Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis

Authors


Dr Masakatsu Yanagimachi, Department of Pediatrics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Tel.: +81 45 787 2800
Fax: +81 45 787 0461
E-mail: m-yanagi@mvi.biglobe.ne.jp

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Methotrexate (MTX), which causes adverse effects, such as liver and/or renal dysfunction, is the most common disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis and articular-type juvenile idiopathic arthritis (JIA).

• Pharmacogenetic studies analysing the MTX pathway genes would aid in the development of more personalized therapy.

• Results regarding the influence of gene polymorphisms on the toxicity and efficacy of MTX are conflicting, and there are marked differences between racial groups in pharmacogenetics.

WHAT THIS STUDY ADDS

• The non-TT genotype at γ-glutamyl hydrolase (GGH) T16C is associated with a high risk of liver dysfunction due to MTX, even after adjustment for duration of MTX treatment.

• Longer time interval from disease onset to MTX treatment and rheumatoid factor positivity are associated with lower efficacy of MTX in Japanese patients, as reported previously in Caucasian patients with JIA.

AIMS We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA).

METHODS Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics.

RESULTS The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P = 0.028, odds ratio = 6.90, 95% confidence interval 1.38–34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P = 0.029) and rheumatoid factor positivity (P = 0.026, odds ratio = 2.87, 95% confidence interval 1.11–7.39) were associated with lower efficacy of MTX.

CONCLUSIONS The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients.

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