Esophagus to Small Intestine

Gastroenterology. 2023;165(1):149–61.e7

Kappelman MD, Wohl DA, Herfarth HH, Firestine AM, Adler J, Ammoury RF, Aronow JE, Bass DM, Bass JA, Benkov K, Berenblum Tobi C, Boccieri ME, Boyle BM, Brinkman WB, Cabera JM, Chun K, Colletti RB, Dodds CM, Dorsey JM, Ebach DR, Entrena E, Forrest CB, Galanko JA, Grunow JE, Gulati AS, Ivanova A, Jester TW, Kaplan JL, Kugathasan S, Kusek ME, Leibowitz IH, Linville TM, Lipstein EA, Margolis PA, Minar P, Molle-Rios Z, Moses J, Olano KK, Osaba L, Palomo PJ, Pappa H, Park KT, Pashankar DS, Pitch L, Robinson M, Samson CM, Sandberg KC, Schuchard JR, Seid M, Shelly KA, Steiner SJ, Strople JA, Sullivan JS, Tung J, Wali P, Zikry M, Weinberger M, Saeed SA, Bousvaros A

Comparative effectiveness of anti-TNF in combination with low-dose methotrexate vs. anti-TNF monotherapy in pediatric Crohn’s disease: A pragmatic randomized trial

Background and aims: Tumor necrosis factor (TNF) inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn’s disease therapy; however, non-response and loss of response are common. As combination therapy with methotrexate may improve response, the authors performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare TNF inhibitors with oral methotrexate to TNF inhibitor monotherapy.
Methods: Patients with pediatric Crohn’s disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12–36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected.
Results: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (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). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (HR = 0.40; 95% CI: 0.19–0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio [OR] = 0.72; 95% CI: 0.49–1.07; adalimumab: OR = 0.71; 95% CI: 0.24–2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs.

Conclusions: Among adalimumab but not infliximab initiators, patients with pediatric Crohn’s disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile.

DOI: 10.1053/j.gastro.2023.03.224