[Stevens-Johnson syndrome in a patient with positive lymphocyte transformation test]. / Síndrome de Stevens-Johnson en una paciente con prueba positiva de transformación linfocitaria.

BACKGROUND: Stevens-Johnson syndrome is a severe drug reaction. Sulfonamides have been associated with drug reactions, complications, sequelae, even death. CASE REPORT: A 40-year-old female patient with a medical history of endometriosis and recently diagnosed chronic inflammatory ulcerative colitis. She was treated at the Allergology service of the San Juan de Dios Hospital of the Costa Rican Social Security Fund, and after 20 days of treatment with sulfasalazine she had a severe drug reaction on the skin, compatible with Stevens-Johnson syndrome. The lymphocyte transformation test was positive, confirming sulfasalazine as the causative agent. CONCLUSION: The lymphocyte transformation test is a useful method that can confirm the causative agent and prevent important complications in the future.

ANTECEDENTES: El síndrome de Stevens-Johnson es una reacción medicamentosa severa. Las sulfamidas se han asociado con reacciones medicamentosas, complicaciones, secuelas, incluso la muerte. REPORTE DE CASO: Paciente femenina de 40 años, con antecedentes médicos de endometriosis y colitis ulcerativa crónica inflamatoria de reciente diagnóstico. Fue atendida en el servicio de Alergología del Hospital San Juan de Dios de la Caja Costarricense del Seguro Social, y luego de 20 días de tratamiento con sulfasalazina tuvo una reacción medicamentosa severa en la piel, compatible con síndrome de Stevens-Johnson. La prueba de transformación linfocitaria resultó positiva, con lo que se confirmó la sulfasalazina como el agente causal. CONCLUSIÓN: La prueba de transformación linfocitaria es un método útil que puede confirmar el agente causal y prevenir complicaciones importantes a futuro.

A Comprehensive Assessment of Long-Term Complications in Patients with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

INTRODUCTION: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are rare severe hypersensitivity reactions that lead to epithelial sloughing. Studies investigating the chronic multisystem effects of these syndromes and assessing patients in terms of quality of life (QOL), depression, and anxiety in the pediatric population are limited. In this study, we aimed to investigate the long-term effects of these diseases from a multisystem perspective. METHOD: Sixteen pediatric patients diagnosed with SJS, TEN, and SJS/TEN overlap syndrome were evaluated between September 2020 and March 2021. Physical and eye examinations were performed. To evaluate QOL and psychological status, Children's Dermatology Life Quality Index (CDLQI), Screen for Child Anxiety-Related Emotional Disorders (SCARED), and Children's Depression Inventory (CDI) were conducted. The patients' general characteristics, symptoms, and examination findings at their first admission were retrospectively obtained from the hospital's electronic records. RESULTS: Nineteen percent of the patients were female (n = 3). There were 7 patients (44%) with the diagnosis of SJS, 5 patients (31%) with TEN, and 4 patients (25%) with SJS/TEN overlap. The median follow-up time of the subjects was 6.5 years. The most common sequelae in the chronic period were skin changes (n = 13, 81%). Hyperpigmentation was the most common skin change (n = 9, 56%). In the last evaluation, 9 cases had eye involvement. In two cases, eye examination was normal in the acute phase, while ocular involvement was present in the chronic period. In 4 (50%) patients, there was height and/or weight percentile loss. Three patients' SCARED scores and 2 patients' CDI scores were high. According to the CDLQI survey, SJS, TEN, or SJS/TEN overlap syndrome had a small to moderate effect on the QOL in the 43% (n = 6) of the patients. The ANA values of 3 patients (60%) were positive at the follow-up and negative at the first admission. CONCLUSION: SJS, TEN, and SJS/TEN overlap syndrome may cause sequelae even after a long time of the onset of the disease. Patients' QOL and psychological status can be affected negatively. Ocular symptoms may develop in the follow-up, even without involvement in the acute period. Patients with SJS, TEN, and SJS/TEN overlap syndrome should be followed up in the chronic period and approached multidisciplinary.

Lifetime risk, life expectancy, loss-of-life expectancy and lifetime healthcare expenditure for Stevens-Johnson syndrome/toxic epidermal necrolysis in Taiwan: follow-up of a nationwide cohort from 2008 to 2019.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) not only cause acute, devastating mucocutaneous reactions but also have long-lasting implications on survivors' lives. OBJECTIVES: To quantify the lifetime burden of SJS/TEN. METHODS: The cumulative incidence rate (CIR), life expectancy (LE), loss-of-life expectancy (LoLE) and lifetime healthcare expenditure (HE) for SJS/TEN were estimated over the period from 2008 to 2019 using data from the National Health Insurance Research Database of Taiwan and life tables of vital statistics. RESULTS: In this nationwide cohort of 6552 incident SJS/TEN cases, a trend towards a decrease in the CIR was observed between 2008 and 2019. Compared with the general population, patients with SJS/TEN experience a tremendous loss of 9.43 (1.06) [mean (SEM)] years of LE after diagnosis of SJS/TEN. Male patients with SJS/TEN had higher LoLE [10.74 (1.22) vs. 7.69 (1.43) years] and annual HE than females. Younger age at diagnosis of SJS/TEN was associated with longer LE but greater LoLE and higher lifetime HE. Patients with intensive care unit admission on diagnosis, malignancy, diabetes mellitus, end-stage renal disease and SJS/TEN-associated sequelae experienced substantially greater LoLE and HE per life year. CONCLUSIONS: Patients with SJS/TEN suffer substantial loss-of-LE and HE, particularly young patients, compared with the general population. These data provide a reference estimate of the lifetime burden of SJS/TEN to help health authorities evaluate the cost-effectiveness of future preventive and treatment strategies to minimize the burden of SJS/TEN.

Assessment of Need for Improved Identification of a Culprit Drug in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Importance: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe hypersensitivity reaction. Identifying a culprit drug is critical for patient care, yet identification is based on clinical judgment. Data are limited on the accuracy in or approach to identifying a culprit drug. Objective: To evaluate patient allergy list outcomes, current approaches in identifying culprit drugs, and potential methods of improving culprit drug identification. Design, Setting, and Participants: This retrospective cohort study spanned 18 years (January 2000 to July 2018), was conducted at Brigham and Women's Hospital and Massachusetts General Hospital (Boston), and included patients with clinically and histologically confirmed cases of SJS/TEN overlap and TEN. Main Outcomes and Measures: This study descriptively analyzed potential culprits to SJS/TEN, patients' allergy lists, and currently used approaches that led to those lists. It then tested the theoretical contribution of incorporating various parameters to allergy list outcomes. Results: Of 48 patients (29 women [60.4%]; 4 Asian [8.3%], 6 Black [12.5%], 5 Hispanic [10.4%], and 25 White [52.1%] individuals; median age, 40 years [range, 1-82 years]), the mean (SD) number of drugs taken per patient at disease onset was 6.5 (4.7). Physicians labeled 17 patients as allergic to a single culprit drug. Comparatively, 104 drugs were added to allergy lists across all patients. Physicians' approaches relied largely on heuristic identification of high-notoriety drugs and the timing of drug exposure. Use of a vetted database for drug risk improved sensitivity. Algorithm for Drug Causality for Epidermal Necrolysis scoring was discordant in 28 cases, labeling an additional 9 drugs missed by physicians and clearing 43 drugs labeled as allergens by physicians. Human leukocyte antigen testing could have potentially affected 20 cases. Consideration of infection as a culprit was limited. Conclusions and Relevance: The results of this cohort study suggest that currently used approaches to identify culprit drugs in SJS/TEN are associated with overlabeling patients allergic to likely nonculprit drugs and less commonly missed possible culprit drugs. Incorporation of a systematized unbiased approach could potentially improve culprit drug identification, although ultimately a diagnostic test is necessary.

Postmarket Assessment for Drugs and Biologics Used in Dermatology and Cutaneous Adverse Drug Reactions.

Postmarket surveillance is critical for the identification of rare safety risks, which are unlikely to be identified during clinical trials and the drug development program. Rare adverse drug reactions with the potential for serious outcomes, including fatalities, include the severe cutaneous adverse reactions of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Dermatologists play an important role in the diagnosis of these serious drug reactions and contribute to drug safety by reporting cases of suspected cutaneous adverse drug reactions.

Agreement Among Different Scales for Causality Assessment in Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

BACKGROUND AND OBJECTIVE: Identification of the offending drug is crucial and challenging in cases of severe cutaneous adverse drug reactions (CADR) like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Poor reproducibility and varying levels of agreement have been observed among different causality assessment tools (CATs) in assessing severe CADRs. This study was conducted to examine the agreement among four different CATs in assessing cases of drug-induced SJS, TEN and SJS/TEN overlap. METHODS: All cases of drug-induced SJS, TEN and SJS/TEN overlap, which were reported between January 2012 and January 2020, were identified from the ADR register at an ADR monitoring centre. Causality assessment was done in these reported cases using the following CATs: The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale, Naranjo algorithm, Liverpool algorithm and Algorithm of drug causality for epidermal necrolysis (ALDEN). Weighted kappa (κw) test was used to evaluate the agreement among four CATs. RESULTS: A total of 30 cases of drug-induced SJS, TEN and SJS/TEN overlap were included in our analyses. The most common offending groups of drugs were anticonvulsants (46.7%), antimicrobials (40%) and nonsteroidal anti-inflammatory drugs (13.3%). Of the anticonvulsants, phenytoin (13.3%), carbamazepine (10%), and valproate (10%) were the commonly reported offending drugs. Poor agreement was observed among the four different causality assessment scales. CONCLUSION: Discrepancies were observed among four different CATs in assessing drug-induced SJS and TEN. A CAT, which is more specific to drug-induced SJS and TEN, simple, user-friendly with limited subjective interpretation, incorporating new immunological and pharmacogenetic markers, is necessary.

Assessment of Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Insights From a Pan-European Multicenter Study.

IMPORTANCE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug reactions associated with a high rate of mortality and morbidity. There is no consensus on the treatment strategy. OBJECTIVE: To explore treatment approaches across Europe and outcomes associated with the SJS/TEN disease course, as well as risk factors and culprit drugs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective pan-European multicenter cohort study including 13 referral centers belonging to the ToxiTEN ERN-skin subgroup was conducted. A total of 212 adults with SJS/TEN were included between January 1, 2015, and December 31, 2019, and data were collected from a follow-up period of 6 weeks. MAIN OUTCOMES AND MEASURES: Risk factors for severe acute-phase complications (acute kidney failure, septicemia, and need for mechanical ventilation) and mortality 6 weeks following admission were evaluated using a multivariable-adjusted logistic regression model. One tool used in evaluation of severity was the Score of Toxic Epidermal Necrolysis (SCORTEN), which ranges from 0 to 7, with 7 the highest level of severity. RESULTS: Of 212 patients (134 of 211 [63.7%] women; mean [SD] age, 51.0 [19.3] years), the mean (SD) body surface area detachment was 27% (32.8%). In 176 (83.0%) patients, a culprit drug was identified. Antibiotics (21.2%), followed by anticonvulsants (18.9%), nonsteroidal anti-inflammatory drugs (11.8%), allopurinol (11.3%), and sulfonamides (10.4%), were the most common suspected agents. Treatment approaches ranged from best supportive care only (38.2%) to systemic glucocorticoids (35.4%), intravenous immunoglobulins (23.6%), cyclosporine (10.4%), and antitumor necrosis factor agents (3.3%). Most patients (63.7%) developed severe acute-phase complications. The 6-week mortality rate was 20.8%. Maximal body surface area detachment (≥30%) was found to be independently associated with severe acute-phase complications (fully adjusted odds ratio [OR], 2.49; 95% CI, 1.21-5.12; P = .01) and SCORTEN greater than or equal to 2 was significantly associated with mortality (fully adjusted OR, 10.30; 95% CI, 3.82-27.78; P < .001). Cyclosporine was associated with a higher frequency of greater than or equal to 20% increase in body surface area detachment in the acute phase (adjusted OR, 3.44; 95% CI, 1.12-10.52; P = .03) and an increased risk of infections (adjusted OR, 7.16; 95% CI, 1.52-33.74; P = .01). Systemic glucocorticoids and intravenous immunoglobulins were associated with a decreased risk of infections (adjusted OR, 0.40; 95% CI, 0.18-0.88; P = .02). No significant difference in 6-week mortality was found between treatment groups. CONCLUSIONS AND RELEVANCE: This cohort study noted differences in treatment strategies for SJS/TEN in Europe; the findings suggest the need for prospective therapeutic studies to be conducted and registries to be developed.

Assessment and Comparison of Performance of ABCD-10 and SCORTEN in Prognostication of Epidermal Necrolysis.

Importance: Epidermal necrolysis is a rare severe cutaneous drug reaction associated with high mortality. The ABCD-10 score (age, bicarbonate, cancer, dialysis, 10% body surface area), a new prognostic score for mortality in epidermal necrolysis, was recently developed and validated in the US. However, to our knowledge, it remains to be externally validated in other cohorts. Objective: To assess ABCD-10 among patients in a contemporary Asian cohort and compare its performance with the Score of Toxic Epidermal Necrosis (SCORTEN) and study the associations of time and immunomodulatory therapy with the performance of ABCD-10 and SCORTEN. Design, Setting, and Participants: This retrospective cohort study was conducted over a 17-year period from January 2003 to March 2019 and included 196 patients with epidermal necrolysis who were recruited from Singapore General Hospital, the national referral center for epidermal necrolysis. Main Outcomes and Measures: In-hospital mortality. Discrimination and calibration of each risk score were assessed and compared using the area under the receiver operating characteristic curve and calibration plot, respectively. Results: Among 196 patients (median [interquartile range] age, 56 [42-70] years; 116 women [59.2%]), 45 (23.0%) did not survive to discharge. All risk factors in ABCD-10 were significantly associated with in-hospital mortality. However, dialysis before admission, the most heavily weighted factor in ABCD-10, performed weaker in this cohort (odds ratio, 3.7; 95% CI, 1.0-13.2, P = .04). Although the discrimination of ABCD-10 and SCORTEN did not differ (area under the curve: ABCD-10, 0.78; 95% CI, 0.72-0.85; vs SCORTEN, 0.77; 95% CI, 0.69-0.84; P = .53), the calibration of ABCD-10 was poorer compared with SCORTEN. From graphical analysis of the calibration plots, ABCD-10 showed mortality underestimation at lower score ranges and overestimation at higher score ranges. By contrast, SCORTEN was generally well calibrated, although at higher score ranges mortality may be overestimated. Assessment of calibration plots showed that there was increasing overestimation of mortality by SCORTEN during the later period or when immunomodulatory therapy was used compared with patients treated with supportive care alone. Calibration of ABCD-10 remained poor even during the later period or among patients treated with immunomodulatory therapy. Conclusions and Relevance: In this cohort of patients, the performance of SCORTEN was superior to ABCD-10 in mortality prognostication in epidermal necrolysis. However, it did display time-associated deterioration in calibration leading to overestimation of mortality risk. Future studies may consider revising the existing SCORTEN given its current good discrimination.

Predictors of 30-day readmission in Stevens-Johnson syndrome and toxic epidermal necrolysis: A cross-sectional database study.

BACKGROUND: The predictors of readmission in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) have not been characterized. OBJECTIVE: To determine the variables predictive of 30-day readmission after SJS/TEN hospitalization. METHODS: We performed a cross-sectional study of the 2010-2014 Nationwide Readmissions Database. Bivariate and multivariable logistic regression was used to evaluate associations of patient demographics, comorbidities, and hospital characteristics with readmission. Aggregate and per-readmission costs were calculated. RESULTS: There were 8837 index admissions with SJS/TEN reported; of these, 910 (10.3%) were readmitted, with diagnoses including systemic infection (22.0%), SJS/TEN (20.6%), and cutaneous infection (9.1%). Associated characteristics included age 45 to 64 years (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.43-2.49), Medicaid insurance (OR, 1.83; 95% CI, 1.48-2.27), and nonmetropolitan hospital admission (OR, 1.67; 95% CI, 1.31-2.13). Associated comorbidities included HIV/AIDS (OR, 2.48; 95% CI, 1.63-3.75), collagen vascular disease (OR, 2.38; 95% CI, 1.88-3.00), and metastatic cancer (OR, 2.16; 95% CI, 1.35-3.46). The median per-readmission cost was $10,019 (interquartile range, $4,788-$16,485). LIMITATIONS: The Nationwide Readmissions Database lacks the ability to track the same patient across calendar years. The diagnostic code lacks specificity for hospitalizations <3 days. CONCLUSIONS: Thirty-day readmissions after SJS/TEN hospitalizations are common. Dedicated efforts to identify at-risk patients may improve peridischarge continuity.

Validation of a clinical assessment tool for cicatrising conjunctivitis.

PURPOSE: This study was designed to validate a semi-quantitative clinical assessment tool for cicatrising conjunctivitis (CC). METHODS: Fifty-five patients (109 eyes) with mucous membrane pemphigoid (MMP) and 31 patients (61 eyes) with Stevens-Johnson syndrome (SJS) were included. Three methods were used for validation: (1) comparison of inter- and intra-observer reproducibility for the components selected for the initial version of the tool, (2) quantitative measurement of the scarring component with a fornix depth measurer, compared with qualitative Tauber grading methodology, (3) the final version of the tool was compared with the published Sotozono SJS grading system. Main outcome measures included: inter- and intra-observer reproducibility, calculation of composite measures of scarring and morbidity, component redundancy, and correlation with other grading systems. RESULTS: Inter- and intra-observer agreement was moderate-to-excellent for graded components of conjunctival hyperaemia, upper and lower symblepharon, upper and lower fornix depth, corneal vascularisation, and corneal opacity. There was poor-to-good agreement for limitation of motility which was rejected from inclusion in the final tool. Composite scores for scarring components and morbidity components showed good-to-excellent agreement and distribution of ocular disease severity. Analysis of the composite components showed no redundancy - all components contributed independently. Comparison with both Tauber and Sotozono grading methodologies showed good concordance. CONCLUSIONS: This study has developed the first validated assessment tool applicable to causes of CC. The tool is concise and discriminates patients with varying disease severity. It measures both disease activity and severity and is suitable for clinical and research applications.

Manifestações e tratamento da necrólise epidérmica tóxica e da síndrome de Stevens Johnson / Manifestations and treatment of toxic epidermic necrolysis and Stevens Johnson's syndrome / Manifestaciones y tratamiento de la necrolisis epidérmica tóxica y del síndrome de Stevens Johnson

Objetivo: identificar as manifestações clínicas da necrólise epidérmica tóxica (NET) e síndrome de Stevens Johnson (SSJ). Método: trata-se de uma revisão narrativa. A busca dos artigos utilizou a ferramenta Publish or Perish, que ranqueia os trabalhos com base no número de citações recebidas. Foram realizadas duas buscas, pois apesar das doenças se relacionarem, possuem diagnósticos diferentes. Na primeira, os descritores utilizados foram: "necrólise epidérmica tóxica" e "manifestações clínicas", e na segunda os descritores foram: "Síndrome de Stevens-Johnson" e "manifestações clínicas". Resultados: após a leitura dos 12 artigos selecionados, entendeu-se que a patogênese da necrólise epidérmica tóxica e Síndrome de Stevens Johnson se dá pela hipersensibilidade tardia a fármacos. As manifestações clínicas se dão pelo aparecimento do eritema cutâneo com formação de máculas, pápulas, vesículas e bolhas associadas ou isoladas, como placas de urticária ou eritema extenso. Na NET é possível notar desprendimento extenso da epiderme maior que 30% da superfície corpórea, conhecido como sinal de Nikolsky, com acometimento de mucosas. Conclusão: A NET e SSJ são farmacodermias graves, com baixas incidências, mas elevada mortalidade. O reconhecimento precoce das doenças e a retirada do fármaco causador são essenciais para conduzir o tratamento, diminuindo por sua vez a taxa de mortalidade.(AU)

Objective: to identify the clinical manifestations of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS). Method: the articles search was done using the Publish or Perish computational tool, which ranks the articles based on the number of citations. Two separate searches were performed, because although the diseases are related, they have different diagnoses. In the first, the descriptors used were "Toxic Epidermal Necrolysis" and "clinical manifestations", and in the second the descriptors were "Stevens-Johnson Syndrome" and "clinical manifestations". Results: in total, 12 articles constituted the present revision. It was understood that the pathogenesis of TEN and SJS is due to late drugs hypersensitivity. The clinical manifestations are due to the appearance of cutaneous erythema with the formation of macules, papules, vesicles and associated or isolated blisters, such as urticaria plaques or extensive erythema. In the TEN it is possible to notice extensive detachment of the epidermis greater than 30% of the body surface, known as Nikolsky's signal, with mucous involvement. Conclusion: TEN and SJS are serious skin diseases, with low incidences but high mortality. Early recognition of disease and withdrawal of the causative drug are essential for conducting treatment, thus decreasing the mortality rate. Descriptors: Nursing; Dermatology; Signs and Symptoms; Treatment; Health Management.(AU)

Objectivo: identificar las manifestaciones clínicas de la necrólisis epidérmica tóxica (NET) y el síndrome de Stevens Johnson (SSJ). Método: la selección de los artículos consideró el número de citas recibidas por otras publicaciones. Se realizaron dos búsquedas, pues a pesar de las enfermedades se relacionan, poseen diferentes diagnósticos. En la primera, los descriptores utilizados fueron: "Toxic Epidermal Necrolysis" y "clinical manifestations", y en los segundos los descriptores fueron: "Stevens-Johnson Syndrome" y "clinical manifestations". Resultados: en total, 12 artículos constituyeron la presente revisión. Se ha comprobado que la patogénesis de TEN y SJS se debe a las drogas de larga duración. Las manifestaciones clínicas se deben a la apariencia de cutánea erythema con la formación de macules, papules, vesicles y asociados, o blister, tales como urticaria plaquetas o extensión erythema. En el TEN es posible que tenga un detalle detallado de las epidermis mayor que el 30% de la superficie del cuerpo, conocidas la Nikolsky de la señal, con mucous. Conclusión: la NET y SSJ son farmacodermias graves, con bajas incidencias pero elevada mortalidad. El reconocimiento precoz de las enfermedades y la retirada del fármaco causante son esenciales para conducir el tratamiento, disminuyendo a su vez la tasa de mortalidad. Descriptores: Enfermería; Dermatología; Signos y Síntomas; Tratamiento; Gestión en Salud.(AU)

Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement.

PURPOSE: Establishment of causality between drug exposure and adverse drug reactions (ADR) is challenging even for serious ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Several causality assessment tools (CAT) exist, but the reliability and validity of such tools is variable. The objective of this study was to compare the reliability and validity of existing ADR CATs on SJS/TEN cases. METHODS: Seven investigators completed three CAT (ALDEN, Naranjo, Liverpool) for 10 SJS/TEN cases. Each CAT categorized the causality of 30 potential drugs as definite/very probable, probable, possible, or doubtful/unlikely. An additional reviewer provided expert opinion by designating the implicated drug(s) for each case. A Kappa score was generated to compare CAT responses both by method (reliability of all 7 reviewers, by CATs) and by reviewer (reliability of the 3 CAT, by reviewer). A c statistic was calculated to assess validity. RESULTS: Inter-rater reliability by CAT was poor to fair: ALDEN 0.22, Naranjo 0.11, and Liverpool 0.12. Reliability was highest when causality classification was definite/very probable (0.16-0.41). Similarly, intra-rater reliability by reviewer was poor. When comparing the validity of the overall CAT to expert reviewer, area under the curve was highest for ALDEN (c statistic 0.65) as compared to Liverpool (0.55) or Naranjo (0.54). CONCLUSION: Available CAT have poor reliability and validity for drug-induced SJS/TEN. Due to the importance of determining ADR causality for research, industry, and regulatory purposes, development of an enhanced tool that can incorporate data from immunological testing and pharmacogenetic results may strengthen CAT usefulness and applicability for drug-induced SJS/TEN.

A novel multiplex polymerase chain reaction assay for detection of both HLA-A*31:01/HLA-B*15:02 alleles, which confer susceptibility to carbamazepine-induced severe cutaneous adverse reactions.

HLA-A*31:01 and HLA-B*15:02 have been widely reported to confer genetic susceptibility to carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCARs). Accordingly, the screening for these alleles has been highly recommended to prevent SCAR prior to introducing CBZ therapy. Although a number of methods are available for screening of HLA-A*31:01 or HLA-B*15:02 alleles separately, developing an assay that can detect both these alleles would be more clinically practical, cost-effective and less time-consuming. Therefore, in this study, a multiplex polymerase chain reaction (PCR) using TaqMan Probe was designed and validated to be able to detect HLA-A*31:01 and HLA-B*15:02. In comparison with Luminex-SSO/SBT/SSB, the multiplex PCR assay for detection of HLA-A*31:01 and HLA-B*15:02 had a perfect agreement in the validation group of 125 samples. The method was able to detect the target genes at the DNA concentration of 0.037 ng/µL. The unit cost of this assay is less than $5 USD with total time of 110 minutes.

Life-threatening Skin Disorders Treated in the Burn Center: Impact of Health care-associated Infections on Length of Stay, Survival, and Hospital Charges.

This article reviews a single burn center experience with life-threatening skin disorders, over a 10-year period. It explores the incidence of health care-associated infections and the impact on length of stay, hospital charges, and mortality.

Incidence of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Nationwide Population-Based Study Using National Health Insurance Database in Korea.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Overall, our data suggest that SJS, and TEN are infrequent but constantly arise throughout the years.

In vitro drug causality assessment in Stevens-Johnson syndrome - alternatives for lymphocyte transformation test.

BACKGROUND: Patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) are often exposed simultaneously to a few potentially culprit drugs. However, both the standard lymphocyte transformation tests (LTT) with proliferation as the assay end-point as well as skin tests, if done, are often negative. OBJECTIVE: As provocation tests are considered too dangerous, there is an urgent need to identify the relevant drug in SJS/TEN and to improve sensitivity of tests able to identify the causative drug. METHODS: Fifteen patients with SJS/TEN with the ALDEN score ≥ 6 and 18 drug-exposed controls were included. Peripheral blood mononuclear cells (PBMC) were isolated and cultured under defined conditions with drugs. LTT was compared to the following end-points: cytokine levels in cell culture supernatant, number of granzyme B secreting cells by ELISpot and intracellular staining for granulysin and IFNγ in CD3(+) CD4(+), CD3(+) CD8(+) and NKp46(+) cells. To further enhance sensitivity, the effect of IL-7/IL-15 pre-incubation of PBMC was evaluated. RESULTS: Lymphocyte transformation tests was positive in only 4/15 patients (sensitivity 27%, CI: 8-55%). Similarly, with granzyme B-ELISpot culprit drugs were positive in 5/15 patients (sensitivity 33%, CI: 12-62%). The expression of granulysin was significantly induced in NKp46(+) and CD3(+) CD4(+) cells (sensitivity 40%, CI: 16-68% and 53%, CI: 27-79% respectively). Cytokine production could be demonstrated in 38%, CI: 14-68% and 43%, CI: 18-71% of patients for IL-2 and IL-5, respectively, and in 55%, CI: 23-83% for IFNγ. Pre-incubation with IL-7/IL-15 enhanced drug-specific response only in a few patients. Specificities of tested assays were in the range of 95 (CI: 80-99%)-100% (CI: 90-100%). CONCLUSIONS AND CLINICAL RELEVANCE: Granulysin expression in CD3(+) CD4(+) , Granzyme B-ELISpot and IFNγ production considered together provided a sensitivity of 80% (CI: 52-96%) and specificity of 95% (80-99%). Thus, this study demonstrated that combining different assays may be a feasible approach to identify the causative drug of SJS/TEN reactions; however, confirmation on another group of patients is necessary.

A systematic review of validated methods for identifying erythema multiforme major/minor/not otherwise specified, Stevens-Johnson Syndrome, or toxic epidermal necrolysis using administrative and claims data.

PURPOSE: The Food and Drug Administration's (FDA) Mini-Sentinel pilot program aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest (HOIs) from administrative and claims data. This paper summarizes the process and findings of the algorithm review of erythema multiforme and related conditions. METHODS: PubMed and Iowa Drug Information Service searches were conducted to identify citations applicable to the erythema multiforme HOI. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles that used administrative and claims data to identify erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis and that included validation estimates of the coding algorithms. RESULTS: Our search revealed limited literature focusing on erythema multiforme and related conditions that provided administrative and claims data-based algorithms and validation estimates. Only four studies provided validated algorithms and all studies used the same International Classification of Diseases code, 695.1. Approximately half of cases subjected to expert review were consistent with erythema multiforme and related conditions. CONCLUSIONS: Updated research needs to be conducted on designing validation studies that test algorithms for erythema multiforme and related conditions and that take into account recent changes in the diagnostic coding of these diseases.