Erythema multiforme

What is erythema multiforme?

Erythema multiforme is an immune-mediated, typically self-limiting, mucocutaneous condition characterised by ‘target’ lesions. Significant mucosal involvement distinguishes erythema multiforme major from multiforme minor. Episodes can be isolated, recurrent, or persistent.

In most cases, erythema multiforme is precipitated by herpes simplex virus (HSV) infection; alternative triggers include other infections, medications, and vaccinations. Classic ‘target’ lesions present as concentric rings of colour variation which develop symmetrically in an acral distribution, with or without involvement of mucous membranes.

Erythema multiforme is a distinct entity from Steven Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Cutaneous adverse reaction to anticonvulsant, erythema multiforme target lesions 

Erythema multiforme minor 

Erythema multiforme 

Erythema multiforme 

Lip involvement in erythema multiforme 

Erythema multiforme of eye 

Who gets erythema multiforme?

Erythema multiforme affects less than 1% of the population. It is most common in young adults (aged 20–40 years) with a modest predominance in males. There is no association with race.

There appears to be a genetic predisposition in people carrying the HLA-DQB1*0301 allele, which shares an even stronger association with herpes-related erythema multiforme. Multiple other alleles have been associated with its recurrent form.

What causes erythema multiforme?

Infection precipitates 90% of cases, with HSV type 1 being the predominant cause. Other infectious triggers include:

• HSV type 2
• Cytomegalovirus
• Epstein-Barr virus
• Influenza virus
• Vulvovaginal candidiasis
• SARS-CoV-2
• Orf.

Mycoplasma pneumoniae infection is often listed as a trigger of erythema multiforme, however mucocutaneous manifestations associated with this infection have recently been classified as their own independent entity, Mycoplasma pneumoniae-induced rash and mucositis (MIRM).

Medications which may trigger erythema multiforme include:

• Antibiotics (including erythromycin, nitrofurantoin, penicillins, sulfonamides, and tetracyclines)
• Anti-epileptics
• Non-steroidal anti-inflammatory drugs
• Vaccinations (most common cause in infants).

Other conditions associated with erythema multiforme (usually in persistent disease) include:

• Inflammatory bowel disease
• Hepatitis C
• Leukaemia
• Lymphoma
• Solid organ cancer malignancy.

In many cases, the inciting factor remains unknown.

Most research on the mechanism of disease has focused on the herpes-associated presentation. The herpes virus is phagocytosed by mononuclear cells which express cutaneous lymphocyte antigen (a skin-homing receptor). Engulfed viral DNA is then transferred to the epidermis and into keratinocytes. Within the keratinocyte layer, expression of viral DNA fragments induces a cell-mediated immune response, including the production of interferon-γ which upregulates the inflammatory process.

What are the clinical features of erythema multiforme?

Many patients report prodromal symptoms including fatigue, malaise, myalgia, or fever. These likely represent the course of precipitating illness rather than true prodrome.

Cutaneous features

• Cutaneous lesions develop at the peripheries before spreading centrally.
• Distribution is usually symmetrical with a preference for extensor surfaces.
• May be painful, pruritic, or swollen.
• Early lesions present as round, erythematous papules which later develop into target lesions.
• Target lesions consist of three concentric rings of colour variation:
  • A central, dusky area of epidermal necrosis
  • Surrounded by a lighter oedematous area
  • With a peripheral erythematous margin.
• Atypical lesions may be present with typical lesions. Atypical lesions are raised with poorly defined borders and/or fewer zones of colour variation.
• In severe disease, up to hundreds of lesions may be present in different developmental stages, at times making it difficult to identify characteristic lesions.

Mucosal features

• Lesions develop as blisters, which then break to reveal shallow erosions with a white overlying pseudo-membrane.
• Erythema multiforme favours oral membranes, but may also present with urogenital and, rarely, ocular lesions.
• Mucous membrane involvement can be painful and significantly limit oral intake; lesions may precede or follow cutaneous lesions.

Symptoms are expected to self-resolve within 4 weeks from onset (or up to 6 weeks in severe disease).

How do clinical features vary in differing types of skin?

• No documented variation across skin type.
• No known associations with race.

What are the complications of erythema multiforme?

Cutaneous lesions resolve without scarring, though hyperpigmentation may persist for several months.

Ocular involvement can lead to more serious complications including:

• Keratitis
• Conjunctival scarring
• Uveitis
• Permanent visual impairment.

How is erythema multiforme diagnosed?

Diagnosis is often made based on history and clinical examination.

Where there is doubt about the diagnosis, consider:

• Complete blood examination
• Liver functions tests
• ESR
• Serological testing for infectious causes
• Chest x-ray.

Skin biopsy with histopathology and direct immunofluorescence can be non-specific but helps to distinguish erythema multiforme from other more serious differentials, such as autoimmune blistering diseases. Upper dermal oedema and individual epidermal keratinocyte necrosis are suggestive pathological features.

All patients with recurrent erythema multiforme should be tested for herpes simplex virus, including sampling of skin or mucosal lesions. In recurrent or persistent erythema multiforme without a clear precipitant, consider work up for solid organ or haematological malignancies.

What is the differential diagnosis for erythema multiforme?

• Urticaria
• Viral exanthem
• Stevens-Johnson syndrome
• Fixed drug eruption
• Bullous pemphigoid
• Paraneoplastic pemphigus
• Polymorphous light eruption
• Rowell syndrome (erythema multiforme-like lesions in systemic lupus erythematosus)

What is the treatment for erythema multiforme?

Treatment is often not needed as episodes are typically self-limiting with no ongoing complications. However, ocular involvement should always prompt ophthalmology referral given the risk for more serious sequelae.

Treatment of symptomatic mild cases:

• Itch — oral antihistamines and/or topical steroids for itch or discomfort associated with cutaneous lesions
• Pain — for mild mucosal involvement, oral washes containing antiseptic or local anaesthetic.

Other treatments are dependent on cause:

• Precipitating infections — treat appropriately (note treatment of HSV does not significantly alter the course of single episode erythema multiforme)
• Offending medications — cease and avoid in future.

Severe mucosal disease:

• May require hospital admission for support of oral intake
• Although evidence is limited, prednisone has been suggested to reduce the severity and duration of symptoms in these cases.

Recurrent disease:

• At least 6 months of continuous oral antiviral therapy (typically acyclovir/aciclovir), even if a clear cause has not been identified
• Remission can be difficult to achieve; may require trial of more prolonged therapy or alternative antiviral.
• Other systemic agents used (with variable evidence) for antiviral-resistant cases include azathioprine, dapsone, mycophenolate mofetil, and antimalarials.

What is the outcome for erythema multiforme?

Erythema multiforme is self-limiting with little to no ongoing complication in most patients. Recurrent or persistent disease comes with additional treatment challenges, but remission can be achieved.