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Methylprednisolone and Cyclophosphamide, Alone or in Combination, in Patients with Lupus Nephritis: A Randomized, Controlled Trial

Mark F. Gourley, MD; Howard A. Austin III, MD; Dorothy Scott, MD; Cheryl H. Yarboro, RN; Ellen M. Vaughan, RN; Joanne Muir, RN; Dimitrios T. Boumpas, MD; John H. Klippel, MD; James E. Balow, MD; and Alfred D. Steinberg, MD
[+] Article and Author Information

From the National Institutes of Health, Bethesda, Maryland. Acknowledgments: The authors thank the members of Arthritis and Rheumatism Branch senior staff, medical staff fellows, clinical associates, Clinical Center nursing staff, and the referring physicians, without whose assistance this study would not have been possible. Grant Support: In part by a fellowship from the Arthritis Foundation (Dr. Gourley). Requests for Reprints: Mark Gourley, MD, Section of Rheumatology, Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010-2975. Current Author Addresses: Dr. Gourley: Section of Rheumatology, Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010-2975.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;125(7):549-557. doi:10.7326/0003-4819-125-7-199610010-00003
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Background: Uncertainty exists about the efficacy and toxicity of bolus therapy with methylprednisolone or of the combination of methylprednisolone and cyclophosphamide in the treatment of lupus nephritis.

Objective: To determine 1) whether intensive bolus therapy with methylprednisolone is an adequate substitute for bolus therapy with cyclophosphamide and 2) whether the combination of methylprednisolone and cyclophosphamide is superior to bolus therapy with methylprednisolone or cyclophosphamide alone.

Design: Randomized, controlled trial with at least 5 years of follow-up.

Setting: Government referral-based research hospital.

Patients: 82 patients with lupus nephritis who had 10 or more erythrocytes per high-power field, cellular casts, proteinuria (>1 g of protein per day), and a renal biopsy specimen that showed proliferative nephritis.

Interventions: Bolus therapy with methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m2 body surface area), given monthly for 6 months and then quarterly; or bolus therapy with both methylprednisolone and cyclophosphamide.

Measurements: 1) Renal remission (defined as <10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of <1 g of protein per day without doubling of the serum creatinine level), 2) prevention of doubling of the serum creatinine level, and 3) prevention of renal failure requiring dialysis.

Results: Renal remission occurred in 17 of 20 patients in the combination therapy group (85%), 13 of 21 patients in the cyclophosphamide group (62%), and 7 of 24 patients in the methylprednisolone group (29%) (P < 0.001). Twenty-eight patients (43%) did not achieve renal remission. By life-table analysis, the likelihood of remission during the study period was greater in the combination therapy group than in the methylprednisolone group (P = 0.028). Combination therapy and cyclophosphamide therapy were not statistically different. Adverse events were amenorrhea (seen in 41% of the cyclophosphamide group, 43% of the combination therapy group, and 7.4% of the methylprednisolone group), cervical dysplasia (seen in 11% of the cyclophosphamide group, 7.1% of the combination therapy group, and 0% of the methylprednisolone group), avascular necrosis (seen in 11% of the cyclophosphamide group, 18% of the combination therapy group, and 22% of the methylprednisolone group), herpes zoster (seen in 15% of the cyclophosphamide group, 21% of the combination therapy group, and 3.7% of the methylprednisolone group) and at least one infection (seen in 26% of the cyclophosphamide group, 32% of the combination therapy group, and 7.4% of the methylprednisolone group).

Conclusions: Monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide. A trend toward greater efficacy with combination therapy was seen.

Figures

Grahic Jump Location
Figure 1.
Treatment regimens and decision pathways used in this clinical trial for lupus nephritis.
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Grahic Jump Location
Figure 2. Kaplan-Meier survival analyses are shown. The number of patients at risk in each group is shown above the survival curve for each year of the study. The probability that the serum creatinine level would not double during the study did not differ in the combination therapy group (MP + CY) and the cyclophosphamide group (CY) ( > 0.2). The probability that the serum creatinine level would not double tended to be greater for the methylprednisolone group (MP) than for the combination therapy group ( = 0.057). The symbols represent either an event or the censorship of an individual patient.
Probability that the serum creatinine level would not double during the study period by treatment group.PP
Grahic Jump Location
Grahic Jump Location
Figure 3. The number of patients at risk in each group is shown above the survival curve for each year of the study. The combination therapy group (MP + CY) differs from the methylprednisolone group (MP) ( = 0.028); the cyclophosphamide group (CY) did not differ from the combination therapy group ( > 0.2) or the methylprednisolone group ( = 0.16).
Probability of remission during the study period by treatment group.PPP
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