title: Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group.
abstract: BACKGROUND
  Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement.
  
  
  METHODS
  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 in two divided doses at 12-hour intervals) 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.
  
  
  RESULTS
  The mean (+/- SD) dose of cyclosporine at the final treatment was 2.97 +/- 1.02 mg per kilogram per day. 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). The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group (P = 0.006). 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). Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study; 2 patients in the cyclosporine group died, 1 from viral pneumonia and the other in a motor vehicle accident. 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).
  
  
  CONCLUSIONS
  In a six-month study, 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.
authors.affiliation: Department of Medicine, University of Ottawa, Ont., Canada.
authors.forename: P
authors.initials: P
authors.lastname: Tugwell
authors.forename: T
authors.initials: T
authors.lastname: Pincus
authors.forename: D
authors.initials: D
authors.lastname: Yocum
authors.forename: M
authors.initials: M
authors.lastname: Stein
authors.forename: O
authors.initials: O
authors.lastname: Gluck
authors.forename: G
authors.initials: G
authors.lastname: Kraag
authors.forename: R
authors.initials: R
authors.lastname: McKendry
authors.forename: J
authors.initials: J
authors.lastname: Tesser
authors.forename: P
authors.initials: P
authors.lastname: Baker
authors.forename: G
authors.initials: G
authors.lastname: Wells
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D016572:Cyclosporine; D008727:Methotrexate