Impact of Prior Biologic Exposure on Upadacitinib Efficacy in Inflammatory Bowel Disease: A Systematic Review of...

Whether prior biologic exposure attenuates the efficacy of upadacitinib (UPA), a selective JAK-1 inhibitor, in inflammatory bowel disease (IBD) remains unresolved. This systematic review addresses this question across the induction and maintenance phases of ulcerative colitis (UC) and Crohn's disease (CD). PubMed/MEDLINE, ScienceDirect, Scopus, and ClinicalTrials.gov were searched through from inception to January 2026 per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 (PROSPERO: CRD420261287632). Eligible studies were Phase 3 randomised controlled trials (RCTs) in moderate-to-severe UC or CD reporting subgroup data by biologic exposure status. Risk of bias was assessed with Cochrane RoB 2; narrative synthesis followed the Synthesis Without Meta-analysis (SWiM) framework. Three studies with six Phase 3 programs were included, all at low overall risk of bias. While therapeutic response rates were numerically lower in patients with prior biologic exposure, UPA demonstrated sustained therapeutic benefit observed across all subgroups. In Crohn's disease, stratified risk differences (RD) for clinical remission consistently favored UPA over placebo (RD range: 14.5-33.0 pp). While biologic-naive patients achieved numerically higher remission rates, biologic-experienced patients retained meaningful clinical and endoscopic benefit at one year. In ulcerative colitis, UPA demonstrated superior efficacy across all primary endpoints compared to placebo. Safety data revealed a dose-dependent increase in adverse events (e.g., herpes zoster, hepatic enzyme elevations) at 30 mg compared to 15 mg in the maintenance phase. UPA provides clinically meaningful remission in biologic-experienced IBD patients across both UC and CD. Although prior biologic exposure is associated with lower absolute remission rates, the sustained therapeutic benefit supports UPA as a viable salvage option. Further research with head-to-head trials is needed.