Life-threatening dermatoses: Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Impact on the Spanish public health system (2010-2015)

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are serious mucocutaneous reactions. In Spain, the epidemiology and resulting expenses of these diseases are not well established.  Retrospective descriptive study using the Minimum Basic Data Set (CMBD in Spanish) in patients admitted to hospitals of the National Health System between 2010 and 2015 with a diagnosis of SJS and TEN (combination of ICD-9 codes 695.13, 695.14, and 695.15, along with length of hospital stay).  A total of 1,468 patients were recorded, 773 were men (52.7%). The mean age (± SD) was 52.25 ± 26.15 years. The mean incidence rate for all diagnoses was 5.19 cases per million person-years (2.96 in SJS, 0.31 in SJS/TEN and 1.90 in TEN). 148 patients died (10.1%), 47 due to SJS (5.6%) and 90 (16.7%) due to TEN. The estimated total medical cost of SJS, SJS/TEN, and TEN in Spain was €11.576.456,18, and the average medical cost per patient was €7.885,86 ± €11.686,26, higher medical cost in TEN (€10352.46 ± €16319,93) than in SJS (€6340,05 ± €7078,85) (p<0.001).  Older patients have a more severe clinical picture and higher mortality rates. The overall mortality of both diseases is approximately 10%, and clinical diagnosis and age were the variables with the greatest influence on mortality. This study describes a stable incidence and a similar prevalence to other European countries. Additionally, the data show a high cost due to hospitalizations. Finally, the CMBD could be a good system of epidemiological analysis for the study of infrequent diseases and hospital management of conditions such as SJS and TEN.

Related papers:

title: Clinical, etiologic, and histopathologic features of Stevens-Johnson syndrome during an 8-year period at Mayo Clinic.
abstract: To examine clinical, etiologic, and histologic features of Stevens-Johnson syndrome and to identify possible correlates of clinical disease severity related to etiologic and histopathologic findings.



This is a retrospective review of patients seen at Mayo Clinic between January 1, 2000, and December 31, 2007.



Of 27 patients (mean age, 28.1 years), 22 (81%) had involvement of 2 or more mucous membranes, and 19 (70%) had ocular involvement. Medications, most commonly antibiotics and anticonvulsants, were causative in 20 patients. Mycoplasma pneumoniae infection caused 6 of the 27 cases. Corticosteroids were the most common systemic therapy. No patients with mycoplasma-induced Stevens-Johnson syndrome had internal organ involvement or required treatment in the intensive care unit, in contrast to 4 patients each in the drug-induced group. Three patients had chronic ocular sequelae, and 1 died of complications. Biopsy specimens from 13 patients (48%) showed epidermal necrosis (8 patients), basal vacuolar change (10 patients), and subepidermal bullae (10 patients). Biopsy specimens from 11 patients displayed moderate or dense dermal infiltrate. Histologic features in drug-induced cases included individual necrotic keratinocytes, dense dermal infiltrate, red blood cell extravasation, pigment incontinence, parakeratosis, and substantial eosinophils or neutrophils.



Our clinical and etiologic findings corroborate those in previous reports. M pneumoniae-induced Stevens-Johnson syndrome manifested less severely than its drug-induced counterpart. The limited number of biopsies precludes unequivocal demonstration of histopathologic differences between drug-induced and M pneumoniae-induced Stevens-Johnson syndrome.

title: Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?
abstract: Withdrawal of the drug(s) that cause severe cutaneous adverse reactions is usually recommended without proof that it alters the course of those reactions.



To determine whether the timing of causative drug withdrawal is related to the prognosis of patients with toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS).



A 10-year observational study (January 1, 1987, through October 30, 1997) of patients admitted to a dermatological intensive care unit, using binary logistic regression analysis.



A single referral unit in a university hospital.



Consecutive sample of 203 patients with TEN or SJS. Exclusion criteria included causative drug undetermined, lack of information on disease evolution, the date of causative drug(s) withdrawal, or the date when the first definite sign of TEN or SJS appeared.



Death before hospital discharge.



One hundred thirteen patients were included; 74 had TEN and 39 had SJS; 20 died. The drug causing TEN or SJS was withdrawn early in 64 patients and late (after the first definite sign of TEN or SJS) in 49 patients. After adjustment for confounding variables (age, maximum extent of detachment, admission year, human immunodeficiency virus status), our model showed that the earlier the causative drug was withdrawn, the better the prognosis (odds ratio, 0.69 for each day; 95% confidence interval, 0.53-0.89). Patients exposed to causative drugs with long half-lives had an increased risk of dying (odds ratio, 4.9; 95% confidence interval, 1.3-18.9). The variables did not interact.



Prompt withdrawal of drug(s) that are suspected to cause SJS or TEN may decrease mortality. Prompt withdrawal of causative drugs should be a priority when blisters or erosions appear in the course of a drug eruption.

title: SCORTEN: a severity-of-illness score for toxic epidermal necrolysis.
abstract: The mortality of toxic epidermal necrolysis is about 30%. Our purpose was to develop and validate a specific severity-of-illness score for cases of toxic epidermal necrolysis admitted to a specialized unit and to compare it with the Simplified Acute Physiology Score and a burn scoring system. A sample of 165 patients was used to develop the toxic epidermal necrolysis-specific severity-of-illness score and evaluate the other scores, a sample of 75 for validation. Model development used logistic regression equations that were translated into probability of hospital mortality; validation used measures of calibration and discrimination. We identified seven independent risk factors for death and constituted the toxic epidermal necrolysis-specific severity-of-illness score: age above 40 y, malignancy, tachycardia above 120 per min, initial percentage of epidermal detachment above 10%, serum urea above 10 mmol per liter, serum glucose above 14 mmol per liter, and bicarbonate below 20 mmol per liter. For each toxic epidermal necrolysis-specific severity-of-illness score point the odds ratio was 3.45 (confidence interval 2.26-5.25). Probability of death was: P(death) = elogit/1 + elogit with logit = -4.448 + 1.237 (toxic epidermal nec-rolysis-specific severity-of-illness score). Calibration demonstrated excellent agreement between expected (19. 6%) and actual (20%) mortality; discrimination was also excellent with a receiver operating characteristic area of 82%. The Simplified Acute Physiology Score and the burn score were also associated with mortality. The discriminatory powers were poorer (receiver operating characteristic area: 72 and 75%) and calibration of the Simplified Acute Physiology Score indicated a poor agreement between expected (9.1%) and actual (26.7%) mortality. This study demonstrates that the risk of death of toxic epidermal necrolysis patients can be accurately predicted by the toxic epidermal necrolysis-specific severity-of-illness score. The Simplified Acute Physiology Score and burn score appear to be less adequate.

title: Experience with toxic epidermal necrolysis treated in a burn center.
abstract: Toxic epidermal necrolysis syndrome is one of several clinically similar, severe acute, exfoliative skin disorders that have become of increasing interest to burn surgeons in recent years. Recognition of a clinical course similar to extensive second-degree burns has resulted in the development of treatment protocols that are best carried out in a burn unit by personnel experienced in critical care techniques, the management of extensive cutaneous injuries, fluid and electrolyte derangements, and intensive nutritional support of critically ill patients. Current evidence suggests that in most instances toxic epidermal necrolysis syndrome is a CD8 lymphocyte-mediated reaction triggered by exposure to certain drugs. The target organs of the immune reaction are skin and mucous membranes. Appropriate management of the extensive skin wounds and the nutritional and critical care support afforded by treatment in burn units appears to have contributed significantly to the increasing survival of patients with this devastating and potentially lethal illness.

title: The Epidemiology of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in the UK.
abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening mucocutaneous diseases. SJS/TEN mostly manifest as a reaction to new drug use, but little is known about their incidence and epidemiology. We conducted a large observational study on the epidemiology of SJS/TEN using data from the UK-based Clinical Practice Research Datalink. Among 551 validated SJS/TEN patients, we calculated an incidence rate of 5.76 SJS/TEN cases per million person-years between 1995 and 2013, which was consistent throughout the study period and was highest in patients aged 1-10 years and 80 years or older. Within a 1:4 matched case-control analysis, black and Asian patients were at a 2-fold risk of SJS/TEN when compared with white patients. Among patients with epilepsy and gout, odds ratios for SJS/TEN were significantly increased only in the presence of recent new drug treatment with antiepileptics or allopurinol, respectively. We observed statistically significant associations between SJS/TEN and pre-existing depression, lupus erythematosus, recent pneumonia, chronic kidney disease, and active cancer, but confounding by drug use needs to be followed up. This large and longitudinal observational study on the epidemiology of SJS/TEN contributes to the understanding of this still underinvestigated severe skin disease in a European and largely white study population.

title: Morbidity and Mortality of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in United States Adults.
abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening disorders. Our study objective was to describe the incidence, costs of care, length of stay, comorbidities, and mortality of SJS and TEN in US adults. The Nationwide Inpatient Sample 2009-2012, containing a 20% sample of all US hospitalizations, was analyzed. We used a validated approach involving International Classification of Disease, 9th edition, Clinical Modification codes to identify SJS, SJS/TEN, and TEN (n = 2,591, n = 502, and n = 564, respectively). The mean estimated incidences of SJS, SJS/TEN, and TEN were 9.2, 1.6, and 1.9 per million adults per year, respectively. SJS/TEN was associated with nonwhite race, particularly Asians (odds ratio = 3.27, 95% confidence interval = 3.02-3.54) and blacks (odds ratio = 2.01, 95% confidence interval = 1.92-2.10). Significantly prolonged length of stay and higher costs of care (SJS: 9.8 ± 0.3 days, $21,437 ± $807; SJS/TEN: 16.5 ± 1.0 days, $58,954 ± $5,238; TEN: 16.2 ± 1.0 days, $53,695 ± $4,037) were observed compared with all other admissions (4.7 ± 0.02 days, $11,281 ± $98). Mean adjusted mortality was 4.8% for SJS, 19.4% for SJS/TEN, and 14.8% for TEN. SJS, SJS/TEN, and TEN pose a substantial health care burden. Predictors of mortality included increasing age, increasing number of chronic conditions, infection (septicemia, pneumonia, tuberculosis), hematological malignancy (non-Hodgkin's lymphoma, leukemia), and renal failure (P ≤ 0.03 for all). Further studies are needed to confirm mortality findings to improve prognostication of SJS/TEN.

title: Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry.
abstract: The severe skin reactions erythema exsudativum multiforme majus (EEM with mucosal involvement, EEMM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are difficult to study as they are very rare diseases with an incidence of about two cases per 1 million inhabitants per year. We report on the structure of a registry with the aim of ascertaining all hospitalized cases of EEMM, SJS, and TEN in western Germany and Berlin. The registry is structured as an intensive reporting system, regularly contacting more than 1500 departments including 100% of the burn units (n = 34), departments of pediatrics (n = 241), departments of dermatology (n = 106), and 100% of all internal medicine departments in hospitals with intensive care facilities or with more than 200 beds (n = 1161). With a coverage rate up to 95% based on the number of responding departments between April 1, 1990 and December 31, 1992, from a total of 767 reported cases 353 patients with EEMM, SJS, and TEN were finally included in the registry. Most of these patients were directly reported to the registry; only 2.54% (9 of 353) were primarily registered by the German spontaneous reporting systems. Assuming an average population of 64.5 million for western Germany and Berlin an incidence up to 1.89 per 1 million inhabitants per year could be calculated for SJS and TEN.

title: Toxic epidermal necrolysis (Lyell syndrome). Incidence and drug etiology in France, 1981-1985.
abstract: We looked retrospectively for all cases of toxic epidermal necrolysis that occurred in France over a 5-year period to appreciate the incidence of this disorder and its drug etiology. Of the 399 cases identified, we obtained detailed information on 344 cases and validated 253 cases. From response rates (66% to 98%), we estimated the actual total number of cases to be 333, and the incidence of toxic epidermal necrolysis in France to 1.2 cases per million per year. An independent estimation derived from death certificates gave a figure of 1.3 cases per million per year. When the number of cases with a given drug present were related to the defined daily doses of that drug sold over the 5-year period, the highest ratios were for sulfadiazin (230.10(-8], isoxica (41.10(-8], oxyphenbutazone (18.10(-8], phenytoin (14.10(-8], fenbufen (13.10(-8], and cotrimoxazole (12.10(-8]. This first nationwide study confirmed the rarity of toxic epidermal necrolysis. Within the two main classes of responsible drugs (antibacterial sulfonamides and nonsteroidal anti-inflammatory agents) the risks linked to different drugs appeared quite different, even for closely chemically related products.

title: The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients.
abstract: We carried out a study to estimate the incidence of erythema multiforme (EM), Stevens Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) requiring hospitalization and to determine which drug therapies were associated with these reactions. We reviewed the clinical records of all patients who were hospitalized with these discharge diagnoses at Group Health Cooperative (GHC) of Puget Sound, Seattle, Wash, from 1972 through 1986. During this 14-year period, an average of about 260,000 persons, with demographic characteristics similar to those of the general population, received their care from GHC, and there were about 25,000 admissions to hospitals per year at the GHC hospitals. Based on International Classification of Diseases-Adapted coding, a total of 61 suspect cases of EM, SJS, or TEN were identified from the computerized hospital discharge file. Based on record review and the application of a uniform set of diagnostic criteria, a total of 37 patients (61%) were classified as having EM, SJS, or TEN. Of these, 16 cases (43%) were attributed to drugs administered to these patients prior to hospitalization. The overall incidence of hospitalization for EM, SJS, or TEN due to all causes was 4.2 per 10(6) person-years. The incidence of TEN alone due to all causes was 0.5 per 10(6) person-years. The incidence of EM, SJS, or TEN associated with drug use were 7.0, 1.8, and 9.0 per 10(6) person-years, respectively, for persons younger than 20 years of age, 20 to 64 years of age, and 65 years of age and older. Drug therapies with reaction rates in excess of 1 per 100,000 exposed individuals include phenobarbital (20 per 100,000), nitrofurantoin (7 per 100,000), sulfamethoxazole and trimethoprim, and ampicillin (both 3 per 100,000), and amoxicillin (2 per 100,000). Overall, our data suggest that cases of EM, SJS, and TEN sufficiently severe to require hospitalization are infrequent among outpatients using well-established drug therapies. A continuing challenge is the evaluation of these severe cutaneous reactions that are associated with newly marketed or less frequently prescribed drug therapies.

title: Using a claims database to investigate drug-induced Stevens-Johnson syndrome.
abstract: In order to explore a priori hypotheses about drug-induced Stevens-Johnson Syndrome (SJS), a case-control study was initiated using data from COMPASS, a computerized data base consisting of Medicaid claims data. The records of 3.8 million patients in five U.S. states were searched to identify patients with an inpatient diagnosis of ICD-9-CM code 695.1 (erythema multiforme-EM). Out of the total of 367 cases that were identified, primary medical records for 249 were sought and 128 (51.4 per cent) of these were obtained. The remainder could not be obtained because: in 36 (29.8 per cent) the hospital refused to provide medical records; in 33 (27.3 per cent) there were transcription errors; in 20 (16.5 per cent) the state could not translate the identification number, primarily because the patients lost Medicaid eligibility too long before our request; in 27 (22.3 per cent) the hospital could not locate the patient's record; and in 5 (4.1 per cent) there were other reasons. Of those with a medical record, 121 (94.5 per cent) had a skin diagnosis and 109 (85.2 per cent) had a diagnosis compatible with ICD-9-CM code 695.1 specified on their discharge summary. However, in 35 (27.3 per cent) an expert reviewer felt that the discharge diagnosis was incorrect. In 50 (39 per cent) the computer diagnosis was incorrect. Only 19 (14.8 per cent) were judged by the expert reviewer to truly have Stevens-Johnson Syndrome, and an additional 37 (28.9 per cent) were judged to have erythema multiforme minor. Thus, the computerized diagnosis agreed very well with the diagnoses specified on the discharge summary. However, EM is frequently misdiagnosed, ICD-9-CM code 695.1 contains multiple other diagnoses which are not EM, and much of hospitalized EM is EM minor. Thus, studies of SJS cannot be performed except in patients whose medical records are available.

title: Incidence of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Nationwide Population-Based Study Using National Health Insurance Database in Korea
abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases; however, it is hard to estimate their incidence due to the rarity of these diseases. We evaluated the incidence of SJS and TEN using a nationwide administrative database.  We used a national medical insurance review system (Health Insurance Review and Assessment) database which contained the claim data of the entire nation from 2009 to 2013 to estimate the accurate incidence of SJS and TEN in Korea. The diagnostic codes of L511 (SJS) or L512 (TEN) from the International Classification of Diseases-10th revision were used to define the target study population. We also retrospectively followed up a 2011 SJS and TEN cohort for 24 months in order to assess the in-hospital mortality, related complications and total claims cost due to SJS and TEN.  A total of 1,167 (938 SJS and 229 TEN) cases were newly diagnosed from 2010 to 2013. The age- and sex-standardized annual incidences estimated in this study were 3.96 to 5.03 in SJS and 0.94 to 1.45 in TEN per million. There was no significant change in annual incidence throughout the study periods. When analyzed by 10-year age groups, the annual incidence was the lowest in group 20–29 years and the highest in group 70 for both SJS and TEN. Based on the 2011 cohort analysis, the in-hospital mortality were 5.7 and 15.1% for SJS and TEN, respectively. The mortality increased with age, particularly, after 40 years of age. Among the complications related with SJS or TEN, ocular sequelae was the most common (43.1 and 43.4% of SJS and TEN patients, respectively) followed by urethral sequelae (5.7 and 9.4% of SJS and TEN patients, respectively).  Overall, our data suggest that SJS, and TEN are infrequent but constantly arise throughout the years.

title: Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.
abstract: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous adverse reactions that are of major concern because of high mortality rates. On the basis of data collected in the RegiSCAR study, the aim was to assess risk factors (including modalities of patient management) for mortality, regardless of the cause, up to 1 year after the reaction. Within this cohort, the mortality rate was 23% (95% confidence interval (CI) 19-27%) at 6 weeks and 34% (95% CI 30-39%) at 1 year. Severity of reaction was a risk factor for mortality only in the first 90 days after onset, whereas serious comorbidities and age influenced mortality beyond 90 days and up to 1 year after onset of reaction. The risk of death for patients with identified drug cause was borderline lower than for patients with a reaction of unknown cause (hazard ratio 0.66, 95% CI 0.45-0.96). The study could not provide conclusive evidence regarding patient management. This large-scale population-based follow-up study of such patients confirmed high in-hospital mortality and revealed a remarkable number of deaths after discharge, which could mainly be attributed to severe comorbidities and older age, whereas the impact of severity of reaction on the risk of death was limited to the first few weeks.

title: Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study.
abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse reactions (SCAR) related to a variety of medications. They have a significant public health impact because of high mortality and morbidity. A multinational case-control study conducted in Europe between 1997 and 2001 evaluated the risk of medications to induce SCAR. Cases were actively detected through a hospital network covering more than 100 million inhabitants. Three hospitalized patients per case matched on age, gender, and date of interview were enrolled as controls. After validation by an expert committee blinded to exposures, 379 SCAR cases and 1,505 controls were included. Among drugs recently introduced into the market, strong associations were documented for nevirapine (relative risk (RR)>22) and lamotrigine (RR>14), and weaker associations for sertraline (RR=11 [2.7-46]), pantoprazole (RR=18 [3.9-85]), and tramadol (RR=20 [4.4-93]). Strong associations were confirmed for anti-infective sulfonamides, allopurinol, carbamazapine, phenobarbital, phenytoin, and oxicam-NSAIDs , with some changes in relative numbers of exposed cases. Thus, many cases were still related to a few "old" drugs with a known high risk. Risk was restricted to the first few weeks of drug intake. The use of such drugs as first-line therapies should be considered carefully, especially when safer alternative treatments exist. A number of widely used drugs did not show any risk for SJS and TEN.

title: Pediatric Stevens‐Johnson syndrome and toxic epidermal necrolysis in the United States
abstract: Little is known about the epidemiology of Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in children.  We sought to determine the morbidity, mortality, and comorbid health conditions of SJS and TEN in US children.  This was a cross‐sectional study of the 2009 to 2012 Nationwide Inpatient Sample, which contains a representative 20% sample of all US hospitalizations. Sociodemographics, inflation‐adjusted cost, length of stay, comorbidities, and mortality were analyzed using descriptive statistics and multivariate regression analyses.  The incidences of SJS, SJS‐TEN, and TEN were a mean 5.3, 0.8, and 0.4 cases per million children per year in the US, respectively. Prolonged length of stay and higher costs of care (SJS: 9.4 ± 0.6 days, $24,947 ± $3171; SJS‐TEN: 15.7 ± 1.5 days, $63,787 ± $8014; TEN: 20.4 ± 6.3 days, $102,243 ± $37,588) were observed compared with all other admissions (4.6 ± 0.1 days, $10,496 ± $424). Mortality was 0% for SJS, 4% for SJS‐TEN, and 16% for TEN. In regression models, predictors of mortality included renal failure (adjusted OR [aOR] 300.28, 95% confidence interval [CI] 48.59‐>999.99), malignancy (aOR 54.33, 95% CI 9.40‐314.22), septicemia (aOR 30.45, 95% CI 7.91‐117.19), bacterial infection (aOR 20.38, 95% CI 5.44‐76.36), and epilepsy (aOR 5.56, 95% CI 1.37‐26.2).  Data regarding treatment were not available. Date of diagnosis of comorbidities was not present, precluding temporal analysis.  Pediatric SJS/TEN poses a substantial health burden in the United States.

title: Recurrence and mortality following severe cutaneous adverse reactions.
abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions. Both primarily develop as idiosyncratic responses to drugs,1 resulting in extensive epidermal detachment. Recurrence has been reported in isolated cases, and the overall risk of recurrence is unknown. Given the rarity of SJS and TEN, valid inferences about recurrence rates require the study of large populations over an extended period. We examined the long-term risk of recurrence following a first SJS or TEN episode.