Combination Therapy with Cyclosporine and Methotrexate in Severe Rheumatoid Arthritis

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Abstract
Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement. In a six-month randomized, double-blind trial, we compared combination therapy with cyclosporine (2.5 to 5 mg per kilogram of body weight per day) and methotrexate (at the maximal tolerated dose) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment. The primary outcome measure was the change in the number of tender joints. As compared with the placebo group, the patients in the treatment group had a net improvement in the tender-joint count 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 25 percent, or 3.8 joints (95 percent confidence interval, 1.3 to 6.3; P = 0.005); improvement in overall disease activity as assessed by the physician (19 percent, P<0.001) and the patient (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 cyclosporine group and 12 patients (16 percent) in the placebo group (P<0.001) met the 1993 criteria for improvement of the American College of Rheumatology (more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables). Serum creatinine concentrations increased by a mean of 0.14±0.27 mg per deciliter (12±24 mmol per liter) in the cyclosporine group and by 0.05±0.19 mg per deciliter (4±17 mmol per liter) in the placebo group (P = 0.02). Patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinically important improvement after combination therapy with cyclosporine and methotrexate. Side effects were not substantially increased. Long-term follow-up of patients treated with this combination is needed.