Abstract
Methotrexate (MTX) is one of the most commonly prescribed and most effective drugs for the treatment of rheumatoid arthritis (RA). Given the partial response of many patients and the side effect profile of the drug, there is considerable interest in identifying biomarkers to guide MTX therapy in RA. Upon entering cells, MTX is polyglutamated. Measuring MTX polyglutamate (MTX PG) levels in circulating red blood cells has been proposed as an objective measure to help optimize MTX therapy in RA. Data are conflicting with regard to the clinical utility of MTX PG measurements as a predictor of the efficacy or toxicity of low-dose MTX effects in RA. Should large, randomized clinical trials of this assay show consistent, reproducible, long-term correlations between MTX PG levels and efficacy or toxicity, this test could become a prominent tool for clinicians to optimize the use of MTX in treating RA.
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Weinblatt ME, Coblyn JS, Fox DA, et al.: Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985, 312:818–822
Kremer JM, Lee JK: The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986, 29:822–831
Weinblatt ME, Kaplan H, Germain BF, et al.: Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study. Arthritis Rheum 1994, 37:1492–1498
Finckh A, Bansback N, Marra CA, et al.: Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis. Ann Intern Med 2009, 151:612–621
• Emery P, Breedveld F, van der Heijde D, et al.: Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study. Arthritis Rheum 2010, 62:674–682. This randomized clinical trial showed that combination therapy resulted in clinical and radiographic benefits over 2 study years when compared with monotherapy with MTX, without significant additional safety risk
• Schoels M, Knevel R, Aletaha D, et al.: Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis 2010, 69:638–643. This meta-analysis summarizes available evidence on a target-oriented approach to RA
Walker AM, Funch D, Dreyer NA, et al.: Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis Rheum 1993, 36:329–335
• Salliot C, van der Heijde D: Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009, 68:1100–1104. This systematic literature search on low-dose MTX monotherapy showed favorable long-term safety
Dervieux T, Greenstein N, Kremer J: Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum 2006, 54:3095–3103
Tishler M, Caspi D, Graff E, et al.: Synovial and serum levels of methotrexate during methotrexate therapy of rheumatoid arthritis. Br J Rheumatol 1989, 28:422–423
Chabner BA, Allegra CJ, Curt GA, et al.: Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest 1985, 76:907–912
Baggott JE, Vaughn WH, Hudson BB: Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5'-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide. Biochem J 1986, 236:193–200
• Becker ML, van Haandel L, Gaedigk R, et al.: Analysis of intracellular methotrexate polyglutamates in juvenile idiopathic arthritis: effect of route of administration upon intracellular methotrexate polyglutamate variability. Arthritis Rheum 2010, 62:1803–1812. This study shows that MTX PGs vary widely in a population of juvenile inflammatory arthritis patients and that route of administration contributes to this variability
•• Dalrymple JM, Stamp LK, O’Donnell JL, et al.: Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 2008, 58:3299–3308. This study showed a wide interpatient variability of RBC MTX PGs accumulation and elimination in adults with RA and that at least 6 months are required to reach MTX PG steady state
Dervieux T, Orentas Lein D, Marcelletti J, et al.: HPLC determination of erythrocyte methotrexate polyglutamates after low-dose methotrexate therapy in patients with rheumatoid arthritis. Clin Chem 2003, 49:1632–1641
Schroder H, Fogh K: Methotrexate and its polyglutamate derivatives in erythrocytes during and after weekly low-dose oral methotrexate therapy of children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 1988, 21:145–149
Dervieux T, Furst D, Lein DO, et al.: Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004, 50:2766–2774
•• Stamp LK, O’Donnell JL, Chapman PT, et al.: Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy. Arthritis Rheum 2010, 62:359–368. In contrast to other studies, this study did not show a relationship between the MTX PG concentration and reduced disease activity in patients with RA who were receiving long-term MTX therapy
Kremer JM: Toward a better understanding of methotrexate. Arthritis Rheum 2004, 50:1370–1382
Montesinos MC, Desai A, Delano D, et al.: Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. Arthritis Rheum 2003, 48:240–247
Kremer JM, Galivan J, Streckfuss A, et al.: Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum 1986, 29:832–835
Angelis-Stoforidis P, Vajda FJ, Christophidis N: Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis. Clin Exp Rheumatol 1999, 17:313–320
Dervieux T, Furst D, Lein DO, et al.: 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. Ann Rheum Dis 2005, 64:1180–1185
Baggott JE, Morgan SL: Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation. Arthritis Rheum 2009, 60:2257–2261
Hornung N, Ellingsen T, Attermann J, et al.: Patients with rheumatoid arthritis treated with methotrexate (MTX): concentrations of steady-state erythrocyte MTX correlate to plasma concentrations and clinical efficacy. J Rheumatol 2008, 35:1709–1715
•• Stamp LK, O’Donnell JL, Chapman PT, et al.: Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long-term methotrexate treatment. Arthritis Rheum 2009, 60:2248–2256. Interpatient variability in MTX PG concentrations is caused by multiple factors, including age, MTX dosage, and renal function
Dervieux T, Kremer J, Lein DO, et al.: Contribution of common polymorphisms in reduced folate carrier and gamma-glutamyl hydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 2004, 14:733–739
Cheng Q, Wu B, Kager L, et al.: A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics 2004, 14:557–567
Cypress Bioscience: Test requisition and specimen collection and handling procedures. Available at http://www.avisetest.com/PDF/Cypress%20Test%20Req%2030-0071.A%20INTERACTIVE.pdf. Accessed May 9, 2010.
Acknowledgments
This work was supported by National Institutes of Health grants 2P60 AR048095-06 (University of Alabama at Birmingham Multidisciplinary Clinical Research Center, R. P. Kimberly, principal investigator) and the MCRC Project 1 (D. K. Arnett, principal investigator).
Disclosure
Drs. Brown, Morgan, Arnett, and Bridges are investigators on a National Institutes of Health–funded study on which investigators from Cypress Bioscience have collaborated.
Dr. Bridges was paid for his attendance at a meeting of an advisory board from Cypress Bioscience. No other potential conflicts of interest relevant to this article were reported.
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Danila, M.I., Hughes, L.B., Brown, E.E. et al. Measurement of Erythrocyte Methotrexate Polyglutamate Levels: Ready for Clinical Use in Rheumatoid Arthritis?. Curr Rheumatol Rep 12, 342–347 (2010). https://doi.org/10.1007/s11926-010-0120-3
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DOI: https://doi.org/10.1007/s11926-010-0120-3