Using the novel combination of belimumab after rituximab significantly reduces serum IgG anti-dsDNA antibody levels and the risk of severe flares in patients with SLE refractory to conventional therapy, according to UK research.
A phase 2 RCT compared outcomes in all patients treated with rituximab who, 1-2 months later, started treatment with either IV belimumab or placebo for 52 weeks. Most of the 52 patients in the UK study were also taking prednisolone, an immunosuppressant, or both.
The BEAT-LUPUS study, published in Annals of Internal Medicine, found that treatment with belimumab after rituximab reduced serum IgG anti-dsDNA antibody levels by 70% compared to rituximab alone.
Compared with placebo, belimumab also reduced risk for a severe flare (BILAG-2004 grade A) over 52 weeks by 73% (hazard ratio, 0.27 [CI, 0.07 to 0.98].
There was no difference between groups with respect to the cumulative steroid dose, the proportion of patients successfully reducing their steroid dose by 50% without having a flare at 6 and 12 months, and the proportion with a prednisolone dose of 7.5 mg/d or less at weeks 48 and 52.
There was also no difference between the two groups of patients in infections of any grade, serious or total adverse events, or withdrawal due to adverse events.
The investigators said their findings were consistent with the hypothesis that a surge in B-cell activating factor (BAFF) levels after rituximab can trigger SLE exacerbations.
“Elevated serum BAFF levels can be sustained beyond initial B-cell repopulation and can distinguish lupus relapse from ongoing disease remission after rituximab,” they said.
“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.”
“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.”
However an editorial in the journal questioned the use of a biomarker as a primary outcome measure and said the clinical significance of the lower anti-dsDNA levels among patients randomised to belimumab was difficult to interpret.
“While the investigators demonstrated reduction in flares in their secondary analysis, use of a primary clinical composite endpoint may provide better clinical interpretability and improve the ability to compare results with other SLE trials.”
They said future studies were needed to determine the optimal sequence of treatments, clinical responses, characterisation of patients likely to respond, and adverse event profiles in larger populations.
Professor Eric Morand, director of rheumatology at Monash Health, told the limbic that belimumab was not on PBS in Australia and therefore hardly used.
“This study will not change that so there remains no easy option for access to this therapy for SLE,” he said.
As well, all use of rituximab here was off label for lupus.
“This could increase post news that rituximab may become unrestricted but we should all be aware that notwithstanding powerful anecdotal evidence, two RCTs were negative.”
“My own interpretation of BEAT-LUPUS is different to that of the authors. In my opinion this trial does not provide any evidence regarding the combination of belimumab and rituximab. It simply confirms that belimumab treatment is associated with serological improvement and reduced flares – which is what we already knew about belimumab, regardless of what treatment preceded it.”
“As the authors do point out, rituximab is more widely used in the UK than in most places. Only about half the patients in this study would have been eligible for ‘usual’ active RCTs on the basis of disease activity at recruitment.”
The BEAT-LUPUS study was partly supported by GlaxoSmithKline.