Ustekinumab Shows Promise for Perianal Fistulizing Crohn’s Disease, Review Finds

Perianal fistulizing Crohn’s disease is one of the most disabling forms of inflammatory bowel disease, affecting roughly 17 to 43 percent of people with Crohn’s disease and rising above 90 percent among those with rectal involvement. In 70 to 80 percent of cases the fistulas are classified as complex, weaving through sphincter muscle and demanding individualized, multidisciplinary care. A new narrative review published in Drugs in R&D pulls together the accumulated evidence on ustekinumab, a monoclonal antibody that blocks the interleukin-12/23 inflammatory pathway, and concludes that the drug has genuine therapeutic potential both in patients who have failed anti-tumor necrosis factor therapy and in selected biologic-naïve patients, though the authors stress that prospective fistula-specific trials are still needed.

The mechanistic rationale is central to the story. Ustekinumab is a fully human monoclonal antibody that binds the shared p40 subunit of interleukin-12 and interleukin-23, shutting down signaling through both Th1 and Th17 pathways. That suppresses downstream production of pro-inflammatory cytokines including interferon-gamma, TNF-alpha, interleukin-17 and interleukin-22, which are implicated in sustaining mucosal damage, impairing epithelial repair and keeping fistula tracts open. In fistulizing disease specifically, interleukin-23 has been shown to induce epithelial-to-mesenchymal transition, a process thought to underlie the formation of fistula tracts, and ustekinumab’s suppression of that signaling may disrupt the associated tissue remodeling. By downregulating matrix metalloproteinases and cytokine-driven neutrophil infiltration, the drug may also limit tissue destruction. Unlike anti-TNF agents, which target a single cytokine, ustekinumab acts upstream of multiple inflammatory routes, a broader mechanism that is particularly relevant for patients who have failed or cannot tolerate TNF inhibitors.

The clinical evidence base is a patchwork of post hoc analyses and real-world cohorts rather than dedicated randomized trials. In the randomized USTAP trial, 32 adults with active draining perianal fistulas were randomized to ustekinumab or placebo after seton placement. At week 12, clinical remission was 69 percent with ustekinumab versus 31 percent with placebo, while radiologic remission was 87.5 percent versus 75 percent. Pooled data from the UNITI-1, UNITI-2 and CERTIFI studies in moderate-to-severe Crohn’s disease showed that at week 8, 26.0 percent of ustekinumab-treated patients with active fistulas at baseline achieved a fistula response, defined as at least a 50 percent reduction in draining fistulas, compared with 16.9 percent on placebo, and complete fistula resolution occurred in 24.7 percent versus 14.1 percent. Those differences did not reach statistical significance, likely because of limited sample sizes and trial designs that were never built around perianal endpoints.

Maintenance data hint that the drug’s effects may deepen over time. Fistula response rates were consistently higher with ustekinumab than placebo in the maintenance phase: 47 percent versus 30 percent at week 22 in CERTIFI and 80 percent versus 45.5 percent at week 44 in IM-UNITI. The phase IIIb STARDUST and SEAVUE trials reported complete fistula closure in 47.4 percent at week 48 and 53.8 percent at week 52 of ustekinumab-treated patients, respectively. The review’s authors caution that these figures come from retrospective subgroup analyses with small samples and no statistical power for perianal outcomes, and they note that high placebo response rates in recent perianal fistula trials complicate interpretation, arguing for trial designs that minimize placebo rates.

Real-world studies fill in much of the picture. Multiple retrospective cohorts have documented fistula response rates of 35.7 to 48.9 percent and clinical remission rates of 26.7 to 59.4 percent over follow-up periods of 16 to 52 weeks. Kopylov and colleagues observed early response in 69.2 percent of TNF-refractory patients at week 12, with sustained response in 23.1 percent at week 52. A large French multicenter study by Chapuis-Biron and colleagues found 38.5 percent treatment success at six months in patients with heterogeneous fistula presentations, with MRI improvement in half of imaged patients and recurrence-free survival of 75.1 percent at week 52 among those with previously inactive disease. A meta-analysis by Attauabi and colleagues estimated pooled fistula response and remission rates of 41.0 percent and 17.1 percent at week 8, maintained at 55.9 percent and 16.7 percent by week 52, though inter-study heterogeneity was high and the observational design limits firm conclusions.

Evidence in complex fistulas, which are notoriously treatment-resistant, is described as encouraging. Zhang and colleagues reported clinical response climbing from 41.7 percent at week 8 to 63.3 percent at weeks 22 to 26, with remission rising from 21.7 to 43.3 percent, alongside radiological improvement in 73.7 percent and endoscopic improvement in 45.0 percent of patients. A retrospective study by Chen and colleagues followed 131 patients for more than a year and found week 52 remission rates of 77.1 percent for intestinal disease and 55.0 percent for fistulas, rising to 84.7 percent and 62.6 percent at last follow-up. In a more recent study in Chinese patients, most of whom had prior biologic exposure and active fistulas, 73.9 percent achieved clinical remission, 40 percent of evaluable patients reached deep remission, and 83 patients, or 69.7 percent, maintained sustained remission without relapse, with a two-year relapse-free survival rate of 93.4 percent.

The most provocative question the review raises is whether ustekinumab could move from second-line to first-line therapy. In the only available head-to-head comparison, a subgroup analysis of the SEAVUE trial in biologic-naïve patients showed a numerically greater rate of complete fistula resolution with ustekinumab than adalimumab at week 52, 53.8 percent versus 37.5 percent, though the analysis was not powered for fistula-specific outcomes and the difference was not statistically significant. Real-world data are similarly exploratory but suggestive: Chen and colleagues reported perianal lesion closure in 84.1 percent of 44 biologic-naïve patients at week 24 and 100 percent at week 48, while Zhang and Yao and their respective teams found significantly higher fistula clinical remission, MRI-based healing and endoscopic remission in biologic-naïve or TNF-naïve patients compared with previously exposed patients. The authors argue these findings support considering ustekinumab as a first-line biologic in patients with high-risk features, TNF intolerance or contraindications such as serious infection risk, demyelinating disorders or elevated malignancy risk, a positioning consistent with the American Gastroenterological Association’s conditional recommendation for ustekinumab in adults with active perianal fistula.

Perhaps the review’s strongest practical message is that ustekinumab rarely works alone. Surgical optimization, particularly seton placement to control sepsis and maintain tract drainage, appears to create conditions in which biologic therapy can succeed; Chapuis-Biron’s group found that 32.9 percent of patients starting ustekinumab with setons in place achieved successful seton removal during follow-up, and Li and colleagues reported a 46.9 percent clinical remission rate and 23.4 percent fistula response rate by week 8 when ustekinumab was combined with sphincter-preserving surgery. Adjunctive antibiotics such as ciprofloxacin or metronidazole may offer short-term benefit during induction, especially with persistent drainage or local infection, though direct evidence for antibiotics alongside ustekinumab is limited and drawn largely by extrapolation from the anti-TNF literature. Current evidence supports continuing therapy for at least six months after clinical remission to reduce relapse risk, and clinical response should be evaluated within 8 to 12 weeks of initiation, with pelvic MRI used to assess deep tract healing when symptoms alone are ambiguous.

The review is candid about its limits. Nearly all supporting data come from post hoc analyses, retrospective cohorts and subgroup analyses, with only infliximab backed by randomized controlled trial evidence specifically in perianal fistulizing Crohn’s disease. Predictors of response are beginning to emerge, including the association of prior biologic exposure with lower odds of deep remission, ileocolonic disease location as an independent negative predictor, and supra-sphincteric fistulas as a marker of poor outcomes. The authors call for prospective, adequately powered trials with standardized fistula-specific endpoints, validated composite measures combining clinical, radiological and patient-reported outcomes, head-to-head comparisons against agents such as vedolizumab, risankizumab and Janus kinase inhibitors, and precision-medicine research into biomarkers, microbiome signatures and host genetics. Until those trials arrive, ustekinumab stands as a mechanistically plausible and increasingly evidence-supported option for a phenotype of Crohn’s disease that has long resisted easy answers, best deployed within a staged, multimodal strategy that pairs the drug with surgical drainage and careful monitoring.

Subject of Research: Evidence for ustekinumab in treating perianal fistulizing Crohn's disease

Article Title: Ustekinumab in the Management of Perianal Fistulizing Crohn’s Disease: Current Evidence and Practical Strategies

Article References: Yang, B. (2026). Ustekinumab in the Management of Perianal Fistulizing Crohn’s Disease: Current Evidence and Practical Strategies. Drugs in R&D, 26(2), 141-153. https://doi.org/10.1007/s40268-026-00545-w

Image Credits: AI Generated

DOI: 10.1007/s40268-026-00545-w

Keywords: ustekinumab, Crohn's disease, perianal fistulas, IL-12/23, biologic therapy, anti-TNF failure, seton drainage, real-world evidence, clinical remission, MRI monitoring, gastroenterology, immunology