Safety profile of upadacitinib in inflammatory Bowel disease: a dual-source pharmacovigilance study integrating FAERS signal detection and real-world clinical cohort analysis.

Background: Upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, has demonstrated efficacy in inflammatory bowel disease (IBD). However, safety data in real-world Asian populations remain limited. This study aimed to characterize the adverse event (AE) profile of upadacitinib by integrating large-scale pharmacovigilance data with real-world clinical evidence. Methods: We conducted a dual-source analysis comprising spontaneous reports from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS; Q1 2018-Q3 2025) and a retrospective single-center clinical cohort in China (April 2023-September 2025). In the FAERS database, disproportionality analyses were performed using four algorithms (ROR, PRR, EBGM, and IC) to detect safety signals. In the clinical cohort, we assessed AE incidence, severity, timing, and management strategies. Subgroup analyses were descriptive, and Kaplan-Meier methods were used to estimate the time to the first AE. Results: The clinical cohort included 183 patients, of whom 85 (46.4%) experienced at least one AE. The most common events were laboratory abnormalities, infections, and dermatologic conditions. Serious events, including intestinal perforation and venous thrombosis, were rare. A distinct early clustering of toxicity was observed: 38.8% of first events occurred within 30 days and 67.0% within 60 days of treatment initiation. Male reproductive safety appeared favorable; one patient experienced transient semen discoloration, which resolved following dose reduction. The FAERS analysis identified rare signals absent in the clinical cohort, notably Pneumocystis jirovecii pneumonia (PJP) and pseudostroke, highlighting potential high-risk scenarios. Signal classification revealed strong signals for herpes zoster and acne, moderate signals for venous thrombosis and laboratory abnormalities, and weak signals for rare events. AE patterns varied by age, disease type, and induction dose, consistent with the mechanistic expectations of JAK1 inhibition. Conclusion: Upadacitinib demonstrates a manageable safety profile in patients with IBD, with most AEs controllable through vigilant monitoring and individualized management. The integration of clinical cohort data with FAERS pharmacovigilance provides a comprehensive view of both common and rare risks. These findings offer critical real-world evidence from an Asian population, complementing global data to inform clinical decision-making.