Erythema multiforme

Erythema multiforme is a relatively common cutaneous reaction pattern that usually presents as well-demarcated plaques on the trunk and extremities, often with target, or "iris," lesions. Lesions may also occur as widespread plaques or erosions on the oral mucosa, conjunctiva and genitalia. Erythema multiforme can have a varied clinical presentation, which can make diagnosis difficult.

Most clinicians separate erythema multiforme into two clinical subsets in the mild cutaneous syndrome (erythema multiforme minor) and the more severe syndrome with marked mucosal damage (erythema multiforme major or Stevens-Johnson syndrome). The two types of erythema multiforme are distinguished by the duration of disease and the degree of mucosal damage. The Stevens-Johnson subtype is characterized by hemorrhagic oral mucosal and conjunctival lesions that can cause severe discomfort and disability.

Clinical Manifestations

Lesions resembling a target (or the iris of an eye) are the hallmark of erythema multiforme (Figure 1 ), although erythematous macules or papules may lack this feature. The target-like lesion develops from either a central blister or a central area of epidermal necrosis within the erythematous macule or papule. Symmetric involvement of the extremities, specifically the extensor aspects, is the classic pattern of cutaneous distribution. The morphologic pattern may vary from patient to patient.

The cutaneous lesions often evolve during the course of the disease. The initial primary lesions are often erythematous macules, which become papules, vesicles or bullae. Surrounding areas may be blanched or hyperpigmented circumferentially, further adding to the target-like appearance. These clinical manifestations are reflected in the histology: the central gray color of the blisters and erosions results from epidermal necrosis, while the surrounding reddish-purple rings result from extravasated erythrocytes and superficial vascular dilatation.(10)

Mucous membrane and genital involvement is severe in erythema multiforme major. Painful superficial ulcerations of the buccal mucosa and genitalia and hemorrhagic crusting of the lips are characteristic. Examination of mucosal lesions may initially reveal only erythematous patches; within hours, however, superficial erosions with pseudomembrane formation mav develop(2) (Figure 2 ).

Prodromal symptoms of fever, headache, malaise, cough, prostration and sore throat may be present for a week before the onset of erythema multiforme. It is unclear, however, whether these nonspecific symptoms are secondary to the disease that triggered erythema multiforme or whether they are are a primary manifestation of erythema multiforme. The prodromal symptoms occur in onethird of cases and, with mucosal involvement, are more prominent in erythema multiforme major than in erythema multiforme minor. In severe erythema multiforme major, there is a risk of visceral organ damage to the larynx, bronchi and esophagus from mucosal ulcerations. Inflammatory renal lesions, clinically and histologically similar to acute glomerulonephritis, have been reported.(3)

Pathophysiology

Erythema multiforme is a reactive inflammatory disorder, appearing as a hostspecific immune response to a variety of antigenic stimuli.(4) Both type III (immunecomplex) and type IV (cell-mediated) hypersensitivity reactions have been proposed as the pathogenesis of erythema multiforme. Immune complexes have been demonstrated in serum and blister fluid,(5) and the inflammatory infiltrate has been shown to consist of monocytes/macrophages and T lymphocytes. (6)

In erythema multiforme caused by herpes simplex virus (HSV), it is thought that the herpes antigen induces a cytologic response within the epithelium secondary to a hypersensitivity reaction to the antigen. This cytologic response is reflected in the characteristic histologic picture of erythema multiforme, which primarily involves a lymphohistiocytic infiltrate surrounding the upper dermal blood vessels and epidermal keratinocyte necrosis (Figure 3). Intraepidermal and subepidermal blisters and edema may be seen on histologic examination and correlate with the clinical picture of vesicles or bullae.

Immunofluorescence may show granular IgM or C3 around the superficial dermal vessels and the dermatoepidermal junction, suggesting an underlying immunologic process. A case of erythema multiforme with documented atypical epidermal autoantibodies seen on immunohistologic examination has been reported.(7) Additional support for the theory that certain antigens induce a cytologic response in the epidermis is provided by Brice and colleagues,(8) who demonstrated the presence of HSV DNA within the skin using polymerase chain reaction and HSV-specific RNA probes.

A genetic predisposition to erythema multiforme is thought to exist. Erythema multiforme and certain subtypes of the disorder have been found to be more prevalent in patients with human leukocyte antigens B15 and DQw3, respectively. (9)

Etiology

The three most common causes of erythema multiforme are herpes infection, mycoplasma infection and drug reactions(10) (Table 1). Collagen diseases, protozoan infections, mycotic infections, vaccines, skin allergens, carcinoma, lymphoma and leukemia have all been associated with erythema multiforme but represent a minority of cases.

Although erythema multiforme tends to be considered a disease of adolescents and young adults, drug-associated erythema multiforme can occur at any age. Erythema multiforme due to drug reaction or mycoplasma infection tends to have clinical features consistent with the erythema multiforme major subtype, while disease due to herpes infection represents the classic mild syndrome.

HSV may account for up to two-thirds of all cases of erythema multiforme. Both types I and II HSV infections have been associated with erythema multiforme.(12) The typical lesions of erythema multiforme are usually noted about 10 days after the initial herpes infection. Patients with frequently recurring herpetic infections and secondary erythema multiforme may experience significant morbidity.

Mycoplasma infection is the most commonly recognized bacterial infection associated with erythema multiforme. Both cultural and serologic evidence of mycoplasma infection has been documented in patients with erythema multiforme. Although the onset of erythema multiforme may occur one to three weeks after the respiratory illness, the constitutional symptoms are usually more severe. Mucosal lesions usually involve multiple surfaces, and the skin lesions may be of the bullous type. Unlike HSV-associated erythema multiforme, recurrences are unusual in mycoplasma-induced erythema multiforme.

Drug reactions are the best documented of the three major causes of erythema multiforme. Causative agents include antibiotics, such as penicillin and sulfonamides, and chemotherapeutic agents, such as methotrexate.(13-15) Classic erythema multiforme lesions have been reported after vaccination against diphtheria-pertussis-tetanus (DPT)(13 and hepatitis B.

Some of the many drugs that have been reported to cause erythema mu]tiforme are listed in Table 2.

Drug-associated erythema multiforme may begin one to three weeks after drug therapy is initiated. However, the time interval is variable. Months may elapse between the first dose of a particular drug and the development of clinically evident erythema multiforme. In a person who has previously been sensitized to a drug, erythema multiforme may begin within hours of administration.

Drug reactions cause the majority of erythema multiforme cases that progress to toxic epidermal necrolysis, the most severe clinical form of erythema multiforme major. Toxic epidermal necrolysis is characterized by rapid onset and diffuse confluent epidermal desquamation, which leaves red, raw surfaces similar to those in a second-degree bum. Cutaneous pain, prostration and increased risk of sepsis are common features of toxic epidermal necrolysis.

Differential Diagnosis

The differential diagnosis of erythema multiforme is given in Table 3. Although target-like lesions are characteristic of erythema multiforme, they may not always be clinically apparent. The maculopapular annular lesions of erythema multiforme may be confused with those of urticaria, pityriasis rosea, ringworm, lupus erythematosus, mucocutaneous lymph node syndrome and maculopapular syphilis.

The bullous lesions of erythema multiforme may be difficult to differentiate from the typical lesions of bullous pemphigoid, dermatitis herpetiformis, pemphigus and bullous contact dermatitis.(16) Rarely, bullous pemphigoid may mimic bullous erythema multiforme, showing target-like lesions and tense bullae.(17) The clinical finding of superficial oral mucosal erosions may warrant an evaluation for herpetic gingivostomatitis, recurrent aphthous stomatitis, erosive lichen planus, Behcet's disease and Reiter's syndrome.

An appropriately directed history and physical examination often can eliminate many of the previously mentioned conditions. For example, bullous pemphigoid and pemphigus vulgaris tend to affect middle-aged and elderly persons; aphthous stomatitis rarely affects the dorsum of the tongue or hard palate,(18) and mucocutaneous lymph node syndrome primarily occurs in infants and is associated with fever and lymphadenitis.

Treatment

The therapeutic problems in erythema multiforme are that the rate of disease progression cannot be predicted from the initial manifestations and that the precipitating cause is often difficult to identify. Table 4 outlines an approach to the treatment of erythema multiforme.(19)

Classic or mild erythema multiforme is often best managed with local supportive care and antibacterial preparations to prevent secondary infection. The use of oral corticosteroids is controversial. Some clinicians believe that the early administration of systemic corticosteroids may prevent disease progression and obviate the need for hospitalization. Patterson and colleagues20 advocate the administration of at least 1 mg per kg per day of prednisone in patients with erythema multiforme major. Conversely, Rasmussen(21) suggests that treatment with systemic corticosteroids may be associated with significant side effects that actually prolong recovery time. We have had success in preventing recurrent HSV-associated erythema multiforme with maintenance doses of acyclovir (Zovirax), as have others.(22)

Each patient with erythema multiforme must be carefully evaluated to identify the precipitating cause. Termination of nonessential drug therapy, the use of fluid replacement, and ophthalmologic and dermatologic consultations should be considered in severe cases.

COPYRIGHT 1992 American Academy of Family Physicians
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