ALMS
“Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis”
by the Aspreva Lupus Management Study (ALMS) Group
JASN May 2009, 20 (5) 1103-1112. [full text]
Lupus Nephritis (LN) occurs in up to 60% of systemic lupus erythematosus (SLE) cases,
although prevalence and treatment response vary widely by age, gender, location, and
race/ethnicity. LN is a predictor of poor survival, disproportionately affecting black and Hispanic
patients. Historically, LN is treated with IV cyclophosphamide (IVC), although response is
typically slow and patients are affected by a range of adverse effects, such as bladder and
gonadal toxicity. Mycophenolate mofetil (MMF) is an alternative immune suppressant with less
severe side effects and has showed equivalent efficacy as IVC in induction treatment studies,
with initial trials suggesting that MMF may actually be advantageous to IVC.
This study is a prospective, randomized, open label, parallel group multicenter study that
sought to compare MMF and IVC as induction of a renal response for active LN. Three hundred
and seventy patients with class III- V lupus nephritis were randomly assigned to MMF or IVC in
a 24 week induction study. Both groups received a prednisone tape starting at a 60mg/d dose.
The primary endpoint of this study was a prespecified decrease in urine protein/creatinine ratio
and stabilization or improvement in urine creatinine. The secondary endpoints included complete renal remission, systemic disease activity and damage, and safety.
Patient Population
In this study, 460 patients were screened in 20 different countries in North America, Asia, Australia, Latin America and Europe with 370 patients ultimately randomly assigned to each treatment arm. The inclusion criteria for this study were patients aged 12-75 with a diagnosis of SLE and active lupus nephritis confirmed by kidney biopsy within 6 months prior to randomization. The study additionally required that patients were class III, IV-S, IV-G, V, III+V, or IV+V or ≥2 g/day proteinuria required for patients with class III or V histology.
Baseline characteristics for the patient population included in this study a mean age of 32 years, primarily female participants (85%), and several racial groups (39.7% White, 33.2% Asian, 27% Other; 35.4% Hispanic). The mean urine P/Cr ratio was 4.1 with eGFRs of 45% ≥90; 28.5% 60-90; 17.9% 30-60; 8.7% <30.
Outcomes
This study did not meet its primary objective of showing that MMF was superior to IVC in induction treatment for lupus nephritis over 24 weeks of treatment. Renal response, defined by a defined reduction in urine protein/creatinine ratio and stabilization or improvement in serum creatinine, was 56.2% in the MMF group vs. 53.0% in the IVC group (OR 1.2; 95% CI 0.8-1.8; P=0.58).
Results
Results were similar for subgroup analysis; there were no significant differences in adverse events, serious adverse events, infection or GI disorders. There were seven deaths in the MMF group and five in the IVC group. Of note, five of the deaths in the MMF group were due to infection and none were related to SLE, whereas two deaths in the IVC group were infection related and two deaths were secondary to SLE.
Discussion
While this study did not show superiority of MMF over IVC for induction therapy, it showed that MMF with prednisone is at least as effective as IVC and prednisone. Interestingly, the authors also noted a significant difference between treatment group and race. More patients in the black and Hispanic groups responded to MMF over IVC in comparison to the white and Asian treatment groups, with a response of 60.4% vs. 38.5% (OR 2.4; 95% CI 1.1-5.4; P=0.033) in the black and mixed race group and 60.9% vs. 38.8% (OR 2.5; 95% CI 1.2-5.1; P=0.011) in the Hispanic group. These differences were not explained by variance in baseline characteristics between the groups. A racial difference in response to treatment represents an important finding, as Hispanic and black patients are at higher risk for advanced renal disease.
There were several limitations in this study. First, 24 weeks may not have been a sufficient duration of time to determine the efficacy of MMF vs IVC. There may have been differences in efficacy that would emerge during the maintenance phase of treatment. An additional limitation is that socioeconomic data was not recorded in this study. Thus, the subgroup analysis that showed difference between racial groups should be viewed cautiously, as socioeconomic factors may have contributed to this variance. Finally, it is important to note that several of the most severe side effects of IVC, such as malignancy and gonadal toxicity, would not be seen in such an acute time period and are important considerations in determining drug therapy.
Summary
In summation, the study did not meet its primary objective of showing the MMF is superior to IVC as induction therapy for lupus nephritis, although some findings suggest that MMF may be advantageous over IVC for some groups. This study did show that MMF with steroids is at least as effective as IVC with steroids for renal response in induction therapy.
Summary by Kelly Colas
