An open-label safety and efficacy study of an anti-CD20 antibody (rituximab, Rituxan) for anti-B-cell therapy in the treatment of systemic lupus erythematosus

B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE) [1]. The availability of a highly effective and relatively safe B-cell-depleting drug, rituximab (Rituxan®; Genentech, South San Francisco, CA, USA, and Biogen Idec, San Diego, CA, USA), has permitted us to begin to test the hypothesis that removal of B cells would provide a therapeutic benefit for SLE patients [2]. An initial phase I safety trial was undertaken to ensure that rituximab did not have any unexpected toxicities in this new population. Patients with moderately active SLE (SLE Disease Activity Index > 1) who had failed at least one cytotoxic agent and had current involvement of a major organ system were eligible to enroll in the study. The treatment regimen was the same approved for B-cell lymphoma: a single course of four weekly doses of rituximab intravenously at 375 mg/m2. Patients received 100 mg methylprednisolone intravenously before each infusion. During the treatment period, they could not be on immunosuppressives, and prednisone doses were kept constant. Patients were followed for 1 year after treatment with repeated laboratory screens, measures of clinical disease activity, and analyses of the subsets of peripheral blood lymphocytes. To date, 20 patients have been enrolled in the study. The first two patients received lower doses of rituximab, and were found to develop positive human anti-chimeric antibody tests. One patient developed a serious adverse event (hyptotension and bradycardia), which may have been related to the medication. All subsequent patients were scheduled to receive the full therapeutic dose. The results discussed here pertain to the nine patients on whom data were available at the time of abstract submission. All patients tested so far depleted their peripheral blood B cells by at least 95%. Six of eight patients who received the full dose showed an improvement in SLE Disease Activity Index, although four of these 'responders' required the addition of azathioprine or mycophenolate mofetil after 1–6 months. B cells returned to the peripheral blood as early as 3 months after treatment, although some patients remained depleted after 1 year. Low titer, transient human anti-chimeric antibody positivity was observed in two patients. Rituximab was well tolerated, without infusion-related serious adverse effects. One death occurred in a patient due to severely active SLE. Serum immunoglobulins, anti-DNA and antinuclear antibody titers did not fall, nor did complement levels change. Patients had antibody titers against pneumococcal polysaccharides and tetanus tested before and after treatment, and then received booster immunizations (Pneumovax and tetanus toxoid) approximately 6 months after treatment. For the four patients in whom results are available, three failed to respond to this antigenic challenge. This experience suggests that rituximab is potentially effective and reasonably safe for patients with SLE. It remains to be determined how best it should be used (timing and amount of doses, concomitant medications) and whether it will add significantly to the toxicity of immuno-suppressive therapies. Randomized, double-blind, placebo-controlled trials are necessary at this point to approach these questions.