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

J Rheumatol. 2017 Aug;44(8):1216-1223. doi: 10.3899/jrheum.160950. Epub 2017 Jun 1.


Objective: To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time.

Methods: 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.

Results: 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. AMPD1 rs17602729 and MTHFD1 rs2236225 were associated with gastrointestinal AE while the latter together with MTRR rs1801394 also demonstrated associations with developing hepatoxicity. MTHFR rs1801131, ABCG2 rs2231137, wild-type of MTR rs1805087, and wild-type of ABCC2 rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. MTHFR rs1801133, MTRR rs1801394, and ABCC2 rs2273697 were associated with switching to biologics.

Conclusion: SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy.


MeSH terms

  • AMP Deaminase / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Juvenile / diagnostic imaging
  • Arthritis, Juvenile / drug therapy
  • Arthritis, Juvenile / genetics*
  • Child
  • Child, Preschool
  • Female
  • Ferredoxin-NADP Reductase / genetics
  • Genotype*
  • Humans
  • Infant
  • Male
  • Methotrexate / therapeutic use*
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Minor Histocompatibility Antigens / genetics
  • Multidrug Resistance-Associated Protein 2
  • Neoplasm Proteins / genetics
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide*
  • Severity of Illness Index
  • Treatment Outcome


  • ABCC2 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antirheumatic Agents
  • Minor Histocompatibility Antigens
  • Multidrug Resistance-Associated Protein 2
  • Neoplasm Proteins
  • methionine synthase reductase
  • Ferredoxin-NADP Reductase
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • MTHFD1 protein, human
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • AMP Deaminase
  • AMPD1 protein, human
  • Methotrexate