Abstract
One-hundred-five patients diagnosed with drug-induced severe cutaneous adverse reactions (SCARs) were recruited for this study. The results demonstrated that Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptom (DRESS) were caused by similar culprit drug groups, which were different from acute generalized exanthematous pustulosis (AGEP). SJS/TEN phenotype, advanced age, high neutrophil/lymphocyte ratio (NLR) and systemic infections independently increased the risk of in-hospital mortality. The application of NLR to predict mortality in SCARs should be reconfirmed in a large-scale study. The combined measurement of drug-induced IFN-gamma (IFN-γ), granzyme B and IL-22 releasing cells could confirm the causative drugs in 77.8% of SCAR subjects, while α-GalCer supplementation significantly increased the frequencies of drug-induced IFN-γ releasing cells. The appropriate in vitro test panel yields optimal diagnostic values, and cost-effectiveness should be determined. Although SJS/TEN and DRESS are caused by similar drug groups, clinical manifestations and long-term prognosis are clearly different. Our study suggested that keratinocyte death observed in SJS/TEN was partly due to drug-specific exosomes released from peripheral blood mononuclear cells upon stimulation with the culprit drugs in SJS/TEN, but not in DRESS. Five exosomal microsomal RNAs (miRNA-486-5p, miRNA-183-5p, miRNA-96-5p, miRNA-132-3p and miRNA4488) were confirmed statistically different between SJS/TEN and DRESS by microRNA sequencing. The regulatory roles of these exosomal miRNAs on keratinocyte death in SJS/TEN and might be used as the therapeutic roles of exosome inhibitors to prevent SJS/TEN progression warrant further study. The different fates of regulatory T cells (Treg) were observed between SJS/TEN and DRESS patients. While Treg functions in DRESS were stimulated during the acute drug allergic phase, the regulatory/suppressive functions of Tregs in DRESS were subsequently diminished compared to SJS/TEN when followed up during the recovery phase. According to the comparative analyses of Treg mRNA profiles during the acute drug allergic phase, genes regulating T cell differentiation and genes regulating interleukin-10 production were found downregulated in DRESS patients who developed autoimmune consequences compared to healthy individuals and might be used as prognostic factors for long-term complications in DRESS subjects.
