Where MMF is being used with substantial success is in remission maintenance. Following the approach described by Contreras (N Engl J Med. 2004;350:971-980), remission is induced with IV cyclophosphamide, and then maintained by MMF. This approach has largely replaced the NIH-derived regimen of IV cyclophosphamide administered every three months as the standard of care for remission maintenance.
Perhaps the trouble with existing trials and with the use of MMF in general is that we still dose this drug on a model of “one size fits all” rather than individualizing the dose based on pharmacokinetic and pharmacogenomic personal information. An interesting hypothesis related to pharmacokinetic factors may provide another explanation for the variable response rates of MMF in lupus nephritis.
In a soon-to-be published report, Joy et al spotlight significant increases in the clearance of MMF in patients with lupus nephritis on the basis of creatinine clearance and urine protein excretion greater than 1 g/day (Pharmacotherapy. 2008; in press). MMF is known to be a highly protein-bound drug, but until now, studies assessing the effect of proteinuria and hypoalbuminemia on the clearance of MMF have not been done.
It will be interesting to see the results of future studies assessing the relationship of proteinuria, hypoalbuminemia, and increased MMF clearance among a wider range of creatinine clearances, especially when the decline in creatinine clearance is significant at presentation. Consideration of these factors may translate into dose titration based upon an individual’s clearance profile rather than standard dosing ranges.
Role for a monoclonal antibody?
Several small prospective and retrospective studies have pointed to the potential benefits of B-cell depletion therapy with rituximab in the treatment of lupus nephritis. This chimeric monoclonal antibody is directed against CD20 protein on B cells. Rituximab has been approved for the treatment of non-Hodgkin’s lymphoma and moderate-to-severe rheumatoid arthritis. Since original reports of open-label uncontrolled trials by Leandro in 2002, rituximab has been used off-label mostly as an option for the treatment of severe, resistant forms of lupus nephritis (Arthritis Rheum. 2002;46:2673-2677). Many of these individuals have received IV cyclophosphamide and other therapies prior to receiving rituximab.
Initial treatment response rates from a randomized, controlled, multicenter phase 2/3 trial assessing the safety and efficacy of rituximab with MMF compared with MMF alone for maintenance therapy in patients with class III or IV lupus nephritis (LUNAR) are expected in early 2009. Preliminary results from its sister phase 2/3 trial, EXPLORER, which evaluated rituximab for SLE disease without nephritis, have failed to demonstrate clinical efficacy.
Yet an interesting case report published earlier this year describes three patients in France who received rituximab and corticosteroids for induction and rituximab alone as their sole maintenance therapy (Am J Kidney Dis. 2008;52:346-352). With an average of 3.5 years’ follow-up, investigators report complete remission in these patients documented by clinical parameters and a control repeat renal biopsy.
Some patients with lupus nephritis certainly do well with this drug. But which patients will benefit the most? Moreover, what is the best protocol for rituximab administration? What is the best approach to determining efficacy of this drug? Should we follow B-cell depletion or diminution of autoantibody titer? When should another dose be given? The answers to these questions are especially germane, as this drug remains incredibly expensive at almost $10,000 for a course of therapy.