In an article recently published in Arthritis Care & Research, Lu et al presented the largest series of patients with systemic lupus erythematosus (SLE) treated with rituximab reported from a single center (1). Two characteristics of this study deserve mention. First, the 50 patients had SLE that was refractory to conventional therapy, and second, only 11% of patients did not respond to treatment (no change in the British Isles Lupus Assessment Group activity index A or B score after treatment). These excellent results are very similar to those we found in a recent systematic review of ∼200 SLE patients treated with rituximab (2).
These promising results in uncontrolled studies of refractory SLE patients are in clear contrast with the poor results of the recently completed Efficacy and Safety of Rituximab in Patients with Severe SLE (EXPLORER) and Efficacy and Safety of Rituximab in Subjects with ISN/RPS Class III or IV Lupus Nephritis (LUNAR) randomized controlled trials (RCTs). The EXPLORER trial was a phase II/III randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety profile of rituximab in patients with active SLE but excluding patients with lupus nephritis or those treated with prednisone (1 mg/kg of body weight per day) and/or cyclophosphamide/calcineurin inhibitors. A total of 257 patients were randomized from ∼55 sites in the US and Canada. The preliminary results published in abstract form showed that rituximab was not superior to prednisone in these patients (3). The LUNAR trial was a phase III, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of rituximab plus mycophenolate versus placebo plus mycophenolate in SLE patients with proliferative nephritis (types III/IV). In this trial, patients treated with cyclophosphamide, calcineurin inhibitors, or mycophenolate within the 3 months prior to screening were excluded. Once again, the preliminary results showed that rituximab plus mycophenolate was not superior to mycophenolate (4).
Although definite conclusions must await full details of these trials, the negative preliminary results are discouraging for advocates of new therapeutic agents for SLE (5), especially given the good results for the off-label use of rituximab reported by various centers with long clinical experience in the management of SLE (6–12). Before concluding that B cell depletion is not a good therapy for SLE, a careful evaluation of the design of the EXPLORER and LUNAR trials is necessary. The following 4 points should be considered. In regard to disease severity, a significant percentage of patients included probably had mild to moderate SLE (especially in the EXPLORER trial) with no history of lack of response to standard therapies (corticosteroids, cyclophosphamide, and/or mycophenolate). This, in itself, may explain why rituximab was not superior to the other drugs in these predominantly noncomplicated patients. Considering concomitant therapies, the high doses of corticosteroids permitted in both arms of these trials could lead to significant differences not being apparent in a short-term evaluation. In addition, the possible synergistic effect of rituximab in combination with immunosuppressive agents (cyclophosphamide or mycophenolate), suggested by some authors to have significant advantages in complicated, refractory SLE cases (1, 9), was not evaluated in these RCTs. Regarding ethnic factors, the 2 RCTs included American patients, predominantly from the US and Canada, but also from Mexico, Brazil, and Argentina. However, the majority of patients from recent uncontrolled studies were European (1, 6, 7, 9, 11, 12). This ethnicity is important because some studies have suggested a variable therapeutic response to the main immunosuppressive agents in different ethnic groups (13).
Finally, in regard to primary end point definition, current trials in SLE require demonstration of the superiority of rituximab over current first-line therapies in SLE (corticosteroids, cyclophosphamide, and mycophenolate). This does not correlate with the use of rituximab in clinical practice, i.e., its overwhelming use in patients with SLE refractory to these therapies. Furthermore, the fact that rituximab was not shown to be superior to other therapies does not necessarily signify that it is inferior.
The patients included in the 2 recently completed RCTs of rituximab in SLE seem to be completely different from the individual patients who have been receiving rituximab off-label since 2000. This may help to explain the apparent differences between these trials and uncontrolled studies. Thought should be given to the design of future trials in SLE treatment which, compared with rheumatoid arthritis (the paradigm for the licensed use of biologic therapies), is more clinically heterogeneous and infrequent, and occurs in a younger population.
In summary, while the use of B cell depletion therapies as first-line treatment or in patients with a predominantly mild form of the disease is not recommended, its off-label use in severe, refractory SLE cases appears to be sufficiently positive to warrant the continued use in these patients.