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Publications // 2024
Dolovich C, Shafer LA, Graff LA, Vagianos K, Witges K, Targownik LE, Bernstein CN. Hormonal contraceptives reduce IBD related symptoms but may increase intestinal inflammation in IBD. Journal of Clinical Gastroenterology 2024; 58(3):271-276.
Background: Among women of reproductive age with inflammatory bowel disease (IBD), we aimed to assess the relationship of hormonal contraceptives with IBD-related symptoms, and intestinal inflammation.
Methods: A cohort of women in the longitudinal Manitoba Living with IBD Study, ages 18 to 49, were followed for 1 year, with online surveys every second week. This included a validated measure of disease activity called the IBD Symptom Inventory (IBDSI) that was developed by the University of Manitoba IBD Clinical and Research Centre team. The IBDSI and stool samples were obtained at 3 time-points for assessment of fecal calprotectin (FCAL). Use of hormonal contraceptives included oral and vaginal intrauterine devices. Logistic regression analysis was used to assess the association between hormonal contraceptives and IBD-related symptoms (IBDSI>14 for Crohn disease, >13 for ulcerative colitis), or inflammation (FCAL>250 ug/g) at any measurement point in the study.
Results: Of 71 women, 17 (24%) reported taking hormonal contraceptives in the 1 year period. Adjusting for age, disease type, disease duration, and smoking status, the odds of having increased IBD-related symptoms (IBDSI) during the year were 84% lower for women using hormonal contraceptives compared with women not using hormonal contraceptives [adjusted odds ratio 0.16, 95% CI, 0.02-0.90]. Conversely, women using hormonal contraceptives were nearly 6x more likely to have inflammation during the year [adjusted odds ratio 5.7, 95% CI, 1.23-43.6].
Conclusions: Hormonal contraceptives use among women with IBD was associated with a lower likelihood of IBD-related symptoms but a higher likelihood of experiencing intestinal inflammation (FCAL>250 ug/g) over 1 year. Further work is needed to examine this dichotomous result, potentially examining aspects such as duration of hormonal contraceptives use, and the types of hormonal contraceptives.
Bernstein CN, Dolovich C, Prichodko M, Fisk JD, Graff LA, Patten SB, Bolton J, Hitchon C, Marrie RA. Perceived need for mental health care in a cohort of persons with inflammatory bowel disease. Journal of Clinical Gastroenterology 2024; 58(5):464-470.
Background: Psychiatric comorbidity is common in IBD and can negatively affect disease outcomes. We explored the perceived need for mental health care among persons with IBD.
Methods: Persons with IBD completed self-report questionnaires, including the Hospital Anxiety and Depression Scale (HADS), and reported whether they wanted help with their mood. Each was also assessed using the Structured Clinical Interview for DSM-IV-TR Axis-I Disorders (SCIDs). We used logistic regression analyses to determine factors associated with the perceived need for mental health care.
Results: Of 245 participants, 28% met the criteria for a past diagnosis of depression or anxiety disorder by SCID, and nearly 23% met the criteria for a current diagnosis of depression or anxiety disorder. One-third (n=74) reported a perceived need for mental health care. Among those meeting criteria for a current SCID diagnosis of depression or anxiety, only 58% reported needing mental health care. Need for mental health care was reported by 79% of persons currently treated for either depression or 71% treated for anxiety. Persons with a perceived need for mental health care had higher mean HADS for depression and HADS for anxiety scores and also higher IBD symptom activity scores. Of those reporting no perceived need for mental health care, 13% had a current diagnosis of depression or anxiety disorder by SCID; even fewer had symptoms of depression or anxiety.
Conclusions: Symptoms of depression or anxiety are more important than a formal diagnosis of depression or anxiety in predicting which persons with IBD will perceive a need for mental health care.
Zhu F, Zhao Y, Arnold D, Bar-Or A, Bernstein CN, Bonner C, Graham M, Hart J, Knox N, Marrie RA, Mirza AI, O'Mahony J, Van Domselaar G, Yeh EA, Banwell B, Waubant E , Tremlett H; US Network of Pediatric MS Centers, the Canadian Pediatric Demyelinating Disease Network. A cross-sectional study of MRI features and the gut microbiome in pediatric-onset multiple sclerosis. Annals of Clinical Translational Neurology. 2024; Feb;11(2):486-496.
Objective: To identify gut microbiome features associated with MRI lesion burden in persons with pediatric-onset multiple sclerosis (symptom onset for those less than 18 years).
Methods: A cross-sectional study involving the Canadian Paediatric Demyelinating Disease Network study participants. Gut microbiome features (alpha diversity, phylum- and genus-level taxa) were derived using 16S rRNA sequencing from stool samples. T1- and T2-weighted lesion volumes were measured on brain MRI obtained within 6 months of stool sample procurement. Associations between the gut microbiota and MRI metrics (cube-root-transformed) were assessed using standard and Lasso regression models.
Results: Thirty-four participants were included; mean ages at symptom onset and MRI were 15.1 and 19.0 years, respectively, and 79% were female. The T1- and T2-weighted lesion volumes were not significantly associated with alpha diversity (age and sex-adjusted p > 0.08). At the phylum level, high Tenericutes (relative abundance) was associated with higher T1 and T2 volumes (β coefficient = 0.25, 0.37) and high Firmicutes, Patescibacteria or Actinobacteria with lower lesion volumes (β coefficient = -0.30 to -0.07). At the genus level, high Ruminiclostridium, whereas low Coprococcus 3 and low Erysipelatoclostridium were associated with higher lesion volumes.
Conclusion: Our study characterized the gut microbiota features associated with MRI lesion burden in pediatric-onset MS, shedding light onto possible pathophysiological mechanisms.
Vagianos K, Dolovich C, Witges K, Graff LA, Bernstein CN. Ultra-processed food, disease activity and inflammation in Ulcerative Colitis: The Manitoba Living with IBD Study. American Journal of Gastroenterology 2024; Jun 1;119(6):1102-1109.
Background: The purpose of this study was to investigate the relationship between ultra-processed food (UPF) consumption and (i) symptomatic disease and (ii) intestinal inflammation among adults with inflammatory bowel disease (IBD).
Methods: We identified participants from the Manitoba Living with IBD study. Active disease was defined using the IBD Symptom Inventory (score >14 for Crohn’s disease; >13 for ulcerative colitis); fecal calprotectin was measured for intestinal inflammation (>250 μg/g). Diet data were collected using the Harvard Food Frequency Questionnaire. UPF consumption was determined by the NOVA classification system. Percentage of energy consumption from UPFs was calculated and divided into 3 tertiles (T1 = low; T3 = high). Multiple linear regression analysis was used for active disease and inflammation predicted by UPF consumption.
Results: Among 135 participants (65% with Crohn’s disease), mean number of episodes of active disease (14.2 vs 6.21) and active inflammation (1.6 vs 0.6) was significantly higher among participants with ulcerative colitis in T3 compared with T1 of UPF consumption ( P < 0.05). When adjusting for age, sex, disease type, and duration, number of episodes of active disease was lower in T1 compared with T3 (β = -7.11, P = 0.02); similarly, number of episodes of intestinal inflammation was lower in T1 (β = -0.95, P = 0.03). No significant differences were observed among participants with Crohn’s disease.
Conclusions: Ultra-processed food (UPF) consumption may be a predictor of active symptomatic disease and inflammation among participants with ulcerative colitis. Reducing UPF consumption is a dietary strategy that can be suggested for minimizing symptoms and inflammation among people living with IBD.
Bernstein CN, Fisk JD, Dolovich C, Hitchon C, Graff LA, El Gabalawy R, Lix L, Bolton J, Patten S, Marrie RA. Understanding predictors of fatigue over time in persons with IBD: The importance of depressive and anxiety symptoms. American Journal of Gastroenterology 2024; May 1;119(5):922-929.
Introduction: Fatigue is a complex and frequent symptom in persons with IBD, with detrimental impact. We aimed to determine predictors of fatigue over time.
Methods: Two hundred forty-seven adults with IBD participated in a prospective study conducted in Manitoba, Canada, providing data at baseline and annually for 3 years. Participants reported fatigue impact (Daily Fatigue Impact Scale [DFIS]), depression and anxiety symptoms (Hospital Anxiety and Depression Scale [HADS]), and pain (Pain Effects Scale [PES]). Physician-diagnosed comorbidities, IBD characteristics, and physical and cognitive functioning were also assessed. We tested factors associated with fatigue using multivariable generalized linear models that estimated within-person and between-person effects.
Results: Most participants were women (63.2%), White (85.4%), and had Crohn's disease (62%). At baseline, 27.9% reported moderate-severe fatigue impact, 16.7% had clinically elevated anxiety (HADS-A ≥11), and 6.5% had clinically elevated depression (HADS-D ≥11). Overall fatigue burden was stable over time, although approximately half the participants showed improved or worsening fatigue impact between annual visits during the study. On multivariable analysis, participants with a one-point higher HADS-D score had, on average, a 0.63-point higher DFIS score, whereas participants with a one-point higher PES score had a 0.78-point higher DFIS score. Within individuals, a one-point increase in HADS-D scores was associated with 0.61-point higher DFIS scores, in HADS-A scores with 0.23-point higher DFIS scores, and in PES scores with 0.38-point higher DFIS scores. No other variables predicted fatigue.
Discussion: Anxiety, depression, and pain predicted fatigue impact over time in IBD, suggesting that targeting psychological factors and pain for intervention may lessen fatigue burden.
Murthy SK, Bernstein CN, Nguyen GC, Jairath V, Riddell R, Ferguson D, Canadian IBD Research Consortium and Affiliated Investigators. Interim Analysis of a Trial Evaluating the Utility of Non-Targeted Biopsies for Colorectal Neoplasia Detection in Inflammatory Bowel Disease. Clinical Gastroenterology Hepatology 2024 Jul;22(7):1535-1538.
IBD affecting the colorectum (cIBD) have a 1.5- to 2-fold higher risk of developing colorectal cancer (CRC) relative to age- and sex-matched members of the general population. Intensive surveillance colonoscopy is recommended in this population to detect and treat early neoplastic lesions before they evolve to incurable cancers. Some societies advocate for widespread non-targeted ("random") biopsies throughout the colorectum to screen for "invisible" neoplastic lesions, in addition to targeted biopsies and/or resection of visible lesions. Despite the theoretical value of non-targeted biopsies in this setting, there are no high-quality, controlled data to support this practice. In addition to adding significant time and costs to colonoscopy screening, extensive biopsy sampling may also increase the risk of colorectal bleeding and bowel perforation, particularly in elderly patients and those receiving anticoagulant/antiplatelet therapies. With the widespread adoption of disease-modifying biologic and small molecule therapies, mucosal healing as a treatment end point, high-definition endoscopes, and endoscopy quality standards, as well as reports of very low neoplasia yield for non-targeted biopsies (0.1%-0.2% of biopsies), many experts have started to question the value of non-targeted biopsies as an adjunct for neoplasia surveillance in persons with cIBD. However, a recent large French cohort study reported that non-targeted biopsies still identify up to 20% of all neoplastic foci in persons with cIBD, albeit primarily in individuals with other major CRC risk factors.
Murthy SK, Marderfeld L, Fergusson D, Ramsay T, Bernstein CN, Nguyen GC, Jairath V, Riddell R. A randomized trial evaluating the utility of non-targeted biopsies for colorectal neoplasia detection in adults with inflammatory bowel disease: a pilot study protocol. Pilot and Feasibility Studies 2024 Feb 1;10(1):20.
Background: Persons with IBD are at increased risk of developing colorectal cancer and require frequent colonoscopy surveillance. Guidelines recommend taking 30 to 40 non-targeted biopsies throughout the colorectum to detect "invisible" neoplasia in this setting, despite a lack of evidence supporting this practice. We sought to assess the utility of this practice through a randomized controlled trial. We first propose an internal pilot study to assess recruitment potential, protocol adherence and data capture to guide the full trial.
Methods: We have designed a multi-centre, parallel-group, non-inferiority randomized controlled trial to test the utility of non-targeted biopsies as an adjunct to colonoscopy surveillance for neoplasia detection in persons with inflammatory bowel disease involving the colorectum in routine clinical practice. Participants are randomized 1:1, stratified by study site, to either standard of care high-definition white-light colonoscopy with 32 to 40 non-targeted biopsies of non-neoplastic-appearing mucosa along with a sampling of abnormal-appearing mucosa (control group) or modified colonoscopy with targeted sampling alone (intervention group). The primary outcome for the full trial will be the proportion of persons with at least 1 neoplastic focus detected during colonoscopy. For the pilot phase, we will assess the feasibility of recruiting a minimum of 15% of the estimated sample size within 1 year, under identical conditions as the full trial, while maintaining ≥ 90-95% rate of protocol adherence and data capture. These participants will contribute data to the full trial. The trial is being conducted at 12 centres across Canada, with a total sample size of 1952 persons.
Discussion: The trial protocol has been approved by the ethics committees of all participating sites, and the pilot study has received funding through the Canadian Institutes of Health Research (PJT 159607). If feasibility metrics are met during the pilot phase, we will complete the full trial. The trial outcomes will contribute to update the practice guidelines in this area.
Wijnands AM, Penning Devries BBL, Lutgen WMMD, Bakhshi Z, Al Bakir I, Beaugerie L, Bernstein CN, Choi RC, Coelho-Prabhu N, Graham TA, Hart AR, Ten Hove J, Itzkowitz S, Kirchgesner J, Mooiweer E, Shaffer SR, Shah, SC, Elias, SG, Oldenburg B., Dynamic prediction of advanced colorectal neoplasia in inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2024; 22(8):1697-1708.
Background: Colonoscopic surveillance is recommended in patients with IBD given their increased risk of colorectal cancer. We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (including high-grade dysplasia and colorectal cancer) in IBD.
Methods: We pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior advanced colorectal neoplasia, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal-external cross-validation.
Results: The surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with advanced colorectal neoplasia. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal-external cross-validation results showed medium discrimination and reasonable to good calibration.
Conclusions: The new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted advanced colorectal neoplasia risks to surveillance intervals before clinical application.
Coward S, Benchimol EI, Bernstein CN, Avina-Zubieta A, Bittonn A, Carroll MW, Cui Y, Hoentgen F, Hracs L, Jacobson K, Jones JL, King K, Kuenzig ME, Lu N, El Matary W, Murthy S, Otley A, El Matary W, Nugent Z, Otley AR, Panaccione R, Peña-Sánchez JN, Singh H, Targownik LE, White D, Windsor JW, Kaplan GG on behalf of the Canadian Gastro-Intestinal Epidemiology Consortium (CanGIEC). Forecasting the incidence and prevalence of inflammatory bowel disease: A Canadian nationwide analysis. American Journal of Gastroenterology 2024; Aug 1;119(8):1563-1570[CB3] .
Introduction: Canada has a high burden of IBD. Historical trends of IBD incidence and prevalence were analyzed to forecast the Canadian burden over the next decade.
Methods: Population-based surveillance cohorts in 8 provinces derived from health administrative data assessed the national incidence (newly diagnosed cases) (2007-2014) and prevalence (all known cases, newly and previously diagnosed) (2002-2014) of IBD. Autoregressive integrated moving average models were used to forecast incidence and prevalence, stratified by age, with 95% prediction intervals (PI), to 2035. The average annual percentage change (AAPC) with 95% confidence interval (CI) was calculated for the forecasted incidence and prevalence.
Results: The national incidence of IBD is estimated to be 29.9 per 100,000 (95% PI 28.3-31.5) in 2023. With a stable AAPC of 0.36% (95% CI -0.05 to 0.72), the incidence of IBD is forecasted to be 31.2 per 100,000 (95% PI 28.1-34.3) in 2035. The incidence in pediatric patients (younger than 18 years) is increasing (AAPC 1.27%; 95% CI 0.82-1.67), but it is stable in adults (AAPC 0.26%; 95% CI -0.42 to 0.82). The prevalence of IBD in Canada was 843 per 100,000 (95% PI 716-735) in 2023 and is expected to steadily climb (AAPC 2.43%; 95% CI 2.32-2.54) to 1,098 per 100,000 (95% PI 1,068-1,127) by 2035. The highest prevalence was in seniors with IBD (1,174 per 100,000 in 2023; AAPC 2.78%; 95% CI 2.75-2.81).
Conclusion: Over the next decade, the Canadian health care systems will contend with the juxtaposition of rising incidence of pediatric IBD and a rising prevalence of overall IBD driven by the aging population. Well over 1 in 100 Canadians will have a diagnosis of IBD.
Kuenzig ME, Bitton A, Carroll MW, Otley AR, Singh H, Kaplan GG, Stukel TA, Mack DR, Jacobson K, Griffiths AM, El Matary W, Targownik LE, Nguyen GC, Jones JL, Murthy SK, Bernstein CN, Lix LM, Pena Sanchez JN, Dummer TJB, Spruin S, Fung SG, Nugent Z, Coward S, Cui Y, Coulombe J, Filiter C, Benchimol EI. Health services utilization and specialist care in pediatric inflammatory bowel disease: A multiprovince population-based cohort study. Inflammatory Bowel Diseases 2024; 30(12):2356-2369.
Background: Patterns of health services utilization among children with IBD are important to understand as the number of children with IBD continues to increase. We compared health services utilization and surgery among children diagnosed younger than 10 years of age (Paris classification: A1a) and between 10 and 16 years of age (A1b).
Methods: Newly diagnosed cases of IBD diagnosed less than 16 years of age were identified using validated algorithms from deterministically linked health administrative data in 5 Canadian provinces (Alberta, Manitoba, Nova Scotia, Ontario, Quebec) to conduct a retrospective cohort study. We compared the frequency of IBD-specific outpatient visits, emergency department visits, and hospitalizations across age groups (A1a vs A1b [reference]) using negative binomial regression. The risk of surgery was compared across age groups using Cox proportional hazards models. Models were adjusted for sex, rural/urban residence location, and mean neighborhood income quintile. Province-specific estimates were pooled using random-effects meta-analysis.
Results: Among the 1165 (65.7% Crohn's disease) children with IBD included in our study, there were no age differences in the frequency of hospitalizations (rate ratio [RR], 0.88; 95% confidence interval [CI], 0.74-1.06) or outpatient visits (RR, 0.95; 95% CI, 0.78-1.16). A1a children (less than 10 years at diagnosis) had 30% fewer emergency department visits (RR, 0.70; 95% CI, 0.50-0.97) and were 50% less likely to require a Crohn's-related surgery (hazard ratio, 0.49; 95% CI, 0.26-0.92). The risk of colectomy was similar among children with ulcerative colitis in both age groups (hazard ratio, 0.71; 95% CI, 0.49-1.01).
Conclusions: Patterns of health services utilization are generally similar when comparing children diagnosed across age groups, although children diagnosed before age 10 with Crohn’s disease were less likel to have a Crohn’s disease related surgery.
Kuenzig ME, Stukel T, Carroll MW, Kaplan GG, Anthony R. Otley AR, Singh H, Bitton A, Fung SG, Spruin S, Coward S, Cui Y, Nugent Z, Griffiths AM, Mack DR, acobson K, Nguyen GC, Targownik LE, El-Matary W, Bernstein CN, Dummer TJB, Jones JL, Lix LM, Murthy SK, Peña-Sánchez JN, Nasiri S, Benchimol EI. Variation in the care of children with inflammatory bowel disease within and across Canadian provinces: a multi-province population-based cohort study. Clinical Epidemiology 2024; Feb 14; 16: 91-108.
Background: The incidence of childhood-onset IBD is rising. We described variation in health services utilization and need for surgery among children with IBD between six and 60 months following IBD diagnosis across Canadian pediatric centers and evaluated the associations between care provided at diagnosis at each center and the variation in these outcomes.
Methods: Using population-based deterministically-linked health administrative data from four Canadian provinces (Alberta, Manitoba, Nova Scotia, Ontario) we identified children diagnosed with IBD younger than 16 years of age using validated algorithms. Children were assigned to a pediatric center of care using a hierarchical approach based on where they received their initial care. Outcomes included IBD-related hospitalizations, emergency department visits, and IBD-related abdominal surgery occurring between 6 and sixty months after diagnosis. Mixed-effects meta-analysis was used to pool results and examine the association between center-level care provision and outcomes.
Results: We identified 3784 incident cases of pediatric IBD, of whom 2937 (77.6%) were treated at pediatric centers. Almost a third (31.4%) of children had at least 1 IBD-related hospitalization and there were 0.66 hospitalizations per person during follow-up. More than half (55.8%) of children had at least 1 emergency department visit and there were 1.64 emergency department visits per person. Between-center heterogeneity was high for both outcomes; centers where more children visited the emergency department at diagnosis had more IBD-related hospitalizations and more emergency department visits during follow-up. Between-center heterogeneity was high for intestinal resection in Crohn's disease but not colectomy in ulcerative colitis.
Conclusion: There is variation in health services utilization among children with IBD and risk of undergoing intestinal resection in those with Crohn's disease, but not colectomy among children with ulcerative colitis, across Canadian pediatric tertiary-care centers. Improvements in clinical care pathways are needed to ensure all children have equitable and timely access to high quality care.
Habib M, Dayam RM, Hitchon CA, Chandran V, Fortin PR, Bowdish D, Gingras AC, Larche MJ, Colmegna I, Lukusa L, Lee J, Pereira D, Bernstein CN, Lalonde N, Turnbull E, Bernatsky S, and SUCCEED investigative team. Duration of Post-vaccination Neutralizing Antibodies to SARS-COV2 and Medication Effects in Immune-mediated Inflammatory Diseases: Results from the SUCCEED Initiative. ACR Open Rheumatology 2024; Sep;6(9):581-586.
Background: In the face of the ongoing circulation of SARS-CoV-2, the durability of neutralization post-COVID-19 vaccination in immune-mediated inflammatory disease (IMID) is a key issue, as are the effects of medications.
Methods: Adults (n=112) with IBD, psoriasis/psoriatic arthritis, rheumatoid arthritis, spondylarthritis, and systemic lupus were recruited from participating Canadian medical centers from 2021 to 2023. We focused on log-transformed neutralization (lentivirus methods) as a continuous outcome, with separate models for wild-type and Omicron strains BA.1 and BA.5.
Results: Compared with 30-120 days postvaccination, subsequent periods were associated with greater neutralization in unadjusted models for wild-type, BA.1, and BA.5 strains and against the BA.1 strain in adjusted models. Rituximab was associated with lower neutralization for the BA.1 strain in adjusted models, with a similar trend for BA.5. In methotrexate users, there were trends for less neutralization of BA.1 and BA.5 in all unadjusted models, whereas in adjusted models, there was significantly lower neutralization only for the wild type. Three or more doses and Omicron-specific vaccines were both independently associated with better neutralization ability for all three strains. A COVID-19 infection within six months before sampling was associated with higher neutralization of wild type and BA.1 in adjusted analyses. Anti-tumor necrosis factor agents were associated with lower neutralization ability for BA.5 in adjusted analyses.
Conclusion: Neutralization responses in immunosuppressed individuals with IMID were durable over time and were augmented by more than three doses and Omicron-specific vaccines. Less neutralization was seen with certain medications. Our work clarifies the joint effects of vaccine history, infection, and medications on COVID-19 immunity.
Murthy S, Singh H, Kaplan GG, Tandon P, Benchimol EI, Matthews P, Kuenzig E, Coward S, Targownik L, Bernstein CN. A Population-Based Matched Cohort Study of Digestive System Cancer Incidence and Mortality in Individuals with and without Inflammatory Bowel Disease. American Journal of Gastroenterology 2024;119(11):2275-2287.
Background: To study digestive system cancer risks in individuals with IBD in the biologic era.
Methods: We used population-level administrative and cancer registry data from Ontario, Canada, (1994-2020) to compare people with IBD to matched controls (1:10 by sex and birth year) on trends in age-sex standardized cancer incidence and risk ratios of incident cancers and cancer-related deaths.
Results: Among 110,919 people with IBD and 1,109,190 controls, colorectal cancer incidence (newly diagnosed cases per 100,000 person-years) declined similarly in people with ulcerative colitis (average annual percentage change [AAPC] -1.81; 95% confidence interval [CI] -2.48 to -1.156) and controls (AAPC -2.79; 95% CI -3.44 to -2.14), while small bowel cancer incidence rose faster in those with Crohn's disease (AAPC 9.68; 95% CI 2.51-17.3) than controls (AAPC 3.64; 95% CI 1.52-5.80). Extraintestinal digestive cancer incidence rose faster in people with IBD (AAPC 3.27; 95% CI 1.83-4.73) than controls (AAPC -1.87; 95% CI -2.33 to -1.42), particularly for liver (IBD AAPC 8.48; 95% CI 4.11-13.1) and bile duct (IBD AAPC 7.22; 95% CI 3.74-10.8) cancers. Beyond 2010, the incidences (and respective mortality rates) of colorectal (1.60; 95% CI 1.46-1.75), small bowel (4.10; 95% CI 3.37-4.99), bile duct (2.33; 95% CI 1.96-2.77), and pancreatic (1.19; 95% CI 1.00-1.40) cancers were higher in people with IBD.
Discussion: Cancer incidence is declining for colorectal cancer and rising for other digestive cancers in people with IBD. Incidence (newly diagnosed cases) and mortality remain higher in people with IBD than controls for colorectal, small bowel, bile duct, and pancreatic cancers.
Zheng J, Sun Q, Zhang M, Liu C, Su Q, Zhang L, Xu Z, Lu W, Ching J, Tang W, Cheung CP, Hamilton AI, Wilson O’Brien AL, Bernstein CN, Rubin D, Chang EB, Morrison M, Kamm MA Chan FKL, Zhang J, Ng SC. Metagenomic analysis of faecal microbiome as a tool for targeted non-invasive biomarkers for inflammatory bowel disease. Nature Medicine 2024; 30(12):3555-3567.
Despite recent progress in our understanding of the association between the gut microbiome and inflammatory bowel disease (IBD), the role of microbiome biomarkers in IBD diagnosis remains underexplored. Here we developed a microbiome-based diagnostic test for IBD. By utilization of metagenomic data from 5,979 fecal samples with and without IBD from different geographies and ethnicities, we identified microbiota alterations in IBD and selected ten and nine bacterial species for construction of diagnostic models for ulcerative colitis and Crohn's disease, respectively. These diagnostic models achieved areas under the curve >0.90 for distinguishing IBD from controls in the discovery cohort, and maintained satisfactory performance in transethnic validation cohorts from eight populations. We further developed a multiplex droplet digital polymerase chain reaction test targeting selected IBD-associated bacterial species, and models based on this test showed numerically higher performance than fecal calprotectin in discriminating ulcerative colitis and Crohn's disease from controls. Here we discovered universal IBD-associated bacteria and show the potential applicability of a multibacteria biomarker panel as a noninvasive tool for IBD diagnosis.
O'Mahony J, Bernstein CN, Marrie RA. Adverse childhood experiences and psychiatric comorbidity in multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis in the Canadian longitudinal study on aging. Journal of Psychosomatic Research 2024 Sep 13;187:111893.
Objectives: Adverse childhood experiences are associated with immune-mediated inflammatory diseases. We evaluated whether: (i) Adverse childhood experiences associated with psychiatric comorbidity among individuals with immune-mediated inflammatory diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS), and inflammatory bowel disease (IBD); (ii) whether psychiatric disorders mediate the relationship between adverse childhood experiences and immune-mediated inflammatory diseases; and (iii) whether these findings differ from those in individuals with other chronic physical disorders.
Methods: Using data from the Canadian Longitudinal Study on Aging we performed a retrospective case-control study of participants aged 45-85 years recruited between 2010 and 2015. Adverse childhood experiences were queried using questions derived from the Childhood Experiences of Violence Questionnaire-Short Form and the National Longitudinal Study of Adolescent to Adult Health Wave III questionnaire. We used multivariable logistic regression and causal mediation analysis to address our objectives.
Results: We included 13,977 Canadian Longitudinal Study on Aging participants. Among the 31% of immune-mediated inflammatory diseases participants who reported a comorbid psychiatric disorder, 79% reported a history of adverse childhood experiences. Adverse childhood experiences associated with increased odds (OR [95 % CI]) of a psychiatric disorder (2.55 [1.02-6.35]) among participants with immune-mediated inflammatory diseases; this did not differ across the different immune-mediated inflammatory diseases. The total effect (OR [95 % CI]) of adverse childhood experiences on immune-mediated inflammatory diseases was 1.11 (1.07-1.16), of which 10.60 % (8.04-17.47) was mediated by psychiatric disorders. We found similar associations among participants with other chronic physical disorders.
Conclusion: Our findings suggest that psychiatric disorders partially mediate the association between adverse childhood experiences and immune-mediated inflammatory diseases. Most participants with immune-mediated inflammatory diseases and comorbid psychiatric disorders report a history of adverse childhood experiences and may benefit from trauma-informed mental health care.
Hesampour F, Bernstein CN, Ghia JE. Brain-gut axis: Invasive and non-invasive vagus nerve stimulation, limitations and potential therapeutic approaches. Inflammatory Bowel Diseases 2024;30 (3): 482-495.
IBD is a chronic relapsing condition with no known etiology and is characterized by disrupted gut homeostasis, chronic inflammation, and ulcerative lesions. Although current treatments can reduce disease activity, IBD frequently recurs once treatments are discontinued, indicating that treatments are ineffective in providing long-term remission. The lack of responsiveness and reluctance of some affected persons to take medications because of potential adverse effects has enhanced the need for novel therapeutic approaches. The vagus nerve is likely important in the pathogenesis of IBD, considering the decreased activity of the parasympathetic nervous system, especially the vagus nerve, and the impaired interaction between the enteric nervous system and central nervous system in patients with IBD. Vagus nerve stimulation has demonstrated anti-inflammatory effects in various inflammatory disorders, including IBD, by inhibiting the production of inflammatory cytokines by immune cells. It has been suggested that stimulating the vagus nerve to induce its anti-inflammatory effects may be a potential therapeutic approach for IBD. Noninvasive techniques for vagus nerve stimulation have been developed. Considering the importance of vagus nerve function in the brain-gut axis, Vagus nerve stimulation is a promising treatment option for IBD. This review discusses the potential therapeutic advantages and drawbacks of vagus nerve stimulation, particularly the use of noninvasive transcutaneous auricular vagus nerve stimulation.
Patel R, Marrie RA, Bernstein CN, Bolton JM. Graff LA, Marriott JJ, Figley CR, Kornelsen J, Mazerolle EL, Helmick C, Uddin N, Fisk JD. Vascular disease is associated with differences in brain structure and lower cognitive functioning in inflammatory bowel disease: A cross-sectional study. Inflammatory Bowel Diseases 2024; 30(8):1309-1318.
Background: Vascular disease and cognitive impairment have been increasingly documented in IBD, and both have been individually correlated with changes in brain structure. This study aimed to determine if both macro- and microstructural brain changes are prevalent in IBD and whether alterations in brain structure mediate the relationship between vascular disease and cognitive functioning.
Methods: Eighty-four IBD participants underwent multimodal magnetic resonance imaging. Volumetric and mean diffusivity measures of the thalamus, hippocampus, normal-appearing white matter, and white matter lesions were converted to age- and sex-adjusted z scores. Vascular comorbidity was assessed using a modified Framingham Risk Score and cognition was assessed using a battery of neuropsychological tests. Test scores were standardized using local regression-based norms. We generated summary statistics for the magnetic resonance imaging metrics and cognitive tests, and these were examined using canonical correlation analysis and linear regression modeling.
Results: Greater vascular comorbidity was negatively correlated with thalamic, normal-appearing white matter, and white matter lesion volumes. Higher Framingham Risk Score were also correlated with lower processing speed, learning and memory, and verbal fluency. Increased vascular comorbidity was predictive of poorer cognitive functioning, and this effect was almost entirely mediated (94.76%) by differences in brain structure.
Conclusions: Vascular comorbidity is associated with deleterious effects on brain structure and lower cognitive functioning in IBD. These findings suggest that proper identification and treatment of vascular disease is essential to the overall management of IBD, and that certain brain areas may serve as critical targets for predicting the response to therapeutic interventions.
Herauf M, Coward S, Peña-Sánchez JN, Bernstein CN, Benchimol EI, Kaplan GG. A commentary on the epidemiology of inflammatory bowel disease in compounding prevalence nations: Towards sustaining healthcare delivery. Gastroenterology 2024; 166(6):949-956.
IBD, namely Crohn’s disease and ulcerative colitis, affects millions of individuals worldwide. IBD is characterized geographically by epidemiologic stages: Stage 1 (emergence) includes developing regions with low incidence and prevalence; stage 2 (acceleration in incidence) includes newly industrialized regions in Asia and Latin America with rapidly rising incidence but low prevalence; and stage 3 (compounding prevalence) includes early industrialized regions in North America, Europe, and Oceania with steadily climbing prevalence due to the cumulative effect of incidence greatly exceeding mortality over time. Demographics are changing in regions entrenched in the third epidemiologic stage: Incidence is stabilizing in adult onset IBD while continuing to rise in children with IBD. The IBD population is aging, making seniors the fastest growing prevalent demographic with IBD. Consequently, compounding prevalence regions face the unique challenge of providing equitable, high quality care for an IBD population that is both rising in number and aging over time. The Canadian Gastro-Intestinal Epidemiology Consortium invited IBD epidemiologists from Catalonia (representing Southern Europe), Denmark (representing Scandinavia), Hungary (representing Eastern Europe), Israel, New Zealand (representing Oceania), Scotland (representing Western Europe), and the United States to an in-person symposium (May 31, 2023) with lectures and round-table discussions. Epidemiologists were invited to the symposium based on availability, feasibility, and geographic representation of stage 3 regions. Further, these jurisdictions have advanced much of the known stage 3 epidemiology worldwide. This meeting’s goal was to prepare healthcare systems in stage 3 regions to address the rising burden and changing population demographics of IBD. The objectives of this meeting were to describe the current epidemiology of IBD in stage 3 regions; to explore methodological heterogeneity in studying the epidemiology of IBD; to discuss how to provide accessible, equitable, and quality IBD healthcare in a sustainable manner; and to strategize future steps in the prediction and prevention of disease. Addressing these objectives helps clinicians and researchers prioritize activities that counteract the rising burden of IBD
Epidemiology of IBD in Stage 3 Regions: Lectures during the meeting described the most current epidemiologic data on incidence and prevalence in the 21st century in stage 3 regions. Overall, the annual incidence and prevalence of IBD presented at the symposium ranged from 20.9 to 44.4 per 100,000 and 519 to 893 per 100,000, respectively. Scandinavia has the highest incidence and prevalence of IBD in the world; in 2017, the incidence and prevalence of IBD in Denmark was 44.4 and 890 per 100,000, respectively. The lowest reported
incidence of IBD among the regions listed above was 21.0 per 100,000 person-years from 2007 to 2018 in Hungary. Israel reported the lowest prevalence of IBD at 519 per 100,000 in 2018. The hallmark of stage 3 is steadily rising prevalence. For example, the prevalence of IBD increased by 4.3% per year from 2008 to 2018 in Scotland and by 2.4% per year from 2002 to 2014 in Canada. In Scotland, the forecasted prevalence in 2028 was 1023 per 100,000, whereas in Canada, the forecasted prevalence in 2030 was 981 per 100,000.
Lessons learned from the meeting:
1.The prevalence of IBD is climbing in early industrialized nations in North America, Europe, and Oceania and is
forecasted to be 1% of the population over the next decade.
2. Heterogeneity in epidemiologic data between regions is influenced by methodological differences of studies. These differences may be overcome by consortia that standardize data collection and research methodologies used across regions, while ensuring transparency of research methods to allow for accurate interpretation of results.
3. High-quality, accessible, and equitable care to those with IBD are attainable. However, achieving these goals requires a concerted effort to innovate healthcare delivery such as virtual clinics.
4. Increased funding, training, and integration of multidisciplinary clinics are needed to address the changing demographics of IBD populations where adult gastroenterologists manage older individuals with IBD and other age-related comorbidities and pediatric gastroenterologists handle the rising incidence of young children with IBD.
5. Prioritizing research toward preventing IBD through modifying environmental and behavioral determinates may
slow the rising prevalence in compounding prevalence nations.
Behr M, Mehes I, Bernstein CN. It’s time to change tack in IBD treatment. Gastroenterology 2024; Nov;167(6):1065-1070.
Contemporary reviews on the pathogenesis of IBDs (most commonly Crohn’s disease and ulcerative colitis) consistently invoke the triad of genetics, the environment, and the immune system in the etiology of these diseases. Yet, the current treatment paradigm for all IBDs exclusively seeks to dampen or modulate what is presumed to be an excessive or aberrant immune response. Despite the widespread recognition that environmental factors (microbes, diet and/or other exposures associated with a Western lifestyle) are critical contributors to both the etiology and the maintenance of disease, current guideline-based therapies are immunomodulatory; in this essay, we call these immune-directed therapies (small molecule and biologics drugs). Modifications of environmental factors, including dietary changes, antibiotics and fecal microbiota transplant, have proven successful in other gastrointestinal diseases, such as celiac disease, enteric fever and Clostridium difficile colitis, respectively. In contrast, the development of IBD therapies along these lines has been slow to emerge. We ask: what has impeded the evolution of these therapies along the lines of the revolution in immune-directed therapies seen since the advent of infliximab over two decades ago? More specifically: are environmental modifications ineffective, or are they merely perceived as ineffective?
In this essay we argued that some environmental modifications for IBD are much more than just minimally beneficial. Rather, in some instances some environmental modifications have been shown to be as efficacious as some current standard-of-care treatments but are undervalued. Why? They are undervalued partly because of the different outcomes measured and how clinicians and decision-makers interpret these outcomes. The results of environmental modifications, such as exclusive enteral nutrition, antibiotics and fecal microbiota transplant, are not inferior to the results seen with some of the more expensive biologic agents and newer small molecules. Recently, some newer therapies have been associated with more robust remission outcomes (i.e. upatacitinib) but still have a net remission rate (net=active therapy-placebo) of less than 50%. With the recent interest in combining immunotherapies (i.e. golimumab and guselkumab in the GALAXI and DUET studies) we believe that combinations of immune therapies and environmental therapies may not only provide comparable enhanced benefit, but also potentially less toxicity and less cost. There are, however, no large marketing machines to promote large scale environmental modification studies as lone or combined therapies. We argue that this is important for patients who want to consider all treatment options, now. We also argue that the perception that environmental modifications are ineffective is an impediment to innovation. After more than two decades of biologic and small molecule agents, we have learned what is working (symptomatic relief and mucosal healing for many but not necessarily the majority of patients) and what is not happening (cure), despite a plethora of recently approved anti-cytokine medications, including ustekinumab, vedolizumab, tofacitinib, ozanimod, etrasimod, upadacitinib. Mirikizumab, and risankizumab. Despite these advancements, the therapeutic ceiling remains stubbornly low and surgery remains a mainstay of treatment (10% ulcerative colitis, 40% Crohn’s disease at 10 years in the modern era). Further, the costs of immune therapies have driven up the overall cost of IBD care to unsustainable levels. There is also the issue of the developing world, where IBD is quickly emerging and where accessibility to immune therapies can be limited. Less expensive environmental modifications are often studied in underpowered studies, yet these agents may have benefit and may be widely available in developed and developing countries.
Marshall DA, MacDonald KV, Kao D, Bernstein CN, Kaplan GG, Jijon H, Hazlewood G, Panaccione R, Nasser Y, Raman M, Moayyedi P, on behalf of the IMAGINE Network. Patient Preferences for Active Ulcerative Colitis Treatments and Fecal Microbiota Transplantation. Therapeutic Advances in Chronic Diseases 2024; Mar 26; 15: 20406223241239168.
Background: Fecal microbiota transplantation is a promising treatment for active ulcerative colitis. Understanding patient preferences can identify treatment features that may impact treatment decisions, improve shared decision-making, and contribute to patient-centered care, which is especially important in the context of novel treatments like fecal microbiota transplantation. We aimed to quantify preferences for active ulcerative colitis treatments, specifically fecal microbiota transplantation and biologics, and identify patient characteristics associated with different preference patterns.
Methods: We administered a discrete choice experiment survey to elicit preferences in a sample of Canadian adults with ulcerative colitis. Discrete choice experiment data were analyzed using a main-effects mixed logit model and used to predict uptake of hypothetical scenarios reflecting alternative combinations of treatment features. Latent class modeling identified heterogeneity in patient preference patterns.
Results: Participants' (n = 201) mean age was 47.1 years (SD: 14.5 years), 58% were female, and most (84%) had at least some post-secondary education. Almost half were willing to undergo fecal microbiota transplantation. When considering treatments for active ulcerative colitis, the most important attributes were chance of remission and severity of rare unknown side effects. All else equal, participants were most likely to uptake treatment that involves oral capsules/pills. Participants in the class with the highest utility for chance of remission were younger, had more severe disease, and 58% indicated that they would be willing to undergo fecal microbiota transplantation.
Conclusion: We identified characteristics of ulcerative colitis patients who are more likely to be interested in fecal microbiota transplantation using preference elicitation methods. Patient-centered care can be enhanced by knowing which patients are more likely to be interested in fecal microbiota transplantation, potentially improving satisfaction with and adherence to treatments for active ulcerative colitis to maximize the effectiveness of treatment while considering heterogeneity in patient preferences.
Kowalec K, Harder A, Dolovich C, Fitzgerald KC, Salter A, Lu Y, Bernstein CN, Bolton JM, Cutter G, Fisk JD, Gelernter J, Graff LA, Hägg S, Hitchon CA, Levey D, Lublin FD, McKay K, Patten S, Patki A, Stein M, Tiwari HK, Wolinsky JS, Marrie RA. Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis. Annals of Clinical and Translational Neurology 2024; Jun;11(6):1393-1404.
Objective: Comorbid anxiety occurs often in multiple sclerosis and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in multiple sclerosis.
Methods: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (multiple sclerosis/comorbid anxiety) or controls (multiple sclerosis/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression.
Results: A total of 71,343 individuals of European genetic ancestry were used: Canada (n=334; 212 multiple sclerosis), UK Biobank (n=70,431; 1,390 multiple sclerosis), and the USA (n = 578 multiple sclerosis). Meta-analyses identified that in multiple sclerosis, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. Multiple sclerosis had a similar anxiety genetic burden compared to people with anxiety as the index disease.
Conclusion: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in multiple sclerosis of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in multiple sclerosis.
Bowdish DME, Chandran V, Hitchon CA, Kaplan GG, Avina-Zubieta JA, Fortin PR, Larché MJ, Boire G, Gingras AC, Dayam RM, Colmegna I, Lukusa L, Lee JLF, Richards DP, Pereira D, Watts TH, Silverberg MS, Bernstein CN, Lacaille D, Benoit J, Kim J, Lalonde N, Gunderson J, Allard-Chamard H, Roux S, Quan J, Hracs L, Turnbull E, Valerio V, Bernatsky S, SUCCEED investigative team. SUrveillance of responses to COVID-19 vaCcines in systEmic immunE mediated inflammatory Diseases (SUCCEED). Journal of Rheumatology 2024; Jul 1;51(7):721-727.
Objective: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors.
Methods: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain IgG titers; we also measured antinucleocapsid IgG.
Results: Positive associations for log-transformed anti-receptor-binding domain titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of antinucleocapsid positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Antinucleocapsid positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti- receptor-binding domain titers, particularly after 210 days.
Conclusion: Ours is the first pan-Canadian immune-mediated inflammatory diseases assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.
Xue M, Leibovitzh H, Neustaeter A, Dong M, Xu W, Espin-Garcia O, Griffiths AM, Steinhart AH, Turner D, Huynh H, Dieleman LA, Panaccione R, Aumais G, Bressler B, Bitton A, Murthy S, Marshall JK, Hyams JS, Otley A, Bernstein CN, Moayyedi P, El-Matary W, Fich A, Denson LA, Ropeleski MJ, Abreu MT, Deslandres C, Cino M, Avni-Biron I, Lee SH, Turpin W, Croitoru K. Environmental Factors Associated with Risk of Crohn’s Disease Development in A Prospective Cohort of Healthy First-Degree Relatives of Crohn’s disease Patients. Clinical Gastroenterology and Hepatology 2024 Sep;22(9):1889-1897.
Background: To date, it is unclear how environmental factors influence Crohn's disease risk and how they interact with biological processes. This study investigates the association between environmental exposures and Crohn's disease risk and evaluates their association with pre-disease biomarkers.
Methods: We studied 4289 healthy first-degree relatives of patients with Crohn's disease from the Crohn's and Colitis Canada - Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio; gut inflammation via fecal calprotectin levels; and fecal microbiome composition through 16S rRNA sequencing.
Results: Over a 5.62-year median follow-up, 86 first degree relatives developed Crohn's disease. Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40-0.96; P = .034), and living with a large family size in the first year of life (HR, 0.43; 95% CI, 0.21-0.85; P = .016) were associated with decreased Crohn's disease risk, whereas having a bird at the time of recruitment (HR, 2.78; 95% CI, 1.36-5.68; P = .005) was associated with an increased Crohn's disease risk. Furthermore, living with a dog was associated with reduced lactulose to mannitol ratio; altered relative abundance of multiple bacterial genera, and increased Chao1 diversity, whereas bird owners had higher fecal calprotectin levels. Large family during participants' first year of life was associated with altered microbiota composition without affecting fecal calprotectin or lactulose to mannitol ratio.
Conclusion: This study identifies environmental variables associated with Crohn's disease risk. These variables were also associated with altered barrier function, subclinical inflammation, and gut microbiome composition shifts, suggesting potential roles in Crohn's disease pathogenesis.
Bitarafan S, Zhu F, Mirza A, Bernstein CN, Van Domselaar G, Marrie RA, Yeh EA, Zhao Y, Banwell B, Waubant E, Tremlett H. Assessment of Dietary Intake and its Inflammatory Potential in Persons with Pediatric-onset Multiple Sclerosis. Multiple Sclerosis and Related Disorders 2024; June; 86:105599.
Objective: To compare diet and the modified dietary inflammatory index between individuals with pediatric-onset multiple sclerosis, monophasic acquired demyelinating syndromes, and controls.
Methods: The association between diet, the modified dietary inflammatory index, and disease status was examined in 131 individuals with pediatric-onset multiple sclerosis (n=38) monophasic acquired demyelinating syndromes (n=45), controls (n=48) using logistic regression.
Results: The associations between diet and pediatric-onset multiple sclerosis were modest, reaching significance for whole grain intake (adjusted odds ratio, aOR=0.964, 95 % confidence intervals, CI:0.934-0.995) but not modified dietary inflammatory index (aOR=1.20, 95 %CI:0.995-1.46) versus controls. No findings for monophasic acquired demyelinating syndromes, reached significance versus controls.
Conclusions: Individuals with pediatric-onset multiple sclerosis, but not monophasic acquired demyelinating syndromes, had lower dietary whole grain intake than controls.
Cadogan K, Shaffer S, Singer A, Reimer A, Knox N, Rumore J, Christianson S, Alexander DC, Forbes JD, Bernstein CN. Physician perspectives of Helicobacter pylori diagnostic and treatment practices in Canada: Results of a Canadian Survey. BMC Gastroenterology 2024; Jun 17;24(1):204.
Background: Helicobacter pylori infection is prevalent worldwide and can lead to peptic ulcer disease (PUD) and gastric cancer. Effective diagnosis and treatment of H. pylori infection by gastroenterologists and family physicians is crucial. However, there are differing views on optimal diagnosis and treatment. The objective of this study is to understand the impressions of Canadian physicians regarding H. pylori diagnosis and treatment and whether impressions differ between gastroenterologists and family physicians. A second objective is to understand physician perspectives on rising antibiotic resistance and how that guides empiric management.
Methods: A survey facilitated via REDCap was administered to Canadian gastroenterologists and family physicians. A total of 105 participants completed the survey, including 43 gastroenterologists and 62 family physicians. Gastroenterologists were recruited from across the country and family physicians were recruited from Manitoba.
Results: For diagnosis of H. pylori, 67% of gastroenterologists reported endoscopic biopsies for histology assessment as most common and 73% of family physicians reported serology as their main diagnostic test. While nearly all gastroenterologists believed antibiotic resistance to be a problem, nearly one quarter of family physicians did not believe it was a problem.
Conclusions: There is variability in practices among both gastroenterologists and family physicians regarding diagnosis of H. pylori infection. There was consensus that local antibiotic resistance patterns should guide management. If known, the degree and patterns of antibiotic resistance could bring a more uniform consensus to H. pylori management. Greater education of physicians, especially family physicians regarding management of H pylori is needed.
Shaffer S, Dolovich C, El Gabalawy R, Graff LA, Singh H, Ly Jackson G, Chochinov S, Shaw S, Bernstein CN. The impact of source and consumption of news on mental health disorders among IBD patients during the COVID-19 pandemic. Journal of Canadian Association of Gastroenterology 2024; 7 (2): 212-218.
Background: We sought to understand the trends in media use, and how consumption and source affected mental health of persons with IBD during the early parts of the pandemic. Dissemination of news during the COVID-19 pandemic was integral to educating the public but also could be harmful if constantly consumed, leading to worsening anxiety.
Methods: We performed a survey study in autumn 2020 during the second wave of COVID-19 in Manitoba. The survey included questions on consumption of COVID-19 news, along with validated measures of perceived stress, generalized anxiety, health anxiety, and depression. We used multivariable logistic regression analysis to assess trusted sources of news as a predictor of clinically significant mental health symptoms.
Results: Of the 2940 participants in the registry, 1384 (47.1%) persons responded. The most trusted sources of news were television (64.2%), internet (46.1%), newspaper (27.6%), friends/family (21.7%), social media (16.9%), and radio (16.6%). Those who trusted social media had a 50% higher odds of depression (aOR 1.52, 95%CI 1.04-2.22), and 2-3 times higher perceived stress (aOR 2.56, 95%CI 1.09-2.21). Persons who reported extreme difficulty limiting their time-consuming news about COVID-19 and who spent more than 1hour daily consuming information on COVID-19 both had increased odds of any clinically significant mental health symptoms.
Conclusions: It is unknown if consumption of COVID-19 news led to heightened mental health symptoms or if increasing anxieties and concerns led to consuming more news. Further research is needed to assess whether these elevated mental health symptoms led to worse disease outcomes.
Harel D, Wu Y, Levis B, Fan S, Sun Y, Xu M, Rice DB, Boruff J, Markham S, Ioannidis JPA, Takwoingi Y, Patten SB, Ziegelstein RC, Cuijpers P, Gilbody S, Vigod S, Akena D, Benedetti A, Thombs BD; DEPRESsion Screening Data (DEPRESSD) Collaboration. Comparison of scores on Patient Health Questionnaire-9, Edinburgh Postnatal Depression Scale and Hospital Anxiety and Depression - Depression subscale scores by administration mode: An individual participant data differential item functioning meta-analysis. Journal of Affective Disorders 2024; Sep 15; 361: 674-683.
Objective: In the face of the ongoing circulation of SARS-CoV-2, the durability of neutralization post-COVID-19 vaccination in immune-mediated inflammatory disease (IMID) is a key issue, as are the effects of medications.
Methods: Adults (n = 112) with inflammatory bowel disease, psoriasis/psoriatic arthritis, rheumatoid arthritis, spondylarthritis, and systemic lupus were recruited from participating Canadian medical centers from 2021 to 2023. We focused on log-transformed neutralization (lentivirus methods) as a continuous outcome, with separate models for wild-type and Omicron strains BA.1 and BA.5.
Results: Compared with 30 to 120 days postvaccination, subsequent periods were associated with greater neutralization in unadjusted models for wild-type, BA.1, and BA.5 strains and against the BA.1 strain in adjusted models. Rituximab was associated with lower neutralization for the BA.1 strain in adjusted models, with a similar trend for BA.5. In methotrexate users, there were trends for less neutralization of BA.1 and BA.5 in all unadjusted models, whereas in adjusted models, there was significantly lower neutralization only for the wild type. Three or more doses and Omicron-specific vaccines were both independently associated with better neutralization ability for all three strains. A COVID-19 infection within six months before sampling was associated with higher neutralization of wild type and BA.1 in adjusted analyses. Anti-tumor necrosis factor agents were associated with lower neutralization ability for BA.5 in adjusted analyses.
Conclusion: Neutralization responses in immunosuppressed individuals with IMID were durable over time and were augmented by more than three doses and Omicron-specific vaccines. Less neutralization was seen with certain medications. Our work clarifies the joint effects of vaccine history, infection, and medications on COVID-19 immunity.
Mirza AI, Zhu F, Knox N, Black L, Daly A, Bonner C, Van Domselaar G, Bernstein CN, Graham M, Marrie RA, Hart J, Yeh EA, Arnold DL, Bar-Or A, O’Mahoney J, Zhao Y, Hsiao W, Banweell B, Waubant E, Tremlett H. Mediterranean diet and associations with the gut microbiota and pediatric-onset multiple sclerosis using trivariate analysis. Communications Medicine (London) 2024; Jul 19;4(1):148.
Background: The interplay between diet and the gut microbiota in multiple sclerosis is poorly understood. We aimed to assess the interrelationship between diet, the gut microbiota, and multiple sclerosis.
Methods: We conducted a case-control study including 95 participants (44 pediatric-onset multiple sclerosis cases, 51 unaffected controls) enrolled from the Canadian Pediatric Demyelinating Disease Network study. All had completed a food frequency questionnaire ≤21-years of age, and 59 also provided a stool sample.
Results: Here we show that a 1-point increase in a Mediterranean diet score is associated with 37% reduced likelihood of developing multiple sclerosis (95%CI: 10%-53%). Higher fiber and iron intakes are also associated with reduced odds for developing multiple sclerosis. Diet, not multiple sclerosis, explains inter-individual gut microbiota variation. Several gut microbes abundances are associated with both the Mediterranean diet score and having multiple sclerosis, and these microbes are potential mediators of the protective associations of a healthier diet.
Conclusions: Our findings suggest that the potential interaction between diet and the gut microbiota is relevant in multiple sclerosis.
Levis B, Bhandari PM, Neupane D, Fan S, Sun Y, He C, Wu Y, Krishnan A, Negeri Z, Imran M, Rice DB, Riehm KE, Azar M, Levis AW, Boruff J, Cuijpers P, Gilbody S, Ioannidis JPA, Kloda LA, Patten SB, Ziegelstein RC, Harel D, Takwoingi Y, Markham S, Alamri SH, Amtmann D, Arroll B, Ayalon L, Baradaran HR, Beraldi A, Bernstein CN, Bhana A, Bombardier CH, Buji RI, Butterworth P, Carter G, Chagas MH, Chan JCN, Chan LF, Chibanda D, Clover K, Conway A, Conwell Y, Daray FM, de Man-van Ginkel JM, Fann JR, Fischer FH, Field S, Fisher JRW, Fung DSS, Gelaye B, Gholizadeh L, Goodyear-Smith F, Green EP, Greeno CG, Hall BJ, Hantsoo L, Härter M, Hides L, Hobfoll SE, Honikman S, Hyphantis T, Inagaki M, Iglesias-Gonzalez M, Jeon HJ, Jetté N, Khamseh ME, Kiely KM, Kohrt BA, Kwan Y, Lara MA, Levin-Aspenson HF, Liu SI, Lotrakul M, Loureiro SR, Löwe B, Luitel NP, Lund C, Marrie RA, Marsh L, Marx BP, McGuire A, Mohd Sidik S, Munhoz TN, Muramatsu K, Nakku JEM, Navarrete L, Osório FL, Pence BW, Persoons P, Petersen I, Picardi A, Pugh SL, Quinn TJ, Rancans E, Rathod SD, Reuter K, Rooney AG, Santos IS, Schram MT, Shaaban J, Shinn EH, Sidebottom A, Simning A, Spangenberg L, Stafford L, Sung SC, Suzuki K, Tan PLL, Taylor-Rowan M, Tran TD, Turner A, van der Feltz-Cornelis CM, van Heyningen T, Vöhringer PA, Wagner LI, Wang JI, Watson D, White J, Whooley MA, Winkley K, Wynter K, Yamada M, Zeng QZ, Zhang Y, Thombs BD, Benedetti A; Depression Screening Data (DEPRESSD) PHQ Group. Data-Driven Cutoff Selection for the Patient Health Questionnaire-9 Depression Screening Tool. JAMA Network Open 2024 Nov 4;7(11):e2429630.
Objective: To evaluate the degree to which using data-driven methods to simultaneously select an optimal Patient Health Questionnaire-9 (PHQ-9) cutoff score and estimate accuracy yields (1) optimal cutoff scores that differ from the population-level optimal cutoff score and (2) biased accuracy estimates.
Methods This study used cross-sectional data from an existing individual participant data meta-analysis database on PHQ-9 screening accuracy to represent a hypothetical population. Studies in the individual participant data meta-analysis database compared participant PHQ-9 scores with a major depression classification. From the individual participant data meta-analysis population, 1000 studies of 100, 200, 500, and 1000 participants each were resampled. For the full individual participant data meta-analysis population and each simulated study, an optimal cutoff score was selected by maximizing the Youden index. Accuracy estimates for optimal cutoff scores in simulated studies were compared with accuracy in the full population.
Results: The individual participant data meta-analysis database included 100 primary studies with 44 503 participants (4541 [10%] cases of major depression). The population-level optimal cutoff score was 8 or higher. Optimal cutoff scores in simulated studies ranged from 2 or higher to 21 or higher in samples of 100 participants and 5 or higher to 11 or higher in samples of 1000 participants. The percentage of simulated studies that identified the true optimal cutoff score of 8 or higher was 17% for samples of 100 participants and 33% for samples of 1000 participants. Compared with estimates for a cutoff score of 8 or higher in the population, sensitivity was overestimated by 6.4 (95% CI, 5.7-7.1) percentage points in samples of 100 participants, 4.9 (95% CI, 4.3-5.5) percentage points in samples of 200 participants, 2.2 (95% CI, 1.8-2.6) percentage points in samples of 500 participants, and 1.8 (95% CI, 1.5-2.1) percentage points in samples of 1000 participants. Specificity was within 1 percentage point across sample sizes.
Conclusions: This study of cross-sectional data found that optimal cutoff scores and accuracy estimates differed substantially from population values when data-driven methods were used to simultaneously identify an optimal cutoff score and estimate accuracy. Users of diagnostic accuracy evidence should evaluate studies of accuracy with caution and ensure that cutoff score recommendations are based on adequately powered research or well-conducted meta-analyses.