Stevens-Johnson Syndrome And Toxic Epidermal Necrolysis Research Articles

Effect of Early Cyclosporine Treatment on Survival in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Early cyclosporine administration is a potentially useful treatment in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). However, previous studies have reported conflicting results regarding the survival benefits. Therefore, in this study, we evaluated the survival of patients with SJS/TEN according to whether they received early cyclosporine administration. This retrospective cohort study was conducted using a Japanese national administrative claims database. Data on patients admitted to the hospital with SJS/TEN between April 1, 2016, and March 31, 2021, were extracted. Patients with missing data, those discharged within two days of admission, pregnant women, and children aged <16 years were excluded. Patients who received cyclosporine on the day of admission (early cyclosporine group) were compared with those who did not (comparison group). The primary endpoint was in-hospital mortality. Secondary endpoints were 30- and 50-day mortality and length of hospital stay. The effect of early cyclosporine treatment was evaluated after baseline adjustment using doubly robust estimation. Among 3807 enrolled patients (mean age, 65.5 years; 53.8% women), the early cyclosporine and comparison groups included 115 and 3692 patients, respectively. After adjustment, cyclosporine treatment decreased in-hospital mortality by 6.03% (95% confidence interval (CI), 5.27-6.82%), 30-day mortality by 2.94% (95% CI, 2.43-3.50%), and 50-day mortality by 4.38% (95% CI, 3.70-5.04%), but increased the length of hospital stay by 9.45 days (95% CI, 1.00-20.23 days). Early cyclosporine administration can improve the survival of patients with SJS/TEN but is associated with a longer hospital stay.

Clinical Characteristics and Treatment of Ophthalmic Sequelae of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis at a Tertiary Eyecare Centre in Hungary.

This study analysed the causative factors and clinical characteristics of acute and chronic ocular sequelae of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) treated at a large third-referral centre in a developed country (Hungary) over a 15-year period. This was a retrospective review of patients with acute and/or chronic SJS/TEN who were managed between 2006 and 2020 at the Department of Ophthalmology of Semmelweis University in Budapest, Hungary. For each subject, clinical data, including patient demographics, clinical history, causative agents of SJS/TEN, and conservative and surgical treatment details, were reviewed. Ninety-six eyes of 48 patients were included (28 female; 58.3%); the age at disease onset was 32.1 ± 22.4years. The most common causative factors were medicines (n = 36; 75.0%). Among these drugs, 29.2% were nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 14), 20.8% were antibiotics (n = 10) and 14.6% were antiepileptic drugs (n = 7). In patients with chronic SJS/TEN, the most commonly found ocular sequelae were conjunctival hyperaemia in 45 (56.3%) eyes, symblepharon in 38 (47.5%) eyes, trichiasis/distichiasis in 37 (46.3%) eyes, corneal neovascularization in 31 (38.8%) eyes and corneal scarring in 29 (36.3%) eyes. In patients with chronic SJS/TEN, the most frequently used topical conservative treatment included antibiotics in 53 (66.3%) eyes, preservative-free artificial tears in 50 (62.5%) eyes and topical corticosteroids in 42 (52.5%) eyes of 40 patients. The most frequently performed ocular surgeries for managing chronic ocular sequelae in patients with SJS/TEN were epilation for trichiasis (n = 27; 33.8%), cataract surgery (n = 14; 17.5%), entropion surgery (n = 12; 15.0%), penetrating keratoplasty (PK) (n = 11; 13.8%) and amniotic membrane transplantation (n = 4; 5.0%). Our results suggest that NSAIDs, antibiotics and antiepileptic drugs are the most common causative factors for SJS/TEN in Hungary. Like in other countries, in Hungary, the ocular management of patients with acute and chronic SJS/TEN is heterogeneous, and most cases do not follow modern therapeutic guidelines.

Effectiveness of early treatment with plasma exchange in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially fatal medical conditions that lack established treatment. Therapeutic plasma exchange (PE) is a potential treatment option; however, its effectiveness is unclear. We aimed to evaluate the effectiveness of PE in patients with SJS/TEN. A retrospective cohort study was conducted using data from the Japanese National Administrative Claims database from 2016 to 2021. The analysis included 256 patients diagnosed with SJS/TEN who were admitted to the intensive care unit, of whom 38 received PE and 218 did not. The outcomes of patients who did and did not receive PE within the first 24h of admission were compared. The risk ratios and 95% confidence intervals of the PE group compared with those of the no-PE group were as follows: in-hospital mortality, 0.983 (0.870-1.155); 30-day mortality rate, 1.057 (0.954-1.217); 50-day mortality rate, 1.023 (0.916-1.186); and length of hospital stay, 1.163 (0.762-1.365). This study does not provide evidence of a benefit of PE in reducing mortality or length of hospital stay in patients with severe SJS/TEN.

Clinical Profiles of Japanese Patients with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Collected by a Nationwide System from 2006 to 2023.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening severe cutaneous adverse drug reactions. These diseases are rare, and their onset is difficult to predict because of their idiosyncratic reactivity. The Japan Severe Adverse Reactions Research Group, led by the National Institute of Health Sciences, has operated a nationwide to collect clinical information and genomic samples from patients with SJS/TEN since 2006. This study evaluated the associations of clinical symptoms with sequelae and specific causative drugs/drug groups in Japanese patients with SJS/TEN to identify clinical clues for SJS/TEN treatment and prognosis. Acetaminophen, antibiotics, and carbocisteine were linked to high frequencies of severe ocular symptoms and ocular sequelae (p < 0.05). For erythema and erosion areas, antipyretic analgesics had higher rates of skin symptom affecting <10% of the skin than the other drugs, suggesting narrower lesions (p < 0.004). Hepatic dysfunction, was common in both SJS and TEN, and antiepileptic drugs carried higher risks of hepatic dysfunction than the other drug groups (p = 0.0032). This study revealed that the clinical manifestations of SJS/TEN vary according to the causative drugs.

Characterization of Drug-Specific CD4+ T-Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions

Carbamazepine (CBZ) is an aromatic anticonvulsant known to cause drug hypersensitivity reactions, which range in severity from relatively mild maculopapular exanthema to potentially fatal Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). These reactions are known to be associated with human leukocyte antigen (HLA) class I alleles, and CBZ interacts preferentially with the related HLA proteins to activate CD8+ T-cells. This study aimed to evaluate the contribution of HLA class II in the effector mechanism(s) of CBZ hypersensitivity. CBZ-specific T-cells clones were generated from two healthy donors and two hypersensitive patients with high-risk HLA class I markers. Phenotype, function, HLA allele restriction, response pathways, and cross-reactivity of CBZ-specific T-cells were assessed using flow cytometry, proliferation analysis, enzyme-linked immunosorbent spot, and enzyme-linked immunosorbent assay. The association between HLA class II allele restriction and CBZ hypersensitivity was reviewed using Allele Frequency Net Database. Forty-four polyclonal CD4+ CBZ-specific T-cell clones were generated and found to be restricted to HLA-DR, particularly HLA-DRB1*07:01. This CD4+-mediated response proceeded through a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the CD8+ response, CBZ-stimulated CD4+ clones secreted granulysin, a key mediator of SJS-TEN. Our database review revealed an association between HLA-DRB1*07:01 and CBZ-induced SJS-TEN. These findings implicate HLA class II antigen presentation as an additional pathogenic factor for CBZ hypersensitivity reactions. Both HLA class II molecules and drug-responsive CD4+ T-cells should be evaluated further to gain better insights into the pathogenesis of drug hypersensitivity reactions.

Worldwide Prevalence of Antibiotic-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Antibiotics are an important risk for Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), which are the most severe types of drug hypersensitivity reaction with a mortality rate up to 50%. To our knowledge, no global systematic review has described antibiotic-associated SJS/TEN. To evaluate the prevalence of antibiotics associated with SJS/TEN worldwide. The MEDLINE and Embase databases were searched for experimental and observational studies that described SJS/TEN risks since database inception to February 22, 2022. Included studies adequately described SJS/TEN origins and specified the antibiotics associated with SJS/TEN. Two reviewers (E.Y.L. and C.K.) independently selected the studies, extracted the data, and assessed the risk of bias. A meta-analysis using a random-effects model was performed in the studies that described patient-level associations. Subgroup analyses were performed to explore the heterogeneity. The risk of bias was assessed using the Joanna Briggs Institute checklist, and the certainty of evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Prevalence of antibiotic-associated SJS/TEN was presented as pooled proportions with 95% CIs. Among the 64 studies included in the systematic review, there were 38 studies that described patient-level associations; the meta-analysis included these 38 studies with 2917 patients to determine the prevalence of single antibiotics associated with SJS/TEN. The pooled proportion of antibiotics associated with SJS/TEN was 28% (95% CI, 24%-33%), with moderate certainty of evidence. Among antibiotic-associated SJS/TEN, the sulfonamide class was associated with 32% (95% CI, 22%-44%) of cases, followed by penicillins (22%; 95% CI, 17%-28%), cephalosporins (11%; 95% CI, 6%-17%), fluoroquinolones (4%; 95% CI, 1%-7%), and macrolides (2%; 95% CI, 1%-5%). There was a statistically significant heterogeneity in the meta-analysis, which could be partially explained in the subgroup analysis by continents. The overall risk of bias was low using the Joanna Briggs Institute checklist for case series. In this systematic review and meta-analysis of all case series, antibiotics were associated with more than one-quarter of SJS/TEN cases described worldwide, and sulfonamide antibiotics remained the most important association. These findings highlight the importance of antibiotic stewardship, clinician education and awareness, and weighing the risk-benefit assessment of antibiotic choice and duration.

Validation of a genotyping technique for a surrogate marker of HLA-B∗58:01 for allopurinol-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in the Japanese population

Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe cutaneous adverse drug reactions. Certain human leukocyte antigen (HLA) types have been associated with SJS/TEN onset, e.g., HLA-B∗58:01 with allopurinol-induced SJS/TEN, but HLA typing is time-consuming and expensive; thus, it is not commonly used in clinical situations. In the previous work, we demonstrated that the single-nucleotide polymorphisms (SNP) rs9263726 was in absolute linkage disequilibrium with HLA-B∗58:01 in the Japanese population, and can be used as a surrogate marker for the HLA. Here, we developed a new genotyping method for the surrogate SNP using the single-stranded tag hybridization chromatographic printed-array strip (STH-PAS) technique and performed an analytical validation. The results of genotyping rs9263726 using STH-PAS correlated well with those obtained using the TaqMan SNP Genotyping Assay for 15 HLA-B∗58:01-positive and 13 HLA-B∗58:01-negative patients (analytical sensitivity and specificity were both 100%). Additionally, at least 1.11 ng of genomic DNA was sufficient to digitally and manually detect positive signals on the strip. Robustness studies showed that the annealing temperature (66 °C) was the most important condition related to reliable results. Collectively, we developed an STH-PAS method that can rapidly and easily detect rs9263726 for predicting SJS/TEN onset.

Prevalence of antibiotic-induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN): a systematic review and meta-analysis

Antibiotics are an important cause of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN), but no global systematic review has described antibiotic-induced SJS/TEN. Herein, we evaluated the prevalence of antibiotics causing SJS/TEN worldwide.

TNF-α‒Mediated Keratinocyte Expression and Release of Matrix Metalloproteinase 9: Putative Mechanism of Pathogenesis in Stevens‒Johnson Syndrome/Toxic Epidermal Necrolysis

Stevens‒Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions characterized by widespread keratinocyte cell death and epidermal detachment. At present, there is little understanding of how the detachment occurs or how it is abrogated by the TNF-α inhibitor etanercept, an effective SJS/TEN treatment. RNA sequencing was used to identify upregulated transcripts in formalin-fixed paraffin-embedded SJS/TEN skin biopsies. Epidermal matrix metalloproteinase 9 (MMP9) expression was assessed by immunohistochemistry in skin biopsies and cultured human skin explants exposed to serum from patients with cutaneous adverse drug reactions. TNF-α‒induced MMP9 expression and activity and its abrogation by etanercept were determined using the HaCaT immortalized keratinocyte cell line. Epidermal MMP9 expression was significantly higher in SJS/TEN skin (70.6%) than in healthy control skin (0%) (P= 0.0098) and nonbullous skin reactions (10.7%) (P= 0.0002). SJS/TEN serum induced significant MMP9 expression and collagenase activity in healthy skin explants, which was reduced by etanercept. Etanercept was also able to negate the TNF-α‒induced MMP9 expression in the HaCaT cell line. Data suggest that elevated epidermal MMP9 expression and collagenase activity are a putative pathogenic mechanism in SJS/TEN, which is limited by etanercept. Modulation of MMP9 expression and activity represents, to our knowledge, a previously unreported therapeutic target for the treatment of SJS/TEN.

An alternative model for assessing mortality risk in Stevens Johnson syndrome/toxic epidermal necrolysis using a random forests classifier: A pilot study.

Mortality risk prediction is an important part of the clinical assessment in the Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) patient. The SCORTEN and ABCD-10 scoring systems have been used as predictive clinical tools for assessing this risk. However, some of the metrics required in calculating these scores, such as the total body surface area (TBSA) involvement, are difficult to calculate. In addition, TBSA involvement is calculated in a variety of ways and is observer dependent and subjective. The goal of this study was to develop an alternative method to predict mortality in patients with SJS/TEN. Data was split into training and test datasets and preprocessed. Models were trained using five-fold cross validation. Out of several possible candidates, a random forests model was evaluated as being the most robust in predictive power for this dataset. Upon feature selection, a final random forests model was developed which was used for comparison against SCORTEN. The differences in both accuracy (p = 0.324) and area under the receiver operating characteristic curve (AUROC) (p = 0.318) between the final random forests model and the SCORTEN and ABCD-10 models were not statistically significant. As such, this alternative method performs similarly to SCORTEN while only requiring simple laboratory tests from the day of admission. This new alternative can make the mortality prediction process more efficient, along with providing a seamless implementation of the patient laboratory tests directly into the model from existing electronic health record (EHR) systems. Once the model was developed, a web application was built to deploy the model which integrates with the Epic EHR system on the Fast Healthcare Interoperability Resources (FHIR) Application Programming Interface (API); this only requires the patient medical record number and a date of the lab tests as parameters. This model ultimately allows clinicians to calculate patient mortality risk with only a few clicks. Further studies are needed for validation of this tool.

Disease severity and status in Stevens-Johnson syndrome and toxic epidermal necrolysis: Key knowledge gaps and research needs.

Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are on a spectrum of cutaneous drug reactions characterized by pan-epidermal necrosis with SJS affecting < 10% of body surface area (BSA), TEN > 30%, and SJS/TEN overlap between 10 and 30%. Severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is a validated tool to predict mortality rates based on age, heart rate, BSA, malignancy and serum urea, bicarbonate, and glucose. Despite improved understanding, SJS/TEN mortality remains constant and therapeutic interventions are not universally accepted for a number of reasons, including rarity of SJS/TEN; inconsistent definition of cases, disease severity, and endpoints in studies; low efficacy of interventions; and variations in treatment protocols. Apart from mortality, none of the other endpoints used to evaluate interventions, including duration of hospitalization, is sufficiently standardized to be reproducible across cases and treatment centers. Some of the gaps in SJS/TEN research can be narrowed through international collaboration to harmonize research endpoints. A case is made for an urgent international collaborative effort to develop consensus on definitions of endpoints such as disease status, progression, cessation, and complete re-epithelialization in interventional studies. The deficiencies of using BSA as the sole determinant of SJS/TEN severity, excluding internal organ involvement and extension of skin necrosis beyond the epidermis, are discussed and the role these factors play on time to healing and mortality beyond the acute stage is highlighted. The potential role of artificial intelligence, biomarkers, and PET/CT scan with radiolabeled glucose as markers of disease status, activity, and therapeutic response is also discussed.

High Grade Dermatologic Adverse Events Associated With Immune Checkpoint Blockade for Cancer.

Immune checkpoint blockade (ICB) improves survival in many types of cancers including melanoma, non-small cell lung, renal cell, breast, and cervical cancers. However, many of these therapies are also associated with high grade dermatologic adverse events (DAEs), including Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), SJS/TEN-like reactions, high grade maculopapular and psoriasiform rashes, autoimmune bullous eruptions, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may limit their tolerability and use. It is important to properly identify and treat DAEs to ICB because these DAEs may be associated with positive anti-tumor response and patients may have limited options for alternative anti-cancer therapeutics. In this review, we describe high grade DAEs to increasingly used ICB agents, which target CTLA-4 and PD-1 or its ligand, PD-L1 and enable the immune system to target cancer cells. We further differentiate life-threatening adverse reactions from mimickers and report cases of serious DAEs which have been recorded in association with ICB through the FDA Adverse Events Reporting System (FAERS), which is an archive of adverse events associated with various drugs and therapeutic biologic products reported voluntarily by consumers and healthcare professionals as well as mandatorily by manufacturers. Lastly, we summarize management recommendations for these adverse events and discuss knowledge and evidence gaps in this area.

Characteristics associated with disease prevalence, SCORTEN, length of stay, and mortality in hospitalized SJS/TEN patients: A single-center, eleven-year experience

Stevens-Johnson syndrome (SJS), toxic-epidermal necrolysis (TEN), and SJS-TEN overlap syndrome form a continuum of rare, life-threatening disease that often warrants immediate and intensive treatment in a burn center. Our objective in this study was to determine factors associated with the prevalence, severity, and mortality in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) admitted to our center. We performed a retrospective analysis of 192 patients admitted to our burn center from 1 January 2009 to 31 December 2019 for SJS/TEN. Severity-of-illness Score for TEN (SCORTEN), length of stay, and inpatient mortality were analyzed. Of 192 patients, 104 (54%) were Black, 117 (61%) were female, and 39 (20%) had a pre-existing psychiatric illness. Overall, 43 (22%) patients died. Female patients had significantly longer lengths of stay, with a median length of stay of 21 days versus 11 days for males (P =.001). Among female patients, 31/117 (26%) died compared to 12/75 (16%) of male patients (P =.056). Females tended to have a higher SCORTEN, but the difference was not statistically significant (P =.061). Hypertension, chronic obstructive pulmonary disease, and diabetes mellitus were all associated with mortality (P <.001). Black and female patients each represented a seemingly disproportionate percentage of our patients and females had longer lengths of stay. Future studies looking at sex- and race-based differences are needed to better understand these potential disparities.

Side Effect of Lamotrigine in the Emergency Department; Stevens-Johnson Syndrome

Aim: Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) is a life-threatening mucocutaneous skin reaction that usually develops against drugs, although there are various factors in its etiology. In this case report, SJS due to antiepileptic drug use will be briefly reviewed. Case:20-year-old female patient was seen in the emergency department with a generalized tonic-clonic seizure. With the detailed anamnesis and laboratory findings obtained, the patient was started lamothyrigine therapy. While the dose was titrated in the treatment, treatment was stopped in the patient who developed SJS, and a new antiepileptic drug was started. Conclusion: SJS/TEN is the same disease spectrum with different severity. They are classified according to the percentage of skin detachment area. The pathogenesis of SJS/TEN is still unclear and optimal treatment options are still controversial.

Single-cell multi-omic approaches define common molecular and cellular signals of dominant antigen-driven cells at the site of drug-induced Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) tissue damage

Human leukocyte antigen (HLA)-restricted CD8+ T-cells expressing dominant T-cell receptor (TCR) clonotypes are recently implicated drivers of keratinocyte cell death, cutaneous blistering, and mortality in drug-induced Stevens Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN). Signatures of these effector population(s) remain undefined in affected tissue but hold utility for early diagnosis and targeted therapy.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in the FDA Adverse Event Reporting System (FAERS) from 1995-2020

There is a lack of knowledge of patterns of long-standing versus emergent drug causes of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and their epidemiology and mortality over time.

Performance of ABCD-10 and SCORTEN mortality prediction models in a cohort of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis

Age, bicarbonate, cancer, dialysis, 10% body surface area risk model (ABCD-10) has recently been proposed as an alternative to the SCORe of toxic epidermal necrolysis (SCORTEN) model for predicting in-hospital mortality in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). In contrast to SCORTEN, ABCD-10 incorporates prior dialysis and upweights the impact of cancer. To determine the performance of ABCD-10 compared with that of SCORTEN in mortality prediction at a large, tertiary burn center. A retrospective analysis of 192 patients with SJS/TEN admitted to the North Carolina Jaycee Burn Center from January 1, 2009, to December 31, 2019, was conducted.Data on these patients were collected using the burn registry and a manual chart review. The performance of both the mortality prediction models was assessed using univariate logistic regression and the Hosmer-Lemeshow test. The overall mortality was 22% (n=43). Nine (5%) patients had cancer, and 7 (4%) had undergone prior dialysis; neither factor was associated with mortality (P=.11 and P=.62, respectively). SCORTEN was well calibrated to predict inpatient mortality (P=.82), whereas ABCD-10 appeared to have a poorer fit (P<.001) in these patients. Both the models showed good discrimination. Small sample size. SCORTEN was a better predictor of inpatient mortality than ABCD-10 in a North American cohort of patients treated at the tertiary burn center.

Cost-effectiveness analysis of genotyping for HLA-B*15:02 in Indonesian patients with epilepsy using a generic model.

Carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are strongly associated with the HLA-B*15:02 allele. Screening HLA-B*15:02 before CBZ administration might prevent CBZ-induced SJS/TEN by enabling clinicians to prescribe alternative therapy for positive patients. Similar to other Southeastern Asian countries, HLA-B*15:02 is highly prevalent in Indonesia. Therefore, we assessed the economic value of HLA-B*15:02 screening before CBZ prescription to patients with epilepsy in Indonesia. A generic cost-effectiveness model and decision support tool, developed to enable users to perform an initial cost-effectiveness analysis from a healthcare provider/payer perspective, were used to assess the value of HLA-B*15:02 genotyping. The incremental cost-effectiveness ratio of adopting universal HLA-B*15:02 screening was 656,444,671 Indonesian Rupiah (IDR)/quality-adjusted life year (QALY) gained for patients compared with 2,634,975,574 IDR/QALY gained for providing valproic acid (alternative drug) without screening. Thus, neither HLA-B*15:02 screening nor substitution with VPA meets the Indonesian threshold for cost effectiveness. However, the improved outcomes with this test in other Asian countries may inform the desirability of implementation in Indonesia even with suboptimal cost-effectiveness.

Validation of two predictive models designed to aid clinicians in identifying Stevens-Johnson syndrome/toxic epidermal necrolysis: A single institution retrospective review

To the Editor: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe cutaneous drug reactions resulting in epidermal necrolysis of the skin as well as the mucosal membranes. Early recognition can facilitate appropriate triage; however, clinically diagnosing SJS/TEN may be challenging due to variability in disease presentation.1Lerch M. Mainetti C. Terziroli Beretta-Piccoli B. Harr T. Current perspectives on Stevens-Johnson syndrome and toxic epidermal necrolysis.Clin Rev Allergy Immunol. 2018; 54: 147-176Crossref PubMed Scopus (131) Google Scholar In 2019, 2 predictive models were first proposed to aid in distinguishing SJS/TEN from its clinical mimickers.2Weinkle A. Pettit C. Jani A. et al.Distinguishing Stevens-Johnson syndrome/toxic epidermal necrolysis from clinical mimickers during inpatient dermatologic consultation—a retrospective chart review.J Am Acad Dermatol. 2019; 81: 749-757Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar We sought to externally validate these models among patients transferred due to the concerns of SJS/TEN. A retrospective chart review of patients transferred to Parkland Memorial Hospital for suspected SJS/TEN from October 1, 2012 to December 31, 2018 was performed. Two groups of patients were identified from an internal dermatology consultation list: those with a confirmed diagnosis of SJS/TEN and those with other conditions. Biopsies were performed for patients with an unclear diagnosis at presentation. If the biopsy results were non-specific, the final diagnosis was based on both clinical and histopathologic data. Initial dermatology consult notes were reviewed for the presence or absence of 5 characteristics (Nikolsky sign, atypical target, fever, lymphopenia, and mucosal involvement), and the numerical predictive probability was calculated using the 2 previously published predictive models (Supplemental material available via Mendeley at https://doi.org/10.17632/22h4ghj8wk.1).2Weinkle A. Pettit C. Jani A. et al.Distinguishing Stevens-Johnson syndrome/toxic epidermal necrolysis from clinical mimickers during inpatient dermatologic consultation—a retrospective chart review.J Am Acad Dermatol. 2019; 81: 749-757Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Receiver operating characteristic curves and area under the curve (AUC) were used to assess the models’ discriminatory capability, with a maximum AUC of 1 meaning that the diagnostic test was perfect in differentiating between the 2 groups.3Hajian-Tilaki K. Receiver operating characteristic (ROC) curve analysis for medical diagnostic test evaluation.Caspian J Intern Med. 2013; 4: 627-635PubMed Google Scholar Statistical analysis was also applied to evaluate additional clinical characteristics in our cohort that could aid in diagnosing SJS/TEN. A total of 193 patients were transferred for the evaluation of possible SJS/TEN. Of these, 68 patients had an ultimate diagnosis of SJS/TEN, and 125 patients had an alternative diagnosis. Using the predictive models, we were able to detect an AUC of 0.9251 (95% confidence interval, 0.8875-0.9628; P < .0001) when lymphopenia was included in the model and an AUC of 0.9451 (95% confidence interval, 0.9144-0.9757; P < .0001) when mucosal involvement was included in the model (Fig 1). Additional clinical characteristics that were compared between the groups are listed in Table I.Table IDemographic and clinical characteristics of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis compared to non–Stevens-Johnson syndrome and toxic epidermal necrolysis diagnosesDemographic and clinical characteristicsSJS/TEN (N = 68)Non-SJS/TEN (N = 125)P value∗Continuous data were analyzed using an unpaired 2-tailed Student t test, and categorical data were analyzed using Fisher exact test in GraphPad Prism version 9.0.0. P values are reported for tests of statistical significance. All comparisons were 2-tailed and the α error was set at 5%.Demographic characteristics (N, %) Gender.4496Male28 (41.2%)60 (48.0%)Female40 (58.8%)65 (52.0%) Age in years, mean (SD)48.47 (21.74)53.28 (21.33).1389Clinical characteristics (N, %) Biopsy performed45 (66.2%)58 (46.4%).0103†Statistically significant result, with P value of < .05. Specialty requesting the consultEmergency department24 (35.3%)77 (61.6%).0005†Statistically significant result, with P value of < .05.Burn surgery39 (57.4%)31 (24.8%)<.0001†Statistically significant result, with P value of < .05.Internal medicine5 (7.4%)17 (13.6%).2400 Mucosal involvement66 (97.1%)60 (48.0%)<.0001†Statistically significant result, with P value of < .05.Ocular mucosa39 (57.4%)9 (7.2%)<.0001†Statistically significant result, with P value of < .05.Oral mucosa61 (89.7%)49 (39.2%)<.0001†Statistically significant result, with P value of < .05.Genital mucosa54 (79.4%)35 (28.0%)<.0001†Statistically significant result, with P value of < .05. Nikolsky sign (+)‡Nikolsky (+) sign was recorded at initial dermatology consultation by either explicit documentation of Nikolsky status, or by evidence of sloughing, desquamation, erosions, or full-thickness necrosis at areas adjacent to lesions and at seemingly unaffected skin.65 (95.6%)51 (40.8%)<.0001†Statistically significant result, with P value of < .05. Atypical target§Atypical target defined as a 2-zone targetoid lesion with poorly defined borders or a dusky macule with a dusky center.254 (79.4%)21 (16.8%)<.0001†Statistically significant result, with P value of < .05. Lymphopenia10 (14.7%)10 (8.0%).2151WBC count,‖Normal range: 3.90-10.70 × 109 cells/L. mean (SD)7.40 (3.47)11.55 (8.53).0002†Statistically significant result, with P value of < .05. Skin pain48 (70.6%)33 (26.4%)<.0001†Statistically significant result, with P value of < .05. Skin itch33 (48.5%)73 (58.4%).2261 Vesicles/bullae55 (80.9%)78 (62.4%).0091†Statistically significant result, with P value of < .05. Fever >100.4 °F¶Fever was documented positive if the patient had an outside value >100.4 °F before transfer or if their first value on arrival at the ED was >100.4 °F.35 (51.5%)18 (14.4%)<.0001†Statistically significant result, with P value of < .05. Body surface area >10%24 (35.3%)18 (14.4%).0016†Statistically significant result, with P value of < .05. Transfer distance in miles, mean (SD)56.74 (78.21)76.62 (236)<.0001†Statistically significant result, with P value of < .05. Length of stay in hospital in days, mean (SD)#Length of stay in hospital in days was counted from the date of admission at Parkland Memorial Hospital and did not include the time spent at outside facilities.15.40 (12.87)10.32 (29.9).1839 Most common alternative diagnosesFixed drug eruption−18 (14.4%)AGEP−10 (8.0%)GBFDE−10 (8.0%)Morbilliform−9 (7.2%)Bullous pemphigoid−9 (7.2%)Erythema multiforme−7 (5.6%)DRESS−7 (5.6%)AGEP, Acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; GBFDE, generalized bullous fixed drug eruption; N, number; SD, standard deviation; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; WBC, white blood cell.∗ Continuous data were analyzed using an unpaired 2-tailed Student t test, and categorical data were analyzed using Fisher exact test in GraphPad Prism version 9.0.0. P values are reported for tests of statistical significance. All comparisons were 2-tailed and the α error was set at 5%.† Statistically significant result, with P value of < .05.‡ Nikolsky (+) sign was recorded at initial dermatology consultation by either explicit documentation of Nikolsky status, or by evidence of sloughing, desquamation, erosions, or full-thickness necrosis at areas adjacent to lesions and at seemingly unaffected skin.§ Atypical target defined as a 2-zone targetoid lesion with poorly defined borders or a dusky macule with a dusky center.2Weinkle A. Pettit C. Jani A. et al.Distinguishing Stevens-Johnson syndrome/toxic epidermal necrolysis from clinical mimickers during inpatient dermatologic consultation—a retrospective chart review.J Am Acad Dermatol. 2019; 81: 749-757Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar‖ Normal range: 3.90-10.70 × 109 cells/L.¶ Fever was documented positive if the patient had an outside value >100.4 °F before transfer or if their first value on arrival at the ED was >100.4 °F.# Length of stay in hospital in days was counted from the date of admission at Parkland Memorial Hospital and did not include the time spent at outside facilities. Open table in a new tab AGEP, Acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; GBFDE, generalized bullous fixed drug eruption; N, number; SD, standard deviation; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; WBC, white blood cell. At this time, there are no standardized guidelines for determining the likelihood of a true diagnosis of SJS/TEN. A survey of burn units demonstrated that 74% of patients are admitted based only upon clinical suspicion for SJS/TEN, with 61% having their own protocol in place at the time of admission.4Richard E.B. Hamer D. Musso M.W. Short T. O'Neal Jr., H.R. Variability in management of patients With SJS/TEN: a survey of burn unit directors.J Burn Care Res. 2018; 39: 585-592Crossref PubMed Scopus (11) Google Scholar The misdiagnosis of more benign conditions, such as urticaria, contact dermatitis, or morbilliform eruptions, leads to unnecessary transfers and exorbitant costs.5Georgesen C. Karim S.A. Liu R. Moorhead A. Falo L.D. English J.C. Response: “Distinguishing Stevens-Johnson syndrome/toxic epidermal necrolysis from clinical mimickers during inpatient dermatologic consultation—a retrospective chart review”.J Am Acad Dermatol. 2020; 82: e111-e112Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Our data corroborate with previously reported differences and support the need for a predictive model to aid in distinguishing SJS/TEN.2Weinkle A. Pettit C. Jani A. et al.Distinguishing Stevens-Johnson syndrome/toxic epidermal necrolysis from clinical mimickers during inpatient dermatologic consultation—a retrospective chart review.J Am Acad Dermatol. 2019; 81: 749-757Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar We demonstrated that the predictive model that includes mucosal involvement rather than lymphopenia has improved the discrimination for SJS/TEN. Although our study externally validates both models, there are limitations to their use in clinical practice. For example, the models were developed based on physical examination features identified by experienced dermatologists. Non-dermatologists are less skilled in identifying morphologic features such as atypical targets, which are essential for this predictive model. Future studies to evaluate the performance of these models when applied prospectively by non-dermatologists are needed. None disclosed.

Associations Between Stevens-Johnson Syndrome and Infection: Overview of Pharmacoepidemiological Studies.

Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are classified as type B adverse drug reactions, and are severe, potentially fatal rare disorders. However, the pathogenesis of SJS/TEN is not fully understood. The onset of SJS/TEN is triggered by the immune system in response to antigens with or by drugs. As activation of the immune system is important, infection could be a risk factor for the onset of SJS/TEN. Based on the hypothesis that infections induce the onset of SJS/TEN, we conducted pharmacoepidemiological investigations using two spontaneous adverse drug reaction reporting databases (Japanese Adverse Drug Event Report database and Food and Drug Administration Adverse Event Reporting System) and Japanese medical information database. These data suggest that infection could be a risk factor for the development of SJS/TEN. In this mini-review, we discuss the association between infection and the development of SJS/TEN.