Mycophenolate Mofetil Superior to Azathioprine for Lupus Nephritis

Results of a randomized, double-blind, double-dummy, phase 3 study [N Engl J Med. 2011;365(20):1886-1895] found that patients with active lupus who underwent 36 months of maintenance therapy with mycophenolate mofetil after successful treatment with induction therapy have superior maintenance of renal response to therapy and prevention of relapse compared with patients who undergo maintenance therapy with azathioprine. After induction therapy to achieve remission, patients with lupus nephritis require long-term maintenance therapy to prevent relapse, progression to end-stage renal disease, and death. Many options are available for long-term maintenance therapy. Although many countries have used intravenous cyclophosphamide as the standard of care, more recent data suggested that oral mycophenolate mofetil and oral azathioprine are both superior. To compare the long-term efficacy of mycophenolate mofetil to azathioprine as maintenance therapy in patients with active lupus, the study randomized 227 patients with active lupus to 36-month maintenance therapy with mycophenolate mofetil (2 g/day) (n=116) or azathioprine (2 mg/kilogram of body weight/day) (n=111). All patients were 12 to 75 years of age, had active class III, IV, or V lupus nephritis, and had a clinical response during a 6-month induction trial, Aspreva Lupus Management Study. Patients were permitted up to 10 mg/day of prednisone or its equivalent. The primary efficacy outcome of the study was time to treatment failure, defined as death, end-stage renal disease, doubling of the serum creatinine level, renal flare, or the need for rescue therapy for lupus. Secondary outcomes included time to each component of treatment failure and adverse events. Based on an intent-to-treat analysis, the study found that mycophenolate mofetil was superior to azathioprine in the time to treatment failure (primary end point) with a hazard ratio (HR) of 0.44 (95% confidence interval [CI], 0.25-0.77; P=.003). Overall, 19 of 116 (16.4%) patients in the mycophenolate mofetil group and 36 of 111 (32.4%) patients in the azathioprine group had treatment failure. The study also found the superiority of mycophenolate mofetil over azathioprine in terms of secondary outcomes, including the time to treatment renal flare (HR, 0.50; 95% CI, 0.26-0.93; P=.03) and time to rescue therapy (HR, 0.39; 95% CI, 0.18-0.87; P=.02). Overall, renal flares occurred in 15 of 116 (12.9%) patients treated with mycophenolate mofetil and 26 of 111 (23.4%) patients treated with azathioprine. The rates of rescue therapy were 7.8% (9 of 116) of patients and 17.1% (19 of 111) of patients, respectively. No difference was found in the incidence of adverse events during treatments, which occurred in 98.3% of patients treated with mycophenolate mofetil and 97.3% in those treated with azathioprine (P=.68). Most adverse events were minor infections and gastrointestinal disorders. Of the serious adverse events reported, 23.5% occurred in the patients treated with mycophenolate mofetil and 33.3% in patients treated with azathioprine (P=.11). Overall, significantly more patients withdrew from treatment because of adverse events in the azathioprine group compared with the mycophenolate mofetil group (39.6% vs 25.2%; P=.02). According to the investigators, although this study included more patients with substantially longer follow-up than other controlled trials, further follow-up beyond the 36 months of the study is not planned. Therefore, there is no way to assess potential outcomes such as cardiovascular complications and end-stage renal disease that may appear more frequently after 5 to 20 years of treatment. Because of this, the authors state that it remains unknown how long treatment with mycophenolate mofetil needs to be continued. They emphasize, therefore, the need for improved biomarkers of response to distinguish disease remission from remission that occurs during treatment. Other limitations of the study include the possibility that patients may have been excluded who had disease that was more difficult to treat, and there were very few black patients who met clinical response criteria.