History of the disease Nosology

History of the disease: Nosology/classification, and diagnosis
Evolution of concepts on causality The concept that medications were a frequent, if not the only, cause of TEN was rapidly accepted by the medical filipin … may be too quickly in the opinion of Lyell. Strong evidence of such causality (and also of relationship between SJS and TEN) was provided by several mass campaigns of prevention of infectious diseases by long-acting sulfonamides, as these resulted in “epidemics” of SJS and TEN. It is anyhow important to keep in mind that no drug cause was suspected in the two original cases published by Stevens and Johnson. However, only one of the four original cases was reported by Lyell. In 1990, I contributed a review on SJS and TEN stating that “Drugs are the most important, if not the only, cause of TEN … Infections are well-recognized causes of SJS but not of TEN.” Both statements were erroneous: the hypothesis of different causes for SJS and TEN was wrong and so is the suggestion that TEN had no other cause than drugs. The results of the SCAR case-control study clearly indicated that the “etiologic fraction” for “associated medications” was very similar for SJS, overlap SJS–TEN, and TEN and around 0.65 in all three groups. Because the etiologic fraction was calculated only for drugs with a statistically significant association, it was underestimated by lack of statistical power. Further experience on larger numbers of cases confirmed the existence of low percentage of cases without any exposure to medications (2–3%) and a larger number (10–15%) of cases exposed to several drugs that all were unlikely the cause. In 20–25% of cases, one or several medications were possibly the cause without any definite certainty. In conclusion, no more than 70–80% of cases are drug induced and the percentages are similar for SJS, TEN, and overlaps. The percentage of “idiopathic cases” is probably higher in children. Up to now only a very low proportion of cases of EN (≈1%) had an established nondrug cause. These causes include acute graft-versus-host-disease (GVHD), some variants of acute LE, and infections. Infection-related EN was especially demonstrated with Mycoplasma pneumoniae but other agents were also suspected (Klebsiella pneumoniae, viruses). Over dosages of methotrexate or colchicine may also induce damages of skin and mucous membrane that closely resemble EN.
Progress on comprehension of mechanisms
The future
Introduction Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered a spectrum of rare but potentially fatal cutaneous diseases, differing only in their extent of skin detachment [with the degree of epidermal detachment less than 10% of body surface area (BSA) being classified as SJS, greater than 30% as TEN, and 10–30% as SJS/TEN overlap] (Figure 1). Histopathology typically shows widespread keratinocyte apoptosis and full-thickness epidermal necrosis and detachment with a sparse dermal monocytic (predominantly T cell) infiltrate. Without immediate medical intervention, uncontrolled separation of the epidermis can lead to large denuded areas that cause extreme pain, massive loss of fluid and protein, bleeding, evaporative heat loss with subsequent hypothermia, and infection. Although microbial infections have occasionally been reported as the causes of SJS/TEN, this devastating disease is mainly triggered by drug exposure. To date, more than 100 drugs have been associated with SJS and TEN, among which aromatic anticonvulsants, sulfonamide antibiotics, allopurinol, oxicam nonsteroidal anti-inflammatory drugs, and nevirapine exhibit a high relative risk. In this article, we primarily review the current advances in exploring the genetic predisposing factor and pathogenic mechanism of drug-induced SJS/TEN.
Epidemiology The incidence of SJS/TEN is estimated at one to six cases per million inhabitants per year in Europe and the US, yet the mortality rate is 10% for patients with SJS, approximately 30% for patients with SJS/TEN overlap, and almost 50% for patients with TEN. The condition is more common in adults than in children, and females are affected more frequently than males. In addition, people over 60 years old seem to be more likely to develop TEN. This disease occurs sporadically and as a singular event, but the incidence and prevalence can arise in specific populations while exposed to particular drugs. Pharmacogenomic studies have demonstrated that ethnicity and HLA types may predispose patients to SJS/TEN caused by certain drugs, which will be discussed later in this article. Although SJS/TEN has been mainly attributed to drug exposure, approximately 5% of SJS/TEN cases were reported to be associated with HIV infection in Europe. Furthermore, other agents such as Mycoplasma pneumonia, Herpes simplex virus, and some neoplastic and autoimmune diseases may have an impact on the incidence of SJS/TEN. However, there are still cases of SJS/TEN without any identifiable cause.