Erythema multiforme L51.0

Ferdinand v. Hebra 1866

Relatively frequent, polyetiological, mucocutaneous clinical picture characterized by an acute to sub-acute, self-limiting exanthema with characteristic, ring-in-ring structured spots and plaques and a possible mucosal infection. Strictly speaking, it is not an entity but a group of polyaetiological diseases with the described clinical leading symptoms, which is pathogenetically characterized by a common cytotoxic immune reaction directed against keratinocytes.

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

In the majority of adolescents and adults, herpes simplex type 1 (HSV-1) infections precede exanthema or become clinically apparent after the onset of exanthema. By molecular biological methods HSV DNA could be detected in lesioned skin.

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

Associations with other infectious diseases such as HSV type II (HSV-2), varicella, parapoxvirus(Orf virus), parvovirus-B19, hepatitis C, histoplasma capsulatum, EBV infections, streptococci or mycoplasma (mycoplasma infections are more common in children) have been reported.

More rarely, severe mycotic or Gardnerella vaginalis infections are the cause.

It is not uncommon for vaccinations (mass-mumps-rubella vaccinations, hepatitis B vaccinations, vaccinations with the polyvalent HPV vaccine) to precede an EEM.

EEM is often observed in combination with infections after taking medication.

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.

Sudden onset without significant prodromies. Within 48-72 hours development of a disseminated, symptomless or slightly burning to itchy exanthema which may also occur in groups in the area of the elbow or knee. Initially 0.1-0.3 cm large reddish papules, which expand within 24 hours to form (almost pathognomic) shooting disc-shaped (cockades) plaques. Their color is reddish-livid, also hemorrhagic. In the centre of the plaques blistering is possible. Often a linear arrangement of the lesions is detectable ( Koebner phenomenon).

The histological picture corresponds to that of classical acute cytotoxic interface dermatitis. A distinction must be made between:

• Early stage: plexus-like orthokeratotic stratum corneum, oedema of the papillary body with a thin lymphocytic infiltrate, isolated eosinophil granulocytes, distinct exocytosis with compression of the lymphocytes in the lower epithelial layers. Few dyskeratotic keratinocytes (amorphous eosinophilic cytoplasm in pynotically condensed nuclei). Significant hydropic degeneration of the lower epithelial cell layers.
• Later stage: plexus-like orthokeratotic stratum corneum, pronounced intra- and subepidermal edema up to subepithelial blistering; vacuum degeneration of the epidermis. Strong lymphocytic infiltrate with varying admixture of eosinophil granulocytes. Numerous dyskeratotic keratinocytes, which can also be aggregated to nests.

• Clinical:
  • Acute febrile neutrophilic dermatosis(Sweet syndrome): Clinically and morphologically similar in the early phase of the disease. However, Sweet syndrome lacks the erythema exsudativum multiforme cocardia. Always fever, severe feeling of illness and neutrophil leucocytosis.
  • Polymorphic light dermatosis: Occurs after UV exposure (sun pattern!); severe itching, never involving the mucous membranes.
  • Acute urticaria: Clinical determination of the wheals (volatility is proven by marking). No erythema exsudativum multiforme-cocards.
  • Urticarial vasculitis: pronounced intermittent chronicity. Small spots, maculopapular, itchy or painful exanthema accompanied by fever attacks. Neutrophilic leukocytosis is possible. Frequently 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: Especially in highly acute course with disseminated plaques a picture similar to the erythema exsudativum multiforme can develop. Histology and immunohistology are diagnostic.
  • Drug exanthema (maculo-papular): No real DD, because erythema exsudativum multiforme can be triggered by drugs. A maculo-papular drug exanthema can be diagnosed if a connection can be made with altered or intercurrent drug administration.
  • Bullous pemphigoid: In some cases, especially in the initial phase of bullous pemphigoid, the pathological blisters may be absent. Thus, the clinical leading symptom "bulging (firm) bladder" and the clear clinical assignment to the blister-forming diseases is not applicable. Histology and IF are conclusive.
  • Stevens-Johnson syndrome: Initially febrile, catarrhal prodromal symptoms, generalized lymphadenopathy, liver and spleen involvement. Always mucous membrane symptoms. Skin manifestations of varying degrees: from a few single lesions like a shooting target to a large, scarlatinous exanthema.
• Histological

  :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 bladder, broad necrosis of the entire epidermis, pronounced dermal oedema. Only slight, diffuse lymphocyte infiltration; erythrocyte extravasation.
  • Staphylococcal Scalded Skin Syndrome (SSSS): Same as TEN, but blister formation subcorneal.
  • Drug reaction, fixed: Interface dermatitis with numerous apoptotic keratinocytes, lichenoid and perivascular inflammatory reaction of the upper and middle (usually also of the deep) dermis; usually pronounced pigment incontinence.
  • Graft-versus-host disease, acute: apoptotic keratinocytes, possibly subepithelial blistering, lichenoid infiltrate, eosinophil granulocytes.
  • Urticaria: Only low infiltrate; no apoptotic keratinocytes.
  • Pityriasis lichenoides et varioliformis acuta: Interface dermatitis with irregular acanthosis, two-layer structure of the stratum corneum with plexus-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 and 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.

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

Recurrent course is possible, with irregular occurrence of mostly 1-2 relapses/year, less frequently (up to 10 relapses/year).

More frequent episodes are observed in immunocompromised patients.

Some patients relapse 1 time per year in spring.

Depending on the expressivity, severity and localisation of the skin and mucous membrane changes, different terms were used in the past, the originality of which is doubted today:

• Erythema multiforme major
• Dermatostomatitis Baader
• Stevens-Johnson-Fuchs syndrome (syndrome muco-cutaneo-ocular fox)
• Fiessinger-Rendu syndrome (Ectodermosis érosive pluriorificielle).

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

1. Ayangco L et al (2003) Oral manifestations of erythema multiforme. Dermatol Clin 21: 195-205
2. S et al (2000) Herpes simplex virus type 1 as a cause of widespread intracorneal blistering of the lower limbs. Clin Exp Dermatol 25: 119-121
3. Hidajat C et al (2014) Drug-mediated rash: erythema multiforme versus Stevens-Johnson syndrome. BMJ Case Rep 22 PubMed PMID: 25246464.
4. Johnston GA et al (2002) Neonatal erythema multiforme major. Clin Exp Dermatol 27: 661-664
5. Molnar I, Matulis M. (2002) Arthritis associated with recurrent erythema multiforme responding to oral acyclovir. Clin Rheumatol 21: 415-417
6. Samim F et al(2013) Erythema multiforme: a review of epidemiology, pathogenesis, clinical features,
7. and treatment. Dent Clinic North Am 57:583-96.
8. Seishima M, Oyama Z, Yamamura M (2001) Erythema multiforme associated with cytomegalovirus infection in nonimmunosuppressed patients. Dermatology 203: 299-302
9. Sun J et al (2014) Stevens-Johnson Syndrome and toxic epidermal necrolysis: a multi-aspect comparative 7-year study from the People's Republic of China. Drug of Devel Ther 8:2539-1547
10. Tatnall FM et al (1995) A double-blind, placebo-controlled trial of continous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 132: 267-270
11. Trayes KP et al (2019) Erythema Multiforme: Recognition and Management. On Fam Physician. 100: 82-88.
12. by Hebra F, Kaposi M (1860) Textbook of skin diseases. Volume 1, Enke, Erlangen