HDCN Article Review/Hyperlink

Gourley MF, Austin HA, Scott D, et al

Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis: a randomized, controlled trial

Ann Int Med (Sep) 125:549-557 1996

Investigators at the NIH randomized 82 patients with lupus nephritis into three treatment groups: 1) intravenous methylprednisolone (MP) as a bolus on three consecutive days followed by a minimum of twelve monthly infusions; 2) boluses of intravenous cyclophosphamide once monthly for six consecutive months, then q 3 months for at least two more years; or 3) a combination of these two regimens. Patients were re-evaluated after one year of study and those receiving only MP who were in remission had therapy discontinued; however, if they continued to have persistent activity as defined by ten dysmorphic RBC's/HPF, cellular casts and more than one gram of protein per day, treatment was continued and re-evaluated at further six month intervals. Cyclophosphamide-treated patients who were also receiving MP had this agent withdrawn if they were improved at one year. In addition to these agents, all patients received oral prednisone 0.5 mg/kg daily for four weeks which was then tapered to 0.25 mg/kg q OD if possible.

Outcome was measured as the percentage of patients who achieved renal remission, number of nonresponders which included doubling of the serum creatinine in the definition, and percentage of adverse events, five years after the last patient was enrolled. Secondary outcome measures included development of end stage renal disease, stable doubling of the serum creatinine and the number of renal relapses. All groups were comparable regarding demographics, and clinical and serologic lupus activity.

Of the patients in the MP group, four had doubling of their serum creatinine and three developed ESRD; one patient in the cyclophosphamide group had serum creatinine doubling and one developed ESRD. These outcomes did not occur in any of the combination group. Renal remission occurred in 26% of the MP group compared to 48% of the cyclophosphamide group (P=.038) vs. 61% of the combination therapy group (P < .001). Relapse was greatest in the MP group (36%). This compared to 0% in the combination therapy group (P=.016). Patients were much more likely to have doubling of serum creatinine in the MP group and the probability of having remission was decreased in this group (P=.028). There were three deaths in the cyclophosphamide-treated patients and a much higher incidence of amenorrhea. Avascular necrosis was most prevalent in the MP group.

Comment: It was not clear how much total prednisone was received by the cyclophosphamide only group. While the best results were achieved with the combination group, it would be important to know if the adverse affects of using more steroids is outweighed by the higher renal remission rate this group achieved. This study provides more data to support the use of monthly cyclophosphamide in the treatment of lupus nephritis, with the best renal outcomes being achieved in those patients who received this therapy in combination with MP. (N. Kevin Krane, M.D., Tulane University)