Efficacy and safety of IL-23p19 and IL-12/23p40 inhibitors in moderate-to-severe Crohn’s disease: a systematic review and network meta-analysis

Interleukin (IL)-23 inhibitors—including IL-23p19 inhibitors (guselkumab, mirikizumab, risankizumab) and the IL-12/23p40 inhibitor ustekinumab—are emerging treatments for Crohn’s disease (CD), but comparative data among them remain limited. Most previous network meta-analyses (NMAs) compared IL-23 inhibitors with other biologic classes or examined a specific IL-23 inhibitor against multiple comparators, often excluding some trials due to design heterogeneity or publication timing. Safety outcomes were also underreported. We conducted the first comprehensive NMA focused exclusively on IL-23 inhibitors to provide practice-oriented evidence. We systematically searched PubMed, Embase, and Cochrane CENTRAL on May 11, 2025, for randomised controlled trials (RCTs) comparing guselkumab, mirikizumab, risankizumab, or ustekinumab in adults with moderate-to-severe CD. We analysed induction (weeks 8–12) and maintenance (weeks 48–64) phases, evaluating approved regimens in the main analysis and all reported regimens in a secondary analysis. Outcomes were clinical and endoscopic efficacy, adverse events, and serious adverse events. Fourteen RCTs (induction phase <i>n</i> = 4,834, maintenance phase <i>n</i> = 3,632) were included, enrolling adults with moderate-to-severe CD (mean age 35–40 years; 40–60% male; baseline Crohn’s Disease Activity Index [CDAI] around 300). Guselkumab showed the highest induction efficacy among IL-23 inhibitors and versus placebo but had the greatest risk of adverse events than placebo during maintenance. Mirikizumab had the lowest risk of serious adverse events across both phases. Risankizumab ranked highest for endoscopic outcomes with a balanced efficacy-safety profile. Ustekinumab showed modest effects. The differences in efficacy and safety may be interpreted in relation to variations in Fc structure and IgG subclass. This is the first NMA comparing IL-23 inhibitors using contemporary evidence. The results offer practical insights for personalized CD treatment: guselkumab may be preferred for rapid response, mirikizumab for safety, and risankizumab for balanced efficacy. This study represents the first network meta-analysis of IL-23 inhibitors, providing a comprehensive comparison of their clinical efficacy, endoscopic outcomes, and safety profiles across the phases of induction and maintenance.Guselkumab demonstrated the most potent clinical efficacy but was associated with a higher risk of adverse events in the maintenance phase, risankizumab showed superior performance in endoscopic outcomes with a favourable overall safety balance, and mirikizumab was associated with the lowest incidence of serious adverse events.Each agent may possess a unique pharmacological profile based on differences in Fc region structure and molecular targets, and this study provides comparative insights that may inform the development of individualised treatment strategies tailored to patient goals and risks in Crohn’s disease. This study represents the first network meta-analysis of IL-23 inhibitors, providing a comprehensive comparison of their clinical efficacy, endoscopic outcomes, and safety profiles across the phases of induction and maintenance. Guselkumab demonstrated the most potent clinical efficacy but was associated with a higher risk of adverse events in the maintenance phase, risankizumab showed superior performance in endoscopic outcomes with a favourable overall safety balance, and mirikizumab was associated with the lowest incidence of serious adverse events. Each agent may possess a unique pharmacological profile based on differences in Fc region structure and molecular targets, and this study provides comparative insights that may inform the development of individualised treatment strategies tailored to patient goals and risks in Crohn’s disease.