Superior Effectiveness of Upadacitinib Over Tofacitinib and Ustekinumab in Bio-Exposed Ulcerative Colitis: The TRIDENT-UC Study.

BACKGROUND: Despite the progress in advanced therapies (AT) for ulcerative colitis (UC), selecting a second-line treatment after failure remains challenging. Recent guidelines recommend upadacitinib, tofacitinib or ustekinumab as high-efficacy options after prior AT failure. However, real-world comparative data among these three agents are lacking. METHODS: Retrospective multicenter study (9 centers) including patients with UC who failed ≥1 AT. Patients were stratified into upadacitinib, tofacitinib, or ustekinumab and assessed at weeks 16 (w16) and 52 (w52). The primary outcome was steroid-free clinical remission (SFCR) and secondary outcomes included biochemical and endoscopic remission. Weighted outcomes were analyzed using multivariable logistic regression after propensity score-based inverse probability weighting (IPTW). RESULTS: We evaluated 312 patients [57.1% (n=178) female; mean age at diagnosis 32.6 ± 8.4 years] who initiated upadacitinib (n=103; 33.0%), tofacitinib (n=74; 23.7%) or ustekinumab (n=135; 43.3%). SFCR rates at w16/w52 were 47.6%/75.0% for upadacitinib, 27.0%/52.4% for tofacitinib, and 26.7%/53.4% for ustekinumab. Corresponding endoscopic remission rates were 38.1%/56.8%, 13.2%/32.7%, and 24.6%/22.5%. After IPTW, upadacitinib was associated with higher odds of SFCR compared with tofacitinib (w16: OR 2.56, 95% CI 1.16-5.64; w52: OR 3.14, 95% CI 1.22-8.12) and ustekinumab (w16: OR 3.71, 95% CI 1.88-7.29; w52: OR 4.68, 95% CI 1.96-11.18). Upadacitinib outperformed tofacitinib (w16: OR 7.44; 95% CI 2.09-26.53; w52: OR 3.51; 95% CI 1.22-10.12) and ustekinumab (w16: OR 3.34; 95% CI 1.38-8.09; w52: OR 8.69; 95% CI 3.07-24.60) for endoscopic remission at both timepoints. CONCLUSION: Upadacitinib showed higher effectiveness than tofacitinib and ustekinumab in bio-experienced UC.