Publications 2022 | ibdmanitoba

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Publications // 2022

Shaffer SR, Nugent Z, Yu BN, Lix LM, Bernstein CN, Walkty A, Singh H. Effect of clinical vs. administrative data definitions on the epidemiology of C. difficile among hospitalized individuals with IBD: A population-based cohort study. BMC Gastroenterology 2022; Mar 26; 22(1):140.

Hospitalization admissions and discharge databases using the International Classification of Diseases (ICD) codes are often used to describe the epidemiology of Clostridioides difficile infections among those with IBD, even though discharge databases Clostridioides difficile infections definition can miss many cases of Clostridioides difficile infections. There are no data comparing the assessment of the epidemiology of Clostridioides difficile infections among those with IBD by discharge databases versus laboratory diagnosis. We used a population-based dataset to determine the effect of using discharge databases versus laboratory Clostridioides difficile infections diagnosis on Clostridioides difficile infections assessment among those with IBD. We linked the University of Manitoba IBD Epidemiology Database to the provincial Clostridioides difficile infections laboratory dataset for the years 2005-2014. Time trends of Clostridioides difficile infections were assessed using joinpoint analyses. We used stratified logistic regression analysis to assess factors associated with Clostridioides difficile infections among individuals with IBD. Results: Time trends of Clostridioides difficile infections among hospitalized individuals with IBD were similar when using discharge databases or the laboratory Clostridioides difficile infections diagnosis. Prior hospital admission and antibiotic exposure were associated with Clostridioides difficile infections using either of the Clostridioides difficile infections definitions, 5-ASA use was associated with Clostridioides difficile infections using discharge databases but not laboratory diagnosis, whereas corticosteroid exposure was associated with laboratory-based Clostridioides difficile infections diagnosis. Using laboratory results as gold standard, discharge databases had a sensitivity and specificity of 75.4% and 99.6% for Clostridioides difficile infections among those with IBD. Conclusions: Using ICD codes in the discharge databases for Clostridioides difficile infections provides similar epidemiological time trend patterns as identifying Clostridioides difficile infections in the laboratory dataset. Hence, ICD codes are reliable to determine Clostridioides difficile infections epidemiology among hospitalized individuals with IBD.

Targownik LE, Bernstein CN, Benchimol EI, Kaplan GG, Singh H, Tennakoon A, Nugent Z, Coward SB, Kuenzig ME, Murthy SK. Earlier Anti-TNF initiation leads to long term lower health care utilization in Crohn’s disease but not in ulcerative colitis. Clinical Gastroenterology and Hepatology 2022:20: 2507-2618.

The timing of initiating biologic therapy in persons with Crohn's disease and ulcerative colitis is an area of ongoing controversy. In particular, there is concern that delaying the initiation of biologic therapy may lead to more treatment-resistant disease, which can result in more complications and hospitalizations. We used health administrative data from Manitoba, Canada to identify all persons with a new diagnosis of IBD between 2001 and 2018 who received tumor necrosis factor antagonists (anti-TNF) therapy and had at least 1 year of post anti-TNF initiation follow-up. We measured the rates of hospitalization, surgery, and outpatient visits, prior to and for up to 5 years following anti-TNF initiation. We compared the rates of these health care utilization outcomes between persons receiving anti-TNFs within 2 years following diagnosis and those receiving anti-TNFs more than 2 years following IBD diagnosis. We used inverse probability treatment weighting to adjust for baseline differences in risk between the 2 groups. Results: Among 742 persons with Crohn's disease, early anti-TNF initiators had fewer IBD-specific and overall hospitalizations over the 5 years following the start of therapy. Incidence of surgical resection was also lower in earlier anti-TNF initiators with Crohn's disease if the first year following initiation was excluded from the analysis. In 318 cases of ulcerative colitis, there was no impact of the timing of anti-TNF therapy on the rates of hospitalization and surgery. Conclusions: Earlier administration of anti-TNF therapy is associated with reduced downstream health care resource utilization in Crohn’s disease, though these impacts are not evident in ulcerative colitis. These were real world data showing that early initiation of biologic therapy in Crohn’s disease is advantageous.

Vagianos K, Shafer LA, Graff LA, Witges K, Targownik LE, Bernstein CN. Self-reported flares among people living with IBD are associated with stress and worry but not associated with recent diet changes: The Manitoba Living with IBD Study. Journal of Parenteral and Enteral Nutrition 2022; 46: 1686-1698.

In this matched case-control longitudinal study among people living with IBD, we investigated beliefs about what triggers a flare. Adults with confirmed IBD and active disease within 2 years were enrolled in the Manitoba Living with IBD Study and followed biweekly with online surveys for 1 year. The 7-point IBD Symptom Change Indicator was used for participant identification of a flare. Flare cases were matched to non-flare controls by sex and disease type. Members of each matched pair completed supplemental information on diet changes and psychological functioning in the previous two weeks, and provided stool samples to assess fecal calprotectin (FCAL). Results: Of 128 enrolled participants, 95 matched flare/non-flare pairs were created. Those reporting a flare were more likely to have elevated FCAL (51% vs 34% among non-flares, p=0.043). Although 61% of study participants believed at baseline that a food may trigger flares, and 25% of those in a flare believed that a food may have triggered their current flare, there was no difference in consumption of assessed foods between flares and non-flares in the previous two weeks. Flares were more likely to be having difficulties in emotional state than controls (40% vs 18%, p=0.001) and more likely to be stressed or worried (64% vs 33%, p=0.001). Conclusion: While a majority of individuals with IBD believe that specific foods trigger their disease flares, this was not supported by the current findings. Recent psychological functioning was associated with self-reported IBD flare.

Tandon P, Tennakoon A, Huang V, Bernstein CN, Goetgebuer R, Targownik L. Pregnancy and live birth rates in women with inflammatory bowel disease: A Canadian population-based cohort study. Journal of Canadian Association of Gastroenterology 2022; 5: 184-191.

IBD negatively affects fertility and fecundity. We aimed to determine longitudinal trends in and factors that affect pregnancy rates in women with ulcerative colitis and Crohn's disease. Women in the University of Manitoba IBD Epidemiology Database aged 15 to 45 were identified between 1992 and 2018 and matched up to 10 non-IBD controls. Pregnancy and live birth rates were compared between women with and without ulcerative colitis or Crohn's disease stratified by time-period, disease duration and maternal age at conception. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were calculated. Poisson regression was used to adjust these rates for year of pregnancy, disease duration, maternal age, severity of IBD, and prior IBD-related surgery. Results: Compared to controls, women with ulcerative colitis had lower rates of pregnancies (IRR 0.91, 95% CI: 0.82-0.99) and women with Crohn's disease had lower rates of pregnancies (IRR 0.85, 95% CI: 0.79-0.93) and live births (IRR 0.83, 95% CI: 0.75-0.92). Although rates of pregnancies and live births were significantly lower in women with ulcerative colitis and Crohn's disease compared to controls prior to 2010, there appeared to be no differences between the two groups after 2010. Prior intestinal surgery and active disease at conception appeared to lower pregnancy rates in women with ulcerative colitis and Crohn's disease, respectively. Conclusion: This study demonstrates that women with IBD have lower pregnancy rates compared to those without IBD, though these differences are no longer evident after 2010. Factors that continue to reduce these rates include prior colectomy and underlying disease activity.

Liang G, Zhu F, Mirza AI, Arnold D, Bar-Or A, Bernstein CN, Bonner C, Forbes JD, Graham M, Hart J, Knox NC, Marrie RA, Mahony JO, Van Domselaar G, Yeh EA, Zhao Y, Banwell B, Waubant E, Tremlett H, and the Canadian Paediatric Demyelinating Disease Network. Stability of the gut microbiota in persons with pediatric-onset multiple sclerosis and related demyelinating diseases. Multiple Sclerosis Journal 2022; 28:1819-1824

We established a biobank of stool from children with pediatric onset multiple sclerosis and monophasic-acquired demyelinating syndromes (monoADS) and unaffected controls. In this study we examined if the gut microbiota composition changes across repeated samples in paediatric-onset multiple sclerosis (MS) or monophasic-acquired demyelinating syndromes (monoADS). A total of 36 individuals (18 MS/18 monoADS) with at least 2 stool samples were included. Stool sample-derived DNA was sequenced. Alpha/beta diversities and genus-level taxa were analysed. Results: Mean ages at first sample procurement (MS/monoADS) = 18.0/13.8 years. Median time (months) between first/second samples = 11.2 and second/third = 10.3. Alpha/beta diversities did not differ between stool samples (p > 0.09), while one genus - Solobacterium did (p = 0.001). Conclusions: The gut microbiota composition in paediatric-onset MS and monoADS exhibited stability, suggesting that single stool sample procurement is a reasonable first approach.

Uddin MD, Figley TD, Kornelsen J, Mazerolle EL, Helmick CA, O’Grady CB, Pirzada S, Patel R, Carter S, Wong K, Essig MR, Graff LA, Bolton JM, Marriott JJ, Bernstein CN, Fisk JD, Marrie RA, Figley CR. The Comorbidity and Cognition in Multiple Sclerosis (CCOMS) neuroimaging protocol: study rationale, MRI acquisition and minimal image processing pipelines. Frontiers in Neuroimaging 2022 Aug 24:1:970385.

The Comorbidity and Cognition in Multiple Sclerosis (CCOMS) study represents a coordinated effort by a team of clinicians, neuropsychologists, and neuroimaging experts to investigate the neural basis of cognitive changes and their association with comorbidities among persons with multiple sclerosis (MS). The objectives are to determine the relationships among psychiatric (e.g., depression or anxiety) and vascular (e.g., diabetes, hypertension, etc.) comorbidities, cognitive performance, and MRI measures of brain structure and function, including changes over time. Because neuroimaging forms the basis for several investigations of specific neural correlates that will be reported in future publications, the goal of the current manuscript is to briefly review the CCOMS study design and baseline characteristics for participants enrolled in the three study cohorts (MS, psychiatric control, and healthy control), and provide a detailed description of the MRI hardware, neuroimaging acquisition parameters, and image processing pipelines for the volumetric, microstructural, functional, and perfusion MRI data.

Li Y, Bernstein CN, Xu W, Hu P. Polygenic risk and causal inference of psychiatric comorbidity in inflammatory bowel disease among patients with European ancestry. Journal of Translational Medicine 2022; Jan 27;20(1): 43.

Approximately 40% of persons with IBD experience psychiatric comorbidities. Previous studies demonstrated the polygenetic effect on both IBD and psychiatric comorbidities. In this study, we evaluated the contribution of genetic variants to psychiatric comorbidities among the IBD population. Additionally, we evaluated whether this effect is mediated by the expression level of the RBPMS gene, which was identified in our previous studies as a potential risk factor of psychiatric comorbidities in persons with IBD. The polygenic risk score (PRS) was estimated among persons with IBD of European ancestry (n = 240) from the Manitoba IBD Cohort Study by using external genome-wide association studies (GWAS). The association and prediction performance were examined between the estimated PRS and psychiatric comorbidities status among persons with IBD. Finally, regression-based models were applied to explore whether the imputed expression level of the RBPMS gene is a mediator between estimated PRS and psychiatric comorbidities status in IBD. Results: The estimated PRS had a significantly positive association with psychiatric comorbidities status (for the highest effect: P-value threshold = 5 × 10-3, odds ratio = 2.0, P-value = 1.5 × 10-5). Around 13% of the causal effect between the PRS and psychiatric comorbidity status in IBD was mediated by the expression level of the RBPMS gene. The area under the curve of the PRS-based psychiatric comorbidity prediction model is around 0.7 at the threshold of 5 × 10-4. Conclusion: Psychiatric comorbidity status in IBD depends on genetic influences among persons with European ancestry. The PRS could potentially be applied to psychiatric comorbidities risk screening to identify persons with IBD at a high risk of psychiatric comorbidities. Around 13% of this genetic influence could be explained by the expression level of the RBPMS gene.

Lo B, Trindade IA, Ferreira M, Acosta MB, Knowles SR, Burisch J, Bernstein CN, Mokrowiecka A, Mikocka-Walus A, Gearry RB. Fear of COVID-19 among persons with inflammatory bowel disease as compared to persons with other gastrointestinal conditions. Turkish Journal of Gastroenterology 2022; 33: 664-672.

Although several studies have reported the impact of fears relating to COVID-19 on several chronic illnesses, there are few studies focused on gastrointestinal conditions. Therefore, the aim of this study was to compare the fear of COVID-19 in patients with IBD to other gastrointestinal conditions and how the fear of COVID-19 manifests across different demographical backgrounds among inflammatory bowel disease respondents. Participants with gastrointestinal conditions (age at least 18) were recruited from 27 countries. Demographic, clinical, and psychosocial information was collected. An adapted scale for IBD patients measuring the fear of COVID-19 and gastrointestinal-specific fear of COVID-19 was used. Results: In 831 participants (312 IBD), only significant increases in gastrointestinal-fear of COVID-19 were found in between IBD and other gastrointestinal conditions (mean [standard deviation]: 13.5 [5.5] vs 10.9 [5.0], P < .01). Among IBD respondents, persons on sick leave had significantly more fear of COVID-19 than those employed (median [IQR], 31.0 [28.5-39.5] vs 26.0 [20.0-33.0], P = .035) and significantly more gastrointestinal-fear of COVID-19 compared to the employed (18.0 [14.5-22.0] vs 13.0 [9.0-17.0], P = .033) or respondents outside of the labor market (12.0 [7.0-16.0], P = .022). Persons living in a rural setting had significantly more fear of COVID-19 compared to persons living in regional setting (29.5 [22.0-37.8] vs 25.0 [20.0-31.3], P = .007) and gastrointestinal-fear of COVID-19 (15.0 [11.0-19.8] vs 12.0 [9.0-16.0], P = .02). Conclusion: Respondents with IBD are more afraid of COVID-19 regarding their disease; especially, persons on sick leave or persons living in a rural setting. This should be taken into consideration to personalize the support that health care providers can offer in mitigating fear related to COVID-19.

Mirza AI, Zhu F, Knox N, Forbes JD, Van Domselaar G, Bernstein CN, Graham M, Marrie RA, Hart, J Yeh EA, Arnold D, Bar-Or A, O’Mahony J, Zhao Y, Hsiao W, Banwell B, Waubant E, Tremlett H. Metagenomic analysis of the pediatric-onset multiple sclerosis gut microbiome. Neurology 2022; 98(10): e1050-e1063.

Little is known of the functional potential of the gut microbiome in pediatric-onset multiple sclerosis. More research is being done on the gut microbiome on non-gastrointestinal diseases, like multiple sclerosis. We performed metagenomic analyses using stool samples from individuals with pediatric-onset multiple sclerosis and unaffected controls. Persons 21 years old or younger enrolled in the Canadian Pediatric Demyelinating Disease Network providing a stool sample were eligible. Twenty patients with multiple sclerosis (McDonald criteria) with symptom onset under age 18 years were matched to 20 controls by sex, age (±3 years), stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (multiple sclerosis vs controls) and disease-modifying drug exposure using alpha diversity, relative abundance, and prevalence using Wilcoxon rank sum, ALDEx2, and Fisher exact tests, respectively. Results: Individuals with multiple sclerosis were aged 13.6 years (mean) at symptom onset and 8 were disease-modifying drug-naive. Mean ages at stool sample were 16.1 and 15.4 years for multiple sclerosis and control participants, respectively; 80% were girls. Alpha diversity of enzymes and proteins did not differ by disease or disease-modifying drug status (p > 0.20), but metabolic pathways, gene annotations, and microbial taxonomy did. Individuals with multiple sclerosis (vs controls) exhibited higher methanogenesis prevalence (odds ratio 10, p = 0.044) and Methanobrevibacter abundance (log2 fold change [LFC] 1.7, p = 0.0014), but lower homolactic fermentation abundance (LFC -0.48, p = 0.039). Differences by disease-modifying drug status included lower phosphate butyryl transferase for disease-modifying drug-naive vs exposed patients with multiple sclerosis (LFC -1.0, p = 0.033). Discussion: The gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset multiple sclerosis vs controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. Disease-modifying drug exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with multiple sclerosis may have a disturbed functional potential.

Su S, Marrie RA, Bernstein CN. Factors associated with social participation in persons living with inflammatory bowel disease. Journal of Canadian Association of Gastroenterology 2022; 5: 59-67.

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

Wang H, Labus JS, Griffin F, Gupta A, Bhatt RR, Sauk JS, Turkiewicz J, Bernstein CN, Kornelsen J, Mayer EA. Functional Brain Rewiring and Altered Cortical Stability in Ulcerative Colitis. Molecular Psychiatry 2022; 27:1792-1804.

Despite recent advances, there is still a major need to better understand the interactions between brain function and chronic gut inflammation and its clinical implications. Alterations in executive function have previously been identified in several chronic inflammatory conditions, including IBD. Inflammation-associated brain alterations can be captured by connectome analysis. Here, we used the resting-state fMRI data from 222 participants comprising three groups ulcerative colitis, irritable bowel syndrome, and healthy controls, N = 74 each) to investigate the alterations in functional brain wiring and cortical stability in ulcerative colitis compared to the two control groups and identify possible correlations of these alterations with clinical parameters. Globally, ulcerative colitis participants showed increased functional connectivity and decreased modularity compared to IBS and healthy controls groups. Regionally, ulcerative colitis showed decreased eigenvector centrality in the executive control network (ulcerative colitis < irritable bowel syndrome < healthy controls) and increased eigenvector centrality in the visual network (ulcerative colitis > irritable bowel syndrome > healthy controls). Ulcerative colitis also showed increased connectivity in dorsal attention, somatomotor network, and visual networks, and these enhanced subnetwork connectivities were able to distinguish ulcerative colitis participants from healthy controls and IBS with high accuracy. Dynamic functional connectome analysis revealed that ulcerative colitis showed enhanced cortical stability in the medial prefrontal cortex (mPFC), which correlated with severe depression and anxiety-related measures. None of the observed brain changes were correlated with disease duration. Together, these findings are consistent with compromised functioning of networks involved in executive function and sensory integration in ulcerative colitis.

Witges K, Sexton K, Graff LA, Targownik LE, Lix LM, Haviva C, Stone J, Shafer LA, Vagianos K, Bernstein CN. What is a flare? The Manitoba Living with IBD study. Inflammatory Bowel Diseases 2022; 28: 862-869.

Flare is a poorly defined term used by patients and clinicians to indicate IBD status. This study aimed to evaluate the validity of a single item 7-point flare indicator, relative to other measures of disease flare. The longitudinal Manitoba Living with IBD Study followed persons with IBD for one year; they completed biweekly online surveys and provided 3 stool samples. Disease flare on a single item flare indicator with seven possible responses developed for the study was defined by report of symptoms as ‘moderately’ or ‘much’ worse. The flare indicator was evaluated against five measures of disease activity: fecal calprotectin score (FCAL), a 2-point disease status indicator, a 4-point flare certainty indicator, the IBD Symptom Index short form (SIBDSI), and the short form IBD Questionnaire (SIBDQ). Participants in a flare, based on the 7-point measure, were matched to a non-flaring participant, and a stool sample was collected. Results: Of the 155 IBD participants, almost half (n=74) experienced a flare. Of those who flared, 97.0% endorsed active IBD on the 2-point indicator (controls 42.5%; p<0.001); 91.9% endorsed active IBD on the 4-point certainty indicator (controls 32.9%; p<0.001); 90.5% endorsed active disease on the SIBDSI (controls 34.2%; p<0.001); and 48.5% had an elevated FCAL (controls 34.3%; p < 0.05). The mean SIBDQ was lower for the flare group compared to controls [43.9(SD 11.1) vs 58.3(SD 8.5) p<0.001], indicating worse disease. Conclusions: The 7-point flare indicator robustly identified symptomatic flares. This patient self-report indicator reflected meaningful changes in more complex clinical indices, and had only weak concordance with the presence of inflammation.

Wan A, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM, Hitchon C, Marriott JJ, Marrie RA. Childhood maltreatment and psychiatric comorbidity in immune-mediated inflammatory disorders. Psychosomatic Medicine 2022; 84:10-19.

We aimed to determine whether childhood maltreatment is associated with immune-mediated inflammatory disorders (multiple sclerosis [MS], inflammatory bowel disease [IBD], and rheumatoid arthritis [RA]). We further aimed to determine the relationship between maltreatment and psychiatric comorbidity in immune-mediated inflammatory disorders and whether these relationships differed across immune-mediated inflammatory disorders. 681 participants (MS, 232; IBD, 216; RA, 130; healthy controls, 103) completed a structured psychiatric interview to identify psychiatric disorders, and the Childhood Trauma Questionnaire to evaluate 5 types of maltreatment: emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. We evaluated associations between maltreatment, IMID, and psychiatric comorbidity using multivariable logistic regression models. Results: The prevalence of having at least1 maltreatment was similar across immune-mediated inflammatory disorders but higher than in controls (MS, 63.8%; IBD, 61.6%; RA, 62.3%; healthy controls, 45.6%). Emotional abuse was associated with having an immune-mediated inflammatory disorder (adjusted odds ratio [aOR] = 2.37; 1.15-4.89). In the sex-specific analysis, this association was only present in women. History of childhood maltreatment was associated with a lifetime diagnosis of a psychiatric disorder in the immune-mediated inflammatory disorders cohort (OR = 2.24; 1.58-3.16), but this association did not differ across diseases. In those with an immune-mediated inflammatory disorder, total types of maltreatments (aOR = 1.36; 1.17-1.59) and emotional abuse (aOR = 2.64; 1.66-4.21) were associated with psychiatric comorbidity. Conclusions: Childhood maltreatment is more common in immune-mediated inflammatory disorders than in a healthy population and is associated with psychiatric comorbidity. Given the high burden of psychiatric disorders in the immune-mediated inflammatory disorders population, clinicians should be aware of the contribution of maltreatment and the potential need for trauma-informed care strategies.

Shafer LA, Shaffer S, Witt J, Nugent Z, Bernstein CN. IBD Disability Index (IBDDI) is associated with both direct and indirect costs of inflammatory bowel disease. Inflammatory Bowel Diseases 2022; 28(8):1189-1197.

We aimed to determine both direct (medical) and indirect (lost wages) costs of IBD and the association between the degree of IBD-related disability and extent of IBD-related costs. Persons age 18-65 from the population-based University of Manitoba IBD Research Registry completed a survey including the IBD Disability Index (IBDDI) and questions related to employment, missed work (absenteeism), and reduced productivity at work (presenteeism). Administrative health data including surgeries, hospitalizations, physician claims, and prescriptions were linked to the survey and assessed. To calculate annual wage loss, number of days of missed work was multiplied by the average wage in Manitoba for the given occupation per Statistics Canada. Costs were adjusted to 2016-17 Canadian dollars. Using descriptive and regression analysis, we explored the association between IBDDI and annual direct and indirect costs associated with IBD. Results: Average annual medical costs rose from $1918 among those with IBDDI 0-4 to $9,993 among those with IBDDI 80-86. Average annual cost of lost work rose from $0 among those with IBDDI 0-4 to $30,101 among those with IBDDI 80-86. Using linear regression, each additional unit of IBDDI was associated with an increase of $77 in annual medical cost (95% CI, $52-102; P <.001) and an increase of $341 in annual cost of lost wages (95% CI, $288-395; P < .001). Conclusions: Costs related to IBD are significantly associated with the degree of IBD-related disability. Among the approximate 30% of the IBD population with IBDDI scores of at least 40, the indirect costs of absenteeism and presenteeism accounts for ~75% of the total IBD-related costs.

Wang H, Labus JS, Griffin F, Gupta A, Bhatt RR, Sauk JS , Turkiewicz J, Bernstein CN, Kornelsen J, Mayer EA. Functional Brain Rewiring and Altered Cortical Stability in Ulcerative Colitis. Molecular Psychiatry 2022; Mar;27(3):1792-1804.

Despite recent advances, there is still a major need to better understand the interactions between brain function and chronic gut inflammation and its clinical implications. Alterations in executive function have previously been identified in several chronic inflammatory conditions, including inflammatory bowel diseases. Inflammation-associated brain alterations can be captured by connectome analysis. Here, we used the resting-state fMRI data from 222 participants comprising three groups (ulcerative colitis (UC), irritable bowel syndrome (IBS), and healthy controls (HC), N = 74 each) to investigate the alterations in functional brain wiring and cortical stability in UC compared to the two control groups and identify possible correlations of these alterations with clinical parameters. Globally, UC participants showed increased functional connectivity and decreased modularity compared to IBS and HC groups. Regionally, UC showed decreased eigenvector centrality in the executive control network (UC < IBS < HC) and increased eigenvector centrality in the visual network (UC > IBS > HC). UC also showed increased connectivity in dorsal attention, somatomotor network, and visual networks, and these enhanced subnetwork connectivities were able to distinguish UC participants from HCs and IBS with high accuracy. Dynamic functional connectome analysis revealed that UC showed enhanced cortical stability in the medial prefrontal cortex (mPFC), which correlated with severe depression and anxiety-related measures. None of the observed brain changes were correlated with disease duration. Together, these findings are consistent with compromised functioning of networks involved in executive function and sensory integration in UC.

The timing of initiating biologic therapy in persons with Crohn’s disease and ulcerative colitis is an area of ongoing controversy. In particular, there is concern that delaying the initiation of biologic therapy may lead to more treatment resistant disease, which can result in more complications and hospitalizations. We used the University of Manitoba IBD Epidemiologic Database derived from health administrative data to identify all persons with a new diagnosis of IBD between 2001 and 2018 who received anti-TNF therapy and had at least one year of post anti-TNF initiation follow-up. We measured the rates of hospitalization, surgery, and outpatient visits, prior to and for up to 5 years following anti-TNF initiation. We compared the rates of these health care utilization outcomes between persons receiving anti-TNFs at less than 2 years following diagnosis and those receiving anti-TNFs at more than 2 years following IBD diagnosis. We used inverse probability treatment weighting (IPTW) to adjust for baseline differences in risk between the two groups. In persons with Crohn’s disease, early anti-TNF initiators had fewer IBD-specific and overall hospitalizations over the 5 years following the start of therapy. Incidence of resective surgery was also lower in earlier anti-TNF initiators with Crohn’s disease if the first year following initiation was excluded from the analysis. There was no impact of the timing of anti-TNF therapy on the rates of hospitalization and surgery for persons with ulcerative colitis.

Earlier administration of anti-TNF therapy is associated with reduced downstream health care resource utilization in Crohn’s disease, though these impacts are not as evident in ulcerative colitis.

Liang G, Zhu F, Mirza AI, Arnold D, Bar-Or A, Bernstein CN, Bonner C, Forbes JD, Graham M, Hart J, Knox NC, Marrie RA,Mahony JO, Van Domselaar G, Yeh EA, Zhao Y, Banwell B, Waubant E, Tremlett H, and the Canadian Paediatric Demyelinating Disease Network. Stability of the gut microbiota in persons with pediatric-onset multiple sclerosis and related demyelinating diseases. Multiple Sclerosis Journal 2022; Oct;28(11):1819-1824.

We aimed to determine if the gut microbiota composition changes across repeated samples collected over the short-term in individuals with pediatric-onset MS or monophasic acquired demyelinating syndromes (monoADS). Individuals who provided stool samples on at least 2 occasions were eligible. Stool samples were collected across the Canadian Pediatric Demyelinating Disease Network and banked at the University of Manitoba IBD Clinical and Research Centre Biobank. Metagenome analysis was undertaken at the National Microbiology Laboratory, Winnipeg, Canada. Stool sample-derived DNA was amplified, sequenced, and clustered into amplicon sequence variants (ASVs). Alpha/beta diversities were explored, and genus-level ASVs were analysed using nonparametric microbial interdependence tests (NMIT) and linear mixed effect models. 36 individuals were eligible (18 MS/18 monoADS). 15 MS/16 monoADS participants provided two samples, and the remainder three, totalling 77 samples. Alpha/beta diversities did not differ between stool samples (P>0.09). Solobacterium genus varied significantly over-time (P=0.001). Nonparametric microbial interdependence tests revealed no difference in longitudinal sample composition between MS and monoADS participants (P>0.2).

We concluded that the gut microbiota composition in individuals with pediatric-onset MS and monoADS exhibited stability between stool samples over a 2-25 month period. While preliminary, findings suggest that procurement of single stool samples is a reasonable first approach.

IBD negatively affects fertility and fecundity. We aimed to determine longitudinal trends in and factors that affect pregnancy rates in women with ulcerative colitis and Crohn’s disease. Women in the University of Manitoba IBD Epidemiology Database aged 15-45, in Manitoba, Canada were identified between 1992-2018 and matched up to 10 non-IBD controls. Pregnancy and live birth rates were compared between women with and without ulcerative colitis or Crohn’s disease stratified by time period, disease duration, and maternal age at conception. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were calculated. Poisson regression was used to adjust these rates for year of pregnancy, disease duration, maternal age, severity of IBD, and prior IBD-related surgery. Compared to controls, women with ulcerative colitis had lower rates of pregnancies (IRR 0.91, 95% CI, 0.82-0.99) and women with Crohn’s disease had lower rates of pregnancies (IRR 0.85, 95% CI, 0.79-0.93) and live births (IRR 0.83, 95% CI, 0.75-0.92). There were no differences in rates of pregnancies between cases and controls from 2010 to 2018. Factors that significantly lowered pregnancy rates included a new IBD diagnosis and maternal age at conception less than 35 for Crohn’s disease. Furthermore, prior IBD-related surgery and active disease at conception also appeared to lower pregnancy rates in women with ulcerative colitis and Crohn’s disease respectively.

In conclusion shorter disease duration, younger age at conception, active disease, and prior IBD-surgery negatively impact pregnancy and live birth rates in women with ulcerative colitis and Crohn’s disease.

The polygenic risk score was estimated among persons with IBD of European ancestry (n = 240) from the Manitoba IBD Cohort Study by using external genome-wide association studies (GWAS). The association and prediction performance were examined between the estimated polygenic risk score and psychiatric comorbidities status among persons with IBD. Finally, regression-based models were applied to explore whether the imputed expression level of the RBPMS gene is a mediator between estimated polygenic risk score and psychiatric comorbidities status in IBD.

The estimated polygenic risk score had a significantly positive association with psychiatric comorbidities status (for the highest effect: P-value threshold = 5 × 10-3, odds ratio = 2.0, P-value = 1.5 × 10-5). Around 13% of the causal effect between the polygenic risk score and psychiatric comorbidities status in IBD was mediated by the expression level of the RBPMS gene. The area under the curve of the PRS-based psychiatric comorbidities prediction model is around 0.7 at the threshold of 5 × 10-4.

PC status in IBD depends on genetic influences among persons with European ancestry. The polygenic risk score could potentially be applied to psychiatric comorbidities risk screening to identify persons with IBD at a high risk of psychiatric comorbidities. Around 13% of this genetic influence could be explained by the expression level of the RBPMS gene.

This study examined the gut metagenome in individuals with and without pediatric-onset multiple sclerosis (MS). Stool samples were collected across the Canadian Pediatric Demyelinating Disease Network and banked at the University of Manitoba IBD Clinical and Research Centre Biobank. Metagenome analysis was undertaken at the National Microbiology Laboratory, Winnipeg, Canada. Study participants were 21 years old or younger, with MS (disease-modifying drug [DMD] exposed and naïve) or unaffected controls all less than age 22. 20 MS patients (McDonald criteria) with symptom onset prior to age18 years were matched to 20 controls by sex, age, stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha-diversity, relative abundance, and prevalence using Wilcoxon rank-sum, ALDEx2 and Fisher's exact tests, respectively. Alpha-diversity of enzymes and proteins did not differ by disease or DMD status (p>0.20), but metabolic pathways, gene annotations and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio=10, p=0.044), and Methanobrevibacter abundance (log2 fold-change [LFC]=1.7, p=0.0014), but lower homolactic fermentation abundance (LFC=-0.48, p=0.039). Differences by DMD status included lower phosphate butyryltransferase for DMD-naïve vs exposed MS patients (LFC=-1.0, p=0.033).

We concluded that the gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS versus controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.

Furer P, Graff LA, Jackson GL, Kredenster M, Anderson S, Dirkse D, Pryor T, Bernstein CN. Development of an Internet-delivered Cognitive Behavioral Program for Inflammatory Bowel Disease: A Pilot Study. Journal of Depression and Anxiety Disorders 2022; 4(1):106-114.

Background

The prevalence of IBD varies worldwide and is rapidly rising, with the highest rates being reported in Europe and North America. The approximately 2 million individuals with IBD in the US and Canada are projected to double over the next decade. The disease has a high burden for patients, with unpredictable, painful symptoms that can interfere with home and work life.

It is well established that individuals with IBD have significantly higher rates of anxiety and depression than the general population. Persistent high levels of stress predict worsening IBD symptoms, which in turn increases the risk of developing chronic anxiety and depression.

This pilot study examined a new internet-delivered cognitive behavior therapy program (iCBT) for anxiety, depression and/or stress in adults with inflammatory bowel disease (IBD).

The internet-delivered cognitive behavioral therapy (iCBT) intervention tailored for adults with IBD to address stress, anxiety and/or depression is outlined in Table 1. The program included 9 core modules and 1 optional module. Modules took approximately 1-2 hours each to complete and included

text, patient videos illustrating learning points, and practice exercises to complete between modules.

Methods

Adults were recruited from the Manitoba sample of the Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects (IMAGINE) study, a large cohort of Canadian patients with physician-confirmed IBD. Eighteen of 21 participants completed the 9-module program.

Measures of anxiety, depression, and stress were administered at baseline, and at 6-, 12-, and 24-weeks post-baseline.

Results

Compared to baseline, there was a significant reduction in anxiety (HADS-A) and in stress (PSS-4) over time. There were no statistically significant changes in depression scores (HADS-D). However, inspection of average depression scores over time suggests a trend for a decrease in scores at the 6- and 12-week points, with a subsequent increase at 24 weeks.

Participant satisfaction on the CSQ-8 ranged from 18 to 28 with a mean of 23.65 reflecting good satisfaction with the online intervention.

Conclusion

The results of this pilot study suggest it is a promising clinical intervention and support further investigation of this online CBT intervention for adults with IBD. Clinically meaningful reductions in anxiety and stress were achieved with this relatively low-resource intensity and accessible intervention. Participant engagement was high, with an excellent completion rate.

Shen B, Kochhar GS, Rubin DT, Kane SV, Navaneethan U, Bernstein CN, Cross RK, Sugita A, Schairer J, Kiran RP, Fleshner P, McCormick JT, D'Hoore A, Shah SA, Farraye FA, Kariv R, Liu X, Rosh J, Chang S, Scherl E, Schwartz DA, Kotze PG, Bruining DH, Philpott J, Abraham B, Segal J, Sedano R, Kayal M, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sehgal P, Picoraro JA, Vermeire S, Sandborn WJ, Silverberg MS, Pardi DS. Treatment of pouchitis, Crohn's disease, cuffitis, and other inflammatory disorders of the pouch: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterology and Hepatology 2022 Jan;7(1):69-95.

Pouchitis, Crohn's disease of the pouch, cuffitis, polyps, and extraintestinal manifestations of inflammatory bowel disease are common inflammatory disorders of the ileal pouch. Acute pouchitis is treated with oral antibiotics and chronic pouchitis often requires anti-inflammatory therapy, including the use of biologics. Aetiological factors for secondary pouchitis should be evaluated and managed accordingly. Crohn's disease of the pouch is usually treated with biologics and its stricturing and fistulising complications can be treated with endoscopy or surgery. The underlying cause of cuffitis determines treatment strategies. Endoscopic polypectomy is recommended for large, symptomatic inflammatory polyps and polyps in the cuff. The management principles of extraintestinal manifestations of IBD in patients with pouches are similar to those in patients without pouches.

Ananthakrishnan AN, Kaplan GG, Bernstein CN, Burke KE, Lochhead PJ, Sasson AN, Agrawal M, Tion HT, Steinberg J, Kruis W, Steinwurz F, Ahuja V, Ng SC, Rubin DT, Colombel JF, Gearry R, International Organization for the Study of Inflammatory Bowel Diseases. IOIBD consensus on lifestyle, behavior, and environmental modification for the management of patients with inflammatory bowel diseases. Lancet Gastroenterology and Hepatology 2022; Jul;7(7):666-678.

The external environment plays an important role in the natural history of Crohn’s disease (CD) and ulcerative colitis (UC). There is no comprehensive guidance on the role of beneficial lifestyle and behavioral modifications while avoiding adverse influences as part of the treatment of these diseases.

Under the auspices of the International Organization for Study of Inflammatory Bowel Diseases (IOIBD), we developed a series of consensus statements addressing various lifestyle and behavioral modifications in patients with established CD or UC. A review of literature was performed. International experts participated in a two-stage voting process to arrive at the final set of consensus statements. Statements that achieved at least 75% agreement among the panel members were considered adopted.

We generated a series of 20 consensus statements that were voted on by 62 experts in the first stage, and 41 in the second stage. Nineteen of the statements were considered adopted, achieving > 70% agreement (range 76 – 100%). The statements advocated for smoking cessation in both CD and UC, recognition of the adverse impact and systematic evaluation for mood disturbances and stress, an informed choice for selection of therapeutic diets while monitoring inflammation and deficiencies, encouraging physical activity and normal body weight, as well as minimizing use of high-dose NSAIDs. The statements identified lack of sufficient data on safety of e-cigarettes and use of cannabis to treat CD or UC. A shared decision-making approach maximizing therapeutic adherence was also determined to be important.

We identified a series of consensus statements addressing behavior and lifestyle that are beneficial in the management of patients with CD or UC.

Shen B, Kochhar GS, Kariv R, Rex DR, Sugita A, Rubin DT, Navaneethan U, Hull TL, Ko HM, Liu X, Kachnic LA, Strong S, Iacucci M, Bemelman W, Fleshner P, Safyan RA, Kotze PG, D'Hoore A, Faiz O, Lo S, Ashburn JH, Spineli A, Bernstein CN, Kane SV, Cross RK, Schairer J, McCormick JT, Farraye FA, Chang S, Scherl E, Schwartz DA, Bruining DH, Philpott J, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sandborn WJ, Silverberg MS, Pardi DS, Church J, Kiran RP. Management of Pouch Neoplasia: A Consensus Guideline from the International Ileal Pouch Consortium. Lancet Gastroenterology and Hepatology 2022; in press.

Stone JA, Shafer LA, Graff LA, Witges K, Lix L. Sexton KA, Haviva C, Targownik LE, Bernstein CN. The association of efficacy, optimism, uncertainty and health anxiety with inflammatory bowel disease activity. Journal of Psychosomatic Research 2022; Mar:154:110719.

Positive and negative psychological attributes have been shown to influence disease outcomes in many chronic health conditions. We aimed to evaluate the association between self-efficacy, optimism, health anxiety and intolerance of uncertainty and disease activity in IBD. Adults with confirmed and recently active IBD enrolled in a prospective cohort study. Demographics, disease information, validated measures of psychological functioning related to general self-efficacy, optimism, health anxiety and intolerance of uncertainty were collected at baseline, week 26 and week 52. Clinical disease activity was assessed using the Inflammatory Bowel Disease Symptom Inventory (IBDSI), self-reported flares, and intestinal inflammation using fecal calprotectin (FCAL), collected at baseline, weeks 26 and 52. Generalized estimating equations were used to test the association between psychological functioning and disease activity. There were 154 participants of whom 64.1% had Crohn's disease. Adjusting for demographic variables, higher self-efficacy was associated with lower likelihood of flare by self-report (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.71, 0.91) and IBDSI (OR 0.89, 95% CI 0.80, 0.99), while higher health anxiety was associated with greater likelihood of flare by self-report (OR 1.07, 95% CI 1.01, 1.18) and higher symptomatic disease activity (IBDSI; OR 1.14, 95% CI 1.05, 1.24). The psychological attributes were not significantly associated with active disease as measured by inflammation (FCAL).

We concluded that general self-efficacy and health anxiety are relevant in understanding patient experience with disease activity, and may be appropriate targets for psychological intervention in the care of individuals with IBD.

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

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

Pratt M, Forbes JD, Knox NC, Van Domselaar G, Bernstein CN. Colorectal cancer screening in IBD - can characterization of GI microbiome signatures enhance neoplasia detection? Gastroenterology. 2022 Jan 5: S0016-5085.

Current non-invasive colorectal cancer screening methods are not optimized for persons with IBD, requiring patients to undergo frequent interval screening via colonoscopy. Although colonoscopy-based screening reduces colorectal cancer incidence in IBD patients, rates of interval colorectal cancer remain relatively high, highlighting the need for more targeted approaches. In recent years, the discovery of disease-specific microbiome signatures for both IBD and colorectal cancer has begun to emerge, suggesting that stool-based biomarker detection using metagenomics and other culture-independent technologies may be useful for personalized, early, non-invasive colorectal cancer screening in IBD patients. Here we discuss the utility of the stool microbiome as a non-invasive colorectal cancer screening tool. Comparing the performance of multiple microbiome-based colorectal cancer classifiers, including several multi-cohort meta-analyses, we find that non-invasive detection of colorectal adenomas and carcinomas from microbial biomarkers is an active area of study with promising early results.

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.

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.

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. Use of benzodiazepines and Z-drugs in multiple sclerosis. Frontiers in Neurology 2022; May 24; 13: 910014.

Use of benzodiazepines and Z-drugs (non-benzodiazepine sedative hypnotics) is controversial due to adverse health outcomes in the general population. However, little is known about their use in people with multiple sclerosis. We estimated the incidence and prevalence of benzodiazepine and Z-drug use (jointly BZD) in the multiple sclerosis population as compared to an age-, sex- and geographically-matched population without multiple sclerosis, and examined the association of mood/anxiety disorders with the use of BZD over a twenty-year period. Using administrative data from Manitoba, Canada, we identified 2,985 persons with incident multiple sclerosis and 14,891 persons without multiple sclerosis matched 5:1 on sex, birth year and region. We applied validated case definitions to identify persons with any mood/anxiety disorder. Dispensations of BZD were identified. To assess the association between multiple sclerosis, mood/anxiety disorders and BZD use we constructed generalized linear models adjusting for age, sex, index year, socioeconomic status, urban/rural residence, physical comorbidities, and health care use. We also examined patterns of BZD use. Results: In 2016, the crude incidence of benzodiazepine use in the multiple sclerosis cohort was 2.10% (95%CI: 1.43-2.98%), 50% higher than in the non-multiple sclerosis cohort (1.41%; 95%CI: 1.18-1.67%). The crude incidence of Z-drug use in the multiple sclerosis cohort was 1.77% (95%CI: 1.20-2.51%), 80% higher than in the non-MS cohort (0.99%; 95%CI: 0.81-1.21%). After adjusting for covariates, among individuals without an active mood/anxiety disorder, the multiple sclerosis cohort had a 39% increased incidence rate of benzodiazepine use and a 72% increased incidence rate of Z-drug use as compared to the non- multiple sclerosis cohort. Among individuals with an active mood/anxiety disorder, the incidence of BZD use did not differ between the multiple sclerosis and non- multiple sclerosis cohorts. A higher proportion of people with multiple sclerosis used BZD for ≥6 months than people without multiple sclerosis. Conclusion: Use of BZD is more common in people with multiple sclerosis than in general population controls, and use of these agents is in persons with multiple sclerosis is often chronic.

Kowalec K, Salter A, Fitzgerald KC, Patel M, Han J, Lu Y, Bolton JM, Hitchon C, Bernstein CN, Patten S, Graff LA, Marriott JJ, Marrie RA, for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Depressive symptom trajectories and polygenic risk scores in individuals with an immune-mediated inflammatory disease. General Hospital Psychiatry 2022; Jul-Aug; 77: 21-28.

To develop group-based trajectories of depressive symptoms in immune-mediated inflammatory disease to understand their evolution and identify any associated factors, with the overall goal of identifying those at highest risk of higher depressive symptom burden. 922 participants had an immune-mediated inflammatory disease or anxiety/depression. The PHQ-9 was administered at four visits, and polygenic risk scores for major depressive disorder, depressive symptoms, and body mass index (BMI) were generated. Group-based trajectory modelling of PHQ-9 scores estimated distinct trajectories. Regression tested whether specific factors were associated with the trajectories. Mediation analyses assessed whether immune-mediated inflammatory disease mediated the association between BMI PRS and trajectories. Results: Three trajectories were identified. Regression demonstrated those in Group 3 ('high symptoms') had significantly higher polygenic risk scores for the three traits, compared to Group 1 ('minimal symptoms') (OR: 1.34-1.66, P < 0.01). Stratified analyses in the immune-mediated inflammatory disease subgroup revealed an increased effect for BMI polygenic risk scores in Group 3 (OR: 2.31, P < 0.001), in contrast, BMI polygenic risk scores was no longer associated in the non- immune-mediated inflammatory disease sample. No significant indirect effect of BMI polygenic risk scores on depressive symptoms trajectories was identified via immune-mediated inflammatory disease. Conclusions: A significant association between polygenicity and PHQ-9 trajectories supports a role for genetic inheritance in the variability in depressive symptoms in immune-mediated inflammatory disease.

Heron V, Panaccione N, Restellini S, Germain P, Candido K, Bernstein CN, Bessissow T, Bitton A, Chauhan UK, Lakatos PL, Marshall JK, Michetti P, Seow CH, Rosenfeld G, Panaccione R, Afif W. Efficacy of intravenous ustekinumab reinduction in patients with Crohn’s disease with a loss of response. Journal of the Canadian Association of Gastroenterology 2022; 5: 208-213.

In patients receiving ustekinumab for treatment of Crohn's disease, there is no proven strategy to enhance or re-capture response. We assessed the utility of ustekinumab intravenous (IV) reinduction (~6 mg/kg) to achieve clinical, biochemical and endoscopic response or remission, in patients with partial or loss of response to ustekinumab maintenance therapy. A multicentre, retrospective cohort study was performed. Adults who received an IV reinduction dose of ustekinumab for either partial response or secondary loss of response to ustekinumab were assessed. The primary outcome was clinical remission off corticosteroids (Harvey Bradshaw Index less than 5), with biochemical response (defined as at least 50% decrease of CRP or fecal calprotectin and/or endoscopic response (defined as a decrease in Simple Endoscopic Score-CD greater than 50%). Secondary outcomes included clinical, biomarker and endoscopic response/remission, as well as safety. Results: 65 patients (median age 38 years, 54.7% women) underwent IV ustekinumab reinduction between January 2017 and April 2019. Most patients (88.3%) were already on escalated maintenance dosing of ustekinumab 90 mg subcutaneous every 4 weeks. Clinical outcomes were assessed at a median of 14 weeks (IQR: 12-19) post-reinduction. The primary outcome of clinical remission off corticosteroids with biochemical and/or endoscopic response was achieved in 31.0% (n = 18). Pre-reinduction ustekinumab concentrations were ≥1 μg/mL in 88.6% (mean 3.2 ± 2.0 μg/mL). No serious adverse events were reported. Conclusions: Ustekinumab IV reinduction can be effective in patients with Crohn's disease with partial or loss of response to ustekinumab maintenance therapy. Further studies evaluating this strategy are warranted.

Kornelsen J, Witges K, Labus J, Mayer EA, Bernstein CN. Brain structure and function changes in inflammatory bowel disease. NeuroImage Reports 2022; 2 (2): 10009.

As the importance of the brain-gut axis in the pathobiology of IBD continues to evolve, a greater understanding of brain structure and functional connectivity is necessary. In this magnetic resonance imaging (MRI) study, we investigated differences in brain structure and in functional connectivity of brain regions in 111 participants with IBD (76 ulcerative colitis (UC) and 35 Crohn's disease (CD)) and 74 healthy controls. Significant differences between IBD and healthy controls were observed in the three analyses used (voxel based morphometry, region-of-interest, and independent component analysis) in brain regions of the default mode, cerebellar, and visual networks. Significant differences between IBD subtypes (UC, CD) were found. The results of the current study establish that a relationship between brain functional connectivity and the brain-gut axis exists in IBD.

Marrie RA, Patel R, Figley CR, Kornelsen J, Bolton J, Graff LA, Mazerolle EL, Helmick C, O’Grady C, Uddin N, Marriott JJ, Bernstein CN, Fisk JD for the Comorbidity and Cognition in Multiple Sclerosis (CCOMS) Study Group. Effects of vascular comorbidity on cognition in multiple sclerosis are partially mediated by changes in brain structure. Frontiers in Neurology 2022; Apr 14; 13: 874724.

Vascular comorbidities are associated with reduced cognitive performance and with changes in brain structure in people with multiple sclerosis. Understanding causal pathways is necessary to support the design of interventions to mitigate the impacts of comorbidities, and to monitor their effectiveness. We assessed the inter-relationships among vascular comorbidity, cognition and brain structure in people with multiple sclerosis. Adults with neurologist-confirmed multiple sclerosis reported comorbidities, and underwent assessment of their blood pressure, HbA1c, and cognitive functioning (i.e., Symbol Digit Modalities Test, California Verbal Learning Test, Brief Visuospatial Memory Test-Revised, and verbal fluency). Test scores were converted to age-, sex-, and education-adjusted z-scores. Whole brain magnetic resonance imaging (MRI) was completed, from which measures of thalamic and hippocampal volumes, and mean diffusivity of gray matter and normal-appearing white matter were converted to age and sex-adjusted z-scores. Canonical correlation analysis was used to identify linear combinations of cognitive measures (cognitive variate) and MRI measures (MRI variate) that accounted for the most correlation between the cognitive and MRI measures. Regression analyses were used to test whether MRI measures mediated the relationships between the number of vascular comorbidities and cognition measures. Results: Of 105 participants, most were women (84.8%) with a mean (SD) age of 51.8 (12.8) years and age of symptom onset of 29.4 (10.5) years. Vascular comorbidity was common, with 35.2% of participants reporting one, 15.2% reporting two, and 8.6% reporting three or more. Canonical correlation analysis of the cognitive and MRI variables identified one pair of variates (Pillai's trace = 0.45, p = 0.0035). The biggest contributors to the cognitive variate were the Symbol Digit Modalities Test and California Verbal Learning Test-II, and to the MRI variate were gray matter MD and thalamic volume. The correlation between cognitive and MRI variates was 0.50; these variates were used in regression analyses. On regression analysis, vascular comorbidity was associated with the MRI variate, and with the cognitive variate. After adjusting for the MRI variate, vascular comorbidity was not associated with the cognitive variate. Conclusion: Vascular comorbidity is associated with lower cognitive function in people with multiple sclerosis and this association is partially mediated via changes in brain macrostructure and microstructure.

Turpin W, Dong M, Sasson G, Garay JAR, Espin-Garcia O, Lee SH, Neustaeter A, Smith MI, Lebovic H, Guttman DS, Griffiths AM, Huynh H, Dieleman L, Panaccione R, Steinhart AH, Silverberg MS, Aumais G, Jacobson K, Mack D, Murthy S, Marshall JK, Bernstein CN, Abreu M, Moayyedi P, Xu W, Paterson AD, The CCC GEM Project Research Consortium, Croitoru K. Mediterranean-like dietary pattern associations with gut microbiome composition and sub-clinical gastrointestinal inflammation.Gastroenterology 2022; 163: 685-698.

Case-control studies have shown that patients with Crohn's disease have a microbial composition different from healthy individuals. Although the causes of Crohn's disease are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives of patients with Crohn's disease. As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy first-degree relatives of patients with Crohn's disease. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters. Results: DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota. Conclusions: Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.

Quan J, Ma C, Panaccione R, Hracs L, Sharifi N, Herauf M, Markovinovic A, Coward S, Windsor JW, Caplan L, Ingram RJM, Charlton C, Kanji JN, Tipples G, Holodinsky JK, Bernstein CN, Mahoney DJ, Bernatsky S, Benchimol EI, Kaplan GG and the STOP COVID-19 in IBD Research Group. Serological responses to the first four doses of SARS-CoV-2 vaccine in patients with inflammatory bowel disease. Lancet Gastroenterology and Hepatology 2022; 7:1077-1079.

Although serological response to SARS-CoV-2 may wane overtime, those who are immunocompromised may not mount or sustain an adequate immune response post-infection. A multicenter study in the United Kingdom demonstrated a diminished serological response to SARS-CoV-2 in individuals with IBD on TNF antagonists, but not on vedolizumab. We assessed the prevalence of antibodies to SARS-CoV-2 in those with IBD during the second wave of the pandemic in Canada and evaluated the presence of antibodies up to 10 months following diagnosis of COVID-19. Individuals with Crohn’s disease CD or ulcerative colitis were identified through a survey of gastroenterologists in Calgary, Alberta, Canada. Individuals with IBD were stratified into two cohorts: 1) Serosurveillance defined as those who were not previously diagnosed with COVID-19; and 2) COVID-19 recovered, defined as those with a confirmed diagnosis of SARS-CoV-2 infection. A positive antibody test was defined as an Index Signal/Cut-off (S/C) ≥ 1.4 as per manufacturer’s instructions. The assay has been validated with a 95% sensitivity and 100% specificity 12 days following symptom onset and correlates to neutralizing antibodies. We assessed the proportion of individuals with IBD who mounted an antibody response among those undergoing serosurveillance and among those following infection with SARS-CoV-2 from October 23, 2020 to March 17, 2021. Among individuals with IBD who recovered from COVID-19 infection, a logistic regression model assessed the effect of time from diagnosis to serology testing on nucleocapsid positivity adjusted for age, sex and anti-TNF use. Results In total, 230 individuals with IBD underwent serological assessment including 196 undergoing serosurveillance and 34 individuals with IBD recovered from known COVID-19. Two individuals tested positive for nucleocapsid antibody for a seropositivity of 1.03% (95% CI: 0.13 to 3.67). Among those who recovered from COVID-19, 52.9% (95% CI: 35.1 to 70.2) overall had a positive nucleocapsid antibody test. 51% of the serosurveillance cohort was on anti-TNF therapy compared to 62.8% of COVID-19 recovered patients (p>0.05). Among those who recovered from COVID-19, anti-TNF use was similar in those who were nucleocapsid antibody positive (66.7%) and negative (56.3%) (p>0.05). The proportion of patients who were nucleocapsid antibody positive fell from 76.9% (95% CI: 46.2, 95.0) at 0 to 59 days from diagnosis to 61.5% (95% CI: 31.6, 86.1) at 60 to 119 days. No patients were nucleocapsid antibody positive after 119 days. The likelihood of testing positive for nucleocapsid antibody was associated with time from diagnosis (Odds Ratio=0.97 per day; 95% CI: 0.95 to 0.99) after adjusting for age, sex, and anti-TNF use. An interactive dashboard displaying these data is here: Conclusions: These data have important clinical implications for individuals with IBD, particularly those who are immunocompromised. Serosurveillance studies in IBD are likely only reliable for a 2-3 month window of testing and may underestimate seroprevalence by up to a25% of the population. Moreover, 3 months after COVID-19 diagnosis, patients with IBD should be considered susceptible to SARS-CoV-2 even after recovering from infection. While early data suggest that patients with IBD have a robust serological response after completing mRNA vaccine series, our data highlight the importance of studying sustained antibody response over time in order to develop strategies to ensure durable protection and inform public health policy.

Kuenzig ME, Benchimol EI, Bernstein CN, Bitton A, Carroll MW, Griffiths AM, Kaplan GG, Nguyen GC, Otley AR, Stukel TA, Dummer TJB, El-Matary W, Jacobson K, Jones JL, Lix LM, Mack DR, Murthy SK, Peña-Sánchez JN, Targownik LE, Fung SG, Spruin S, Coward S, Cui Y, Filliter C, Nugent Z, Siddiq S, Singh H; Canadian Gastro-Intestinal Epidemiology Consortium (CanGIEC). Hospitalization with Clostridioides difficile in pediatric inflammatory bowel disease: a population-based study. Journal of Pediatric Gastroenterology and Nutrition 2022; 75: 173-180.

Several studies have demonstrated higher rates of Clostridioides difficile infection (CDI) in adults with inflammatory bowel disease (IBD). We conducted a population-based study comparing the risk of hospitalization with CDI in children with and without IBD.Using health administrative data and validated algorithms, we identified all children (less than 6 years) diagnosed with IBD in 5 Canadian provinces, then age and sex matched to 5 children without IBD). Province-specific 5-year incidence rates of hospitalization with CDI were pooled and generalized linear mixed-effects models were used to estimate the crude incidence rate ratio (IRR) comparing (1) children with and without IBD and (2) children with Crohn disease and ulcerative colitis. Hazard ratios (HR) from Cox proportional hazards models adjusting for age, sex, rural/urban household, and income were pooled using fixed-effects models. Results: The incidence rate of CDI identified during hospitalization was 49.06 [95% confidence interval (CI), 39.40–61.08] per 10,000 person-years (PY) in 3593 children with IBD compared to 0.39 (95% CI, 0.13–1.21) per 10,000 PY in 16,284 children without IBD (crude IRR, 133.4, 95% CI, 42.1–422.7; adjusted HR, 68.2, 95% CI, 24.4–190.4). CDI was identified less often in children with Crohn disease than ulcerative colitis (crude IRR, 0.51, 95% CI, 0.32–0.82; adjusted HR, 0.69, 95% CI, 0.46–1.05). Conclusions: Children with IBD have a markedly higher incidence of CDI identified during a hospitalization relative to children without IBD. Consequently, symptomatic children with IBD who are hospitalized

Ma C, Hanzel J, Panaccione R, Sandborn WJ, D’Haens GR, Ahuja V, Atreya R, Bernstein CN, Bossuyt P, Bressler B, Bryant RV, Cohen B, Colombel JF, Danese S, Dignass A, Dubinsky MC, Fleshner PR, Gearry RB, Hanauer SB, Hart A, Kotze PG, Kucharzik T, Lakatos PL, Leong RW, Magro F, Panes J, Peyrin-Biroulet L, Ran Z, Regueiro M, Singh S, Spinelli A, Steinhart AH, Travis SP, van der Woude CJ, Yacyshyn B, Yamamoto T, Allez M, Bemelman WA, Lightner AL, Louis E, Rubin DT, Scherl EJ, Siegel CA, Silverberg MS, Vermeire S, Parker CE, McFarlane SC, Guizzetti L, Smith MI, Vande Casteele N, Feagan BG, Jairath V. CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease. Gastroenterology 2022; 163: 950-964.

End points to determine the efficacy and safety of medical therapies for Crohn's disease and ulcerative colitis are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in IBD. Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. Results: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for ulcerative colitis. In Crohn’s disease, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In ulcerative colitis, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. Conclusions: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of Crohn’s disease and ulcerative colitis.

Leibovitzh H, Lee SH, Xue M, Raygoza Garay JA, Hernandez-Rocha C, Madsen KL, Meddings JB, Guttman DS, Espin-Garcia O, Smith M, Goethel M, Griffiths AM, Moayyedi P, Steinhart AH, Panancionne R, Huynh H, Jacobson K, Aumais G, Mack D, Abreu M, Bernstein CN, Marshall JK, Turner D, Xu W, Turpin W, Croitoru K, on behalf of the Crohn’s and Colitis Canada Genetics Environment Microbial Project Research Consortium. Altered gut microbiome composition and function are associated with gut barrier dysfunction in healthy relatives of patients with Crohn’s disease. Gastroenterology 2022; 163:1364-1376.

The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. We therefore aimed to assess whether alterations in gut microbial composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn's disease. Methods: We used the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn's disease. Gut barrier function was assessed using the urinary fractional excretion of lactulose-to-mannitol ratio (LMR). Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. The cohort was divided into a discovery cohort (n = 2472) and a validation cohort (n = 655). A regression model was used to assess microbial associations with the LMR. A random forest classifier algorithm was performed to assess microbial community contribution to barrier function. Results: Individuals with impaired barrier function (LMR >0.025) had reduced alpha-diversity (Chao1 index, P = 4.0e-4) and altered beta-diversity (Bray-Curtis dissimilarity index, R2 = 0.001, P = 1.0e-3) compared with individuals with an LMR ≤0.025. When taxa were assessed individually, we identified 8 genera and 52 microbial pathways associated with an LMR >0.025 (q < 0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and 8 pathways (including decreased biosynthesis of glutamate, tryptophan, and threonine) were replicated in the validation cohort. The random forest approach revealed that the bacterial community is associated with gut barrier function (area under the curve, 0.63; P = 1.4e-6). Conclusions: The gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier.

Hansen TM, Nugent Z, Bernstein CN, Murthy S, Sammader NJ, Singh H. Characteristics of colorectal cancer and use of colonoscopy before colorectal cancer diagnosis among individuals with inflammatory bowel disease: A population-based study. PLOS One 2022; 17:1-13.

There are limited recent data on the characteristics of IBD-associated colorectal cancer and the use of colonoscopy prior to colorectal cancer diagnosis among persons with IBD. We analyzed IBD-colorectal cancer characteristics, survival after IBD-colorectal cancer diagnosis and the use of colonoscopy prior to IBD-colorectal cancer diagnosis over time. We identified individuals with and without IBD from the University of Manitoba IBD Epidemiology Database and colorectal cancer from linkage to the Manitoba Cancer Registry. We compared characteristics of IBD-colorectal cancer and sporadic-colorectal cancer using logistic regression and survival after colorectal cancer diagnosis using Cox regression analysis. We assessed rate and predictors of colonoscopy use 5 years to 6 months prior to IBD-colorectal cancer. Results: 1,262 individuals with colorectal cancer were included (212 IBD-colorectal cancer). IBD was associated with an increased risk of death after colorectal cancer diagnosis in 2004-2011 (HR 1.89; 95% CI 1.25-2.88) but not in 2012-2017 (HR = 1.002; CI 0.50-2.03). In the 5 years to 6 months prior to IBD- colorectal cancer (1989-2018), 51% underwent colonoscopy, which was very similar to IBD without CRC and contrasted to 9% among sporadic colorectal cancers. Exposure to colonoscopy pre IBD-colorectal cancer remained stable through the study period (1989-2002 odds ratio = 1.25; CI 0.77-2.01; 2003-2011 odds ratio = 1.21; CI 0.56-1.70; reference 2012-2018). Exposure to colonoscopy pre-IBD- colorectal cancer was not associated with improved post- colorectal cancer survival. Conclusion: The risk of death following colorectal cancer diagnosis is not impacted by a diagnosis of IBD in recent years. There is a very high proportion of post colonoscopy colorectal cancer among IBD-colorectal cancer, which has not changed over the years and needs detailed root-cause analysis and interventions.

Buie M, Quan J, Windsor JW, Coward S, Hansen TM, King JA, Kotze PG, Gearry RB, Ng SC, Mak JWY, Abreu MT, Rubin DT, Bernstein CN, Banerjee R, Yamamoto-Furusho J, Panaccione R, Seow CH, Ma C, Underwood FE, Ahuja V, Pannaccione N, Shaeen AA, Holroyd-Leduc J, Kaplan GG, On Behalf of the GIVES-21 Consortia. Global Hospitalization Trends for Crohn’s Disease and Ulcerative Colitis in the 21 st Century: A Systematic Review with Temporal Analyses. Clinical Gastroenterology and Hepatology 2022; Jul 19:S1542-3565(22)00670-X.

The evolving epidemiologic patterns of IBD throughout the world, in conjunction with advances in therapeutic treatments, may influence hospitalization rates of IBD. We performed a systematic review with temporal analysis of hospitalization rates for IBD across the world in the 21st century. We systematically reviewed Medline and Embase for population-based studies reporting hospitalization rates for IBD, Crohn's disease, or ulcerative colitis in the 21st century. Log-linear models were used to calculate the average annual percentage change (AAPC) with associated 95% confidence intervals (95% CIs). Random-effects meta-analysis pooled country-level AAPCs. Data were stratified by the epidemiologic stage of a region: compounding prevalence (stage 3) in North America, Western Europe, and Oceania vs acceleration of incidence (stage 2) in Asia, Eastern Europe, and Latin America vs emergence (stage 1) in developing countries. Results: Hospitalization rates for a primary diagnosis of IBD were stable in countries in stage 3 (AAPC, -0.13%; 95% CI, -0.72 to 0.97), CD (AAPC, 0.20%; 95% CI, -1.78 to 2.17), and ulcerative colitis (AAPC, 0.02%; 95% CI, -0.91 to 0.94). In contrast, hospitalization rates for a primary diagnosis were increasing in countries in stage 2 for IBD (AAPC, 4.44%; 95% CI, 2.75 to 6.14), Crohn's disease (AAPC, 8.34%; 95% CI, 4.38 to 12.29), and ulcerative colitis (AAPC, 3.90; 95% CI, 1.29 to 6.52). No population-based studies were available for developing regions in stage 1 (emergence). Conclusions: Hospitalization rates for IBD are stabilizing in countries in stage 3, whereas newly industrialized countries in stage 2 have rapidly increasing hospitalization rates, contributing to an increasing burden on global health care systems.

Bernstein CN, Fisk JD, Walld R, Bolton JM, Sareen J, Patten SB, Singer A, Lix LM, Hitchon CA, El-Gabalawy R, Graff LA, Katz A, Marriott JJ, Marrie RA for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Use of Benzodiazepines and Z-Drugs in Inflammatory Bowel Disease. American Journal of Gastroenterology 2022; 117:2046-2054.

We estimated the incidence and prevalence of Z-drug use (typically used for sleep like zopiclone) and benzodiazepine (separately and jointly as BZD) in the IBD population compared to matched controls without IBD, and examined the association of mood/anxiety disorders with the use of BZD from 1997-2017. Using administrative data from Manitoba, Canada, we identified 5741 persons with incident IBD who were matched 1:5 to controls on sex, birth year and region. Validated case definitions were used to identify mood/anxiety disorders. Dispensations of BZD were identified. Multivariable generalized linear models were used to assess the association between IBD, mood/anxiety disorders and BZD use. Results: In 2016, the incident age/sex-standardized benzodiazepine use rates per 1000 were 28.06 (95%CI 26.41-29.81) in the IBD cohort and 16.83 in controls (95%CI16.28-17.39), [adjusted rate ratio (RR)=1.69 (95%CI 1.56-1.79)]. Benzodiazepine incidence rates were higher for females with IBD than males but the RR between cases and controls were similar for males and females. The incident age/sex standardized Z-drug use rates per 1000 were 21.07 (95%CI 19.69-22.41) in the IBD cohort. This was 1.87-fold higher than in controls (95%CI 1.73-2.01). In 2017 approximately 20% of persons with IBD used benzodiazepines and 20% used Z drugs. There was a sub-additive effect of both benzodiazepine and Z drug use between IBD and M/AD after adjusting for covariates (meaning that 20% +20% did not add to 40% since several patients were using both benzodiazepines and Z drugs). We concluded that the use of BZD is more common in people with IBD than in population controls. As these drugs are addictive strategies to reduce use of BZDs in persons with IBD and to offer alternative management strategies for mood/anxiety disorders, sleep disorders and other symptomatic concerns are needed.

El-Matary W, Witt J, Bernstein CN, Jacobson K, Mack D, Otley A, Walters TD, Huynh HQ, deBruyn J, Griffiths AM, Benchimol EI. Indirect and Out-Of-Pocket Disease-Associated Costs in Pediatric Inflammatory Bowel Disease: A Cross-Sectional Analysis. Journal of Pediatric Gastroenterology and Nutrition 2022; 75: 466-472.

Data on out of pocket (OOP) and indirect costs associated with paediatric IBD are limited. We aimed to estimate indirect and OOP costs associated with pediatric IBD in Canada. In a nation-wide cross-sectional analysis, caregivers of patients diagnosed with IBD (younger than 17y) were invited to complete a questionnaire on lost work hours and OOP costs related to IBD in the 4 weeks prior to the survey. Random participants were re-invited to answer the same questionnaire every 6-9 months for 2 years. Lost productivity was calculated using the Human Capital method and costs were reported in 2018 inflation-adjusted Canadian dollars. Predictors of high cost users (top 25%) were examined using negative binomial regression. Results: Overall, 243 of 262 (92.7%) patients completed the first survey with a total completion of 458 surveys. The median annual indirect costs per patient, using combined data from all surveys, were $5,951 (IQR $1,812- $12,278), with $5,776 (IQR $1,465-$11,733) for Crohn disease (CD) and $6,084 (IQR $2,470-$13,371) for ulcerative colitis (UC) (p = 0.77). The annual median per patient OOP costs, using all survey data, were $2,925 (IQR $978- $8,125) with $3,021 (IQR $978- $8,125) for CD and $2,600 (IQR $975- $8,125) for UC (p = 0.55). Older age at diagnosis (p=0.04) and parents in part-time employment (p=0.01) were predictors of higher indirect costs, while male patients (p<0.001), parents with a lower education level (p<0.001) and lower annual income (p<0.01) were associated with higher OOP costs. Conclusions: Indirect and OOP costs are substantial. More resources are needed particularly for those with lower family income.

Sazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B, Abreu MT, Ahmad T, Allez M, Ananthakrishnan AN, Atzmon G, Baras A, Barrett JC, Barzilai N, Beaugerie L, Beecham A, Bernstein CN, Bitton A, Bokemeyer B, Chung D, Cleynen I, Cosnes J, Cutler DJ, Daly A, Damas OM, Datta LM, Dawany N, Devoto M, Dodge S, Ellinghaus E, Fachal L, Farkkila M, Faubion W, Ferreira M, Franchimont D, Gabrie SB, Ge T, Georges M, Gettler K, Giri M, Glaser B, Goerg S, Goyette P, Graham D, Hämäläinen E, Haritunians T, Heap GA, Hiltunen M, Hoeppner M, Horowitz JE, Iyer IP, Jalas C, Kelsen J, Khalili H, Kirschner BS, Kontula K, Koskela JT, Kugathasan S J, Lamb CA, Laudes M, Lévesque C, Levine AP, Lewis JD, Liefferinckx C, Loescher BS, Louis E, Mansfield J, May S, McCauley JL, Mengesha E, Mni M, Moayyedi P, Moran CJ, Newberry RD, O’Charoen S, Okou DT, Oldenburg B, Ostrer H, Palotie A, Paquette J, Pekow J, Peter I, Pierik MJ, PonsioenCY, Pontikos N, Prescott N, Pulver AE, Rahmouni S, Daniel L. Rice DL, Saavalainen P, Sand B, Sartor RB, Schiff ER, Schreiber S, Schumm LP, Segal AW, Seksik P, Shawky R, Sheikh SZ, Silverberg M, Simmons A, Skeiceviciene J, Sokol H, Solomonson M, Somineni H, Sun D, Targan S, Turner D, Uhlig HH, van der Meulen AE, Vermeire S, VerstocktS, Voskuil MD, Winter HS, Young J, Duerr RH, Franke A, Brant SR, Cho J, Weersma RK, Parkes M, Xavier RJ, Rivas MA, Rioux JD, McGovern DPB, Huang H, Anderson CA, Daly MJ. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility. Nature Genetics 2022; 54: 1275-1283.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease. However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with Crohn's disease and 80,000 population controls. We directly implicate ten genes in general onset Crohn's disease for the first time to our knowledge via association to coding variation, four of which lie within established Crohn's disease GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in Crohn's disease cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in Crohn's disease pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

Kulyk A, Shafer LA, Graff LA, Stone J, Witges K, Targownik LE, Bernstein CN. Urgency for bowel movements is a highly discriminatory symptom for active disease in persons with IBD (the Manitoba Living with IBD study). Alimentary Pharmacology & Therapeutics 2022; 56:1570-80.

We aimed to assess the prevalence of symptoms, and examine which symptoms are most associated with disease activity as measured by a symptom index or an objective measure of inflammation. The Manitoba Living with IBD Study is a prospective study of 156 participants with confirmed IBD who completed bi-weekly Inflammatory Bowel Disease Symptom Inventory (IBDSI) surveys. Relative risks (RR), positive and negative predictive values (PPV, NPV) were reported for each symptom to predict active disease, independently defined as: (1) active IBDSI, (2) self-reported flare, and (3) elevated fecal calprotectin (FCAL, greater than 250ug/g). Analyses were undertaken following stratification based on sex, and disease type (Crohn’s disease, CD ulcerative colitis, UC). Results: 69.2% of participants were female; 64.7% had CD. Fatigue was the most prevalent symptom in both inactive and active disease, respectively, across all 3 disease measures (IBDSI: 24.5% and 75.1%, self-reported flare: 42.2% and 72.2%, FCAL: 46.0% and 60.6%). Absence of fatigue had a high NPV for active IBDSI in both CD and UC. Urgency had a strong NPV and PPV across all three disease measures in both CD and UC and females and males. Number of loose/liquid bowel movements predicted elevated FCAL in UC males and females. In CD, excessive bowel gas and urgency predicted increased FCAL in males. No symptom significantly predicted FCAL in females with CD. Conclusions: Fatigue was the most prevalent symptom irrespective of disease activity measure. Individual symptoms have different impacts on whether IBDSI (subjective measure) or FCAL (objective measure) is increased in IBD.

Eckenberger J, Butler J, Bernstein CN, Shanahan F, Claesson M. Interactions between medications and the gut microbiome in inflammatory bowel disease. Microorganisms 2022; 10:1-18.

In view of the increasing evidence that commonly prescribed, non-antibiotic drugs interact with the gut microbiome, we re-examined the microbiota variance in inflammatory bowel disease (IBD) to determine the degree to which medication and supplement intake might account for compositional differences between disease-subtypes and geographic location. We assessed the confounding effects of various treatments on the faecal microbiota composition (16S rRNA gene sequencing) in persons with Crohn’s disease (n=188) or ulcerative colitis (n = 161) from either Cork (Ireland) or Manitoba (Canada) sampled at 3 time points. We confirmed the overall trends of significant differences of microbial composition and diversity across IBD-subtypes and geographic locations from our previous study. Treatments explained more microbiota variance than all other factors combined and more than half of the tested medications and supplements showed significant associations with at least one taxon in the gut microbiota. The medication profiles between patients with Crohn’s disease and ulcerative colitis and from different countries varied in number and type of drugs taken. While treatments accounted for a relatively small proportion of the geographic contribution to microbiome variance between Irish and Canadian patients, additive effects from multiple medications contributed significantly to microbiome differences between Crohn’s disease and ulcerative colitis.

Stone JK, Shafer LA, Graff LA, Witges K, Lix L, Sexton KA, Haviva C, Targownik LE, Bernstein CN. The association of efficacy, optimism, uncertainty and health anxiety with inflammatory bowel disease activity. Journal of Psychosomatic Research 2022; Mar; 154: 110719.

Positive and negative psychological attributes have been shown to influence disease outcomes in many chronic health conditions. We aimed to evaluate the association between self-efficacy, optimism, health anxiety and intolerance of uncertainty and disease activity in IBD. Adults with confirmed and recently active IBD enrolled in a prospective cohort study. Demographics, disease information, validated measures of psychological functioning related to general self-efficacy, optimism, health anxiety and intolerance of uncertainty were collected at baseline, week 26 and week 52. Clinical disease activity was assessed using the Inflammatory Bowel Disease Symptom Inventory (IBDSI), self-reported flares, and intestinal inflammation using fecal calprotectin (FCAL), collected at baseline, weeks 26 and 52. Generalized estimating equations were used to test the association between psychological functioning and disease activity. Results: 154 participants mean age was 43.4 years (SD 12.5), 69.5% were women and 64.1% had Crohn’s disease. Adjusting for demographic variables, higher self-efficacy was associated with a 20% lower likelihood of flare by self-report (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.71,0.91) and 11% by IBDSI (OR 0.89, 95%CI 0.80,0.99), while higher health anxiety was associated with a slightly greater likelihood of flare by self-report (OR 1.07, 95% CI 1.01,1.18) and higher symptomatic disease activity (IBDSI; OR 1.14, 95% CI 1.05,1.24). The psychological attributes were not significantly associated with active disease as measured by inflammation (FCAL). Conclusion: General self-efficacy and health anxiety are relevant in understanding patient experience with disease activity, and may be appropriate targets for psychological intervention in the care of individuals with IBD.

Mirza AI, Zhu F, Knox N, Forbes JD, Bonner C, Van Domselaar G, Bernstein CN, Graham M, Marrie RA, Hart J, Yeh EA, Arnold DL, Bar-Or A, O’Mahony J, Zhao Y, Hsiao W, Banwell B, Waubant E, Tremlett H. The metabolic potential of the paediatric-onset multiple sclerosis gut microbiome. Multiple Sclerosis and Related Disorders 2022; Jul 63: 103829.

The aim of this study was to examine the gut microbiome's metabolic potential in paediatric-onset multiple sclerosis patients (symptom onset <18 years). We included 17 multiple sclerosis participants and 20 controls similar for sex, age, race, and stool consistency from the Canadian Paediatric Demyelinating Disease Network study. Stool-derived gut metagenome gene abundances were used to estimate relative abundances and turnover scores of individual microbial metabolites and the composition and diversity of carbohydrate-active enzymes (CAZymes). Multiple sclerosis participants and controls were compared using the Wilcoxon rank-sum test, as were the disease-modifying drug exposed and naïve multiple sclerosis participants. Results: The median age(s) at multiple sclerosis symptom onset=16.1 years (interquartile range [IQR]=1.7), and at stool sample procurement=16.9/15.8 years (IQR=2.0/1.4), for the multiple sclerosis participants/controls. Most multiple sclerosis and control participants were girls (80-82%). Five (29%) of the multiple sclerosis participants had never been exposed to a disease-modifying drug pre-stool sample and 12 (71%) had (7 to beta-interferon and 5 glatiramer acetate). While the relative abundance of metabolites did not differ between multiple sclerosis participants and controls, turnover scores did. Multiple sclerosis participants had a greater potential to metabolize lipopolysaccharides than controls (score difference=1.6E-04, p = 0.034) but lower potential to metabolize peptidoglycan molecules and starch (score differences<2.2E-02, p<0.040). Further, although CAZymes diversity did not differ (p>0.050), starch-degrading subfamilies were underrepresented in MS participants versus controls (relative abundance differences >-0.34, p<0.040) and in the disease-modifying drug exposed verses disease-modifying drug naïve multiple sclerosis participants (relative abundance differences>-0.20, p<0.049). Conclusion: Paediatric-onset multiple sclerosis participants had an altered gut microbiome-related metabolic potential compared to controls, including higher breakdown of lipopolysaccharide molecules, but lower resistant starch

metabolism.

Singh N, Bernstein CN. Environmental Risk Factors for Inflammatory Bowel Disease (IBD). United European Gastroenterology Journal 2022 Dec;10(10):1047-1053.

IBD is a chronic, progressive immune-mediated inflammatory condition of the gastrointestinal tract. Environmental risk factors play a role in developing either type of IBD, Crohn’s disease and ulcerative colitis; although the exact mechanism is still unknown. Herein, we review environmental risks from early life exposures, lifestyle and hygiene, vaccinations, surgeries, exposure to drugs and gastrointestinal pathogens that may increase the risk of developing IBD.

Venner JM, Bernstein CN. Immunomodulators: Still having a role? Gastroenterology Reports (Oxf). 2022 Nov 8:10.

Immunomodulators, particularly the thiopurines and to a lesser extent methotrexate, were standard-of-care for inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, for over 40 years. While there has been a renaissance in available therapies with the advent of biologics and small molecules, an impetus remains for the ongoing use of thiopurines and methotrexate. This is particularly true for the maintenance of remission and when used in combination therapy with infliximab to suppress anti-biologic antibodies. This article summarizes the data behind immunomodulator use in Crohn’s disease, focusing on the beneficial role these drugs still have while acknowledging their clinical limitations.

Publications // from the Manitoba IBD Epidemiology Database