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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]."
N Engl J Med. 2004;350:971-980, 1044-1046
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