Publications // 2023

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Patel R, Marrie RA, Bernstein CN, Bolton JM, Graff LA, Marriott JJ, Figley CR, Kornelsen J, Mazerolle EL, Helmick C, Uddin M, Fisk JD. Vascular comorbidity is associated with decreased cognitive functioning in inflammatory bowel disease. Scientific Reports 2023; Mar 15;13(1):4317.

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Reports of cognitive impairment in IBD have been mixed. IBD and cardiovascular disease are often co-morbid, yet it remains unknown whether vascular comorbidity confers a risk for decreased cognitive functioning, as observed in other populations. Participants with IBD were recruited from a longitudinal study of immune-mediated disease. Participants were administered a standardized neuropsychological test protocol, evaluating information processing speed, verbal learning and memory, visual learning and memory, and verbal fluency/executive function. Cognitive test scores were standardized using local regression-based norms, adjusting for age, sex, and education. Vascular risk was calculated using a modified Framingham Risk Score. We tested the association between Framingham Risk Score and cognitive test scores using a quantile regression model, adjusting for IBD type. Results: Of 84 IBD participants, 54 had ulcerative colitis and 30 had Crohn's disease; mean (SD) age was 53.36 (13.95) years, and a high proportion were females (n = 58). As the Framingham Risk Score increased, participants demonstrated lower performance in information processing speed (β = - 0.12; 95% CI - 0.24, - 0.006) and verbal learning (β = - 0.14; 95% CI - 0.28, - 0.01) at the 50th percentile. After adjusting for IBD type and disease activity, higher Framingham Risk Score remained associated with lower information processing speed (β = - 0.14; 95% CI - 0.27, - 0.065). Vascular comorbidity is associated with lower cognitive functioning in persons with IBD, particularly in the area of information processing speed. Conclusions: These findings suggest that prevention, identification, and treatment of vascular comorbidity in IBD may play a critical role for improving functional outcomes in IBD.

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Mak JWY, Sun Y, Limsrivilai J, Abdullah M, Kaibullayeva J, Balderramo D, Vergara BI, Paudel MS, Banerjee R, Hilmi I, Ali RAR, Wei SC, Ng KK, Altuwaijri M, Kelly P, Yamamoto-Furusho JK, Kotze PG, Ahuja V, Chong VH, Dao HV, Abbey Y, Ching JYL, Ho A, Chan AKW, Bernstein CN, Gearry RB, Abreu M, Rubin DT, Dotan I, Hracs L, Kaplan GG, Ng SC; GIVES-21 Consortium.  Development of the global inflammatory bowel disease visualization of epidemiology studies in the 21st century (GIVES-21). BMC Medical Research Methodology 2023 May 25;23(1):129.

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There is a rapid increase in the incidence of IBD in newly industrialized countries, yet epidemiological data is incomplete. We herein report the methodology adopted to study the incidence of IBD in newly industrialized countries and to evaluate the effect of environmental factors including diet on IBD development. Global IBD Visualization of Epidemiology Studies in the 21st Century (GIVES-21) is a population-based cohort of newly diagnosed persons with Crohn's disease and ulcerative colitis in Asia, Africa, and Latin America to be followed prospectively for 12 months. New cases were ascertained from multiple sources and were entered into a secured online system. Cases were confirmed using standard diagnostic criteria. In addition, endoscopy, pathology and pharmacy records from each local site were searched to ensure completeness of case capture. Validated environmental and dietary questionnaires were used to determine exposure in incident cases prior to diagnosis. Results: Through November 2022, 106 hospitals from 24 regions (16 Asia; 6 Latin America; 2 Africa) have joined the GIVES-21 Consortium. To date, over 290 incident cases have been reported. All patients have demographic data, clinical disease characteristics, and disease course data including healthcare utilization, medication history and environmental and dietary exposures data collected. We have established a comprehensive platform and infrastructure required to examine disease incidence, risk factors and disease course of IBD in the real-world setting. We conclude that the GIVES-21 consortium offers a unique opportunity to investigate the epidemiology of IBD and explores new clinical research questions on the association between environmental and dietary factors and IBD development in newly industrialized countries.

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Stone JK, Mehta NA, Singh H, El-Matary W, Bernstein CN. Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome. Familial Cancer 2023; 22: 413-422.

Familial Adenomatous Polyposis is an autosomal dominant syndrome predisposing affected individuals to gastrointestinal (GI) cancers through a high burden of polyposis. Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood. Endoscopic therapy of gastric, duodenal, ampullary and rectal pouch polyps is critical to reduce morbidity and cancer related mortality. Management of these lesions is not uniform, and is dependent on their location, size, histology, and risk of malignant potential. Medical therapies targeting pathways that reduce the malignant progression of pre-cancerous lesions have been studied for many years. While studies on the use of aspirin and non-steroidal anti-inflammatories (NSAIDs) in chemoprevention have shown encouraging results in Lynch syndrome and primary colorectal cancer, the potential benefits of these medications have not been duplicated in Familial Adenomatous Polyposis cohorts. While data remains limited on chemoprevention in Familial Adenomatous Polyposis, a number of randomized trials are currently underway examining targeted therapies with the potential to slow the progression of the disease. This review aims to provide an in-depth review of the literature on current endoscopic options and chemopreventive therapies targeting Familial Adenomatous Polyposis. While the endoscopic management has robust data for its use, chemoprevention in Familial Adenomatous Polyposis is still in its infancy. The complementary use of chemopreventive agents and endoscopic therapy for Familial Adenomatous Polyposis patients is quickly becoming a growing and exciting area of research.

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Bernstein CN, Regueiro M. Post-operative Crohn’s disease. Journal of Clinical Gastroenterology 2023; 57(8):749-753.

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Although surgery rates in Crohn's disease are declining in the past twenty years, bowel resection remains an important and still commonly used therapeutic option in Crohn's disease. Preoperatively, patients clinical status must be optimized including preparation for perioperative recovery including with nutrition optimization and preparation for postoperative pharmacotherapy. Postoperatively a medical therapy is often required and in recent years it has often been a biological therapy. One randomized controlled study suggested that infliximab is more likely to prevent endoscopic recurrence than placebo. But other biologicals have been used as well. Ileocolonoscopy should be undertaken by 6 months after an ileal or ileocecal resection especially. Adjunctive imaging such as transabdominal ultrasound, capsule endoscopy or cross sectional imaging may be required. Biomarker measurement with fecal calprotectin especially, or C-reactive protein, serum ferritin, serum albumin and serum hemoglobin will also be helpful.

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Kornelsen J, McIver T,  Uddin MN,  Figley CR,  Marrie RA, Patel R, Fisk JD , Carter S, Graff LA,  Mazerolle E,  Bernstein CN. Altered voxel-based and surface-based morphometry in inflammatory bowel disease. Brain Research Bulletin 2023 Oct 15:203:110771.

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 IBD is a disorder of the brain-gut axis. Neuroimaging studies of brain function and structure have helped better understand the relationships between the brain, gut, and comorbidity in IBD. Studies of brain structure have primarily employed voxel-based morphometry to measure grey matter volume and surface-based morphometry to measure cortical thickness. Far fewer studies have employed other surface-based morphometry metrics such as gyrification, cortical complexity, and sulcal depth. In this study, brain structure differences between 72 adults with IBD and 90 healthy controls were assessed using all five metrics. Significant differences were found for cortical thickness with the IBD group showing extensive left-lateralized thinning, and for cortical complexity with the IBD group showing greater complexity in the left fusiform and right posterior cingulate. No significant differences were found in grey matter volume, gyrification, or sulcal depth. Within the IBD group, a post hoc analysis identified that disease duration is associated with cortical complexity of the right supramarginal gyrus, albeit with a more lenient threshold applied.

Carter SL, Patel R, Fisk JD, Figley CR, Marrie RA, Mazerolle EL, Uddin N, Wong K,  Graff LA,  Bolton JM,  Marriott JM,  Bernstein CN, Kornelsen J. Differences in resting state functional connectivity relative to multiple sclerosis and impaired information processing speed. Frontiers in Neurology 2023 Oct 19:14:1250894.

51% of individuals with multiple sclerosis develop cognitive impairment in information processing speed. Although information processing speed scores are associated with health and well-being, neural changes that underlie information processing speed impairments in multiple sclerosis are not understood. Resting state fMRI can provide insight into brain function changes underlying impairment in persons with multiple sclerosis. We aimed to assess functional connectivity differences in (i) persons with multiple sclerosis compared to healthy controls, (ii) persons with both multiple sclerosis and cognitive impairment compared to healthy controls, (iii) persons with multiple sclerosis that are cognitively preserved compared to healthy controls, (iv) multiple sclerosis-cognitively impaired compared to multiple sclerosis-cognitively preserved, and (v) in relation to cognition within the multiple sclerosis group.  We included 107 participants with multiple sclerosis (age 49.5 ± 12.9, 82% women), and 94 controls (age 37.9 ± 15.4, 66% women). Each participant was administered the Symbol Digit Modalities Test and underwent a resting state fMRI scan. The multiple sclerosis-cognitively impaired group was created by applying a z-score cut-off of ≤≤-1.5 to locally normalized Symbol Digit Modalities Test scores. The multiple sclerosis-cognitively preserved group was created by applying a z-score of ≥0. Control groups were based on the nearest age-matched healthy controls participants. A whole-brain Region of Interest to Region of Interest (ROI-to-ROI) analysis was performed followed by specific contrasts and a regression. Results: Individuals with multiple sclerosis showed functional connectivity differences compared to healthy controls that involved the cerebellum, visual and language-associated brain regions, and the thalamus, hippocampus, and basal ganglia. The multiple sclerosis-cognitively impaired showed functional connectivity differences compared to healthy controls that involved the cerebellum, visual and language-associated areas, thalamus, and caudate. Symbol Digit Modalities Test scores were correlated with functional connectivity between the cerebellum and lateral occipital cortex in multiple sclerosis. No differences were observed between the multiple sclerosis-cognitively preserved and healthy controls or multiple sclerosis-cognitively impaired and multiple sclerosis-cognitively preserved groups. Conclusions: Our findings emphasize functional connectivity changes of cerebellar, visual, and language-associated areas in persons with multiple sclerosis. These differences were apparent for (i) all multiple sclerosis participants compared to healthy controls, (ii) multiple sclerosis-cognitively impaired subgroup and their matched controls, and (iii) the association between functional connectivity and Symbol Digit Modalities Test scores within the multiple sclerosis group. Our findings strongly suggest that future work that examines the associations between functional connectivity and information processing speed impairments in multiple sclerosis should focus on the involvement of these regions.

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Joyees J, Marrie RA, Bernstein CN, Bolton JM, Fisk JD, Graff LA, Hitchon CA, Patten SB , Kowalec K; CIHR team in defining the burden and managing the effects of psychiatric comorbidity in chronic immunoinflammatory disease. Sex differences evident in elevated anxiety symptoms in multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Frontiers in Psychiatry 2023 Nov 22:14:1260420.

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Immune-mediated inflammatory diseases, such as IBD, multiple sclerosis (MS), or rheumatoid arthritis (RA) have high rates of elevated anxiety symptoms. This can may worsen functioning and increase the burden of these immune-mediated inflammatory diseases. The rate of and factors associated with elevated anxiety symptoms may differ between males and females, which, in turn can affect diagnosis and disease management. We evaluated whether the frequency and factors associated with comorbid elevated anxiety symptoms in those with an immune-mediated inflammatory diseases differed by sex.  Participants with an Immune-mediated inflammatory disease (IBD, MS or RA) completed two anxiety measures (HADS, GAD-7). We used logistic regression to investigate whether sex differences exist in the presence of comorbid elevated anxiety symptoms or in the endorsement of individual anxiety items in those with an IMID. Results: Of 656 participants, females with an immune-mediated inflammatory diseases were more likely to have elevated anxiety symptoms compared to males (adjusted odds ratio [aOR] 2.05; 95%CI: 1.2, 3.6). Younger age, higher depressive symptoms and income were also associated with elevated anxiety symptoms in immune-mediated inflammatory diseases. Lower income in males with an IMID, but not females, was associated with elevated anxiety symptoms (aOR: 4.8; 95%CI: 1.5, 15.6). No other factors demonstrated a sex difference. Males had nearly twice the odds of endorsing restlessness on the GAD-7 (OR = 1.8, 95%CI: 1.07, 3.15) compared to females. Conclusion: We found evidence for sex differences in the factors associated with experiencing elevated anxiety symptoms in those with an immune-mediated inflammatory diseases. These findings could be helpful to sensitize clinicians to monitor for comorbid anxiety symptoms in males with an immune-mediated inflammatory diseases.

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Schoeps VA, Zhou X,  Horton MK, Zhu F,  McCauley KE, Nasr Z,  Virupakshaiah A, Gorman MP,  Benson LA, Weinstock-Guttman B, Waldman A,  Banwell BL, Bar Or A,  Marrie RA, van Domselaar G, O'Mahony J,  Mirza AI,  Bernstein CN,  Yeh EA,  Casper TC,  Lynch SV, Tremlett H, Baranzini S, Waubant E; US Network of Pediatric MS Centers. Short-chain fatty acid producers in the gut are associated with pediatric multiple sclerosis onset. Annals of Clinical and Translational Neurology 2023 Nov 13.

The relationship between multiple sclerosis and the gut microbiome has been supported by animal models in which commensal microbes are required for the development of experimental autoimmune encephalomyelitis. However, observational study findings in humans have only occasionally converged when comparing multiple sclerosis cases and controls which may in part reflect confounding by comorbidities and disease duration. The study of microbiome in pediatric-onset multiple sclerosis offers unique opportunities as it is closer to biological disease onset and minimizes confounding by comorbidities and environmental exposures. We undertook a multicenter case-control study in which 35 pediatric-onset multiple sclerosis cases were 1:1 matched to healthy controls on age, sex, self-reported race, ethnicity, and recruiting site. Linear mixed effects models, weighted correlation network analyses, and PICRUSt2 were used to identify microbial co-occurrence networks and for predicting functional abundances based on marker gene sequences. Results: Two microbial co-occurrence networks (one reaching significance after adjustment for multiple comparisons; q < 0.2) were identified, suggesting interdependent bacterial taxa that exhibited association with disease status. Both networks indicated a potentially protective effect of higher relative abundance of bacteria observed in these clusters. Functional predictions from the significant network suggested a contribution of short-chain fatty acid producers through anaerobic fermentation pathways in healthy controls. Consistent family-level findings from an independent Canadian-US study (19 case/control pairs) included Ruminococaccaeae and Lachnospiraceae (p < 0.05). Macronutrient intake was not significantly different between cases and controls, minimizing the potential for dietary confounding. Conclusions: Our results suggest that short-chain fatty acid producers may be important contributors to multiple sclerosis onset.

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Narous M, Nugent Z, Singh H, Bernstein CN. Risks of melanoma and non-melanoma skin cancers pre- and post-inflammatory bowel disease diagnosis. Inflammatory Bowel Diseases 2023; 29:1047-1056.

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We aimed to compare risks of nonmelanoma skin cancer (NMSC) and melanoma preceding and following a diagnosis of IBD and to evaluate the effect of thiopurines and anti-TNFa on skin cancer risk in IBD. This is a retrospective, historical cohort study using the population-based University of Manitoba IBD Epidemiology Database (11,228 IBD cases and 104,725 matched controls) linked to the Manitoba Cancer Registry. Logistic and Cox regression analyses were performed to calculate skin cancers risks prior to and after IBD diagnosis. Results: Persons with IBD were more likely to have basal cell carcinoma (BCC) pre-dating their IBD diagnosis (odds ratio (OR) 1.32, 95% CI1.08-1.60). Risks of squamous cell carcinoma (SCC), other NMSC or melanoma prior to IBD diagnosis were not significantly increased. Post-IBD diagnosis, risk of BCC (HR 1.53, 95% CI1.37-1.70) and SCC (HR 1.61, 95% CI1.29-2.01) were significantly increased across all IBD groups except for SCC in ulcerative colitis. There was no significant association between melanoma and IBD post-IBD diagnosis. The risks of BCC and melanoma were increased in thiopurine and anti-TNF users and risk of SCC was increased in only thiopurine users. Nested cohort analysis of persons with IBD with censoring at both thiopurines and anti-TNF use confirmed a higher baseline risk of BCC and no effect on SCC, comparable to pre-IBD diagnosis findings. Conclusions: The risk of BCC preceding a diagnosis of IBD is higher than in non-IBD controls, compared to a generally increased risk of all NMSC post-IBD diagnosis. Thiopurine and anti-TNF therapy increase the risks for skin cancers in persons with IBD after their diagnoses. Persons using thiopurines should see a dermatologist once yearly for a thorough skin examination to assess for skin cancers.

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Alenezy N, Nugent Z, Herman S, Zaborniak K, Ramsey CD, Bernstein CN. Aeroallergen-related diseases predate the diagnosis of inflammatory bowel disease. Inflammatory Bowel Diseases 2023; 29:1073-1079.

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We aimed to determine if having a diagnosis of asthma or allergic rhinitis (AR) increased the risk of being diagnosed with inflammatory bowel disease (IBD) and whether there was increased incidence of these diseases after a diagnosis of IBD. We performed a retrospective, historical cohort-based study. We used the administrative data of Manitoba Health and the population-based University of Manitoba IBD Epidemiology Database. We used numbers of prescriptions for drugs used to treat asthma and to treat AR to identify diagnoses of asthma and AR respectively. We calculated relative risks (RR) to assess incidence of IBD compared with matched controls, after diagnoses of asthma and AR and hazard ratios (HR) to determine the incidence of asthma and AR after IBD diagnosis. Results: Compared to controls, a diagnosis of asthma or AR preceding a diagnosis of IBD were increased by 60% in cases (RR=1.62, 95%confidence interval [CI] 1.50-1.75 and more than 2-fold RR=2.10, 95%CI 1.97-2.24) with a similar outcome by subtype of IBD (Crohn’s disease vs ulcerative colitis) and by sex. On sensitivity analysis diagnoses of asthma or AR were comparable whether considering at least 5, 10, 15 or 20 drug prescriptions. Persons with IBD were more likely to develop asthma or AR than controls, post IBD diagnosis (HR for asthma 1.31, 95%CI 1.18-1.45, and HR for AR 2.62, 95%CI 2.45-2.80). Conclusions: The association between asthma and AR and IBD suggest the possibility that whatever triggers the onset of these atopic diseases may trigger the onset of IBD as well and aeroallergens are plausible culprits.

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Thomann AK, Knödler LL, Karthikeyan S, Atanasova K, Bernstein CN, Ebert MP, Lis S, Reindl W. The interplay of biopsychosocial factors and quality of life in inflammatory bowel diseases – a network analysis. Journal of Clinical Gastroenterology 2023; 57:57-65.

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We aimed to investigate the network of biopsychosocial factors and quality of life in persons with IBD and explore the influence of psychological factors on the course of quality of life of persons with IBD depends on disease activity, but also on numerous interacting psychosocial factors. The influence of psychosocial factors on the disease course in controversially discussed. In two independent IBD-samples (sample 1: n=209, anonymous internet survey; sample 2: n=84, outpatients with active disease), we measured quality of life, anxiety, depression, illness identity, self-esteem, loneliness, childhood trauma, and visceral sensitivity with questionnaires. Additionally, fatigue, haemoglobin levels and response to therapy were assessed in sample 2. We estimated multiple regularized partial correlation networks and conducted accuracy and stability tests of the networks.  Results: In both samples, quality of life had the strongest relationships with visceral sensitivity and the illness identity engulfment. Depression was the most central factor in the networks. Baseline depression scores, visceral sensitivity and engulfment were associated with response to therapy in sample 2. Conclusion: This first network study to assess the interplay between biopsychosocial factors and quality of life in IBD reveals a comparable network structure in two samples. Results partly replicate findings from previous studies with regard to the importance of depression and yield information on the central role of the newly introduced concepts of illness identity and visceral sensitivity. Preliminary findings point to an influence of these parameters on the disease course, which indicates their role as a possible target in individualized therapy.

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Wu Y, Levis B, Daray FM, Ioannidis JPA, Patten SB, Cuijpers P, iegelstein RC, Gilbody S, Fischer FH, Fan S, Sun Y, Benedetti A, Thombs BD, and the DEPRESsion Screening Data (DEPRESSD) HADS Group.  Comparison of the accuracy of the 7-item HADS Depression subscale and 14-item total HADS for screening for major depression: a systematic review and individual participant data meta-analysis. Psychological Assessment 2023;35(2):95-114.

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The seven-item Hospital Anxiety and Depression Scale Depression subscale (HADS-D) and the total score of the 14-item HADS (HADS-T) are both used for major depression screening. Compared to the HADS-D, the HADS-T includes anxiety items and requires more time to complete. We compared the screening accuracy of the HADS-D and HADS-T for major depression detection. We conducted an individual participant data meta-analysis and fit bivariate random effects models to assess diagnostic accuracy among participants with both HADS-D and HADS-T scores. We identified optimal cutoffs, estimated sensitivity and specificity with 95% confidence intervals, and compared screening accuracy across paired cutoffs via two-stage and individual-level models. We used a 0.05 equivalence margin to assess equivalency in sensitivity and specificity. 20,700 participants (2,285 major depression cases) from 98 studies were included. Cutoffs of ≥7 for the HADS-D (sensitivity 0.79 [0.75, 0.83], specificity 0.78 [0.75, 0.80]) and ≥15 for the HADS-T (sensitivity 0.79 [0.76, 0.82], specificity 0.81 [0.78, 0.83]) minimized the distance to the top-left corner of the receiver operating characteristic curve. Across all sets of paired cutoffs evaluated, differences of sensitivity between HADS-T and HADS-D ranged from -0.05 to 0.01 (0.00 at paired optimal cutoffs), and differences of specificity were within 0.03 for all cutoffs (0.02-0.03). The pattern was similar among outpatients, although the HADS-T was slightly (not nonequivalently) more specific among inpatients. The accuracy of HADS-T was equivalent to the HADS-D for detecting major depression. In most settings, the shorter HADS-D would be preferred.

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Marrie RA, Fisk JD, Walld R, Bolton JM, Sareen J, Patten SB, Singer A, Lix LM, Hitchon CA, El-Gabalawy R, Katz A, Marriott JJ, Bernstein CN for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Prescription Opioid Use in Multiple Sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry 2023; 94:167-169.

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We identified Manitobans with multiple sclerosis from 1984 to 2016 using a validated definition relying on health claims; the earliest demyelinating disease claim constituted the index date. A general population cohort was matched 5:1 on sex, year of birth (±5 years) and residence region to the multiple sclerosis cohort, after excluding anyone with diagnosis codes for demyelinating disease or multiple sclerosis disease-modifying therapies. Each control was assigned the index date of their matched case. From these cohorts, we selected incident multiple sclerosis cases and matched controls with an index date ≥1997, excluding individuals with cancer/palliative care. Using validated definitions, we updated mood/anxiety disorder status annually (active vs inactive/absent). Individuals with schizophrenia were not excluded. We estimated the crude annual incidence and prevalence of opioid use, overall and stratified by sex and age. We age and sex standardised the estimates. Results There were 2918 persons with multiple sclerosis and 14 539 persons without. In 2016, the crude incidence/1000 persons of opioid use was 1.49-fold higher (rate ratio [RR] 1.49, 95% CI 1.35 to 1.64) in the multiple sclerosis cohort (62.94, 95% CI 58.34 to 67.54) than in the non- multiple sclerosis cohort (43.89, 95% CI 42.39 to 45.40). Opioid use was higher in the multiple sclerosis than in the non-multiple sclerosis cohorts at all ages; this effect was greatest in those aged ≥65 years. Among incident opioid users with at least 5 years of follow-up who had multiple sclerosis but no mood/anxiety disorder, 30.0% obtained only one opioid dispensation, and 8.4% used opioids continuously for ≥3 months. In contrast, among individuals with multiple sclerosis and a mood/anxiety disorder, few had only one dispensation (11.4%), and 11.4% used opioids continuously for at least3 months (11.4%). After adjusting for covariates, the multiple sclerosis cohort had an increased incidence (RR 1.18, 95% CI 1.08 to 1.29) and prevalence of opioid use (RR 1.49, 95% CI 1.41 to 1.57) than the non- multiple sclerosis cohort. There were no statistically significant interactions between cohort and mood/anxiety disorders on opioid use. Conclusions: The annual prevalence of opioid use was 226/1000 persons with MS, but only 132/1000 persons without multiple sclerosis, an adjusted relative increase of 49% in the multiple sclerosis cohort. This higher use of opioids was irrespective of the presence of a mood/anxiety disorder.  Notably, average incidence of opioid use in those with multiple sclerosis aged ≥65 years was quite high, at 83/1000 persons, and prevalent use affected one in four persons.

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Marrie RA,  Bernstein CN,  Dolovich C,  Bolton JM, Graff LA,  Hitchon CA,  Lix LM,  Marriott JJ, Fisk JD.  Within-person fluctuations over three years in depression, anxiety, fatigue, and health-related quality of life in multiple sclerosis. Multiple Sclerosis 2023 Oct;29(11-12):1503-1513.

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Longitudinal studies of health-related quality of life in multiple sclerosis are limited. Most have examined average changes within the population, rather than dynamic changes within individuals. We aimed to assess the between- and within-individual association between depression, anxiety, fatigue, cognition, physical functioning, and physical comorbidities and health-related quality of life. Adults with multiple sclerosis underwent physical and cognitive assessments and reported symptoms of fatigue (Daily Fatigue Impact Scale), depression and anxiety (Hospital Anxiety and Depression Scale (HADS)), and HRQoL (RAND-36) (Hospital Anxiety and Depression Scale (HADS)), and health-related quality of life (RAND-36) annually (n = 4 visits). We evaluated associations of elevated symptoms of anxiety (HADS-A) and depression (HADS-D), fatigue, physical function (timed-walk and nine-hole peg test), cognitive function and comorbidity count with physical (PCS-36) and mental (MCS-36) health-related quality of life using multivariable linear models-estimating between-person and within-person effects. Results: Of 255 participants with multiple sclerosis enrolled, 81.6% were women. After adjustment, within-person increases in depression and fatigue were associated with decreases in physical health-related quality of life. Increases in depression, anxiety, and comorbidity count were associated with decreases in mental health-related quality of life. Conclusions: Within-person increases in symptoms of depression, anxiety and fatigue, and comorbidity count are associated with health-related quality of life decreases among adults with multiple sclerosis, highlighting the potential magnitude of individual benefit of intervention for these symptoms.

Li L, Aviña-Zubieta JA, Bernstein CN, Kaplan GG, Tremlett H, Xie H, Peña-Sánchez JN, Marrie RA, Etminan M. The Risk of Multiple Sclerosis Among Users of Anti-tumor Necrosis Factor Alpha in four Canadian provinces: A Population-Based Study. Neurology 2023; 100: e558-e567.

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Antitumor necrosis factor α (TNFα) agents are a class of biologic drugs used for the treatment of several immune-mediated conditions. An increased risk of multiple sclerosis with their use has been suggested, but studies have been limited. Relevant population-based epidemiologic data linking anti-TNFα to multiple sclerosis are scarce. The objective was to compare the risk of multiple sclerosis in anti-TNFα users with nonusers among patients with rheumatic disease or IBD. A nested case-control study was conducted. Population-based health care-linked databases from 4 Canadian provinces were used. All patients with rheumatic diseases or IBD residing within a participating province between January 2000 and March 2018 were identified by validated case definitions. Any anti-TNFα dispensation in the 2 years before the index date (Multiple sclerosis onset) was identified. Incident onset multiple sclerosis cases were ascertained using a validated algorithm. Up to 5 controls were matched to each multiple sclerosis case based on birth year ±3 years, disease duration, and health authority (based on region of residence). Conditional logistic regressions were used to calculate the incidence rate ratio after adjusting for potential confounders. A meta-analysis was conducted to provide pooled estimates across provinces using random-effects models. Results: Among 296,918 patients with rheumatic diseases patients, 462 multiple sclerosis cases (80.1% female, mean [SD] age, 47.4 [14.6] years) were matched with 2,296 controls (59.5% female, mean [SD] age, 47.4 [14.5] years). Exposure to anti-TNFα occurred in 18 multiple sclerosis cases and 42 controls. After adjusting for matching variables, sex, and the Charlson Comorbidity Index, the pooled incidence rate ratio was 2.05 (95% CI, 1.13-3.72). Among 84,458 patients with IBD, 190 multiple sclerosis cases (69.5% female, mean [SD] age, 44.3 [12.3] years) were matched with 943 controls (54.1% female, mean [SD] age, 44.2 [12.2] years). Exposure to anti-TNFα occurred in 23 multiple sclerosis cases and 98 controls. The pooled adjusted IRR was 1.35 (95% CI, 0.70-2.59). Conclusions: The use of anti-TNFα was associated with an increased risk of multiple sclerosis compared with nonusers, especially among patients with RD. These findings could help clinicians and patients with rheumatic diseases to make more informed treatment decisions. Further studies are needed to validate these results for patients with IBD.

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Quan J, Ma C, Panaccione R, Hracs L, Sharifi N, Herauf M, Makovinović A, Coward S, Windsor JW, Caplan L, Ingram RJM, Kanji JN, Tipples G, Holodinsky JK, Bernstein CN, Mahoney DJ, Bernatsky S, Benchimol EI, Kaplan GG; STOP COVID-19 in IBD Research Group. Serological responses to three doses of SARS-CoV-2 vaccination in inflammatory bowel disease. Gut 2023; 72:802-804.

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Despite recommendations for three-dose vaccine regimens for individuals with IBD, the uptake has been low in this population. We examined the serological response following three doses of mRNA SARS-CoV-2 vaccines in persons with IBD, the factors associated with antibody titres and the decay of antibody titres over time. Adults aged 18 years or older with a confirmed diagnosis of IBD who received three doses of an mRNA SARS-CoV-2 vaccine (Pfizer-BioNTech BNT162b2 mRNA (Comirnaty) or NIH-Moderna mRNA-1273 (Spikevax)) were recruited from 25 June 2021 to 6 January 2022. Serum samples were drawn at least 1 week following the third dose of vaccine and processed by Alberta Precision Laboratories using the Abbott SARS-CoV-2 IgG II Quant assay to detect antibodies to the S1 subunit of the spike protein (anti-S). The threshold for seroconversion was defined as ≥50 AU/mL for anti-S antibodies. Age, sex, vaccination date and type, IBD type, and IBD medications at time of vaccination were collected through medical chart review. Vaccine schedule between second and third vaccine doses was defined as ‘scheduled’ for 4–18 weeks between dose administration and ‘delayed’ for >18 weeks. Prior history of COVID-19 was defined by either nucleocapsid seroconversion or molecular-confirmed diagnosis of SARS-CoV-2 infection via PCR. Geometric mean titres with associated 95% CIs were used to report anti-S concentrations. Multivariable linear regression was used to determine the effect of independent predictors determined a priori on log-transformed anti-S concentration. Exponentiated coefficients represented the fold change (FC) associated with each binary covariate and the FC in log anti-S concentration per unit change for continuous variables. Results: In total, 232 participants (mean age 52.7 years;42.7% male) with IBD and three doses of an mRNA vaccine were included. The seroconversion rate among this sample was 99.6% and the geometric mean titre was 14 569 AU/mL (95% CI 12 846 to 16 472 AU/mL). Multivariable linear regression identified significantly increased log anti-S concentration for prior SARS-CoV-2 infection (FC: 1.97 (95% CI 1.22 to 3.18)) and decreased log anti-S concentration for corticosteroid use (FC: 0.07 (95% CI 0.03 to 0.20). Antibodies decayed by 12% per week (95% CI 8% to 15%) following third dose vaccination. Age, sex, IBD type, vaccine type and vaccine schedule were not associated with anti-S concentration. The data can be viewed in an online dashboard (https://kaplan-gi.shinyapps.io/COVID_Serology/) using the Shiny: Web Application Framework for R package. A three-dose SARS-CoV-2 vaccination regimen for individuals with IBD has been proposed based on impaired serological responses to two-dose regimens. Our study demonstrates near complete seroconversion and high antibody titres following a three-dose mRNA vaccine regimen, similar to an American cohort of individuals with IBD that demonstrated a robust antibody response following an extra dose from the initial vaccine series. Conclusions: Antibody responses following three doses are consistently high across all IBD therapies for maintenance of remission, including biologic and immunomodulator therapies. In contrast, prednisone use at the time of vaccine dosing was associated with lower antibody responses. Our study also indicated significant decay of antibody titres over time following third-dose vaccination at a rate of 12% per week. While these data support widespread implementation of a three-dose vaccine regimen, future studies are necessary to determine if additional doses will be required to maintain sufficient antibody levels over time.

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Armstrong HK, Bording-Jorgensen M, Santer DM, Zhamg Z, Valcheva R, Rieger AM, Kim JSH, Dijk SI, Mahmood R, Ogungbola O, Jovel J, Moreau F, Gorman H, Dickner R, Jerasi J, Mander IK, Lafleur D, Cheng C, Petrova A, Jeanson TL, Mason A, Sergi CM, Levine A, Chadee K, Armstrong D, Rauscher S, Bermstein CN, Carroll MW, Huynh HQ, Walter J, Madsen KL, Dieleman LA, Wine A. Unfermented B fructans fibers fuel inflammation in select inflammatory bowel disease patients. Gastroenterology 2023; 164:228-240.

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IBD are impacted by dietary factors, including non-digestible carbohydrates (fibers), which are fermented by colonic microbes. Fibers are overall beneficial but not all fibers are alike and some IBD patients report intolerance to fiber consumption. Given reproducible evidence of reduced fiber-fermenting microbes in IBD patients, we hypothesized that fibers remain intact in select patients with reduced fiber-fermenting microbes and can then bind host cell receptors, subsequently promoting gut inflammation. Colonic biopsies cultured ex vivo and cell lines in vitro were incubated with oligofructose (5g/L), or fermentation supernatants (24hr anaerobic fermentation) and immune responses (cytokine secretion [ELISA/MSD] and expression [qPCR]) were assessed. Influence of microbiota in mediating host response was examined and taxonomic classification of microbiota was conducted with Kraken2 and metabolic profiling by HUMAnN2, using R software.  Results: Unfermented dietary β-fructan fibers induced pro-inflammatory cytokines in a subset of IBD intestinal biopsies cultured ex vivo, and immune cells (including peripheral blood mononuclear cells). Results were validated in an adult IBD randomized controlled trial examining β-fructan supplementation. The pro-inflammatory response to intact β-fructan required activation of the NLRP3 and TLR2 pathways. Fermentation of β-fructans by human gut whole-microbiota cultures reduced the pro-inflammatory response, but only when microbes were collected from non-IBD or inactive IBD patients. Fiber-induced immune responses correlated with microbe functions, luminal metabolites, and dietary fiber avoidance. Conclusion: While fibers are typically beneficial in individuals with normal microbial fermentative potential, some dietary fibers have detrimental effects in select patients with active IBD who lack fermentative microbe activities

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El Zimaity H, Shaffer S, Riddell RH, Pai R, Bernstein CN. Beyond Neutrophils for predicting relapse and remission in ulcerative colitis. Journal of Crohn’s and Colitis 2023; 17:767-776.

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This study examines colonic histologic features in ulcerative colitis in endoscopic remission to determine which cell types and biopsy sites best predict a patient's likelihood of remaining in remission.  This is a retrospective chart, endoscopy and histology review of 166 persons with ulcerative colitis in endoscopic remission followed in a single IBD practice over a median of 6 years (range, 2-11 years). Clinical remission was based on global physician assessment and colonoscopy reports, and clinical relapse on chart review. Histologic features of previous injury and also number and location of plasma cells and eosinophils were assessed. We evaluated all semi-quantitatively using a standard set of illustrations for the grade to maintain consistency. Multiple logistic regression analysis and survival analysis were used to identify features associated with relapse. Results: Clinical relapse occurred in 44 persons. Ulceration, especially in the left colon. was highly predictive of relapse. In the absence of acute inflammation of ulceration, the variables most predictive of relapse were increased plasma cells in the basal 20% of the lamina propria, and eosinophils in the left colon. The variable most predictive of persistent remission was the presence of intraepithelial eosinophils whether in the surface epithelium or within crypts, especially in the right colon. Lamina propria eosinophils (grade>2) throughout the colon predicted relapse.  Conclusion: In the absence of neutrophils or ulceration, left-sided plasmacytosis in the basal 20% of the lamina propria and increased lamina propria eosinophils provide the best indicators of relapse in UC in clinical and endoscopic remission.

Vasileiou ES, Hu C, Bernstein CN, Lublin F, Wolinsky JS, Cutter GR, Sotirchos ES, Kowalec K, Salter A, Saidha S, Mowry EM, Calabresi PA, Marrie RA, Fitzgerald KC. Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis. Neurology Neuroimmunology and Neuroinflammation. 2023: 10:1-13.

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Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis. Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. We generated 25(OH)D PGS for 1,924 people with multiple sclerosis with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10-5) and applying Mendelian randomization (MR) rather than using PGS. Results: Initial analyses demonstrated a positive association between generated 25(OH)D-polygenic scores and circulating 25(OH)D levels (per 1SD increase in 25[OH]D polygenic scores: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-polygenic scores and relapse rate (per 1SD increase in 25[OH]D-polygenic scores: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-polygenic scores were not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. We concluded that genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in people with multiple sclerosis and raises questions about the plausibility of a treatment effect of vitamin D in established multiple sclerosis.

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Knowles SR, Möller SP, Stengel A, Mikocka-Walus A, Ferreira N, Trindade IA, Mokrowiecka A, Burisch J, Barreiro-de Acosta M, Bernstein CN, Lo B, Skvarc D. Exploring the impact of COVID-19 related perceptions on psychological distress and quality of life in an international gastrointestinal cohort over time guided by the common sense model. Journal of Clinical Psychology in Medical Settings 2023; Dec; 30 (4):804-820.

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The aim of this longitudinal study was to examine changes in COVID-19 and illness-related perceptions, gastrointestinal symptoms, coping, catastrophising, psychological distress, and QoL during the COVID-19 pandemic. A total of 831 adults with a gastrointestinal condition completed an online questionnaire at baseline (May-October 2020). Of those, 270 (32.5%) participants (85.2% female, mean age = 47.3 years) provided follow-up data (March-May 2021). Repeated-measures multiple analysis of variance and a cross-lagged panel model were used to test the study hypotheses. Gastrointestinal symptoms and COVID-19 perceptions at follow-up were strongly predicted by their baseline values, while illness perceptions were predicted by baseline gastrointestinal symptoms. Cross-lagged relationships indicated a reciprocal relationship between gastrointestinal symptoms and psychological distress. Moreover, gastrointestinal symptoms had substantial predictive utility, strongly predicting future gastrointestinal symptoms, and to a lesser extent, more negative illness perceptions, greater psychological distress, and greater use of adaptive coping strategies across time.

D'Ascenzo F, Bruno F, Iannaccone M, Testa G, De Filippo O, Giannino G, Caviglia GP, Bernstein CN, De Ferrari GM, Bugianesi E, Armandi A, Ribaldone DG. Patients with inflammatory bowel disease are at increased risk of atherothrombotic disease: A systematic review with meta-analysis. International Journal of Cardiology 2023; 378: 96-104.

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Patients with IBD are known to be at increased risk for venous thrombosis, while their risk for arterial ischemic events is debated. The purpose of this study was to conduct a systematic review of the published literature on the risk of myocardial infarction in IBD patients and to identify any potential risk factors. The present study was performed according to PRISMA, with a systematic search on PubMed, Cochrane, and Google Scholar. Risk of MI was the primary end point, while all causes of death and stroke were secondary endpoints. Both univariate and multivariate pooled analysis were performed. Results: An overall population of 515,455 controls and 77,140 persons with IBD (26,852, 34.8% Crohn's disease and 50,288, 65.2% ulcerative colitis was included. Mean age was similar across controls and IBD. Persons with Crohn’s disease and ulcerative colitis had lower rates of hypertension (14.5% vs. 14.6% vs. 25%), diabetes (2.9% vs. 5.2% vs. 9.2%) and dyslipidaemia (3.3% vs. 6.5% vs. 16.1%) compared to controls. Smoking did not significantly differ (17% vs. 17.5% vs. 10.6%). Pooled results of multivariate adjustment showed that, after a 5 years-follow-up, both Crohn’s disease and ulcerative colitis were at increased risk of myocardial infarction (respectively HR 1.36 [1.12-1.64] and HR 1.24 [1.05-1.46]), of death (HR 1.55 [1.27-1.90] and HR 1.29 [1.01-1.64]), and of other cardiovascular disease as stroke (HR 1.22 [1.01-1.49] and HR 1.09 [1.03-1.15], all 95% CI). We concluded that persons with IBD are at increased risk of myocardial infarction, despite a lower prevalence of the classic risk factors for myocardial infarction (hypertension, diabetes, dyslipidemia).

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Raygoza Garay JA, Turpin W, Lee SH, Smith MI, Goethel A, Griffiths AM, Moayyedi P, Espin-Garcia O, Abreu M, Aumais GL, Bernstein CN, Biron IA, Cino M, Deslandres C, Dotan I, El-Matary W, Feagan B, Guttman DS, Huynh H, Dieleman LA, Hyams JS, Jacobson K, Mack D, Marshall JK, Otley A, Panaccione R, Ropeleski M, Silverberg MS, Steinhart AH, Turner D, Yerushalmi B, Paterson AD, Xu W; CCC GEM Project Research Consortium; Croitoru K. Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives. Gastroenterology 2023;165(3):670-681.

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The cause of Crohn's disease is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with Crohn's disease have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of Crohn's disease or is the result of inflammation or drug treatment. In this prospective cohort study, 3483 healthy first-degree relatives of patients with Crohn's disease were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing Crohn's disease. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of Crohn's disease. The performance of the model was assessed in an independent validation cohort. Results: In the validation cohort, the microbiome risk score model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the microbiome risk score from the discovery cohort as the threshold. The microbiome risk score demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. Conclusion: This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.

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Marrie RA, Bernstein CN, Dolovich C,  Bolton JM,  Graff LA, Hitchon CA, Lix LM,  Marriott JJ,  Fisk JD. Within-person fluctuations over three years in depression, anxiety, fatigue, and health-related quality of life in multiple sclerosis. Multiple Sclerosis 2023 Oct;29(11-12):1503-1513.

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Longitudinal studies of health-related quality of life in multiple sclerosis are limited. Most have examined average changes within the population, rather than dynamic changes within individuals. We aimed to assess the between- and within-individual association between depression, anxiety, fatigue, cognition, physical functioning, and physical comorbidities and health-related quality of life. Adults with multiple sclerosis underwent physical and cognitive assessments and reported symptoms of fatigue (Daily Fatigue Impact Scale), depression and anxiety (Hospital Anxiety and Depression Scale (HADS)), and health-related quality of life (RAND-36) annually (n = 4 visits). We evaluated associations of elevated symptoms of anxiety (HADS-A) and depression (HADS-D), fatigue, physical function (timed-walk and nine-hole peg test), cognitive function and comorbidity count with physical (PCS-36) and mental (MCS-36), health-related quality of life using multivariable linear models-estimating between-person and within-person effects. Results: Of 255 participants with multiple sclerosis enrolled, 81.6% were women. After adjustment, within-person increases in depression and fatigue were associated with decreases in physical health-related quality of life. Increases in depression, anxiety, and comorbidity count were associated with decreases in mental health-related quality of life. We concluded that within-person increases in symptoms of depression, anxiety and fatigue, and comorbidity count are associated with health-related quality of life decreases among adults with multiple sclerosis, highlighting the potential magnitude of individual benefit of intervention for these symptoms.

Almweisheer S, Bernstein CN, Graff LA, Patten SB, Bolton JM, Fisk JD, Hitchon CD Marriott JJ, Marrie RA. A Cross-Sectional Study of Well-Being and Flourishing Mental Health in Adults with Inflammatory Bowel Disease, Multiple Sclerosis and Rheumatoid Arthritis in Manitoba, Canada. BMJ Open 2023;13: e073782.

Objectives Among people with immune-mediated inflammatory disease (IMID), including multiple sclerosis (MS), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) most research has focused on mental illness rather than on mental health. We assessed dimensions of mental health among persons with IMID and compared them across IMID. We also evaluated demographic and clinical characteristics associated with flourishing mental health. Adults with an IMID (MS, 239; IBD, 225; RA 134; total 598) who were participating in a cohort study at a tertiary care centre in Manitoba, Canada. Participants completed the Mental Health Continuum Short-Form (MHC-SF), which measures emotional, psychological and social well-being, and identifies flourishing mental health. This outcome was added midway through the study on the advice of the patient advisory group. Depression, anxiety, pain, fatigue and physical function were also assessed. Results Total MHC-SF and subscale scores were similar across IMID groups. Nearly 60% of participants were considered to have flourishing mental health, with similar proportions across disease types (MS 56.5%; IBD 58.7%; RA 59%, p=0.95). Older age was associated with a 2% increased odds of flourishing mental health per year of age (OR 1.02; 95% CI: 1.01 to 1.04). Clinically meaningful elevations in anxiety (OR 0.25; 95% CI: 0.12 to 0.51) and depressive symptoms (OR 0.074; 95% CI: 0.009 to 0.61) were associated with lower odds. Higher levels of pain, anxiety and depressive symptoms were associated with lower total Mental Health Continuum scores at the 50th quantile. Conclusions Over half of people with MS, IBD and RA reported flourishing mental health, with levels similar across the disease groups. Interventions targeting symptoms of depression and anxiety, and upper limb impairments, as well as resilience training may help a higher proportion of the IMID population achieve flourishing mental health.

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Kowalec K, Fitzgerald KC, Salter A, Dolovich C, Harder A, Bernstein CN, Bolton J, Cutter GR, Graff LA, Hägg S, Hitchon CA, Lu Y, Lublin FD, McKay KA, Patten SB, Patki A, Tiwari HK, Wolinsky JS, Marrie RA. Polygenicity of comorbid depression in multiple sclerosis. Neurology 2023; Aug 1: 101(5): e522-e532.

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Depression is common in multiple sclerosis and is associated with faster disability progression. The etiology of comorbid depression in multiple sclerosis remains poorly understood. Identification of individuals with a high risk of depression, through polygenic scores, may facilitate earlier identification. Previous genetic studies of depression considered depression as a primary disorder, not a comorbidity, and thus, findings may not generalize to multiple sclerosis. Body mass index (BMI) is a risk factor of both multiple sclerosis and depression, and its association may highlight differences in depression in multiple sclerosis. To improve the understanding of comorbid depression in multiple sclerosis, we will investigate polygenic scores in people with multiple sclerosis, with the hypothesis that a higher depression polygenic scores is associated with increased odds for comorbid depression in multiple sclerosis. Samples from 3 sources (Canada, UK Biobank, and the United States) were used. Individuals were grouped into cases (multiple sclerosis/comorbid depression) and compared with 3 control groups: multiple sclerosis/no depression, depression/no immune disease, and healthy persons. We used 3 depression definitions: lifetime clinical diagnoses, self-reported diagnoses, and depressive symptoms. The polygenic scores were tested in association with depression using regression. Results: A total of 106,682 individuals of European genetic ancestry were used: Canada (n = 370; 213 with multiple sclerosis), UK Biobank (n = 105,734; 1,390 with multiple sclerosis), and the United States (n = 578 with multiple sclerosis). Meta-analyses revealed individuals with multiple sclerosis and depression had a higher depression polygenic scores compared with both individuals with multiple sclerosis without depression (odds ratio range per SD 1.29-1.38, p < 0.05) and healthy controls (odds ratio range per SD 1.49-1.53, p < 0.025), regardless of the definition applied and when sex stratified. The BMI polygenic scores were associated with depressive symptoms (p ≤ 0.001). The depression polygenic scores did not differ between depression occurring as a comorbid condition with multiple sclerosis or as the primary condition (odds ratio range per SD 1.03-1.13, all p > 0.05). A higher depression genetic burden was associated with approximately 30%-40% increased odds of depression in European genetic ancestry participants with multiple sclerosis compared with those without depression and was no different compared with those with depression and no comorbid immune disease. Conclusions This study paves the way for further investigations into the possible use of polygenic scores for assessing psychiatric disorder risk in multiple sclerosis and its application to non-European genetic ancestries.

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Marrie RA, Fisk JD, Dolovich C, Lix L, Graff LA, Patten SB, Bernstein CN. Psychometric performance of fatigue scales in inflammatory bowel diseases. Inflammatory Bowel Diseases 2024, Jan 5;30(1):53-63.

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Fatigue is highly prevalent in people with IBD. Fatigue scales are important for studies testing fatigue interventions, but information about psychometric properties of many scales is insufficient in IBD. We compared the psychometric properties of multiple generic fatigue scales in participants with IBD. Individuals with IBD (n = 216) completed the Daily Fatigue Impact Scale (DFIS), the vitality subscale of the RAND-36, and the Patient Health Questionnaire-9 (PHQ-9) fatigue item twice. A subgroup (n = 84) also completed the Fatigue Impact Scale (FIS) once, from which we also scored the 21 items from the Modified Fatigue Impact Scale (MFIS-IBD). We assessed floor/ceiling effects, construct validity, and internal consistency reliability. We compared discriminating ability and comparative responsiveness of the measures regarding disease activity and employment status and changes, using relative efficiency (RE). Results: The FIS, MFIS and RAND-36-vitality scales did not exhibit floor or ceiling effects. The DFIS showed mild floor effects (19.4%) while the PHQ-9 fatigue item showed floor (18.1%) and ceiling (20.8%) effects. Internal consistency reliability exceeded 0.93 for FIS, MFIS-IBD and DFIS, and was 0.81 for the RAND-36-vitality scale. In the subgroup analysis, the FIS, MFIS-IBD and DFIS were strongly correlated with each other (r ≥0.90). The ability to discriminate between disease activity groups was highest for the FIS and MFIS-IBD, followed by the DFIS. The FIS, MFIS-IBD and DFIS were responsive to changes in work impairment. Conclusion: The FIS, MFIS-IBD and DFIS had adequate validity and reliability for assessing fatigue in IBD.

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