Erythema multiforme: characteristics and histological mechanisms.

Histology of erythema multiform

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

• Apoptotic individual keratinocytes (cellular self-destruction, the earliest histological change)
• hydropic degeneration of basal keratinocytes (swollen degenerated cells at the base of the epidermis)
• Intercellular edema (spongiosis)
• Blisters within and below the epidermis/epithelium
• Epithelial/ /epidermal necrosis no 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 dermal-epidermal junction (DEJ)
• Superficial skin edema
• Eosinophilic infiltrators.

Direct immunofluorescence of erythema multiforme

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

Proposed mechanisms

Herpes simplex associated EM (HSV) 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 lead to signs of clinical infection.
2. CD34+ cells (Langerhans precursor cells) carry HSV DNA fragments to distant keratinocytes.
3. HSV gene The fragments are expressed in these distant keratinocytes. HSV DNA and HSV-encoded proteins can be detected in the epidermis affected by MS. However, the HSV virus cannot be cultured.
4. HSV-encoded proteins recruit HSV-specific CD4+ helper T cells.
5. CD4+ T cells react to HSV antigens producing gamma interferon.
6. Gamma interferon initiates a inflammatory waterfall resulting in skin eruption of MS.

Drug-induced MS involves a different mechanism with elevated tumor necrosis factor alpha instead of 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 generally be distinguished from SJS/TEN on a number of clinical criteria.

1. skin type injury – the predominant skin lesion of MS is typical and atypical objective papules and plates and not macules which develop into shedding sheets of skin as seen in SJS/TEN. Skin shedding of more than 1% from the body surface area is common in SJS/TEN but rare in MS.
2. Distribution of skin lesions: In MS, the lesions are predominantly acral in distribution, ie they start on the hands and feet. In SJS/TEN the rash starts on the trunk.
3. Mucous membrane participation – although in major MS more than two mucous membranes may be affected, this is less common in MS and is milder (less severe and extent) compared to SJS/TEN.
4. Systemic symptoms like fever and discomfort, are absent or mild in MS but prominent in SJS/TEN, especially in prodromal period. Fever, when present in MS, is mild (<38.5 C) en comparación con las fiebres altas con SJS / TEN. Los pacientes con SSJ / NET están sistémicamente enfermos.
5. Result and forecast – Virtually all MS patients recover without aftermath. SJS/TEN has a significant morbidity and mortality.
6. Recurrences: EM can recur frequently while reappearance it's rare in SJS/TEN. Furthermore, EM is predominantly a disease of young adults (median age 24 years), especially men, whereas SJS/TEN generally affects an older population (median age 45 years).

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

Other points of distinction.

1. Skin biopsy histology: in EM there is more dermis inflammation and individual keratinocytes necrosis compared to SJS/TEN showing minimal inflammation and sheets of epidermal necrosis.
2. Triggers: MS is triggered by infection in most cases compared to SJS/TEN which is mainly caused by medication.
3. Associations: EM is not associated with HIV, Cancer and connective tissue disease, as reported with SJS/TEN. The associations of tissue type markers are different.
4. Mechanisms: EM involves CD4+ T cells and interferon gamma, while SJS/TEN involves Fas ligand, tumor necrosis factor alpha, and CD8+ cells.

In most cases, MS can be diagnosed as a distinct entity from SJS/TEN, although there remain a few patients where the distinction is not as clear cut.