Dysregulation of T helper-type cytokines appears prior to and concurrent with appearance of autoantibody specificities during early SLE pathogenesis and contributes to prognosis of transition to classified disease

Autoantibodies and immune dysregulation are associated with systemic lupus erythematosus (SLE), but how these factors influence disease development is unknown. This study evaluates timing and changes in SLE-linked autoantibodies and soluble mediator pathways in the years preceding SLE classification. Serial sera from 84 SLE cases spanning pre- and post-SLE classification (average time = 5.98 years) and matched healthy controls (HC) were obtained from the Department of Defense Serum Repository. Adjusting for multiple comparison, a number of soluble mediators, including IL-5 ( q=4.35 × 10 −6 ), IL-6 ( q=8.26 × 10 −6 ), and IFN-γ ( q=0.037 ), were significantly elevated in cases vs. HC >3.5 years pre-classification, prior to (IL-5 and IL-6) and concurrent with (IFN-γ) the earliest SLE-specific autoantibody specificity, anti-Ro/SSA. Th 1 -type, Th 17 -type, and TNF superfamily soluble mediators increased longitudinally in cases approaching SLE classification, but not in HC ( q ). In particular, serum levels of BLyS and APRIL were comparable in cases and HC until q=0.003 and q=0.019 , respectively). Random forest models incorporating IL-5, IL-6, and IFN-γ levels (79–82% accuracy) distinguished future SLE patients better than models with ANA alone (58% accuracy) >3.5 years before classification. These data indicate that pre-clinical immune system perturbations allow for the accumulation of autoantibodies preceding clinical symptoms and SLE classification.