Combination Therapy with Cyclosporine and Methotrexate in Severe Rheumatoid Arthritis
Peter Tugwell, M.D., Theodore Pincus, M.D., David Yocum, M.D., Michael Stein, M.D., Oscar Gluck, M.D., Gunnar Kraag, M.D., Robert McKendry, M.D., John Tesser, M.D., Philip Baker, B.Sc., George Wells, Ph.D., for The Methotrexate–Cyclosporine Combination Study Group
Background Patients with severe rheumatoid arthritis who aretreated with methotrexate frequently have only partial improvement.
Methods In a six-month randomized, double-blind trial, we comparedcombination therapy with cyclosporine (2.5 to 5 mg per kilogramof body weight per day) and methotrexate (at the maximal tolerateddose) with methotrexate and placebo in 148 patients with rheumatoidarthritis who had residual inflammation and disability despitepartial but substantial responses to prior methotrexate treatment.The primary outcome measure was the change in the number oftender joints.
Results As compared with the placebo group, the patients inthe treatment group had a net improvement in the tender-jointcount of 25 percent, or 4.8 joints (95 percent confidence interval,0.7 to 8.9; P = 0.02), and in the swollen-joint count of 25percent, or 3.8 joints (95 percent confidence interval, 1.3to 6.3; P = 0.005); improvement in overall disease activityas assessed by the physician (19 percent, P<0.001) and thepatient (21 percent, P<0.001); and improvement in joint pain(23 percent, P = 0.04) and in the degree of disability (26 percent,P<0.001). Thirty-six patients (48 percent) in the cyclosporinegroup and 12 patients (16 percent) in the placebo group (P<0.001)met the 1993 criteria for improvement of the American Collegeof Rheumatology (more than 20 percent improvement in the numbersof both swollen and tender joints and improvement in three offive other variables). Serum creatinine concentrations increasedby a mean of 0.14±0.27 mg per deciliter (12±24mmol per liter) in the cyclosporine group and by 0.05±0.19mg per deciliter (4±17 mmol per liter) in the placebogroup (P = 0.02).
Conclusions Patients with severe rheumatoid arthritis and onlypartial responses to methotrexate had clinically important improvementafter combination therapy with cyclosporine and methotrexate.Side effects were not substantially increased. Long-term follow-upof patients treated with this combination is needed.
Source Information
From the Department of Medicine and the Clinical Epidemiology Unit, University of Ottawa, Ottawa, Ont., Canada (P.T., G.K., R.M., P.B., G.W.); the Division of Rheumatology and Immunology, Vanderbilt University, Nashville (T.P., M.S.); the Division of Rheumatology and Immunology, University of Arizona, Tucson (D.Y.); and the Arizona Rheumatology Center, Phoenix (O.G., J.T.).
Address reprint requests to Dr. Tugwell at the Department of Medicine, University of Ottawa and Ottawa General Hospital, 501 Smyth Rd., Rm. LM12, Ottawa, ON K1H 8L6, Canada.
Cyclosporine and Methotrexate for Severe Rheumatoid Arthritis
Schlesinger N., Huppert A., Hoch S., Malleson P., Steinberg A. D., Rosh J. R., Birnbaum A. H., van de Rijn M., Kamel O. W., Storb R., Thomas E. D., Tugwell P., Yocum D., Pincus T., Wells G.
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N Engl J Med 1995;
333:1567-1569, Dec 7, 1995.
Correspondence
Etanercept in Rheumatoid Arthritis
Cook D. A., Dimick J. B., Gallagher D. C., Escalante A., del Rincón I., Ferraccioli G.F., Di Poi E., Weinblatt M. E., Burge D. J.
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N Engl J Med 1999;
340:2000-2001, Jun 24, 1999.
Correspondence
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