Numerous observations implicate interferon‐α (IFNα) in the pathophysiology of systemic lupus erythematosus (SLE); however, the potential impact of endogenous anti‐IFNα autoantibodies (AIAAs) on IFN‐pathway and disease activity is unclear. The aim of this study was to characterize IFN‐pathway activity and the serologic and clinical profiles of AIAA‐positive patients with SLE.

Sera obtained from patients with SLE (n = 49), patients with rheumatoid arthritis (n = 25), and healthy control subjects (n = 25) were examined for the presence of AIAAs, using a biosensor immunoassay. Serum type I IFN bioactivity and the ability of AIAA‐positive sera to neutralize IFNα activity were determined using U937 cells. Levels of IFN‐regulated gene expression in peripheral blood were determined by microarray, and serum levels of BAFF, IFN‐inducible chemokines, and other autoantibodies were measured using immunoassays.

AIAAs were detected in 27% of the serum samples from patients with SLE, using a biosensor immunoassay. Unsupervised hierarchical clustering analysis identified 2 subgroups of patients, IFN^low and IFN^high, that differed in the levels of serum type I IFN bioactivity, IFN‐regulated gene expression, BAFF, anti–ribosomal P, and anti‐chromatin autoantibodies, and in AIAA status. The majority of AIAA‐positive patients had significantly lower levels of serum type I IFN bioactivity, reduced downstream IFN‐pathway activity, and lower disease activity compared with the IFN^high patients. AIAA‐positive sera were able to effectively neutralize type I IFN activity in vitro.

Patients with SLE commonly harbor AIAAs. AIAA‐positive patients have lower levels of serum type I IFN bioactivity and evidence for reduced downstream IFN‐pathway and disease activity. AIAAs may influence the clinical course in SLE by blunting the effects produced by IFNα.