Epidermal nekrolysis L51.2

Today, epidermal necrolysis (EN) refers to a spectrum of diseases that combines two conditions— Stevens-Johnson syndrome and toxic epidermal necrolysis—which were previously considered separate, under a single umbrella diagnosis. These two blistering conditions differ only in the extent and severity of the epitheliolytic skin and mucosal lesions.

• For Stevens-Johnson syndrome (SJS), a consensus classification defined epidermolytic involvement relative to the body surface area (KOF) as <10%;
• and for toxic epidermal necrolysis (TEN), a KOF >30% (Grünwald P et al. 2020).
• A CSO between 10% and 30% is classified as SJS/TEN overlap syndrome.  

EN is triggered by medications in 65–85% of all cases; however, in children, this is true in only about one-third of cases (Maverakis E et al., 2017; Creamer D et al., 2016). More than 100 medications (see notes below) are associated with EN in the literature. Large-scale epidemiological studies have shown that about half of the cases are triggered by high-risk medications (so-called “highly suspected” triggers) and about two-thirds of the cases by high- and moderate-risk medications (so-called “highly suspected” and “suspected” triggers). 

Epidermal necrolysis (EN) is considered a T-cell-mediated disease. In EN, apoptosis of the epithelial keratinocytes leads to necrosis of the epidermis and mucosal epithelia. ^CD8+T lymphocytes, stimulated by the triggering agent (primarily drugs, but also microbial triggers or a combination of both), play a central role in the immune-mediated cell death of keratinocytes .

Currently, there are three theories regarding the formation of a postulated “neoantigenic agent-tissue complex” and how the resulting T-cell-mediated cellular damage is subsequently induced (Paulmann M et al. 2024):

• covalent binding of the agent to a cellular peptide (hapten/pro-hapten concept),
• non-covalent, direct interaction of the agent with a specific MHC class I molecule and the T-cell receptor (p-i concept),
• presentation of an altered self-repertoire through direct interaction between the agent and an MHC class I molecule ( altered peptide concept).

Granulysin: The cytolytic protein granulysin, produced by cytotoxic T cells and NK cells, is considered a key mediator of epithelial apoptosis in EN. Furthermore, the inflammatory cytokines interleukin (IL-6), tumor necrosis factor alpha (TNF-alpha), interferon gamma, IL-18, and Fas ligand have been detected in lesional skin samples and/or blister fluid. The Fas ligand (FasL, CD95L), a cell surface molecule that induces apoptosis upon binding to the Fas receptor (CD95, Apo-1), is also believed to play an important role in the pathogenesis of EN.

In addition, strong expression of the CD40 ligand (CD40L) has been detected during the acute phase of the disease; this ligand triggers signaling pathways leading to the release of TNF-alpha, nitric oxide (NO), IL-8, and cell adhesion molecules (such as annexin). Other soluble pro-apoptotic molecules associated with the pathogenesis of EN include IL-15, perforin, andgranzyme B (Caproni M et al. 2006a; Caproni M et al. 2006b; Viard-Leveugle I et al. 2013).

The developing rash progresses rapidly, such that within a day or a few days, it can progress from initial localized erythema to extensive epidermolysis. At the same time, mucosal detachment of varying severity is almost always present. In most cases, multiple mucosal areas are affected simultaneously: the oral and genital mucosa, the conjunctiva, the nasal mucosa, and, less commonly, the trachea or bronchi. These erosive mucosal lesions are very painful and typically hemorrhagic; depending on the affected site, they lead to difficulty eating, dysuria, or photophobia. The resulting fibrinous deposits lead to adhesions, which further increase pain and further impair the corresponding functions. Mucosal detachment occurs in SJS, the SJS/TEN overlap syndrome, and TEN alike; therefore, the various severity grades of EN cannot be distinguished based on the extent of mucosal involvement. In isolated cases (in less than 10% of all cases), there is no hemorrhagic-erosive mucosal involvement (Bastuji-Garin S et al. 1993).

The individual efflorescences of epidermal necrolysis are characterized by:

• red, often poorly defined patches (an important differential diagnosis compared to the well-defined “cocarde” of erythema multiforme/Grünwald P et al. 2020)
• “atypical cocardes,” whose annular, target-like formations are less clearly recognizable (maximum of 2 ring structures) than in erythema multiforme with its clearly defined borders.

As the severity increases, the eruptions coalesce into extensive areas of epidermolytic erythema. The extent of epidermolysis increases, as evidenced by a positive Nikolski I phenomenon (tangential pressure on the erythematous areas, as well as on the non-erythematous peripheral regions, causes the skin to shift). TheNikolski II phenomenon (blisters can be displaced by pressure) is also positive (Salopek T 1997). Another helpful distinguishing feature is the appearance of the base of the blister, which appears moist in EN due to subepidermal detachment (moist Nikolski phenomenon). In contrast, there is the “dry” Nikolski phenomenon, in which the blister may appear moist on the surface, but the base of the blister is dry (for example, in “staphylococcal scalded skin syndrome” or in acute generalized exanthematous pustulosis) (Sidoroff A et al. 2001)

TEN is a severe, life-threatening condition. Causes of death are often septic in nature (e.g., catheter-related infections leading to sepsis, urosepsis, pneumonia), as well as respiratory and multiple organ failure.

There are no specific laboratory parameters available as diagnostic markers for EN.

An increase in inflammatory markers (including C-reactive protein (CRP)) is to be expected.

Initially, in cases of elevated CRP, a relevant medical history, and clinical signs of infection, a targeted evaluation of an infection-based etiology (e.g., (para-)influenza, adenovirus, Mycoplasma pneumoniae, Chlamydophila pneumoniae) should be conducted.

Furthermore, diagnostic swab tests of affected skin and mucous membranes are helpful for bacterial and mycological analysis.

Evidence of necrotic keratinocytes, which are present at the basal layer but also distributed throughout the epidermis, sometimes in larger clusters, leading to subepidermal detachment. Due to the rapid progression of the condition, the stratum corneum remains orthokeratotic. Particularly in the peripheral areas of the epidermolysis, the still-intact epidermis shows vacuolization of the basement membrane zone and, frequently, isolated cases of keratinocyte necrosis.

In the upper dermis, there is often only a sparse perivascular infiltrate. However, the intensity of the infiltrate is not a decisive criterion, as the inflammatory infiltrate also depends on the timing of the biopsy and, if applicable, on secondary changes that may have already occurred.

The histological findings are not specific to EN but may also be consistent with generalized bullous fixed drug eruption (GBFAE), EEM (if the sample is taken from the central portions of a cocard), or toxic erythema following chemotherapy. In GBFAE, however, accumulations of melanophages may also be found in the upper dermis, and the infiltrate is more frequently characterized by an interstitial distribution of eosinophils and neutrophils. Autoimmune bullous dermatoses (pemphigus vulgaris, bullous pemphigoid, IgA linear dermatosis) can be further specified immunohistologically.

The following parameters should be evaluated for the diagnostic assessment of an epidermolytic skin condition: 

• Medication history: The patient’s medical history and clinical findings—including an assessment of the temporal progression of skin changes and other symptoms—are crucial for confirming the diagnosis. In addition, a complete medication history is necessary, which should include not only daily prescribed medications but also those taken sporadically. The focus should be on the past four weeks. In individual cases, medications (for example, those with a long half-life) taken up to three months prior may be considered potential triggers (Mockenhaupt M et al. 2019).
• Acute onset (<1 week)
• General symptoms: Even before the development of an exanthem, enanthem, or erosive mucosal involvement, nonspecific general symptoms often occur, such as fever, headache, and a general feeling of illness accompanied by fever, difficulty swallowing, and cough
• History of taking a new medication
• Evidence of a painful (burning) rash, typically with diffuse but also patterned, large erythematous areas, and occasionally with cocarde-like spots
• Skin sloughing <10% of body surface area (KOF), atypical cocard-like lesions = SJS
• Skin sloughing >30% of the body surface area, atypical rosette-like lesions = TEN
• Evidence of epidermolysis
• Positive Nikolski phenomenon(Nikolski I + Nikolski II) ( the Nikolski I phenomenon isparticularly significant—detachment of previously non-epidermolytic skin upon sliding pressure)
• Evidence of extensive, epitheliolytic mucositis (oral mucosa and lips, possibly upper respiratory tract, conjunctiva, and genital mucosa adjacent to the skin)
• Biopsy (5-mm punch biopsy—HE/PAS staining) from still-intact lesional skin—for light microscopy and immunofluorescence
• A frozen-section analysis allows for rapid differentiation between subepidermal and intraepidermal cleavage. The latter is expected in“staphylococcal scalded skin syndrome”(triggered by staphylococcal exotoxins). Microscopic examination of the blister roof also allows for determination of the cleavage plane. When arranging specimen shipment and processing, it is important to ensure that the skin specimen is marked and processed as an urgent “express” or “Cito” case.
• Determination of the SCORTEN

Erythema (exsudativum) multiforme (EMM/major form) with predominant involvement of the mucous membranes (Fuchs syndrome, or pluriorificial ectodermosis; see also the so-called NIME syndrome). The minor variant of EEM usually shows only minimal mucosal involvement.  

Mucosal pemphigoid (chronic course, leading to scarring and functional impairment of the mucous membranes of the conjunctiva, mouth, pharynx, esophagus, genitals, and anus. The disease shows immunohistological findings identical to those of bullous pemphigoid).

Fixed drug eruption of the mucous membranes: a rare, temporally and locally limited mucositis. There is usually a temporal association with drug intake.  

Severe herpangina, acute herpetic gingivostomatitis, or severe aphthous stomatitis (acute onset with a rise in fever, biphasic fever course). Flu-like and catarrhal symptoms. Appearance of glass-pinhead-sized, chain-like clusters of yellowish-pink, frog-spawn-like vesicles on the soft palate and the palatal arches. Transformation into erosions with a greasy coating in a hyperemic area.

Pemphigus vulgaris: no drug-related cause, chronic clinical picture, chronic formation of flaccid blisters, older adults. Nikolsky’s sign is always positive.

See the respective clinical pictures below. In general, intensive medical therapies are unavoidable.

Depending on the clinic, the following specialist disciplines should be consulted (repeatedly if necessary) during the acute treatment phase: nutritional medicine, gastroenterology, ear, nose and throat medicine, infectiology, nephrology, pneumology. Patients should receive physiotherapy if necessary. Patients with pain can be offered a pain medicine consultation, regardless of the level of pain.

Drugs (extract from AWMF register no.: 013-103)

Highly suspected triggers

• Sulfadiazine-silver (topical)
• Sulfadoxine
• Sulfafurazole
• Sulfamethoxazole
• Sulfasalazine
• Tenoxicam

Suspected triggers

• Doxycycline
• erythromycin
• Levofloxacin
• Oxcarbazepine
• pipemidic acid
• rifampicin
• Sertraline

Under observation

• Cefaclor
• Cefazolin
• Cefepime
• Cefotiam
• cefpodoxime
• ceftazidime
• estradiol
• celecoxib
• Chlortetracycline
• clindamycin
• clobetasol
• cloxacillin
• cortisone
• Cortivasol/Cortivazole
• deflazacort
• dexamethasone
• esomeprazole
• ethambutol
• Etravirine
• Febuxostat
• Flucloxacillin
• flumetasone
• fluticasone
• hydrocortisone
• imipenem
• isoniazid
• lansoprazole
• lenalidomide
• levetiracetam
• lincomycin
• Loracarbef
• Loratadine
• Lymecycline
• meropenem

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