Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid arthritis
- James R O'Dell, MD
James R O'Dell, MD
- Section Editor — Rheumatoid Arthritis
- Bruce Professor and Vice Chairman Internal Medicine
- University of Nebraska Medical Center
- 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
More than a dozen traditional disease-modifying antirheumatic drugs (DMARDs) and biologic agents, respectively termed nonbiologic and biologic DMARDs, are currently available; thus, there are more than 100 and 1000 potential combinations of two and three DMARDs, respectively. Of these, only a few have been directly compared in randomized clinical trials. Some well-designed studies have demonstrated clinically significant efficacy with a generally acceptable risk of toxicity.
Representative clinical trials of various combinations of nonbiologic DMARDs in early and established rheumatoid arthritis (RA) will be reviewed here. The general approach to management of RA and randomized controlled trials of biologic agents in this disease are discussed separately. (See "General principles of management of rheumatoid arthritis in adults" and "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis" and "Rituximab and other B cell targeted therapies for rheumatoid arthritis" and "T-cell targeted therapies for rheumatoid arthritis" and "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL".)
Gold and MTX — The clinical effectiveness of the combination of intramuscular gold when added to ongoing methotrexate (MTX) was best illustrated in a study in which 65 patients with rheumatoid arthritis (RA) and a partial response to MTX (mean dose of 18.5 mg per week) continued MTX therapy and were randomly assigned to receive gold sodium thioglucose (initial dose of 10 mg, followed by 25 mg at week one and 50 mg per week thereafter) or placebo injections for 48 weeks . At the end of the trial, those who received gold injections did significantly better than the placebo group:
●American College of Rheumatology (ACR) 20 percent improvement (ACR20 responses) occurred in a significantly greater proportion of gold plus MTX-treated subjects (61 versus 30 percent).
●ACR50 responses also occurred more often in those receiving gold (26 versus 4 percent).
- Lehman AJ, Esdaile JM, Klinkhoff AV, et al. A 48-week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the METGO study. Arthritis Rheum 2005; 52:1360.
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- Stein CM, Pincus T, Yocum D, et al. Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks: an open-label extension study. The Methotrexate-Cyclosporine Combination Study Group. Arthritis Rheum 1997; 40:1843.
- Gerards AH, Landewé RB, Prins AP, et al. Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial. Ann Rheum Dis 2003; 62:291.
- Marchesoni A, Battafarano N, Arreghini M, et al. Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology (Oxford) 2003; 42:1545.
- Hetland ML, Stengaard-Pedersen K, Junker P, et al. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum 2006; 54:1401.
- 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.
- Proudman SM, Conaghan PG, Richardson C, et al. Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone. Arthritis Rheum 2000; 43:1809.
- Kremer JM, Habros JS, Kolba KS, et al. Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate: a six-month, open-label study. Arthritis Rheum 2003; 48:2763.
- Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999; 42:1322.
- Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002; 137:726.
- Kremer J, Genovese M, Cannon GW, et al. Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial. J Rheumatol 2004; 31:1521.
- O'Dell JR, Elliott JR, Mallek JA, et al. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum 2006; 54:621.
- METHOTREXATE-BASED COMBINATIONS
- Gold and MTX
- SSZ and MTX
- SSZ, HCQ, and MTX
- HCQ/MTX versus SSZ/MTX versus HCQ/SSZ/MTX
- SSZ, prednisolone, and MTX
- SSZ, HCQ, prednisolone, and MTX
- Calcineurin inhibitor plus MTX
- - Cyclosporine and MTX
- - Tacrolimus and MTX
- Leflunomide and MTX
- Doxycycline and MTX
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS