Next-Generation Therapeutics for Perianal Fistulizing Crohn’s Disease: The Anticipated Impact of IL-23 Inhibitors

Background: Perianal fistulizing Crohn’s disease (PFCD) remains a formidable complication of Crohn’s disease (CD), affecting up to 30%–50% of patients and associated with significant morbidity. Current therapeutic approaches, including anti-tumor necrosis factor (TNF) agents and surgical interventions, often result in suboptimal and transient responses. Objectives: This review explores the immunopathogenic role of interleukin-23 (IL-23) in PFCD and critically evaluates the emerging clinical evidence supporting the use of selective IL-23 inhibitors—risankizumab, guselkumab, and mirikizumab. It also highlights future therapeutic directions, including combination biologic strategies and biomarker-driven personalization. Materials and Methods: A comprehensive narrative review was conducted by analyzing pivotal phase II/III trials, post hoc analyses, observational studies, and updated clinical guidelines (2018–2025). Real-world insights and trial projections were synthesized, including from Bertin et al. (2024) and related peer-reviewed literature. Results: Selective blockade of IL-23 via p19 inhibition effectively attenuates the IL-23/T helper 17 pathway, a key driver of mucosal and fistulizing inflammation, while preserving IL-12-mediated host defense. Risankizumab demonstrated clinical remission in 42%–45% of CD patients at week 12 and achieved fistula closure in 28.6% (week 12) and 57.1% (week 52). Guselkumab and mirikizumab yielded comparable efficacy in luminal CD, with emerging data suggesting benefit in PFCD. Across studies, IL-23 inhibitors showed favorable safety profiles with reduced risk of serious infections versus anti-TNF therapies. Updated European Crohn’s and Colitis Organization and American Gastroenterological Association guidelines support IL-23 inhibitors, particularly for anti-TNF-refractory cases. Conclusion: IL-23 inhibitors represent a mechanism-based, targeted therapy with promising efficacy and tolerability in PFCD. As data from ongoing fistula-specific trials mature and combination strategies evolve, these agents are positioned to redefine treatment algorithms for refractory perianal CD.