Toxic epidermal necrolysis

Abstract

Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. The exact pathogenic mechanism of TEN is still uncertain. Recent advances in this field have led to the identification of several factors that might contribute to the induction of excessive apoptosis of keratinocytes. In addition, specific human leukocyte antigen types seem to be associated with certain drugs and the development of TEN. As well-controlled studies are lacking, patients are treated with various immunomodulators (e.g. intravenous immunoglobulin) in addition to the best supportive care.

Keywords: Stevens-Johnson syndrome; Toxic epidermal necrolysis; keratinocyte cell death; skin detachment.

Figure 1.. Toxic epidermal necrolysis (TEN) after carbamazepine administration.

( A) Skin detachment with facial erosions, including involvement of the lips and conjunctiva. ( B) TEN with an extensive cutaneous involvement marked by detached and detachable apoptotic skin erosions on the trunk.

Figure 2.. Conceptual models concerning T cell stimulation by drugs in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).

( A) Drugs inducing an adverse skin reaction are not antigenic by themselves. Instead, their immunogenicity may result from binding to carrier proteins, which allows the formation of neoantigens that are recognized by T cells upon presentation by antigen-presenting cells (APCs). ( B) The p-i concept is based on the pharmacological interactions of drugs with immune receptors. Consistent with this concept, chemically inert drugs, which are unable to bind covalently to proteins, may activate specific T cells by binding directly to T cell receptors and/or major histocompatibility complex molecules. ( C) The association of peptides with HLA molecules is highly specific. According to the “altered peptide model”, specific HLA molecules form a complex with certain drugs, thereby modifying the pool of self-peptides presented to T cells. This may result in increased autoimmunity. Concepts for immunological responses of SJS/TEN modified from Abe et al. .

Figure 3.. Proposed pathogenic mechanisms in toxic epidermal necrolysis (TEN).

( A) The causative medication might induce upregulation of Fas-L by keratinocytes constitutively expressing Fas, leading to activation of a death receptor-mediated apoptotic pathway. ( B) The drug might interact with major histocompatibility complex class I-expressing cells, causing drug-specific CD8 ⁺ cytotoxic T cells to accumulate within epidermal blisters, releasing perforin and granzyme B that can kill keratinocytes. ( C) Drug-activated monocytes secrete annexin A1, which induces necroptosis in keratinocytes. ( D) The drug may also trigger the activation of CD8 ⁺ T cells, NK cells and NKT cells to secrete granulysin, which can induce keratinocyte death without the need for cell contact. This figure has been modified from French et al. . (APC, antigen-presenting cell; NK cell, natural killer cell; NKT cell, natural killer T cell).