Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn's disease: a systematic review and network meta-analysis

Abstract

SUMMARY Background: Data to inform positioning of biologic therapy, both first line and after previous biologic exposure in the treatment of moderate-to-severe Crohn’s disease (CD) is required. We assessed the comparative efficacy and safety of biologics in CD. Methods: A systematic review and network meta-analysis including induction (≥14 days) or maintenance (≥22 weeks) randomized controlled trials (RCTs) in adults (≥18 years) with moderate-to-severe CD (Crohn’s Disease Activity Index CDAI 220–450) treated with tumor necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12/23p40, or anti-IL23p19 agents, relative to placebo or an active comparator, was conducted. MEDLINE, EMBASE, CENTRAL, conference proceedings, trial registries and unpublished data were searched from inception to 03/06/2021. The primary endpoint was induction of clinical remission (CDAI <150), extracted from published reports. Network meta-analysis using multivariate consistency model random-effects meta-regression was performed, with rankings based on surface under the cumulative ranking (SUCRA) probability. Findings: Based on 15 RCTs in 2,931 biologic-naïve patients, infliximab monotherapy (OR 4.53 [95% CI: 1.49, 13.79]) or combined with azathioprine (OR 7.49 [95% CI: 2.04, 27.49]), adalimumab (OR 3.01 [95% CI: 1.25, 7.27]), and ustekinumab (OR 2.63 [95% CI: 1.10, 6.28]), were associated with higher odds of inducing remission compared to certolizumab pegol; infliximab and azathioprine was also associated with higher odds of inducing remission compared to vedolizumab (OR 3.76 [95% CI: 1.01, 14.03]). There was no significant heterogeneity for any of the estimates. Based on 10 RCTs in 2,479 patients with previous biologic exposure, adalimumab after infliximab loss of response (OR 2.82 [95% CI: 1.20, 6.62]) and risankizumab (OR 2.10 [95% CI: 1.12, 3.92]) were associated with higher odds of inducing remission compared to vedolizumab, without significant heterogeneity. Most trials were at low or uncertain risk of bias. Interpretation: Although biologic treatment choices in patients with moderate-to-severe CD must be individualized for each patient, this analysis suggests that infliximab with azathioprine and adalimumab may be preferred first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab may be preferred second-line therapy for induction of clinical remission. Funding: Siddharth Singh is supported by the NIH/NIDDK K23DK117058 and R03DK129631 and IOIBD Operating Grant 2019 (grants not specifically for this unfunded study). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. No authors are employees of NIH. This study was not funded by industry.