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Review
. 2020 Jun 16:9:F1000 Faculty Rev-612.
doi: 10.12688/f1000research.24748.1. eCollection 2020.

Recent advances in managing and understanding Stevens-Johnson syndrome and toxic epidermal necrolysis

Akito Hasegawa  1 , Riichiro Abe  1
Affiliations
Review

Recent advances in managing and understanding Stevens-Johnson syndrome and toxic epidermal necrolysis

Akito Hasegawa et al. F1000Res. .

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane. SJS/TEN are considered to be on the same spectrum of diseases with different severities. They are classified by the percentage of skin detachment area. SJS/TEN can also cause several complications in the liver, kidneys, and respiratory tract. The pathogenesis of SJS/TEN is still unclear. Although it is difficult to diagnose early stage SJS/TEN, biomarkers for diagnosis or severity prediction have not been well established. Furthermore, optimal therapeutic options for SJS/TEN are still controversial. Several drugs, such as carbamazepine and allopurinol, are reported to have a strong relationship with a specific human leukocyte antigen (HLA) type. This relationship differs between different ethnicities. Recently, the usefulness of HLA screening before administering specific drugs to decrease the incidence of SJS/TEN has been investigated. Skin detachment in SJS/TEN skin lesions is caused by extensive epidermal cell death, which has been considered to be apoptosis via the Fas-FasL pathway or perforin/granzyme pathway. We reported that necroptosis, i.e. programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, and its interaction with the formyl peptide receptor 1 induce necroptosis. Several diagnostic or prognostic biomarkers for SJS/TEN have been reported, such as CCL-27, IL-15, galectin-7, and RIP3. Supportive care is recommended for the treatment of SJS/TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α antagonists are still controversial. Recently, the beneficial effects of cyclosporine and TNF-α antagonists have been explored. In this review, we discuss recent advances in the pathophysiology and management of SJS/TEN.

Keywords: Stevens-Johnson syndrome; drug reaction; erythema multiforme; necroptosis; toxic epidermal necrolysis.

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Conflict of interest statement

No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Models of T cell activation in Stevens-Johnson syndrome/toxic epidermal necrolysis.
( A) Hapten/pro-hapten model: drugs or drug metabolites form a complex with carrier proteins and are presented as haptenated peptides in the peptide-binding groove of the HLA molecules. ( B) p-i concept: drugs directly bind to HLA and TCR non-covalently. ( C) Altered peptide model: drugs bind to the peptide-binding groove of HLA, resulting in the alteration of the HLA-binding peptide repertoire. APC, antigen-presenting cell; HLA, human leukocyte antigen; TCR, T cell receptor.
Figure 2.
Figure 2.. Necroptosis pathway in Stevens-Johnson syndrome/toxic epidermal necrolysis.
Drug-stimulated monocytes secrete annexin A1. Annexin A1 binds to FPR1, RIP1 and RIP3 form the necrosome, and MLKL is phosphorylated by RIP3. Phosphorylated MLKL translocates to the plasma membrane and induces cell death. FPR1, formyl peptide receptor 1; MLKL, mixed lineage kinase domain-like; RIP1, receptor interacting kinase 1.
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Grants and funding

The author(s) declared that no grants were involved in supporting this work.