SKINIPEDIA - Erythema Multiforme Stevens Jonhson Sydrome
Erythema Multiforme (Stevens-Jonhson Syndrome), a Study by Don R Revis Jr, MD
Background
Erythema multiforme (also known as Stevens-Johnson syndrome [SJS]) and toxic epidermal necrolysis (TEN) are often confused in the medical literature. In 1860, Ferdinand von Hebra initially described erythema multiforme as an acute, self-limited condition with characteristic red papular skin lesions. The papules evolve into pathognomonic target lesions or iris lesions that appear within a 72-hour period and begin on the extremities. Lesions remain in a fixed location for at least 7 days and then begin to heal. Precipitating factors include herpes simplex virus (HSV), Epstein-Barr virus, and histoplasmosis. Because this condition may be related to a persistent antigenic stimulus, recurrence is the rule rather than the exception, with most affected individuals experiencing 1-2 recurrences per year. Erythema multiforme is typically a benign, self-limited disorder.
SJS is a mucocutaneous disorder. It was first described by Stevens and Johnson in 1922 as febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption. Lesions typically begin on the face and trunk. They are flat, atypical lesions, described as irregular purpuric macules with occasional blistering. Most patients also have extensive mucosal involvement. More than 50% of all cases are attributed to medications. This is a more serious illness and is potentially life threatening.
The confusion between these two separate clinical entities began in 1950, when Thomas coined the terms erythema multiforme minor and erythema multiforme major to describe conditions he encountered.
- Erythema multiforme minor was applied to patients with the illness originally described by von Hebra as erythema multiforme.
- Erythema multiforme major was applied to patients who also displayed oral mucosal involvement, similar to that described by Stevens and Johnson.
Up to 50% of patients with HSV-associated erythema multiforme have been found to have oral ulcers. However, this is now recognized as a variant of erythema multiforme, rather than SJS. Because SJS and erythema multiforme have different precipitating factors and different clinical patterns, the terms erythema multiforme major and erythema multiforme minor should no longer be used.
- Erythema multiforme with mucosal involvement is now termed bullous erythema multiforme.
- SJS is recognized as a separate clinical entity.
Lyell first described TEN in 1956. His original description made no reference to the work of Stevens and Johnson. The distinction between SJS and TEN is not clear. In fact, these conditions probably represent differing severities of the same disease process.
SJS and TEN have similar precipitating factors, identical histopathologic lesions, and similar clinical patterns. By current convention, the following terminology is used:
- The term SJS is used when the disease involves less than 10% of the total body surface area.
- TEN is used when the disease involves more than 30% of the body surface area.
- Patients whose disease involves 10-30% of their body surface area are said to have SJS/TEN overlap. Mortality increases as the percentage of involved body surface increases, making TEN the more severe of the skin reactions.
This article explores SJS in greater detail.
Pathophysiology
The pathophysiology of SJS is not completely understood. The disease process is probably immunologically mediated and often involves an abnormal metabolism of the responsible drug. The keratinocyte is the ultimate target of this disease process with keratinocyte necrosis being the earliest pathological finding.
Patients frequently display an altered metabolism of the responsible drug, and are considered to be slow acetylators, both genotypically and phenotypically. This means that an increased proportion of drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 system, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may then behave as haptens by binding covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction.
Cell-mediated immunity appears to be responsible for the destruction of epithelial cells observed in SJS. Early in the disease process, the epidermis becomes infiltrated with CD8 T lymphocytes and macrophages, while the dermis displays a slight influx of CD4 lymphocytes. These immunologically active cells are not present in sufficient numbers to be directly responsible for epithelial cell death. Instead, they release diffusable cytokines, which mediate the inflammatory reaction and resultant apoptosis of epithelial cells. In some patients, circulating T cells transiently demonstrate (for <30 d) a TH1 cytokine response (interferon gamma, tumor necrosis factor [TNF] alpha, interleukin 2). Results of immunohistochemical analysis have also shown lesion blister fluid to contain TNF, an important proinflammatory cytokine.
Other evidence supports the hypothesis that SJS is the result of cell-mediated immune reactions. Individuals possessing HLA-B12 are 3 times more likely to develop this disorder. The classic timing for a primary cell-mediated immune reaction is 9-14 days after the initiation of the offending drug. In recurrent exposure, the reaction occurs within several hours to 1-2 days, which is consistent with the timing of a secondary cell-mediated immune response.
Erythema Multiforme (Stevens-Johnson Syndrome) Study by
Don R Revis Jr, MD PART 2 is HERE
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