Serum and blister‐fluid elevation and decreased epidermal content of high‐mobility group box 1 protein in drug‐induced Stevens–Johnson syndrome/toxic epidermal necrolysis

Abstract

Summary Background High‐mobility group box 1 ( HMGB 1) is a damage‐associated molecular‐pattern protein. Stevens–Johnson syndrome ( SJS )/toxic epidermal necrolysis ( TEN ) are serious, immune‐mediated skin‐blistering conditions. Objectives To determine serum and/or blister‐fluid total HMGB 1 levels in SJS / TEN cohorts, and HMGB 1 expression in formalin‐fixed, paraffin‐embedded ( FFPE ) SJS / TEN skin vs. healthy and maculopapular exanthema ( MPE ) skin. Methods Serum HMGB 1 was quantified in Malawian nevirapine‐induced hypersensitivity, Taiwanese SJS / TEN and Spanish SJS / TEN cohorts. FFPE skin (healthy skin, MPE , SJS / TEN ) was stained and assessed for HMGB 1 expression. Results Serum total HMGB 1 was not significantly elevated in patients with nevirapine‐induced SJS / TEN (3·98 ± 2·17 ng mL −1 ), MPE (3·92 ± 2·75 ng mL −1 ) or drug reaction with eosinophilia and systemic symptoms (4·73 ± 3·00 ng mL −1 ) vs. tolerant controls (2·97 ± 3·00 ng mL −1 ). HMGB 1 was significantly elevated in Taiwanese patients with SJS / TEN , highest during the acute phase (32·6 ± 26·6 ng mL −1 ) vs. the maximal (19·7 ± 23·2 ng mL −1 ; P = 0·007) and recovery (24·6 ± 25·3 ng mL −1 ; P = 0·027) phases. In blister fluid from Spanish patients with SJS / TEN , HMGB 1 (486·8 ± 687·9 ng mL −1 ) was significantly higher than in serum (8·8 ± 7·6 ng mL −1 ; P <0·001). Preblistered SJS / TEN skin showed decreased epidermal nuclear HMGB 1 expression in upper epidermis vs. healthy or MPE skin but retained basal/suprabasal expression. ...

Role of Oxidative Stress in Hypersensitivity Reactions to Sulfonamides

“…Interesting, RIPK3 was found to be upregulated in skin sections from patients with severe forms of drug hypersensitivity with increased phosphorylation of mixed‐lineage kinase domain‐like protein, a key downstream component of RIPK3 . Furthermore, very recently, Carr et al described that high mobility group box 1 (HMGB1), a damage‐associated molecular pattern indicative of cell injury, elevate in serum and blister fluids of some patients with drug‐induced SJS/TEN during the acute phase of the reaction . These data further support the role of cell damage in the pathophysiology of drug hypersensitivity reactions.…”

Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

“…High-mobility group box 1 protein (HMGB1) is a damage-associated molecular-pattern protein. Serum level of HMGB1 was found significantly higher in SJS/TEN compared with healthy controls in Japanese ( Fujita et al, 2014 ) and Taiwanese patients ( Carr et al, 2019 ), but its expression level varied on a case-to-case basis ( Adachi et al, 2019 ).…”

Diagnostic Tools and Biomarkers for Severe Drug Eruptions

“…On the contrary to these functional roles, HMGB1 is also useful as a biomarker in various diseases [ 60 , 61 ]. HMGB1 is noticed in serum in patients with severe cutaneous adverse reactions [ 62 , 63 ]. Serum HMGB1 levels in patients with SJS/TEN from 7 days before the onset and 21 after the onset of diseases were significantly increased compared with healthy controls and patients with ordinal drug eruption [ 62 ].…”

“…Twenty-two healthy subjects and 13 patients with SJS/TEN were enrolled in this study and the sera were obtained from multiple institutions. In addition to the high serum level of HMGB1, HMGB1 concentration is also increased in bullous fluids in patients with SJS/TEN [ 63 ]. This study was conducted by three independent SJS/TEN patient cohorts and was then brought together for the purpose of this study.…”