title: Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis.
abstract: BACKGROUND
  Methotrexate (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.
  
  
  METHODS
  Consecutive 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.
  
  
  RESULTS
  196 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.
  
  
  CONCLUSIONS
  Mutations 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.
authors.affiliation: German Center for Pediatric and Adolescent Rheumatology (DZKJR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scheuern
authors.affiliation: German Center for Pediatric and Adolescent Rheumatology (DZKJR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Fischer
authors.affiliation: Department of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: McDonald
authors.affiliation: Department of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Hermine I
authors.initials: HI
authors.lastname: Brunner
authors.affiliation: German Center for Pediatric and Adolescent Rheumatology (DZKJR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Haas
authors.affiliation: German Center for Pediatric and Adolescent Rheumatology (DZKJR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany. huegle.boris@rheuma-kinderklinik.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Hügle
mesh_terms: D000293:Adolescent; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004361:Drug Tolerance / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D012189:Retrospective Studies
chemical_list: D018501:Antirheumatic Agents; D004247:DNA; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate