Erythema multiforme: Pathogenesis, Clinical features, Histopathology & Treatment

Erythema multiforme: Pathogenesis, Clinical features, Histopathology & Treatment


Erythema multiforme (EM) is an ulcerative, blistering inflammatory condition which affects either the skin or the mucous membranes, most often manifesting as a mucocutaneous lesion. Depending on the severity of the condition and the extent of mucosal involvement, it can be classified as EM minor and major. Previously two other conditions called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were considered to be a part of the spectrum of EM, although on the more severe end of the disease. They involve wider areas of the muco-cutaneous region and can be life threatening. However, these two conditions are now not considered to be part of the EM spectrum and are designated as distinct entities. Erythema multiforme is most commonly triggered by microbes although a small but significant number of cases are also caused by drugs. On the other hand SJS and TEN are almost always caused by drugs. Herpes virus is most commonly implicated in causing EM. Other infectious agents implicated are Mycoplasma pnuemoniae (bacteria) and Histoplasma capsulatum (fungus). Drugs such as sulphonamides, NSAIDs, cephalosporins, barbiturates and even corticosteroids have been known to cause this condition. EM has been hypothesized to be an immunological disease where tissue damage is a result of the body’s reaction against the microbial
antigens or antigens from the drug metabolites. In herpes associated EM, the herpes viral
DNA is engulfed by macrophages and presented to the CD 4 T cells, thus activating them. Also, the fragments of the viral DNA antigens are deposited in the keratinocytes of the skin and the mucous membranes. Activated T cells release a cytokine called
IFN γ, a pro-inflammatory cytokine. IFN γ up-regulates the production of other
cytokines and chemokines. Cytokines damage keratinocytes and chemokines further recruit macrophages, CD 8 T cells also called cytotoxic T cells and natural
killer cells all of which cause epithelial damage! Keratinocytes may also present these antigens to CD 8 T cells via MHC molecules. These CD 8 T cells recognise these antigens and induce apoptotic cell death of the keratinocyte. Drug induced lesions on the other hand cause tissue damage via TNF-α. Macrophages produce TNF-α, also a pro-inflammatory cytokine implicated to be predominantly involved in tissue damage in drug induced EM. EM commonly occurs in young adults usually within 20-30 years predominantly in males. The disease may have a 3-7 day prodromal period of fever, fatigue and malaise before the appearance of lesions on the skin and mucous membrane. EM minor is the milder form of the disease and is characterized by appearance of skin lesions with involvement of only one mucosal site, predominantly the oral mucous membrane. Sometimes the disease may manifest with only the oral mucosa affected. Skin lesions are characterized by the appearance of symmetric erythematous macules, papules or sometimes even blisters predominantly on the arms and legs. A very characteristic feature of the disease is the appearance of what are called “target lesions” or “bull’s eye lesions”. These are concentric ring like lesions that
are less than 3 cms in size and have two or more (usually two) erythematous rings that are paler than the central disc they encircle. Oral lesions may start as macules or papules which may progress to become blisters. Blisters may erupt or erode causing ulcerations and bleeding in the oral cavity. The disease commonly affects the anterior oral cavity and patients commonly present with swollen, ulcerated, bleeding and crusted lips. The oral lesions are very painful and patients have difficulty eating and drinking. Ulceration is usually diffuse and other sites like the buccal mucosa, tongue, floor of the mouth and soft palate are also commonly affected. EM major has similar skin and oral manifestations as the minor form of the disease except that the lesions are more widespread and may involve two or more mucosal sites. EM major may additionally involve laryngeal, oesophageal, genital or ocular mucous membranes apart from the oral cavity. The histopathology of EM is not diagnostic and may resemble other vesiculo-bullous lesions. Hence diagnosis is more often based on the clinical features. There may be a sub-epithelial lichenoid infiltrate consisting of inflammatory cells comprising of lymphocytes, neutrophils and monocytes. The spinous layer may be edematous and the epithelium may show necrosis in the basal as well as supra-basal regions. This may result in the formation of supra-basal as well as a sub-epithelial bullae. EM is usually self-limiting and may resolve in 2-6 weeks. Treatment is symptomatic and supportive and may consist of oral irrigation, sufficient fluid intake along with topical anesthetics to reduce pain. If the disease is suspected to be due to herpes infection, acyclovir therapy should be initiated.

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