Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Belimumab and rituximab significantly reduced IgG anti-dsDNA antibody levels in patients with systemic lupus erythematosus.

2. The combination of belimumab and rituximab reduced the risk for 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 levels of B-cell activating factor (BAFF) neutralizing antibody, leading to increased IgG anti-dsDNA antibodies, which have been suspected as the cause of flares. The study; therefore, investigated the inhibition of BAFF-neutralizing antibodies by belimumab to improve therapeutic outcomes. 52 patients with refractory SLE were randomized in a 1:1 ratio to receive placebo treatment or Belimumab 4-8 weeks following rituximab therapy. After 52 weeks, the primary endpoint was measured levels of anti-dsDNA antibodies in the serum, and secondary endpoints were the incidence of severe flares and adverse events. The study found that patients receiving belimumab had significantly reduced serum levels of anti-dsDNA antibodies by approximately 70% and reduced the frequency of severe flares by 73% 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. Moreover, given the lack of safety data on Belimumab, the dosages given were lower than typically prescribed. Overall, the study supports the continued investigation of belimumab in combination with rituximab for first-line or refractory treatment of SLE.

In-Depth [randomized controlled trial]:

In this multi-center, double-blind, parallel-group, placebo-controlled, superiority randomized controlled IIb clinical trial known as BEAT-LUPUS, 172 patients diagnosed with stage IV systemic lupus erythematosus (SLE) were screened. 52 patients who received rituximab were subsequently randomized in a 1:1 ratio into two groups: one receiving intravenous 10mg/kg belimumab 4-8 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. Patients were also followed for incidence of severe flares, defined by BILAG-2004, as well as any other severe adverse events. Belimumab therapy was able to significantly reduce the serum levels of anti-dsDNA antibodies compared to the placebo group (P < 0.001). These experimental patients achieved a 71% 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 (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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