.11-5.36), lifetime anxiety disorder (aOR, 2.41; 95% CI, 1.08-5.37), and higher pain impact (aOR, 1.08; 95% CI, 1.01-1.16).

We concluded that one in six persons with IBD experienced a substance use disorder, suggesting that clinicians should maintain high index of suspicion regarding possible substance use disorders, and inquiries about substance use should be a part of care for IBD patients, particularly for men, smokers, and patients with anxiety disorders.

Shafer LA, Sofia MA, Rubin DT, Steinhart AH, Ng SC, Reches L, Israeli E, Bernstein CN. An International Multicentre Comparison of IBD Related Disability and Validation of the IBDDI. Clinical Gastroenterology and Hepatology 2020; in press. 

The IBD disability index (IBDDI) has been shown to be valid and reliable. We compared the distributional and predictive properties of the IBDDI, when collected from five populations of people living with IBD- from Winnipeg, Chicago, Toronto, Hong Kong, and Jerusalem. People with IBD from 5 jurisdictions were invited to complete a survey including the IBDDI, the World Health Organization Disability Assessment Scale, the Work and Social Adjustment Scale, the IBDQ, the Kessler-6 distress scale, and the Stanford presenteeism scale. Between sites, we compared the correlation between IBDDI and the other 4 measures of disability/quality of life/distress, and the association between IBDDI and presenteeism and having been hospitalized in the past year. There were 1121 participants from Winnipeg, 511 from Chicago, 147 from Toronto, 97 from Hong Kong, and 96 from Jerusalem. The majority had Crohn's disease. Although the mean IBDDI score varied by site, the correlation between IBDDI and each of the other 4 measures of disability/QOL/distress was nearly identical. Similarly, the regression coefficient showing the association between IBDDI and presenteeism was nearly identical in all sites, and the risk ratios showing the association between hospitalization and high IBDDI was similar in all sites.

We concluded that the correlation between IBDDI and different measures of disability/QOL/distress was similar across all sites. There is strong evidence of the association between IBD-related disability and presenteeism, and between hospitalization and high IBD-related disability, and that the associations are the same across different populations. The severity of disability that an individual with a given IBDDI score has is directly comparable across populations.

Sood A, Singh A, Midha V Mahajan R, Kao D, Rubin D, Bernstein CN. Faecal Microbiota Transplantation; for Ulcerative Colitis: An Evolving Therapy. Crohn’s and Colitis 360 2020; in press. 


Fecal microbiota transplantation is an established treatment for recurrent and refractory Clostridioides difficile infection. However, its use in inflammatory bowel disease, ulcerative colitis in particular, is at an early stage and significant gaps remain in our understanding of the mechanisms and logistics of practical application. This article aims to assess unsettled issues for fecal microbiota transplantation in UC. Experts with experience in different modes of fecal microbiota transplantation reviewed the published and grey scientific literature to synthesize information regarding methods of performance and outcomes for fecal microbiota transplantation. This includes proposed mechanisms of action, donor and recipient selection, route of administration, need for maintenance therapy, impact of diet, response assessments, outcomes from randomized controlled trials and the current state of fecal microbiota transplantation regulations. The science of the gut microbiome is still rudimentary and clinical use of fecal microbiota transplantation outside clinical trials is not recommended at the moment. Current methods of performing fecal microbiota transplantation are crude and primordial.  Advancements in fecal slurry preparation and mode of delivery are necessary. It remains to be seen whether shifting to selective microbiota transplantation tailored according to a particular disease can substitute the whole stool; or whether donors and recipients should be matched for genotype, diet, or environment. We recommend the term fecal microbiota transplantation should be replaced by intestinal microbiome transfer (IMT).

The future holds much promise for the potential applications of this approach to management of ulcerative colitis, however more research refining the technique is warranted before it can become an accepted clinical practice.

Chen Y, Yu Q, Farraye FA, Kochhar GS, Bernstein CN, Navaneethan U, Wu K, Zhong J, Schwartz DA, Wu H, Zheng JJ, Iacucci M, Kiran RP, Shen B. Patterns of endoscopy during COVID-19 pandemic: a global survey of interventional inflammatory bowel disease practice. Intestinal Research 2021; 19(3): 332-340. 


Performance of diagnostic or therapeutic endoscopic procedures in IBD patients can be challenging during a viral pandemic; the main concerns being the safety and protection of patients and health care providers. The aim of this study was to identify endoscopic practice patterns and outcomes of IBD and coronavirus disease 19 (COVID-19) with a worldwide survey of health care providers. A 20-item survey questionnaire was sent to physician members of the American Society for Gastrointestinal Endoscopy Special Interest Group in Interventional IBD, Chinese IBD Society Endoscopy Interest Group, and the China Crohn's and Colitis Foundation. A total of 141 respondents submitted valid responses. Nighty-five respondents (67.9%) reported that at least 25% of their scheduled emergent endoscopic procedures were canceled or postponed during the pandemic. Fifty-six respondents (40.0%) have performed emergent endoscopy during the pandemic. A few respondents (9/140, 6.4%) estimated that more than 25% of their patients had worsened disease due to delayed or canceled emergent endoscopy procedures. More than 80% of respondents believed that personal protective equipment (PPE) for the endoscopy team, room sterilization, and pre-procedure screening of patients for COVID-19 were necessary. Out of 140 respondents, 16 (11.4%) reported that several of their patients had COVID-19. Eight clinicians (5.7%) reported that they or their endoscopy colleagues developed work-related COVID-19.

We concluded that cancellation of elective and emergent endoscopy in IBD care during the pandemic was common. Few respondents reported that their patients' disease conditions worsened due to the cancellation of the endoscopy procedure. Most respondents voiced the need for proper PPE during the procedure regardless of patients' COVID-19 status and screening the patients for COVID-19.



Fischer F, Levis L, Falk C, Sun Y, Ioannidis JPA, Cuijpers P, Shrier I, Benedetti A, Thombs BD, and the Depression Screening Data (DEPRESSD) PHQ Collaboration (C Bernstein member of group authorship). Comparison of different scoring methods based on latent variable models of the PHQ-9: an individual participant data meta-analysis. Psychological Medicine 2021; Feb 22:1-12


Previous research on the depression scale of the Patient Health Questionnaire (PHQ-9) has found that different latent factor models have maximized empirical measures of goodness-of-fit. The clinical relevance of these differences is unclear. We aimed to investigate whether depression screening accuracy may be improved by employing latent factor model-based scoring rather than sum scores. We used an individual participant data meta-analysis (IPDMA) database compiled to assess the screening accuracy of the PHQ-9. We included studies that used the Structured Clinical Interview for DSM (SCID) as a reference standard and split those into calibration and validation datasets. In the calibration dataset, we estimated unidimensional, two-dimensional (separating cognitive/affective and somatic symptoms of depression), and bi-factor models, and the respective cut-offs to maximize combined sensitivity and specificity. In the validation dataset, we assessed the differences in (combined) sensitivity and specificity between the latent variable approaches and the optimal sum score (⩾10), using bootstrapping to estimate 95% confidence intervals for the differences. The calibration dataset included 24 studies (4378 participants, 652 major depression cases); the validation dataset 17 studies (4252 participants, 568 cases). In the validation dataset, optimal cut-offs of the unidimensional, two-dimensional, and bi-factor models had higher sensitivity (by 0.036, 0.050, 0.049 points, respectively) but lower specificity (0.017, 0.026, 0.019, respectively) compared to the sum score cut-off of ⩾10.


We concluded that in a comprehensive dataset of diagnostic studies, scoring using complex latent variable models do not improve screening accuracy of the PHQ-9 meaningfully as compared to the simple sum score approach.

Chhibba T, Guizzetti L, Seow CH, Lu C, Novak KL, Ananthakrishnan AN, Bernstein CN, Kaplan GG, Panaccione R, Ma C. Frequency of Opioid Prescription at Emergency Department Discharge in Patients with Inflammatory Bowel Disease: A Nationwide Analysis. Clinical Gastroenterology Hepatology 2021 Oct; 19(10): 2064-2071.

Patients with IBD frequently experience chronic pain. Patients will often seek out care in the emergency department where short-term opioid use may be associated with potential treatment-related complications. We aimed to assess the rate and factors associated with opioid prescription in IBD patients discharged from the emergency department. We conducted a cross-sectional analysis of data collected in the US National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2006-2017. We determined the proportion of adult patients (≥18 years) with IBD prescribed an opioid in emergency department or at emergency department discharge. We identified ∼965,000 weighted discharges from the emergency department for patients with IBD. In total, 51.9% [95% CI: 42.2% -61.6%] of visits resulted in opioid administration in the emergency department and 35.3% [95% CI: 26.5% -45.2%] of IBD-related emergency department discharges were associated with an opioid prescription. IBD patients with moderate/severe pain (adjusted odds ratio aOR 5.06 [95% CI: 1.72 -14.90], p < 0.01) were more likely to receive opioids whereas older age (aOR 0.73 per decade [95% CI: 0.55 -0.98], p = 0.04) were less likely. In temporal analysis, a trend towards decreasing opioid use in the emergency department and opioid prescriptions at discharge was observed in 2015-2017.

More than one third of IBD patients are prescribed an opioid at discharge from the emergency department, highlighting a potential gap in care for accessing effective pain management solutions in this population.

Publications // from the Manitoba IBD Epidemiology Database