Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis

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.

Increased methotrexate intolerance in juvenile idiopathic arthritis compared to acute lymphoblastic leukaemia in children

“…This Danish version of the MISS had a high internal consistency in the JIA group, indicating the Danish translation of the MISS was satisfactory and supporting other studies in the MISS being easy to adapt to a new language [15–17]. For the ALL group the analysis of internal consistency questioned whether the behaviour domain fits properly with the remaining MISS.…”

Successful treatment of methotrexate intolerance in juvenile idiopathic arthritis using eye movement desensitization and reprocessing – treatment protocol and preliminary results

“…MTX intolerance as a unified construct of the anticipatory and associative side effects associated with prolonged use of MTX has only recently been described, and the MISS questionnaire tries to capture this construct [ 7 ]. So far, genetic studies have been unsuccessful in finding a causal link to MTX intolerance [ 5 , 23 , 24 ]. Interaction between the patient and his parents, physicians and other caregivers as well as psychological and social background factors can all influence frequency and severity of MTX intolerance symptoms, and therefore the efficacy of any intervention.…”

“…Treatment with low-dose MTX therapy exhibits few serious adverse effects; treatment is usually discontinued due to intolerance symptoms such as anticipatory nausea and refusal to take the medication [ 3 , 4 ]. The origin of MTX intolerance is still unclear, and common countermeasures have been shown to be ineffective in suppressing MTX intolerance [ 5 , 6 ]. Current studies demonstrate high rates of intolerance for JIA patients on treatment with low-dose MTX, while high-dose regimens e.g.…”

Relationship Between Polymorphisms in Methotrexate Pathway Genes and Outcome of Methotrexate Treatment in a Cohort of 119 Patients with Juvenile Idiopathic Arthritis

“…SNP in its gene are widely researched and believed to contribute to reduced enzymatic activity. The role of MTHFR rs1801131 is not consistent; in a study on RA, it was associated with toxicity 34 , but some studies found different or no association 5,10,13,32 . To our knowledge, ABCC2 rs2273697 and rs2804402 have not yet been evaluated in relation to MTX treatment.…”

“…In the previous pharmacogenetic studies in patients with JIA, AE were not assessed and not subdivided according to the organ system or severity 8,11,12,31,32 , or only a limited number of SNP were analyzed 13,14,33 . Identifying patients with AE that make them discontinue MTX would be of major clinical importance.…”