Comparative efficacy of advanced therapies in biological-exposed ulcerative colitis – a network meta-analysis of randomized trials

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Patients with ulcerative colitis who fail biological therapy represent a challenging population with limited comparative evidence to guide the sequencing of advanced treatments. The present network meta-analysis aimed to compare the efficacy of biologics and small molecules for the induction and maintenance of remission in biological-exposed ulcerative colitis. We conducted a systematic review of randomized controlled trials (RCTs) from MEDLINE, Embase, and Scopus enrolling adults with moderate-to-severe ulcerative colitis and prior exposure or failure to biologicals from inception to March 2025. Outcomes included induction and maintenance of clinical remission. Frequentist and Bayesian random-effects models were applied, and comparative efficacy was ranked using surface under the cumulative ranking curve (SUCRA) values. Twenty-one RCTs (n = 5417 induction; n = 3076 maintenance) were included. For induction, most advanced therapies outperformed placebo, though adalimumab, vedolizumab, ozanimod, and mirikizumab did not reach statistical significance. Upadacitinib ranked highest for induction (SUCRA: 89.3), followed by tofacitinib (88.5) and ustekinumab (77.5). For maintenance, all evaluated agents were superior to placebo. Upadacitinib ranked highest (SUCRA: 85.9), followed by vedolizumab (73.6) and etrasimod (71.8). Subgroup analysis of re-randomized studies confirmed the superiority of upadacitinib and vedolizumab. Certainty of evidence was generally low due to imprecision and publication bias. In biologic-experienced ulcerative colitis, upadacitinib demonstrated the highest efficacy for both induction and maintenance of remission, with tofacitinib and ustekinumab effective alternatives for induction, and vedolizumab a strong option for long-term maintenance. Further head-to-head trials in biologic-experienced populations are warranted.