Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults
- Stanley Cohen, MD
Stanley Cohen, MD
- Clinical Professor of Medicine
- University of Texas Southwestern Medical School
- Ted R Mikuls, MD, MSPH
Ted R Mikuls, MD, MSPH
- Umbach Professor of Rheumatology
- University of Nebraska Medical Center and Omaha VA Medical Center
The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint damage, which begins early in the course of disease and may ultimately result in disability. Patients are less likely to respond well to therapy the longer active disease persists, and it is widely accepted that patients with active RA should be treated with disease-modifying antirheumatic drugs (DMARDs) at the earliest stage of disease, ideally within less than three months of symptom onset. (See "General principles of management of rheumatoid arthritis in adults", section on 'Prognosis' and "General principles of management of rheumatoid arthritis in adults", section on 'Early use of DMARDs'.)
The most commonly used DMARD for the initial treatment of RA is methotrexate (MTX), although some patients are unable or reluctant to take this drug, and alternative agents are sometimes necessary as the initial DMARD in place of MTX. The choice of therapeutic agents, including both antiinflammatories and DMARDs, is influenced by multiple factors. (See 'Approach to management' below and "Initial treatment of rheumatoid arthritis in adults".)
The alternatives to MTX as the initial DMARD for the treatment of patients with active RA will be reviewed here. A more comprehensive description of the general principles of RA management and the initial treatment of RA, as well as the diagnosis and differential diagnosis of RA and the treatment of disease resistant to initial therapy, are presented separately. (See "General principles of management of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults" and "Diagnosis and differential diagnosis of rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)
APPROACH TO MANAGEMENT
Alternatives to methotrexate (MTX) are sometimes used for the initial treatment of rheumatoid arthritis (RA) because of either comorbidities that present an absolute or relative contraindication to MTX, the initial disease-modifying antirheumatic drug (DMARD) usually employed for treating RA, or because of patient or clinician preferences. (See "Initial treatment of rheumatoid arthritis in adults".)
The choice of the alternative agent to MTX is largely based upon evidence from indirect comparisons and limited head-to-head comparisons; and upon disease severity and prognostic features; comorbidities; patient preferences regarding relative risks and benefits and route of administration; and regulatory, insurance, and cost limitations. (See 'Choice of therapy' below.)
- Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016; 68:1.
- Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73:492.
- Kloppenburg M, Breedveld FC, Terwiel JP, et al. Minocycline in active rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum 1994; 37:629.
- 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.
- Maddison P, Kiely P, Kirkham B, et al. Leflunomide in rheumatoid arthritis: recommendations through a process of consensus. Rheumatology (Oxford) 2005; 44:280.
- Donahue KE, Gartlehner G, Jonas DE, et al. Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med 2008; 148:124.
- Scott DL, Smolen JS, Kalden JR, et al. Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis 2001; 60:913.
- Kalden JR, Scott DL, Smolen JS, et al. Improved functional ability in patients with rheumatoid arthritis--longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group. J Rheumatol 2001; 28:1983.
- Larsen A, Kvien TK, Schattenkirchner M, et al. Slowing of disease progression in rheumatoid arthritis patients during long-term treatment with leflunomide or sulfasalazine. Scand J Rheumatol 2001; 30:135.
- Osiri M, Shea B, Robinson V, et al. Leflunomide for treating rheumatoid arthritis. Cochrane Database Syst Rev 2003; :CD002047.
- Sharp JT, Strand V, Leung H, et al. Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group. Arthritis Rheum 2000; 43:495.
- Hewitson PJ, Debroe S, McBride A, Milne R. Leflunomide and rheumatoid arthritis: a systematic review of effectiveness, safety and cost implications. J Clin Pharm Ther 2000; 25:295.
- Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2000; 39:655.
- Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999; 159:2542.
- Osiri M, Shea B, Robinson V, et al. Leflunomide for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 2003; 30:1182.
- 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.
- Weinblatt ME, Reda D, Henderson W, et al. Sulfasalazine treatment for rheumatoid arthritis: a metaanalysis of 15 randomized trials. J Rheumatol 1999; 26:2123.
- van der Heijde DM, van Riel PL, Nuver-Zwart IH, et al. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989; 1:1036.
- Pullar T, Hunter JA, Capell HA. Effect of sulphasalazine on the radiological progression of rheumatoid arthritis. Ann Rheum Dis 1987; 46:398.
- van der Heijde DM, van Riel PL, Nuver-Zwart IH, van de Putte LB. Sulphasalazine versus hydroxychloroquine in rheumatoid arthritis: 3-year follow-up. Lancet 1990; 335:539.
- Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999; 353:259.
- Dougados M. Sulfasalazine. In: Therapy of Systemic Rheumatic Disorders, van de Putte LBA, Furst DE, Williams HJ, van Riel PLCM (Eds), Marcel Dekker, New York 1998. p.165.
- Box SA, Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997; 36:382.
- American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 2002; 46:328.
- Maetzel A, Wong A, Strand V, et al. Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs. Rheumatology (Oxford) 2000; 39:975.
- Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343:1586.
- Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006; 54:26.
- Ma MH, Kingsley GH, Scott DL. A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis. Rheumatology (Oxford) 2010; 49:91.
- Singh JA, Christensen R, Wells GA, et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 2009; 181:787.
- Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014; 370:2377.
- Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010; 69:88.
- Bijlsma JW, Welsing PM, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 2016; 388:343.
- O'Dell JR, Haire CE, Palmer W, et al. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1997; 40:842.
- Tilley BC, Alarcón GS, Heyse SP, et al. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group. Ann Intern Med 1995; 122:81.
- O'Dell JR, Paulsen G, Haire CE, et al. Treatment of early seropositive rheumatoid arthritis with minocycline: four-year followup of a double-blind, placebo-controlled trial. Arthritis Rheum 1999; 42:1691.
- O'Dell JR, Blakely KW, Mallek JA, et al. Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine. Arthritis Rheum 2001; 44:2235.
- Davis MJ, Dawes PT, Fowler PD, et al. Should disease-modifying agents be used in mild rheumatoid arthritis? Br J Rheumatol 1991; 30:451.
- 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.
- Wasko MC, Hubert HB, Lingala VB, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA 2007; 298:187.
- Tam LS, Gladman DD, Hallett DC, et al. Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J Rheumatol 2000; 27:2142.
- Clark P, Casas E, Tugwell P, et al. Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial. Ann Intern Med 1993; 119:1067.
- A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA Study. Am J Med 1995; 98:156.
- Das SK, Pareek A, Mathur DS, et al. Efficacy and safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized, double-blind, placebo controlled clinical trial--an Indian experience. Curr Med Res Opin 2007; 23:2227.
- Suarez-Almazor ME, Belseck E, Shea B, et al. Antimalarials for treating rheumatoid arthritis. Cochrane Database Syst Rev 2000; :CD000959.
- Jain R, Lipsky PE. Treatment of rheumatoid arthritis. Med Clin North Am 1997; 81:57.
- Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39:723.
- APPROACH TO MANAGEMENT
- GENERAL PRINCIPLES
- ASSESSMENT OF DISEASE ACTIVITY AND PROGNOSIS
- Disease activity
- Prognostic markers
- OTHER MANAGEMENT ISSUES
- PRINCIPAL TREATMENT CHOICES
- Choice of therapy
- Nonbiologic traditional DMARD alternatives to methotrexate
- - Leflunomide
- - Sulfasalazine
- Tumor necrosis factor inhibitors
- Other alternative agents
- - Tofacitinib
- - Tocilizumab
- - Other agents
- SPECIAL POPULATIONS
- Limited arthritis without adverse prognostic signs
- - General approach
- - Hydroxychloroquine
- Pregnancy, comorbidities, and other special considerations
- MONITORING AND REEVALUATION
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS