How did cyclophosphamide become the drug of choice for lupus nephritis?

Thirty years ago, Donadio and colleagues published the results of a randomized study in 50 patients with diffuse proliferative lupus nephritis and reduced creatinine clearance [1]. The patients were randomly assigned to either prednisone alone or prednisone in combination with oral cyclophosphamide (CTX). The corticosteroid-only group received 60 mg daily for 1 to 3 months, and then tapered to receive 20 mg daily by 6 months. Those in the second group received, in addition, oral CTX 2 mg/kg body weight, which was subsequently titrated to the peripheral white cell count. The majority of patients in both groups improved with therapy. The patients who quickly progressed to ESRD were equally divided between the two treatment regimens. It was in the long-term follow-up that the CTX group appeared to do better: after a mean of 43 months, 10 of 21 patients in the prednisone-only group relapsed, compared to 3 of 21 in the prednisone-CTX group. Despite the difference in flare rates, though, the proportion of the patients alive with stable or even improved renal function was similar with the two treatment regimens. The stated key point from this study was that patients on combined treatment were less likely to flare compared to those receiving only prednisone. However,several other important observations were made: