Therapeutic studies in NZB/W mice. I. Synergy of azathioprine, cyclophosphamide and methylprednisolone in combination

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Abstract
This study compares different immunosuppressive regimens in the treatment of the lupus‐like nephritis of NZB/W mice. Groups of 5‐month‐old female NZB/W mice were given azathioprine, cyclophosphamide and methylprednisolone in all one‐, two‐ and three‐drug regimens, each drug in the relatively low dose of 1.5 mg/kg/day. Treatment for 3 months with one or two drugs resulted in modest suppression of NZB/W disease. Mice receiving all three drugs had significantly less proteinuria, lower titers of anti‐DNA antibody and less severe, histologically evident renal involvement than mice treated with one or two drugs. Survival at 1 year was 10% for untreated controls, 44% for one‐drug‐treated, 37% for two‐drug‐treated and 86% for the three‐drug‐treated mice. The survival for the three‐drug regimen was significantly longer than any other group (P < 0.01). The three‐drug regimen was synergistic, since mice treated with each drug at three times the dose had significantly more proteinuria after 3 months of treatment and lowered 1 year survival (33%). The beneficial effects of triple‐drug therapy were attained without increased toxicity. This study represents the first controlled evaluation of single versus combination therapy in a model of autoimmune disease. Based on these results, a controlled evaluation of triple‐drug therapy in human systemic lupus erythematosus appears warranted.