Erythema Multiforme

What is Erythema Multiforme?

Erythema multiforme is a skin condition considered to be a hypersensitivity reaction to infections or drugs. It consists of a polymorphous eruption of macules, papules, and characteristic “target” lesions that are symmetrically distributed with a propensity for the distal extremities. There is minimal mucosal involvement. Management involves treating the existing infectious agent or discontinuing the causal drug. Mild cases resolve without sequelae and do not require treatment. Recurrent cases have been prevented with continuous acyclovir. Patients who have no response to acyclovir may have a response to valacyclovir or famciclovir, which have greater oral bioavailability and more convenient dosing. Patients with recurrent erythema multiforme despite suppressive antiviral therapy should be referred to a dermatologist for further treatment.


Erythema multiforme is an acute, self-limited, and sometimes recurring skin condition considered to be a hypersensitivity reaction associated with certain infections and medications (see table belwo). Previously, the condition was thought to be part of a clinical spectrum of disease that included erythema minor, erythema major (often equated with Stevens-Johnson syndrome [SJS]), and toxic epidermal necrolysis (TEN), with erythema minor being the most mild and TEN the most severe.  An often-cited study from 1993 proposed a useful clinical classification of erythema multiforme, SJS, and TEN based on the pattern of individual skin lesions and the estimation of body surface area with detachment of the epidermis (i.e., blisters, denuded areas, or erosions) at the worst stage of the disease. Although SJS and TEN may represent the same process with differing severity, erythema multiforme, with its minimal mucous membrane involvement and less than 10 percent epidermal detachment, now is accepted as a distinct condition. The remainder of this article will focus on erythema multiforme.


Causes of Erythema Multiforme:

– Infections*
– Herpes simplex virus 1 and 2
– Mycoplasma pneumoniae
– Fungal infections
– Medications
– Barbiturates
– Hydantoins
– Nonsteroidal anti-inflammatory drugs (NSAIDs)
– Penicillins
– Phenothiazines
– Sulfonamides


Clinical Presentation:

Erythema Multiforme

Erythema multiforme is a self-limited eruption that usually has mild or no prodromal symptoms. Patients may experience itching and burning at the site of the eruption. The individual lesions begin acutely as numerous sharply demarcated red or pink macules that then become papular. The papules may enlarge gradually into plaques several centimeters in diameter. The central portion of the papules or plaques gradually becomes darker red, brown, dusky, or purpuric. Crusting or blistering sometimes occurs in the center of the lesions. The characteristic “target” or “iris” lesion has a regular round shape and three concentric zones: a central dusky or darker red area, a paler pink or edematous zone, and a peripheral red ring. Some target lesions have only two zones, the dusky or darker red center and a pink or lighter red border. Target lesions may not be apparent until several days after the onset, when lesions of various clinical morphology usually are present, hence the name erythema “multiforme.”



Erythema multiforme is diagnosed clinically. In patients who have target lesions with a preceding or coexisting HSV infection, the diagnosis can be made easily. Skin biopsy is not necessary when the clinical picture is clear because biopsy findings are not specific for erythema multiforme. In unclear cases, such as an atypical presentation or recurrent erythema multiforme without documented HSV infection, biopsy may help rule out other diagnoses. Laboratory tests (e.g., HSV-1 and -2, immunoglobulin M and G) may confirm a suspected history of HSV infection, but they are not required.

Skin biopsy results vary depending on the clinical morphology and the duration of the lesions’ existence as well as the area of the lesion from which the specimen is obtained (i.e., the center portion or the outer zone). The early stage of the red macules and papules shows a perivascular mononuclear cell infiltrate. Biopsy of the edematous zone of the target lesion may show pronounced dermal edema histologically; necrotic keratinocytes or epidermal changes usually occur in the central portion of the target lesion.

The differential diagnosis of early erythema multiforme includes drug eruption, polymorphic light eruption, urticaria, urticarial vasculitis, viral exanthems, and other hypersensitivity reactions. Because erythema multiforme often resembles urticaria at the onset of the eruption, it is important to distinguish the clinical features. The individual lesions of erythema multiforme in typical cases are present and fixed for at least one week, and some evolve into target lesions. In contrast, the individual lesions of urticaria exist at the same site for less than 24 hours, and the centers of the lesions appear normal or as red as the borders. Target lesions with dusky or purpuric centers may resemble pityriasis rosea, lupus erythematosus, vasculitis, or figurate erythema. When bullous lesions are present, erythema multiforme must be distinguished from the autoimmune bullous diseases.



References for Erythema multiforme:

Dr. Carlo Oller talks about erythema multiforme: causes, treatment, complications, and follow up.

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