Belimumab after rituximab reduces IgG anti-dsDNA antibody levels, flare risk in lupus
Belimumab after rituximab reduces serum IgG anti-double-stranded DNA antibody levels and the risk for severe flare in systemic lupus erythematosus refractory to conventional therapy, according to data.
“Over the past 20 years, B-cell depletion with rituximab, a chimeric anti-CD20 monoclonal antibody, has shown benefit in open-label studies, but 2 large phase 3, double-blind, randomized, placebo-controlled trials in nonrenal lupus and renal lupus did not find statistically significant differences for their primary end points,” Michael R. Ehrenstein, MBBS, PhD, of University College London, and colleagues wrote in the Annals of Internal Medicine. “Nevertheless, national and international guidelines recommend rituximab for patients with lupus that is refractory to conventional therapy, supported by real-world evidence from registries that continue to report its widespread use and effectiveness.”
“The B-cell activating factor (BAFF) neutralizing monoclonal antibody belimumab was the first biologic licensed for treatment of lupus following two large phase 3 clinical trials (BLISS 52 and BLISS 76) and has recently been shown to be effective for renal lupus,” they added. “However, the limited criteria permitting its use in England — based on an assessment by the National Institute for Health and Clinical Excellence, which accounted for therapeutic benefit and cost-effectiveness — result in far fewer patients with active, refractory disease receiving belimumab compared with rituximab.”
To analyze the efficacy of belimumab (Benlysta, GlaxoSmithKline) following rituximab (Rituxan; Genentech, Biogen) in patients with SLE, and hypothesizing that targeting BAFF would reduce flare frequency after rituximab, Ehrenstein and colleagues conducted the phase 2, randomized, double-blind, placebo-controlled, parallel-group, superiority BEAT-LUPUS trial. The researchers recruited adults aged 18 to 75 years with SLE refractory to conventional treatment, and whose physicians had recommended rituximab, from 16 centers in England between February 2017 and March 2019.
After receiving rituximab for 4 to 8 weeks, a total of 52 participants were randomized 1:1 to receive either intravenous belimumab or placebo for 52 weeks. The primary endpoint was serum IgG anti-dsDNA antibody levels at 52 weeks. Secondary outcomes included disease flare incidence and adverse events.
According to the researchers, IgG anti-dsDNA antibody levels at 52 weeks were lower in patients who received belimumab (geometric mean = 47 IU/mL; 95% CI, 25-88), compared with placebo (103; 95% CI, 49-213), with a 70% greater reduction from baseline (95% CI, 46% to 84%). In addition, belimumab lowered the risk for severe flare compared with placebo (HR = 0.27; 95% CI, 0.07-0.98). In all, there were 10 severe flares in the placebo group and 3 in those who received belimumab.
Belimumab did not increase incidence of serious adverse events, the researchers wrote. At 52 weeks, the drug significantly suppressed B-cell repopulation (geometric mean = 0.012 × 109/L; CI, 0.006-0.014), compared with placebo (0.037; CI, 0.021-0.081), in 25 participants with available data.
“Our data provide preliminary evidence of clinical benefit of belimumab after rituximab in a double-blind, placebo-controlled trial and are consistent with the hypothesis that a surge in BAFF levels after rituximab can trigger SLE exacerbations,” Ehrenstein and colleagues wrote. “These findings support further exploration of belimumab after rituximab as the first combination biologic therapy for patients with SLE, at least in those whose disease is refractory to conventional therapy and/or requires high corticosteroid dosages.”