New and future therapies for lupus nephritis

In a US study, mycophenolate or azathioprine was better than cyclophosphamide as maintenance

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.