Background: B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness.
Objective: To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE.
Design: Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003).
Setting: England.
Participants: Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019.
Intervention: Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks.
Measurements: The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events.
Results: At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data.
Limitations: Small sample size; biomarker primary end point.
Conclusion: Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy.
Primary funding source: Versus Arthritis.