Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe and potentially fatal mucocutaneous diseases characterized by widespread epidermal necrosis and mucosal involvement [1,2]. At least 80% of TEN cases are believed to be drug-induced, whereas the proportion of SJS cases attributable to drugs is somewhat lower, with the estimates ranging between 50% and 80% [2,3]. We recently encountered more non-drug-related SJS and TEN cases than expected in our clinical practice. Several infectious etiologies have also been implicated in SJS and TEN. Mycoplasma pneumoniae and herpes simplex virus are the most commonly reported [4-7]. A severity-of-illness score for TEN, abbreviated as SCORTEN, was developed by Bastuji-Garin et al. [8]. In another study conducted in 2008, the risk of death was strongly correlated to the patient's age and to the severity of the disease [9]. However, few reports on the prognostic factors of SJS and TEN have also included their etiologies. Therefore, in the present study, the etiologies, clinical characteristics, and treatment outcomes for a number of adult patients with SJS or TEN were evaluated.

SJS and TEN are rare diseases (two cases/million population/year), but have significant impacts on public health because of their high mortality rates (20-25%) and complications, such as persistent corneal opacity, skin pigmentation, and skin scarring [2,12].

In a previous study that evaluated 207 patients with erythema multiforme (EM), SJS, or TEN, the most frequent cause of these ailments was found to be drugs [13]. Another study found that only 1 (3.1%) of 32 patients with SJS or TEN was a non-drug-related case [14]. In the present study, drug-related cases were common (43, 52.4%) but so were non-drug-related cases (39, 47.6%). All non-drug-related patients complained of various constitutional symptoms, such as fever, chills, myalgia, or sore throat, and the important and inevitable inclusion criteria were the symptoms preceding the drug that was prescribed to reduce such symptoms or not having a drug history. Non-drug-related or post-upper respiratory tract infection-related SJS or TEN may be more common clinically, but patients or doctors usually ignore its constitutional symptoms and do not pay attention to the drugs that may have caused it. To clarify the precise etiologies of SJS or TEN, and to prevent mistakes related to such, careful attention must be paid to patient history and medical history.

The most common triggering drugs in this study were anticonvulsants (carbamazepine) and antibiotics (cephalosporins). NSAIDs showed a lower risk in this study than in a previous study [2]. The so-called EuroSCAR study reported similar results, where the high-risk drugs included carbamazepine, cotrimoxazole, nevirapine, phenobarbital, phenytoin, and lamotrigine, whereas NSAIDs showed a lower risk [15]. Jeung et al. [16] studied 11 patients with drug rash with eosinophilia and systemic symptoms syndrome and 20 patients with SJS. The most common causative agents in both diseases were antibiotics, followed by anticonvulsants. Anticonvulsants and antibiotics are traditionally the drugs that are highly suspected of causing SJS or TEN, along with NSAIDs and allopurinol. The use of such drugs as first-line therapies should be carefully considered, especially when a safer alternative treatment modality exists.

In the present study, drug-related cases showed a frequently severe clinical course in contrast to the non-drug-related cases, consistent with previous findings [17]. The non-drug-related patients represented a large part of the etiologies, and patient hesitation to accept hospital visits or to acknowledge vague symptoms may have contributed to the delay in early diagnosis. Physicians should suspect early-phase SJS or TEN in patients with a short febrile history as well as sore throat and chills, although without a drug history.

SJS-related mortalities in previous studies have amounted to 0-10% of all mortalities, and TEN-related mortalities have amounted to 25-27% of all mortalities [10,18-22]. Optimal medical treatment for SJS and TEN requires early diagnosis, immediate discontinuation of the administration of the causative drug(s), provision of supportive care, and specific therapy [23]. The role of corticosteroids in the treatment of SJS is controversial. Some investigators have reported that corticosteroids may promote infectious complications and may lead to a poorer prognosis [24]. However, in recent years, steroid pulse therapy (e.g., with dexamethasone) in the acute stage of SJS/TEN has been proposed [25]. In that study, mortality of such patients was not higher and the time to re-epithelialization was not longer than expected, although small numbers of patients did not reach statistical significance. A small series of five patients from Japan suggested that early steroid pulse therapy may help to prevent ocular complications [26]. In the EuroSCAR-study, which evaluated 281 patients with SJS/TEN from France and Germany, mortality was chosen as the end point and linked to treatment with corticosteroids, IVIG, the combination of both, and supportive care only. ORs were calculated, and they suggested a benefit for treatment with corticosteroids but not for treatment with IVIG. Although such a retrospective analysis has some pitfalls, two major conclusions could be drawn: first, IVIG is not the best treatment for SJS/TEN and cannot generally be recommended; second, a controlled therapeutic trial using corticosteroids should be undertaken [9]. IVIG, which had been reported as an effective treatment for TEN based on the hypothesis that antibodies in pooled human IVIG block the Fas-mediated necrosis of keratinocytes in vitro, is still controversial. Other studies have shown that IVIG does not have an overall positive effect [27]. Two further studies undertaken in North American burn units suggested that IVIG does not improve the outcome of patients with TEN [28,29]. In the present study, IV steroids were used in most of the patients, and the mortality rate (9.8%) was lower compared to that of previous studies. Further well-designed studies are required to compare the effects and hazards of treatment modalities for SJS or TEN.

The SCORTEN was developed by Bastuji-Garin et al. [8] and can be used to predict the mortality risk based on seven independent risk factors (age of ≥ 40 years, heart rate of ≥ 120/min, history of malignancy, total body surface area detached > 10%, serum urea nitrogen of > 10 mmol/L, serum bicarbonate of < 20 mmol/L, and serum glucose of > 14 mmol/L). In the present study, kidney function abnormality, pneumonia, low hemoglobin (< 10 g/dL), and underlying diseases showed a significant negative correlation with survival in the univariate analysis. Only pneumonia, however, was shown to be a negative prognostic factor in the multivariate logistic regression analysis.

Ocular involvement is common in SJS and TEN [17]. In a previous study, 70% of the patients manifested ocular involvement and the common signs and symptoms were conjunctivitis, exudates, photophobia, and cicatrizing changes [17]. In contrast, less ocular involvement was found in the present study.

The limitations of this study include the fact that the causative agents were determined by history and did not depend on immunologic tests, and the treatment patterns differed among patients.

SJS and TEN have traditionally been known as drug-related systemic immune reactions. However, a definitive treatment regimen among the various supportive therapies that have been tried has not been established. In this study, the etiologies and clinical characteristics of non-drug-related and drug-related groups were reviewed. Only pneumonia was found to be a statistically significant negative prognostic factor. The overall mortality of the present study was lower than in previous studies, which may stem from the fact that steroid treatment was a major regimen in the present study. Hence, our results suggest that early steroid therapy should be performed along with other supportive management measures as well as careful documentation of patient history for vague constitutional symptoms and upper respiratory tract infection.