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Dorough Lupus Foundation

MMF May Be Helpful for Maintenance Therapy in Lupus Nephritis

Author: Laurie Barclay, MD , N Engl J Med. 2004; 350:971-980, 1044-1046

March 3, 2004 � After induction with cyclophosphamide, maintenance therapy in lupus nephritis is better with either mycophenolate mofetil (MMF) or azathioprine than with cyclophosphamide, according to the results of a randomized trial published in the March 4 issue of the New England Journal of Medicine. The editorialist warns of significant study limitations.

"Long-term therapy with cyclophosphamide enhances renal survival in patients with proliferative lupus nephritis; however, the beneficial effect of cyclophosphamide must be weighed against its considerable toxic effects," write Gabriel Contreras, MD, MPH, and colleagues from the Veterans Affairs Medical Center and University of Miami in Florida. "The efficacy and safety of [MMF], which inhibits purine synthesis and has antiproliferative effects on lymphocytes and profoundly attenuates the production of autoantibodies by B cells, have been demonstrated in a rodent model of lupus nephritis and in patients with diffuse proliferative lupus nephritis."

After induction therapy consisting of a maximum of seven monthly boluses of intravenous cyclophosphamide (0.5-1.0 g/m2) plus corticosteroids, 59 patients with lupus nephritis were randomized to maintenance therapy with quarterly intravenous injections of cyclophosphamide, oral azathioprine (1.0-3.0 mg/kg/day), or oral MMF (500-3,000 mg/day) for one to three years.

At baseline, World Health Organization (WHO) category was class III in 12 patients, class IV in 46 patients, and class Vb in one patient. Clinical characteristics were similar between the three treatment groups, except that the chronicity index was 1.9 points lower in the cyclophosphamide group than in the MMF group (P = .009).

Of five patients who died during maintenance therapy, four were in the cyclophosphamide group and one was in the MMF group. Chronic renal failure developed in five patients, including three in the cyclophosphamide group and one each in the azathioprine and MMF groups.

Compared with the cyclophosphamide group, the MMF and azathioprine groups had a higher 72-month event-free survival rate for the composite end point of death or chronic renal failure (P = .05 and P = .009, respectively). The rate of relapse-free survival was higher with MMF than with cyclophosphamide (P = .02). Compared with the other two groups, the cyclophosphamide group fared worse in terms of incidence of hospitalization, amenorrhea, infections, nausea, and vomiting.

The authors note that the study was not powered to detect small differences between the two sequential-therapy groups, and that the results cannot be generalized to children with lupus nephritis or to patients with mild forms of lupus nephritis.

"Short-term therapy with intravenous cyclophosphamide followed by maintenance therapy with MMF or azathioprine was more efficacious and safer than long-term therapy with intravenous cyclophosphamide for the treatment of proliferative lupus nephritis," they write. "Maintenance therapy with [MMF] was associated with a significantly lower relapse rate than was long-term therapy with intravenous cyclophosphamide."

Roche Pharmaceuticals provided research-nurse support and MMF from 1999 through 2003, as well as lecture fees and a grant to Dr. Contreras and lecture fees to another author.

In an accompanying editorial, James E. Balow, MD, and Howard A. Austin III, MD, from the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, discuss various limitations of this study. Azathioprine and MMF were superior to cyclophosphamide only when the outcomes of patient survival and renal survival were combined, and there were no significant differences among the treatment groups in renal survival. They discuss several reasons why these findings may not be generalizable to other patient populations.

"None of these potential caveats are meant to undermine the value of this controlled trial examining the risks and benefits of widely used maintenance therapies for proliferative lupus nephritis," they write. "In our opinion, the most reliable take-home message of [this study] is that azathioprine and [MMF] are good options for maintenance therapy in patients with proliferative lupus nephritis. Nonetheless, there is clearly a need for further studies, with longer follow-up, conducted in a more broadly representative population of patients with systemic lupus erythematosus."

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