Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study

Abstract

Objective: To investigate the contribution of red blood cell (RBC) methotrexate polyglutamates (MTX PGs), RBC folate polyglutamates (folate PGs), and a pharmacogenetic index to the clinical status of patients with rheumatoid arthritis treated with MTX. Methods: 226 adult patients treated with weekly MTX for more than 3 months were enrolled at three sites in a multicentred cross sectional observational study. Clinical status was assessed by the number of joint counts, physician's global assessment of disease activity, and a modified Health Assessment Questionnaire (mHAQ). RBC MTX PG and folate PG metabolite levels were measured by high performance liquid chromatography fluorometry and radioassay, respectively. A composite pharmacogenetic index comprising low penetrance genetic polymorphisms in reduced folate carrier (RFC-1 G80A), AICAR transformylase (ATIC C347G), and thymidylate synthase (TSER*2/*3) was calculated. Statistical analyses were by multivariate linear regression with clinical measures as dependent variables and metabolite levels and the pharmacogenetic index as independent variables after adjustment for other covariates. Results: Multivariate analysis showed that lower RBC MTX PG levels (median 40 nmol/l) and a lower pharmacogenetic index (median 2) were associated with a higher number of joint counts, higher disease activity, and higher mHAQ (p,0.09). Multivariate analysis also established that higher RBC folate PG levels (median 1062 nmol/l) were associated with a higher number of tender and swollen joints after adjustment for RBC MTX PG levels and the pharmacogenetic index (p,0.05). Conclusion: Pharmacogenetic and metabolite measurements may be useful in optimising MTX treatment. Prospective studies are warranted to investigate the predictive value of these markers for MTX efficacy.

Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations

“…There are certainly other mechanisms yet to be discovered that may be contributing to this phenomenon. If higher concentrations of long-chain MTXGlu [3][4][5] are truly associated with improvement in disease, as some authors have suggested (16)(17)(18), these findings would support the use of subcutaneous dosing for more patients. However, prospective studies evaluating the effect of route of MTX administration on cellular folate status will be necessary to confirm this notion.…”

“…Recent literature suggests that intracellular MTX polyglutamation may be correlated with the efficacy of MTX in adult patients with rheumatoid arthritis (RA) (16)(17)(18). One may also speculate that increased intracellular concentrations of MTX contribute to the risk of toxicity, but this has not been rigorously evaluated to date.…”

Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis

“…[6][7][8] In the present study, we examined the association between RFC-1 G80A polymorphism and treatment outcome in patients with RA administered MTX.…”

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

“…Serum MTX concentrations have been shown to have no correlation with disease activity (19). However, recent studies suggest a correlation between RBC MTXGlu n concentrations and disease activity (18,20,21). The first of these studies in 65 patients with RA showed that RBC MTXGlu 1-5 concentrations were significantly higher in responders (mean Ϯ SD 60.7 Ϯ 18.9 nmoles/liter) and partial responders (50.8 Ϯ 23.3 nmoles/liter) to treatment than in nonresponders (21.5 Ϯ 10.5 nmoles/liter) (20).…”

“…The first of these studies in 65 patients with RA showed that RBC MTXGlu 1-5 concentrations were significantly higher in responders (mean Ϯ SD 60.7 Ϯ 18.9 nmoles/liter) and partial responders (50.8 Ϯ 23.3 nmoles/liter) to treatment than in nonresponders (21.5 Ϯ 10.5 nmoles/liter) (20). The initial study by Dervieux and colleagues (18) of 108 patients was then extended to 226 patients (21), and patients with RBC MTXGlu 3 levels Ͻ60 nmoles/liter were more likely to have a poor clinical response. In addition, in a small group of 23 patients commencing MTX treatment, a higher RBC MTXGlu 3 concentration at 3 months was associated with a greater chance of better disease control at 6 months (22).…”