Epidemiology

There is no register and no valid estimate of the number of cases, especially of the milder kind; however, it may represent 1% of dermatology outpatient attendance. Males are affected slightly more often than females. Most patients are aged 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 Stevens-Johnson syndrome (SJS) with HLA-B*1502 has recently been described in the Han Chinese population.^[3]

Aetiology

• A common cause of erythema multiforme (EM) is herpes simplex infection. As with oral herpes simplex, it may be precipitated by exposure to sunlight. Much minor disease is probably associated with herpes simplex virus (HSV) infection.
• Other infections have also been implicated, ranging from viruses (for example, measles, mumps, adenoviruses and influenza) to bacterial infections (for example, pneumonia, syphilis and typhoid).^[4]
• More serious disease, including Stevens-Johnson syndrome, is associated with use of drugs.
• Sulphonamides are usually considered to be the most common cause of EM, accounting for around 30% of cases. This will change as the use of antibiotics changes.
• 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.

Presentation

History

• In erythema multiforme (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 EM 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 24-48 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.
• Köbner's 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 most common 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.

Images

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

Investigations

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

Differential diagnosis

Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses. Mechanical or autoimmune blistering are also potential misdiagnoses of toxic epidermal necrolysis (TEN)/Stevens-Johnson syndrome (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.^[7]

• Behçet's disease
• Drug reactions
• Urticarial vasculitis

Associated diseases

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

Management

Most of the advice on management appears to be expert opinion, and based on case reports rather than high-quality research, 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 herpes simplex virus (HSV), antiviral therapy is beneficial.^[8]
• Symptomatic treatment may include analgesics, mouthwash 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 the eyes may be required.
• Systemic steroids in Stevens-Johnson syndrome (SJS) may impair the immune response. Their use in this condition has not been tested by randomised controlled trial (RCT).^[9] A large retrospective study showed a trend towards a benefit with steroids but more studies are needed.^[10] 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.

Complications

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.

Prognosis

Most minor disease subsides completely in 2-3 weeks without any complications. Major disease usually takes 3-6 weeks to resolve. In Stevens-Johnson syndrome (SJS), 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.

History

In 1860, Ferdinand von Hebra^[11] initially described erythema multiforme (EM) as an acute, self-limited condition with characteristic red papular skin lesions.^[12] A more serious variant was first described by Stevens and Johnson in 1922^[13] 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.