Long-Term Efficacy of Anti-Tumor Necrosis Factor Agents in Pediatric Luminal Crohn's Disease: A Systematic Review of Real-World Evidence Studies

Abstract

Purpose: To determine the long-term efficacy of the anti-tumor necrosis factor (TNF) agents, infliximab (IFX) and adalimumab (ADA), in pediatric luminal Crohn's disease (CD) by performing a systematic literature review.

Methods: An electronic search was performed in Medline, Embase, and the Cochrane Library from inception to September 26, 2019. Eligible studies were cohort studies with observation periods that exceeded 1 year. Studies that reported time-to-event analyses were included. Events were defined as discontinuation of anti-TNF therapy for secondary loss of response. We extracted the probabilities of continuing anti-TNF therapy 1, 2, and 3 years after initiation.

Results: In total, 2,464 papers were screened, 94 were selected for full text review, and 13 studies (11 on IFX, 2 on ADA) met our eligibility criteria for inclusion. After 1 year, 83-97% of patients were still receiving IFX therapy. After 2 and 3 years the probability of continuing IFX therapy decreased to 67-91% and 61-85%, respectively. In total, 5 of the 11 studies subgrouped by concomitant medication consistently showed that the probabilities of continuing IFX therapy in patients with prolonged immunomodulator use were higher than those in patients on IFX monotherapy.

Conclusion: This review of real-world evidence studies confirms the long-term therapeutic benefit of IFX therapy in diverse cohorts of children with luminal CD. Moreover, it supports the view that combination therapy with an immunomodulator prolongs the durability of IFX therapy in patients who previously failed to recover following first-line therapy. The limited number of time-to-event studies in patients on ADA prevented us from drawing definite conclusions about its long-term efficacy.

Keywords: Adalimumab; Crohn disease; Infliximab; Pediatrics; Survival analysis; Systematic review; Treatment outcome.

Fig. 1. Flow diagram of the systematic literature search. Reasons for exclusion at the last stage (^*) included an observation period shorter than 1 year, adult patients, language other than English, case mix of ulcerative colitis and Crohn's disease, unacceptably high proportion lost-to-follow-up, no time-to-event analysis, randomized controlled trial or case-series, mix of infliximab and adalimumab therapy.

Fig. 2. Summary of probabilities of continuing infliximab at 1, 2, and 3 years after initiation. Plots display the probabilities of continuing infliximab therapy in included studies. The upper panel (A) shows the results of the entire cohort and the lower panel (B) shows the results of sub cohorts on either infliximab monotherapy or short combination therapy (white dots) vs. prolonged combination therapy (dark grey).

IFX: infliximab, IM: immunomodulator.