Pharmacological Therapies for the Management of Fistulizing Crohn’s Disease: A Systematic Review and Meta-Analysis

BACKGROUND: Fistulas are a debilitating complication of Crohn's disease [CD]. We conducted a systematic review to assess the efficacy of medical therapies for fistulizing CD. METHODS: MEDLINE, Embase, and CENTRAL were searched on May 26, 2022, for randomized controlled trials [RCTs] of pharmacological therapy in adults with fistulizing CD. The primary outcome was induction and maintenance of fistula response. Pooled risk ratios [RRs] and 95% confidence intervals [CIs] were calculated. GRADE was used to assess the certainty of evidence. RESULTS: Thirty-eight RCTs were included. Nineteen trials [50%] exclusively involved perianal fistula. The remaining studies included some participants with non-perianal fistula. Pooled RRs for anti-tumour necrosis factor [TNF] agents were not statistically significant for induction [RR 1.36, 95% CI 0.97-1.91] or maintenance of fistula response [RR 1.48, 95% CI 0.97-2.27]. However, in a sensitivity analysis of studies with fistula response as the primary outcome, anti-TNFs were superior to placebo for induction [RR 1.94, 95% CI 1.10-3.41] and maintenance [RR 1.88, 95% CI 1.23-2.88] of fistula response. Oral small molecules [RR 2.56, 95% CI 1.18-5.53] and mesenchymal stem cell [MSC] therapy [RR 1.26, 95% CI 1.01-1.57] were effective for induction of fistula response. Ustekinumab was associated with maintenance of fistula response [RR 1.80, 95% CI 1.04-3.11]. Vedolizumab was not superior to placebo. The certainty of evidence ranged from very low to moderate. CONCLUSION: Very low- to moderate-certainty evidence suggests that anti-TNF therapy, oral small molecules, ustekinumab, and MSCs are effective for perianal fistulizing CD. Dedicated fistula studies evaluating biologics and small molecules are needed.