7Th Drug Hypersensitivity Meeting: Part One

Abstract

Background: Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious, life threatening severe immune-mediated cutaneous reactions with mortality ranging from 10 to 30 %. The commonest causes are drugs. SJS/TEN is characterised by widespread epidermal detachment due to keratinocyte cell death. Increased concentrations of cytotoxic molecules may act as potential serum biomarkers of SJS/TEN. However, to date no mechanism based biomarker has been validated for diagnostic utility in this field. HMGB1 is a well-validated biomarker of cell death and inflammation. This study investigated whether HMGB1 represents a valid, utilisable biomarkers for drug-induced SJS/TEN. Materials and methods: Serum samples from nevirapine-treated Malawian HIV patients (27 MPE, 12 DRESS, 12 SJS/TEN cases and matched tolerant controls) were analysed for total HMGB1 by ELISA. Novel mass-spectrometric protocols were also used to analyse posttranslationally modified forms of HMGB1. In addition serum from 20 Taiwanese SJS patients (five carbamazepine, eight allopurinol, five phenytoin, two sulfamethoxazole) both during and post-reaction were analysed for HMGB1 isoforms. Results: There was a significant elevation of mean total serum HMGB1 at time of reaction in patients with nevirapine-induced MPE (6.0 ng/ ml), HSS (6.3 ng/ml) and SJS/TEN (15.9 ng/ml) compared to tolerant controls at weeks (1.3 ng/ml) (p < 0.001). Analysis of post-translationally modified isoforms of the HMGB1 in the different phenotypes (Fig. 1) showed patients with MPE and DRESS had elevation the acetylated form of HMGB1 which is a marker of innate immunity. By contrast, SJS/ TEN patient sera contained comparable levels of acetylated HMGB1, but also had very high levels of the non-acetylated form, which is associated with cell death/tissue injury. The tolerant control patients had low levels of the unacetylated form. This pattern of HMGB1 isoform elevation was replicated in the Taiwanese SJS cohort. As patients recovered, the total HMGB1 concentrations went down, although there wasstill significant elevation of the sulphonyl (partially reduced) HMGB1 isoform which has no known immune function and may represent a marker of innate immunity returning to “steady state”. Conclusions: In conclusion, our data suggest that post-translationally modified HMGB1 may represent mechanism-based diagnostic and prognostic markers for drug-induced SJS/TEN. This needs to be studied in more patients