Managing Lupus Nephritis: An Update
Researchers are making headway, but the best therapy with the fewest side effects remains unclear.
Systemic lupus erythematosus (SLE) is a chronic autoimmune vasculitis that affects 1.5 million people in the United States, with approximately 160,000 new cases each year.
The clinical manifestations of this disease range from mild skin involvement to severe multi-organ involvement, including kidney and central nervous system disease. More than half of those with SLE will develop lupus nephritis, and a proportion of those patients will progress to end-stage renal disease (ESRD) despite aggressive therapy.
Randomized trials from the mid-1980s and forward have shaped our approach to treatment induction and maintenance in patients with the most severe forms of lupus nephritis (N Engl J Med. 1986;314:614-619). More than 20 years later, we find ourselves still searching for pharmaceutical novelties that will finally usurp the gold standard title still allotted to glucocorticoids and cyclophosphamide. Interest in newer therapies, including mycophenolate mofetil (MMF) and the anti-CD20 monoclonal antibody rituximab, have provided potentially new approaches for the treatment of lupus nephritis.
In fact, more than a dozen experimental approaches to quell specific inflammatory mediators are being tried in human SLE. Yet the question remains as to what is the best therapy with the fewest side effects that will result in rapid induction and then maintenance of persistent lupus nephritis remission.
Signs of progress
There has been some progress. Cyclophosphamide is used more intelligently when given IV rather than orally, for shorter times, and with less and less glucocorticoid exposure (Ann Intern Med. 2001;135:248-257). Yet it has been the use of MMF and now rituximab that has provided the most promising alternatives to these therapies. MMF was first introduced in 1995 for immunosuppression in transplant patients and since then has been used for multiple immune-mediated glomerular diseases.
MMF for the treatment of lupus nephritis has been reported in multiple abstracts, case series, and small randomized trials. An FDA-sponsored study provided evidence suggesting the equivalence of MMF when compared with IV cyclophosphamide in remission induction in patients with proliferative lupus nephritis (N Engl J Med. 2005;353:2219-2228). MMF benefited from a more favorable side-effect profile. This trial followed on the heels of similar results from Hong Kong (J Am Soc Nephrol. 2005;16:1076-1084).
Yet a large, multicenter, phase 3 trial, the Aspreva Lupus Management Study (ALMS), failed to meet the primary objective of demonstrating that MMF was superior to IV cyclophosphamide in in-ducing remission of severe lupus nephritis. Additionally, there were no significant differences in the number of adverse events. The preliminary reports, presented at the American Society of Nephrology Renal Week in November 2007 and still in abstract form, were based on treatment responses during the initial 24-week induction phase of therapy (Appel GB et al. Abstract no. SC-FA307).
With 370 subjects randomized 1:1 to the IV cyclophosphamide arm (dose 0.5-1 gram/m2) or MMF (target dose 3 g/day), a total of 53% and 56.2%, respectively, achieved the criteria for a favorable treatment response, defined by reduction of proteinuria and stabilization of creatinine clearance. Despite the inability to prove superiority, this study may further support comparable remission rates between MMF and cyclophosphamide.