Erythema multiforme (EM) is an acute, immunemediated disorder. Ninety percent of EM cases are attributable to infection, the most common being herpes simplex virus (HSV). Clinical findings in HSV-associated EM are thought to be secondary to an immune-mediated response against viral antigen-positive cells containing HSV DNA polymerase pol. Additional etiologic factors implicated in the development of EM, including medications and other infections, are listed in Table 14-1. Medications are believed to incite less than 10% of EM cases.

EM presents with isolated cutaneous lesions, isolated mucosal lesions, or a combination of the two. Previously, EM was considered to represent a spectrum of disease, including EM minor and major, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Now, however, EM major and SJS are considered distinct clinical entities with similar mucosal erosions, but differing cutaneous lesions.

Prodromal symptoms, including fever, malaise, and myalgias, may be present, most commonly when there is mucosal involvement. The classic lesions of EM are targetoid in appearance and comprise the following features: a central area of dusky epidermal necrosis, a concentric dark red inflammatory ring surrounded by a lighter, edematous ring with an outer zone of erythema. The lesions may change in morphology over the course of the episode, and geographic, polycyclic, and annular configurations have been described. In addition, some lesions may appear “atypical” in that they consist of ill-defined, two-zoned targets. Figure 14-1 depicts typical targetoid lesions.

Mucosal lesions occur in 25% to 60% of EM episodes (Fig. 14-2). The oral mucosa is most commonly involved. Lesions present with erythema and
edema and progress to superficial erosions. Symptoms of burning, swelling, and pain can lead to poor oral intake. Importantly, involvement of the ocular and upper respiratory mucosa may occur. Sequelae from mucosal involvement include keratitis, conjunctival scarring, uveitis, permanent visual impairment, esophagitis with strictures, and upper airway erosions leading to pneumonia.

Classic EM is an isolated, self-limiting disease. The time from disease onset to resolution is usually less than 4 weeks, but can take up to 6 weeks if mucous
membranes are involved. A subset of EM cases are recurrent (≥six episodes per year) and are mostly triggered by recurrent HSV infection. Other cases of EM can be persistent, in that lesions are continuous and uninterrupted.

No laboratory markers or histopathologic evaluation are required for the diagnosis of EM. Clinical history is paramount in rendering the diagnosis. It is important to inquire about signs and symptoms of infection (HSV or Mycoplasma pneumoniae) and to review the use of new medications. The timing of symptoms is also relevant in determining if the patient has an isolated, episodic, or persistent case of EM.

While it is not necessary for diagnostic confirmation, a skin biopsy may be helpful to exclude other conditions. If HSV lesions are suspected on physical examination, viral culture, HSV polymerase chain reaction (PCR), and/or direct fluorescent antibody should be obtained. When respiratory symptoms are present, M. pneumoniae serologic testing, chest radiograph, and/or throat swab PCR for M. pneumoniae can be obtained. Recurrent idiopathic EM or persistent EM may be further investigated with serologic HSV testing, molecular in situ hybridization/PCR of tissue for HSV, and selected laboratory tests to rule out underlying infectious, inflammatory, autoimmune, or malignant disorders.

Although exceedingly rare, there have been reports linking EM with underlying leukemias and lymphomas. In patients with persistent, recalcitrant EM, solid organ cancers have been described, including gastric adenocarcinoma, renal cell carcinoma, and extrahepatic cholangiocarcinoma.