S4011 Upadacitinib-Associated Colitis: A Potential Adverse Effect

Introduction: Upadacitinib, a Janus kinase inhibitor approved for use in 2019, is used to treat rheumatoid arthritis (RA), inflammatory bowel disease and other chronic inflammatory conditions. We present a case of acute diarrhea and colitis developing within 2 days of upadacitinib initiation, with rapid symptom resolution upon discontinuation. Case Description/Methods: A 65-year-old woman with a history of RA, mixed connective tissue disease, scleroderma, and Raynaud’s disease presented with acute-onset, high-volume, non-bloody watery diarrhea and abdominal pain. Upadacitinib had been initiated 2 days earlier for refractory RA flares unresponsive to first-line therapies. Abdominal computed tomography with contrast revealed significant diffuse colonic inflammation consistent with colitis. She was treated empirically with azithromycin for 5 days, after which she remained symptomatic at outpatient follow-up. Laboratory studies showed elevated C-reactive protein (CRP) and fecal calprotectin. Stool studies for bacterial, viral, and parasitic pathogens, C. difficile toxin A/B, HIV antigen/antibodies, cytomegalovirus IgM, and tissue transglutaminase IgA were negative. Due to persistent diarrhea, she was admitted for fluid resuscitation. Upadacitinib was discontinued, while other chronic medications were continued. Her symptoms resolved within 48 hours, and follow-up labs showed normalization of C-reactive protein and fecal calprotectin. Discussion: This case may represent the first report of potential drug-induced colitis associated with upadacitinib, as this adverse event has not been documented in phase 3 clinical trials, systematic reviews, or large-scale post-marketing pharmacovigilance analyses in patients with RA or inflammatory bowel disease. The most frequently observed gastrointestinal (GI) adverse events with upadacitinib have included abdominal pain, diarrhea, and rarely GI perforation, but colitis has not been reported as a distinct entity. The temporal association between drug initiation and symptom onset, exclusion of infectious etiologies, and rapid resolution following drug discontinuation in this case support a possible causal relationship. This case highlights the importance of ongoing pharmacovigilance and clinician awareness for rare or previously unrecognized GI adverse events, particularly as upadacitinib use expands across multiple indications. Further case reports and long-term safety data are needed to clarify the true incidence and clinical significance of this potential adverse effect.