Epidermal nekrolysis L51.2

Epidermal necrolysis (EN) is the name given today to a disease entity that combines 2 previously separate clinical pictures - Stevens-Johnson syndrome/toxic epidermal necrolysis- under one diagnosis. Both blistering clinical pictures differ only in the extent and severity of the epitheliolytic skin and mucous membrane lesions. For Stevens-Johnson syndrome (SJS), a consensus classification defined an epidermolytic infestation in relation to the body surface area (KOF) <10%, for toxic epidermal necrolysis (TEN) a KOF >30% (Grünwald P et al. 2020). A KOF between 10-30% is considered SJS/TEN overlap syndrome.

EN is triggered by a drug in 65-85% of all cases, in children only in around a third of cases (Maverakis E et al. 2017; Creamer D et al. 2016). More than 100 drugs (see references below) are associated with EN in the literature. However, large-scale epidemiological studies have shown that around half of the cases can be explained by high-risk medications (so-called "highly suspected" triggers) and around 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 necrotic detachment of the epidermis and mucosal epithelia. CD8+ T lymphocytes stimulated by the triggering agent (predominantly drugs, but also infections or a combination thereof) play a central role in the immune-mediated cell death of keratinocytes. There are currently three theories for the formation of a postulated "neoantigenic agent-tissue complex" and how the T cell-mediated cell damage is consecutively 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 agent and MHC class I molecule (altered peptide concept).

Granulysin: The cytolytic protein granulysin produced by cytotoxic T cells and NK cells is considered to be 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 were detected in lesional skin samples and/or blister fluid. The Fas ligand (FasL, CD95L), a cell surface molecule that induces apoptosis after binding to the Fas receptor (CD95, Apo-1), is also attributed a role in the pathogenesis of EN.

In addition, strong expression of the CD40 ligand (CD40L), which leads to the release of TNF-alpha, nitric oxide (NO), IL-8 and cell adhesion molecules (e.g. annnexin) via signaling pathways, has also been demonstrated in the acute phase of the disease. Other soluble pro-apoptotic molecules associated with the pathogenesis of EN are IL-15, perforin and granzyme B (Caproni M et al. 2006a; Caproni M et al. 2006b; Viard-Leveugle I et al. 2013).

The developing exanthema shows a rapid dynamic, so that within a day or a few days it can progress from initial localized reddening of the skin to a generalized finding with epidermolysis. At the same time, a more or less pronounced detachment of the mucous membrane is almost always detectable. Usually several mucosal areas are affected at the same time: oral and genital mucosa, conjunctiva, nasal mucosa, more rarely the trachea or bronchi. These erosive mucosal lesions are very painful and typically hemorrhagic and, depending on the location affected, lead to impaired food intake, dysuria or photophobia. The resulting fibrinous deposits lead to adhesions, which further increase the pain and further restrict the corresponding functions. Mucosal detachment occurs in SJS, SJS/TEN transitional form as well as TEN, which is why the different degrees of severity of EN cannot be differentiated on the basis of their mucosal involvement. Occasionally (in less than 10 % of all cases) there is no hemorrhagic-erosive mucosal involvement (Bastuji-Garin S et al. 1993).

The individual efflorescences of the skin are characterized by red, often blurred patches (important differential diagnosis to the cockade of erythema exsudativum multiforme, which can be palpated as a plaque-like elevation (Grünwald P et al. 202o), partly in the form of atypical cockades, whose annular, shooting-disk-like formations are less clearly recognizable (maximum 2 ring structures) than in erythema exsudativum multiforme with its clearly marked edges.

With increasing severity, the efflorescences confluent to form large areas of erythema. The extent of epidermolysis increases, verifiable by a positive Nikolski I phenomenon (tangential pressure on the erythema areas, but also on the non-erythematous marginal areas, leads to detachment of the skin). The Nikolski II phenomenon (blisters can be displaced by pressure) also proves to be positive (Salopek T 1997). As a further differentiating feature, it can be helpful to look at the base of the blister, which is 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 blister base is dry (for example in "staphylococcal scalded skin syndrome" or in acute generalized exanthematous pustulosis) (Sidoroff A et al. 2001)

TEN is a serious life-threatening disease. The causes of death are usually catheter infections with subsequent sepsis, urosepsis, pneumonia, pulmonary and multiple organ failure and, not infrequently, complications of comorbidities.

Specific laboratory parameters as diagnostic markers of EN are not available. An increase in inflammatory parameters (including C-reactive protein (CRP)) is to be expected. Initially, if CRP is elevated, there is a corresponding medical history and clinical signs of infection, a targeted clarification of an infection-based genesis (e.g. (para)influenza, adenovirus, Mycoplasma pneumoniae, Chlamydophila pneumoniae) should be carried out.

Diagnostic smear tests of lesional skin and mucous membrane for bacterial/mycological analysis.

Detection of necrotic keratinocytes, which are present basally, but also distributed throughout the epidermis, sometimes in larger clusters, resulting in subepidermal detachment. Due to the speed of development, the horny layer remains orthokeratotic. Especially in marginal areas of the epidermolysis, the still intact epidermis shows vacuolization of the basement membrane zone and often already individual keratinocyte necroses. 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 time at which the biopsy was taken and any secondary changes. The histological findings are not specific for EN, but can also be indicative of a generalized bullous fixed drug erythema (GBFAE), an EEM (when a sample is taken from the central bladder of a cockade) or a toxic erythema following chemotherapy. In GBFAE, however, there may be additional accumulations of melanophages in the upper dermis, and the infiltrate is often characterized by an interstitial distribution of eosinophils and neutrophils Autoimmunological blistering dermatoses (pemphigus vulgaris, bullous pemphigoid, IgA linear dermatosis) can be ruled out immunohistologically.

The following parameters must be evaluated for a diagnostic assessment of an epidermolytic skin condition:

• Drug history: The history and clinical findings are decisive for confirming the diagnosis, including an assessment of the temporal dynamics of the skin changes and other symptoms. In addition, there is a need for a complete medication history, which should include sporadically taken preparations as well as daily prescribed medications. The focus here is on the period of the last four weeks. In individual cases, medications that were taken up to three months ago (e.g. with a long half-life) can be considered triggers (Mockenhaupt M et al. 2019).
• Acute onset (<1 week)
• General symptoms: Even before the development of exanthema, enanthema or erosive mucosal involvement, there are often non-specific general symptoms such as fever, headache and a general feeling of illness with fever, difficulty swallowing, coughing
• Anamnestic connection with the intake of a new medication
• Evidence of a painful (burning) exanthema with mostly diffuse but also figured, large areas of erythema, occasionally also coccoid-like patches
• Skin detachment <10% KOF, atpic cockades = SJS
• Skin detachment >30% KOF, atpic cockades = TEN
• Detection of epidermolysis
• Positive Nikolski phenomenon (Nikolski I+Nikolski II) (the Nikolski I phenomenon - detachment of previously non-epidermolytic skin in response to sliding pressure - is particularly significant)
• Detection of extensive, epitheliolytic mucositis (oral mucosa and lips, possibly upper respiratory tract, conjunctiva and genital mucosa close to the skin
• Sample biopsy (5mm punch biopsy - HE/PAS staining) from still intact lesional skin - for light microscopy and immunofluorescence
• A frozen section diagnosis enables rapid differentiation between subepidermal and intraepidermal cleft formation. The latter is to be expected in "staphylococcal scalded skin syndrome" (triggered by a staphylococcal exotoxin). A microscopic examination of the blister roof also makes it possible to determine the cleavage plane. In the logistics of sample shipment and processing, it must be taken into account that the skin sample is marked and processed as an urgent or cito case.
• Determination of the SCORTEN

• Erythema (exsudativum) multiforme (EEM/major form) with preferential infestation of the mucous membranes (Fuchs syndrome, or pluriorificial ectodermis, see also NIME syndrome). The minor variant of EEM usually shows only minor infestation of the mucous membranes.
• Mucous membrane pemphigoid (chronic course, leads to scarring and functional loss of the mucous membranes of the conjunctiva, mouth, pharynx, oesophagus, genitals and anus. Immunohistologically, the disease has identical findings to bullous pemphigoid)
• Fixed drug exanthema of the mucous membranes: rare, temporally and locally limited mucositis. Connection with drug intake is usually given.
• Severe herpangina, acute gingivostomatitis herpetica or severe aphthous stomatitis (cautious onset with rise in fever, biphasic course of fever. Influenza-catarrhal symptoms. Appearance of glass pinhead-sized, chain-like, yellowish-pink, frogspawn-like vesicles on the soft palate and palatal arches. Transformation into greasy erosions with hyperemic surroundings.
• Pemphigus vulgaris: no reference to medication, chronic clinical picture, older people

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

1. Bastuji-Garin S et al. (1993) Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129: 92-6.
2. Caproni M et al. (2006) Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis.Br J Dermatol155: 722-728.
3. Caproni M et al. (2006) Elevated circulating CD40 ligand in patients with erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Br J Dermatol 154: 1006-1007;
4. Creamer D et al. (2016) UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. J Plast Reconstr Aesthet Surg. 69: 736-741).
5. Grünwald P et al. (2020) Erythema exsudativum multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis - diagnosis and therapy. J Dtsch Dermatol Ges 18: 547-53.
6. Lyell A (1979) Toxic epidermal necrolysis (the scalded skin syndrome): a reappraisal. Br J Dermatol 100: 69-86.
7. Maverakis E et al.(2017) Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Standard Reporting and Evaluation Guidelines: Results of a National Institutes of Health Working Group. JAMA Dermatol 153: 587-92.
8. Mockenhaupt M et al. (2019) Epidermal Necrolysis (Stevens-Johnson Syndrome and ToxicEpidermal Necrolysis). In: Kang S et al. Fitzpatrick's Dermatology, 9e. New York, NY: McGraw-Hill Education, 2019.
9. Paulmann M et al. (2024) Diagnosis and therapy of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis) AWMF Registry No.: 013-103
10. Roujeau JC (1994) Severe adverse cutaneous reactions to drugs. N Engl J Med 331:
11. Salopek T (1997) Nikolsky's sign: is it 'dry'or is it 'wet'? Br J Dermatol136: 762-67; Paulmann M (2015) Severe drug-induced skin reactions: clinic, diagnostics, etiology and therapy. J Dtsch Dermatol Ges13: 625-645.
12. Sidoroff A et al. (2001) Acute generalized exanthematous pustulosis (AGEP)-a clinical reaction pattern. J Cutan Pathol 28: 113-119; Mockenhaupt M et al. (2005) Epidemiology of staphylococcal scalded skin syndrome in Germany. J Invest Dermatol 124: 700-703).
13. Viard-Leveugle I et al. (2013) TNF-alpha and IFN-gamma are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis. J Invest Dermatol133: 489-498.