Background Methotrexate (MTX) is the gold standard disease modifying antirheumatic drug (DMARD) with established efficacy in the treatment of RA. The dose of MTX required to achieve good response vary between patients, which is partially attributed to variation in individual pharmacokinetics of MTX. MTX is transported into a variety of cells and retained within the cells as an active form of MTX-polyglutamate (PG), and MTX-PG has been reported to be possibly useful to monitor clinical response.1) Moreover, it appears that good clinical response and adverse events such as liver injury are more often observed in Japanese patients with RA with very low dose of MTX (sometimes even 7.5-10 mg/week) than in Caucasian patients, suggesting MTX-PG concentrations are different between Japanese and Caucasians.
Objectives To investigate if MTX-PG concentrations in erythrocyte in Japanese patients with rheumatoid arthritis (RA) are associated with disease activity or adverse events.
Methods his multicenter prospective study has been conducted in Japan since Dec 2012. We enrolled 71 patients with rheumatoid arthritis diagnosed according to 2010 American College of Rheumatology (ACR)/European League Arthritis Rheumatism (EULAR) classification criteria, who had never been treated with MTX or biologic agents. MTX was started with a dose of 8mg/week with 5mg/week folic acid and increased by 4mg by every 4 weeks until reached 16mg/week unless adverse events occurred. Blood samples were taken at baseline, week 4, 8 and 12, and after that every 12 weeks. MTX-PG 1-5 concentrations in the erythrocytes were measured using liquid chromatography. Clinical response and adverse events were collected from their charts, and the correlation between them and MTX-PG levels were analyzed.
Results We analyzed MTX-PG1-5 concentrations from baseline to 12 weeks in 24 patients. The mean MTX doses at week 4, 8, and 12 were 7.8mg/w, 10.7mg/w, and 13.4mg/w, respectively. Mean SDAI was significantly decreased from 18.2±8.58 at baseline to 7.50±5.84 at week 12. The proportion of patients at week 12 achieving low disease activity (SDAI<11) was 72.7%. As MTX dose was increased, MTX-PG1-5 concentrations were increased (Fig. 1), and a high total concentration of total MTX-PG (114.2nmol/L) could be obtained with relatively low dose of MTX (13.4mg/w) at 12 week. The total MTX-PG concentration was significantly correlated with ΔSDAI (R=0.433, p=0.044) (Fig. 2), and ΔHAQ (R=0.610, p=0.003). In this study, 9 patients (19.5%) presented with hepatotoxicity. MTXPG1-5 concentration was higher in patients with hepatotoxicity than in those without (132.67 vs 117.23), but this was not significant (p=0.25) assumingly due to the small number of patients with hepatotoxicity.
Conclusions Japanese patients with RA showed high MTX-PG concentration in red blood cells with very low dose MTX, and the MTX-PG concentration might be useful to predict clinical response and hepatotoxicity during MTX treatment.
Dalrymple JM, et al. Pharmacokinetics of oral MTX in patients with RA. Arthritis Rheumatism 2008; 58:3299-308.
Disclosure of Interest : None declared
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