Epidemiology Publications // 2019

Torabi M, Bernstein CN, Yu BN, Wickramasinghe L, Blanchard JF, Singh H. Geographical variation and factors associated with inflammatory bowel disease in a central Canadian province. Inflammatory Bowel Diseases 2019; in press.

 

We investigated temporal trends, geographical variation, and geographical risk factors for incidence of inflammatory bowel disease (IBD). We used the University of Manitoba IBD Epidemiology Database to identify incident IBD cases diagnosed between 1990 and 2012, which were then geocoded to 296 small geographic areas. Sociodemographic characteristics of the SGAs (proportions of immigrants, visible minorities, Indigenous people, and average household income) were obtained from the 2006 Canadian Census. The geographical variation of IBD incidence was modeled using a Bayesian spatial Poisson model. Time trends of IBD incidence were plotted using Joinpoint regression. We found that the incidence of IBD decreased over the study years from 23.6 (per 100,000 population) in 1990 to 16.3 (per 100,000 population) in 2012. For both Crohn's disease and ulcerative colitis, the highest incidence was in Winnipeg and the southern and central regions of Manitoba, whereas most of northern Manitoba had lower incidence. There was no effect of sociodemographic characteristics of small geographic areas, other than the proportion of Indigenous people, which was associated with lower IBD incidence.

We concluded that the incidence of IBD in Manitoba is decreasing over time. We have identified geographic areas with persistently higher IBD incidence that warrant further study for etiologic clues.

 

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 2019; 17:1788-1798.

 

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.

​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 2019; 17: 1807-1813.

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

ten Hove JR, Shah SC, Shaffer SR, Bernstein CN, Castaneda D, Palmela C, Mooiweer E, Elman J, Kumar A, Glass J, Ullman TA, Colombel JF, Torres J, van Bodegraven AA, Hoentjen F, Jansen JM, de Jong M, Mahmmod N, van der Meulen-de Jong AE, Ponsioen CY, van der Woude CJ, Itzkowitz SH, Oldenburg B. Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with longstanding colitis: results of a 15-year multicenter, multinational cohort study. Gut 2019; 68: 615-622.

 

Surveillance colonoscopy is thought to prevent colorectal cancer in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk. A multicentre (Manitoba, NY, Holland) database of patients with long-standing IBD colitis without high-risk features and undergoing regular colorectal cancer surveillance was constructed. A 'negative' surveillance colonoscopy was predefined as a technically adequate procedure having no postinflammatory polyps, no strictures, no endoscopic disease activity and no evidence of neoplasia; a 'positive' colonoscopy was a technically adequate procedure that included at least one of these criteria. The primary endpoint was advanced colorectal neoplasia defined as high-grade dysplasia or colorectal cancer. Of 775 patients with long-standing IBD colitis, 44% (n=340) had at least 1 negative colonoscopy. Patients with consecutive negative surveillance colonoscopies were compared with those who had at least one positive colonoscopy. Both groups had similar demographics, disease-related characteristics, number of surveillance colonoscopies and time intervals between colonoscopies. No advanced colorectal neoplasia occurred in those with consecutive negative surveillance, compared with an incidence rate of 0.29 to 0.76/100 patient-years (P=0.02) in those having at least 1 positive colonoscopy on follow-up of 6.1 years after the index procedure. Within this large surveillance cohort of patients with colonic IBD and no additional high-risk features, having two consecutive negative colonoscopies predicted a very low risk of advanced colorectal neoplasia occurrence on follow-up. Our findings suggest that longer surveillance intervals in this selected population may be safe.​

Witges K, Bernstein CN, Sexton K, Afifi T, Walker JR, Nugent Z, Lix L. The relationship between adverse childhood experiences and healthcare use in the Manitoba IBD cohort study. Inflammatory Bowel Diseases 2019; 25: 1700-1710.

 

We aimed to determine the prevalence of adverse childhood experiences in persons with IBD and whether having adverse childhood experiences was associated with health care utilization post IBD diagnosis. 345 participants from the population-based Manitoba IBD Cohort Study self-reported adverse childhood experiences (i.e., physical abuse, sexual abuse, death of a very close friend or family member, severe illness or injury, upheaval between parents, and any other experience thought to significantly impacts one’s life or personality) at a median of 5.3 years following IBD diagnosis. Cohort Study data were linked to administrative health databases that captured use of hospitals, physician visits, and prescription drugs; use was classified as IBD- and non-IBD-related. The prevalence of at least one adverse childhood experiences was 74.2%. There was no statistically significant association between having experienced an adverse childhood experience and health care use. However, mean annual non-IBD-related general practitioner visits were significantly higher for participants exposed to physical and sexual abuse than those not exposed. Selected rates of IBD-related healthcare use were lower for participants who reported exposure to an upheaval between parents and high perceived trauma from adverse childhood experiences. In summary, the estimated prevalence of at least one self-reported adverse childhood experience in persons with diagnosed IBD was high. Health care use among those who experienced adverse childhood experiences may reflect the impacts of adverse childhood experiences on health care anxiety.

Frenkel S, Bernstein CN, Sargent M, Jiang W, Kuang Q, Xu W, Hu P. Copy number variation-based gene set analysis reveals cytokine signaling pathways associated with psychiatric comorbidity in patients with inflammatory bowel disease. Genomics 2019; S0888-7543(19);30081-3.​

 

Recent studies discovered many genetic variants associated with both psychiatric and inflammatory disorders, but the role of genetic factors in the development of psychiatric comorbidity in inflammatory bowel disease is underexplored. Particularly, it has been shown that some of the genetic variants have been linked to the concentrations of circulating cytokines and symptoms of the inflammatory cytokine-associated depression.  We analysed genomic features of individuals with IBD by comparing IBD patients with psychiatric comorbidity with those who have IBD but without psychiatric comorbidity. We hypothesized that cytokine related signaling pathways may be significantly associated with the psychiatric comorbidity in patients with IBD.  Individuals enrolled in the Manitoba IBD Cohort Study were separated to two groups accordingly to the presence of psychiatric comorbidity. A sample set comprising 97 IBD individuals with psychiatric comorbidity and 146 IBD individuals without psychiatric comorbidity was first used to identify copy number variations (CNVs) from genome-wide genetic data  using three different detection algorithms. IBD + psychiatric comorbidity and IBD without psychiatric comorbidity groups were compared by the number of CNVs overlapping each gene; deletions and duplications were analysed separately. Medium-sized CNV (size between 100 and 500 kilobase pairs)-burden is significantly higher in IBD + psychiatric comorbidity than the IBD without psychiatric comorbidity group. Gene-based CNV association analysis did not show significant differences between the two IBD groups. Gene set overrepresentation analysis demonstrated the significant enrichment of gene sets related to cytokine signalling pathways by the genes overlapped by deletions in the IBD individuals with psychiatric comorbidity. Our results confirm the role of cytokine signalling pathways in the development of psychiatric comorbidity in IBD. Additionally, our results warrant further study with a larger sample size focusing on cytokine SNPs to further understand the relationship between inflammatory and psychiatric disorders.

 

Lee E, Shafer LA, Walker JR, Waldman C, Michaud V, Yang C, Bernstein CN, Park J, Sisler J, Wittmeier K, Hathout L, Restall G, Singh H. Information experiences, needs, and preferences of colonoscopy patients: A pre-colonoscopy survey. Medicine 2019; 98(2):e15738.

 

Inadequate preparation for colonoscopy is associated with missed diagnoses and avoidable repeat procedures. Better pre-colonoscopy education may lead to improved bowel preparation, decreased anxiety, and a willingness to go direct to colonoscopy. We assessed the experiences, needs and preferences for information of patients undergoing colonoscopy. A self-administered survey was distributed between 08/2015-06/2016 to patients in Winnipeg, Canada when they attended an outpatient colonoscopy. The amount, type, helpfulness, and satisfaction with information provided were analyzed. Predictors of overall satisfaction and amount of information received were determined. 1,580 respondents answered parts of or all of the survey questions. Only half of respondents coming for a repeat colonoscopy and 40-44% of those coming for first colonoscopy received just the right amount of information from their endoscopy doctor (directly or by brochure). One quarter or less of the respondents indicated that they had received just the right amount of information from any source other than their colonoscopy doctor, and many indicated that they had received no information from the sources. 38% coming for a first colonoscopy and 44% coming for a repeat colonoscopy indicated that they had received no information from their family physicians. Those coming for their first colonoscopy had a lower average score (9.7 vs 11.1, p<0.001) for amount of information received (scale 0-15)), were less likely to be satisfied or very satisfied with the information they received (p=0.005) and were less likely to have found the information clear or very clear (p=0.004).  We concluded that patients going for colonoscopy are inadequately informed about the procedure and it is significantly worse for those going for first time rather than repeat colonoscopy.

Restall GA, Michaud V, Walker JR, Waldman C, Bernstein CN, Park J, Wittmeier K, Singh H. Patient experiences with colonoscopy: A qualitative study. Journal of Canadian Association of Gastroenterology 2019; in press.

Patient perspectives have important roles in improving the quality of colonoscopy services. The purpose of this qualitative study was to obtain the perspectives of patients who recently had undergone colonoscopy procedures, about their experiences with bowel preparation, the procedure itself, and communication of follow-up results and recommendations. We recruited adults who had undergone a colonoscopy, to participate in semi-structured interviews. Interviews were audiotaped, transcribed and analyzed using inductive qualitative methods. Twenty-four adults (58% female) with an average age of 53.8 years participated. Results were categorized within the themes of bowel preparation, the colonoscopy procedure and communication of the results. Participants appreciated having clear consistent plain language messages about bowel preparation. Some participants experienced additional challenges to understanding, and navigating, colonoscopy procedures. At the time of the procedure, positive and reassuring interactions with, and between, members of the health care team, in addition to management of physical pain and discomfort, were important. Participants wanted clear and timely information about the results of their test. In summary, understanding patients’ needs for information and support can promote higher quality colonoscopy services. Our findings suggest that quality indicators should include: patients’ perspectives of the clarity of bowel instructions; the need for supports that are not routinely provided; the extent to which concerns about the procedure are addressed; interactions with the endoscopy team; the endoscopy team’s interactions with each other; comfort during the procedure, and the timeliness and clarity of results and follow-up instructions. These indicators should be included in annual patient surveys.​

 

Knox N, Forbes JD, Van Domselaar, Bernstein CN.  The gut microbiome in other chronic immune disease: lessons for IBD. American Journal of Gastroenterology 2019; 114:1051-70.

 

There is a growing appreciation for the role of the gut microbiome in human health and disease. Aided by advances in sequencing technologies and analytical methods, recent research has shown the healthy gut microbiome to possess considerable diversity and functional capacity. Dysbiosis of the gut microbiota is believed to be involved in the pathogenesis of not only diseases that primarily affect the gastrointestinal tract, but of other less obvious diseases, including neurologic, rheumatologic, metabolic, hepatic, and other illnesses. Chronic immune-mediated inflammatory diseases represent a group of diseases that share many underlying etiological factors including genetics, aberrant immunological responses, and environmental factors. Gut dysbiosis has been reported to be common to immune-mediated inflammatory diseases as a whole, and much effort is currently being directed towards elucidating microbiome-mediated disease mechanisms and their implications for causality. In this review, we discuss gut microbiome studies in several immune-mediated inflammatory diseases and show how these studies can inform our understanding of the role of the gut microbiome in inflammatory bowel disease.

Knox N, Forbes JD, Van Domselaar, Bernstein CN. The gut microbiome as a target for IBD treatment: are we there yet? Current Treatment Options in Gastroenterology 2019; 17(1):115-126.

This review aims to highlight recent research on the gut microbiome in IBD and the application of microbiome-modulating therapies for the treatment of IBD including the use of the microbiome as an indicator for disease severity and treatment response. Despite the high number of gut microbiome studies and emerging evidence supporting the gut microbiome's involvement in disease pathogenesis, no single microorganism has been identified as a pathogenic agent in IBD. Retrospective studies and meta-analyses on antibiotic use in ulcerative colitis and Crohn's disease and long-term outcomes are conflicting. Similarly, the use of probiotics for the treatment of IBD remains inconclusive; however, some encouraging results are emerging as microbial concoctions are optimized to include beneficial bacterial strains. Fecal microbial transplantation is currently emerging as one of the more promising microbiome-modulating IBD therapies. Fecal microbial transplantation studies in ulcerative colitis have shown improved remission rates compared to placebo; however, relatively small study sample sizes and varied treatment methods, limit definitive conclusions. With clear evidence of an IBD gut dysbiosis, novel therapies to treat and prevent disease relapse will undoubtedly require a microbiome-modulating approach. The complexity and variability of IBD disease pathogenesis (disease phenotype, gut microbiome, host genetic susceptibility, and environmental factors) will likely require a personalized and multidimensional treatment approach where microbiome-modulating therapy is coupled with other therapies to target other IBD disease components.

Forbes JD, Bernstein CN, Tremlett H, Van Domselaar G, Knox NC. A fungal world: could the gut mycobiome be involved in neurological disease. Frontiers in Microbiology 2019; pages 1-13: doi:10.3389/fmicb.2018.03249.

The human microbiome has received decades of attention from scientific and medical research communities. The human gastrointestinal tract is host to immense populations of microorganisms including bacteria, viruses, archaea, and fungi (the gut microbiota). High-throughput sequencing and computational advancements provide unprecedented ability to investigate the structure and function of microbial communities associated with the human body in health and disease. Most research to date has largely focused on elucidating the bacterial component of the human gut microbiota. Study of the gut "mycobiota," which refers to the diverse array of fungal species, is a relatively new and rapidly progressing field. Though omnipresent, the number and abundance of fungi occupying the human gut is orders of magnitude smaller than that of bacteria. Recent insights however, have suggested that the gut mycobiota may be intricately linked to health and disease. Evaluation of the gut mycobiota has shown that not only are the fungal communities altered in disease, but they also play a role in maintaining intestinal homeostasis and influencing systemic immunity. In addition, it is now widely accepted that host-fungi and bacteria-fungi associations are critical to host health. While research of the gut mycobiota in health and disease is on the rise, little research has been performed in the context of neuroimmune and neurodegenerative conditions. Gut microbiota dysbiosis (specifically bacteria and archaea) have been reported in neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's, among others. Given the widely accepted bacteria-fungi associations and paucity of mycobiota-specific studies in neurological disease, this review discusses the potential role fungi may play in multiple sclerosis and other neurological diseases. Herein, we provide an overview of recent advances in gut mycobiome research and discuss the plausible role of both intestinal and non-intestinal fungi in the context of neuroimmune and neurodegenerative conditions.

Samarani S, Mack DR, Bernstein CN, Iannello A, Debbeche O, Jantchou P, Faure C, Deslandres C, Amre DA, Ahmad A. Activating Killer-cell Immunoglobulin-like Receptor genes confer risk for Crohn’s disease in children and adults of the Western European descent: Findings based on case-control studies. PLOS One 2019;14(6):e0217767. Published 2019 Jun 13

Killer-cell Immunoglobulin-like Receptor genes encode receptors, which are mainly expressed on, and control functional activities of, Natural Killer (NK) cells. These cells are important in the inflammatory response. Activated NK cells can potentially cause tissue destruction, which might be important in development Crohn disease. In this study we performed case control studies on three independent Canadian Crohn’s disease patient cohorts (all of Western European descent): two comprising children [one from Montreal (438 children) and one from Ottawa (213 children)] and one comprising predominantly adults (from Winnipeg having 364 adults)]. We assess the gene types for for activating Killer-cell Immunoglobulin-like Receptor. We observed strong associations between all the six Killer-cell Immunoglobulin-like Receptor genes and Crohn’s disease in Ottawa children. The results were mostly replicated in the Montreal cohort of children nd the Winnipeg cohort of adults. Similarly associations between five genes were observed in the adult Winnipeg cohort. An overall analysis for all cohorts showed strong associations with four of the genes, with the strongest association evident for a gene called KIR2DS5. In the combined analysis for four Killer-cell Immunoglobulin-like Receptor genes, individuals carrying one or more of the Killer-cell Immunoglobulin-like Receptor genes were at significantly higher risks for acquiring Crohn’s disease.

We concluded that activating Killer-cell Immunoglobulin-like Receptor genes are associated with risk for developing CD in both children and adults. 

 

Frenkel S, Bernstein CN, Sargent M, Kuang Q, Jiang W, Wei J, Thiruvahindrapuram B, Spriggs E, Scherer SW, Hu P. Genome-wide analysis identifies rare copy number variations associated with inflammatory bowel disease. PLOS One 2019; 14(6): e0217846. Published 2019 Jun 11.

We hypothesized that rare (<0.1% population frequency) gene copy number variations (CNVs) could play an important mechanism for risk of IBD. We aimed to examine changes in DNA copy number in a population-based cohort of patients with IBD and search for novel genetic risk factors for IBD. DNA samples from 243 individuals with IBD from the Manitoba IBD Cohort Study and 2988 healthy controls were analyzed using genome-wide SNP microarray technology. We identified IBD-associated genes affected by rare CNV from comparing the number of overlapping CNVs in IBD samples with the number of overlapping CNVs in controls for each gene. 4,402 CNVs detected by two or three algorithms intersected 7,061 genes, in at least one analyzed sample. Four genes (e.g. DUSP22 and IP6K3) intersected by rare deletions and fourteen genes (e.g. SLC25A10, PSPN, GTF2F1) intersected by rare duplications demonstrated significant association with IBD (FDR-adjusted p-value < 0.01). Of these, ten genes were functionally related to immune response and intracellular signalling pathways. Some of these genes were also identified in other IBD related genome-wide association studies. These suggested that the identified genes may play a role in the risk of IBD.

Our results revealed new genomic loci associated with IBD, which suggested the role of rare CNVs in IBD risk.

Frenkel S, Bernstein CN, Jin YW, Sargent M, Kuang Q, Jiang W, Wei J, Thiruvahindrapuram B, Scherer SW, Hu P. Genome-wide copy number variant data for inflammatory bowel disease in a Caucasian population. Data in Brief 2019; Jul 2; 25:104203.

 

Genome-wide copy-number association studies offer new opportunities to identify the mechanisms underlying complex diseases, including chronic inflammatory, psychiatric disorders and others. We have used genotyping microarrays to analyse the copy-number variants (CNVs) from 243 Caucasian individuals with inflammatory bowel disease. The CNV data was obtained by using multiple quality control measures and merging the results of three different CNV detection algorithms: PennCNV, iPattern, and QuantiSNP. The final dataset contains 4,402 CNVs detected by two or three algorithms independently with high confidence. This paper provides a detailed description of the data generation and quality control steps. For further interpretation of the data presented in this article, please see the research article entitled Copy number variation-based gene set analysis reveals cytokine signalling pathways associated with psychiatric comorbidity in patients with inflammatory bowel disease.

Sexton K, Walker JR, Targownik LE, Graff LA, Haviva C, Beattie B, Petty S, Bernstein MT, Singh H, Miller N, Bernstein CN. The Inflammatory Bowel Disease Symptom Inventory: A patient-report scale for research and clinical application. Inflammatory Bowel Diseases 2019; 25: 1277-1290.

Existing measures of inflammatory bowel disease symptoms are not well suited to self-report, inadequate in measurement properties, insufficiently specific, or burdensome for brief or repeated administration. We aimed to develop a patient-reported outcome measure to assess a broader range of IBD symptoms. The IBD Symptoms Inventory (IBDSI) was developed by adapting symptom items from existing clinician-rated or diary-format inventories; after factor analysis, 38 items were retained on 5 subscales: bowel symptoms, abdominal discomfort, fatigue, bowel complications, and systemic complications. Participants completed the IBDSI and other self-report measures during a clinic visit. A nurse administered the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) or the Powell-Tuck Index (PTI) for ulcerative colitis (UC), and a gastroenterologist completed a global assessment of disease severity (PGA).  The 267 participants with CD (n = 142) or UC (n = 125), ages 18 to 81 (Mean = 43.4 years) were 58.1% female, with a mean disease duration of 13.9 years. Confirmatory factor analysis supported the 5 subscales. The total scale and subscales showed good reliability and significant correlations with self-report symptom and IBD quality of life measures, the HBI, PTI, and PGA. The IBDSI showed strong measurement properties: a supported factor structure, very good internal consistency, convergent validity, and excellent sensitivity and specificity to clinician-rated active disease. Self-report HBI and PTI items, when extracted from this measure, produced scores comparable to clinician-administered versions. The 38-item IBDSI, or 26-item short form, can be used as a brief survey of common IBD symptoms in clinic or research settings

 

Elias E, Targownik LE, Singh H, Bernstein CN. A population-based study of combination versus monotherapy of anti-TNF in persons with IBD. Inflammatory Bowel Diseases 2019; 26: 150-157.

Little data exist about the utilization of combination therapy (anti-TNF plus immunosuppressives) in clinical practice. We assessed the prevalence and predictors of combination therapy use versus anti-TNF monotherapy in inflammatory bowel disease in the Canadian province of Manitoba. All 23 prescribers of anti-TNF medications for IBD in Manitoba facilitated chart review of their comprehensive lists of adult anti-TNF patients from 2005-2015. Subjects were stratified by year of first anti-TNF exposure. Patient, disease, and prescriber factors influencing combination therapy use were explored. 774 patients met inclusion criteria. 71.1% had Crohn’s disease, 28.3% had ulcerative colitis, and 0.6% had IBD unclassified. 45.3% received combination therapy with no difference between Crohn’s disease and UC. Crohn’s disease subjects receiving combination therapy were more likely to have penetrating or perianal disease (56.9% vs 42.8%) and less likely to have had previous IBD-related surgeries (36.2% vs 46.2%). Median age at diagnosis and at anti-TNF initiation was lower among combination therapy users. Adalimumab users were as likely as infliximab users to receive combination therapy but persisted with treatment for a shorter time. The proportion of new anti-TNF users receiving combination therapy did not change over time. There was substantial variation in combination therapy use between prescribers (p=0.002). The most frequently encountered reasons for avoiding combination therapy were previous intolerance or ineffectiveness of immunosuppressive monotherapy. We concluded tht the use of combination therapy has remained unchanged over time despite the publication of high-quality data supporting its efficacy over anti-TNF monotherapy.

 

Singh H, Bernstein CN. Sorting Through the Risks and Benefits of Thiopurine Therapy for Inflammatory Bowel Diseases. Clinical Gastroenterology and Hepatology 2019; 17: 2171-2.

In this editorial we discuss the merits of thiopurine (azathioprine or 6-mercaptopurine) therapy including as monotherapy viz aviz the potential adverse effects. On balance we feel that thiopurines have animportant role as monotherapy or when used in combination with anti-TNF therapy.

 

Panaccione R, Steinhart AH, Bressler B, Khanna R, Marshall JK, Targownik L, Afif W, Bitton A, Borgaonkar M, Chauhan U, Halloran B, Jones J, Kennedy E, Leontiadis GI, Loftus EV Jr, Meddings J, Moayyedi P, Murthy S, Plamondon S, Rosenfeld G, Schwartz D, Seow CH, Williams C, Bernstein CN. Clinical Practice Guideline for the Management of Luminal Crohn's Disease: The Toronto Consensus. Clinical Gastroenterology and Hepatology 2019; 17: 1680-1713.

Crohn's disease is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. In these guidelines we provide guidance for treatment of ambulatory patients with mild to severe active luminal Crohn’s disease. We performed a systematic review to identify published studies of the management of Crohn’s disease. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent Crohn’s disease. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent.

 

Steinhart AH, Panaccione R, Targownik L, Bressler B, Khanna R, Marshall JK, Afif W, , Bitton A, Borgaonkar M, Chauhan U, Halloran B, Jones J, Kennedy E, Leontiadis GI, Loftus EV Jr, Meddings J, Moayyedi P, Murthy S, Plamondon S, Rosenfeld G, Schwartz D, Seow CH, Williams C. Clinical practice guideline for the medical management of perianal fistulizing Crohn's disease: The Toronto Consensus. Inflammatory Bowel Diseases 2019 Jan 1;25(1):1-13.

 

A group of experts in Canada got together to review the literature regarding treatment of perianal fistulizing Crohn’s disease. This review serves as a clinical practice guideline for management of perianal fistulising disease.

 

Nugent Z, Singh H, Targownik LE, Bernstein CN. Herpes Zoster infection and Herpes Zoster vaccination in a population based sample of persons with IBD: Is there still an unmet need? Inflammatory Bowel Disease 2019 Feb 21;25(3): 532-540.

In this study we aimed to report the rates of herpes zoster infection before and after the introduction of herpes zoster vaccine (HZVac) and to determine the rates of HZVac after it became available in Manitoba in 2009. We used the population-based University of Manitoba IBD Epidemiology Database to identify cases of IBD and controls (1984-2016) who were diagnosed with HZI before and after 2009 and to determine the rate of HZVac in those older than age 50 years. Further, we explored predictors of receipt of HZVac among persons with IBD. Persons with IBD vs matched controls have higher rates of herpes zoster infection before diagnosis and postdiagnosis. Herpes zoster infection rates before 2009 per 1000 person-years were increased in persons with IBD (9.2) vs controls (7.2, P < 0.0001). Persons with IBD compared with controls were more likely to get HZVac (15.5 vs 12 per 1000 person-years). Persons newly diagnosed with IBD after 2009 and of higher socioeconomic status were more likely to get HZVac. Despite the introduction of HZVac, there was a steady rise in herpes zoster infection throughout the study period (annual percent change in infection rates of +0.54, P < 0.0001). The increased risk of herpes zoster infection in IBD may reflect an inherent risk associated with the disease or, in those already diagnosed, an increased risk secondary to the use of immunomodulating drugs. HZVac rates are very low, which may reflect physician and patient knowledge of the vaccine's availability and utility and the fact that it is not covered by the provincially provided health care plan.

Shafer LA, Walker JR, Chhibba T, Targownik LE, Singh H, Ivekovic M, Bernstein CN. Health care indicators of moderate to severe IBD-related disability; A longitudinal study. Inflammatory Bowel Diseases 2019;25: 1996-2005.

We aimed to determine how health care utilization indicators in IBD that reflect moderate to severe disease relate to disability later in life. Persons in the population-based University of Manitoba IBD Research Registry completed a survey and gave permission to access their Manitoba Health records. Of 2478 people in the Registry aged 18 to 65 years, 854 participated between April 2015 and March 2016. The survey included the IBD Disability Index (IBDDI). The health data included surgeries and hospitalizations since 1984 and prescriptions since 1995. We explored the association between indicators of moderate to severe disease (ie, surgeries, hospitalization, and new corticosteroids and anti-tumor necrosis factor [anti-TNF] prescriptions) and high IBD-related disability (IBDDI greater than or 34). In addition, among those who had at least 1 IBD-related surgery, we determined predictors of low or no postsurgery disability (IBDDI less than 21). We found that 85% required at least 1 IBD-related surgery since diagnosis or had greater than 2 hospitalizations or were ever prescribed corticosteroids or anti-TNF. Surgery was more common in Crohn's disease (55%) than in UC (13%, P < 0.001). High disability was more prevalent among those ever prescribed anti-TNF (49%) vs never prescribed (28%, P < 0.001), those ever prescribed corticosteroids (35%) vs never prescribed (26%, P = 0.02), and those who had had 1 IBD-related surgery (36%) or greater than 1 surgery (53%) vs those who had had none (28%, P < 0.001).

We concluded that health care utilization indicators of moderate to severe disease (ie, surgeries, hospitalizations, corticosteroid or anti-TNF use) were associated with subsequent higher IBD-related disability. Persons experiencing those indicators should be followed more closely for social, mental, and physical consequences of IBD-related disability. Previous health care utilization can serve as a proxy for IBD-related disability.

 

Paulides E, Gearry RB, de Boer NKH, Mulder CJJ, Bernstein CN, McCombie AM. Accommodations and adaptations to overcome workplace disability in inflammatory bowel disease patients: A systematic review. Inflammatory Intestinal Diseases 2019;3(3):138-144.

Inflammatory bowel diseases, are chronic, incurable diseases which are often characterized by unpredictable flares and troubling symptoms which can interfere with a patient’s ability to work. Accommodations in the workplace can help persons with IBD to cope with their illness and work effectively. We systematically reviewed all studies regarding workplace disability in IBD patients. Systematic searches were undertaken on February to March 2018, for the following databases: Pubmed, Medline (Ovid), Cochrane Central Register of Controlled Trials and CINAHL for studies that addressed workplace needs, accommodations and adaptations using survey tools. Of 430 studies screened, 54 met initial eligibility criteria and then six studies were ultimately included, with a total of 7700 participants. Five studies were quantitative, 1 study was qualitative. Common themes were the importance of reasonable adjustments and accommodations in the workplace, mixed with the finding that a significant proportion reported that they had some difficulty arranging accommodations. Adaptations most required were access to a toilet or toilet breaks and time to go to medical appointments. People with IBD often need accommodations, but many do not ask or have difficulty arranging it. Better resources are needed to inform people with IBD about the possibilities for workplace accommodations and practical strategies to request them.

Shafer LA, Walker JR, Restall G, Chhibba T, Ivekovic M, Singh H, Targownik LE, Bernstein CN. Association between IBD Disability and Reduced Work Productivity (Presenteeism): a population-based study in Manitoba, Canada. Inflammatory Bowel Disease 2019 Jan 10;25(2): 352-359.

One effect of IBD disability is reduced productivity when at work (presenteeism). We explored potential predictors of work presenteeism and compared the predictive ability of the recently developed IBD Disability Index (IBDDI) with 4 other scales in predicting presenteeism. Participants (aged 18-65 years) were recruited from the University of Manitoba IBD Research Registry. We calculated a presenteeism score (range, 0-24) from the Stanford Presenteeism Scale, with higher scores representing greater degrees of presenteeism. We explored associations between presenteeism and the IBDDI, the World Health Organization Disability Assessment Schedule (WHODAS 2.0), the Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Kessler-6 (K6) distress scale. Out of 744 respondents working at least half-time (20+ hours/wk), 472 (63%) reported no reduced productivity in the previous 14 days. Reduced productivity was reported for 1-2 days by 131 (18%), for 3-9 days by 119 (16%), and on most days by 22 (3%). When predicting the Stanford Presenteeism Scale, similar model fits were found for the IBDDI, WHODAS, WSAS, IBDQ, and K6. Each increase of 10 on the IBDDI score was associated with an increase of 2.19 (95% confidence interval, 2.00-2.37) on the Stanford Presenteeism Scale. Each additional year of disease duration was associated with a reduction in Stanford Presenteeism Scale score of 0.08 (P < 0.01). We concluded that more than one-third of persons with IBD report presenteeism. We found strong associations between presenteeism and disability, lower quality of life, and emotional distress. The IBDDI performs equally as well as the more established scales in predicting presenteeism.

Bernstein CN, Nugent Z, Targownik LE, Singh H, Snider C, Witt J. The cost of use of the Emergency Department by persons with inflammatory bowel disease living in a Canadian health region: A retrospective population based study. Journal of the Canadian Association of Gastroenterology 2019; in press.

 

We aimed to determine the costs of Emergency Department attendance by persons with inflammatory bowel disease not admitted to hospital from the Emergency Department. This was a population-based administrative database study linking the University of Manitoba IBD Epidemiology Database with the Winnipeg Regional Health Authority (WRHA) Emergency Department Information Service database.  We identified persons with IBD who presented to the Emergency Department and were not admitted between January 1, 2009 and March 31, 2012. We then applied costs in Canadian dollars for these visits including an average ED visit cost plus 26% for overhead (total=$508), an average estimated cost of laboratory investigations ($50), and costs for each of radiographic imaging, lower endoscopy, and consultation with an internist/gastroenterologist or a surgeon. We tallied the costs of each unique Emergency Department presentation. We determined average costs for visits associated with specific consultations or investigations.1682 persons with IBD (4853 individual visits) attended the Emergency Department and did not get hospitalized. The average cost per Emergency Department visit by a person with IBD who did not get hospitalized was $650. This resulted in a total expenditure of $3,152,227 on these persons for their Emergency Department attendance or $969,916 per year. The visits with the highest mean costs were those associated with an abdominal CT scan ($979), those associated with surgical consultation ($1019) and those associated with an internist/gastroenterologist consultation ($942). Better strategies for management of acute issues for persons with IBD that can reduce the use of an Emergency Department are needed and can be considerably cost saving.

Lewis K, Marrie RA, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM; CIHR Team in Defining the Burden and Managing the Effects of Immune-Mediated Inflammatory Disease. The prevalence and risk factors of undiagnosed depression and anxiety disorders among patients with inflammatory bowel disease. Inflammatory Bowel Diseases 2019; 25 (10), 1674-1680.

Inflammatory bowel disease is associated with a high prevalence of comorbid depressive and anxiety disorders. A significant proportion of IBD patients with comorbid psychiatric disorders remain undiagnosed and untreated, but factors associated with diagnosis are unknown. We evaluated the prevalence of undiagnosed depression and anxiety in an IBD cohort, along with the associated demographic and clinical characteristics. We obtained data from the enrollment visit of a cohort study of psychiatric comorbidity in immune-mediated diseases including IBD. Each participant underwent a Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) to identify participants who met lifetime criteria for a diagnosis of depression or anxiety. Those with a SCID-based diagnosis were classified as diagnosed or undiagnosed based on participant report of a physician diagnosis. Of 242 eligible participants, 97 (40.1%) met SCID criteria for depression, and 74 (30.6%) met criteria for anxiety. One-third of participants with depression and two-thirds with anxiety were undiagnosed. Males were nearly 3.5x more likely to have an undiagnosed depressive disorder. Nonwhite participants were 80% less likely to have an undiagnosed anxiety disorder. Our findings highlight the importance of screening for depression and anxiety in patients with IBD, with particular attention to those of male sex and with a lower education level.

 

Bernstein CN, Hitchon CA, Walld R, Bolton JM, Sareen J, Walker JR, Graff LA, Pattem SB, Singer A, Lix LM, El-Gabalawy R, Katz A Fisk JD, Marrie RA. Increased burden of psychiatric disorders in inflammatory bowel disease. Inflammatory Bowel Disease 2019 Jan 10;25(2): 352-359.

Psychiatric comorbidity in inflammatory bowel disease (IBD) is well known; however, data from a truly representative sample are sparse. We aimed to estimate the incidence and prevalence of psychiatric disorders in an IBD cohort compared with a matched cohort without IBD. Using the population-based University of Manitoba IBD Epidemiology Database, we identified all persons with incident IBD from 1989 to 2012 and a general population matched cohort (5:1). We applied validated algorithms for IBD, depression, anxiety disorders, bipolar disorder, and schizophrenia to determine the annual incidence of these conditions post-IBD diagnosis and their lifetime and current prevalence. There were 6119 incident cases of IBD and 30,573 matched individuals. After adjustment for age, sex, socioeconomic status, region of residence, and year, there was a 60% higher incidence in the IBD cohort compared with controls for depression (incidence rate ratio [IRR], 1.58; 95% confidence interval [CI], 1.41-1.76), 40% for anxiety disorder (IRR, 1.39; 95% CI, 1.26-1.53), 80% for bipolar disorder (IRR, 1.82; 95% CI, 1.44-2.30), and 65% for schizophrenia (IRR, 1.64; 95% CI, 0.95-2.84). Incidence rate ratios were similar for Crohn's disease and ulcerative colitis and between males and females and were stable over time. However, within the IBD cohort, the incidence rates of depression, anxiety, and bipolar disorders were higher among females, those aged 18-24 years vs those older than 44 years, urbanites, and those of lower socioeconomic status. The lifetime and current prevalence rates of psychiatric disorders were also higher in the IBD than the matched cohort. We concluded that the incidence and prevalence of psychiatric disorders are elevated in the IBD population.

Marrie RA, Walker JR, Graff LA, Patten SB, Bolton JM, Marriott JJ, Fisk JD, Hitchon C, Bernstein CN for the CIHR Team in Defining the Burden and Managing the Effects of Immune-mediated Inflammatory Disease. Gender differences in information needs and preferences regarding depression among individuals with multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. Patient and Education Counseling 2019; Apr 6. pii: S0738-3991(19)30132-6.

We assessed the information needs of persons with any of three immune-mediated inflammatory diseases (multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis) regarding depression, as a first step toward developing patient-relevant information resources, ultimately to facilitate self-management and appropriate care. We also compared information needs across genders. We surveyed participants with multiple sclerosis, IBD and rheumatoid arthritis regarding depression-related information needs including types of treatments, effectiveness, risks, benefits, and perceived helpfulness of treatments. We compared responses between groups using multivariate regression. 328 participants provided complete responses (Multiple sclerosis: 141, IBD: 114, rheumatoid arthritis: 73). Most of the topics queried were perceived as very important, and similarly important for all groups. Women placed higher importance than men on most topics. The most popular formats for receiving information were discussion with a counselor (very preferred: 67.4%) and written information (very preferred: 65.5%); this did not differ between groups. We concluded that persons affected by multiple sclerosis, IBD and rheumatoid arthritis are interested in receiving information about multiple topics related to depression treatment, from multiple sources. Women desire more information than men. PRACTICE IMPLICATIONS: These findings can be used to design information resources to meet information needs regarding depression in multiple sclerosis, IBD and rheumatoid arthritis.

Coward S, Clement F, Benchimol EI, Bernstein CN, Avina-Zubieta JA, Bitton A, Carroll MW, Hazlewood G, Jacobson K, Jelinski S, Deardon R, Jones JL, Kuenzig ME, Leddin D, McBrien KA, Murthy SK, Nguyen GC, Otley AR, Panaccione R, Rezaie A, Rosenfeld G, Peña-Sánchez JN, Singh H, Targownik LE, Kaplan GG. Past and future burden of inflammatory bowel diseases based on modeling of population-based data. Gastroenterology 2019; 156:1345-1353.

 

Inflammatory bowel diseases exist worldwide, with high prevalence in North America. IBD is complex and costly, and its increasing prevalence places a greater stress on health care systems. In this study we aimed to determine the past current, and future prevalences of IBD in Canada. We used administrative health data from Alberta (2002-2015), British Columbia (1997-2014), Manitoba (1990-2013), Nova Scotia (1996-2009), Ontario (1999-2014), Quebec (2001-2008), and Saskatchewan (1998-2016). In 2018, the prevalence of IBD in Canada was estimated at 725 per 100,000 (95% PI 716-735) and the annual average percent change increase was nearly 3% per year. The prevalence in 2030 was forecasted to be 981 per 100,000 159 per 100,000 in children, 1118 per 100,000  in adults, and 1370 per 100,000 in the elderly. In 2018, 267,983 Canadians were estimated to be living with IBD, which was forecasted to increase to 402,853 by 2030.

 

Targownik LE, Benchimol E, Witt J, Bernstein CN, Singh H, Lix L, Tennakoon A, Zubieta AA, Coward S, Jones J, Kuenzig E, Murthy S, Nguyen G, Peña Sánchez JN, Kaplan GG. The effect of initiation of anti-TNF therapy on the subsequent direct healthcare costs of inflammatory bowel disease. Inflammatory Bowel Diseases 2019; 25: 1718-1728.

Background: The prevalence of inflammatory bowel disease (IBD) is known to be increasing. The total direct costs of IBD have not been assessed on a population wide level in the era of biologic therapy. We identified all persons with IBD in Manitoba in the University of Manitoba Inflammatory Bowel Disease Epidemiology Database between January 2005 and December 2015, with each matched to 10 controls on age, sex, and geographic area of residence. Costs of all hospitalizations, outpatient physician-patient contacts and prescription medication use were enumerated for cases and controls. Total and per-capital annual costs attributable to IBD were determined by taking the difference between the costs accrued by an IBD case and their control. The number of people with IBD in Manitoba increased from 6,323 to 7,603 between 2005 and 2015. The total per capita annual costs attributable to IBD rose from $3,354 in 2005 to $7,801 in 2015, primarily driven by an increase in pre capital annual anti-TNF drug (i.e. infliximab and adalimumab) costs, which rose from $181 in 2005 to  $5,270 in 2015.  There was a significant decline in inpatient costs for CD ($180±35/year. p=0.0006), but not for UC ($56±35/year, p=0.23), In summary, the direct health care costs attributable to IBD have more than doubled over the 10 years between 2005 and 2015, driven mostly by increasing expenditures on biological medications (i.e. anti-TNF drugs). IBD-attributable hospitalization costs have declined modestly over time for persons with CD, though no change was seen for patients with UC.

Bernstein CN, Burchill C, Targownik LE, Singh H, Roos LL. Events within the first year of life, but not the neonatal period, affect risk for later development of inflammatory bowel diseases. Gastroenterology 2019; 156(8): 2190-2197.

We performed a population-based study to determine whether there was an increased risk of inflammatory bowel diseases (IBD) in persons with critical events at birth and within 1 year of age. We collected data from the University of Manitoba IBD Epidemiology Database, which contains records on all Manitobans diagnosed with IBD from 1984 through 2010 and matched controls. From 1970 individuals' records can be linked with those of their mothers, so we were able to identify siblings. All health care visits or hospitalizations during the neonatal and postnatal periods were available from 1970 through 2010. In previous studies using this data source we showed that development of IBD was not associated with being born by caesarean section (versus vaginal delivery) and was not associated with mothers’ having antenatal or perinatal infections. In this study we collected data on infections, gastrointestinal illnesses, failure to thrive, and hospital readmission in the first year of life and sociodemographic factors at birth. From 1979, data were available on gestational age, Apgar score, neonatal admission to the intensive care unit, and birth weight. We compared incident rate of infections, gastrointestinal illnesses, and failure to thrive between IBD cases and matched controls as well as between IBD cases and siblings. Data on 825 IBD cases and 5999 matched controls were available from 1979. Maternal diagnosis of IBD was the greatest risk factor for IBD in offspring (increased the risk for IBD development in offspring 4.5x). When we assessed neonatal events, only being in the highest vs lowest socioeconomic quintile increased risk for later development of IBD. For events within the first year of life, being in the highest socioeconomic quintile at birth and infections increased risk for developing IBD at any age. Infection in the first year of life was associated with diagnosis of IBD before age 10 years (by 3x)  and before age 20 years (by 1.5x) Risk for IBD was not affected by gastrointestinal infections, gastrointestinal disease, or abdominal pain in the first year of life. In a population-based study, we concluded that infection within the first year of life was associated with a diagnosis of IBD. This might be due to use of antibiotics or a physiologic defect at a critical age for gut microbiome development.

 

El Matary W, Nugent Z, Yu BN, Lix LM, Targwonik LE, Bernstein CN, Singh H. Trends and predictors of Clostridium difficile infection among children: A Canadian population-based study. Journal of Pediatrics 2019 Mar; 206:20-25.

 

In this paper we report on the incidence rates over time of children with IBD presenting with Clostridium difficile infection. We explored our provincial database on all persons with Clostridium difficile infection between 2005-2014 so that we could identify the rates of this infection in children and what diseases increased the risk for Clostridium difficile infection. In children. The overall Clostridium difficile infection rate over the study period was 7.77 per 100,000. There was no significant increase in Clostridium difficile infection rates over the observation period. Co-morbid conditions that were more prevalent among children with Clostridium difficile infection than matched controls included Hirschsprung’s disease (p<0.001) and IBD (p<0.0001). Recurrent Clostridium difficile infections were responsible for 10.4% of CDI episodes (range 2-6 infections). Children with cancer were 3 times as likely to have recurrent Clostridium difficile infection (Hazard ratio (HR) = 3.0, 95% confidence interval (CI) 1.1, 8.8), children with diabetes were nearly 5 times as likely to have recurrent Clostridium difficile infection (HR=4.8, 95% CI 1.1, 21.4) and children with neurodegenerative diseases were over 8 times as likely to have recurrent Clostridium difficile infection (HR=8.4, 95% CI 1.9, 37.5). We concluded that the incidence of Clostridium difficile infection was not increasing among children in Manitoba. Children with malignancy, diabetes and neurodegenerative disorders are more likely to have recurrent Clostridium difficile infection.

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El-Matary W, Leung S, TennakoonA, Benchimol EI, Bernstein CN, Targownik LE. Trends of utilization of tumor necrosis factor antagonists in children with inflammatory bowel disease: A Canadian population-based study. Inflammatory Bowel Diseases 2019; 206: 20-25.

We aimed to describe the trend of utilization of anti-TNF drugs (infliximab and adalimumab) in children with IBD over time. We assessed all persons diagnosed with IBD prior to age 18y identified in the University of Manitoba IBD Epidemiology Database to determine the time from diagnosis to first anti-TNF in different eras (2005-2008, 2008-2012, 2012-2016). There were 291 persons diagnosed with IBD (157 CD, 134 UC) prior to age 18y. The likelihood of being initiated on anti-TNFs by 1, 2 and 5 years post-diagnosis was 18.4%, 30.5% and 42.6% respectively. The proportion of persons <18 using anti-TNFs increased over time; in 2010, 13.0% of Crohn’s disease (CD) and 4.9% of ulcerative colitis (UC); by 2016 60.0% of CD and 25.5% of UC were actively using an anti-TNF agent. For those diagnosed after 2012, 42.5% of CD and 28.4% of UC had been started on an anti-TNF agent within 1 year of IBD diagnosis. The median cumulative dose of corticosteroids in the year prior to anti-TNF initiation significantly decreased over time (prior to 2008: 4360mg; 2008-2012: 2010mg, 2012-present 1395mg prednisone equivalents) meaning the use of anti-TNF drugs has likely translated into a reduced use of corticosteroids.

Eissa N, Hussein H, Diarra A, Kapoor K, Gounni AS, Bernstein CN, Ghia JE. Semaphorin 3E regulates apoptosis in the intestinal epithelium during the development of colitis. Biochemical Pharmacology 2019; 166:264-273.

 

Semaphorin 3E is a protein that regulates various biological processes including immune responses and apoptosis. However, its role in the pathophysiology of colitis is not fully known. We investigated the role of Semaphorin 3E  in intestinal epithelial cells activation, using biopsies from patients with active ulcerative colitis (UC), a mouse model of UC, and an in-vitro model of intestinal mucosal healing. In this study, we confirmed that the mRNA level of Semaphorin 3E is reduced significantly in patients with UC and demonstrated a negative linear association between Semaphorin 3E mRNA and p53-associated genes. In mice, genetic deletion of Sema3e (gene for Semaphorin 3E) resulted in an increase in onset and severity of colitis, p53-associated genes, apoptosis, and IL-1beta production. Recombinant Semaphorin 3E treatment protected against colitis and decreased these effects. Furthermore, in stimulated epithelial cells, recombinant Semaphorin 3E treatment enhanced wound healing, resistance to oxidative stress and decreased apoptosis and p53-associated genes.

Together, these findings identify Semaphorin 3E as a novel regulator in intestinal inflammation that regulates intestinal epithelial cells apoptosis and suggest a potential novel approach to treat UC.

Benchimol E, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Siddq S, Windsor JW, Carroll M, Coward S, El-Matary W, Griffiths AM, Jones J, Kuenzig E, Lee L, Mack DR, Mawani M, Otley A, Singh H, Targownik LE, Weizman AV, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: A Scientific Report from the Canadian Gastro-Intestinal Epidemiology Consortium to Crohn's and Colitis Canada. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S1-S5.

 

Kaplan GG, Bernstein CN, Coward S, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Benchimol E. The Impact of Inflammatory Bowel Disease in Canada 2018: Epidemiology. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S6-S16.

 

Carroll M, Kuenzig E, Mack DR, Otley A, Griffiths AM, Kaplan GG, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Benchimol E. The Impact of Inflammatory Bowel Disease in Canada 2018: Children and Adolescents with IBD. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S49-S67.

 

Nguyen GC, Targownik LE, Singh H, Benchimol E, Bitton A, Murthy SK, Bernstein CN, Lee K, Cooke-Lauder J, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: IBD in Seniors. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S68-S72.

 

Bernstein CN, Benchimol E, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: Extra-intestinal Diseases in IBD. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S73-S80.

 

Rose K, Sherman PM, Cooke-Lauder J, Mawani M, Benchimol E, Kaplan GG, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K. The Impact of Inflammatory Bowel Disease in Canada 2018: IBD Research Landscape in Canada. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S81-S91.

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Jones J, Nguyen GC, Benchimol E, Bernstein CN, Bitton A, Kaplan GG, Murthy SK, Lee K, Cooke-Lauder J, Otley A. The Impact of Inflammatory Bowel Disease in Canada 2018: Quality of Life. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S42-S48.

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Keunzig ME, Lee L, El-Matary W, Weizman AV, Benchimol EI, Targownik LE, Singh H, Kaplan GG, Bernstein CN, Bitton A, Nguyen GC, Lee K, Cooke-Lauder J, Murthy S. The Impact of Inflammatory Bowel Disease in Canada 2018: Direct Costs and Health Services Utilization. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S17-S33.

 

Keunzig ME, Benchimol E, Lee L, Targownik LE, Singh H, Kaplan GG, Nguyen GC, Bernstein CN, Bitton A, Lee K, Cooke-Lauder J, Murthy S. The Impact of Inflammatory Bowel Disease in Canada 2018: Indirect costs of IBD care. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S34-S41.

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