Risk of Progression to Autoimmune Disease in Severe Drug Eruption: Risk Factors and the Factor-Guided Stratification

The identification of risk factors is key not only to uncover the pathogenesis of autoimmune disease but also to predict progression to autoimmune disease. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms is likely the best prototypic example for analyzing the sequential events. We conducted a retrospective study of 55 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms followed up for the possibility of later development of autoimmune disease ∼18 years after resolution. Nine patients progressed to autoimmune sequelae regardless of treatment. The generation of autoantibodies was preceded by 8 years in eight of the nine patients. The combination of increases in lymphocyte counts, severe liver damage, a rebound increase in globulin, persistent reactivations of Epstein‒Barr virus and human herpesvirus-6, and low IL-2 and IL-4 at the acute/subacute phases were significant risk factors for the future development of autoimmune disease. On the basis of these factors, we established a scoring system that can identify high-risk patients. When stratified these patients into three risk categories (low/intermediate/high), occurrence of autoimmune disease was exclusively detected in the high group. Our data represent a scoring system to identify patients at high risk of developing autoimmune disease, although a larger study is required to validate the scoring system.