Erythema Multiforme

Article Author:
Wissem Hafsi
Article Editor:
Talel Badri
5/2/2019 9:41:58 PM
PubMed Link:
Erythema Multiforme


Erythema multiforme (EM) is a cutaneous and mucosal hypersensitivity reaction with characteristic lesions in target triggered by certain antigenic stimuli. It represents an acute condition, sometimes recurrent, of the skin and mucosal membranes manifested by papular, bullous, and necrotic lesions. Its causes are variable and numerous, and its evolution is generally favorable.[1][2][3][4]


The etiology of EM is dominated by Herpes simplex virus (HSV) type 1 and 2 infections and Mycoplasma pneumoniae, but many other viral and bacterial infections have been implicated. More rarely, and in a more questionable way, vaccines have been incriminated.[5][6][7]


EM is reported worldwide without any ethnic predilection. It occurs at any age, more frequently in young adults. The average age is between 20 and 30 years, and 20% of cases occur in children. It is more common in men with a sex ratio of 1 in 5. Prevalence is not known but appears to be well below 1%. As the classification is not always clear, cases of Stevens-Johnson syndrome (SJS) have frequently been included in studies on EM.


EM is often associated with viral or bacterial infections, especially HSV. Studies have demonstrated the presence of HSV-DNA by polymerase chain reaction in acute or sequellar EM lesions. The predisposing factors are unknown. HLA-DQ3 is reported to be associated with postherpetic EM and has been suggested as an additional diagnostic marker. Other human leukocyte antigen groups have also been reported as markers of the recurrent EM.

History and Physical

A fever and a feeling of general unease may precede and/or accompany the eruption the first days. Sometimes there is arthralgia or even joint swelling. 

Clinically, the typical lesion of the EM is the target, described as a rounded lesion that is regular with three concentric circles and a well-defined border. The peripheral ring is erythematous, sometimes microvesicular; the middle zone is often clearer, oedematous, and palpable, and the center is erythematous, covered by a blister. These different aspects evoke different stages of the evolving lesion.

The lesions measure less than 3 centimeters, and their location is mainly acral. They are symmetrical in the palms and backs of the hands, the feet, and the extended faces of the limbs. The trunk is often spared, but the face and ears can be reached. There is no pruritus, but rather sensations of burning in some patients.

Mucosal lesions are common, mostly in the mouth, but also in the genital and ocular mucous membranes. They are initially bullous, then quickly turn into painful erosions. Thick hemorrhagic crusts may cover the labial lesions, and a fibrin-whitish coating may line the mucosal erosions of the cheeks, palate, and genitalia. These mucosal lesions occur most often at the same time as the skin lesions but can be shifted a few days before or after the eruption of targets. While skin lesions are nonpainful, mucosal lesions are frequently painful.

Pulmonary signs may also be present, such as a cough and dyspnea. They testify to a respiratory attack most often related to the inducing infection of the EM (mainly due to Mycoplasma pneumoniae).


The diagnosis of EM is clinical. In case of doubt, a skin biopsy of the lesion center can be performed for histological study with immunofluorescence. It then shows an epithelial intercellular edema with keratinocyte necrosis responsible for an intra- or sub-epidermal blister covered with a necrotic epidermis. A peri-vascular lymphohistiocytic infiltrate is present in the superficial dermis without necrotic vascular lesion. Direct immunofluorescence is negative. The biological assessment provides no argument for the diagnosis of EM. However, it is useful to appreciate the severity of the disease. The chest x-ray may show interstitial radiological infiltrate (mainly in EM due to Mycoplasma pneumoniae). Renal, hepatic or hematologic lesions have also been described and are not systematically sought after in the mild forms.[8]

The etiological assessment must be adapted to the symptoms. In no case is an exhaustive report justified:

  • Herpes infection, mainly with HSV-1, is most frequently in the cause. This is most often a minor EM. Herpes lesions precede EM for a few days (7 to 10 days). In contrast, all herpes outbreaks are not accompanied by EM and some outbreaks of EM can be caused by asymptomatic herpes recurrences. Viral research is often negative at the moment of the diagnosis. In the case of a recurrence of EM, a herpes origin must be suspected. It is observed in 70% of cases of recurrent EM. In clinical practice, the diagnosis of the herpes origin is mainly based on the anamnesis.
  • Mycoplasma pneumoniae should be systematically sought for treatment in children. EM complicates 2% to 10% of infections with Mycoplasma pneumoniae in children and most often has a mucosal involvement. It is responsible for about two-thirds of EM with mucosal involvement. It is advisable to systematically perform a chest x-ray in addition to bacteriological research, if possible by gene amplification (PCR). 
  • Other viral (adenovirus, influenza, Epstein Barr, hepatitis virus, Coxsackie, parvovirus B19, human immunodeficiency virus) and bacterial (tuberculosis, streptococci) infections were incriminated.

EM cases have been attributed to some pediatric vaccines. The link is frequently controversial with regard to a large number of vaccines and the rarity of this association.

Treatment / Management

Treatment of the Acute Phase

  • Topical treatment is based on antiseptics for bullous lesions, antiseptic mouthwashes, and anesthetic. Ocular involvement is managed by ophthalmologists. Healing is promoted by the application of vaseline on the lips and vitamin A ointment on the eyes.
  • General treatment is used in cases of general statehood and dietary difficulty, requiring hospitalization to treat the pain, hydrate, or even re-enter the patient. The place of systemic corticosteroids and intravenous immunoglobulins has been discussed without demonstrating its effectiveness. Daily monitoring is necessary in cases of extensive lesions.
  • Etiological treatment must be instituted when a cause is identified (or sometimes probable). Mycoplasma pneumoniae infection justifies treatment with azithromycin for three days without even waiting for the results of the bacteriological examinations, especially if there is a cough or pulmonary radiological abnormalities. Some suggest treating herpes with aciclovir or valaciclovir if herpes is suspected although this has not shown its interest.

Prevention of Recurrent EM Form

  • It is in the majority of the cases of herpes origin. Even if the evidence has not been established by specimens, long-term treatment with aciclovir or valaciclovir should be proposed. 
  • It is indicated, in theory, above 5 EM outbreaks per year or fewer in the case of EP severe forms. Valaciclovir treatment prevents HSV-induced EM outbreaks but appears to have no impact on an EM outbreak if it was started after the beginning of the eruption. 
  • If no germ is identified, other therapeutics may be proposed in the long term, such as hydroxychloroquine (Plaquenil), dapsone (Disulone) or early treatment of sprouts by systemic corticosteroids.[9][10][11]

Differential Diagnosis

Stevens-Johnson Syndrome (SJS): It affects up to 10% of the body surface area, a larger area than in EM. The mucosal involvement is similar. The cutaneous involvement differs from EM by the absence of typical targets and the predominantly axial disposition. The target-like lesions are asymmetrical and made of two concentric zones and purpuric evolution. A drug origin is most often involved, and the outcome is more severe since it can progress into a Lyell syndrome, unlike EM.


Erythema multiforme minor (EMm): It essentially touches the skin with typical lesions symmetrical acral disposition. The mucosal involvement is rare, and when it is present, it is light and affects a single mucosa, often the mouth.

Erythema multiforme major (EMM): The skin lesions are more extensive, but they do not exceed 10% of the body surface area. Typical target lesions are present. The mucosal involvement is severe, and affects at least two different mucosal sites; the oral mucosa typically affected.


The prognosis is mainly related to the body surface area detached. The healing is obtained spontaneously in 2 to 3 weeks for the EMm and in 4 to 6 weeks in the EMM. The mucosal lesions always take longer to heal. The healing of the mucocutaneous lesions is without scarring, but with frequent dyschromia. Recurrences are seen in less than 5% of cases, mainly in forms due to herpes infection.

The main long-term risk is the development of synechias in case of mucosal involvement. Ocular sequelae can be serious, leading to blindness. At the genital level, synechiae can produce functional sequels.

Particular vigilance during the acute episode must be put in place to prevent these sequels. The vital prognosis is only exceptionally brought into play when the care is adapted. Two situations deserve particular vigilance are (1) severe mucosal involvement and (2) bacterial superinfections.

Enhancing Healthcare Team Outcomes

The management of EM is multiforme. While the diagnosis is often made by the dermatologist, the follow up of these patients is with the primary care provider and nurse practitioner. In general, supportive care will suffice in most patients. Patients need to be educated about general skin care. Once the primary condition is managed, EM resolves. However, time to healing may take weeks or even months. Particular vigilance during the acute episode must be put in place to prevent these sequels. The vital prognosis is only exceptionally brought into play when the care is adapted. Two situations deserve particular vigilance are (1) severe mucosal involvement and (2) bacterial superinfections. [12](Level V)

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