COMMENTARY

Keeping Lupus Nephritis at Bay: MMF or Azathioprine?

Lynda A. Szczech, MD

Disclosures

January 06, 2012

Mycophenolate versus Azathioprine as Maintenance Therapy for Lupus Nephritis

Dooley MA, Jayne D, Ginzler EM, ALMS Group, et al
N Engl J Med. 2011;365:1886-1895

The treatment of lupus nephritis has long been controversial due to a number of factors, including the heterogeneity of the disease and the difficulty in performing large enough studies to statistically compare treatment regimens. The role of mycophenolate mofetil (MMF) as a treatment for glomerular disease has been explored in IgA nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, as well as proliferative lupus glomerulonephritis. A trial comparing MMF to intravenous (IV) cyclophosphamide among persons with lupus nephritis recently revealed no significant difference between the 2 regimens.

The trial under discussion is the logical extension of its previously published sister trial[1] and enrolled patients with active class III, IV, or V lupus nephritis who had had a clinical response to induction therapy with either MMF or IV cyclophosphamide randomizing them to either MMF or azathioprine After 24 weeks of induction therapy, patients with a clinical response, as designated by their treating physicians, were randomized to receive either oral MMF dosed at 1 g twice a day or oral azathioprine dosed at 2 mg/kg/day. Patients were followed for primary endpoint, which was the time to treatment failure, as defined by time to death, end-stage renal disease (ESRD), sustained doubling of creatinine, renal flare, or need for rescue therapy. A renal flare was defined as the doubling of urinary protein to creatinine ratio to at least greater than 1 g. Investigators estimated that 114 patients in each group would provide 80% power to assess a failure rate of 37.5% at three years in the azathioprine groups and 20.0% in the MMF group, proving a hazard ratio (HR) of 0.475.

One hundred and sixteen patients were assigned to MMF and 111 to azathioprine. Of these patients, 73 patients in the MMF group and 54 patients in the azathioprine group completed the study. The reasons for withdrawal were balanced except for adverse events, which were frequent in both groups but more common in those receiving azathioprine (43 vs 29 patients).

Patients receiving MMF were less likely to experience a component of the composite endpoint (HR = 0.44, P = .003). The superiority of MMF was also seen when each of the components of the composite endpoint was examined separately. Time to renal flare and time to rescue therapy were significantly reduced in the MMF group (HR = 0.56 with P = .01 and HR = 0.39 with P = .02 for renal flare and rescue therapy, respectively). Time to ESRD and time to sustained doubling of serum creatinine trended to be less frequent in the groups receiving MMF but did not reach conventional levels of statistical significance (rate for ESRD 0% vs 2.7%, P = .07 and rate for sustained doubling of serum creatinine 0.9 vs 4.5%, P = .07 in the MMF and azathioprine groups respectively). An analysis of subgroups, including type of induction therapy, race, or region of the world, suggested no differences in these conclusions.

Supporting the benefit of MMF as maintenance therapy was its effect, as compared to azathioprine, on biomarkers of disease activity. Mean complement levels were lower in the first 3 months in the azathioprine group with a trend toward lesser decreases in double stranded DNA antibodies in the azathioprine group.

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