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

Abstract

To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time. A cohort of 119 consecutive patients with JIA treated with MTX was reviewed. The Juvenile Arthritis Disease Activity Score including 71 joints was used to measure disease activity. Nonresponders were patients who did not reach a minimum of 30% improvement after 6 months of treatment or were switched to biologic drugs in the first 6 months because of inefficacy. All adverse events (AE) were noted. Genotyping of single-nucleotide polymorphisms (SNP) in the genes coding for MTX transporters, folate pathway, and adenosine pathway was performed using real-time PCR methods. Univariate and multivariable penalized logistic and Cox regression were used to analyze data. Thirty patients (25.8%) were defined as nonresponders and 55 (47.2%) were switched to biologics during the followup. Sixty-five patients (54.5%) reported AE in a total of 405 patient-years, and 10 patients (8.4%) discontinued MTX because of AE. <i>AMPD1</i> rs17602729 and <i>MTHFD1</i> rs2236225 were associated with gastrointestinal AE while the latter together with <i>MTRR</i> rs1801394 also demonstrated associations with developing hepatoxicity. <i>MTHFR</i> rs1801131, <i>ABCG2</i> rs2231137, wild-type of <i>MTR</i> rs1805087, and wild-type of <i>ABCC2</i> rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. <i>MTHFR</i> rs1801133, <i>MTRR</i> rs1801394, and <i>ABCC2</i> rs2273697 were associated with switching to biologics. SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy.