Updates in the pathogenesis of SJS/TEN

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions across a spectrum of severity characterized by widespread epidermal detachment and keratinocyte apoptosis. SJS/TEN develops due to a complex immunologic response after exposure to an associated drug antigen and/or its metabolite, and it results in significant morbidity and mortality. Complex immune mechanisms contribute to keratinocyte death. Drug-induced SJS/TEN has been shown to be strongly HLA class I restricted which has contributed to our understanding of mechanisms and has the potential to shape prevention and diagnosis. There is currently no evidence-based treatment outside of aggressive supportive care, and understanding the complete immunopathogenesis of SJS/TEN will be key for the development of efficacious and safe treatments that significantly reduce morbidity and mortality. This article focuses on what is new in the pathogenesis of SJS/TEN, including recent research on the mechanisms of T-cell activation, apoptotic and necroptotic mediators, other related molecules, genetic associations, and possible targeted treatment options.

Keywords: Cytotoxic; HLA antigens; Stevens-Johnson syndrome; T-lymphocytes; Toxic epidermal necrolysis.

Fig. 1.

This figure features images of patients with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. A, B, C, and D are images of one patient throughout the course of their disease. Patients present with rapidly progressive erythematous coalescing macules, tense bullae, and desquamation (A, B - Day 5 of SJS/TEN) which continues to progress (C, Day 12 of SJS/TEN). With time, re-epithelialization initiates (D, Day 20 of SJS/TEN). Cutaneous diseases and erythema can appear differently in patients with darker skin tones (E). Patients may also report ocular and oral skin and mucosal surface involvement (F, G, H).

Fig. 2.

Components of keratinocyte apoptosis and necroptosis in SJS/TEN. Clonal expansion of LAG3+ skin-resident memory T-cells follows TCR/class 1 MHC interaction with keratinocytes. CD8+ T-cells are also recruited to the epidermis, where interferon-γ is released, activating the JAK-STAT Pathway. Keratinocyte apoptosis is triggered by CD8⁺ T cells through Fas/FasL interaction, TCR/class I MHC interactions, and TNF-α release. Natural killer cells induce apoptosis after HLA-E and CD94/NKG2C interaction, while monocytes contribute by releasing annexin A1, which binds to FPR1. Targeted therapies include cyclosporine (CD8⁺ T cells), IVIG (Fas/FasL), etanercept (TNF-α), and JAK inhibitors (JAK-STAT pathway). Figure created with BioRender.com. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis; (SJS/TEN), T-cell receptor (TCR); major histocompatibility complex (MHC); Janus kinase-signal transducer and activator of transcription (JACK/STAT); tumor necrosis factor (TNF); human leukocyte antigen (HLA); formyl peptide receptor 1 (FPR); intravenous immunoglobin (IVIG).