Serum and blister‐fluid elevation and decreased epidermal content of HMGB1 protein in drug‐induced Stevens Johnson syndrome/toxic epidermal necrolysis

Abstract

High‐mobility group box 1 (HMGB1) is a damage‐associated molecular‐pattern protein indicative of cell/tissue injury and innate immune response. Stevens‐Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are serious, immune‐mediated skin‐blistering conditions characterised by widespread keratinocyte death and epidermal detachment.

The purpose of the study was to determine: a) serum and/or blister‐fluid total HMGB1 levels in independent SJS/TEN cohorts: and b) HMGB1 expression in formalin‐fixed, paraffin‐embedded SJS/TEN skin vs. healthy and maculopapular exanthema (MPE).

Total serum HMGB1 was quantified by enzyme‐linked immunosorbent assay (ELISA) in 3 cohorts: i) Malawian, nevirapine‐induced hypersensitivity (51 cases, 102 tolerant); ii) Taiwanese SJS/TEN (n=73) (acute, maximal and recovery stage); iii) Spanish SJS/TEN (n=23) (acute reaction (blister‐fluid (n=13)). FFPE skin (5 healthy, 7 maculopapular exanthema (MPE), 7 SJS/TEN) was immunohistochemically (IHC) stained and semi‐quantitatively assessed for HMGB1 expression.

Serum total HMGB1 was not significantly elevated in nevirapine‐induced SJS/TEN (3·98ng/ml±2·17), MPE (3·92ng/ml±2·75) or DRESS (4·73ng/ml±3·00)) patients vs. tolerant controls (2·97ng/ml±3·00). HMGB1 was significantly elevated in Taiwanese SJS/TEN patients, highest during the acute phase 32·6ng/ml±26·6 vs. maximal (19·7ng/ml±23·2; p=0·007) and recovery (24·6ng/ml±25·3; p=0·027) phases. In blister fluid from Spanish SJS/TEN patients, HMGB1 (486·8ng/ml±687·9) was significantly higher than in serum (8·8ng/ml±7·6; p<0·0005). Pre‐blistered SJS/TEN skin demonstrated decreased epidermal nuclear HMGB1 expression in upper epidermis vs. healthy or MPE skin but retained basal/suprabasal expression.

Epidermal HMGB1 expression was decreased in SJS/TEN skin which may account for elevated serum and blister‐fluid levels. Retained basal/suprabasal epidermal HMGB1 expression, from resident keratinocytes/ infiltrating inflammatory cells, may exacerbate localised injury in SJS/TEN, though further evaluation is required.

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