P1013 Adverse Events of Methotrexate in Paediatric Inflammatory Bowel Disease: A Retrospective Cohort Study

Methotrexate (MTX) is frequently prescribed in paediatric inflammatory bowel disease (IBD), with laboratory monitoring routinely performed to detect adverse events (AEs) such as hepatotoxicity and myelotoxicity. However, data on the incidence of these AEs in paediatric IBD remain limited. This study aims to assess the incidence of MTX-induced AEs in paediatric IBD, and to identify factors associated with AEs.

We conducted a retrospective monocentre cohort study, including all paediatric IBD patients initiating MTX at the Amsterdam UMC between 2010 and 2023. We collected demographic data, disease characteristics, and laboratory results. We specifically evaluated the occurrence of hepatotoxicity, myelotoxicity, and gastrointestinal (GI) side effects (nausea and vomiting). The severity of AEs was assessed according to the Common Terminology Criteria for Adverse Events. Shortly, grade 1 hepatotoxicity was defined as upper limit of normal (ULN)-2.5 times ULN, grade 2 as 2.5-5 times ULN, and grade 3 as 5-20 times ULN. Myelotoxicity was defined as leukopenia, neutropenia and/or thrombocytopenia. Incidence rates were calculated, and regression analyses were performed to assess potential predictors of MTX-induced AEs.

A total of 208 paediatric IBD patients (179 CD, 18 UC, 10 IBD-U) starting MTX therapy were identified, 111 of whom used MTX as immunomodulator alongside a biological. Mean dose at initiation was 13 mg/week (±3.21SD), and 66.5% received MTX orally, versus 33.5% subcutaneous administration. All used folic acid. Hepatotoxicity was observed in 85 patients (40.1%), of which the majority (n=52, 63.4%) classified as grade 1, while 10 patients (12.2%) showed grade 3 toxicity. Myelotoxicity occurred in 43 cases (20.7%), most of which presented as mild toxicity (n=35, 83.3%), with no cases of severe toxicity. GI side effects were reported in 95 patients (45.7%). MTX was permanently discontinued in 24 patients (11.5%) due to hepatotoxicity, in 2 patients (1.0%) due to myelotoxicity, and in 35 patients (16.8%) due to GI side effects. The incidence density of AEs was 0.25 per person-year, with a total of 480 events across 1908 person-years. Female sex (RR 1.4, 95% CI [1.12–1.78], p=0.004) and MTX dose (RR 0.9, 95% CI [0.89– 0.97], p=0.002) were significant predictors of hepato- and/or myelotoxicity. Female sex (RR 1.5, 95% CI [1.17–1.97], p=0.002) and subcutaneous administration of MTX (RR 0.5, 95% CI [0.41–0.73], p<0.01) were significant predictors of GI AEs.

Our findings indicate that severe MTX-induced AEs in paediatric IBD are uncommon, and that MTX-related AEs rarely necessitate therapy cessation. Female sex, MTX dosage, and subcutaneous administration were significant predictors of MTX-induced AEs.