Benefit-risk profiling of advanced therapies in moderate-to-severe ulcerative colitis: a clustered network meta-analysis

The therapeutic landscape for moderate-to-severe ulcerative colitis (UC) has expanded with the introduction of oral small molecules and recently approved biologics. However, the scarcity of head-to-head trials necessitates indirect comparisons to clarify their relative positioning. We aimed to determine the comparative efficacy and tolerability hierarchy of approved and emerging advanced therapies, incorporating the most contemporary evidence.

We retrieved randomized controlled trials (RCTs) from major databases up to November 2025. Efficacy outcomes included clinical remission and endoscopic improvement; tolerability was evaluated via discontinuations due to adverse events. We employed Bayesian network meta-analysis and bivariate clustered ranking to visualize efficacy-tolerability profiles, stratifying by prior biologic exposure.

A total of 32 RCTs were included. In the induction phase, Upadacitinib, Ustekinumab, and Risankizumab co-occupied the "most favorable" quadrant, combining high efficacy with superior tolerability. In the maintenance phase, Upadacitinib 30 mg demonstrated the highest-ranking probability for efficacy, while IL-23 antagonists (Guselkumab, Mirikizumab) and low-dose Upadacitinib exhibited a highly favorable efficacy-tolerability profile. Notably, in biologic-exposed patients, Upadacitinib demonstrated the highest relative efficacy among evaluated therapies, whereas Guselkumab emerged as a highly effective biologic alternative based on current estimates.

Based on current network estimates, Upadacitinib is suggested among the most efficacious options for achieving clinical and endoscopic endpoints, particularly in refractory disease, while IL-23 antagonists present highly favorable tolerability profiles for maintenance without compromising efficacy. These findings support a tailored approach to drug selection, aligning patient-specific profiles of inflammatory burden with current evidence-based safety thresholds.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420261292029, identifier CRD420261292029.