Clinical Challenge: Painful, Recurring Oral Eruption


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A patient, aged 35 years, presented with a painful eruption in his mouth that started five days prior. Two days before the oral symptoms occurred, the patient developed lesions on his hands, elbows, and knees. The eruptions have developed approximately twice a year for the past five years. The patient was otherwise healthy and was taking no medications.

Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disorder marked by the sudden onset of symmetric, fixed, red papules which evolve into target lesions.In EM minor, there is only cutaneous involvement, usually with an acral distribution. In contrast, the lesions...

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Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disorder marked by the sudden onset of symmetric, fixed, red papules which evolve into target lesions.

In EM minor, there is only cutaneous involvement, usually with an acral distribution. In contrast, the lesions of EM major affect mucosal surfaces as well, and the patient may have systemic symptoms such as fever and weakness one week or more preceding the skin outbreak.

Approximately 25% to 60% of cases of EM involve mucosa, with the oral mucosa most commonly affected, demonstrating indurated, erythematous plaques, target lesions, or erosions.

Although most frequently a self-limiting condition that arises over the course of 24 to 72 hours and persists for one to two weeks (or up to six weeks with mucosal involvement) prior to resolution, EM can also remit and recur, or more rarely demonstrate a persistent course. In recurrent EM, usually due to herpes simplex virus (HSV) infection, lesional outbreaks occur one to six times per year during a period of six to 10 years.

In rare EM cases that persist without remission, lesions tend to be widespread, papulonecrotic or bullous, and may or may not involve the mucosal surfaces.

Negative predictive factors that suggest a tendency for EM to recur or to demonstrate a recalcitrant course include:

Inability to identify a specific causeLack of improvement with continuous antiviral therapySevere oral involvementGlucocorticoid use for over one yearHistory of use of two or more immunosuppressants

Although skin findings vary between patients, typical EM morphology is initially characterized by round, erythematous, edematous papules surrounded by areas of blanching similar to insect bites.

Over the next one to two days, papules may enlarge, flatten, and evolve to classic target lesions less than 3 cm in diameter with three concentric zones of color change. Atypical papular lesions have only two zones of color change and indistinct borders.

A central portion of epidermal necrosis may appear dusky or blistered, surrounded by a lighter, elevated ring of edema, with a macular erythematous zone most peripherally.

Acral, facial, and extensor surface involvement is most common, with palmoplantar lesions not unusual. EM lesions frequently demonstrate a predilection for areas of previous trauma (koebnerization) and sunburn (photo-accentuation).

Patients may experience pruritus or painful burning in affected areas, edema of the hands and feet, or poor oral intake due to mucosal lesions. Following resolution, post-inflammatory hyperpigmentation may persist for months.

More serious complications including ocular keratitis, conjunctival scarring, visual impairment, esophagitis with esophageal strictures, or upper airway erosions may arise in rare cases of EM with mucosal involvement.

Mostly a disorder affecting young adults, often in the spring or fall, EM has an estimated incidence far less than 1% of the general population, with no racial predilection.’

In some cases of EM, genetic predisposition by the HLA-DQB1*0301 allele may be implicated, particularly in cases of HSV-associated EM. Other human leukocyte antigen haplotypes may convey susceptibility to the development of recurrent EM.

Although infection is the causative factor in 90% of EM cases (including non-HSV triggers such as Mycoplasma pneumoniae or Epstein-Barr virus), other etiologies have been implicated in EM, including medications, malignancy, autoimmune disease, radiation, immunization, and menstruation.

Less than 10% of EM cases can be attributed to medication use, but common culprits include nonsteroidal anti-inflammatory drugs, sulfonamides, anti-epileptics, and antibiotics. If suspected, these agents should be stopped to facilitate skin clearance.

Idiopathic, persistent EM should prompt a workup for underlying hematologic cancers or solid organ cancers, such as gastric adenocarcinoma, renal cell carcinoma, and extrahepatic cholangiocarcinoma.

In the absence of specific diagnostic criteria, the diagnosis of EM is made based on clinical examination and history, often describing the appearance of lesions three to 14 days following an orolabial herpes outbreak.

The cause of EM is frequently unknown, but polymerase chain reaction (PCR) can be used to demonstrate HSV DNA in lesional skin biopsies, particularly in cases of idiopathic, recurrent EM due to subclinical HSV infection.

Although patients with severe EM may demonstrate elevated erythrocyte sedimentation rate, white blood cell count, or liver enzymes, no specific laboratory tests are available to diagnose this condition. Findings on direct immunofluorescence (DIF) are non-specific and may include granular deposition of C3 and IgM at the dermo-epidermal junction and superficial blood vessels.

On biopsy, the stratum corneum demonstrates normal basket-weave morphology, suggesting an acute process that has not had time to produce abnormal keratin. Liquefactive degeneration of the basal epidermal cells, necrotic keratinocytes, and exocytosis of lymphocytes are all common pathologic findings.

Obscuration of the dermo-epidermal junction may occur in response to lymphohistiocytic infiltrate in a lichenoid pattern. Although papillary dermal edema, vascular dilation, and perivascular mononuclear cell infiltrates predominate in the early papular stage of EM, epidermal changes such as necrosis characterize the dusky centers of the later targetoid lesions and blisters.

The extent of cutaneous and/or mucosal involvement, as well as the natural history of the patient’s illness should inform treatment decision-making. Elimination of triggers forms the cornerstone of therapy.

Patients with EM minor may be managed with supportive care geared toward relieving symptoms through the use of topical corticosteroids and oral anti-histamines. Mild mucosal involvement can be treated with topical corticosteroid gel or “swish and spit” formulations containing lidocaine, benadryl, and kaolin.

Severe cases of EM major may require systemic glucocorticoids to minimize disease severity and duration, and/or hospitalization to ensure adequate fluid intake and electrolyte balance.

First-line therapy for HSV-associated or idiopathic recurrent EM as well as persistent EM is continuous anti-viral prophylaxis for more than six months (ideally one to two years) with acyclovir, valacyclovir, or famciclovir.

The goal is to reduce EM outbreaks and induce remission. Refractory EM can be treated with dapsone, cyclosporine, thalidomide, or other immunosuppressant agents, although these therapies have inconsistent success rates.

Megan Schlichte is a medical student at Baylor College of Medicine.

Adam Rees, MD, a graduate of the David Geffen School of Medicine at UCLA, practices dermatology in Los Angeles.


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