Erythema multiforme L51.0

Ferdinand v. Hebra 1866

Relatively common, polyetiological, mucocutaneous reaction pattern characterized by an acute to subacute, self-limited exanthema prone to recurrence with characteristic, targettoid-structured (disc-in-disc structure) red patches, plaques and blisters as well as possible mucosal involvement (oral, conjunctival, genital and anal mucosa). Strictly speaking, it is not an entity but a group of polyetiological diseases with the main clinical symptoms described, which are pathogenetically characterized by a common cytotoxic immune reaction directed against keratinocytes with epidermal "satellite cell necrosis".

Mainly occurring in young adults, rarely in children. m>w; no ethnic prevalence known.

Genetics: There is evidence of a genetic predisposition to EEM with the following HLA associations: HLA-DQw3, DRw53, AW33.

Infections: In the majority of adolescents and adults, herpes simplex type 1 (HSV-1) infections precede the exanthema or appear clinically after the onset of the exanthema. HSV DNA has been detected in lesional skin using molecular biological methods. Associations with other infectious diseases such as HSV type II (HSV-2), varicella, parapoxviruses(Orf virus), parvovirus B19, hepatitis C, SARS-CoV-2 (Thielmann CM et al. 2022), Histoplasma capsulatum, EBV infections, streptococci or mycoplasma (mycoplasma infections occur more frequently in children - see below). Mycoplasma pneumoniae - see also RIME) have been reported. Severe mycotic or Gardnerella vaginalis infections are less common causes.

EEM and SARS-CoV-2: In a cross-sectional analysis (n= 43,547 patients with a history of SARS-CoV-2 infection), the risk of EM was 6.68 times higher than in patients without COVID-19 (Saleh W et al. 2024).

Vaccinations: Vaccinations (mumps-rubella vaccinations, hepatitis B vaccinations, vaccinations with the polyvalent HPV vaccine) often precede erythema multiforme. At 2.7, the risk of developing EM after a SARS-CoV-2 vaccination is significantly higher than in the general population. The prevalence of EM after SARS-CoV-2 infection or vaccination differs significantly from that of the general population (Saleh W et al. 2024).

Medication: EM is often observed after taking medication (e.g. 5-fluorouracil and actinomycin D), sometimes in combination with viral or bacterial infections (Wang S et al. 2022).

Multiforme "scattering reactions" can also occur with allergic contact eczema (e.g. paraphenylenediamine in tattoos).

Occurs mainly in young adults, low androtrophy. Frequency peak: 20 - 40 LJ. Rarely in infants.

Back of the hands, palms and soles, neck, face and neck, extensor sides of the upper extremity; grouped in the area of the elbow, rarely the knee. The trunk may also be affected (see Fig.). Mild (usually oral) mucosal involvement (lips, buccal mucosa and tongue) in about 50% of cases.

Sudden onset without significant prodromes. Within 48-72 hours, a disseminated, usually symmetrical, asymptomatic or slightly burning to itchy exanthema develops, which may also occur in groups in the elbow or knee area. The exanthema develops rapidly and relapses within a few days with a few to hundreds of lesions. A linear arrangement of the lesions is possible.

Initially there are reddish papules 0.1-0.3 cm in size, which expand to plaques several centimeters in size within 24 hours. Their color is reddish-livid, also hemorrhagic. The center can sink in, show a tendency to regress, but can also show the opposite development, intensify with a purple component or blistering. Concentric rings (shooting target phenomenon - association with cockades) develop due to bursts of activity emanating from the center. The EM lesions do not form necroses and heal without scarring within a few days to weeks.

The histologic picture corresponds to that of classic acute cytotoxic interface dermatitis.

To be distinguished are:

• Early stage: Basket-weave orthokeratotic stratum corneum, edema of the papillary body with sparse lymphocytic infiltrate, scattered eosinophilic granulocytes, marked exocytosis with condensation of lymphocytes in the lower epithelial layers. Few dyskeratotic keratinocytes (amorphous eosinophilic cytoplasm with pyknotic condensed nuclei). Marked hydropic degeneration of the lower epithelial cell layers.
• Later stage: Basket-weave orthokeratotic stratum corneum, marked intra- and subepidermal edema to subepithelial blistering; vacuolar degeneration of epidermis. Vigorous lymphocytic infiltrate with variable admixture of eosinophilic granulocytes. Numerous dyskeratotic keratinocytes, which may also be aggregated into nests.

• Clinical:
  • Acute febrile neutrophilic dermatosis(Sweet syndrome): Clinically and morphologically similar in the early phase of the disease. However, the erythema exsudativum multiforme cocardia are absent in Sweet's syndrome. Always fever, severe feeling of illness and neutrophilic leukocytosis.
  • Polymorphic light dermatosis: Occurs after UV exposure (sun pattern!); severe itching, never involving the mucous membranes.
  • Acute urticaria: Clinical determination of wheals (prove volatility by marking). No erythema exsudativum multiforme cocardia.
  • Urticarial vasculitis: markedly intermittent chronicity. Small-spotted, maculo-papular, itchy or painful exanthema accompanied by fever attacks. Neutrophilic leukocytosis is possible. Frequent arthralgias and arthritides; no erythema exsudativum multiforme cocardia. Swelling of lymph nodes. Possibly positive ANA and signs of systemic lupus erythematosus. Histologically, signs of vasculitis are diagnostic.
  • Subacute cutaneous lupus erythematosus: A picture similar to erythema exsudativum multiforme may develop, particularly in highly acute courses with disseminated plaques. Histology and immunohistology are diagnostic.
  • Drug exanthema (maculo-papular): No real DD, as erythema exsudativum multiforme can be triggered by drugs. A maculo-papular drug erythema can be diagnosed if a connection can be established with altered or intercurrent drug administration.
  • Bullous pemphigoid: In some cases, especially in the initial phase of bullous pemphigoid, the pioneering blisters may be absent. This eliminates the leading clinical symptom of "bulging (firm) blisters" and the clear clinical classification as a blistering disease. Histology and IF are conclusive.
  • Stevens-Johnson syndrome: Initial febrile, catarrhal prodromal symptoms, generalized lymphadenopathy, liver and spleen involvement. Always mucosal manifestations. Skin manifestations of varying extent: from a few atypical cockades with a maximum of two zones to an extensive, scarlatiniform exanthema. In contrast to EEM, Stevens-Johnson syndrome does not show(!) shooting-disk-like efflorescences, but atypical cockades with a maximum of two zones. In addition, unlike erythema multiforme, it can develop into toxic epidermal necrolysis(TEN).
  • RIME/MIRM differs from herpes-related erythema multiforme in its predominant mucosal involvement, relatively sparse skin findings, prevalence in younger patients and excellent prognosis.
• Histologically

  : Note! There are smooth transitions between erythema exsudativum multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. Histologically, all diseases with (occasional) subepidermal blistering must be considered ( dermatitis solaris, graft-versus-host disease, ictus, lichen planus bullosus, lichen sclerosus et atrophícus, polymorphic light dermatosis, systemic amyloidosis, porphyria cutanea tarda).

  • Toxic epidermal necrolysis (TEN ): Subepidermal blister, broad necrosis of the entire epidermis, pronounced dermal edema. Only slight, diffuse lymphocyte infiltration; erythrocyte extravasations.
  • Staphylococcal scalded skin syndrome (SSSS): As previously with TEN; blistering but subcorneal.
  • Drug reaction, fixed: Interface dermatitis with numerous apoptotic keratinocytes, lichenoid and perivascular inflammatory reaction of the upper and middle (usually also the deep) dermis; usually pronounced pigment incontinence.
  • Graft-versus-host disease, acute: Apoptotic keratinocytes, possibly subepithelial blistering, lichenoid infiltrate, eosinophilic granulocytes.
  • Urticaria: Only slight infiltrate; no apoptotic keratinocytes.
  • Pityriasis lichenoides et varioliformis acuta: Interface dermatitis with irregular acanthosis, two-layered structure of the str. corneum with basket-weave-like orthokeratosis over a continuous parakeratosis zone. In the dermis rather wedge-shaped, perivascular or interstitial infiltrate of lymphocytes.
  • Erythema elevatum diutinum: Rare disease! In the early stage always signs of leukocytoclastic vasculitis with leukocytoclasia and nuclear dust as well as fibrin in the vessel walls. Epidermis and skin appendages remain unaffected.

It is an acute, self-liminating disease. In this respect, symptomatic therapy is generally sufficient.

Local treatment with Lotio alba is usually sufficient. For more severe itching and pronounced skin infestation, medium-strength glucocorticoid-containing externals such as 0.1% triamcinolone cream (e.g., Triamgalen, Delphicort,Triamcinolone acetonide cream hydrophilic 0.025/0.05/0.1% (NRF 11.38.), or 0.05-1% betamethasone emulsion (e.g., ^Betagalen®, Betnesol, betamethasone valerate emulsion hydrophilic 0.025/0.05 or 0.1% (NRF 11.47.) are indicated. If the oral mucosa is affected, mouth rinses with antiphlogistic preparations (e.g., chamomile extracts).

If symptoms are pronounced, systemic glucocorticoids such as prednisone (e.g. Decortin Tbl.) 50-75 mg/day. Additionally, in case of itching, antihistamines, e.g. desloratadine (Aerius), levocetirizine (Xyzall), cetirizine (Zyrtec) p.o. In case of frequent (postherpetic) recurrences, oral prophylaxis with aciclovir for 1 year is indicated (10 mg/kg bw/day) (evidence level: IB).

Favorable. Self-limiting course with complete healing after 10 to 14 days.

Recurrent course is possible, with irregular occurrence of usually 1-2 recurrences/year, rarely more frequent (up to 10 recurrences/year).

More frequent episodes are observed in immunosuppressed individuals.

Some patients relapse 1 time/year in spring.

Depending on the expressivity, severity and localization of the skin and mucous membrane changes, different terms have been used in the past, the independence of which is often disputed:

• Erythema multiforme major
• Dermatostomatitis Baader
• Stevens-Johnson-Fuchs syndrome (syndroma muco-cutaneo-oculare Fuchs)
• Fiessinger-Rendu syndrome(ectodermosis érosive pluriorificielle)
• RIME (reactive infectious mucocutaneous eruption)

Together with Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN), these variants are now regarded as a disease spectrum with varying degrees of severity.

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