Methotrexate Polyglutamate Concentrations Are Not Associated With Disease Control in Rheumatoid Arthritis Patients Receiving Long-Term Methotrexate Therapy

University of Otago, Christchurch, New Zealand.
Arthritis & Rheumatology (Impact Factor: 7.76). 02/2010; 62(2):359-68. DOI: 10.1002/art.27201
Source: PubMed


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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Available from: Murray L Barclay, Sep 25, 2014
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    • "Smoking and folate levels also affect MTX-PGs concentrations in red blood cells. They also tried to define a therapeutic range of red blood cell MTX-PGs concentrations, including threshold values for efficacy and adverse effects in patients receiving long-term oral MTX treatment in patients with RA, and reported that there was no relationship between MTX-PGs concentrations and adverse effects [162]. Dervieux et al. [163] measured red blood cell MTX-PGs concentrations in adult RA patients, and reported that the selective emergence of long-chain MTX-PGs is function of dose, time of exposure and hence dosage intensity, and concluded that switching from oral to parenteral MTX produces a selective accumulation of longer chain MTX-PGs that are known to be more potent inhibitors of de novo purine biosynthesis than shorter chain MTX-PGs. "
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    ABSTRACT: Mizoribine is administered orally and excreted into urine without being metabolized. Many research groups have reported a linear relationship between the dose and peak serum concentration, between the dose and AUC, and between AUC and cumulative urinary excretion of mizoribine. In contrast, a significant interindividual variability, with a small intraindividual variability, in oral bioavailability of mizoribine is also reported. The interindividual variability is mostly considered to be due to the polymophisms of transporter genes. Methotrexate (MTX) is administered orally and/or by parenteral routes, depending on the dose. Metabolic enzymes and multiple transporters are involved in the pharmacokinetics of MTX. The oral bioavailability of MTX exhibits a marked interindividual variability and saturation with increase in the dose of MTX, with a small intraindividual variability, where the contribution of gene polymophisms of transporters and enzymes is suggested. Therapeutic drug monitoring of both mizoribine and MTX is expected to improve their clinical efficacy in the treatment of rheumatoid arthritis.
    Pharmaceuticals 12/2012; 5(8):802-836. DOI:10.3390/ph5080802
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    • "A series of studies conducted by Dervieux et al. found that long-chain [30, 38, 39] and short-chain [40] RBC MTX PGs levels correlated with improved clinical outcomes as measured by 28-joint Disease Activity Score (DAS28). However, other investigators have found that total, long, and very long chain MTX PG concentrations were not associated with RA disease control in long-term MTX therapy recipients [41]. In conclusion, at the present time, more research is needed before MTXPG-level measurement is ready for routine clinic use to guide MTX dosing. "
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    ABSTRACT: Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea), or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG) levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX.
    International Journal of Rheumatology 07/2012; 2012(12):978396. DOI:10.1155/2012/978396
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    • "A second cohort consisting of 234 RA patients receiving MTX, were recruited as part of an unrelated cross-sectional study [11]. DNA was extracted from 5 ml samples of peripheral blood using phenol-chloroform [12-14]. "
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