Background Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with great heterogeneity between affected individuals. This leads to difficulties in predicting disease manifestations and developing effective new therapies for SLE. Several immune defects have been described, which lead to the overproduction of autoantibodies against cellular and nuclear antigens and immune-mediated damage of several organs and tissues. The in depth-characterization of the autoantibody repertoire in SLE is an emerging tool to identify biomarkers supporting a personalized disease management approach. We have recently conducted high-content autoantibody profiling studies of SLE, systemic autoimmune diseases (AID), and healthy controls and found in addition to diagnostic autoantibodies novel SLE-associated autoantibodies (1).
Objectives The multiplex bead-based Luminex® xMAP® technology was applied to define a set of autoantigens that were consistently measured in the discovery and validation cohort. Confirmed antigens were employed to identify clustered autoantibodies and their clinical association in SLE.
Methods The discovery phase constituted the broad characterization of serum samples from 130 SLE patients, 794 AID patients (systemic sclerosis, rheumatoid arthritis/RA, early RA, ankylosing spondylitis) and 343 healthy controls. Autoantibody reactivity was tested against 6,912 recombinant human proteins using the bead-based Luminex technology. SLE-specific autoantibody reactivity (p-value <0.05, effect size: Cohen's d >0.3) was observed for 166 antigens, consisting of well-known plus novel AID marker candidates. Serum samples from the SLE discovery cohort and a new SLE cohort (n=101) were then used for technical verification and validation of the markers.
Results Based on autoantibody discovery screens, a list of 166 candidate SLE marker antigens was generated. Following technical replication and validation in independent samples, consistent autoantibody reactivity against 46 antigens was found (p-value <0.05 and Cohen's d effect size <0.3. The final list includes among others known SLE antigens (Ro52/SS-A, ribosomal proteins and components of the U1-RNP complex). Novel antigens comprise proteins that localize to the nucleus, cytoplasm, mitochondria and plasma membrane. The top marker were combined into biomarker panels, which demonstrated a sensitivity of 79% and specificity of 81% in the discovery cohort and a sensitivity of 74% and specificity of 82% in the validation cohort. Furthermore, clustered autoantibody reactivity cluster was observed, which can be employed to define subgroups of SLE patients based on their autoantibody profile.
Conclusions Using a multiplex platform we have discovered novel SLE-associated antigens. The reproducibility of the autoantibody reactivity was verified and validated in new SLE samples applying a stepwise marker refinement approach. This approach yielded novel markers combinations, which improve the diagnostic sensitivity and specificity. The heterogenic and clustered autoantibody reactivity pattern contributes to defining subgroups of SLE patients for personalized disease management approaches.
Lueking A. et al. Ann Rheum Dis 2013;72:A535.
Disclosure of Interest P. Budde Employee of: Protagen AG, S. Vordenbäumen: None declared, D. Chamrad Employee of: Protagen AG, L. Schlieker Employee of: Protagen AG, A. Telaar Employee of: Protagen AG, H.-D. Zucht Employee of: Protagen AG, P. Schulz-Knappe Employee of: Protagen AG, M. Schneider: None declared
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