Background Determining processes that lead to clinical illness in systemic lupus erythematosus (SLE) years before diagnosis would provide insight into the fundamental origins of SLE pathogenesis.
Objectives This study evaluates the temporal relationship between autoantibody production, interferon (IFN) levels and the onset of SLE.
Methods Serial sera from 56 pre-clinical SLE cases leading up to SLE classification (average timespan=4.3 years) and matched healthy controls were obtained from the Department of Defense Serum Repository. Sera samples were tested for autoantibodies (BioPlex2200), IFN-α activity, and soluble inflammatory mediators, including IFN associated chemokines and BLyS (B lymphocyte stimulator). Temporal relationships between IFN activity and autoantibody positivity were determined and confirmed using Path analysis.
Results Serum IFN-α activity scores, as well as IFN-correlated (p<0.001) soluble mediators IFN-γ, IP-10, and BLyS levels increase in patients leading up to SLE disease classification (p≤0.01). IFN activity positive individuals have an increased number of autoantibodies compared to IFN activity negative individuals (p<0.05). Autoantibodies accumulate prior to or concurrent with increases in IFN activity in 84% of IFN positive cases. Of the 3 models of IFN vs. autoantibody positivity determined via Path analysis (autoantibody 1st, IFN activity 1st, or concurrent), autoantibody positivity prior to IFN activity ranked first, irrespective of whether DNA- or RNA-binding autoantibodies were present, as assessed by both Akaike's information criterion (AIC) and root mean square error of approximation (RMSEA).
Conclusions That autoantibodies accumulate prior to the increases in IFN activity levels suggests that the elevated IFN activity observed in SLE patients is a consequence of pre-clinical immune system perturbations.
Disclosure of Interest None declared