title: 677TT genotype is associated with elevated risk of methotrexate (MTX) toxicity in juvenile idiopathic arthritis: treatment outcome, erythrocyte concentrations of MTX and folates, and MTHFR polymorphisms.
abstract: OBJECTIVE
  To investigate whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and erythrocyte concentration of methotrexate (EMTX) could serve as predictors of methotrexate (MTX) efficacy and toxicity in patients with juvenile idiopathic arthritis (JIA).
  
  
  METHODS
  Genetic analyses and EMTX and folate assessment were performed in 69 patients with JIA aged 2.5-19.6 years (30 male) treated with MTX using a dose-escalation protocol and classified as full responders (disease inactivity; n = 51) or nonresponders (< 30% improvement in pediatric American College of Rheumatology-30 criteria while receiving ≥ 15 mg/m(2)/week parenteral MTX for at least 3 months; n = 18).
  
  
  RESULTS
  Nonresponders were treated with the higher median MTX dose (17.2 vs 12.6 mg/m(2)/week; p < 0.0001) and accumulated more EMTX (217 vs 106 nmol/l; p < 0.02) and erythrocyte folates (763 vs 592 nmol/l; p = 0.052) than responders. Analysis of MTHFR allele and genotype frequencies in relation to response failed to detect association. The frequency of any adverse effect was 29.4% in responders and 33.3% in nonresponders (p = 0.77). The frequency of 677T allele was elevated in patients with adverse effects (52.4% vs 20.9%; OR 3.88, 95% CI 1.8-8.6, p < 0.002). The probability of any adverse effect was significantly higher in patients with 677TT compared to the 677CC genotype (OR 55.5, 95% CI 2.9-1080, p < 0.001).
  
  
  CONCLUSIONS
  MTHFR genotyping may have a predictive value for the risk of MTX-associated toxicity in patients with JIA. Despite the lack of therapeutic effect, nonresponders accumulated adequate concentrations of EMTX.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Charles University in Prague, 1st Medical School, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Tuková
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Chládek
authors.forename: Milos
authors.initials: M
authors.lastname: Hroch
authors.forename: Dana
authors.initials: D
authors.lastname: Nemcová
authors.forename: Jozef
authors.initials: J
authors.lastname: Hoza
authors.forename: Pavla
authors.initials: P
authors.lastname: Dolezalová
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000737:chemistry*; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005838:Genotype; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
chemical_list: D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate