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Cyclosporin A in Severe, Treatment-Refractory Rheumatoid Arthritis
A Randomized Study
- David E. Yocum, MD;
- John H. Klippel, MD;
- Ronald L. Wilder, MD, PhD;
- Naomi L. Gerber, MD;
- Howard A. Austin III, MD;
- Sharon M. Wahl, PhD;
- Lawrence Lesko, PhD;
- James R. Minor, PharmD;
- Harry G. Preuss, MD;
- Cheryl Yarboro, RN;
- Carole Berkebile, RN; and
- Suanne Dougherty, BS
Abstract
Study objective: To assess the efficacy and toxicity of cyclosporin A in patients with severe, treatment-refractory rheumatoid arthritis.
Design: Prospective randomized, double-blind 6-month trial.
Patients: Thirty-one patients who had classic seropositive rheumatoid arthritis with active synovitis unresponsive to conventional therapy.
Interventions: Patients were randomly assigned to high-dose (10 mg/kg body weight · d) or low-dose (1 mg/kg · d) cyclosporin A therapy. A reduction in the dose was permitted for adverse side effects. After 6 months of therapy, patients who showed clinically relevant improvement, defined as a 40% or greater reduction in their total joint activity score, were given the option to continue receiving the therapy for an additional 6 months.
Measurements and Main Results: At 6 months, clinically relevant improvement occurred in 10 of 15 patients (95% CI, 38 to 88) receiving high-dose therapy and in 4 of 16 patients (CI, 7 to 52) receiving low-dose therapy (P = 0. 02). Statistically significant improvements in individual measures were shown only in the high-dose group. Improvements were noted in the number of tender joints (-18.8; CI, -24.5 to -13.1) and swollen joints (-12.1; CI, -15.4 to -8.6), as well as in physician's global scores (-1.5; CI, -2.1 to -0.9) and patient's global scores (-1.1; CI, -1.9 to -0.5). Improvement in disease activity was maintained through 12 months in the high-dose group. The clinical responses to cyclosporin A were most evident in patients with depressed in-vitro proliferative responses of peripheral blood mononuclear lymphocytes to soluble recall antigens. Toxicities, such as fatigue, gastrointestinal and neurologic complaints, and hypertrichosis were frequent but often reversible with a reduction in the dose. Nephrotoxicity, with a 20% increase in the serum creatinine level, was seen in 27 of 31 patients (CI, 71 to 97).
Conclusions: Cyclosporin A is an effective therapy for severe, treatment-refractory rheumatoid arthritis. Side effects, particularly nephrotoxicity, are common.
Article and Author Information
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From the National Institutes of Health, Bethesda, Maryland; Georgetown University Medical Center, Washington, D.C; and University of Maryland, Baltimore, Maryland.
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Requests for Reprints: David E. Yocum, MD, Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, College of Medicine, Tucson, AZ 85724.
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Current Author Addresses: Dr. Yocum: Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, College of Medicine, Tucson, AZ 85724.
Drs. Klippel and Wilder and Ms. Yarboro and Berkebile: Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases; Dr. Wahl and Ms. Dougherty: Cellular Immunology Section, Laboratory of Microbiology and Immunology, National Institute of Dental Research; Dr. Austin: Kidney Disease Section, National Institute of Diabetes, Digestive, and Kidney Diseases; Dr. Gerber: Department of Rehabilitation Medicine, and Dr. Minor, Pharmacy Department, Clinical Center; National Institutes of Health, Bethesda, MD 20892.
Dr. Preuss: Department of Medicine, Nephrology Division, Georgetown University Medical Center, Washington, D. C. 20007.
Dr. Lesko: Pharmacokinetic Laboratories, Baltimore, MD 21201.
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