Excerpt from Stevens-Johnson Syndrome

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Background

In 1922, Stevens and Johnson first described 2 patients, boys aged 7 and 8 years, with "an extraordinary, generalized eruption with continued fever, inflamed buccal mucosa, and severe purulent conjunctivitis." Both cases were misdiagnosed by primary care physicians as hemorrhagic measles. Erythema multiforme (EM), originally described by von Hebra in 1866, was part of the differential diagnosis in both cases, but it was excluded because of the "character of skin lesions, the lack of subjective symptoms, the prolonged high fever, and the terminal heavy crusting." In spite of leukopenia in both cases, Stevens and Johnson in their initial report suspected an infectious disease of unknown etiology as the cause.

In 1950, Thomas divided EM into 2 categories, as follows: erythema multiforme minor (von Hebra) and erythema multiforme major (EMM; also known as Stevens-Johnson syndrome, or SJS). Since 1983, the eponym of Stevens-Johnson syndrome had been used as a synonym for EMM.

In the 1990s, Bastuji and Roujeau each proposed that EMM and SJS are 2 distinct disorders.¹ They suggested that the denomination of EM should be restricted to patients with typical targets or raised edematous papules, with or without mucosal involvement. This clinical picture is in accordance with the original description by von Hebra. They further proposed that the denomination of SJS should be used for a syndrome characterized by mucous membrane erosions and widespread small blisters that arise on erythematous or purpuric maculae that are different from classic targets. According to this clinical classification, EMM and SJS could be 2 distinct disorders with similar mucosal erosions, but different patterns of cutaneous lesions. This hypothesis is supported further by a strong correlation between clinical classification and the probable cause.

Conversely, several investigators propose that SJS and toxic epidermal necrolysis (TEN) are the same diseases of various severities. It has been suggested to use a unifying classification of "acute disseminated epidermal necrosis" or "exanthematic necrolysis." A very strong argument against this unifying concept was that infection with herpes simplex virus (HSV) had been described as a frequent cause of SJS/EMM but not of TEN. However, reports showed that HSV infection has not been related to SJS, and they suggested that SJS and TEN, based on clinical manifestations and pathology results, are severity variants of the same disease, which differ from EM.

SJS and TEN are characterized by identical clinical signs and symptoms, identical treatment approach, and identical prognosis. Patients with 90% skin detachment and diagnosed with TEN may have none or only mild ocular involvement with excellent prognosis quod visum, and patients with 10% skin detachment may have severe ocular involvement with blinding consequences, and vice versa.

Pathophysiology

An idiosyncratic, delayed hypersensitivity reaction has been implicated in the pathophysiology of SJS. Certain groups of patients appear more susceptible to develop SJS than the general population. The slow acetylators, patients who are immunocompromised, and patients with brain tumors undergoing radiotherapy with concomitant antiepileptics are among those at most risk. The slow acetylators are incapable of achieving complete detoxification of reactive drug metabolites. Such metabolites can act as haptens that interact with host tissues rendering them to be antigenic.^{2, 3}

Antigen presentation and production of tumor necrosis factor alpha (TNF-alpha) by the local tissue dendrocytes results in the recruitment and augmentation of T-lymphocytes' proliferation and enhances the cytotoxicity of the other immune effector cells.⁴ The activated CD8+ lymphocytes, in turn, can induce epidermal cell apoptosis via several mechanisms, which include the release of granzyme B and perforin. Apoptosis of the keratinocytes can also take place as a result of ligation of their surface death receptors with the appropriate molecules. Those can trigger the activation of the caspase system leading to DNA disorganization and cell death.⁵

Apoptosis of the keratinocytes can be mediated via direct interaction between the cell-death receptor Fas and its ligand. Both can be present on the surfaces of the keratinocytes. Alternatively, activated T-cells can release soluble Fas ligand and interferon-gamma, which induces Fas expression by the keratinocytes.⁶

Once apoptosis ensues, the dying cells provoke recruitment of more chemokines; this can perpetuate the inflammatory process, which leads to extensive epidermal necrolysis.⁷

Frequency

United States

The incidence of SJS is estimated to be 2.6-7.1 cases per 1 million person-years.

International

A study from Germany reports 1.1 cases per 1 million person-years.

Mortality/Morbidity

The mortality rate has been reported to be 1-3%.

Race

SJS can occur in all races worldwide.

Sex

The proportion of females has been estimated to be 33-62%. The largest series reports 39.9% of females in a group of 315 patients with SJS.

Age

In a large cohort, the mean age of patients with SJS is 25 years. In a smaller series, the mean age of patients with SJS has been reported as 47 years.

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