Phase 2 Study Suggests Belimumab After Rituximab Leads to Improvement in SLE

In patients refractory to conventional therapy, the combination resulted in a 70% reduction in a key biomarker compared with placebo.

A new study raises hopes that administration of belimumab (Benlysta) following rituximab (Rituxan) can lead to meaningful improvement in patients with systemic lupus erythematosus (SLE) who are refractory to conventional therapy.

The study, published in the Annals of Internal Medicine,1 offers a potential solution to the variable responses seen among patients treated with rituximab alone.

In patients with SLE, a multisystem autoimmune disease, sharp increases of autoantibodies have been linked with disease flares. Rituximab, a chimeric anti-CD20 monoclonal antibody, depletes B cells by targeting the CD20 antigen. Yet, the drug’s performance in clinical trials has been mixed, explained corresponding author Michael Ehrenstein, MBBS, PhD, of University College London, and colleagues.

Belimumab is a monoclonal antibody targeting B-cell activating factor (BAFF) that has been approved by the FDA to treat SLE and has met its primary clinical endpoint in 4 phase 3 trials.

Ehrenstein and colleagues noted that some patients treated off-label with rituximab ended up with higher levels of anti-double stranded DNA (dsDNA) antibodies, which correlated with disease flares and higher levels of BAFF.

“We therefore hypothesized that targeting BAFF would reduce the frequency of flares after rituximab,” the authors wrote. “Inhibition of BAFF may also delay B-cell repopulation, which has been associated with improved clinical outcomes after rituximab.”

The investigators constructed a phase 2, double-blind, placebo-controlled study, in which 52 patients were eventually enrolled. The patients were all refractory to conventional therapy, and had all been recommended rituximab by their primary physicians.

Each of the patients was then treated with rituximab for between 4 and 8 weeks, and then randomly assigned to receive either belimumab or placebo for 52 weeks. The primary endpoint was serum immunoglobulin G (IgG) anti–dsDNA antibody levels at 52 weeks. The secondary outcomes were disease flares and adverse events.

After a year, the belimumab group had lower anti-dsDNA antibody levels compared with the placebo group (geometric mean, 47; 95% CI, 25-88 vs 103; 95% CI, 49-213 IU/mL). Patients in the belimumab group also had fewer severe flares (10 vs 3), and the drug did not increase the risk of severe adverse events.

“This investigator-initiated trial showed that among patients with SLE receiving standard of care for whom rituximab was indicated, treatment with belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels by 70% at 52 weeks compared with rituximab alone,” Ehrenstein and colleagues said.

In an accompanying editorial,2 Medha Barbhaiya, MD, MPH, and Katherine P. Liao, MD, MPH, of Weill Cornell Medicine and Brigham and Women’s Hospital, respectively, cautioned against drawing overly broad conclusions from the study, in part due to its use of a biomarker as a primary outcome. They noted that while anti-dsDNA is used in the clinic to assess SLE activity, it is used in combination with other clinical signs and symptoms.

“The lower anti-dsDNA levels among subjects randomized to [belimumab] are difficult to interpret—there are no clinically defined anti-dsDNA levels to determine SLE disease activity,” they wrote.

Barbhaiya and Liao added that some patients in the study had undetectable anti-dsNDA levels at screening, further calling into question its use as a surrogate for disease activity.

“In summary, the clinical significance of a reduced, but persistently positive, anti-dsDNA IgG level is not certain,” they said.

In their discussion, Ehrenstein and colleagues described their findings as preliminary, but said the data do offer reason for optimism and the treatment regimen might be meaningful in some patients.

“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,” they concluded.


1. Shipa M, Embleton-Thirsk A, Parvaz M, et al. Effectiveness of belimumab after rituximab in systemic lupus erythematosus: a randomized controlled trial. Ann Intern Med. Published online October 25, 2021. doi:10.7326/M21-2078

2. Barbhaiya M and Liao KP. B-cell targeted therapeutics in systemic lupus erythematosus: from paradox to synergy? Ann Intern Med. Published online October 25, 2021.

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