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21 August 2001 | Volume 135 Issue 4 | Pages 248-257
Background: Controlled trials in lupus nephritis have demonstrated that cyclophosphamide therapy is superior to corticosteroid therapy alone. The long-term effectiveness and side-effect profiles of pulse immunosuppressive regimens warrant further study.
Objective: To define the long-term risk and benefit of monthly treatment with boluses of methylprednisolone, cyclophosphamide, or both.
Design: Extended follow-up (median, 11 years) of a randomized, controlled trial.
Setting: U.S. government research hospital.
Patients: 82 patients with proliferative lupus nephritis.
Measurements: Rates of treatment failure (defined as need for supplemental immunosuppressive therapy or doubling of serum creatinine concentration, or death) and adverse events.
Results: In an intention-to-treat survival analysis, the likelihood of treatment failure was significantly lower in the cyclophosphamide (P = 0.04) and combination therapy (P = 0.002) groups than in the methylprednisolone group. Combination therapy and cyclophosphamide therapy alone did not differ statistically in terms of effectiveness or adverse events. Of patients who completed the protocol (n = 65), the proportion of patients who had doubling of serum creatinine concentration was significantly lower in the combination group than in the cyclophosphamide group (relative risk, 0.095 [95% CI, 0.01 to 0.842]).
Conclusion: With extended follow-up, pulse cyclophosphamide continued to show superior efficacy over pulse methylprednisolone alone for treatment of lupus nephritis. The combination of pulse cyclophosphamide and methylprednisolone appears to provide additional benefit over pulse cyclophosphamide alone and does not confer additional risk for adverse events.
Author and Article Information
From Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases and Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; Washington Hospital Center, Washington, D.C.; and Mitretek Systems, McLean, Virginia.
Acknowledgments: The authors thank Dr. Robert Wesley for expert statistical help; Dr. Dorothy E. Scott, Dr. John C. Davis Jr., and the Rheumatology Fellows of the National Institutes of Health for taking care of the patients; the referring physicians for allowing them to participate in the evaluation of their patients; Frank Pucino, PharmD, for dedicated support; and the Nurses of the Day Hospital and the Rheumatology Outpatient Clinic of the Warren Magnuson Clinical Center of the National Institutes of Health.
Requests for Single Reprints: Gabor G. Illei, MD, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 9S-205, Bethesda, MD 20892; e-mail, illeig{at}exchange.nih.gov.
Current Author Addresses: Dr. Illei, Ms. Crane, Ms. Collins, and Ms. Yarboro: Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 9S-205, Bethesda, MD 20892.
Dr. Austin, Ms. Vaughan, and Dr. Balow: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 9N-222, 9000 Rockville Pike, Bethesda, MD 20892.
Dr. Gourley: Section of Rheumatology, Washington Hospital Center, Room 2A-38H, 110 Irving Street NW, Washington, DC 20010.
Dr. Kuroiwa: Third Department of Internal Medicine, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
Dr. Danning: Division of Rheumatology, Gunderson Lutheran, 1836 South Avenue, LaCrosse, WI 54601-9576.
Dr. Steinberg: Mitretek Systems, 7525 Colshire Drive, McLean, VA 22102-3481.
Dr. Klippel: Arthritis Foundation, Suite 305, 4455 Connecticut Avenue NW, Washington, DC 20008.
Dr. Boumpas: Department of Medicine, University of Crete, PO Box 1352, Heraklion 711 10, Greece.
Author Contributions: Conception and design: G.G. Illei, H.A. Austin, M. Crane, L. Collins, M.F. Gourley, C.H. Yarboro, E.M. Vaughan, T. Kuroiwa, C.L. Danning, A.D. Steinberg, J.H. Klippel, J.E. Balow, D.T. Boumpas.
Analysis and interpretation of the data: G.G. Illei, H.A. Austin, M. Crane, L. Collins, M.F. Gourley, C.H. Yarboro, E.M. Vaughan, T. Kuroiwa, C.L. Danning, A.D. Steinberg, J.H. Klippel, J.E. Balow, D.T. Boumpas.
Drafting of the article: G.G. Illei, H.A. Austin, M. Crane, L. Collins, M.F. Gourley, C.H. Yarboro, E.M. Vaughan, T. Kuroiwa, C.L. Danning, A.D. Steinberg, J.H. Klippel, J.E. Balow, D.T. Boumpas.
Critical revision of the article for important intellectual content: G.G. Illei, H.A. Austin, M.F. Gourley, C.H. Yarboro, T. Kuroiwa, C.L. Danning, A.D. Steinberg, J.H. Klippel, J.E. Balow, D.T. Boumpas.
Final approval of the article: G.G. Illei, H.A. Austin, M. Crane, L. Collins, M.F. Gourley, C.H. Yarboro, E.M. Vaughan, T. Kuroiwa, C.L. Danning, A.D. Steinberg, J.H. Klippel, J.E. Balow, D.T. Boumpas.
Provision of study materials or patients: G.G. Illei, H.A. Austin, E.M. Vaughan, C.L. Danning, J.E. Balow, D.T. Boumpas.
Statistical expertise: G.G. Illei, H.A. Austin,
Obtaining of funding: J.H. Klippel, J.E. Balow, D.T. Boumpas.
Administrative, technical, or logistic support: M. Crane, L. Collins, C.H. Yarboro, E.M. Vaughan, J.E. Balow, D.T. Boumpas.
Collection and assembly of data: G.G. Illei, H.A. Austin, M. Crane, L. Collins, C.H. Yarboro, E.M. Vaughan, T. Kuroiwa, J.E. Balow, D.T. Boumpas. ARTICLE
Combination Therapy with Pulse Cyclophosphamide plus Pulse Methylprednisolone Improves Long-Term Renal Outcome without Adding Toxicity in Patients with Lupus Nephritis
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