Erythema multiforme: histological features and mechanisms

Histology of erythema multiforme

A skin biopsy of erythema multiforme (EM) may show in the epidermis/epithelium:

• Apoptotic individual keratinocytes (cellular self-destruction, earliest histological change)
• Hydropic degeneration of basal keratinocytes (swollen degenerating cells at the base of the epidermis)
• Intercellular oedema (spongiosis)
• Blisters within and under the epidermis/epithelium
• Epithelial/epidermal necrosis without large sheets of epidermal necrosis, as seen in Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN).

Dermal changes may include:

• Moderate/dense perivascular lymphocytic infiltrate in the papillary dermis and along the dermo-epidermal junction (DEJ)
• Superficial dermal oedema
• Eosinophilic infiltrates.

Direct immunofluorescence of erythema multiforme

Direct immunofluorescence is not specific. It may show deposition of immune proteins C3 and fibrin along the DEJ and IgM, C3 and fibrin around blood vessels.

Proposed mechanisms

Herpes simplex (HSV)-associated EM is a delayed type hypersensitivity (DTH) reaction that develops in response to infection in predisposed individuals. The process has been well studied and involves several steps.

1. HSV infection of keratinocytes, which may or may not result in signs of clinical infection.
2. CD34+ cells (Langerhans precursor cells) transport HSV DNA fragments to distant keratinocytes.
3. HSV gene fragments are expressed in these distant keratinocytes. HSV DNA and HSV-encoded proteins can be detected in EM-affected epidermis. However, HSV virus cannot be cultured.
4. HSV-encoded proteins recruit HSV-specific CD4+ T helper cells.
5. CD4+ T cells react to the HSV antigens by producing gamma-interferon.
6. Gamma-interferon initiates an inflammatory cascade resulting in the skin eruption of EM.

Drug-induced EM involves a different mechanism with elevated tumour necrosis factor alpha rather than gamma-interferon and CD8+ cells and not CD4+ T helper cells.

Why is EM major now considered to be distinct from SJS/TEN?

EM major can usually be distinguished from SJS/TEN on a number of clinical criteria.

1. The type of skin lesion – the predominant skin lesion of EM is the typical and atypical target papules and plaques and not macules which develop into sheets of skin detachment as seen in SJS/TEN. Skin detachment of more than 1% of the body surface area is common in SJS/TEN but uncommon in EM.
2. Distribution of the skin lesions – in EM the lesions are predominantly acrally distributed, i.e., begin on hands and feet. In SJS/TEN the eruption begins on the trunk.
3. Mucosal involvement – although in EM major more than two mucous membranes can be affected, this is less common in EM and is milder (lesser severity and extent) compared to SJS/TEN.
4. Systemic symptoms such as fever and malaise, are absent or mild in EM but are prominent in SJS/TEN, especially in the prodromal period. Fever, when present in EM, is mild (< 38.5 C) compared to high fevers with SJS/TEN. Patients with SJS/TEN are systemically ill.
5. Outcome and prognosis – virtually all patients with EM recover with no sequelae. SJS/TEN has significant morbidity and mortality.
6. Recurrences – EM can frequently recur whereas recurrence is rare in SJS/TEN.Also, EM is predominantly a disease of young adults (median age 24 years), especially males, whereas SJS/TEN typically affects an older population (median age 45 years).

EM is predominantly a disease of young adults (median age 24 years), especially males, whereas SJS/TEN typically affects an older population (median age 45 years).

Other points of distinction.

1. Skin biopsy histology – in EM there is more dermal inflammation and individual keratinocyte necrosis compared to SJS/TEN which shows minimal inflammation and sheets of epidermal necrosis.
2. Triggers – EM is triggered by an infection in the majority of cases compared to SJS/TEN which is predominantly caused by drugs.
3. Associations – EM is not associated with HIV, cancer and connective tissue disease, as reported with SJS/TEN. Tissue type marker associations are different.
4. Mechanisms – EM involves CD4+ T cells and gamma-interferon whereas SJS/TEN involves Fas ligand, tumour necrosis factor alpha and CD8+ cells.

In the majority of cases, EM can be diagnosed as a distinct entity from SJS/TEN although there remain some patients in whom the distinction is not so clearcut.