Use of methotrexate in the treatment of rheumatoid arthritis
- Joel M Kremer, MD
Joel M Kremer, MD
- Pfaff Family Professor and Chair in Medicine
- The Albany Medical College
- Section Editor
- Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
- Section Editor — Rheumatoid Arthritis
- Emeritus Professor of Rheumatology, Imperial College London
- Visiting Professor, Oxford University
Methotrexate (MTX) is a designer compound that was first used for the treatment of rheumatoid arthritis (RA) and psoriasis in 1951 . It emerged at the same time as glucocorticoids, however, and received little attention in the therapy of rheumatic diseases until retrospective reports appeared in the early 1980s [2,3]. Short-term placebo-controlled prospective studies in the mid-1980s demonstrated its potent efficacy and superiority to placebo in patients with chronic severe RA, and long-term open prospective studies then showed that the response was sustained and that toxicity was manageable. These insights have led to the metamorphosis of MTX into its present status as the dominant slow-acting drug to treat patients with RA.
The pharmacology of MTX and its use in the treatment of RA will be reviewed here. MTX has also been used effectively in a variety of other mostly rheumatic diseases including ankylosing spondylitis, Felty's syndrome, inclusion body myositis, reactive arthritis, and granulomatosis with polyangiitis (Wegener's). These disorders, as well as the major side effects of MTX, are discussed separately. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)
Methotrexate (MTX) can be given by oral, intramuscular, and subcutaneous routes. Oral MTX is variably absorbed in the dose range used to treat rheumatoid arthritis (RA). Serum levels of MTX consistently increase when the drug is administered parenterally, which is not the case for oral ingestion of doses of 15 mg or greater administered all at one time [4,5]. This difference in absorption may have therapeutic implications, as some patients may respond better to parenteral therapy, presumably because more drug reaches the circulation (see 'Parenteral therapy' below). This difference in drug levels between parenteral and oral administration may be more pronounced at higher doses within the usual therapeutic range.
As an example, a 7.5 mg weekly dose is absorbed better than a 15 to 20 mg dose . Bioavailability (f) is defined as the ratio of oral drug absorption divided by intravenous drug absorption. Since f may drop off by a mean of 13.5 percent as the dose of MTX is increased from a starting dose of 7.5 mg to the typical maintenance weekly doses employed in RA, a patient may do better clinically when switched from oral (PO) to intramuscular (IM) or subcutaneous (SC) administration of the same dose of the drug (see 'Parenteral therapy' below). At a 17.5 to 20 mg weekly dose of MTX, for example, a 13.5 percent difference in f between the PO and IM routes of administration is equivalent to one full 2.5 mg MTX tablet. As the variation in the confidence intervals for the drop-off in f extends to 27 percent, selected patients may have an even greater difference in f between parenteral and oral dosing.
At higher doses, decreased bioavailability may be even more pronounced. This was illustrated in a pharmacokinetic analysis of 15 patients taking more than 25 mg/week of MTX (mean of 30 mg/week); the ratio of oral to subcutaneous absorption was decreased by approximately one-third .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- GUBNER R, AUGUST S, GINSBERG V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951; 221:176.
- Willkens RF, Watson MA. Methotrexate: a perspective of its use in the treatment of rheumatic diseases. J Lab Clin Med 1982; 100:314.
- Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med 1983; 75:69.
- Hamilton RA, Kremer JM. Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis. Br J Rheumatol 1997; 36:86.
- Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis 2014; 73:1549.
- Hoekstra M, Haagsma C, Neef C, et al. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol 2004; 31:645.
- Colebatch AN, Marks JL, Edwards CJ. Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis). Cochrane Database Syst Rev 2011; :CD008872.
- Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol 1995; 22:2072.
- Hamilton RA, Kremer JM. The effects of food on methotrexate absorption. J Rheumatol 1995; 22:630.
- Dalrymple JM, Stamp LK, O'Donnell JL, et al. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 2008; 58:3299.
- 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.
- Morabito L, Montesinos MC, Schreibman DM, et al. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5'-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest 1998; 101:295.
- Cronstein BN. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum 1996; 39:1951.
- Montesinos MC, Yap JS, Desai A, et al. Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis. Arthritis Rheum 2000; 43:656.
- 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.
- Wessels JA, Kooloos WM, De Jonge R, et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2006; 54:2830.
- Gerards AH, de Lathouder S, de Groot ER, et al. Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis. Rheumatology (Oxford) 2003; 42:1189.
- Nesher G, Moore TL. The in vitro effects of methotrexate on peripheral blood mononuclear cells. Modulation by methyl donors and spermidine. Arthritis Rheum 1990; 33:954.
- Genestier L, Paillot R, Fournel S, et al. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 1998; 102:322.
- Ferraccioli GF, Bartoli E. Xenobiotics or biological response modifiers? Methotrexate remains the anchor drug for rheumatoid arthritis. Clin Exp Rheumatol 1998; 16:662.
- Seitz M, Zwicker M, Wider B. Enhanced in vitro induced production of interleukin 10 by peripheral blood mononuclear cells in rheumatoid arthritis is associated with clinical response to methotrexate treatment. J Rheumatol 2001; 28:496.
- Johnston A, Gudjonsson JE, Sigmundsdottir H, et al. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol 2005; 114:154.
- Kremer JM, Lawrence DA, Hamilton R, McInnes IB. Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures. RMD Open 2016; 2:e000287.
- Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985; 312:818.
- Andersen PA, West SG, O'Dell JR, et al. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med 1985; 103:489.
- Lopez-Olivo MA, Siddhanamatha HR, Shea B, et al. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev 2014; :CD000957.
- Weinblatt ME, Weissman BN, Holdsworth DE, et al. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-month update. Arthritis Rheum 1992; 35:129.
- Weinblatt ME, Kaplan H, Germain BF, et al. Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study. Arthritis Rheum 1994; 37:1492.
- Williams HJ, Willkens RF, Samuelson CO Jr, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 1985; 28:721.
- Kremer JM. Safety, efficacy, and mortality in a long-term cohort of patients with rheumatoid arthritis taking methotrexate: followup after a mean of 13.3 years. Arthritis Rheum 1997; 40:984.
- Maravic M, Bologna C, Daures JP, et al. Radiologic progression in early rheumatoid arthritis treated with methotrexate. J Rheumatol 1999; 26:262.
- Rich E, Moreland LW, Alarcón GS. Paucity of radiographic progression in rheumatoid arthritis treated with methotrexate as the first disease modifying antirheumatic drug. J Rheumatol 1999; 26:259.
- Rau R, Schleusser B, Herborn G, Karger T. Long-term treatment of destructive rheumatoid arthritis with methotrexate. J Rheumatol 1997; 24:1881.
- Choi HK, Hernán MA, Seeger JD, et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359:1173.
- Wasko MC, Dasgupta A, Hubert H, et al. Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum 2013; 65:334.
- Reiss AB, Carsons SE, Anwar K, et al. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum 2008; 58:3675.
- Navarro-Millán I, Charles-Schoeman C, Yang S, et al. Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum 2013; 65:1430.
- Weinblatt ME. Rheumatoid arthritis: treat now, not later! Ann Intern Med 1996; 124:773.
- Fuchs HA, Kaye JJ, Callahan LF, et al. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989; 16:585.
- Saag KG, Yazdany J, Alexander C, et al. Defining quality of care in rheumatology: the American College of Rheumatology white paper on quality measurement. Arthritis Care Res (Hoboken) 2011; 63:2.
- Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69:964.
- van Ede AE, Laan RF, Blom HJ, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001; 44:2525.
- Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008; 59:762.
- Karie S, Gandjbakhch F, Janus N, et al. Kidney disease in RA patients: prevalence and implication on RA-related drugs management: the MATRIX study. Rheumatology (Oxford) 2008; 47:350.
- Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009; 68:1086.
- Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis 2009; 68:1094.
- 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.
- Psoriasis-liver-methotrexate interactions. Arch Dermatol 1973; 108:36.
- Braun J, Kästner P, Flaxenberg P, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum 2008; 58:73.
- Bakker MF, Jacobs JW, Welsing PM, et al. Are switches from oral to subcutaneous methotrexate or addition of ciclosporin to methotrexate useful steps in a tight control treatment strategy for rheumatoid arthritis? A post hoc analysis of the CAMERA study. Ann Rheum Dis 2010; 69:1849.
- Luis M, Pacheco-Tena C, Cazarín-Barrientos J, et al. Comparison of two schedules for administering oral low-dose methotrexate (weekly versus every-other-week) in patients with rheumatoid arthritis in remission: a twenty-four week, single blind, randomized study. Arthritis Rheum 1999; 42:2160.
- Kremer JM, Davies JM, Rynes RI, et al. Every-other-week methotrexate in patients with rheumatoid arthritis. A double-blind, placebo-controlled prospective study. Arthritis Rheum 1995; 38:601.
- 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.
- Yazici Y, Sokka T, Kautiainen H, et al. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities. Ann Rheum Dis 2005; 64:207.
- Kremer JM, Rynes RI, Bartholomew LE. Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate therapy. Double-blind study. Am J Med 1987; 82:781.
- van Ede AE, Laan RF, Blom HJ, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford) 2002; 41:658.
- Jansen G, van der Heijden J, Oerlemans R, et al. Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheum 2004; 50:2130.
- Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. N Engl J Med 1995; 333:137.
- O'Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996; 334:1287.
- O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46:1164.
- Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000; 343:1594.
- Moreland LW, O'Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum 2012; 64:2824.
- O'Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med 2013; 369:307.
- Saravanan V, Kelly CA. Reducing the risk of methotrexate pneumonitis in rheumatoid arthritis. Rheumatology (Oxford) 2004; 43:143.
- Mechanism of action
- USE IN PATIENTS WITH RA
- Efficacy for arthritis
- Possible survival benefit
- Patient selection
- - Alcohol use and MTX
- Dosing of MTX
- - Dose titration
- - MTX polyglutamate levels
- - Split dosing
- - Parenteral therapy
- - Every-other-week dosing
- Duration of therapy
- Folic acid supplementation
- Combination with other drugs
- Other manifestations of RA
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS