Erythema multiforme



Erythema multiforme is an immune-mediated reaction that results in characteristic target lesions on the skin.

Erythema multiforme (EM) is a skin hypersensitivity reaction that commonly occurs secondary to an infection or drugs. A hypersensitivity reaction is an exaggerated immune reaction that occurs in response to an antigen or allergen.

EM is characterised by the presence of target lesions that are usually < 3 cm in size. These lesions have three striking features:

  • A central blister or dusky red area
  • A surrounding pale ring of oedema
  • An erythematous halo in the periphery


EM most commonly occurs in young adults (20-40 years old).

The exact epidemiology of the condition is largely unknown, but it commonly affects young adults with a slight male predominance.


EM most commonly develops due to infections or drugs.


The vast majority of EM cases are due to infection (~90%). Viruses, bacteria, and fungi can all lead to EM but the most commonly implicated pathogen is herpes simplex virus (HSV). Another important infectious cause, particularly in children, is Mycoplasma pneumoniae that is a cause of ‘atypical pneumonia’. Mycoplasma pneumoniae lacks a cell wall and replicates intracellularly.


Drugs account for <10% of cases of EM. A large number of medications have been identified including NSAIDs, sulfonamides, anti-epileptics and antibiotics (e.g. penicillins).


A variety of other causes may lead to the development of EM. These include:

  • Malignancy
  • Sarcoidosis
  • Immunisations
  • Immunotherapy drugs


EM is considered a cell-mediated (type IV) hypersensitivity reaction.

A hypersensitivity reaction is an exaggerated or inappropriate immune reaction that occurs in response to an antigen or allergen. EM is considered a type IV hypersensitivity reaction, which is an abnormal cell-mediated reaction initiated by T cells.

The exact mechanism leading to EM is incompletely understood, but it appears to be an abnormal immune reaction to a drug metabolite or viral antigen that becomes expressed by keratinocytes within the skin. This leads to a localised immune reaction within the epidermis that occurs days to weeks after the initial infection. There is evidence for genetic susceptibility with some human leucocyte antigens (HLA) shown to increase the risk of developing EM. HLA genes encode proteins that are involved in antigen processing by the immune system to help immune recognition between ‘self’ and ‘foreign’ substances. There are many different forms (known as alleles) of these genes with some increasing the risk of autoimmune reactions.

Clinical features

EM may cause characteristic target lesions on both cutaneous and mucosal surfaces.

There are two broad forms of EM known as minor and major:

  • Erythema multiforme minor: the presence of EM with no (or minor) mucosal involvement and absence of systemic symptoms
  • Erythema multiforme major: the presence of EM with severe mucosal involvement and often with systemic symptoms (e.g. fever, arthralgia)

NOTE: erythema multiforme major was originally felt to be synonymous with Stevens-Johnson syndrome (SJS), which is a life-threatening skin hypersensitivity reaction most commonly due to drugs. However, these are now considered two separate entities.

Systemic features

Systemic features may be seen in severe cases of EM, but are usually absent in mild cases.

  • Fever
  • Arthralgia
  • Myalgia
  • Malaise

Mucocutaneous features

EM is characterised by the presence of target lesions that are usually < 3 cm in size. These lesions have three striking features:

  • A central blister or dusky red area
  • A surrounding pale ring of oedema
  • An erythematous halo in the periphery

These lesions are usually present in a symmetrical distribution on the extensor surfaces of acral extremities. Acral refers to peripheral parts of the body such as ears, nose, fingers, and toes. Lesions may then progress more centrally and involve other parts of the body such as the face, neck, palms, soles, and trunk. The lesions themselves are usually asymptomatic although mild itching (pruritus) may occur.

Mucosal lesions commonly involve the oral mucosa and can lead to erythema, erosions, and/or bullae. These may be painful and can involve many other mucosal surfaces including the ocular and genital mucosa.

Diagnosis & investigations

EM is typically a clinical diagnosis based on characteristic lesions but skin biopsy can be helpful.

The presence of multiple, typical target lesions is usually enough to make the diagnosis of EM. Features that support the diagnosis include mucosal involvement and temporal association with HSV infection or a new medication.

Skin biopsy

When the diagnosis is in doubt, a skin biopsy can be useful that involves taking a small portion of skin from an affected area. This will show characteristic features under microscopy such as dense lymphohistiocytic deposition within the superficial dermis and dermoepidermal junction. This refers to the presence of both lymphocytes and tissue macrophages (i.e. histiocytes).

Additional investigations

Due to the strong association with an infection patients should be assessed for HSV or mycoplasma that may involve skin swabs of suspected lesions or serology (e.g. mycoplasma antigens, HSV DNA).


EM is usually a transient skin disorder and lesions will resolve spontaneously.

EM typically develops over 3-5 days and improves over 2 weeks. Some patients may get persistent or recurrent episodes.

Acute episodes

Patients with severe disease affecting the ability to swallow and maintain adequate nutrition may need admission to hospital. In milder cases, patients can be managed as outpatients. Basic first steps involve removal of the possible trigger (e.g. stop culprit medication) and treat any underlying cause (e.g. anti-viral treatment for HSV).

Treatment may be needed depending on the severity and can include:

  • Topical corticosteroids
  • Analgesic mouth washes
  • Rarely, systemic corticosteroids

Severe ocular involvement should warrant urgent referral to ophthalmology.

Recurrent episodes

The management of recurrent episodes depends on the underlying aetiology. In the first instance management should be to avoid/remove the precipitating cause if possible. In cases of HSV-induced EM, anti-viral therapy used intermittently or as continuous suppression can be trialed. In severe cases, immunosuppressive agents may be needed.


Severe mucosal involvement may cause ocular damage.

In rare cases, severe ocular involvement can lead to complications such as keratitis, conjunctival scarring, or even visual impairment. Oral intake may be compromised with severe oral mucosal involvement.

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