Network meta-analysis: Efficacy and safety of treatments for fistulising Crohn's disease

Abstract

Background: Fistulas are a debilitating complication of Crohn's disease (CD) and treatment options remain limited, with sub-optimal efficacy. It is essential that other treatment options are considered, and there is a lack of head-to-head comparisons between them making positioning treatments challenging. To our knowledge this is the first network meta-analysis to help position all treatments for fistulising CD. Method(s): MEDLINE, EMBASE, EMBASE classic, the Cochrane central registry and Cochrane Specialised Trial Register were searched between 1978 and 2022 for randomised controlled trials (RCTs) reporting on treatments for fistulising CD. The primary outcomes were the efficacy of medical therapies at achieving fistula remission and maintenance of fistula closure. A network meta-analysis was performed using the frequentist model with pooled relative risks and P scores used to rank treatments, in accordance to PRISMA guidelines [Figure 1]. Result(s): 964 studies were identified with the search criteria, with 28 RCTs after screening included for analysis with a total of 2,239 patients. At the 8 - 12 week end-point, none of the interventions were statistically significant, with tacrolimus ranked first at 4 times better than placebo (RR, 4.56; 95% CI, 0.76 - 27.30) at inducing remission of fistulas [Figure 2]. At the 16 - 24 week time point, infliximab produced the only statistically significant result with the 5mg/kg dose proving most effective (RR, 2.30; 95% CI, 1.40 - 3.77) [Figure 3]. At 44 weeks ustekinumab was found to be most superior with it being 2.38 times (RR, 2.38; 95% CI, 1.24 - 4.56) more superior to placebo, with adalimumab (RR, 2.06; 95% CI, 1. 06 - 3.99) and infliximab 5mg/kg (RR, 1.68; 95% CI, 1.03 - 2.75) also producing a statistically significant result [Figure 4]. A limitation of this network meta-analysis is the significant heterogeneity between studies and variations in end-point definition, with certain small numbers in certain intervention groups limiting generalisability. Conclusion(s): Despite infliximab being favoured in international guidelines for the treatment of perianal fistulising CD, other biologics such as ustekinumab and adalimumab may have a role. Future RCTs with standardised end-points are needed to further investigate biologics, especially ustekinumab and adalimumab, head-to-head against infliximab in the treatment of fistulising CD.