Disproportionate reporting of severe gastrointestinal injury with ruxolitinib among JAK inhibitors in myeloproliferative neoplasms: A FAERS pharmacovigilance analysis.

Abstract

e18600 Background: Janus kinase (JAK) inhibitors are cornerstone therapies for myeloproliferative neoplasms (MPNs). Although gastrointestinal (GI) adverse events have been reported with JAK inhibitors in other disease settings, comparative safety data evaluating severe GI injury among MPN-approved JAK inhibitors remain limited. We performed a pharmacovigilance analysis to assess whether reporting patterns for severe GI injury differ across individual JAK inhibitors used in MPNs. Methods: We conducted a retrospective disproportionality analysis using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) from 2012 through 2025. Reports involving ruxolitinib, fedratinib, pacritinib, or momelotinib were identified using comprehensive generic and brand-name synonyms. To minimize duplicate reporting, analyses were restricted to the most recent report per case. The primary endpoint was a composite of severe GI injury defined by MedDRA preferred terms, including gastrointestinal hemorrhage, ischemic colitis or intestinal ischemia, peritonitis, bowel necrosis, and GI perforation. GI perforation was evaluated as a key secondary endpoint. Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals (CIs), comparing ruxolitinib with all other MPN-approved JAK inhibitors. Sensitivity analyses were performed restricting to primary or secondary suspect (PS/SS) drug roles. Results: Among 16.7 million deduplicated FAERS reports, 67,318 involved MPN-approved JAK inhibitors. Ruxolitinib accounted for the majority of reported exposures (all-role: 62,233; PS/SS: 59,606). Across FAERS, 218,546 unique reports of severe GI injury were identified. In PS/SS analyses, severe GI injury was reported in 692 ruxolitinib-exposed cases compared with 47 cases among all other JAK inhibitors combined. Ruxolitinib was associated with a higher reporting frequency of severe GI injury relative to other agents (ROR >1.2, 95% CI excluding unity), with consistent findings across sensitivity analyses. GI perforation was rare but occurred almost exclusively with ruxolitinib (PS/SS: 41 cases), with no perforation signal observed for other agents. No temporal clustering was identified, and the signal persisted across multiple FAERS reporting periods. Conclusions: In this large FAERS pharmacovigilance analysis, ruxolitinib demonstrated a disproportionate reporting signal for severe GI injury, including rare but serious GI perforation, compared with other MPN-approved JAK inhibitors. These findings are hypothesis-generating and do not establish causality. Given the widespread use of ruxolitinib in MPNs, heightened clinical awareness and further prospective, patient-level studies are warranted to clarify underlying mechanisms and identify high-risk subgroups.