Here, to investigate the relationship between IFN families—individually and collectively—with clinical and transcriptional profiles in SLE, we used a unique and convenient cell-based reporter assay to quantify the specific activity of IFN-I, the IFN-II, and IFN-III in combination with clinical and whole-blood transcriptional data from a large prospective cohort of patients with SLE. Here, IFNA1 is linked to systemic lupus erythematosus.