Clinical and pathogenic aspects of the severe cutaneous adverse reaction epidermal necrolysis (EN)

Abstract

The severe cutaneous adverse reaction epidermal necrolysis (EN) which includes toxic epidermal necrolysis and the milder Stevens‐Johnson syndrome is characterized by epidermal loss due to massive keratinocyte apoptosis and/or necroptosis. EN is often caused by a drug mediating a specific TCR‐HLA interaction via the (pro)hapten, pharmacological interaction or altered peptide loading mechanism involving a self‐peptide presented by keratinocytes. (Memory) CD8 + T cells are activated and exhibit cytotoxicity against keratinocytes via the perforin/granzyme B and granulysin pathway and Fas/FasL interaction. Alternatively drug‐induced annexin release by CD14 + monocytes can induce formyl peptide receptor 1 death of keratinocytes by necroptosis. Subsequent keratinocyte death stimulates local inflammation, activating other immune cells producing pro‐inflammatory molecules and downregulating regulatory T cells. Widespread epidermal necrolysis and inflammation can induce life‐threatening systemic effects, leading to high mortality rates. Research into genetic susceptibility aims to identify risk factors for eventual prevention of EN. Specific HLA class I alleles show the strongest association with EN, but risk variants have also been identified in genes involved in drug metabolism, cellular drug uptake, peptide presentation and function of CD8 + T cells and other immune cells involved in cytotoxic responses. After the acute phase of EN, long‐term symptoms can remain or arise mainly affecting the skin and eyes. Mucosal sequelae are characterized by occlusions and strictures due to adherence of denuded surfaces and fibrosis following mucosal inflammation. In addition, systemic pathology can cause acute and chronic hepatic and renal symptoms. EN has a large psychological impact and strongly affects health‐related quality of life among EN survivors.

Eosinophils in skin diseases

“…Severe DDH are rare, but potentially life-threatening. They include acute general exanthematous pustulosis (AGEP), the hallmark of which are nonfollicular pustules on an erythematous ground and concurrent systemic involvement in about 20% of cases [ 85 ], Stevens–Johnsons syndrome and toxic epidermal necrolysis that are characterized by epidermal detachment and potential mucosal involvement, and drug rash with eosinophilia and systemic symptoms (DRESS), an eosinophil-predominated reaction [ 86 ].…”

Toxic epidermal necrolysis‐like acute cutaneous graft‐versus‐host disease in a stem cell recipient – a diagnostic dilemma

“…1 Toxic epidermal necrolysis represents a rare drug-induced severe skin reaction with an incidence of 0.4-1.2 per million people. 2 Patients initially show a painful, greyish maculopapular confluent exanthema with development of blisters, usually starting in the sternal region with rapid progression to the face including the mucosae 3,4 (Table 1). Affection of internal organs such as lungs and gastrointestinal tract is extremely rare.…”

Chronic pain: a long‐term sequela of epidermal necrolysis (Stevens–Johnson syndrome/toxic epidermal necrolysis) – prevalence, clinical characteristics and risk factors

“…We also cannot rule out the possibility of nociceptive pain related to persistent inflammation. Indeed, the role of persistent inflammation has been emphasized in ocular or mucosal sequelae of SJS/TEN 29 . However, persistent inflammation is less likely for the skin and in this study, the median delay after the acute phase was more than 5 years, which was very long and similar in painful and painless patients.…”