Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study

Abstract

ObjectiveTo assess the utility of erythrocyte methotrexate-polyglutamate (MTX-PG) concentrations in determining the safety and efficacy of MTX in patients with rheumatoid arthritis (RA).Methods79 MTX-naïve patients with RA were enrolled in this prospective 76-week cohort study. MTX was initiated, and a predefined dose-escalation protocol was followed. Erythrocyte MTX-PG concentrations were measured using liquid chromatography. The associations of MTX-PG concentrations with disease activity and adverse events were analysed.ResultsDose escalation of MTX resulted in increased MTX-PG concentrations and a decrease in the mean Disease Activity Score in 28 joints (DAS28). A significant association was observed between total MTX-PG concentrations and ΔDAS28 at week 12 (β=−0.013, p=0.003) and at week 24 (β=−0.014, p=0.003). The maximum MTX-PG levels were significantly higher in patients presenting with elevated transaminases (≥100 IU/L) than in those without (146 vs 106 nmol/L, p=0.009). Receiver operating characteristic curve analysis revealed that a total MTX-PG concentrations of 83 nmol/L at week 12 was the threshold for a DAS28 improvement of ≥1.2 at week 24, and 105 nmol/L was the threshold for transaminases of ≥50 IU/L and 131 nmol/L for transaminases of ≥100 IU/L. MTX-PG concentrations were strongly influenced by body mass index and a serum albumin level.ConclusionsMTX-PG concentrations are a useful biomarker in MTX therapy, in terms of efficacy and safety.

Factors Predicting the Therapeutic Response to Methotrexate in Japanese Patients with Rheumatoid Arthritis: A Hospital-Based Cohort Study

“…If so, SLC19A1 and GGH extracted as genetic variables in this study appear to affect MTX-PG concentrations as part of the pharmacokinetics of MTX. This would also support the results of Takahashi et al 41) The patients with the FPGS 1994G>A A/A and G/A genotypes tended to be better therapeutic response to MTX (OR 3.26 [0.84-12.7]) than patients with the G/G genotype, although the difference was not slightly significant because of type II error. Stranzl et al 42) found an association between FPGS mRNA expression in peripheral blood mononuclear cells and poor response to MTX in RA patients.…”

“…39) This study also found that those with the GGH 16T>C C/C and C/T genotypes had a better therapeutic response to MTX (OR 4.8 [1.21-18.0]) compared with those with the T/T genotype. van der Straaten et al 40) showed that patients with the GGH 16T>C C/C and C/T genotypes were 2.9-fold more likely to reduce the DAS by >1.2 compared with those with the T/T genotype. The present results therefore support the findings of van der Straaten et al, 40) however, it is not reported the function change by the gene variation of GGH16T>C. No research on multivariate analysis of factors affecting the correlation between patient background characteristics including multiple genetic polymorphisms and therapeutic response using EULAR has been conducted in Japanese RA patients.…”

“…van der Straaten et al 40) showed that patients with the GGH 16T>C C/C and C/T genotypes were 2.9-fold more likely to reduce the DAS by >1.2 compared with those with the T/T genotype. The present results therefore support the findings of van der Straaten et al, 40) however, it is not reported the function change by the gene variation of GGH16T>C. No research on multivariate analysis of factors affecting the correlation between patient background characteristics including multiple genetic polymorphisms and therapeutic response using EULAR has been conducted in Japanese RA patients. Therefore, it was possible to conduct analysis excluding the influence of factors related to the therapeutic response using multivariate analysis, and this study revealed that genetic polymorphisms of SLC19A1 and GGH are also related to the response in Japanese RA patients.…”

Elderly onset of early rheumatoid arthritis is a risk factor for bone erosions, refractory to treatment: KURAMA cohort

“…These results imply that MTX was prescribed as much as possible even in EORA patients, provided they exhibited tolerance to it; the average body weight of patients in this cohort was 56.1 kg and the MTX dosage per body weight was 0.153 mg/kg/wk. It is noteworthy that the optimal MTX polyglutamate concentration was achieved at a lower MTX dosage in Japanese patients than in patients from Europe or the USA . Although higher disease activity was observed at baseline, there were no significant differences in the CRP level, TJC, SJC, and disease activity, including DAS28‐ESR, CDAI and SDAI at 1 year.…”

Influence of methotrexate on gastrointestinal symptoms in patients with rheumatoid arthritis

“…However, a prospective study on certolizumab pegol in Japan, in which MTX was initiated at a dose of 8 mg/wk and was increased to 16 mg/wk at week 8 by protocol, showed that MTX dose used in actual clinical settings remains ≤12 mg/wk, owing to adverse events . Concentrations of erythrocyte MTX polyglutamate, a potential biomarker for MTX therapy, were reported to be markedly higher in the Japanese study than what was reported by a US study, suggesting that a lower dose of MTX may be sufficient for Japanese patients …”