These results are notable in finding no difference in short-term efficacy, and no appreciable difference in tolerability, between MMF and intravenous cyclophosphamide as induction treatment of serious lupus nephritis. In contrast, three meta-analyses of previous smaller clinical trials indicated that MMF was more efficacious than cyclophosphamide and that MMF was safer, with a lower risk of infections, and in one meta-analysis, a lower risk of death.1-3 Results of the meta-analyses may have been influenced by chance, publication bias, and differences among studies in the types of patients included or in the definition of endpoints. This study serves as a useful reminder that a meta-analysis of small trials is not a substitute for a large well-done trial.
However, the overall finding that both treatments were “equal” overshadows perhaps the most interesting and clinically useful finding of the study: treatment responses differed by race. The proportion of patients with a renal response was similar between treatment groups among Asians and whites. However, fewer patients of “other” races (largely blacks and mixed-ethnicity Hispanics) had a renal response to intravenous cyclophosphamide than to MMF (38.5% versus 60.4%). Previous observational studies suggested that blacks with lupus nephritis were less likely than whites to respond to treatment with cyclophosphamide, but it was unclear how much of the difference in outcomes might have been due to ethnic differences in socioeconomic conditions and access to care.4,5 The results of ALMS suggests that the poorer responses of blacks and Hispanics to cyclophosphamide is likely not due to socioeconomic differences, and that ethnicity should be considered in treatment decisions. Based on these data, it is reasonable to consider MMF as the first choice for treatment of serious lupus nephritis in black and Hispanic patients.
The question of ethnic differences in response to cyclophosphamide deserves further investigation. Blacks treated with cyclophosphamide-based regimens in clinical trials for breast cancer or multiple myeloma did not have poorer outcomes than whites, suggesting that the association may not be generalizable to other conditions.6,7 More importantly, ethnicity is likely only a poor surrogate for more relevant pharmacogenetic differences that influence cyclophosphamide distribution or metabolism. Understanding these differences would enable more appropriate targeting of cyclophosphamide for patients of all ethnicities, as well as for patients with conditions other than lupus nephritis that are treated with cyclophosphamide.
References
- Moore RA, Derry S. Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthrits Res Ther. 2006; 8:R182.
- Zhu B, Chen N, Lin Y, et al. Mycophenolate mofetil induction and maintenance therapy of severe lupus nephritis: A meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2007; 22:1933-1942.
- Walsh M, James M, Jayne D, et al. Mycophenolate mofetil for induction therapy of lupus nephritis: A systematic review and meta-analysis. Clin J Am Soc Nephrol. 2007; 2:968-975.
- Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: Poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int. 1997; 51:1188-1195.
- Contreras G, Lenz O, Pardo V, et al. Outcomes in African-Americans and Hispanics with lupus nephritis. Kidney Int. 2006; 69:1846-1851.
- Modiano MR, Villar-Werstler P, Crowley J, Salmon SE. Evaluation of race as a prognostic factor in multiple myeloma. An ancillary of Southwest Oncology Group Study 8229. J Clin Oncol. 1996;14:974-97.
- Roach M III, Cirrincione C, Budman D, et al. Race and survival from breast cancer: Based on Cancer and Leukemia Group B trial 8541. Cancer J Sci Am. 1997; 3:107-112.
