Advanced therapies for extraintestinal manifestations of IBD: a systematic review and meta-analysis

Abstract 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.