Methotrexate toxicity and intolerance in paediatric inflammatory bowel disease: A retrospective cohort study

Abstract

Objectives: Methotrexate (MTX) is frequently prescribed in paediatric inflammatory bowel disease (IBD), with routine laboratory monitoring to detect adverse events (AEs), such as hepatotoxicity and myelotoxicity. However, data on the incidence and predictors of these AEs remain limited. This study aimed to assess the incidence of MTX-induced AEs in paediatric IBD, and to identify associated factors. Methods: We conducted a retrospective monocentre cohort study, including paediatric IBD patients initiating MTX at Amsterdam University Medical Centre between 2010 and 2023. We collected demographic, disease and therapy data, and laboratory results. We evaluated biochemical toxicity (hepatotoxicity or myelotoxicity) and nausea and vomiting, classifying AE severity using common terminology criteria for AEs. Results: A total of 207 paediatric IBD patients (181 Crohn's disease, 17 ulcerative colitis, 9 IBD-unclassified) starting MTX therapy were included, 114 of whom used MTX as immunomodulator alongside a biological drug. Hepatotoxicity occurred in 41% (61% grade 1, 12% grade 3), and myelotoxicity in 21% (81% mild, 0 severe cases). Nausea was reported in 46%. MTX was discontinued due to an AE in 60 cases (38%), including 27 following hepatotoxicity, 4 following myelotoxicity, and 27 following nausea. Male sex (relative risk [RR] 1.4, p = 0.003) and lower MTX dose (RR 0.9, p = 0.003) predicted biochemical toxicity. Nausea was associated with male sex (RR 1.7, p = 0.002), oral administration (RR 0.5 for subcutaneous route, p < 0.001), and higher MTX dose (RR 1.1, p = 0.005). Conclusions: MTX-induced AEs are common but rarely severe in paediatric IBD. Male sex, MTX dosage, and oral administration significantly influence the risk of MTX-induced AEs.