Background/Purpose:   Methotrexate (MTX) is the drug used most frequently in the therapy of juvenile idiopathic arthritis (JIA). However, long-term treatment in children frequently leads to intolerance, with marked revulsion and refusal of treatment. Mutations in the gene for methylenetetrahydrofolate reductase (MTHFR) can lead to increased toxicity of MTX and could possibly represent an initial stimulus for this conditioned response.

 The objective of this study was to investigate the relation of common mutations in the MTHFR gene and occurrence of MTX intolerance in pediatric patients with juvenile idiopathic arthritis treated with MTX.

Methods: Consecutive patients admitted to the German Center for Pediatric and Adolescent Rheumatology from October 2012 until April 2014 were included in this study. Inclusion criteria were 1) diagnosis of JIA and 2) treatment with MTX for at least 3 months prior to inclusion. Exclusion criteria were other diseases leading to nausea and/or abdominal complaints, and concomitant medications possibly inducing nausea (excepting biologics and non-steroidal anti-inflammatory drugs). Intolerance to MTX was determined using the validated Methotrexate Intolerance Severity Score (MISS) questionnaire; presence of MTX intolerance was assumed for MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a polymerase chain reaction assay, as described previously. Results were analyzed using descriptive statistics and univariate analysis.                                                       

Results:114 patients were included (71% female, median age at inclusion median 12.6 years, median disease duration 4.1 years). Of those, 49 (43%) showed MTX intolerance. 42% of patients were heterozygous, and 7% homozygous for the C677T mutation of the MTHFR gene, 45% of patients were heterozygous, and 12% homozygous for the A1298C mutation; frequencies of both mutations are comparable to published data. Compared to the homozygous wild type, MTX intolerance was not found significantly more frequent in patients with hetero- and homozygous (p = 1.000) or homozygous (p = 0.125) C677T mutations, nor in patients with hetero- and homozygous (p = 0.775) or homozygous (p = 0.444) A1298C mutations. Compound heterozygous mutations for C677T and A1298C were also not found significantly more frequently in patients with MTX intolerance (p = 0.809).

Conclusion: Mutations in the MTHFR gene are not found significantly more frequently in JIA patients with intolerance to MTX. Development of MTX intolerance appears not to be causally related to toxicity associated with the MTHFR gene.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mutations-in-the-mthfr-gene-are-not-associated-with-methotrexate-intolerance-in-patients-with-juvenile-idiopathic-arthritis/