The disclosure relates to methods and assay that assists in the diagnosis of autoimmune and chronic inflammatory disorders such as systemic lupus erythematosus and rheumatoid arthritis by analyzing drug-responsiveness of an interferon signal in a hematological sample (e.g., blood) obtained from a human subject. The assay involves comparing the interferon signal in a control aliquot of the sample with the same interferon sample in an aliquot that has been exposed to a therapeutic modality (e.g., combined with a drug) that is known to be efficacious to treat the disorder. A significant difference between the interferon signals of the control and treated aliquots that corresponds to a characteristic interferon signature for the disorder indicates that the subject is afflicted with, or is likely to develop, the disorder.