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Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown aetiology affecting the colon and rectum. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been suggested to contribute to UC pathogenesis. UC has evolved into a global burden given its high incidence in developed countries and the substantial increase in incidence in developing countries. An improved understanding of the mechanisms underlying UC has led to the emergence of new treatments. Since the early 2000s, anti-tumour necrosis factor (TNF) treatment has significantly improved treatment outcomes. Advances in medical treatments have enabled a paradigm shift in treatment goals from symptomatic relief to endoscopic and histological healing to achieve better long-term outcomes and, consequently, diagnostic modalities have also been improved to monitor disease activity more tightly. Despite these improvements in patient care, a substantial proportion of patients, for example, those who are refractory to medical treatment or those who develop colitis-associated colorectal dysplasia or cancer, still require restorative proctocolectomy. The development of novel drugs and improvement of the treatment strategy by implementing personalized medicine are warranted to achieve optimal disease control. However, delineating the aetiology of UC is necessary to ultimately achieve disease cure. Ulcerative colitis is a chronic inflammatory bowel disease affecting the rectum and the colon. This Primer describes the epidemiology, the current understanding of ulcerative colitis pathophysiology and its diagnosis. In addition, Hibi and colleagues highlight the current and emerging therapeutic strategies and discuss the most pressing questions in the field.

In a population-based inflammatory bowel disease (IBD) cohort, we aimed to determine whether having lower socioeconomic status (LSS) impacted on outcomes. We identified all 9,298 Manitoba residents with IBD from April 1, 1995, to March 31, 2018 by applying a validated case definition to the Manitoba Health administrative database. We could identify all outpatient physician visits, hospitalizations, surgeries, intensive care unit admissions, and prescription medications. Their data were linked with 2 Manitoba databases, one identifying all persons who received Employment and Income Assistance and another identifying all persons with Child and Family Services contact. Area-level socioeconomic status was defined by a factor score incorporating average household income, single parent households, unemployment rate, and high school education rate. LSS was identified by any of ever being registered for Employment and Income Assistance or with Child and Family Services or being in the lowest area-level socioeconomic status quintile. Comparing persons with LSS vs those without any markers of LSS, there were increased rates of annual outpatient physician visits (relative risk [RR] = 1.10, 95% confidence interval [CI] = 1.06-1.13), hospitalizations (RR = 1.38, 95% CI = 1.31-1.44), intensive care unit admission (RR = 1.94, 95% CI = 1.65-2.27), use of corticosteroids >2,000 mg/yr (RR = 1.12, 95% CI = 1.03-1.21), and death (hazard ratio 1.53, 95% CI = 1.36-1.73). Narcotics (RR = 2.17, 95% CI = 2.01-2.34) and psychotropic medication use (RR = 1.98, 95% CI = 1.84-2.13) were increased. The impact of LSS was greater for those with Crohn's disease than for those with ulcerative colitis. LSS was associated with worse outcomes in persons with IBD. Social determinants of health at time of diagnosis should be highly considered and addressed.

Venous thromboembolism (VTE) is known to be increased in inflammatory bowel disease (IBD). We aimed to determine whether rates of VTE in IBD have reduced over the past 30 years. We used the population-based University of Manitoba IBD Epidemiology Database (1984-2018) to determine the incidence of VTE in IBD and the incidence rate ratio vs matched controls. In persons with IBD with and without VTE, we assessed for variables that were associated with an increased risk of VTE on multivariate logistic regression. The incidence of VTE in the IBD cohort was 7.6% which was significantly greater than in controls (3.3%, P < 0.0001). The overall age-standardized incidence rate of VTE was 433 per 100,000 in IBD and 184 per 100,000 in controls. The incidence of VTE was higher in Crohn's disease (8.4%) than in ulcerative colitis (6.9%, P = 0.0028). The incidence rate ratio in IBD vs controls was 2.36 (95% confidence interval 2.16-2.58). The increased risk was similar in males and females and in Crohn's disease compared with ulcerative colitis. The incidence rate among persons with IBD from 1985 to 2018 decreased very slowly, with annual percent change of -0.7% (P = 0.0003). Hospital admission, high comorbidity, use of antibodies to tumor necrosis factor for less than 3 years up until the time of the VTE, and the combination of steroid and antibodies to tumor necrosis factor increased the risk of VTE. Despite advancements in IBD management in the past 30 years, the rates of VTE have only been slowly decreasing and remain significantly increased compared with controls.

Abstract Brackground We aimed to examine associations between elevated symptoms of depression and anxiety and disease activity in inflammatory bowel disease (IBD). Previous findings have been inconsistent and have not accounted for variability in the courses of these conditions over time. Methods We followed 247 participants with IBD (153 Crohn’s disease [CD], 94 ulcerative colitis [UC]) for 3 years. Annually, participants underwent an abdominal examination, reported therapies used for IBD, and completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. We evaluated associations of elevated symptoms (scores ≥11) of anxiety (HADS-A) and depression (HADS-D) with the presence of active IBD as measured using the Powell Tuck Index for UC and the Harvey-Bradshaw Disease Activity Index for CD. We employed logistic regression with generalized estimating equations, simultaneously estimating between-person and within-person effects. Results Of 247 participants, 15 (6.1%) had elevated symptoms of depression (HADS-D ≥11) at enrollment, 41 (16.6%) had elevated symptoms of anxiety (HADS-A ≥11), and 101 (40.9%) had active IBD. On average, individuals with elevated symptoms of depression (odds ratio [OR], 6.27; 95% CI, 1.39–28.2) and anxiety (OR, 2.17; 95% CI, 1.01–4.66) had increased odds of active IBD. Within individuals, elevations in symptoms of depression over time were associated with increased odds of active IBD (OR, 2.70; 95% CI, 1.15–6.34), but elevated symptoms of anxiety were not. After adjustment for covariates (including disease activity), elevated symptoms of depression were also associated with increased odds of biologic therapy use (OR, 2.02; 95% CI, 1.02–4.00). Conclusion Symptoms of depression and anxiety are associated with disease activity in IBD over time. Reducing these symptoms should be incorporated into the management of IBD.

Previous studies have reported colectomy rates of over 50% in ulcerative colitis (UC), although changes in management may have influenced the rates of colectomy in the modern era. We sought to determine the incidence of colectomy in UC and identify risk factors associated with early colectomy (EC) and late colectomy (LC). We used the University of Manitoba Inflammatory Bowel Disease Epidemiology Database, a population-based data set including UC patients with up to 25 years of post diagnosis follow-up. We tracked the occurrence of total colectomy in all patients with known UC, subdivided into EC (≤90 days from diagnosis date) and LC (>90 days from diagnosis). Survival curves were created and stratified by age, sex, era of diagnosis, and inpatient/hospital diagnosis. Cox proportional hazards modeling was used to determine which risk factors were predictive of either EC or LC. Among 3,752 patients with UC, 367 underwent colectomy. The 5-, 10- and 20-year actuarial risk of requiring colectomy was 7.5%, 10.4%, and 14.8%, respectively. Male sex (hazard ratio (HR): 2.63, [corrected] 95% confidence interval (CI): 1.58-4.36) and being initially diagnosed during a hospitalization (HR: 12.46, 95% CI: 7.40-21.0) were predictive of EC after adjustment for confounders. In-hospital diagnosis was predictive of LC, whereas being diagnosed more recently was protective against LC (HR: 0.96, 95% CI: 0.93-0.98). The cumulative incidence of colectomy in UC is lower than previously reported, and appears to be decreasing further among more recently diagnosed cohorts of patients. Male sex and hospitalization at the time of diagnosis are major risk factors for EC and LC.

The development of commensal flora in infants has been shown to be sensitive to antibiotic use. Altered intestinal flora is thought to contribute to the etiology of inflammatory bowel disease (IBD), an idiopathic chronic condition. We aimed to determine if early use of antibiotics was associated with the development of IBD in childhood. Nested case-control analysis of the population-based University of Manitoba Inflammatory Bowel Disease Epidemiologic Database was carried out. IBD status was determined from a validated administrative database definition. A total of 36 subjects diagnosed between 1996 and 2008 were matched to 360 controls, on the basis of age, sex, and geographic region. Antibiotic data were drawn from the Manitoba Drug Program Information Network, a comprehensive population-based database of all prescription drugs for all Manitobans dating back to 1995. Antibiotic use in the first year of life was compared between IBD cases and controls. The mean age at IBD diagnosis was 8.4 years. Twenty-one cases (58%) had one or more antibiotic dispensations in their first year of life compared with 39% of controls. Crohn's disease was diagnosed in 75% of IBD cases. Those receiving one or more dispensations of antibiotics were at 2.9 times the odds (95% confidence interval: 1.2, 7.0) of being an IBD case. Subjects diagnosed with IBD in childhood are more likely to have used antibiotics in their first year of life.

Background We compared risks of nonmelanoma skin cancers (NMSCs) and melanoma preceding and following a diagnosis of inflammatory bowel disease (IBD) and to evaluate the effect of thiopurines and anti-tumor necrosis factor α (anti-TNF-α) on skin cancer risk in IBD. Methods This was a retrospective, historical cohort study using the population-based University of Manitoba IBD Epidemiology Database (11 228 IBD cases and 104 725 matched controls) linked to the Manitoba Cancer Registry. Logistic and Cox regression analyses were performed to calculate skin cancer risks prior to and after IBD diagnosis. Results Persons with ulcerative colitis (UC) were more likely to have basal cell carcinoma (BCC) predating their UC diagnosis (odds ratio, 1.32; 95% confidence interval [CI], 1.08-1.60). Risks of squamous cell carcinoma (SCC), other NMSCs, or melanoma prior to IBD diagnosis were not significantly increased. Post-IBD diagnosis, risks of BCC (hazard ratio, 1.53; 95% CI, 1.37-1.70) and SCC (hazard ratio, 1.61; 95% CI, 1.29-2.01) were significantly increased across all IBD groups except for SCC in UC. There was no significant association between melanoma and IBD post–IBD diagnosis. The risks of BCC and melanoma were increased in thiopurine and anti-TNF users, and risk of SCC was increased in only thiopurine users. Nested cohort analysis of persons with IBD with censoring at both thiopurines and anti-TNF use confirmed a higher baseline risk of BCC and no effect on SCC, comparable to pre-IBD diagnosis findings. Conclusions The risk of BCC preceding a diagnosis of UC is higher than in non-UC controls, compared with a generally increased risk of all NMSCs post–IBD diagnosis. Thiopurine and anti-TNF therapy increase the risks for skin cancers in persons with IBD after their diagnoses. Lay Summary The risk of basal cell carcinoma preceding a diagnosis of ulcerative colitis is higher than in non–inflammatory bowel disease (IBD) controls, compared with a generally increased risk of all nonmelanoma skin cancers post–IBD diagnosis. There was no significant association between melanoma and IBD post–IBD diagnosis. Anti-tumor necrosis factor therapy increase the risks for melanoma and both anti-tumor necrosis factor and thiopurine therapies increase the risk for nonmelanoma skin cancers in persons with IBD after their diagnoses.

Background Immune-mediated inflammatory disease (IMID) represents a substantial health concern. It is widely recognized that IMID patients are at a higher risk for developing secondary inflammation-related conditions. While an ambiguous etiology is common to all IMIDs, in recent years, considerable knowledge has emerged regarding the plausible role of the gut microbiome in IMIDs. This study used 16S rRNA gene amplicon sequencing to compare the gut microbiota of patients with Crohn’s disease (CD; N  = 20), ulcerative colitis (UC; N  = 19), multiple sclerosis (MS; N = 19), and rheumatoid arthritis (RA; N  = 21) versus healthy controls (HC; N  = 23). Biological replicates were collected from participants within a 2-month interval. This study aimed to identify common (or unique) taxonomic biomarkers of IMIDs using both differential abundance testing and a machine learning approach. Results Significant microbial community differences between cohorts were observed (pseudo F  = 4.56; p  = 0.01). Richness and diversity were significantly different between cohorts (pFDR < 0.001) and were lowest in CD while highest in HC. Abundances of Actinomyces , Eggerthella, Clostridium III , Faecalicoccus , and Streptococcus (pFDR < 0.001) were significantly higher in all disease cohorts relative to HC, whereas significantly lower abundances were observed for Gemmiger , Lachnospira , and Sporobacter (pFDR < 0.001). Several taxa were found to be differentially abundant in IMIDs versus HC including significantly higher abundances of Intestinibacter in CD, Bifidobacterium in UC, and unclassified Erysipelotrichaceae in MS and significantly lower abundances of Coprococcus in CD, Dialister in MS, and Roseburia in RA. A machine learning approach to classify disease versus HC was highest for CD (AUC = 0.93 and AUC = 0.95 for OTU and genus features, respectively) followed by MS, RA, and UC. Gemmiger and Faecalicoccus were identified as important features for classification of subjects to CD and HC. In general, features identified by differential abundance testing were consistent with machine learning feature importance. Conclusions This study identified several gut microbial taxa with differential abundance patterns common to IMIDs. We also found differentially abundant taxa between IMIDs. These taxa may serve as biomarkers for the detection and diagnosis of IMIDs and suggest there may be a common component to IMID etiology.

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

While there has been a great deal of speculation over the years on the importance of emotional factors in inflammatory bowel disease (IBD), it is only in the last decade or so that studies with stronger designs have been available to clarify the nature of this relationship. This review considers recent evidence on the prevalence of anxiety and depressive disorders in IBD, the role of these disorders as a risk factor for IBD onset, the degree to which they affect the course of the IBD, and the contribution of corticosteroid treatment to psychiatric symptom onset. There is evidence that anxiety and depression are more common in patients with IBD and that the symptoms of these conditions are more severe during periods of active disease. The few studies that address the issue of anxiety and depression as risk factors for IBD do not yet provide enough information to support definite conclusions. There is evidence, however, that the course of the disease is worse in depressed patients. Treatment with corticosteroids can induce mood disorders or other psychiatric symptoms. The second part of the review focuses on patient management issues for those with comorbid anxiety or depression. Practical approaches to screening are discussed, and are recommended for routine use in the IBD clinic, especially during periods of active disease. We review evidence-based pharmacological and psychological treatments for anxiety and depression and discuss practical considerations in treating these conditions in the context of IBD to facilitate overall management of the IBD patient.