Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy.
ABSTRACT There are limited data suggesting that methotrexate polyglutamate (MTXGlu) concentrations can guide MTX dosing in patients with rheumatoid arthritis (RA). The aim of this study was to define a therapeutic range of red blood cell (RBC) MTXGlu(n) concentrations (where n refers to the number of glutamate groups), including threshold values for efficacy and adverse effects in patients receiving long-term oral MTX treatment.
A cross-sectional study of 192 patients receiving oral MTX was undertaken. Disease activity was assessed by the swollen and tender joint counts, the C-reactive protein level, and the Disease Activity Score in 28 joints (DAS28). High disease activity was defined as a DAS28 of >3.2. A standardized questionnaire regarding common MTX adverse effects was completed.
The MTX dosage was significantly higher in patients in whom the swollen joint count and DAS28 were higher. The MTXGlu(4), MTXGlu(5), MTXGlu(3-5), and MTXGlu(1-5) concentrations were significantly higher in patients with high disease activity. After correction for age, the estimated glomerular filtration rate, and the MTX dosage, the association remained significant for MTXGlu(5). RBC folate concentrations were significantly higher in the group with high disease activity. There was no association between any MTXGlu(n) concentration and adverse effects.
In contrast to other studies, the results of the present study did not show a relationship between the MTXGlu(n) concentration and reduced disease activity in patients with RA who were receiving long-term MTX therapy. However, disease activity was influenced by the RBC folate level, which may be a more important factor than MTXGlu(n) concentrations for disease control. In accordance with the findings of previous studies, we were unable to show a relationship between MTXGlu(n) concentrations and adverse effects. Prospective studies will be important to determine whether there is a role for measuring MTXGlu(n) concentrations in patients receiving long-term treatment with MTX.
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ABSTRACT: Objective: The folate antagonist methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA), but its mechanism of action related to the impact on folate metabolism remains elusive. Here, we investigated the cellular pharmacologic impact of MTX on peripheral blood cells of MTX-naïve and MTX-treated RA patients and healthy controls. Methods: Gene expression microarray data was used to investigate the expression of 17 genes in the folate pathway by peripheral blood cells in a cohort of 10 MTX-naïve and 25 MTX-treated RA patients, and 15 healthy controls (test cohort). Multiplex real-time PCR was used to validate the results in an independent cohort consisting of 28 MTX-naïve RA patients, 151 RA patients treated with MTX and 24 healthy controls (validation cohort). Results: Multiple folate metabolism-related genes were consistently and significantly altered between the three groups in both cohorts. Concurrent with an immune-activation gene signature, we observed significant upregulation of folate metabolizing enzymes γ-glutamyl hydrolase and dihydrofolate reductase, as well as MTX/folate efflux transporters ABCC2 and ABCC5 in the MTX-naïve RA group compared to healthy controls. Strikingly, MTX treatment normalized these differential gene expression levels to those observed in healthy controls. Conclusion: These results suggest that under inflammatory conditions, basal folate metabolism in blood cells of RA patients is markedly upregulated, whereas MTX treatment restores normal folate metabolism levels. This novel gene signature provides insight into the mechanism of MTX action, hence paving the way for development of novel folate metabolism-targeted therapies. © 2013 American College of Rheumatology.Arthritis & Rheumatology 07/2013; · 7.48 Impact Factor
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ABSTRACT: To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). A prospective derivation cohort (n = 285) and validation cohort (n = 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B12 , serum folate, erythrocyte vitamin B6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype. In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (β = -0.15, P = 0.037) and the validation cohort (β = -0.20, P = 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P = 0.049; validation cohort, P = 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P = 0.066; validation cohort, P = 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events. A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months.Arthritis & Rheumatology 11/2013; 65(11):2803-13. · 7.48 Impact Factor
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ABSTRACT: Rapid and effective suppression of inflammation is a primary goal in the treatment of rheumatic diseases. However, the therapeutic effect of most medications may be slow to manifest, in the order of weeks or months in the case of DMARDs. Monitoring of drug concentrations allows the possibility of appropriate dose adjustment or changes in medication to achieve more rapid or better outcomes. We review the evidence for drug concentration monitoring. Despite the theoretical utility for monitoring of MTX polyglutamate concentrations in red blood cells in patients with RA, studies have not shown a clear association between concentrations and either efficacy or toxicity and routine measurement is not yet recommended. Small studies associating disease control with concentrations of anti-TNF therapies and anti-drug antibodies suggest that routine monitoring may be useful in the future. However, the data are not yet sufficient for this recommendation. With the use of allopurinol in gout, there is a putative therapeutic range for the active metabolite oxypurinol; however, adjusting the allopurinol dose to achieve a target urate concentration is likely to be most effective, and measuring oxypurinol may be best suited to assessing drug adherence. Although measuring thiopurine metabolite concentrations with AZA therapy has been shown to be useful in IBD, studies in rheumatic diseases have so far failed to confirm a useful association between concentrations and disease control or drug toxicity. Whole blood concentrations of HCQ have been associated with disease control in SLE and future studies may be able to determine a therapeutic range.Rheumatology (Oxford, England) 11/2013; · 4.24 Impact Factor