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By Claire Barnard, medwireNews Reporter

medwireNews: Immunoglobulin (Ig)A2 anti-double stranded DNA (dsDNA) antibodies may represent a biomarker of response to B cell-targeted therapies in patients with systemic lupus erythematosus (SLE), suggest study findings from Michael Ehrenstein (University College London, UK) and colleagues.

As outlined in The Lancet Rheumatology, the team carried out an exploratory analysis of BEAT LUPUS, a phase 2b randomised controlled trial investigating treatment with belimumab after rituximab in patients with SLE refractory to standard treatment. This trial previously showed that patients given belimumab after rituximab had significantly lower serum IgG anti-dsDNA antibodies and flare risk than those given placebo after rituximab.

The current exploratory study included 44 BEAT LUPUS participants with available data at the 1-year follow-up, of whom 21 were treated with belimumab after rituximab and 23 with placebo after rituximab. Across the two groups, participants were aged an average of 39.5–42.1 years, 81–91% were women and 62–70% were White.

Ehrenstein and team report that the proportion of participants with a major clinical response at 1 year was 48% in the belimumab group and 35% in the placebo arm. This endpoint was defined as a reduction in the BILAG-2004 index score from A or B to C or D and a score that remained at E in other domains, a decrease in steroid dose to 7.5 mg/day or lower, and a modified SLEDAI-2K score of 2 points or lower.

Using a machine-learning model constructed with clinical and laboratory data, the researchers identified serum IgA2 anti-dsDNA antibodies at baseline as “the most important variable” for predicting major clinical response in belimumab-treated patients.

Specifically, multiple logistic regression analysis showed that each arbitrary unit (AU) increase in IgA2 anti-dsDNA antibody concentration was associated with a significant 7% higher likelihood of achieving a major clinical response at 1 year. The accuracy of IgA2 anti-dsDNA antibody concentration for predicting major clinical response in belimumab-treated patients was 88% on area under the receiver operating characteristic curve analysis.

Using a cutoff of 10.7 AUs to define high versus low IgA2 anti-dsDNA antibody concentrations, Ehrenstein et al found that patients with high antibody concentrations at baseline were significantly more likely to have a major clinical response with belimumab versus placebo, with a between-group difference of 48%. This was “substantially greater” than the between-group difference seen without use of the biomarker, at 13%, report the researchers.

They say that these findings demonstrate “the potential of a simple assay measuring IgA2 anti-dsDNA antibody concentration and how it could be applied in clinical practice to guide patient selection for rituximab followed by belimumab combination therapy.” The authors caution, however, that “these findings need to be confirmed in other studies.”

In addition to their association with treatment response, serum IgA2 anti-dsDNA antibody levels were found to correlate with the presence of active renal disease, with a significant 35% increased risk for each AU increase on multivariate analysis.

Ehrenstein et al also evaluated negative predictors of treatment response in the BEAT LUPUS trial, finding that the “most striking baseline variable associated with non-response” was serum interleukin (IL)-6 levels, which were not altered during treatment with belimumab or placebo after rituximab.

Discussing these data in an accompanying comment, Ioannis Parodis (Karolinska University Hospital, Stockholm, Sweden) says that “[a]lthough predictors of response to different therapeutic regimens are highly relevant in guiding decision making, the importance of predictors of non-response should not be underestimated, not only for their contribution to the choice of treatments, but also for elucidation of unmet needs.”

Parodis believes that as the number of targeted therapies for SLE increases, “a paradigm shift is anticipated”, with a move towards decision-making “based on molecular rather than clinical phenotyping, leading the way for tailored management and improved outcomes.”

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group  

Lancet Rheumatol 2022; doi:10.1016/S2665-9913(22)00332-0
Lancet Rheumatol 2022; doi:10.1016/S2665-9913(22)00358-7