019 Serum RIP3 level as a severity-predictive marker for Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases. It is often difficult to distinguish SJS/TEN and other types of generalized skin eruptions, such as maculopapular exanthema (MPE) and erythema multiforme (EM) at the early stage. Although keratinocytes have been suggested to die as apoptosis in SJS/TEN, our recent study revealed that necroptosis, programmed necrosis, also contribute to keratinocyte death in SJS/TEN. Necroptosis is mediated by receptor-interacting kinase-3 (RIP3) and mixed lineage kinase domain-like pseudokinase phosphorylation. We aim to investigate whether serum RIP3 levels serve as a predictive biomarker for SJS/TEN severity. The serum sampled were obtained from the patients with SJS/TEN (n=13), EM major (n=19), EM minor (n=5) and MPE (n=6) in the acute phase. SJS/TEN group have significantly higher serum RIP3 levels than the other groups (EM major: P<0.002, EM minor: P< 0.003, MPE: P<0.003, healthy controls: P<0.002). Also in the EM major group, serum RIP3 levels are significantly higher than in the healthy controls (P<0.006). In addition, positive correlations were found between serum RIP3 levels and the frequency of keratinocyte death in histopathological examination, body temperature, mucosal involvement, and organ dysfunction. We also analyzed changes in serum RIP3 levels after initiation of treatment (SJS: n=4, EM: n=4) and after clinical recovery (SJS: n=3, EM: n=3). In all these samples, serum RIP3 levels decreased after treatment. We showed the clinical usefulness of serum RIP3 levels as a differential or prognostic marker for MPE, EM or SJS/TEN. By predicting of the severity at the early stage, we can start appropriate treatment earlier.