Should we give up on anti-B-cell antibody therapy in the treatment of lupus nephritis?

For those of us managing patients with active lupus nephritis, the promise of a safe new therapy five years ago - anti-CD20 monoclonal antibody therapy against B cells- seemed like a breath of fresh air. A number of case controlled series of relapsing lupus nephritis (LN) were published highlighting the efficacy of Rituximab, anti-CD20 B cell depleting monoclonal humanized antibodies, in triggering remission. Indeed my own clinical practice, and that of several colleagues, has shown quite remarkable remissions in some patients seemingly brought about by Rituximab in patients who had relapsed on standard therapy including Cyclophosphamide (CYC). In late 2008 the EXPLORER study was reported, in which patients with non-solid organ lupus received Rituximab in addition to standard therapy, and saw no benefit in BILAG (lupus activity scores). Although the study had limitations, and excluded patients with LN, some questions were raised about Rituximab, given the widely accepted efficacy of MMF in Lupus and LN. Last year the LUNAR study reported 144 patients with first presentation LN (class III or IV). In addition to prednisone and MMF, patients were randomized to either 4 doses of Rituximab over 1y or placebo. Although there was a clear trend toward benefit in the Rituximab group, and it was well tolerated, there were no significant differences in remission rates at 52 weeks (Furie et al ACR/ARHP meeting 2009; abstract 1149).


Does this mean that Rituximab does not work and we should not use it? I think that this is not the case:

1. We should reflect on how MMF (which also has anti-B cell activity) has become a widely accepted, and somewhat surprising, therapy. Initially MMF was found to be effective in case controlled series of relapsing patients. Then, in a RCT from Hong Kong, it was tested head to head with CYC (which has anti-B cell activity) in newly-presenting patients with class III and IV LN disease, and proved equally efficacious as CYC at 1yr and 5yrs. This landmark study was equivalent to, but different from, the LUNAR study. Rituximab was given in addition to prednisone + MMF, not head to head with prednisone + MMF as in the LUNAR study. We will never know whether MMF would have added benefit beyond that of prednisone + CYC in the Hong Kong trials. The LUNAR study design may have therefore been flawed, by drawing on experience from cancer trials in its design, where therapies are added to standard regimes (rather than in the Hong Kong LN trial where therapies were studies head to head).
2. Recently a trial of anti-B cell antibody therapy (BLISS-76) using Belimumab, which inhibits the activity of BLys (an activator of B cells), reported positive results in non-solid organ lupus (analogous to the EXPLORER trial). While there will be differences in the efficacy of Rituximab and Belimumab, the differences in the trial design may prove to be more important in providing evidence of efficacy for this anti-B cell therapy. It suggests that anti-B cell therapy may still be a good option for lupus.
3. Without doubt SLE (and lupus nephritis) is not a single disease, rather syndromes with multiple genetic predispositions. It is clear that some patients respond well to one therapy, whereas others respond better to a second regime. It is also true that patients receive different types of therapy during the course of their disease as their responsiveness changes.
4. Rituximab is probably the safest immunotherapy we have for lupus.

In my opinion, Rituximab remains a therapeutic option for relapsing LN, as it is safe and is efficacious in many of these patients. It behooves us to consider carefully whether additive trials, which are now the standard in cancer therapy, are appropriate in lupus nephritis and whether we can justifiably withhold MMF from patients with active disease for a potentially better therapy.