Real‐World Effectiveness and Safety of Upadacitinib in Patients With Crohn's Disease—A Multicentre Prospective Study From the Italian Group for the Study of Inflammatory Bowel Diseases ( IG ‐ IBD )

Background and Aims: Upadacitinib is an oral selective JAK1 inhibitor approved for moderate-to-severe Crohn's disease (CD), but real-world prospective multicentre data in advanced therapy–experienced (AT-experienced) patients are limited. The UPGRADE-CD study evaluated its effectiveness and safety. Methods: In this prospective, multicentre, observational study across 38 Italian centres, we enrolled consecutive AT-experienced CD patients initiating upadacitinib. Effectiveness was assessed at weeks 12 and 24, including clinical response (HBI reduction ≥ 3) and remission (HBI ≤ 4), steroid-free counterparts, biomarker normalisation, resolution of extraintestinal manifestations (EIMs) and endoscopic outcomes. Safety was assessed in all patients receiving ≥ 1 dose. Results: A total of 391 patients were included in the safety analysis and 323 in the efficacy analysis; 48% had failed more than two advanced therapies. Clinical remission reached 51.2% at Week 12 and 54.7% at Week 24 (p = 0.07). Steroid-free clinical response rose from 53.8% to 63.5% (p = 0.09). Active EIMs, present in 39.9% at baseline, resolved completely in 65.7% by Week 24. Higher baseline HBI was the strongest predictor of failure to achieve remission. Discontinuation by Week 24 was 11.3%, mainly from treatment failure (7.2%) and adverse events (3.1%). No major cardiovascular, thromboembolic events or malignancies occurred. Conclusions: Upadacitinib was effective and well-tolerated in AT-experienced CD, including patients with active EIMs, with induction benefit maintained through 6 months without novel safety signals.