Comparative Outcomes and Safety of Vedolizumab vs Tumor Necrosis Factor Antagonists for Older Adults With Inflammatory Bowel Diseases

IMPORTANCE: Observational comparative effectiveness studies can inform the positioning of biologic therapies for older patients with inflammatory bowel disease (IBD) who are underrepresented in clinical trials. OBJECTIVE: To compare the effectiveness and safety of vedolizumab vs tumor necrosis factor (TNF) for older patients with IBD. DESIGN, SETTING, AND PARTICIPANTS: This active comparator, new-user design, comparative effectiveness study was conducted between January 1, 2005, and December 31, 2018, among 754 older patients (aged ≥50 years) with IBD from the Danish National Patient Register. The mean follow-up after treatment initiation took place at 32 to 40 weeks. Statistical analysis was performed from February 1 to April 27, 2022. INTERVENTIONS: Treatment with vedolizumab or TNF antagonists. MAIN OUTCOMES AND MEASURES: The primary effectiveness outcome was treatment failure, defined as the composite risk of IBD-related hospitalization, IBD-related surgery, or a new corticosteroid prescription more than 6 weeks after initiation of treatment with biologic therapy. Secondary effectiveness outcomes were time to each individual component of the composite effectiveness outcome. The primary safety outcome was the risk of serious infections, defined as infections requiring hospitalization. A 1:1 propensity score–matched analysis was conducted, accounting for patient-, disease-, and treatment-associated factors. RESULTS: The study compared 377 older patients with IBD with incident use of vedolizumab (202 women [53.6%]; mean [SD] age, 61.2 [8.3] years; 177 [46.9%] with Crohn disease) vs 377 patients with incident use of TNF antagonists (206 women [54.6%]; mean [SD] age, 61.3 [8.1] years; 182 [48.3%] with Crohn disease). Overall, vedolizumab was associated with an increased risk of treatment failure compared with TNF antagonists (1-year risk, 45.4% vs 34.7%; adjusted hazard ratio [HR], 1.31; 95% CI, 1.02-1.69), including higher risk of IBD-related hospitalization (1-year risk, 27.8% vs 16.3%; adjusted HR, 1.48; 95% CI, 1.03-2.15) and IBD-related major abdominal surgery (1-year risk, 21.3% vs 8.0%; adjusted HR, 2.39; 95% CI, 1.45-3.94). In subgroup analysis by IBD phenotype, among patients with Crohn disease, vedolizumab was associated with a 77% higher risk of treatment failure (adjusted HR, 1.77; 95% CI, 1.21-2.58), while no difference in risk of treatment failure was seen among patients with ulcerative colitis (adjusted HR, 1.04; 95% CI, 0.75-1.43; P = .03 for interaction). There was no significant difference in the risk of serious infections, overall (1-year risk, 8.2% vs 8.7%; adjusted HR, 1.04; 95% CI, 0.58-1.85) and by IBD phenotype. CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study of older patients with IBD, vedolizumab was associated with a higher risk of treatment failure compared with TNF antagonists, particularly among patients with Crohn disease, without offering a significant safety advantage

Characterizing the pre-clinical phase of inflammatory bowel disease

Understanding the biological changes that precede a diagnosis of inflammatory bowel disease (IBD) could facilitate pre-emptive interventions, including risk factor modification, but this pre-clinical phase of disease remains poorly characterized. Using measurements from 17 hematological and biochemical parameters taken up to 10 years before diagnosis in over 20,000 IBD patients and population controls, we address this at massive scale. We observe widespread significant changes in multiple biochemical and hematological parameters that occur up to 8 years before diagnosis of Crohn's disease (CD) and up to 3 years before diagnosis of ulcerative colitis. These changes far exceed previous expectations regarding the length of this pre-diagnostic phase, revealing an opportunity for earlier intervention, especially in CD. In summary, using a nationwide, case-control dataset-obtained from the Danish registers-we provide a comprehensive characterization of the hematological and biochemical changes that occur in the pre-clinical phase of IBD.</p

Alterations in fecal microbiota composition by probiotic supplementation in healthy adults:a systematic review of randomized controlled trials

BACKGROUND: The effects of probiotic supplementation on fecal microbiota composition in healthy adults have not been well established. We aimed to provide a systematic review of the potential evidence for an effect of probiotic supplementation on the composition of human fecal microbiota as assessed by high-throughput molecular approaches in randomized controlled trials (RCTs) of healthy adults. METHODS: The survey of peer-reviewed papers was performed on 17 August 2015 by a literature search through PubMed, SCOPUS, and ISI Web of Science. Additional papers were identified by checking references of relevant papers. Search terms included healthy adult, probiotic, bifidobacterium, lactobacillus, gut microbiota, fecal microbiota, intestinal microbiota, intervention, and (clinical) trial. RCTs of solely probiotic supplementation and placebo in healthy adults that examined alteration in composition of overall fecal microbiota structure assessed by shotgun metagenomic sequencing, 16S ribosomal RNA sequencing, or phylogenetic microarray methods were included. Independent collection and quality assessment of studies were performed by two authors using predefined criteria including methodological quality assessment of reports of the clinical trials based on revised tools from PRISMA/Cochrane and by the Jadad score. RESULTS: Seven RCTs investigating the effect of probiotic supplementation on fecal microbiota in healthy adults were identified and included in the present systematic review. The quality of the studies was assessed as medium to high. Still, no effects were observed on the fecal microbiota composition in terms of α-diversity, richness, or evenness in any of the included studies when compared to placebo. Only one study found that probiotic supplementation significantly modified the overall structure of the fecal bacterial community in terms of β-diversity when compared to placebo. CONCLUSIONS: This systematic review of the pertinent literature demonstrates a lack of evidence for an impact of probiotics on fecal microbiota composition in healthy adults. Future studies would benefit from pre-specifying the primary outcome and transparently reporting the results including effect sizes, confidence intervals, and P values as well as providing a clear distinction of between-group and within-group comparisons

Development of Cancer Among Patients With Pediatric-Onset Inflammatory Bowel Disease:A Meta-analysis of Population-Based Studies

IMPORTANCE: Because the incidence of pediatric-onset inflammatory bowel disease (IBD) is increasing, knowledge of the long-term risk of cancer in this patient population is required. OBJECTIVE: To evaluate the relative rate of cancer among patients with pediatric-onset IBD. DATA SOURCES: A comprehensive systematic search was performed of MEDLINE and Embase from the date of database inception to October 31, 2021. STUDY SELECTION: All unselected, population-based cohort studies of pediatric-onset IBD assessing the risk of cancer were included. Tertiary center referrals and insurance database studies were excluded. All articles were assessed by 2 independent reviewers. DATA EXTRACTION AND SYNTHESIS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline for data extraction and used the Newcastle-Ottawa Scale for assessment of the risk of bias and the quality of included articles. MAIN OUTCOMES AND MEASURES: A random-effects model meta-analysis was conducted of included studies using the inverse-variance method to assess the relative rate of cancer overall and by IBD subtype (Crohn disease or ulcerative colitis), sex, and thiopurine exposure among patients with pediatric-onset IBD. Pooled relative rates (pRRs) along with 95% CIs were calculated for combined studies. RESULTS: Of 4628 articles screened, 5 population-based studies from North America and Europe were eligible for inclusion. These studies comprised 19 812 individuals with pediatric-onset IBD followed up for 283 540 person-years in which 715 cases of cancer were identified. Meta-analysis of pRR estimates showed a 2.4-fold increased rate of cancer among patients with pediatric-onset IBD (pRR, 2.46; 95% CI, 2.06-2.93), seen among patients with Crohn disease (pRR, 2.03; 95% CI, 1.67-2.46) and those with ulcerative colitis (pRR, 2.61; 95% CI, 2.00-3.40). This increased rate is primarily due to an increased rate of liver (pRR, 55.45; 95% CI, 19.59-156.99), colorectal (pRR, 20.29; 95% CI, 15.90-25.90), and small bowel (pRR, 16.20; 95% CI, 3.52-74.66) cancers. The incidence rate of cancer among patients with pediatric-onset IBD was reported by 4 studies and ranged from 1.0 to 3.3 cases per 1000 person-years. CONCLUSIONS AND RELEVANCE: This meta-analysis of unselected, population-based studies showed a greater than 2-fold increased rate of cancer among patients with pediatric-onset IBD compared with the general pediatric populations, primarily owing to an increased rate of gastrointestinal cancers

Eosinophilic oesophagitis in Denmark:Population-based incidence and prevalence in a nationwide study from 2008 to 2018

BACKGROUND: Eosinophilic oesophagitis (EoE) is a chronic immune‐mediated or antigen‐mediated oesophageal disease characterised by symptoms related to oesophageal dysfunction and eosinophil‐predominant inflammation. OBJECTIVE: We aimed to estimate the incidence and prevalence of EoE in Denmark during the period 2008–2018. METHODS: Based on data from nationwide registers we identified cases of EoE using two definitions: a broad definition based solely on oesophageal biopsies registered in the Danish Pathology Register and a narrow definition also including symptoms of oesophageal dysfunction registered in the Danish National Patient Registry. The annual incidence and prevalence were standardised by sex and age in 5‐year intervals to the 2013 study population. RESULTS: From 2008 to 2011, the standardised incidence of EoE was stable, but from 2011 to 2018 it increased from 3.9 (95% CI 3.3–4.4) to 11.7 (95% CI 10.8–12.6) per 100,000 person‐years. Similar temporal trends were observed when using the narrow EoE definition. The increase in incidence was most pronounced in men and in individuals above 40 years of age. In children, the EoE incidence was a fourth of the incidence in adults aged 40–64 years: 4.4 (95% CI 3.2–5.6) versus 17.6 (95% CI 15.7–19.5) per 100,000 person‐years. The EoE incidence varied substantially across the five regions in Denmark. Overall, the biopsy rate as well as the proportion of oesophageal biopsies with detected eosinophilia increased during the study period. CONCLUSION: This study of the entire population of Denmark during the period 2008 to 2018 shows that the incidence and prevalence of EoE is not yet plateauing and that EoE could be severely underdiagnosed, especially in children

Development of Inflammatory Bowel Disease in HIV Patients:A Danish Cohort Study (1983-2018) With American Validation (1999-2018)

BACKGROUND AND AIMS: Human immunodeficiency virus (HIV) infection is associated with several immune-mediated disorders. However, the risk of inflammatory bowel disease (IBD) in people living with HIV (PLWH) remains unclear. We aimed to assess the risk of IBD among PLWH using a nationwide, population-based Danish cohort and to validate findings in a large American insurance-based database. METHODS: Using Danish registries (1983–2018), we identified 8995 PLWH and age- and sex-matched them to 449,750 HIV-negative individuals. Cox regression analysis was undertaken to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for IBD diagnosis. Results were stratified by sex, age, and year of HIV diagnosis. Using an American insurance-based cohort, Explorys (1999–2018), we assessed the prevalence odds ratio (OR) and 95% CI of IBD diagnosis in PLWH compared with HIV-negative individuals. RESULTS: IBD diagnosis among PLWH in Denmark was increased (HR: 2.25, 95% CI: 1.78–2.83) compared with matched HIV-negative individuals. This was seen for both Crohn’s disease (HR: 2.25, 95% CI: 1.47–3.44) and ulcerative colitis (HR: 2.24, 95% CI: 1.70–2.96) and in male (HR: 2.75, 95% CI: 2.15–3.52) but not female (HR: 0.93, 95% CI: 0.48–1.79) PLWH. Explorys analysis also showed an increased odds of IBD diagnoses among PLWH (OR: 1.41; 95% CI: 1.35–1.49). CONCLUSION: This study finds an increased risk of IBD diagnosis among PLWH in both a Danish and US cohort, highlighting a need to consider IBD in PLWH with new-onset gastrointestinal symptoms. Further research into the role of antiretroviral therapy in this relationship is required