Methotrexate use and risk of abnormal alanine aminotransferase elevation in children with rare inflammatory diseases: a self-controlled case series analysis using a pediatric electronic health record database in Japan

Ther Adv Drug Saf. 2025 Nov 12;16:20420986251392451. doi: 10.1177/20420986251392451. eCollection 2025.

ABSTRACT

BACKGROUND: Methotrexate (MTX) is commonly prescribed for pediatric inflammatory diseases. However, clinical data on MTX-induced liver injury in children with rare inflammatory diseases currently remain limited.

OBJECTIVES: To examine the association between MTX treatment and abnormal liver function in children with inflammatory diseases and to characterize the clinical course of suspected MTX-induced liver injury cases.

DESIGN: A self-controlled case series analysis.

METHODS: This study was conducted on children aged <15 years with juvenile idiopathic arthritis, psoriasis, or inflammatory bowel disease between April 2016 and March 2024. Data were obtained from the Pediatric Medical Information Collection System database, which integrates electronic medical records from over 40 pediatric medical institutions in Japan. The risk period was defined as the 7-day interval following MTX administration. In addition, this analysis compared the incidence of outcomes during the risk period with the baseline period within the same individuals. The outcome was alanine aminotransferase (ALT) elevation, defined as serum ALT levels exceeding three times the upper limit of normal. The age-adjusted incidence rate ratio (aIRR) was calculated, and clinical courses were assessed following ALT elevation.

RESULTS: Among 3696 children with inflammatory diseases, 587 received MTX treatment, while 81 developed abnormal ALT elevation. An increased risk of ALT elevation was observed (aIRR: 2.27, 95% confidence interval: 1.45-3.55). Among 45 patients with ALT elevation observed during the risk period, the normalization occurred in 35 patients. The 11 patients experienced a relapse of ALT elevation, while no patients receiving folic acid supplementation showed a relapse of ALT elevation.

CONCLUSION: Methotrexate treatment in children with inflammatory diseases increases the risk of liver enzyme elevation, highlighting the necessity of liver function monitoring. Folic acid supplementation may help mitigate the exacerbation of MTX-induced liver injury in pediatric patients.

PMID:41245094 | PMC:PMC12612511 | DOI:10.1177/20420986251392451