Abstract
BackgroundMethotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX.MethodsConsecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics.Results196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation.ConclusionMutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-016-0071-y) contains supplementary material, which is available to authorized users.
Highlights
Methotrexate (MTX) has become the mainstay of treatment of polyarticular juvenile idiopathic arthritis (JIA) in the course of the last 25 years [1]
Two mutations in the gene for methylene tetrahydrofolate reductase (MTHFR), C667T and A1298C, are the most common cause of toxicity in high-dose MTX therapy, as these mutations lead to delayed drug clearance [7]
Disease duration was significantly associated with occurrence of MTX intolerance
Summary
Methotrexate (MTX) has become the mainstay of treatment of polyarticular JIA in the course of the last 25 years [1]. Low-dose treatment with MTX shows few serious side effects, limited mostly to transient hepatotoxicity and bone marrow suppression in JIA [2, 3]. The most common side effects leading to MTX discontinuation in clinical practice are gastrointestinal symptoms including intolerance in the form of aversion, nausea and vomiting [4]. Two mutations in the gene for methylene tetrahydrofolate reductase (MTHFR), C667T and A1298C, are the most common cause of toxicity in high-dose MTX therapy, as these mutations lead to delayed drug clearance [7]. Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response.
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