Stevens-Johnson syndrome and toxic epidermal necrolysis: Updates in pathophysiology and management

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions characterized by extensive detachment of the epidermis and mucous membranes. These severe disorders carry a high mortality rate, and their pathogenesis remains largely unclear. Furthermore, optimal therapeutic strategies for SJS/TEN remain a subject of ongoing debate. Early diagnosis of SJS/TEN is challenging, and reliable biomarkers for diagnosis or severity prediction have not been firmly established. Certain drugs, such as carbamazepine and allopurinol, have shown a strong association with specific human leukocyte antigen (HLA) types. Recently, the potential benefits of HLA screening prior to administering these drugs to reduce the incidence of SJS/TEN have been explored. Epidermal cell death in SJS/TEN lesions is caused by extensive apoptosis, primarily through the Fas-Fas ligand (FasL) and perforin/granzyme pathways. Our findings suggest that necroptosis, a form of programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, interacts with the formyl peptide receptor 1 to induce necroptosis. Several biomarkers, such as CC chemokine ligand (CCL)-27, interleukin-15, galectin-7, receptor-interacting protein kinases 3 (RIP3), and lipocalin-2, have been identified for diagnostic and prognostic purposes in SJS/TEN. Supportive care is recommended for treating SJS/TEN, but the efficacy of various therapeutic options-including systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and tumor necrosis factor-α antagonists-remains controversial. Recent studies have investigated the potential benefits of tumor necrosis factor-α antagonists. In this review, we discuss recent advances in the understanding and management of SJS/TEN.

Figure 1

Skin manifestations of SJS/TEN. (A,B) Widespread skin detachment in a TEN patient. (C) Atypical targets. Flat erythematous macules with a darker center. SJS: Stevens–Johnson syndrome; TEN: Toxic epidermal necrolysis.

Figure 2

Mucosal involvement of SJS/TEN. (A) Affected eye with conjunctivitis. (B) Lip involvement. Severe cheilitis with hemorrhagic crust. SJS: Stevens–Johnson syndrome; TEN: Toxic epidermal necrolysis.

Figure 3

Models of T cell activation in SJS/TEN. (A) Hapten/pro-hapten model. Drugs or drug metabolites form a complex with carrier proteins and are presented as HLA. (B) p-i concept. Drugs directly bind to HLA and TCR non-covalently. (C) Altered peptide model. Drugs bind to the pocket of HLA resulting alteration of HLA-binding peptide repertoire. APC: Antigen-presenting cells; HLA: Human leukocyte antigen; SJS: Stevens–Johnson syndrome; TCR: T cell receptor; TEN: Toxic epidermal necrolysis.

Figure 4

Apoptosis pathway in SJS/TEN. In SJS/TEN, cytotoxic T cell induces apoptosis through the FasL pathway, perforin/granzyme pathway, or granulysin. FasL: Fas ligand; SJS: Stevens–Johnson syndrome; TEN: Toxic epidermal necrolysis.

Figure 5

Necroptosis pathway in SJS/TEN. Drug-stimulated monocytes secrete annexin A1. Annexin A1 binds to FPR1 and RIP1 and RIP3 form necrosome and MLKL is phosphorylated by RIP3. pMLKL is located on plasma membrane and induces cell death. FPR1: Formyl peptide receptor 1; MLKL: Mixed lineage kinase domain-like; pMLKL: Phosphorylated MLKL; RIP1: Receptor-interacting protein kinases 1; RIP3: Receptor-interacting protein kinases 3; SJS: Stevens–Johnson syndrome; TEN: Toxic epidermal necrolysis.