The addition of belimumab (Benlysta) to standard-of-care maintenance treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis did not reduce the risk of relapse, a multinational study found.
Among patients with ANCA-associated vasculitis receiving azathioprine plus low-dose oral glucocorticoids, 11.3% of those who also were given belimumab experienced a relapse, as did 15.4% of those randomized to placebo, according to David Jayne, MD, of the University of Cambridge in England, and colleagues.
Accordingly, add-on treatment with belimumab was not associated with a lower risk of relapse, with an adjusted hazard ratio of 0.88 (95% CI 0.29-2.65, P=0.821), the investigators reported online in Arthritis & Rheumatology.
The ANCA-associated vasculitides are potentially lethal systemic disorders that are associated with the presence of autoantibodies and pathogenic B cells.
Treatment consists of remission induction, usually with rituximab (Rituxan) or cyclophosphamide, followed by maintenance with azathioprine, mycophenolate mofetil (CellCept), methotrexate, or rituximab. However, relapse is common during maintenance, and the optimal approach for long-term prevention of relapse remains uncertain.
“Several lines of evidence support a role for the B-lymphocyte stimulator (BLyS) in the pathogenesis of ANCA-associated vasculitis. BLyS is expressed by neutrophils, key cells in ANCA-associated vasculitis pathogenesis, and elevated levels of circulating BLyS have been reported in patients with ANCA-associated vasculitis,” Jayne and colleagues wrote.
Belimumab is a monoclonal antibody that targets BLyS, and is approved for the treatment of systemic lupus erythematosus.
To explore a possible role for belimumab in ANCA-associated vasculitis, the investigators enrolled 105 patients from 37 centers worldwide during the years 2013 to 2017. The study had originally been planned to include 300 patients, but recruitment was truncated following a shift in the recommendations for standard of care treatment and the approval of rituximab for vasculitis.
Participants had undergone remission induction with intravenous oral cyclophosphamide or rituximab for either new-onset or relapsing disease. Maintenance treatment then consisted of azathioprine, 2 mg/kg/day, oral prednisone in dosages no higher than 10 mg/day, and either intravenous belimumab, 10 mg/kg once monthly, or placebo.
The primary endpoint was time to a first protocol-specified event, which was defined as a Birmingham Vasculitis Activity Score (BVAS) of 6 or higher; the development of one or more BVAS major items such as respiratory failure or scleritis; or the requirement of a prohibited maintenance medication such as rituximab, cyclophosphamide, or high-dose prednisone.
Patients’ mean age was 55, the sexes were equally represented, and most were white. The induction regimen had been intravenous cyclophosphamide in 46.2%, oral cyclophosphamide in 28.8%, and rituximab in 25%. The median Vasculitis Damage Index total score was 2 for patients in the placebo group and 3 for those in the belimumab group.
There was no difference between the belimumab and placebo groups on the endpoint of first protocol-specified event, with 10 events in the belimumab group and 11 in the placebo group, for an adjusted hazard ratio of 1.07 (95% CI 0.44-2.59, P=0.884).
Only minimal changes were seen on the damage index, and most patients were in remission at week 48 of year 1 of follow-up and at week 24 of year 2.
Among patients receiving placebo, relapses occurred at similar rates regardless of the induction regimen. However, in the belimumab group, there were no relapses (0/14) in patients who had received rituximab as induction. This finding warrants further investigation, the researchers stated, because of earlier reports suggesting that dual B-cell targeting — induction with rituximab followed by maintenance with belimumab — might be more successful than either agent used alone.
The most common adverse events were infections, which were reported in 57.7% of the placebo patients and in 56.6% of the belimumab group, while serious adverse events occurred in 30.8% and 34%, respectively.
Malignancies developed in four patients on belimumab but in none receiving placebo, which may reflect the fact that more patients in the belimumab group were elderly (34% vs 15.4%).
Further studies might consider the use of belimumab as monotherapy for maintenance, the authors noted.
A limitation of the study was its small sample size and low rate of events, “and caution is therefore required in interpretation of the results,” they concluded.
The study was funded by GlaxoSmithKline.
The authors reported financial relationships with multiple entities, including GlaxoSmithKline, Arthritis Research U.K., the Canadian Institutes of Health Research, the Vasculitis Foundation, Roche, MedImmune, Human Genome Sciences, Actelion, Bristol-Myers Squibb, Celgene, Genentech, Kypha, AstraZeneca, the American College of Rheumatology, the European League Against Rheumatism, the National Institutes of Health, the FDA, Alexion, and ChemoCentryx. Several are employees of GlaxoSmithKline.