Background/Purpose: Diagnosis of systemic lupus erythematosus (SLE) is based on a combination of clinical findings and laboratory evidence such as anti-nuclear autoantibodies (ANA), anti-Smith and anti-double stranded DNA (dsDNA) antibodies. However, no biomarker individually displays sufficient performance to diagnose SLE, to predict the disease course or to allow the identification of patient sub-groups. This lack of specific biomarkers also affects clinical development of new SLE therapeutics. Luminex bead-based antigen arrays were employed to characterize in-depth the autoantibody reactivity of SLE as a source to develop improved diagnostic and patient stratification tests for SLE.

Methods: To characterize the autoantigen repertoire in patients with SLE, we performed a large-scale screen of 5,885 recombinant human antigens using the bead-based Luminex xMAP technology. The autoantibody signature of 130 SLE patients was compared against healthy controls (n=350) and samples from patients with other autoimmune diseases including early rheumatoid arthritis (n=75), systemic sclerosis (n=100) and ankylosing spondylitis (n=100). Autoantigens with significant autoantibody response were selected to develop biomarker panels with improved sensitivity and specificity. Spearman’s rank correlation of the top 50 SLE antigens was computed to identify novel autoantigen clusters.

Results: The first analysis included the comparison of autoantigen profiles of SLE patients with healthy controls and active disease samples. This led to the identification of 15 novel autoantigens (adjusted p-value<0.05, 1.5 fold increase). To further improve the sensitivity and specificity of single antigens to diagnose SLE, combinatory antigen panels were defined using 26 biomarkers providing appropriate statistical characteristics. Sequential addition and different combinations of new antigens to a panel of known SLE antigens resulted in a stepwise improvement of the classification performance yielding an AUC of 0.94. In the second analysis the new antigens were applied to capture clusters formed by subsets of antigens across different samples. At first, the seven known SLE antigens (Ro52/SS-A, Ro60/SS-A, ribosomal P0, P1, P2, and SmB/B´protein) were subjected to hierarchical cluster analysis and identified two major antigen clusters in SLE patients. Then, a combination of 50 known and new SLE markers was used to test if the new antigens provide independent information to allow further sub-classification of SLE samples based on autoantigen signatures. Seven different antigen clusters were identified offering a new tool for characterizing SLE sub-groups.

Conclusion: Comprehensive profiling of SLE sera enabled the in-depth characterization of the autoantigen repertoire of SLE patients. The combination of established and new antigens significantly increased the sensitivity to diagnose SLE. Based on their autoreactivity profile SLE sub-groups were revealed. However, further studies are needed to link specific antigen clusters to clinical profiles.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-novel-distinct-autoantigen-clusters-reflecting-the-heterogeneity-of-systemic-lupus-erythematosus/