Background and Aims We conducted a retrospective cohort study comparing the risk of cancer in patients with inflammatory bowel diseases (IBD) initiating advanced therapies (ATs). Methods Using an administrative claims database (OptumLabs® Data Warehouse), we identified patients with IBD with no prior history of cancer, who initiated TNF antagonists, vedolizumab, anti-interleukins or JAK inhibitors between 2016 and 2023 and had insurance coverage for at least 1y before and after treatment initiation. We compared risk of overall cancer (except non-melanoma skin cancer) across different ATs occurring at least 3 months after treatment initiation. Groups were balanced through multinomial propensity score-based inverse probability weighting. We calculated cause-specific hazard ratios (HR) and 95% CI. Results Of 15,687 patients with IBD starting an AT (45±17 years, 52% female, 76% Whites, 14% with obesity) and followed over median 2.6y, 273 developed cancer. The 3-year cumulative incidence of cancer was similar across all agents: TNF antagonists (n=8031), 2.1% (95% CI, 1.7-2.5), vedolizumab (n=3985), 2.7% (95% CI, 2.1-3.3), anti-interleukins (n=3287), 2.0% (95% CI, 1.4-2.6) and JAK inhibitors (n=384), 2.5% (95% CI, 0.5-4.6). After adjusting for confounding variables, risk of cancer with ATs was comparable (HR, vs. TNF antagonists): vedolizumab, 1.01 (95% CI, 0.71-1.42); anti-interleukins, 0.94 (95% CI, 0.61-1.46); JAK inhibitors, 0.85 (95% CI, 0.33-2.16). Findings were similar on subgroup analyses based on type of cancer (solid organ, hematological, melanoma), and on multiple sensitivity analyses. Findings were consistent in agent-level analyses and in an indirect comparison with a cohort of immunomodulator- and advanced therapy-naïve patients with newly diagnosed IBD. Conclusions In a real-world cohort of 15,687 patients with IBD initiating ATs, risk of incident cancer was low and comparable across advanced therapy classes.

INTRODUCTION:Fatigue is a challenging symptom for patients with inflammatory bowel diseases (IBD). Emerging evidence links alterations in the gut microbiome with fatigue in IBD, highlighting the potential of microbiome-targeted treatments. Our aim was to evaluate the clinical efficacy and biological effects of a multistrain probiotic supplementation on fatigue in patients with quiescent IBD. METHODS:This multicenter, placebo-controlled, randomized controlled trial included patients with quiescent IBD, defined as being in clinical remission and a colonoscopy within 1 year which demonstrated no active disease, and with significant fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score ≤43). Patients were randomized to receive either probiotics (Ecologic BARRIER, containing 9 different bacterial strains) or placebo for 12 weeks. Gut microbiome and serum metabolome were analyzed at baseline and at the end of the study. RESULTS:Our study enrolled 100 patients (52 Crohn's disease, 44 ulcerative colitis, 4 IBD-unspecified) with quiescent IBD and with a mean age of 41 years; 61% were women. After 12 weeks, 29.4% of the probiotic group and 40.0% of the placebo group met criteria for no fatigue ( P = 0.34). However, all participants reported an improvement in fatigue ( P < 0.001) with the most striking change noted at 4 weeks in both groups. Probiotic treatment led to beneficial shifts in gut microbiome and serum metabolome composition, particularly an increase in Bifidobacterium animalis after 12 weeks. DISCUSSION:Although 12 weeks of probiotic administration was not associated with relief of fatigue in patients with quiescent IBD, we observed beneficial alterations in the gut microbiome and serum metabolome.

BACKGROUND:A quarter of patients with ulcerative colitis who undergo total proctocolectomy with ileal pouch-anal anastomosis experience chronic pouchitis. While advanced therapies (ATs) are effective in some patients, their impact on antibiotic dependence is unclear. METHODS:In a multicenter, retrospective study, we identified adults with chronic pouchitis during treatment with AT. Those with complete pre-AT antibiotic data formed the "incident AT user" cohort. Those with only post-AT data formed the "prevalent AT user" cohort. Antibiotic prescription was modeled as percentage of time, calculated as the number of weeks of antibiotic prescription during the weeks of observed time. The pooled prevalence of antibiotic use during AT was calculated in a systematic review and meta-analysis,. RESULTS:Of the 67 incident AT users, 24 (36%) initiated treatment with tumor necrosis factor-α antagonist, 17 (25%) with anti-integrin, 23 (34%), with interleukin (IL) inhibitors (anti-IL), and 3 (5%) with Janus kinase inhibitors. The mean time on antibiotics was unchanged from 38% to 33% after AT initiation, and 61% of patients (n = 44) had a reduction in antibiotic use. Compared to the patients without reduction, the reduction group had a higher proportion of patients on anti-IL (46% vs 15%, adjusted odds ratio [OR] 11.1; 95% CI, 2.12-57.62). There were no differences in disease-related parameters. Seventy-nine percent (22/28) of prevalent AT users required antibiotics. On meta-analysis, pooled prevalence of antibiotic use was 0.46 (95% CI, 0.35-0.57). CONCLUSIONS:Just over half of patients on AT for chronic pouchitis saw reduced antibiotic use; however, further studies are needed to identify impact of AT on antibiotic use and define which patients benefit from immune-mediated vs microbiome-directed therapy.

BACKGROUND AND AIMS:Extraintestinal manifestations (EIMs) occur in one-fifth of patients with inflammatory bowel diseases (IBDs) (Crohn's disease[CD]; ulcerative colitis [UC]). As advanced therapies (ATs) for IBD become more targeted, effectiveness for luminal disease may not be extrapolatable to EIMs. We conducted a systematic review to evaluate the efficacy of ATs on EIMs in IBD. METHODS:We conducted searches in PubMed/Embase (inception March 2025) for studies of any of the 5 FDA approved AT classes (tumor necrosis factor [TNF] antagonists, Janus kinase [JAK] inhibitors, anti-integrins, anti-interleukins [anti-ILs], and S1P receptor modulators) for musculoskeletal (arthritis, arthralgias), dermatologic (erythema nodosum, pyoderma gangrenosum), or ocular EIMs in patients with IBD. The primary outcome was clinical improvement. The pooled improvement rates by EIM type and AT class were calculated using a random effects model to account for anticipated heterogeneity. RESULTS:A total of 49 studies were included in the final analysis (6 randomized clinical trials [RCTs], 1 pooled analysis of clinical trials, and 42 observational studies). For musculoskeletal EIMs, TNF antagonists achieved response in 61% of patients, with higher response rates for peripheral (73%) than axial (57%) arthritis. JAK inhibitors were similarly effective (65%) while vedolizumab had significantly lower efficacy (42% improvement), particularly for axial arthritis (12%). For dermatologic EIMs, systemically directed ATs had high efficacy (TNF antagonists 89%, anti-IL 91%). There was a paucity of data on ocular EIMs. CONCLUSION:Systemically directed ATs (TNF-antagonists, JAK inhibitors, anti-ILs) demonstrated strong efficacy for musculoskeletal or cutaneous EIMs; vedolizumab achieved clinical response in lower rates, particularly for axial arthritis.

BACKGROUND AND AIMS:Progressive Crohn's disease (CD) often requires early initiation of biologic or immunomodulator therapy for disease management. However, some patients may have a milder disease course that may be managed with a less aggressive strategy. Our study aims to determine cross-sectional radiographic features that predict progression of CD. METHODS:This was a multi-institution, retrospective cohort of adult CD patients without prior immunomodulator or biologic use, prior surgery, or CD-related hospitalization, who underwent abdominal cross-sectional imaging prior to 2018. Index cross-sectional imaging was reviewed by 2 radiologists who extracted 37 features pertaining to the intestine, mesentery, or extra-luminal complications. The primary outcome was composite progression of disease defined as initiation of an immunomodulator or biologic agent, surgical intestinal resection, or CD-related hospitalization. RESULTS:Our study included 177 CD patients who underwent cross-sectional imaging (81% CT). 81 patients (45.8%) experienced composite progression of disease. On multivariable regression, small bowel wall thickening >5 mm (aOR 8.59; P < .001), distal colonic inflammation (aOR 3.95; P = .03), and segmental mural hyperenhancement (aOR 2.44; P = .04) were independently associated with progression of disease. Absence of radiologic features identified a subgroup with a low rate (13.7%) of disease progression. CONCLUSIONS:Cross-sectional imaging can be used to identify patients with mild CD who are at higher risk for progression. Absence of these features may identify mild CD requiring less aggressive treatment strategies and define a population eligible for trials of management strategies for mild CD.

BACKGROUND:We evaluated the efficacy and safety of ozanimod after 5-aminosalicylic acid (5-ASA) failure in advanced therapy (AT)-naive patients with moderate ulcerative colitis (UC) in True North and its open-label extension (OLE). METHODS:True North was a randomized, 52-week, phase 3 trial with an optional OLE. Efficacy was assessed in True North and the OLE; safety was assessed through OLE week 190. RESULTS:Overall, 203 AT-naive True North patients had moderate UC (Mayo endoscopic subscore of 2 + modified Mayo score of 4-6 + rectal bleeding subscore ≥1). Of these, 139 were also immunomodulator-naive and not receiving corticosteroids (5-ASA-exposed only) at baseline. Patients with moderate UC receiving ozanimod vs placebo achieved greater efficacy rates for all week 10 and week 52 outcomes, regardless of prior immunomodulator/corticosteroid use (eg, week 10 clinical remission: AT-naive = 36.8% vs 10.6%; 5-ASA-exposed only = 37.9% vs 17.2%). Higher symptomatic response rates were achieved by week 2 with ozanimod in AT-naive patients with moderate UC vs the overall AT-naive population (50.5% vs 38.7%); similar trends were observed in patients exposed only to 5-ASA. Efficacy was maintained through OLE week 190 in patients who entered OLE as True North week 52 ozanimod clinical responders. Of those entering OLE as True North week 10 ozanimod clinical nonresponders, 69.0% of AT-naive patients and 68.4% of patients exposed only to 5-ASA achieved symptomatic response by week 5. No new safety signals emerged. CONCLUSIONS:Ozanimod was safe, effective, and durable up to ∼5 years in AT-naive patients with moderate UC who failed conventional therapy. ClinicalTrials.gov: NCT02435992, NCT02531126.

OBJECTIVE:Microscopic colitis (MC) is a colonic inflammatory bowel disease diagnosed via histology. There are no universally accepted guidelines defining treatment goals in MC. Our study evaluated the prognostic significance of histologic normalization in MC. DESIGN:This retrospective cohort study identified patients with histologically confirmed MC who had at least one repeat colonoscopy with available histology. Outcomes included medical therapy use (anti-diarrheals, steroids, mesalamine, and immunosuppressants), hospitalizations, and surgeries (1) prior to or during first repeat colonoscopy or (2) after first repeat colonoscopy. Multivariable adjusted models were created for medical therapy use after first repeat colonoscopy. RESULTS:This study included 380 MC patients. On first repeat colonoscopy, 164 (43.2%) patients normalized by histology and were more likely than those with persistent MC changes to have lymphocytic colitis (56.7% vs 43.3%, P = .036). There were no differences in hospitalization or surgery rates before or after first repeat colonoscopy for patients who normalized and those who did not. When compared to patients with MC at first repeat colonoscopy, those who normalized had statistically significant lower odds of steroids use after their first repeat colonoscopy (OR 0.26; 0.13-0.53) after multivariate adjustment. This association remained significant when restricted to patients with symptoms at first repeat colonoscopy (OR 0.22; 0.08-0.59) but was weaker for patients without symptoms (OR 0.45; 0.16-1.29). CONCLUSION:In patients with MC, histologic normalization at first repeat colonoscopy was associated with reduced need for corticosteroids on follow-up. The effect was slightly attenuated in asymptomatic patients. Future studies of histologic normalization as a treatment target in MC are warranted.

BACKGROUND & AIMS:In the past decade, studies have identified an association between nutrition and the pathogenesis and progression of inflammatory bowel disease as well as the utility of diet as a potential treatment strategy. Despite the growing interest, the current research gaps and priorities have yet to be defined. METHODS:The Nutrition and IBD Research Group is an international working group including 35 adult and pediatric gastroenterologists and dietitians with expertise in nutrition and inflammatory bowel disease research. After defining relevant subdomains within the field of nutrition research, working groups identified research gaps/priorities within each area supported by evidence review. Nutrition and IBD Research Group members independently rated the priority of each statement (1 [highest] to 9 [lowest]) within each domain. The highest priority statements (<4) were included for review/modification. A second independent round of rating was done by all Nutrition and IBD Research Group members. RESULTS:The Nutrition and IBD Research Group identified 7 key domains: Diet as a Treatment for Inflammatory Bowel Disease, Dietary Epidemiology, Malnutrition, Sarcopenia and Obesity, Eating Behaviors and Quality of Life, Implementation of Dietary Trials, Translational Nutrition Research, and Best Practices for Nutrition Research and Study Design. A total of 50 research gaps and priorities were developed. Thirty-four of 35 Nutrition and IBD Research Group members (97%) completed the first rating. After full group review and statement modification to remove repetition and improve clarity, a total of 39 statements were included. CONCLUSIONS:Based on expert consensus, this study identified knowledge gaps and research priorities related to nutrition and inflammatory bowel disease. These gaps, priorities, and best practices will be used to frame future research studies and funding proposals to advance the field.