Society: AGA

Background: Tumor necrosis factor inhibitors (TNFi) are a mainstay of pediatric Crohn’s disease (PCD) therapy; yet not all patients respond, and others lose response over time. Combination therapy with methotrexate may improve response; however, this has not been rigorously evaluated.

Objective: To compare the effectiveness of TNFi in combination with low dose oral methotrexate to TNFi monotherapy in children with PCD.

Methods: We performed a multi-center, randomized, double-blind, placebo-controlled pragmatic trial. Eligible PCD patients initiating infliximab or adalimumab as standard of care were randomized in 1:1 allocation to a weight-based dose of oral methotrexate or placebo and followed for a minimum of 12 months and maximum of 36 months. The primary outcome was a composite indicator of treatment failure, including toxicity. Secondary outcomes included development of anti-drug antibodies (ADA) and patient reported outcomes (PROs) of pain interference and fatigue. Adverse events (AEs) and Serious AEs (SAEs) were collected.

Results: We recruited 297 participants at 35 centers (Table 1), including 156 in the methotrexate arm (110 infliximab and 46 adalimumab initiators) and 141 in the placebo arm (102 infliximab and 39 adalimumab initiators). Overall, 26% of participants in the combination therapy group and 44% of participants in the monotherapy group experienced treatment failure [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.45-1.05]. Among infliximab initiators, there were no differences between combination and monotherapy (HR 0.93, 95% CI 0.55-1.56, p=0.78). Among adalimumab initiators, combination therapy was associated with longer time to failure (HR 0.40, 95% CI 0.19-0.81, p=0.01, Figure 1). In the monotherapy group, adalimumab-treated patients had higher failure rates than those receiving infliximab (HR 2.19, 95% CI 1.23-3.89, p=0.008). Combination therapy patients had numerically lower rates of ADA development [(infliximab odds ratio (OR) 0.72 (0.49-1.07); adalimumab OR 0.71 (0.24-2.07)]. No differences in PROs were observed. In comparison to monotherapy, combination therapy resulted in more AEs, including nausea and vomiting and elevated liver enzymes. However, the combination group had fewer SAEs and did not require treatment discontinuation for toxicity more frequently than the monotherapy group.

Conclusions: Compared to adalimumab monotherapy, PCD patients treated with adalimumab and methotrexate experienced a 2-fold reduction in the risk of treatment failure. In contrast, no differences were observed between infliximab combination and monotherapy. A trend towards reduced immunogenicity in the combination therapy group was observed among both infliximab and adalimumab initiators. Overall, these findings suggest improved effectiveness of combination therapy in adalimumab-treated patients with a tolerable safety profile.

Richard Colletti

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