Erythema Multiforme (EM)

Synonyms: EM, EM minor, EM major.

Erythema multiforme is a distinctive dermatological eruption featuring iris or target lesions. The minor form is an acute, self limiting disease that affects the skin but mucous membranes little, if at all. The major form has more involvement of both skin and mucosa and is a potentially life threatening condition.

It is considered by some as being part of a spectrum of disease which includes, in order of severity, erythema multiforme, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, others argue that as erythema multiforme is associated with infections including herpes simplex virus and Mycoplasma pneumoniae, whereas SJS and TEN are necrolytic bullous reactions to certain drugs, erythema multiforme should not be classified as part of the same disease spectrum.¹

Another classification system works on the fact that SJS and TEN are related conditions that can be differentiated by the degree of skin involvement. Less than 10% of the epidermis sloughs off in Stevens-Johnson syndrome as compared to >30% in TEN.²

There is no register and no valid estimate of the number of cases, especially of the milder kind but it may represent 1% of dermatology outpatient attendance. Males are affected slightly more often than females. Most patients are under 40 with 20% occurring in children and adolescents. For Stevens-Johnson syndrome, the median age is nearly 50. An HLA marker linked to ethnicity has recently been identified. A very strong association of carbamazepine-induced SJS with HLA-B*1502 has recently been described in the Han Chinese population.³

• A common cause of erythema multiforme is herpes simplex infection. As with oral herpes simplex, it may be precipitated by exposure to sunlight. Much minor disease is probably associated with HSV infection.
• More serious disease, including Stevens-Johnson syndrome is associated with use of drugs.
• It is associated with a number of infections including streptococcus, tuberculosis and BCG immunisation.
• It can follow tattooing, radiotherapy and sunlight.
• It can occur with other diseases including, vasculitides, non-Hodgkin's lymphoma, leukaemia, multiple myeloma, myeloid metaplasia and polycythaemia.

History

• In EM minor, there may be no prodrome or a mild upper respiratory tract infection. The rash starts abruptly, usually within 3 days. It starts on the extremities, being symmetrical and spreading centrally.
• In EM major, around half have nonspecific prodromes, including moderate fever, general discomfort, cough, sore throat, vomiting, chest pain, and diarrhoea. These symptoms may precede the eruption for between 1 and 14 days. The lesions begin peripherally and spread centrally as with EM minor.
• There may be some mild burning or itching sensation but the skin is not tender.
• Involvement of the mucosa may be marked in EM major. Erosions in the mouth may produce difficulty in eating, drinking, and in opening the mouth. Eye involvement can cause lacrimation and photophobia. Genital lesions are painful and may result in urinary retention.
• Half of children with the rash have recent herpes labialis. It usually precedes the erythema multiforme by 3 to 14 days but it can sometimes be present at the onset.

Examination

The iris or target lesion is the classical feature of the disease.

• Initially there is a dull red macule or urticarial plaque that enlarges slightly up to 2 cm over 24 to 48 hours. In the middle, a small papule, vesicle, or bulla develops, flattens, and then may clear. The intermediate ring forms and becomes raised, pale, and oedematous. The periphery slowly becomes violaceous and forms a typical concentric target lesion.
• Some lesions are atypical targets with only 2 concentric rings. Polycyclic or arcuate lesions may occur.
• The Koebner phenomenon may occur. This is where a lesion occurs along the line of trauma and it is typical of psoriasis and lichen planus.
• Lesions appear first on the extensor surfaces of the periphery and extend centrally. The palms, neck and face are often involved but the soles and flexures of the extremities less often.
• Even in minor disease there may be mucosal involvement in 70% of patients but it tends to be mild and limited to just one mucosal surface. Oral lesions are commonest with lips, palate and gingiva affected. In major disease, at least 2 mucosal surfaces are involved with crusting and ulceration.
• Occasionally the mucosal involvement is marked with few skin lesions.
• There may be red conjunctivae and lacrimation but eye involvement tends to be mild. Genital involvement can produce painful haemorrhagic bullae and erosions.
• Mucosal involvement is more marked in major than minor disease but it is even more marked in Stevens-Johnson syndrome.

Fig.1. Erythema multiforme after a streptococcal sore throat.

• In minor disease no specific investigations are indicated.
• In major disease get FBC, ESR, U&E, LFTs, blood and sputum culture. No laboratory tests are specific. A punch biopsy may be required to confirm diagnosis.

Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses. Mechanical or autoimmune blistering are also potential misdiagnoses of TEN/SJS. Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is a severe cutaneous drug reaction with often a long duration of eruption and serious other organ involvement. Exfoliative dermatitis, whether caused by psoriasis, dermatitis or lymphoma, can be thought of as a differential diagnosis of DRESS/HSS. Angio-immunoblastic lymphadenopathy, viral eruption and vasculitis are other differential diagnoses of DRESS/HSS.⁶

• Behçet's syndrome
• Drug reactions
• Urticarial vasculitis

It can be associated with:vasculitides, non-Hodgkin's lymphoma, leukaemia, multiple myeloma, myeloid metaplasia and polycythaemia.

Most of the advice on management appears to be expert opinion, differing levels of evidence grade D. RCTs are severely lacking and much of the literature is case reports even though it is not a rare disease.

• If a drug is thought to be responsible it must be withdrawn. If an infection is suspected it should be treated.
• In recurrent disease due to HSV, antiviral therapy is beneficial.⁷
• Symptomatic treatment may include analgesics, mouth wash and local skin care. Steroid creams may be used.
• If the mouth is very sore attention may have to be given to hydration and nutrition.
• Dilute antiseptics such as chlorhexidine may help to prevent secondary infection. Lubricating drops for eyes may be required.
• Systemic steroids in Stevens-Johnson syndrome may impair the immune response. Their use in this condition has not been tested by RCT.⁸ A large retrospective study showed a trend towards a benefit with steroids but more studies are needed.⁹ Prophylactic antibiotics are also not recommended but specific treatment of infections may be required. This syndrome often requires intensive care and a burns unit may be best equipped to cope with the skin deficiency. Recovery of the epithelium takes 10 to 14 days.

Secondary infection of lesions may occur. Serious complications are unusual in an immunocompetent patient. A very sore mouth may lead to dehydration and poor nutrition. Genito-urinary lesions may result in urinary retention. If the eye is involved it is important to prevent infection or conjunctival scarring.

Most minor disease subsides completely in 2 to 3 weeks without any complications. Major disease usually takes 3 to 6 weeks to resolve.
In Stevens-Johnson syndrome, the mortality rate is around 5%, due mostly to overwhelming infection when the skin barrier breaks down. Bad prognostic features include increasing age, elevated blood urea and immune compromise.

In 1860, Ferdinand von Hebra¹⁰ initially described erythema multiforme as an acute, self-limited condition with characteristic red papular skin lesions.¹¹ A more serious variant was first described by Stevens and Johnson in 1922¹² as febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption. In 1950, Thomas coined the terms erythema multiforme minor and erythema multiforme major to describe the condition.