Preliminary study for predicting better methotrexate efficacy in Japanese patients with rheumatoid arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its efficacy and toxicity has not yet been determined. To establish personalized MTX therapy in Japanese patients with rheumatoid arthritis, we performed a preliminary study for predicting better methotrexate efficacy including single-nucleotide polymorphisms (SNPs) for MTX-related transporters/enzymes.


METHODS
Disease control status (good or poor) was judged by the number of Disease Activity Scores (DAS28) of <2 for 6-12 months. The response index R was calculated by the improved area under the curve (AUC) of the DAS28 score for 0-3 or 0-6 months by dividing the cumulative dose of MTX during 0-3 or 0-6 months, respectively. Genotyping of alleles of RFC1 80G > A, RFC1 -43 T > C, FPGS 1994G > A, GGH 401C > T, MTHFR 1298A > C, and TYMS 3'-UTR (-6/+6) was performed using the real-time PCR system.


RESULTS
Seven of 21 patients were judged as good responders in terms of disease control, and the remainder as poor responders. For 0-3 months after starting MTX administration, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 96.0 mg and 25.4 and 118.0 mg and 23.4, respectively. For 0-6 months, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 192.0 mg and 51.0 and 214.0 mg and 47.6, respectively. Statistically significant differences between the 2 groups in the 0-6-month period were observed in DAS28 AUC improvement and index R. A slight tendency for a correlation between G/G genotypes and A allele genotypes in RFC1 80 genotypes was observed, although it did not reach statistical significance.


CONCLUSIONS
This study suggested that aggressive RA treatment with MTX from the early period of administration is necessary to obtain a good response after 6 months, although no SNPs predicting a better treatment response to MTX were identified.
Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512 Japan.
Masayuki
M
Hashiguchi
PS Clinic, LTA Clinical Pharmacology Center, 6-18 Tenyacho, Hakata-ku, Fukuoka, 812-0025 Japan.
Tomomi
T
Tsuru
Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512 Japan.
Kumika
K
Miyawaki
PS Clinic, LTA Clinical Pharmacology Center, 6-18 Tenyacho, Hakata-ku, Fukuoka, 812-0025 Japan.
Midori
M
Suzaki
Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512 Japan.
Jun
J
Hakamata
Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512 Japan.
Mikiko
M
Shimizu
LTA Clinical Pharmacology Center, 6-18 Tenyacho, Hakata-ku, Fukuoka, 812-0025 Japan.
Shin
S
Irie
Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512 Japan.
Mayumi
M
Mochizuki
DAS28; Genetic polymorphism; Interpatient variability; Methotrexate; Rheumatoid arthritis; Therapeutic response