Medical Therapies Beyond Infliximab for Perianal Fistulizing Crohn’s Disease: Current Evidence and Future Perspectives

Perianal fistulizing Crohn’s disease (pfCD) represents one of the most challenging manifestations. Optimal management requires a multidisciplinary approach combining surgical drainage, appropriate imaging, and advanced medical therapies. While infliximab remains the first-line medical therapy, primary non-response or secondary loss of response occurs in many patients, which highlights the need for effective alternative treatments. This narrative review summarizes the current evidence regarding medical therapies beyond infliximab, including biologics, small molecules, and emerging therapeutic strategies. A literature search of PubMed, Embase, and Scopus was conducted up to February 2026 to identify studies evaluating medical treatments of pfCD. Current evidence suggests that ustekinumab and upadacitinib remain effective following anti-TNF failure, while vedolizumab demonstrates limited efficacy. Evidence supporting IL-23 inhibitors, including risankizumab and guselkumab, is limited but rapidly evolving, with ongoing prospective trials expected to clarify their role. Novel approaches such as advanced dual-targeted therapy, subcutaneous infliximab optimization, hyperbaric oxygen therapy, and exclusive enteral nutrition have also shown encouraging preliminary results in selected patients. However, most available data derive from post hoc analyses, retrospective cohorts, or small prospective studies, with considerable heterogeneity in outcome definitions and limited incorporation of standardized radiological endpoints. Future adequately powered randomized controlled trials using harmonized clinical and magnetic resonance imaging -based outcomes are essential to establish optimal treatment sequencing and improve long-term fistula healing. Until then, individualized multidisciplinary management remains fundamental to optimizing outcomes in patients with pfCD.