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Mycophenolate mofetil (Cellcept) was not superior to azathioprine over the long term for maintenance therapy of lupus nephritis, a multicenter European study found.
After nearly 10 years of follow-up, the mean serum creatinine was 0.85 mg/dL for patients treated with either mycophenolate or azathioprine, and the percentage of patients whose estimated glomerular filtration rate was below 60 mL/min/1.73 m2 was 11% for mycophenolate and 19% for azathioprine (P=0.39), according to Frederic A. Houssiau, MD, PhD, of the Universite Catholique de Louvain in Brussels, and colleagues.
Among the 105 patients included in the study known as MAINTAIN, three on mycophenolate had died and three had developed end-stage renal disease (ESRD) by 10 years, while two patients receiving azathioprine had died and one had ESRD, the researchers reported online in Annals of the Rheumatic Diseases.
The study confirmed the lack of superiority of mycophenolate "certainly not for hard outcomes such as death or chronic renal failure," Houssiau and colleagues stated.
Both of these drugs are common treatments for lupus nephritis, and two clinical trials thus far have compared their efficacy.
In the Aspreva Lupus Management Study (ALMS), mycophenolate mofetil was found superior to azathioprine in preventing relapses over 3 years in a group of 227 patients. However, in the MAINTAIN Nephritis Trial, which was designed as a superiority study favoring mycophenolate, fewer renal flares occurred with mycophenolate than azathioprine during the first 4 years (10 versus 13), but the difference was not statistically significant (P=0.486).
All patients in MAINTAIN were given three daily pulses of intravenous methylprednisolone and then oral prednisone in dosages of 0.5 mg/kg/day for the first month, tapered to 5 mg/day by week 52 and subsequently stopped if possible.
Induction therapy consisted of six pulses of 500 mg cyclophosphamide during a 10-week period, followed by azathioprine or mycophenolate for 5 years in target doses of 2 mg/kg/day and 2 g/day, respectively.
After 5 years, further treatment decisions were made by the patients and their treating physicians.
Along with the five deaths, four of which were from sepsis and one from systemic lupus erythematosus, 13 patients were lost to follow-up over the 10 years.
In the current report, at the last follow-up there had been 22 flares in patients on azathioprine and 19 in those receiving mycophenolate. Additional immunosuppressants were required in 36% of patients receiving mycophenolate and in 47% of those in the azathioprine group (P=0.38).
The long-term follow-up study also addressed other treatment questions, such as whether baseline factors or early changes in proteinuria predicted renal outcome. They found that no baseline characteristics, including disease activity scores, blood pressure, or creatinine could differentiate subsequent good or poor outcome.
However, a rapid drop in proteinuria following the initiation of treatment was associated with a favorable long-term outcome. The positive predictive value of a 24-hour proteinuria below 0.5 g/day was 89% at 3 months, 90% at 6 months, and 92% at 1 year, the investigators reported.
"In this report, we show that patients whose proteinuria is less than or equal to 0.5 g/day at 12 months (half of the entire cohort) run a very low risk (8%) of any level of long-term renal impairment at 10 years," the investigators reported.
They also considered whether including serum creatinine and the presence of red blood cells in urine in a predictive model with proteinuria would improve the accuracy.
"The data demonstrate that proteinuria decrease alone drives the positive predictive value of the response at 12 months," they noted.
"Persistent hematuria at 12 months should therefore not influence treatment decisions at the bedside," they wrote.
"Current standard treatment of [lupus nephritis] consists of two phases: an initial phase to induce a sufficient level of response -- and ideally complete renal remission -- and a subsequent phase to maintain the response, keeping in mind that the primary objective is the prevention of any level of renal impairment in the very long term with minimal drug-related toxicity," Houssiau and colleagues stated.
As to the possible reasons why MAINTAIN and ALMS had conflicting results, one is that the studies differed in design. Two induction regimens were used in ALMS (oral mycophenolate or intravenous cyclophosphamide), and patients went on to maintenance therapy with mycophenolate or azathioprine only if they showed an adequate response by 6 months.
In MAINTAIN, both groups were given the same induction therapy and began maintenance therapy with one of the two agents at 3 months whether or not they fully responded to the induction regimen.
Another factor that may have contributed to the different outcome was that more minority patients were included in ALMS (56% versus 17%).
The results of the study support the recommendations of the European League Against Rheumatism and the American College of Rheumatology that azathioprine or mycophenolate can be used for maintenance therapy of lupus nephritis, the investigators concluded.
Limitations included the small number of patients and the variations in treatment permitted between years five and 10 of follow-up.
Houssiau and co-authors disclosed no relevant relationships with industry.
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Reviewed by
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
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