Erythema Multiforme (EM)

Acute mucocutaneous hypersensitivity reaction of variable severity characterized by symmetrical skin eruptions, with or without mucous membrane lesions.

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Erythema Polyforme (French appellation); EM.

EM minor form or EM major form (Stevens-Johnson syndrome).

The terminology of the disorder is confusing, and the many names represent the spectrum of one disease that is part of mucocutaneous syndromes. Historically, erythemas were first described by Willan in 1808, but the fact that they are different clinical presentations of the same entity was first noted by Hebra in 1860. Then, in 1916 Rendu described mucosal lesions with or without skin lesions, which were later named “ectodermosis erosiva pluriorificialis" by Fiessinger in 1923. Meanwhile, in 1922 the American and English literature reported the association of skin and mucosal lesions with a systemic reaction, the Stevens-Johnson syndrome. The common nature of all these conditions was noticed in 1965 by Ströhm, who gave them the term “mucocutaneous fever.” Currently, this entity is considered an immunologic disease that may be linked to the presence of HLA-B15.

The reported incidence of EM is 0.03 to 0.1% in the general population. Males are affected more often than females (ratio of 3:1). The majority of cases occur in individuals younger than 20 years. The disease is almost nonexistent in those younger than 3 years and older than 50 years. The disease is recurrent in approximately 30% of cases. The incidence of drug-related cases of EM major is equal in males and females.

Not a genetic disorder, although a genetic predisposition has been discussed.

Can be caused by drugs (nonsteroidal antiinflammatory drugs (e.g., ibuprofen, naproxen, valdecoxib, oxaprozin), sulfonamides, penicillins, cephalosporins, erythromycin, tuberculostatics, salicylates, pyrazolones, carbamazepine, phenobarbital, phenytoin), viral (e.g., adenovirus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, hepatitis A and B virus, measles virus, varicella virus, mumps virus, influenza virus, coxsackie virus B5), bacterial (e.g., Proteus species, Salmonella species, Mycobacterium species, Brucella species, Corynebacterium diphtheriae), fungal (e.g., histoplasmosis), parasitic (e.g., coccidiosis) or mycoplasma infections, endocrine factors, neoplasms, collagen diseases, sarcoidosis, and physical factors. However, of all the possible causative factors, only drugs, herpes simplex, and mycoplasma have been implicated without doubt. The disease is speculated to be caused mainly by a cell-mediated hypersensitivity reaction to a drug or another type of antigen. Humoral involvement with the presence of IgM and C3 are part of the immunologic reaction. These immune complexes are found in the vasculature and at the dermal-epidermal junction and cause vasculitis and skin lesions.

Results of laboratory tests are nonspecific and may show leukocytosis and an elevated erythrocyte sedimentation rate. The diagnosis is clinical, based on the presence of typical skin and mucosal lesions, with or without systemic involvement. Drug history and possible recent infections should be taken into account.

In its minor form, the disease is characterized by a self-limited course with a duration of 1 to 4 weeks. The prodromal symptoms are compatible with an upper respiratory tract infection, and the skin lesions usually appear after 7 to 10 days. The typical cutaneous manifestations are the target or iris lesions, which are symmetrical and present mostly on the dorsum of the hands and feet, palms, and soles, and finally on the extensor surfaces of the limb. After a few days, the center of the lesion changes to a cyanotic reddish color surrounded by a lighter peripheral ring. Blisters may form in the center. In the end, the lesions retract and leave a transient hyperpigmentation. Symptoms are mild and consist mainly of a burning sensation. Mucosal involvement is present in only 25% of cases and usually limited to modest oral erosions of short duration. In all cases, complete healing takes approximately 2 weeks.

In the majus or major or Stevens-Johnson form, the disease is characterized by a more important prodromal episode with high fever, asthenia, malaise, muscular pain associated with migrant arthralgia, diarrhea, vomiting, and pharyngitis. After a few days, skin and mostly mucosal lesions, which are always present in this form of the disease, appear. The mucosal involvement is severe and usually involves two or more mucosal sites simultaneously (minimum of two sites is required for the diagnosis). In the worst cases, the pharynx, larynx, bronchial mucosa, and esophagus are involved. The mucosal lesions rapidly change to blisters, which in turn ulcerate and produce painful erosions resulting in significant swallowing problems. The eyes can be affected by the disease in the form of purulent conjunctivitis and permanent visual loss in up to 10%. The skin lesions are also more extensive in this form, and massive denudation of the skin can be seen with transudation of proteins. Of note, the skin manifestations are asymmetrical in the Stevens-Johnson form. In the majus form, healing is complete in the great majority of cases, but the course of the disease is longer, lasting for up to 6 weeks. Death is rare but has been reported. Corticosteroids and cyclosporin A can be used for treatment of severe forms.

No patient should undergo an elective surgical procedure during the acute episode, especially with Stevens-Johnson syndrome. However, anesthesia may be required for dressing changes and skin debridement. A complete blood count and serum concentrations of electrolytes and albumin should be obtained. Because fluid losses through the skin defects may be significant, adequate volume status should be ensured before induction of anesthesia. A chest radiograph should be obtained.

Affected patients should be considered like Epidermolysis Bullosa patients. The presence of lesions in the respiratory tract can result in pulmonary blebs and increase the risk of pneumothorax. Vascular access may be challenging in the presence of extensive skin lesions.

Many drugs are involved in the development of EM (see Pathophysiology). In the severe forms, hypalbuminemia results in an increased free fraction and efficacy of drugs with high protein binding.

Epidermolysis Bullosa: Genetic disorder characterized by cutaneous blistering and scarring following already minor trauma. More than 20 different subtypes of the disease have been grouped into three main categories: epidermolysis bullosa simplex, dystrophic epidermolysis bullosa, and junctional epidermolysis bullosa.

Lyell Syndrome: Severe allergic syndrome characterized by extensive bullous eruptions of the skin and mucous membranes, fever, malaise, conjunctivitis, and diffuse erythema. Often lethal in children.

Danbolt-Closs Syndrome: Inherited vesiculobullous disorder characterized by intermittent simultaneous occurrence of diarrhea and bullous dermatitis (dry lesions surrounding the mouth, ears, nose, and eyes, but also affecting the fingers, feet, and knees) and failure to thrive in premature babies. In children, periorificial lesions of the face and anogenital region. Alopecia and absence of eyebrows, eyelashes, and thymus are common.