Comparing the Efficacy of Advanced Interleukin Inhibitors for Crohn's Disease: A Systematic Review and Network Meta-Analysis.

Background: IL-23p19 inhibitors have recently gained approval for treating moderate-to-severe Crohn's disease (CD). Nevertheless, their comparative efficacy relative to each other and to the IL-12/23 inhibitor ustekinumab (UST) is controversial. Therefore, this study evaluated risankizumab (RZB), mirikizumab (MRK), guselkumab (GUS), and UST for inducing and maintaining clinical and endoscopic remission in the moderate-to-severe CD population. Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched until 4 November 2025. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes. The clinical and endoscopic remission/response during induction and maintenance phases was examined through a frequentist network meta-analysis (NMA). Subgroup analyses were carried out in the biologic-naïve population and those with prior biologic failure. Results: This NMA included 15 RCTs within 11 studies with 7747 patients. Relative to UST, IL-23p19 inhibitors demonstrated superior efficacy during induction and maintenance therapy. For clinical remission during the induction, GUS < 600 mg displayed significantly greater efficacy than UST 6 mg/kg (RR: 1.34 [95% CI: 1.06-1.70]). For endoscopic remission during the induction, both RZB > 600 mg (RR: 1.66 [95% CI: 1.14-2.41]) and RZB ≤ 600 mg (RR: 1.65 [95% CI: 1.21-2.25]) were superior to UST 6 mg/kg. During maintenance therapy, 200 mg GUS achieved a higher rate of endoscopic remission than UST (RR: 2.04 [95% CI: 1.09-3.49]). According to the SUCRA rankings, IL-23p19 inhibitors, particularly GUS and RZB, consistently ranked above UST across all evaluated outcomes. Conclusions: IL-23p19 inhibitors demonstrated superior efficacy in comparison to the IL-12/23 inhibitor UST in the moderate-to-severe CD population. Further high-quality, long-term, multicenter RCTs and real-world studies could confirm these findings.