Pharmacovigilance Insights into Gastrointestinal Adverse Events of JAK Inhibitors: FAERS Signal Detection with Clinical and Pharmacological Implicationse

Background: Janus-kinase (JAK) inhibitors are increasingly used across surgical practice for immune-mediated disorders, yet their gastrointestinal (GI) safety profiles remain incompletely defined. Upadacitinib (selective JAK-1) has been linked to severe mucosal complications, whereas ruxolitinib (JAK-1/2) appears better tolerated. Robust real-world comparisons are lacking. Methods: We performed a retrospective, observational pharmacovigilance study of the FDA Adverse Event Reporting System from 1 July 2019 to 31 December 2024. After deduplication, 58 548 upadacitinib and 28 968 ruxolitinib safety reports were retrieved. GI events were coded with MedDRA and grouped into inflammation, ulcer/perforation, bleeding, motility disorders, symptoms and other serious events. Multivariable logistic regression generated adjusted reporting odds ratios (aROR) for ruxolitinib versus upadacitinib, controlling for age, sex, comorbidities and concomitant NSAIDs; sensitivity analyses stratified by age and NSAID use. Results: Compared with upadacitinib, ruxolitinib showed higher reporting of GI motility disorders (803 events; aROR = 1.52, 95% CI 1.05–2.20) but markedly lower reporting of GI inflammation (641 events; aROR = 0.14, 0.07–0.29) and ulcer/perforation (229 events; aROR = 0.27, 0.10–0.68). Upadacitinib-related inflammation was dominated by ulcerative colitis (40.8 %) and Crohn’s disease (28.2 %), while 20.8 % of ulcer/perforation events were frank intestinal perforations. Median onset occurred within the first treatment year for both agents (8 months for upadacitinib ulcers/perforations; 6.5 months for ruxolitinib motility disorders). Age-stratified analyses confirmed an excess of upadacitinib-associated inflammation in adults and children, whereas ruxolitinib-related symptoms were concentrated in patients > 65 years. NSAID co-administration magnified upadacitinib-associated ulcers/perforations but had little effect on ruxolitinib patterns. Conclusions: In real-world practice, upadacitinib carries a substantially higher signal for severe inflammatory and ulcerative GI injury, whereas ruxolitinib is mainly associated with non-serious motility disturbances. Upadacitinib carries a higher signal for severe inflammatory and ulcerative GI injury, whereas ruxolitinib is mainly associated with non-serious motility disturbances. These associations are hypothesis‑generating rather than causal and warrant validation through prospective studies and mechanistic investigations.