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Observational Study
. 2019 Jul;181(1):166-174.
doi: 10.1111/bjd.17610. Epub 2019 Mar 26.

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

D F Carr  1 , C-W Wang  2   3 , T Bellón  4 , L Ressel  5 , G Nwikue  1 , V Shrivastava  6 , W Bergfeld  7 , A L Jorgensen  8 , W-H Chung  2 , M Pirmohamed  1
Affiliations
Observational Study

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

D F Carr et al. Br J Dermatol. 2019 Jul.

Abstract

Background: High-mobility group box 1 (HMGB1) 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 HMGB1 levels in SJS/TEN cohorts, and HMGB1 expression in formalin-fixed, paraffin-embedded (FFPE) SJS/TEN skin vs. healthy and maculopapular exanthema (MPE) skin. Methods Serum HMGB1 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 HMGB1 expression.

Results: Serum total HMGB1 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 ). HMGB1 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, HMGB1 (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 HMGB1 expression in upper epidermis vs. healthy or MPE skin but retained basal/suprabasal expression.

Conclusions: Epidermal HMGB1 expression was decreased in SJS/TEN skin. Retained basal/suprabasal epidermal HMGB1 expression may exacerbate localized injury in SJS/TEN.

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Figures

Figure 1
Figure 1
Serum total high mobility group box 1 (HMGB1) concentration in the Malawian, nevirapine‐exposed HIV cohort at time of reaction. (a) Concentration for different cutaneous hypersensitivity phenotypes (2 weeks after drug initiation for tolerant). The dashed line indicates the defined upper limit of normal (ULN; 2·3 ng mL −1). (b) Number of individuals whose serum concentration was above (black bars) or below the ULN (grey bars). Statistical significance, determined by (a) Kruskal–Wallis test and (b) χ2, is indicated by *P < 0·05 and **P < 0·01. cADRs, cutaneous adverse drug reactions; MPE, maculopapular exanthema; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis.
Figure 2
Figure 2
Total high mobility group box 1 (HMGB1) in serum from the Taiwanese SJS/TEN cohort during the acute phase of the reaction; maximal point of reaction and during the recovery phase. The dashed line indicates the notional upper limit of normal (2·3 ng mL −1). Statistical significance determined by linear mixed modelling is indicated by ***P < 0·001. NS, nonsignificant.
Figure 3
Figure 3
Total high mobility group box 1 (HMGB1) in serum and blister fluid from the Spanish SJS/TEN cohort at time of reaction. The dashed line indicates the notional upper limit of normal (2·3 ng mL −1). Statistical significance determined by linear mixed modelling is indicated by ***P < 0·001. Circles represent SJS/TEN cases and triangles drug reaction with eosinophilia and systemic symptoms/TEN overlap.
Figure 4
Figure 4
Immunohistochemical staining (×100) of high mobility group box 1 (HMGB1) in healthy, maculopapular exanthema and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) skin. H&E, haematoxylin and eosin.
Figure 5
Figure 5
High mobility group box 1 staining (×400) at the epidermal basal/suprabasal layer in healthy, maculopapular exanthema and Stevens–Johnson syndrome/toxic epidermal necrolysis skin. Black arrow indicates the stratum basale; white arrow the stratum spinosum and arrowhead the inflammatory infiltrate. The dashed line indicates the dermal/epidermal junction.
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References

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