Janani Sundaresan, Wout J. Hamelink, Renske C. F. Hebing, Maartje M. van de Meeberg, Montse Janssen Bonás, Inge M. van der Sluis, Pascal H. P. de Jong, Martijn Heymans, Róbert de Jonge, Maurits C. F. J. de Rotte, Maja Bulatović
Background/Objectives: Methotrexate (MTX) is a cornerstone drug used to treat immune-mediated inflammatory diseases (IMIDs) in low doses (10–30 mg/week), and malignancies in high doses (5000 mg/m2/2 weeks). Its active metabolites, Methotrexate polyglutamates (MTX-PG2–5), quantified in erythrocytes, are associated with efficacy. This study aimed to compare erythrocyte MTX-PG concentrations in patients with IMIDs and pediatric acute lymphoblastic leukemia (ped-ALL) treated with low-dose or high-dose MTX, respectively, and to identify clinical, demographic, and treatment-related factors influencing their concentration. Methods: A total of 567 patients with rheumatoid arthritis, juvenile idiopathic arthritis, Crohn’s disease, sarcoidosis, and ped-ALL were included. Erythrocyte MTX-PG concentration data was collected after 3 months (2.5 months for ped-ALL patients) of MTX-use. Multivariate linear regressing modelling adjusting for age, sex, body mass index (BMI), smoking status, starting MTX dose, route of MTX administration, use of predniso(lo)ne, disease-modifying anti-rheumatic drugs (DMARDs), and folic (or folinic) acid was performed. Results: Intravenous high-dose MTX increased MTX-PG4&5 accumulation. Despite 50-fold higher doses in ped-ALL, MTX-PG2–5sum concentrations were similar to those seen with subcutaneous low-dose MTX used in IMIDs. Age positively influenced MTX-PG concentrations, while DMARD use reduced MTX-PG2–3&5 concentrations. Interestingly, predniso(lo)ne use was associated with higher MTX-PG4&5 concentrations and folic (or folinic) acid with higher MTX-PG3–5 concentrations. Conclusions: This is the first study to compare erythrocyte MTX-PG concentration in low-dose and high-dose patients. Intravenous high-dose MTX administration increased long-chain MTX-PG4&5 concentrations, with MTX-PG2–5sum concentrations similar compared to low-dose subcutaneous MTX use. This study demonstrated that route of administration, age, and concomitant therapies such as DMARDs, predniso(lo)ne, and folic (or folinic) acid significantly influence MTX-PG concentrations.