Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research

C Salliot, D van der Heijde, C Salliot, D van der Heijde

Abstract

Objective: To perform a systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA).

Methods: A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied.

Results: 88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine, gold, d-penicillamine and higher than for hydroxychloroquine (level of evidence 2a-2b). Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster (2b-4), and could provide a survival benefit by reducing cardiovascular mortality (2b). The prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, two other studies on sequential liver biopsies did not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b-4).

Conclusion: This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.

Conflict of interest statement

Competing interests: None.

References

    1. Combe B, Landewe R, Lukas C, Bolosiu HD, Breedveld F, Dougados M, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66:34–45
    1. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of non biologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762–84
    1. Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009;68:1086–93
    1. Weinblatt ME, Weissman BN, Holdsworth DE, Fraser PA, Maier AL, Falchuk KR, et al. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-Month update. Arthritis Rheum 1992;35:129–37
    1. McKendry RJ, Cyr M. Toxicity of methotrexate compared with azathioprine in the treatment of rheumatoid arthritis. Arch Intern Med 1989;149:685–9
    1. Weinstein A, Marlowe S, Korn J, Farouhar F. Low-dose methotrexate treatment of rheumatoid arthritis. Long-term observations. Am J Med 1985;79:331–7
    1. Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA. Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis. J Rheumatol 1990;17:1628–35
    1. Alarcon GS, Tracy IC, Blackburn WD., Jr Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 1989;32:671–6
    1. Yamanaka H, Inoue E, Tanaka E, Nakajima A, Taniguchi A, Terai C, et al. Influence of methotrexate dose on its efficacy and safety in rheumatoid arthritis patients: evidence based on the variety of prescribing approaches among practicing Japanese rheumatologists in a single institute-based large observational cohort (IORRA). Mod Rheumatol 2007;17:98–105
    1. Weinblatt ME, Maier AL, Fraser PA, Coblyn JS. Longterm prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy. J Rheumatol 1998;25:238–42
    1. Rau R, Schleusser B, Herborn G, Karger T. Long-term treatment of destructive rheumatoid arthritis with methotrexate. J Rheumatol 1997;24:1881–9
    1. Schnabel A, Herlyn K, Burchardi C, Reinhold-Keller E, Gross WL. Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid arthritis. Rheumatol Int 1996;15:195–200
    1. Salaffi F, Carotti M, Sartini A, Cervini C. A prospective study of the long-term efficacy and toxicity of low-dose methotrexate in rheumatoid arthritis. Clin Exp Rheumatol 1995;13:23–8
    1. Szanto E. Low-dose methotrexate treatment of rheumatoid arthritis; long-term observation of efficacy and safety. Clin Rheumatol 1989;8:323–20
    1. Hanrahan PS, Scrivens GA, Russell AS. Prospective long term follow-up of methotrexate therapy in rheumatoid arthritis: toxicity, efficacy and radiological progression. Br J Rheumatol 1989;28:147–53
    1. Weinblatt ME, Trentham DE, Fraser PA, Holdsworth DE, Falchuk KR, Weissman BN, et al. Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum 1988;31:167–75
    1. Tishler M, Caspi D, Yaron M. Long-term experience with low dose methotrexate in rheumatoid arthritis. Rheumatol Int 1993;13:103–6
    1. Sander O, Herborn G, Bock E, Rau R. Prospective six year follow up of patients withdrawn from a randomised study comparing parenteral gold salt and methotrexate. Ann Rheum Dis 1999;58:281–7
    1. Menninger H, Herborn G, Sander O, Blechschmidt J, Rau R. A 36 month comparative trial of methotrexate and gold sodium thiomalate in the treatment of early active and erosive rheumatoid arthritis. Br J Rheumatol 1998;37:1060–8
    1. Nagashima N, Matsuoka T, Saitoh K, Koyama T, Kikuchi O, Yoshino S. Treatment continuation rate in relation to efficacy and toxicity in long-term therapy with low-dose methotrexate, sulfasalazine, and bucillamine in 1358 Japanese patients with rheumatoid arthritis. Clin Exp Rheumatol 2006;24:260–7
    1. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986;29:822–31
    1. Kremer JM, Lee JK. A long-term prospective study of the use of methotrexate in rheumatoid arthritis. Update after a mean of fifty-three months. Arthritis Rheum 1988;31:577–84
    1. Kremer JM, Phelps CT. Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum 1992;35:138–45
    1. Tilling L, Townsend S, David J. Methotrexate and hepatic toxicity in rheumatoid arthritis and psoriatic arthritis. Clin Drug Investig 2006;26:55–62
    1. 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;40:984–5
    1. Fries JF, Williams CA, Ramey D, Bloch DA. The relative toxicity of disease-modifying antirheumatic drugs. Arthritis Rheum 1993;36:297–306
    1. Fries JF, Spitz PW, Williams CA, Bloch DA, Singh G, Hubert HB. A toxicity index for comparison of side effects among different drugs. Arthritis Rheum 1990;33:121–30
    1. Franck H, Rau R, Herborn G. Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate. Clin Rheumatol 1996;15:163–7
    1. Gutierrez-Urena S, Molina JF, Garcia CO, Cuellar ML, Espinoza LR. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:272–6
    1. Baecklund E, Ekbom A, Sparén P, Feltelius N, Klareskog L. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ 1998;317:180–1
    1. Kamel OW, van de Rijn M, LeBrun DP, Weiss LM, Warnke RA, Dorfman RF. Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression. Hum Pathol 1994;25:638–43
    1. Beyeler C, Reichen J, Thomann SR, Lauterburg BH, Gerber NJ. Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study. Br J Rheumatol 1997;36:338–44
    1. Ros S, Juanola X, Condom E, Canas C, Riera J, Guardiola J, et al. Light and electron microscopic analysis of liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Scand J Rheumatol 2002;31:330–6
    1. Fathi NH, Mitros F, Hoffman J, Straniero N, Labreque D, Koehnke R, et al. Longitudinal measurement of methotrexate liver concentrations does not correlate with liver damage, clinical efficacy, or toxicity during a 3.5 year double blind study in rheumatoid arthritis. J Rheumatol 2002;29:2092–8
    1. Willkens RF, Leonard PA, Clegg DO, Tolman KG, Ward JR, Marks CR, et al. Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis. Ann Rheum Dis 1990;49:591–3
    1. Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med 1983;75:69–73
    1. Arias JM, Morton KA, Albro JE, Patch GG, Valdivia S, Greenberg HE, et al. Comparison of methods for identifying early methotrexate-induced hepatotoxicity in patients with rheumatoid arthritis. J Nucl Med 1993;34:1905–9
    1. Tishler M, Caspi D, Halperin Z, Baratz M, Moshkowitz M, Yaron M. A prospective analysis of liver biopsies in rheumatoid arthritis patients receiving long term methotrexate therapy. Rheumatol Int 1992;12:39–41
    1. van der Heijde D, Klareskog L, Landewé R, Bruyn GA, Cantagrel A, Durez P, et al. Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 2007;56:3928–39
    1. Katchamart W, Ortiz Z, Shea B, Tugwell P, Bombardier C. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (an update systematic review and meta-analysis) EULAR 2008: abstr THU0186.

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