Belimumab after rituximab reduces risk for severe flare in systemic lupus erythematosus

1. Belimumab combined with rituximab was shown to significantly reduce IgG anti-dsDNA antibody levels in patients with systemic lupus erythematosus.

2. Belimumab following rituximab therapy was shown to reduce severe flares in patients with systemic lupus erythematosus.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Rituximab, an anti-CD20 antibody therapy, is used to deplete B-cells in patients with systemic lupus erythematosus (SLE) who don’t respond to conventional immunosuppressive therapy. However, this treatment regimen increases B-cell activating factor (BAFF) neutralizing antibody levels, leading to increased IgG anti-dsDNA antibodies, which have been suspected to cause flares. Therefore, this study investigated the inhibition of BAFF-neutralizing antibodies with belimumab to improve therapeutic outcomes. The study determined patients receiving belimumab had significantly reduced serum levels of anti-dsDNA antibodies and reduced frequency of severe flares compared to the placebo group. Both groups experienced similar frequencies of severe adverse events. The study was limited by the small sample size and the lack of an outcome-oriented primary endpoint. While the significant reduction in anti-dsDNA antibody levels is clear, further investigation is required to correlate its clinical impact. Overall, the study supports the continued investigation of belimumab in combination with rituximab for first-line or refractory treatment of SLE.

Click to read the study in Annals of Internal Medicine

Relevant Reading: The BAFFling effects of rituximab in lupus: danger ahead?

In-Depth [randomized controlled trial]: In this multi-center, double-blind, placebo-controlled, randomized controlled trial known as BEAT-LUPUS, 52 patients participated from 16 centers in the United Kingdom. Participants between 18 to 75 years of age, diagnosed with stage IV systemic lupus erythematosus (SLE), and had a positive anti-dsDNA antibody test within the last five years were included in the study. Participants who had not failed conventional therapy were excluded from the study. The participants were randomized in a 1:1 ratio to receive either one receiving intravenous 10mg/kg belimumab four to eight weeks after rituximab therapy or placebo treatment, respectively. The primary outcome was serum levels of IgG anti-dsDNA antibodies detected by enzyme-linked immunosorbent assay after 52 weeks. Belimumab therapy significantly reduced the serum levels of anti-dsDNA antibodies compared to the placebo group (P < 0.001). These experimental patients achieved a 71% (95% confidence interval [CI], 58% to 81%) greater reduction in IgG anti-dsDNA antibody levels relative to baseline compared to the placebo group. Moreover, patients receiving belimumab experienced 73% fewer severe flares (hazard ratio, 0.27; 95% CI, 0.07 to 0.98; P = 0.033); however, when moderate flares were also accounted for, significance was lost (P = 0.124). No difference in severe adverse events was found between the two groups with depressive symptoms being common. Taken altogether, this study supports the further investigation of combinational rituximab and belimumab therapy for the treatment of SLE as first-line or in refractory patients to conventional therapy.

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