medwireNews: An exploratory analysis of data from the phase 2b BEAT LUPUS trial suggests that immunoglobulin (Ig)A2 anti-double stranded DNA (dsDNA) antibody levels may be able to predict response to B cell-targeted therapies in patients with systemic lupus erythematosus (SLE).
The main findings from BEAT LUPUS, previously reported by medwireNews, demonstrated that treatment with rituximab followed by belimumab significantly reduces serum IgG anti-dsDNA antibodies and flare risk relative to rituximab followed by placebo among patients with SLE refractory to standard treatment.
For the exploratory analysis, Michael Ehrenstein (University College London, UK) and co-investigators investigated the association between molecular immune profiles at baseline and treatment response among 21 BEAT LUPUS participants given belimumab after rituximab and 23 who were given placebo after rituximab.
A total of 48% of patients treated with belimumab and 35% of those given placebo experienced a major clinical response at 1 year, defined as a BILAG-2004 score that decreased from A or B to C or D, and that remained at E in other domains, a reduction in steroid dose to 7.5 mg/day or lower, and a modified SLEDAI-2K score of 2 points or lower.
Machine-learning analysis of the immune and clinical profiles of participants treated with belimumab demonstrated that serum IgA2 anti-dsDNA antibody levels at baseline significantly predicted the likelihood of achieving this endpoint, with a significant odds ratio of 1.07 for each arbitrary unit (AU) increase in IgA2 anti-dsDNA antibody concentration.
Area under the receiver operating characteristic curve analysis showed that baseline IgA2 anti-dsDNA antibody concentration had an accuracy of 88% for predicting major clinical response at 1 year in belimumab-treated patients.
The team identified 10.7 AUs as the optimal cutoff for IgA2 anti-dsDNA antibody levels, giving a sensitivity of 1.00 and specificity of 0.55. When this cutoff was applied to both treatment groups in BEAT LUPUS, belimumab was associated with significantly higher rates of major clinical response than placebo among people with high antibody levels at baseline, with a between-group difference of 48%. This difference lost statistical significance, and was attenuated to 13%, without use of the biomarker.
Ehrenstein and colleagues also investigated potential biomarkers of unfavorable outcome, finding that interleukin (IL)-6 level at baseline was “the strongest negative predictor” of major clinical response at 1 year, irrespective of treatment allocation.
“Notably, high serum IL-6 concentrations have been associated with non-response to rituximab in rheumatoid arthritis,” they write in The Lancet Rheumatology.
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