Epidemiology Publications // 2017-2018

Shafer LA, Walker JR, Waldman C, Michaud V, Yang C, Bernstein CN, Hathout L, Park J, Sisler J, Wittmeier K, Restall G, Singh H. Predictors of patient reluctance to wake early in the morning for bowel preparation for colonoscopy: A precolonoscopy survey in city wide practice. Endoscopy International Open 2018; Jun;6(6):E706-E713.

Many endoscopists do not use split-dose bowel preparation (SDBP) for morning colonoscopies. Despite SDBP being recommended practice, they believe patients will not agree to take early morning bowel preparation. In this study we assessed patients' opinions about waking early for bowel prep. A self-administered survey was distributed between 08/2015 and 06/2016 to patients in Winnipeg when they attended an outpatient colonoscopy. Of the 1336 respondents (52 % female, median age 57 years), 33 % had used SDBP for their current colonoscopy. Of the 1336, 49 % were willing, 24 % neutral, and 27 % reluctant to do early morning BP. Predictors of reluctant versus willing were number of prior colonoscopies (OR 1.20; 95 %CI: 1.07 - 1.35), female gender (OR 1.65; 95 %CI: 1.19 - 2.29), unclear bowel prep information (OR 1.86; 95 %CI: 1.21 - 2.85), high BP anxiety (OR 2.02; 95 %CI: 1.35 - 3.02), purpose of current colonoscopy being bowel symptoms (OR 1.40; 95 %CI: 1.00 - 1.97), use of 4 L of polyethylene glycol laxative (OR 1.45; 95 %CI: 1.02 - 2.06), not having SDBP (OR 1.96; 95 %CI: 1.31 - 2.93), and not having finished the laxative for the current colonoscopy (OR 1.66; 95 %CI: 1.01 - 2.73).  We concluded that almost three-quarters of patients do not express reluctance to get up early for BP. Among those who are reluctant, improving bowel prep information, allaying bowel prep-related anxiety, and use of low volume bowel prep may increase acceptance of SDBP.

Shafer LA, Walker JR, Yang C, Waldman C, Michaud V, Bernstein CN, Hathout L, Park J, Sisler J, Restall G, Wittmeier K, Singh H. Factors Associated with Anxiety about Colonoscopy: The Preparation, the Procedure, and the Anticipated Findings. Digestive Diseases and Sciences 2018; 63: 610-8.

Previous research has assessed anxiety around colonoscopy procedures, but has not considered anxiety related to different aspects related to the colonoscopy process. Before patients underwent colonoscopy, we assessed anxiety about: bowel preparation, the procedure, and the anticipated results.  An anonymous survey was distributed to patients immediately prior to their outpatient colonoscopy in six hospitals and two ambulatory care centers in Winnipeg, Canada. Anxiety was assessed using a visual analog scale. A total of 1316 respondents completed the questions about anxiety (52% female, median age 56 years). Anxiety scores > 70 (high anxiety) were reported by 18% about bowel preparation, 29% about the procedure, and 28% about the procedure results. High anxiety about bowel preparation was associated with female sex, perceived unclear instructions, unfinished laxative, and no previous colonoscopies. High anxiety about the procedure was associated with female sex, no previous colonoscopies, and confusing instructions. High anxiety about the results was associated with symptoms as an indication for colonoscopy and instructions perceived as confusing.  In summary, fewer people had high anxiety about preparation than about the procedure and findings of the procedure. There are unique predictors of anxiety about each colonoscopy aspect. Understanding the nuanced differences in aspects of anxiety may help to design strategies to reduce anxiety, leading to improved acceptance of the procedure, compliance with preparation instructions, and less discomfort with the procedure.

Siegel CA, Whitman CB, Spiegel BMR, Feagan B, Sands B, Loftus EV Jr, Remo Panaccione, D’Haens G, Bernstein CN, Gearry R, Ng S, Mantzaris GJ, Sartor B, Silverberg MS, Riddell R, Koutroubakis I, O’Morain C, Lakatos PL, McGovern DPB, Halfvarson J, Reinisch W, Rogler G, Kruis W, Tysk C, Schreiber S, Danese S, Sandborn W, Griffiths A, Moum B, Gasche C, Pallone F, Travis S, Panes J, Colombel JF, Hanauer S, Peyrin-Biroulet L. Development of an index to define overall disease severity in inflammatory bowel disease. Gut 2018; 67: 244-54.

Disease activity for Crohn's disease and ulcerative colitis is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both Crohn's disease and ulcerative colitis. 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise to create a relative ranking of these attributes. For Crohn’s disease, 16% of overall disease severity was attributed to the presence of mucosal lesions (lesions in the lining of the bowel), 11% to a history of a fistula, 10% to history of abscess and 7% to history of intestinal surgery. For ulcerative colitis, 18% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11% for C reactive protein (a blood measure of inflammation) and 10% for prior experience with biologics. Based on specialist opinion, overall Crohn’s disease severity was associated more with intestinal damage, in contrast to overall ulcerative colitis disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.

 

Forbes JD, Chen CY, Knox NC, Marrie RA, EL Gabalawy H, de Kevit T, Alfa M, Bernstein CN. Van Domselaar G. A comparative study of the gut microbiota in immune-mediated inflammatory diseases - does a common dysbiosis exist? Microbiome 2018 Dec 13: 6 (1): 221: 1-15.

 

Immune-mediated inflammatory disease represents a substantial health concern. It is widely recognized that immune-mediated inflammatory disease patients are at a higher risk for developing secondary inflammation-related conditions. While an ambiguous etiology is common to all immune-mediated inflammatory diseases, in recent years, considerable knowledge has emerged regarding the plausible role of the gut microbiome in immune-mediated inflammatory diseases. This study used 16S rRNA gene amplicon sequencing to compare the gut microbiota of patients with Crohn's disease (N = 20), ulcerative colitis (N = 19), multiple sclerosis (N = 19), and rheumatoid arthritis (N = 21) versus healthy controls (N = 23). Biological replicates were collected from participants within a 2-month interval. This study aimed to identify common (or unique) taxonomic biomarkers of immune-mediated inflammatory disease s using both differential abundance testing and a machine learning approach. Significant microbial community differences between cohorts were observed. Richness and diversity were significantly different between cohorts and were lowest in Crohn’s disease while highest in healthy controls. Abundances of Actinomyces, Eggerthella, Clostridium III, Faecalicoccus, and Streptococcus were significantly higher in all disease cohorts relative to healthy controls, whereas significantly lower abundances were observed for Gemmiger, Lachnospira, and Sporobacter. Several taxa were found to be differentially abundant in immune-mediated inflammatory diseases versus healthy controls including significantly higher abundances of Intestinibacter in Crohn’s disease, Bifidobacterium in UC, and unclassified Erysipelotrichaceae in multiple sclerosis and significantly lower abundances of Coprococcus in Crohn’s disease, Dialister in multiple sclerosis, and Roseburia in rheumatoid arthritis. A machine learning approach to classify disease versus healthy controls was highest for Crohn’s disease followed by multiple sclerosis, rheumatoid arthritis and UC. Gemmiger and Faecalicoccus were identified as important features for classification of subjects to Crohn’s disease and health controls. In general, features identified by differential abundance testing were consistent with machine learning feature importance. This study identified several gut microbial taxa with differential abundance patterns common to immune-mediated inflammatory diseases. We also found differentially abundant taxa between immune-mediated inflammatory diseases. These taxa may serve as biomarkers for the detection and diagnosis of immune-mediated inflammatory diseases and suggest there may be a common component to immune-mediated inflammatory diseases etiology.

 

Bernstein CN. Past time for doctors to lessen their dependence on corticosteroids in the treatment of IBD. American Journal of Gastroenterology 2018; 113:418-420.

 

This editorial reviews the risks of using corticosteroids in treatment of IBD. Corticosteroids are effective treatment for both Crohn’s disease and UC but they are often overused.​

Shafer LA, Walker JR, Chhibba T, Ivekovic M, Singh H, Targownik LE, Peyrin-Biroulet L, Gower-Rousseau, Sarter H, Bernstein CN. Independent validation of a self-report version of the IBD Disability Index (IBDDI) in a population-based cohort of IBD patients. Inflammatory Bowel Diseases 2018; 24: 766-74.

 

A new clinician-administered inflammatory bowel disease (IBD) Disability Index (IBDDI) was recently developed and validated among a population in France. We aimed to validate the IBDDI in a North American setting and adapt for use as a self-report tool. Persons 18-65 years old from the University of Manitoba IBD Research Registry were mailed a self-administered survey. This survey included the IBDDI and several scales that should correlate with a disability measure- the World Health Organization (WHO) Disability Assessment Scale (WHODAS) 2.0, Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the K6-Kessler Emotional Distress Scale. We measured how robust this IBDDI performed compared to other indices. In response to the survey request,1143 (46% of those contacted) participated (61% female, average age 51, 52% with Crohn's disease, 48% with ulcerative colitis). On an index scale from 0-100, we considered a score of greater than or equal to 50  to reflect extreme disability. 14% had a score of greater than 50 (18% of those with Crohn's disease; 10% of those with ulcerative colitis). There were strong correlations between IBDDI and WSAS (0.76), WHODAS (0.76), K6 (0.73), and an expected inverse correlation with IBDQ (-0.86). The findings support the validity of this new self-report version of the IBDDI as a sound measure of disability in IBD.

Schoenfeld R, Nguyen G, Bernstein CN. Integrated Care Models:Optimizing Adult Ambulatory Care in Inflammatory Bowel Disease. Journal of Canadian Association of Gastroenterology 2018; in press.

 

The purpose of this article was to review the literature on outpatient care models used to treat adults with IBD, and to gain insight on how to improve quality of care and reduce costs. A comprehensive review of recent literature on PubMed, Scopus, and Google Scholar databases about care models used to treat IBD was performed. Studies showed that an integrated care model decreases hospital admissions, IBD-related surgeries, and comorbidities of IBD, ultimately decreasing direct and indirect costs of IBD compared to a more traditional patient-physician model.  A gastroenterologist-led multidisciplinary team, involving comprehensive care by IBD nurses, a surgeon, psychologist, dietician, pharmacist, and other members as needed is recommended. We concluded that a holistic approach to IBD care delivered by a multidisciplinary team, with structured monitoring, active follow-up, patient education, and prompt access to care improves outcomes for IBD patients. More research is needed on the cost-effectiveness of integrated care models to demonstrate long-term value and secure funding for implementation.

Whitehouse CE, Fisk JD, Bernstein CN, Berrigan LI, Bolton JM, Graff LA, Hitchon CA, Marriott JA, Peschken CA, Sareen JA, Walker JR, Stewart SH, Marrie RA for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Comorbid anxiety, depression and cognition in MS and other immune-mediated disorders. Neurology 2018; in press.

 

In this report we aimed to determine whether anxiety and depression were associated with cognition in multiple sclerosis, and whether these associations were similar in other immune-mediated inflammatory diseases like IBD, and rheumatoid arthritis, and in anxious/depressed individuals without a chronic immune mediated disease.  There were 255 persons with multiple sclerosis, 247 persons with IBD, 154 persons with rheumatoid arthritis and 308 persons with anxiety and/or depression. All persons completed a structured psychiatric interview (SCID), the Hospital Anxiety and Depression Scale (HADS), and cognitive testing, including the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT-II), and Letter Number Sequencing (LNS). All cohorts exhibited higher rates of cognitive impairment in the domains of processing speed, verbal learning, and delayed recall memory relative to general population norms. Higher levels of anxiety symptoms were associated with slower processing speed, lower verbal learning, and lower working memory performance (all p < 0.001); higher levels of depression symptoms were associated with slower processing speed. These associations did not differ across cohorts.

We concluded that anxiety and depression were associated with lower cognitive function in multiple sclerosis with a similar pattern observed in persons with other IBD and rheumatoid arthritis, and persons without a a chronic immune disease. Managing symptoms of anxiety and of depression in chronic immune diseases is important to mitigate their effect on cognition.

Bernstein CN. Addressing mental health in persons with IBD. Journal of Canadian Association of Gastroenterology 2018;1:97-98.

 

This editorial discusses the importance of addressing mental health issues in patients with IBD.

 

Marrie RA, Graff LA, Walker JR Fisk JD, Patten SB, Walld R, Hitchon C, Lix L, Bolton JM, Sareen J, Singer A, Lix L, Katz A, Berrigan LI, Marriott JM, Singer A, El-Gabalawy R, Peschken CA, Zarychanski R, Bernstein CN. Effects of Psychiatric Comorbidity in Immune-Mediated Inflammatory Disease: Protocol for a Prospective Study. JMIR Research Protocols 2018; Jan 17;7(1):e15.

 

In this paper we reported the research protocol we have pursued in studying psychiatric comorbidity (having a concurrent mental health diagnosis) in persons with a chronic immune disease (any of IBD, multiple sclerosis or rheumatoid arthritis). We described how participants were recruited and how we interviewed participants on an annual basis. We also described the aspects of the research program that did involve direct patient contact. This included using administrative health data (insurance data from Manitoba Health) to understand how common it was in the general population to have both a mental health diagnosis and one of the chronic immune disease diagnoses; and also how likely it was that these mental health disorders occurred long before the onset of the chronic immune disease. Another aspect of our research program was to undertake systematic reviews of the medical research to understand the degree to which research has been undertaken exploring treatment of mental health diseases in these chronic immune diseases and what the outcomes of that research were.

Litster B, Bernstein CN, Graff LA, Walker JR, Fisk JD, Patten SB, Bolton JM, Sareen J, El-Gabalawy R, Marrie RA. Validation of the PHQ-9 for suicidal ideation in persons with inflammatory bowel disease. Inflammatory Bowel Diseases 2018; 24: 1641-8.

Suicide is a leading cause of death worldwide. Transition from suicidal ideation (SI) to suicide attempt is high within a year of SI onset. The risk of suicide and SI is elevated in persons with IBD versus the general population. We aimed to validate the Patient Heath Questionnaire (PHQ)-9 as a screening tool for SI in IBD and to determine factors associated with SI in IBD. IBD participants in our research program exploring psychiatric comorbidity in chronic immune diseases completed the PHQ-9 and participated in the Structured Clinical Interview for DSM-IV (SCID). We determined the sensitivity, specificity, and positive and negative predictive value (PPV and NPV) of the PHQ-9 in identifying SI as compared to the SCID. In other words, we determined how robust a tool the PHQ-9 was at predicting SI.  SI was endorsed by 24 (9.7%) participants on the PHQ-9 and 5 (2.0%) based on the SCID. The PHQ-9 had good sensitivity (100%), specificity (92.2%), and NPV (100%) but low PPV (20.8%) for SI. Factors strongly associated with SI were depression (OR 13.1; 95%CI: 4.46, 40.5), anxiety (OR 11.3; 95%CI: 4.46, 28.6), and active disease (OR 3.87; 95%CI: 1.54, 9.71). On multivariable analysis, the only factors that predicted SI were depression (OR 5.54; 95%CI: 1.67, 18.4) and pain (OR 1.14; 95%CI: 1.03, 1.25). People with depression were more than 5 times as likely to have SI than people without depression.) We concluded that overall the PHQ-9 is a valid screening tool for SI in IBD patients, and routine implementation of this tool would support screening for depression and SI effectively and efficiently in clinical practice.

Marrie RA, Fisk J, Walker JR, Patten S, Lix L, El Gabalawy R, Hitchon CA, Walld R, Katz A, Bernstein CN.  Physical Comorbidities Increase the Risk of Psychiatric Comorbidity in Immune-Mediated Inflammatory Disease. General Hospital Psychiatry; 2018; 51: 71-78.

 

As part of our research program exploring psychiatric comorbidity in chronic immune diseases we tested the association between physical comorbidity and incident depression, anxiety disorder and bipolar disorder in IBD), multiple sclerosis and rheumatoid arthritis compared to matched controls. Using population-based administrative data we identified 6119 persons with IBD, 3514 persons with MS, 10,206 persons with RA and 97,727 matched controls. We identified incident cases of depression, anxiety disorder and bipolar disorder in these populations. The risk of incident depression, anxiety disorders and bipolar disorder was higher in each chronic immune disease cohort compared with controls. The risk of newly diagnosed mental health disorders increased with an increasing number of physical comorbidities for each mental health disorder evaluated, across all 3 immune diseases. In conclusion within each chronic immune disease cohort physical comorbidity increases the risk of psychiatric comorbidity.

Bernstein CN, Zhang L, Lix LM, Graff LA, Walker JR, Fisk JD, Patten SB, Hitchon CA, Bolton JM, Sareen J, El-Gabalawy R, Marriott J, Marrie RA.  The validity and reliability of screening measures for depression and anxiety disorders in inflammatory bowel disease. Inflammatory Bowel Diseases 2018; in press.

We evaluated the validity and reliability of multiple symptom scales for depression and anxiety for persons with IBD. IBD participants in a cohort study completed a Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed the Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Kessler-6 Distress Scale, PROMIS Emotional Distress Depression Short-Form 8a (PROMIS Depression) and Anxiety Short-Form 8a (PROMIS Anxiety), Generalized Anxiety Disorder 7-item Scale, and Overall Anxiety and Severity Impairment Scale. The SCID diagnoses was the reference standard. Of 242 participants, the SCID classified 8.7% as having major depression and 17.8% as having anxiety disorders. Among the depression scales, the PHQ-9 had the highest sensitivity (95%). Specificity was generally higher than sensitivity and was highest for the HADS-D (cut-point of 11; 97%). The area under the ROC curve (AUC) did not differ significantly among depression scales. Among the anxiety scales, sensitivity was highest for the PROMIS (79%). Specificity ranged from 82% to 88% for all tools except the HADS-A (cut-point of 8; 65%). The AUC did not differ between depression and anxiety tools. We concluded that overall, the symptom scales for depression and anxiety were similar in their psychometric properties. The anxiety scales did not perform as well as the depression scales. Alternate cut-points may be more relevant when these scales are used in an IBD sample.

Enns M, Bernstein CN, Kroeker K, Graff LA, Walker JR, Lix LM, Hitchon CA, El-Gabalawy R, Fisk JD, Marrie RA. The association of fatigue, pain, depression and anxiety with work and activity impairment 2 in immune mediated inflammatory diseases. PLOS One 2018; Jun 7;13(6):e0198975.

 

Impairment in work function is a frequent outcome in patients with chronic conditions such as immune-mediated inflammatory diseases (IMID), depression and anxiety disorders. The personal and economic costs of work impairment in these disorders are immense. Symptoms of pain, fatigue, depression and anxiety are potentially remediable forms of distress that may contribute to work impairment in chronic health conditions such as IMID. The present study evaluated the association between pain [Medical Outcomes Study Pain Effects Scale], fatigue [Daily Fatigue Impact Scale], depression and anxiety [Hospital Anxiety and Depression Scale] and work impairment [Work Productivity and Activity Impairment Scale] in four patient populations: multiple sclerosis (n = 255), IBD (n = 248, rheumatoid arthritis (n = 154) and a depression and anxiety group (n = 307), using quantile regression, controlling for the effects of sociodemographic factors, physical disability, and cognitive deficits. Each of pain, depression symptoms, anxiety symptoms, and fatigue individually showed significant associations with work absenteeism, presenteeism, and general activity impairment. When the distress variables were entered concurrently into the regression models, fatigue was a significant predictor of work and activity impairment in all models (quantile regression standardized estimates ranging from 0.2 to 0.5). These findings have important clinical implications for understanding the determinants of work impairment and for improving work-related outcomes in chronic disease.

Marrie RA, Walld R, Bolton J, Sareen J, Patten S, Singer A, Lix L, Hitchon C, El-Gabalawy R, Katz A, Fisk J, Bernstein CN. Psychiatric comorbidity increases mortality in immune-mediated inflammatory diseases. General Hospital Psychiatry 2018; 53:65-72.

We determined the association between any common mental disorder (depression, anxiety disorder, bipolar disorder) and mortality and suicide in three immune-mediated inflammatory diseases (IMID), inflammatory bowel disease (IBD), multiple sclerosis and rheumatoid arthritis, versus age-, sex- and geographically-matched controls. Using administrative data, we identified 28,384 IMID cases (IBD: 8695; Multiple sclerosis: 5496; rheumatoid arthritis: 14,503) and 141,672 matched controls. We determined annual rates of mortality, suicide and suicide attempts. We evaluated the association of any common mental disorder with all-cause mortality and suicide using multivariable Cox regression models. In the IMID cohort, any common mental disorder was associated with increased mortality. We observed a greater than additive interaction between depression and IMID status (attributable proportion 5.2%), but a less than additive interaction with anxiety (attributable proportion -13%). Findings were similar for multiple sclerosis and rheumatoid arthritis. In IBD, a less than additive interaction existed with depression and anxiety on mortality risk. The IMID cohort with any common mental disorder had an increased suicide risk versus the matched cohort without common mental disorder. We concluded that common mental disorders are associated with increased mortality and suicide risk in IMID. In multiple sclerosis and rheumatoid arthritis, the effects of depression on mortality risk are greater than associations of these IMID and depression alone.​

 

Witges K, Targownik LE, Haviva C, Walker JR, Graff LA, Sexton K, Lix L, Sargent M, Vagianos K, Bernstein CN. Living With Inflammatory Bowel disease: Protocol for a longitudinal study of factors associated with symptom exacerbations. Journal of Medical Internet Research Research Protocols 2018 (Nov 12); 7(11):e11317.

 

There has been limited longitudinal research that has comprehensively evaluated possible factors in the exacerbation of inflammatory bowel disease  symptoms with or without associated inflammation. Evolving Web-based technologies facilitate frequent monitoring of patients' experiences and allow a fine-grained assessment of disease course. We aimed to prospectively identify factors associated with symptom exacerbation and inflammation in IBD including psychological functioning, diet, health behaviors, and medication adherence. Between June 2015 and May 2017, we enrolled adults with IBD, recruited from multiple sources, who had been symptomatically active at least once within the prior 2 years. They completed a Web-based survey every 2 weeks for 1 year and submitted a stool sample at baseline, 26 weeks, and 52 weeks. Any participant reporting a symptom exacerbation was matched to a control within the cohort, based on disease type, sex, age, and time of enrollment; both were sent a supplemental survey and stool collection kit. Biweekly surveys included validated measures of the disease course, psychological functioning, health comorbidities, and medication use. Intestinal inflammation was identified through fecal calprotectin (positive level >250 μg/g stool). There were 155 participants enrolled with confirmed IBD, 66.5% (103/155) with Crohn’s disease and 33.5% (52/155) with ulcerative colitis, of whom 98.7% (153/155) completed the study. Over the 1-year period, 47.7% (74/155) participants experienced a symptom exacerbation. The results of analyses on risk factors for symptom exacerbations are pending. We recruited and retained a longitudinal IBD cohort that will allow the determination of risk factors for symptom exacerbation with and without inflammation. This will increase understanding of symptom exacerbations among persons with IBD.

Shah SC, Khalili H, Gower-Rousseau C, Olen O, Benchimol EI, Lynge E, Nielsen KR, Brassard P, Vutcovici M, Bitton A, Bernstein CN, Leddin D, Tamim H, Stefansson T, Loftus EV, Moum B, Tang W, Ng S, Gearry R, Sincic B, Bell S, Sands BE. Lakatos PL, Végh Z, Ott C, Kaplan GG, Burisch J, Colombel JF. Sex-based difference in the incidence of inflammatory bowel disease: a pooled analysis of population-based studies. Gastroenterology 2018 Oct;155(4): 1079-1089.

Although the incidence of IBD varies with age, few studies have examined variations between the sexes. We therefore used population data from established cohorts to analyze sex differences in IBD incidence according to age at diagnosis. We identified population-based cohorts of patients with IBD for which incidence and age data were available (17 distinct cohorts from 16 regions of Europe, North America, Australia, and New Zealand). We collected data through December 2016 on 95,605 incident cases of Crohn's disease (42,831 male and 52,774 female) and 112,004 incident cases of UC (61,672 male and 50,332 female). We pooled incidence rate ratios of Crohn’s disease and UC for the combined cohort and compared differences according to sex using random effects meta-analysis. Female patients had a lower risk of Crohn’s disease during childhood, until the age range of 10-14 years (incidence rate ratio, 0.70; 95% CI, 0.53-0.93), but they had a higher risk of Crohn’s disease thereafter, which was statistically significant for the age groups of 25-29 years and older than 35 years. The incidence of UC did not differ significantly for female vs male patients (except for the age group of 5-9 years) until age 45 years; thereafter, men had a significantly higher incidence of UC than women. We concluded that in a pooled analysis of population-based studies, we found age at IBD onset to vary with sex. Further studies are needed to investigate mechanisms of sex differences in IBD incidence.

Benchimol EI, Kuenzig MI, Bernstein CN, Nguyen GC, Guttmann A, Jones J, Potter BK, Targownik LE, Catley CA, Nugent Z, Tanyingoh D, Mojaverian N, Underwood FE, Siddiq S, Otley AR, Bitton A, Carroll MW, deBruyn J, Dummer TJB, El-Matary W, Griffiths AM, Jacobson K, Leddin D, Lix LM, Mack DR, Murthy SK, Peña-Sánchez JN, Singh H, Kaplan GG, on behalf of the Canadian Gastro-Intestinal Epidemiology Consortium. Rural and urban disparities in the care of Canadian patients with inflammatory bowel disease: A population-based study. Clinical Epidemiology 2018 Nov 8; 10:1613-1626.

Canada’s large geographic area and low population density pose challenges in access to specialized healthcare for remote and rural residents. We compared health services use, surgical rate and specialist gastroenterologist care in rural and urban IBD patients in Canada. We used validated algorithms applied to population-based health administrative data to identify all people living within 3 Canadian provinces: Alberta, Manitoba, and Ontario. We compared rural to urban residents for time to diagnosis, hospitalizations, outpatient visits, emergency department use, surgical rate, and gastroenterologist care. There were 36,656 urban and 5,223 rural residents with newly diagnosed IBD who were included. Outpatient physician visit rate was similar in rural and urban patients. IBD-specific and IBD-related hospitalization rates were higher in rural patients by 17%  and 27% (IRR 1.17, 95% CI 1.02-1.34, and IRR 1.27, 95% CI 1.04-1.56, respectively), Emergency Department in Ontario visit rate was 50% higher (IRR 1.53, 95% CI 1.42-1.65, and IRR 1.33, 95% CI 1.25-1.40) (Emergency Department visit rate could not be tracked in Alberta and Manitoba.  Surgical rates were not different between rural and urban patients, nor was pre-diagnosis lag time. Rural patients had 20% fewer IBD-specific gastroenterologist visits (IRR 0.79, 95% CI 0.73-0.84), and a smaller proportion of their IBD-specific care provided by gastroenterologists (28.3% vs. 55.2%, p<0.0001). This was less pronounced in children under age 10 at diagnosis (59.3% vs. 65.0%, p<0.0001), and the gap was widest in patients over age 65 (33.0% vs. 59.2%, p<0.0001). We concluded that rural IBD patients have less use of gastroenterologists, more hospitalizations and greater rates of Emergency Department visits. These health services use disparities result in costlier care for rural patients. Innovative methods of delivering gastroenterology care to rural IBD patients (such as telehealth, online support, and/or remote clinics) should be explored, especially for communities lacking easy access to gastroenterologists.

Ananthakrishnan A, Bernstein CN, Iliopoulos D, MacPherson A, Neurath M, Affendi RA, Vavricka S, Fiocchi C. Environmental triggers in inflammatory bowel disease: A review of progress and evidence. Nature Reviews Gastroenterology & Hepatology 2018; 15:39-49.

This review article written by authors from around the world discusses the environmental factors that may be important in causing IBD.

Targownik LE, Leung S, Lix L, Singh H, Bernstein CN. Persistence with immunomodulator monotherapy use and incidence of therapeutic ineffectiveness among users of immunomodulator monotherapy in IBD. American Journal of Gastroenterology 2018; 113: 1206-12. 

Immunomodulator-based monotherapy with thiopurines (azathioprine and 6-mercaptopurine) or methotrexate has relatively low cost compared to biological therapy (i.e. infliximab or adalimumab). We used the population-based dataset of the University of Manitoba IBD Epidemiology Database spanning from 1996 until 2014 to assess the initiation and continued use and outcomes of immunomodulator monotherapy. We found that there were 3312 persons diagnosed with IBD (1480 CD, 1832 ulcerative colitis (UC)) in the study period. The cumulative incidence of immunomodulator monotherapy use at 5 years was 46% for CD and 24.9% for UC. Approximately one-third remained on immunomodulator monotherapy continuously for 5 years or more. Roughly three-quarters of immunomodulator users with a history of corticosteroid use had at least a 50% reduction in corticosteroid exposure in the year following immunomodulator initiation. We concluded that although the majority of persons who are initiated on immunomodulator monotherapy discontinue medications and/or have evidence of therapeutic ineffectiveness a significant minority remain free of any negative outcomes over many years of therapy.

 

Targownik LE, Benchimol EI, Bernstein CN, Singh H, Lix ML, Tennakoon A, Leung S, Aviña A, Coward S, Jones J, Kaplan G, Murthy SK, Nguyen GC, Peña-Sánchez JN. Upfront combination therapy, compared with monotherapy, for patients not previously treated with a biologic agent associates with reduced risk of inflammatory bowel disease-related complications in a population-based cohort study. Clinical Gastroenterology and Hepatology 2018; in press.

 

Although guidelines recommend inclusion of immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) in anti-tumor necrosis factor (TNF) initiation therapy for Crohn's disease (CD) there are limited data on the incremental effectiveness of this treatment strategy from the real world. We collected data from the University of Manitoba Inflammatory Bowel Disease Epidemiology database on persons with CD (n=852) or UC (n=303), from 2001 through 2016, who began treatment with anti-TNF drugs (infliximab or adalimumab). New and/or continuing users of immunomodulators at the time anti-TNF therapy began were considered recipients of combination therapy. The main outcome was treatment ineffectiveness during TNF antagonist-based therapy or within 90 days after the anti-TNF agent was discontinued.  In patients with CD, combination therapy was associated with a nearly 40% decrease in likelihood of treatment ineffectiveness. In conclusion, in an analysis of a database of real-world patients with IBD, we associated initiation therapy with a combination immunomodulators and anti-TNF drugs with an increased likelihood of treatment effectiveness for patients with CD.

ten Hove JR, Bernstein CN, Oldenburg B. Putting evidence into practice: IBD dysplasia surveillance, chromoendoscopy and future directions. American Journal of Gastroenterology 2018 Mar;113(3): 313-316.

 

This review article discusses approaches to colonoscopy surveillance for colorectal cancer (and its precursor, dysplasia) in persons with IBD.

 

Samadder NJ, Valentine JF, Guthery S, Singh H, Bernstein CN, Leighton JA, Wan Y, Wong J, Boucher K, Pappas L, Rowe K, Burt RW, Curtin K, Smith KR. Family history is associated with increased risk of colorectal cancer in patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2018; in press .

Individuals with inflammatory bowel diseases have an increased risk of developing colorectal cancer. Although family history of colorectal cancer is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. We aimed to estimate the risk of colorectal cancer in a cohort of patients with IBD from Utah and the significance of family history of CRC in a first-degree relative (FDR). We identified Utah residents with IBD, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. Colorectal cancers were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Colorectal cancer incidence was compared with that of the state population.A cohort of 9505 individuals with IBD was identified (using the administrative definition for IBD developed in Manitoba) and 101 developed CRC during the study period. Patients with Crohn's disease had 3.4X the likelihood of developing colorectal cancer and patients with ulcerative colitis had 5.2X the likelihood of developing colorectal cancer.  Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had nearly 15x the risk of developing colorectal cancer. A history of colorectal cancer in a first degree relative was associated with a nearly 8-fold increase in risk of colorectal cancer in patients with IBD. Hence, family history may act as a simple measure to identify individuals with IBD at highest risk for CRC and indicates the need for enhanced surveillance in this population.

Targownik LE, Tenakaroon A, Leung S, Lix LM, Singh H, Bernstein CN. Temporal Trends in Initiation of Therapy with Tumor Necrosis Factor Antagonists for Patients With Inflammatory Bowel Disease: A Population-Based Analysis. Clinical Gastroenterology and Hepatology 2017 Jul; 15(7): 1061-70.

We aimed to determine the patterns of use and changes over time of anti-TNFs and the use of immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate) [and corticosteroids prior to starting anti-TNF therapy in persons with IBD. We used the University of Manitoba IBD Epidemiology Database to identify all anti-TNF users with Crohn’s disease (CD) and ulcerative colitis (UC) from 2001-2014. We assessed changes in the prevalence and incidence of anti-TNFs over time. We also characterized patterns of corticosteroid use, corticosteroid dependence, and immunomodulator use prior to anti-TNF administration, and how they have changed over time.  We identified 950 persons (761 CD, 189 UC) who received anti-TNF. The cumulative prevalence (number of users ever) of anti-TNF use in 2014 was 20.4% for CD and 6.0% for UC. Within 5 years of diagnosis, the cumulative incidence of anti-TNF exposure was 23.4% for CD and 7.8% for UC. The majority of anti-TNF users had evidence of corticosteroid dependence (>2g prednisone within any 12 month period) prior to anti-TNF initiation. Cumulative corticosteroid exposure prior to anti-TNF use decreased over time for UC, but not significantly for CD. There was no increase over time in the use of concomitant immunomodulators with anti-TNF therapy. We concluded that anti-TNF use is increasing over time. There was a significant decrease in cumulative corticosteroid use in UC prior to starting anti-TNF, but not in CD; and no change in immunomodulator use. This suggests the continuing need for optimizing the use of anti-TNFs in IBD.

Restall GJ, Simms AM,  Walker, JR, Haviva C,  Graff LA, Sexton KA, Miller,. Targownik LE, Bernstein CN. Coping with inflammatory bowel disease: engaging with information to inform health-related decision-making in daily life. Inflammatory Bowel Disease 2017; 23: 1247-56.

We undertook a qualitative study exploring how persons with IBD engage with health-related information in their daily lives. 45 persons underwent in depth open ended interviews exploring a variety of topics related to living with IBD.Data were analyzed using inductive qualitative methods consistent with a phenomenological approach. There was a near equal distribution of males and females. Participants identified 6 contextual factors influencing engagement with information to make health decisions: (1) emotional and attitudinal responses, (2) perceived benefits and risks, (3) trust in the source of the information, (4) knowledge and skills to access and use information, (5) availability of evidence to support decisions, and (6) social and economic environments. Our findings illustrated the changing needs for health-related information over the course of IBD, and with evolving health and life circumstances. Practitioners can be responsive to information needs of people with IBD by having high quality information available at the right time in a variety of formats and by supporting the incorporation of information in daily life.

Enns RA, Hookey L, Armstrong D, Bernstein CN, Heitman SJ, Teshima C, Leontiadis GI, Tse F, Sadowski D. Clinical practice guidelines for the use of video capsule endoscopy. Gastroenterology 2017; 152:497-514

 

In this paper we report consensus guidelines using a Delphi technique and the GRADE scheme on use of capsule endoscopy. Much of the guidelines deal with capsule endoscopy in the setting of bleeding, the most common use fo capsule endoscopy. However, there is also discussion and recommendations for its use in Crohn’s disease and other conditions.​

Singh H, Nugent Z, Yu N, Lix L, Targownik LE, Bernstein CN. Hospital discharge abstracts have limited accuracy in identifying occurrence of Clostridium difficile infections among hospitalized individuals with inflammatory bowel disease: a population-based study. PLOS One 2017; 2017 Feb 15; 12(2):e0171266.

Hospital discharge databases are used to study the epidemiology of Clostridium difficile infections (CDI) among hospitalized patients with IBD. CDI in IBD is increasingly important and accurately estimating its occurrence is critical in understanding its comorbidity. There are limited data on the reliability of the International Classification of Diseases 10th revision (ICD-10) (now widely used in North America) CDI code in determining occurrence of CDI among hospitalized patients. We compared the performance of ICD-10 CDI coding to laboratory confirmed CDI diagnoses.The University of Manitoba IBD Epidemiology Database was used to identify individuals with and without IBD discharged with CDI diagnoses between 07/01/2005 and 3/31/2014.  There were 273 episodes of laboratory confirmed CDI (hospitalized and non-hospitalized) among 7396 individuals with IBD and 536 among 66,297 matched controls. The sensitivity, specificity, positive predictive value and negative predictive value of ICD-10 CDI code in discharge abstracts was 72.8%, 99.6%, 64.1% and 99.7% among those with IBD and 70.8%, 99.9%, 79.0% and 99.9% among those without IBD. Predictors of diagnostic inaccuracy included IBD, older age, increased co-morbidity and earlier years of hospitalization. We concluded that identification of CDI using ICD-10 CDI code in hospital discharge abstracts may not identify up to 30% of CDI cases, with worse performance among those with IBD.

El Matary W, Abej E, Deora V, Singh H, Bernstein CN. Impact of fecal calprotectin measurement on decision-making in children with inflammatory bowel disease. Frontiers in Pediatrics 2017; 25: 5-7.

The use of fecal calprotectin (FCal) as a marker of intestinal inflammation, in the management of IBD is increasing. The aim of this study was to examine the impact of FCal measurements on decision-making and clinical care of children with IBD. FCal, clinical activity indices, and blood markers were measured in children with established diagnoses of IBD. Decisions based on FCal measurements were prospectively documented and participants were evaluated 3-6 months later  A total of 115 fecal samples were collected from 77 children with IBD [median age 14, 42 females, 37 with Crohn's disease]. FCal positively correlated with clinical activity indices and erythrocyte sedimentation rate and negatively correlated with hemoglobin Sixty four out of 74 (86%) positive FCal measurements (at least 250 μg/g of stools) resulted in treatment escalation with subsequent significant clinical improvement while in the FCal negative group, 34 out of 41 (83%) measurements resulted in no change in treatment and were associated with remission on follow-up. We concluded that based on high FCal, the majority of children had treatment escalation that resulted in clinical improvement. FCal measurements were useful and reliable in decision-making and clinical care of children with IBD.

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Cloutier J, Wall D, Paulsen K, Bernstein CN. Upper versus lower endoscopy in the diagnosis of graft-versus-host disease. Journal of Clinical Gastroenterology 2017 Sep;51(8):7701-706.

The optimal endoscopic approach to patients with suspected gut graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT) is uncertain. We aimed to assess the diagnostic yield of upper and lower endoscopies performed in patients post-HSCT. We identified a cohort post-HSCT with acute and chronic GVHD who underwent gastrointestinal endoscopies for GVHD diagnosis. Hospital charts were reviewed and results were stratified according to patients' symptoms. From 1990 to 2013 433 HSCTs were performed. Fifty-six patients underwent 141 endoscopies, of which 117 were done to evaluate for GVHD or an alternative diagnosis. A total of 28/43 (65%) of the lower endoscopies and 41/74 (55%) of the upper endoscopies diagnosed GVHD or an alternative disease process on pathology. A total of 15/43 (35%) of lower endoscopies were flexible sigmoidoscopies, and 11/15 (73%) of these diagnosed GVHD or an alternative diagnosis. Upper endoscopy performed in patients with diarrhea as their only symptom diagnosed GVHD in 44% and an alternative diagnosis in 11%. In comparison, lower endoscopy in patients with only diarrhea diagnosed GVHD in 50%, and 18% offered an alternative diagnosis. Upper endoscopy provided a diagnosis of opportunistic viral and fungal infections of the upper gastrointestinal tract in 7 patients, while lower endoscopy diagnosed pseudomembranous colitis in 2. Upper and lower endoscopy had a similar diagnostic yield in patients with known or suspected GVHD involving the gut, even for patients presenting only with diarrhea. Because of its ease and safety upper endoscopy is the preferred initial endoscopic approach in patients with suspected gut GVHD, however flexible sigmoidoscopy is a reasonable other option.

 

Bernstein CN, Forbes J. Gut microbiome in inflammatory bowel disease and other chronic immune-mediated inflammatory diseases. Intestinal Inflammatory Diseases 2017; 2: 116-123.

We undertook a review of the current scientific research on the gut microbiome not just in IBD but also in other chronic inflammatory diseases (such as rheumatoid arthritis and multiple sclerosis). Our report in frontiers in Microbiology was one of the highest cited papers in that journal for 2016. In our report in Inflammatory Intestinal Diseases we reviewed what could be learned in regards to IBD by studying the gut microbiome of non gut chronic inflammatory diseases (such as rheumatoid arthritis, multiple sclerosis, psoriasis and ankylosing spondylitis. We also reported on some of our own research comparing the gut microbiome from persons wit IBD, rheumatoid arthritis and multiple sclerosis and healthy controls.

 

Ben Horin S, Andrews JM, Katsanos KH, Reider F, Steinwurz F, Karmiris K, Cheon JS, Moran GW, Cesarini M, Stone CD, Schwartz D, Protic M, Roblin X, Roda G, Chin MH, Har-Noy O, . Combination of corticosteroids and 5-aminosalicylaes or corticosteroids alone for patients with moderate-severe ulcerative colitis: A global survey of physicians’ practices. 2017; 23:2995-3002.

 

We aimed to understand gastroenterologists opinions about using 5ASA when more intensive therapy with corticosteroids is required. We pursued an international questionnaire exploring physicians' attitudes toward 5ASA + corticosteroid combination therapy vs corticosteroid alone. The questionnaire was distributed to gastroenterology experts in 12 countries in 5 continents. There were 349 questionnaires received (52.6% response rate). 65% said they would continue 5ASA in a patient hospitalized for intravenous corticosteroid treatment due to a moderate-severe UC flare, while 32% would stop the 5ASA (P < 0.001), and 3% were undecided. 62% would continue 5ASA in an out-patient starting oral corticosteroids. However, only 41% would proactively start 5ASA in a hospitalized patient not receiving 5ASA before admission. Most (94%) physicians consider the safety profile of 5ASA as very good. Only 52% consider them inexpensive, 35% perceive them to be expensive and 12% are undecided. On multi-variable analysis, less years of practice and perception of a plausible additive mechanistic effect of 5ASA + corticosteroids were positively associated with the decision to continue 5ASA with corticosteroids. Despite the absence of data supporting its benefit, most gastroenterologists endorse combination of 5ASA + corticosteroids for patients with active moderate-to-severe UC. Randomized controlled trials are needed to assess if 5ASA confer any benefit for these patients.

Bernstein CN. The impact of the placebo effect in Crohn’s disease. Alimentary Pharmacology and Therapeutics 2017; 45(11):1471-1472.

 

This editorial discusses the role of placebo in Crohn’s disease treatment trials.

Bernstein CN and Kornbluth A. Yes, we are still talking about cyclosporin versus infliximab in steroid resistant acute severe ulcerative colitis. American Journal of Gastroenterology 2017;112(11):1719-1721.

 

This editorial discusses the use of cyclosporine as a useful drug to treat persons with acute severe UC in hospital.

Chhibba T, Walker JR, Sexton K, Restall G, Ivekovic M, Shafer LA, Singh H, Targownik LE, Bernstein CN. Workplace accommodation for persons with IBD: What is needed and what is accessed. 2017; 15:1589-1595.

People with IBD often experience periods of illness that interfere with their ability to work. We aimed to understand the need for workplace accommodation during periods of acute illness among persons with IBD. Participants were recruited from our University of Manitoba Research Registry and received a survey including questions assessing experiences with workplace accommodations. A total of 1143 individuals responded to the survey (46% response rate), of whom 881 had experienced IBD symptoms in the workplace and were included in the analysis. The average age was 48.3 years; 61% were female. The average IBD duration was 20.6 years. 73% of respondents described IBD symptoms experienced in the workplace as severe to very severe. The most commonly required accommodations were time to go to medical appointments during working hours (81%), easy access to a toilet (71%), and a chance to take a break when not feeling well (54%). Most accommodations were arranged informally or through a supervisor. The accommodations required were very or somewhat easy to arrange about half the time. Being female, having high symptom severity, and high level of current distress were associated with a need for more accommodations, difficulty implementing accommodations, and not asking for needed accommodations. This study provides important information as to the types of accommodations that are necessary, common practices arranging for these, and level of difficulty arranging accommodations. Furthermore, characteristics associated with greater need for accommodation, reluctance to ask for them, and difficulty in arranging them were identified.

 

 

Bernstein MT, Walker JR, Chhibba T, Ivekovic M, Singh H, Targownik LE, Bernstein CN. Health care services in IBD: Factors associated with service utilization and preferences for service options for routine and urgent care. Inflammatory Bowel Diseases 2017; 23(9): 1461-1469.

 

We aimed to explore factors associated with health service utilization and preference for services, including alternatives to attending the emergency department when experiencing mild to moderate or severe symptoms. A total of 1143 persons (46% response rate) aged 18 to 65 years in the University of Manitoba IBD Research Registry participated in the survey. Although 61% had a gastroenterologist, when experiencing active symptoms, only 29% felt they could call their gastroenterologist for an urgent appointment, and 42% could call their gastroenterologist for telephone advice. 9% of the respondents visited the Emergency Department in the previous year. If having severe symptoms, 48% said that they would attend the Emergency Department. Visits to the Emergency Department were related to higher bowel symptom severity and high health anxiety. When experiencing severe symptoms, women, persons with Crohn's disease (versus persons with ulcerative colitis) and those with high health anxiety, indicated that they would be more likely to use the Emergency Department. Considering services which could be available in the future respondents indicated that if acutely symptomatic they would be very likely or likely to use the following services: phone contact with IBD nurse (77%), phone contact with a gastroenterologist (75%), and going to a walk-in gastroenterology clinic (71%). We concluded that persons with IBD are receptive to options other than the Emergency Department when experiencing IBD symptoms; however, attending the Emergency Department remains a prominent choice. Improved access to specialized care may improve timeliness of care and reduce Emergency Department attendance. Future research should include the impact of health anxiety on health care utilization.

 

Marrie RA, Walld R,Bolton JM, Sareen J, Walker JR, Patten SB, Singer A, Lix LM, Hitchon CA,El-Gabalawy R, Katz A, Fisk JD, Bernstein CN. Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. Journal of Psychosomatic Research 2017;101:17-23.

We studied the incidence (number of new diagnoses) of psychiatric comorbidity in chronic immune mediated diseases. We used the administrative health data of Manitoba Health, the single provincial health provider, for the years of 1989-2012. We identified 19,572 incident cases of persons with chronic immune diseases including 6119 persons with IBD, 3514 persons with multiple sclerosis, 10,206 persons with RA, and 97,727 age-sex- and geographically-matched controls. The relative 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) were elevated in the chronic immune diseases cohort. This means that persons with these chronic immune diseases were nearly twice as likely to have depression as persons without those diseases and 40% more likely to have an anxiety disorder. Depression and anxiety affected the multiple sclerosis population more often than the IBD and rheumatoid arthritis populations. This increased risk appears non-specific as it is seen for all three chronic immune diseases and for all psychiatric disorders studied, implying a common underlying biology for psychiatric diseases in those with chronic immune diseases.

Marrie RA, Walld R,  Bolton JM, Sareen J, Walker JR, Patten SB, Singer A, Lix L, Hitchon C, El-Gabalawy R, Katz A, Fisk JD, Bernstein CN. Rising Incidence of Psychiatric Disorders Before Diagnosis of Immune-Mediated Inflammatory Diseases. Epidemiology and Psychiatric Sciences 2017; Nov 3:1-10.

 

We have shown that after the diagnosis of chronic immune-mediated inflammatory diseases such as IBD, multiple sclerosis and rheumatoid arthritis, the incidence of psychiatric diagnoses is increased relative to the general population. We aimed to determine whether the incidence of psychiatric disorders is increased in the 5 years before the diagnosis of having chronic immune-mediated inflammatory diseases as compared with the general population. Using administrative health data from Manitoba, we identified all persons with newly diagnosed IBD, multiple sclerosis and rheumatoid arthritis between 1989 and 2012, and matched controls from the general population. We identified 12 141 new cases of chronic immune diseases (3766 IBD, 2190 multiple sclerosis, 6350 rheumatoid arthritis). As early as 5 years before diagnosis, the incidence of depression [incidence rate ratio (IRR) 1.54; 95% CI 1.30-1.84) and anxiety disorders (IRR 1.30; 95% CI 1.12-1.51) were elevated in the chronic immune diseases cohort as compared with the controls. This means that for as long as 5 years prior to the diagnosis of their chronic immune disease these patients were 30-50% more likely to have depression or an anxiety disorder than members of the general population. Similar results were obtained for each of the IBD, multiple sclerosis and rheumatoid arthritis cohorts. We concluded that the incidence of psychiatric diagnoses is elevated in the chronic immune diseases population as compared with a matched population as early as 5 years before diagnosis. Future studies should elucidate whether this reflects shared risk factors for psychiatric disorders and chronic immune diseases, a shared final common inflammatory pathway or other etiology.

Bernstein CN. The brain-gut axis and stress in inflammatory bowel disease. Gastroenterology Clinics in North America 2017; 46(4):839-846.

 

This review article discusses the important connection between the brain and the gut in IBD and how stress may impact on outcomes in IBD.

Melesse DY, Lix L, Nugent Z, Targownik LE, Singh H, Blanchard JF, Bernstein CN. Estimates of disease course in inflammatory bowel disease using administrative data: a population-level study. Journal of Crohn’s and Colitis 2017; 562-570.

In this study we aimed to develop a predictive model of disease course in IBD using health care utilization measures from administrative health data. In other words we wanted to determine if we could assess administrative health data and estimate disease activity status from it. Study participants were IBD patients who were prospectively followed for a one-year period between 2009 and 2010 in a Canadian clinic setting to assess their IBD disease course (i.e., remission, mild, moderate, severe). Clinic data were linked with population-based administrative health data of Manitoba Health. We developed a statistical model to identify patters of health care utilization that matched with each disease state. The model was applied to project the distribution of disease course for the Manitoba IBD population for 1995-2013. There were 407 participants. 41% of participants were clinically in remission, while 14.0% had severe IBD. Mild, moderate, or severe disease was associated with at least 3 gastroenterologist visits or at least 3 general practitioner visits with an IBD diagnosis and at least 1 radiology test . The percentages of the Manitoba IBD population in remission steadily rose from 1995 to 2013 (43.6% to 59.9%), while the percentages of individuals with mild, moderate or severe disease declined. In summary, this study demonstrated that health care utilization measures from administrative data can be used to predict disease course in the IBD population.

 

Targownik LE, Tenakaroon A, Leung S, Lix LM, Nugent Z, Singh H, Bernstein CN. Factors associated with discontinuation of anti-TNF inhibitors among persons with IBD: A population based analysis. Inflammatory Bowel Disease 2017; 23:409-420.

 

Anti-tumor necrosis factor (anti-TNF) medications (i.e. infliximab (IFX) and adalimumab (ADA)) are known to be highly efficacious in persons with moderate-to-severe IBD). There is little data from population based sources to that report on how common it is for users of these drugs to persist with them over time. Discontinuation of anti-TNF therapy is a marker of lack of effectiveness, intolerance and patient/physician practice preferences  We identified all persons with IBD in Manitoba who were dispensed infliximab (IFX) and adalimumab (ADA) between 2001 and 2014 through our University of Manitoba IBD Epidemiology Database. Subjects were followed longitudinally to assess rates of completion of anti-TNF induction and duration of continued use. Overall, 925 of 8651 persons with IBD were prescribed an anti-TNF drug (705 Crohn’s Disease [CD: 523 IFX, 182 ADA), 220 ulcerative colitis (UC: 214 IFX, 6 ADA). Approximately four-fifths of persons starting on anti-TNF therapy completed induction (induction refers to the first 6 weeks of drug treatment to get persons into remission). At 1 and 5 years, persistence rates with the original anti-TNF were approximately 60% and 40%, respectively. Immunomodulator use (such as azathioprine, 6-mercaptopurine and methotrexate) at the time of anti-TNF dispensation was associated with a decreased likelihood of anti-TNF discontinuation in both CD and UC. ADA users with CD who reached maintenance phase had a 65% higher risk of discontinuation than IFX users.  We concluded that approximately two fifths of anti-TNF users discontinue use within one year of initiation, and three-fifths will have discontinued at 5 years. Concomitant IM therapy dereased discontinuation rates. 

Targownik LE, Tenakaroon A, Leung S, Lix LM, Singh H, Bernstein CN. Temporal Trends in Anti-TNF Initiation Among Persons with IBD: A Population Based Analysis. Clinical Gastroenterology and Hepatology 2017 Jul; 15(7): 1061-70.

We aimed to determine the patterns of use and changes over time of anti-TNFs and the use of immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate) [and corticosteroids prior to starting anti-TNF therapy in persons with IBD. We used the University of Manitoba IBD Epidemiology Database to identify all anti-TNF users with Crohn’s disease (CD) and ulcerative colitis (UC) from 2001-2014. We assessed changes in the prevalence and incidence of anti-TNFs over time. We also characterized patterns of corticosteroid use, corticosteroid dependence, and immunomodulator use prior to anti-TNF administration, and how they have changed over time.  We identified 950 persons (761 CD, 189 UC) who received anti-TNF. The cumulative prevalence (number of users ever) of anti-TNF use in 2014 was 20.4% for CD and 6.0% for UC. Within 5 years of diagnosis, the cumulative incidence of anti-TNF exposure was 23.4% for CD and 7.8% for UC. The majority of anti-TNF users had evidence of corticosteroid dependence (>2g prednisone within any 12 month period) prior to anti-TNF initiation. Cumulative corticosteroid exposure prior to anti-TNF use decreased over time for UC, but not significantly for CD. There was no increase over time in the use of concomitant immunomodulators with anti-TNF therapy. We concluded that anti-TNF use is increasing over time. There was a significant decrease in cumulative corticosteroid use in UC prior to starting anti-TNF, but not in CD; and no change in immunomodulator use. This suggests the continuing need for optimizing the use of anti-TNFs in IBD.

Singh H, Nugent Z, Yu BN, Lix LM, Targownik LE, Bernstein CN. Higher incidence of Clostridium difficile infection among individuals with inflammatory bowel disease. Gastroenterology 2017 Aug; 153(2): 430-438.

Studies of Clostridium difficile infections (CDIs) among individuals with IBD have used data from single centers or CDI administrative data codes of limited diagnostic accuracy. We determined the incidence, risk factors, and outcomes after CDI in a population-based cohort of patients with IBD and laboratory confirmation diagnoses of CDI. We searched the University of Manitoba IBD Epidemiology Database and Manitoba Health CDI databases to identify individuals with CDI, with or without IBD, from July 1, 2005 through March 31, 2014. Individuals with IBD had a 4.8-fold increase in risk of CDI than individuals without IBD; we found no difference between individuals with ulcerative colitis vs Crohn's disease. There was no increase in CDI incidence over the study time period in either group. Among individuals with IBD, exposure to corticosteroids, infliximab or adalimumab, metronidazole, hospitalizations, higher ambulatory care visits, shorter duration of IBD, and higher comorbidities were associated with an increased risk of CDI. Although CDI increased mortality among individuals with and without IBD, there was lower mortality after CDI among individuals with IBD than without IBD by 35%. We concluded that CDI incidence is no longer increasing among individuals with IBD. We identified unique risk factors for CDI in patients with IBD. CDI is associated with a greater increase in mortality among individuals without IBD than with IBD.

Bernstein CN, Burchill C, Targownik LE, Singh H, Ghia JE, Roos LL. Maternal Infections That Would Warrant Antibiotic Use Antepartum or Peripartum Are Not a Risk Factor for the Development of IBD: A Population-Based Analysis. Inflammatory Bowel Diseases 2017;23(4):635-640.

We aimed to determine if maternal antenatal or perinatal infections (and thereby use of antibiotics) increase the risk of developing IBD in their offspring. The rationale is that maternal use of antibiotics may change the baby’s gut microbiome and possibly make it more conducive for the baby to ultimately develop IBD. The University of Manitoba IBD Epidemiology Database includes all Manitobans with IBD dating back to 1984 and a control group matched by age, sex and geographic residence. Individuals born in 1970 and later are linkable to their mothers through a 6 digit family health registration number and cross referencing of mothers’ health identification number  on the child’s birth record.  We assessed antenatal (30 days and 9 months prior to delivery) and peripartum (in hospital) maternal infections identified by ICD-8 and ICD-9 codes as a proxy for antibiotic use. Of the 2487 IBD cases born after 1970, 1758 were born in Manitoba, of which 1671 were linkable to mothers (Crohn’s disease=973, ulcerative colitis=698). 10488 matched controls and 1740 siblings from 1615 families were identified. Maternal infections occurred with equal rates in mothers of IBD cases (21.7%) and mothers of controls (23.2%) within 9 months antepartum . Maternal infections occurred with equal rates in mothers of IBD cases (11.4%) and mothers of controls (12.4%) within 30 days antepartum Maternal infections occurred with equal rates in mothers of IBD cases (5.5%) and mothers of controls (7.5%)  peripartum. There was also no difference in the occurrence of antepartum or peripartum infections among mothers of IBD cases vs unaffected siblings. We concluded that maternal infections (and therefore antibiotic use) in the antepartum and peripartum periods do not affect the risk of development of IBD in offspring. Combined with our data that caesarean section is not a risk factor for developing IBD we further concluded that  it appears that events of the immediate postpartum period that shape the developing neonate gut microbiome may not be critical in the development of IBD.

El-Matary W, Dufault B, Moroz SP, Schellenberg J, Bernstein CN. Education, Employment, Income, and Marital Status Among Adults Diagnosed With Inflammatory Bowel Diseases During Childhood or Adolescence. Clinical Gastroenterology and Hepatology 2017 Apr;15(4):518-524.

We aimed to assess levels of education attained, employment, and marital status of adults diagnosed with IBD during childhood or adolescence, compared with healthy individuals in Canada. We performed a cross-sectional study of adults diagnosed with IBD in childhood or adolescence at Children's Hospital in Winnipeg, Manitoba from January 1978 through December 2007. Participants (n = 112) answered a semi-structured questionnaire on educational achievements, employment, and marital status. Patients were matched for age and sex with random healthy individuals from the 2012 Canadian Community Health Survey (controls, 5 per patient).  Patients were followed for a mean duration of 14.3 years (range, 3.1-34.5 years). Persons with IBD were nearly twice as likely to earn more money per year and nearly three times as likely to attain a post-secondary school degree or receive a diploma as controls There was no significant difference between patients and controls in employment or marital status. We concluded that adults diagnosed with IBD during childhood seem to achieve higher education levels than individuals without IBD. This observation should provide reassurance to children with IBD and their parents.

Benchimol EI, Bernstein CN, Bitton A, Carroll MW, Singh H, Otley AR, Vutcovici M, El-Matary W, Nguyen GC, Griffiths AM, Mack DR, Jacobson K, Mojaverian N, Tanyingoh D, Cui Y, Nugent ZJ, Coulombe J, Targownik LE, Jones JL, Leddin D, Murthy SK, Kaplan GG. Trends in epidemiology of pediatric inflammatory bowel disease in Canada: distributed network analysis of multiple population-based provincial health administrative databases. American Journal of Gastroenterology 2017 Jul; 112(7): 1120-1134.

The University of Manitoba IBD Clinical and Research Centre is one of 8 centres participating in Canada-wide network dedicated to the study of the epidemiology of IBD in Canada. The network is call CanGIEC (Canadian GastroIntestinal Epidemiology Consortium). The incidence of pediatric-onset IBD is increasing worldwide. In this study we used population-based health administrative data from Alberta, Manitoba, Nova Scotia, Ontario and Quebec, to determine national Canadian IBD incidence, prevalence, and trends over time of childhood-onset IBD. These 5 provinces comprise 79.2% of the Canadian population. We identified children less than16 years diagnosed with IBD 1999-2010. Standardized incidence and prevalence were calculated per 100,000 children.  5,214 incident cases were diagnosed during the study period (3,462 Crohn's disease, 1,382 ulcerative colitis, 279 type unclassifiable). The incidence in Canada was 9.68  per 100,000 children. Incidence was similar amongst most provinces, but higher in Nova Scotia. The  incidence did not significantly change over the study period in the overall cohort  However, the incidence significantly increased in children aged 0-5y (+7.19%). Prevalence at the end of the study period in Canada was 38.25 per 100,000 children. The prevalence increased significantly over time. We concluded that Canada has amongst the highest incidence of childhood-onset IBD in the world. Prevalence significantly increased over time. Incidence was not statistically changed with the exception of a rapid increase in incidence in the youngest group of children.

Nguyen GC, Bernstein CN, Benchimol E. Risk of surgery and mortality in elderly-onset inflammatory bowel disease: A population-based cohort study. Inflammatory Bowel Disease 2017; 23:218-223.

​In this study the administrative data of the province of Ontario was used and new IBD cases in diagnosed  between 1999 and 2008 were identified. Of 21,218 persons with IBD, there were 1749 cases of elderly-onset (at least 65 years) ulcerative colitis (UC) and 725 cases elderly-onset Crohn's disease (CD). Elderly UC had higher rates of IBD-related surgery than those with young-adult UC  (less than 40 years) (adjusted hazard ratio, 1.34; 95% CI, 1.16-1.55), although there was no difference in surgical rates between age groups in CD. IBD-specific mortality was higher in elderly-onset CD (33.1/10,000 person-year) compared with that in middle-age (40-64 years) CD (5.6/10,000 person-year, P < 0.0001) and young adult CD (1.0/10,000 person-year) but was not different by age in UC. The leading cause of death in elderly UC and CD was solid malignancies accounting for 22.9% and 26.4% of deaths, respectively, whereas IBD was third most frequent cause of death accounting for 6.3% and 9.1% of deaths, respectively.  We concluded that elderly-onset patients with UC were more likely to undergo surgery while elderly-onset patients with CD exhibited higher IBD-specific death rates than those with younger-onset disease. These findings should prompt more optimized disease management in elderly IBD since they are at higher risk for bad outcomes when they are newly diagnosed.

Benchimol EI, Kaplan GG, Otley AR, Nguyen GC, Underwood FE, Guttmann A, Jones JL, Potter BK, Catley CA, Nugent Z, Cui Y, Tanyingoh D, Mojaverian N, Bitton A, Carroll MW, deBruyn J, Dummer TJB, El-Matary W, Griffiths AM, Jacobson K, Kuenzig ME, Leddin D, Lix LM, Mack DR, Murthy S, Peña Sánchez JN, Singh H, Targownik L, Vutcovici M, Bernstein CN. Rural and urban residence during early life is associated with a lower risk of inflammatory bowel disease: A population-based inception and birth cohort study. American Journal of Gastroenterology 2017, 112:1412-1422.

We aimed to determine if growing up in an urban or rural household impacted on being diagnosed with IBD. Using administrative data in each of 4 Canadian provinces we created comprehensive datasets of all persons with IBD in those provinces dating back to 2000.  There were 6,662 rural residents and 38,905 urban residents with IBD. The incidence of IBD per 100,000 (number of new cases) was 30.72 in rural residents and 33.16 in urban residents, (IRR 0.90, 95% CI 0.81-0.99). The protective association was strongest in children <10 years (IRR 0.58, 95% CI 0.43-0.73) and 10-17.9 years (IRR 0.72, 95% CI 0.64-0.81). In the birth cohort, comprising 331 rural and 2,302 urban residents, rurality in the first 1-5 years of life was associated with lower risk of IBD (IRR 0.75-0.78). We concluded that people living in rural households had lower risk of developing IBD. This association is strongest in young children and adolescents, and in children exposed to the rural environment early in life.

 

Bernstein CN. Large registry epidemiology in IBD. Inflammatory Bowel Diseases 2017;23(11):1941-1949.

 

This review article discusses the exploration of the study of the epidemiology of IBD using large databases.

Bernstein CN. Changes in the epidemiology of inflammatory bowel disease - clues for aetiology. Alimentary Pharmacology and Therapeutics 2017;46(10):911-919.

 

This review article discusses how epidemiology studies can be used to search for clues as to what causes IBD.

Samadder NJ, Valentine JF, Guthery S, Singh, H, Bernstein CN, Wan Y, Wong J, Boucher K, Pappas L, Rowe K, Bronner M, Ulrich N, Burt RW, Curtin K and Smith KR. Colorectal cancer in inflammatory bowel diseases: A population-based study in Utah. 2017;62: 2126-32.

 

All newly diagnosed cases of colorectal cancer between 1996 and 2011 were obtained from Utah Cancer Registry. IBD was identified using the validated algorithm developed in Manitoba, from statewide databases of Intermountain Healthcare, University of Utah Health Sciences, and the Utah Population Database. Among 12,578 patients diagnosed with colorectal cancer, 101 (0.8%) had a prior history of IBD (61 ulcerative colitis and 40 Crohn's disease). The mean age at colorectal caner was younger for patients with IBD than those without IBD (52.8 vs 67.1 years, P < 0.001). Individuals with IBD-associated colorectal cancer were nearly twice as likely to be men (odds ratio [OR] 1.90, 95% CI 1.23-2.92), nearly 7 times as likely to be aged less than 65 years (OR 6.77, 95% CI 4.06-11.27), and nearly 3 times as likely to have colorectal cancer located in the proximal colon (OR 2.79, 95% CI 1.85-4.20) than those with sporadic colorectal cancer. Nearly 20% of the IBD-associated colorectal cancers had evidence of primary sclerosing cholangitis. After adjustment for age, gender, and stage at diagnosis, the excess hazard of death after colorectal cancer diagnosis was nearly two times higher in IBD than in non-IBD patients (OR 1.7, 95% CI 1.27-2.33).

Publications // from the Manitoba IBD Epidemiology Database

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