Erythema Multiforme

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare diseases that are characterized by widespread epidermal necrosis and sloughing of skin. They are associated with significant morbidity and mortality, and early diagnosis and treatment is critical in achieving favorable outcomes for patients. In this scoping review, Excerpta Medica dataBASE and PubMed were searched for publications that addressed recent advances in the diagnosis and management of the disease. Multiple proteins (galectin 7 and RIP3) were identified that are promising potential biomarkers for SJS/TEN, although both are still in early phases of research. Regarding treatment, cyclosporine is the most effective therapy for the treatment of SJS, and a combination of intravenous immunoglobulin (IVIg) and corticosteroids is most effective for SJS/TEN overlap and TEN. Due to the rare nature of the disease, there is a lack of prospective, randomized controlled trials and conducting these in the future would provide valuable insights into the management of this disease.

Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue1-3. Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN4-6. Here, to systematically map molecular changes that are associated with TEN and identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics7,8. We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells. This revealed a marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN, as well as phosphorylated STAT1 activation. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Crucially, treatment with JAK inhibitors (JAKi) was safe and associated with rapid cutaneous re-epithelialization and recovery in seven patients with TEN. This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane. SJS/TEN are considered to be on the same spectrum of diseases with different severities. They are classified by the percentage of skin detachment area. SJS/TEN can also cause several complications in the liver, kidneys, and respiratory tract. The pathogenesis of SJS/TEN is still unclear. Although it is difficult to diagnose early stage SJS/TEN, biomarkers for diagnosis or severity prediction have not been well established. Furthermore, optimal therapeutic options for SJS/TEN are still controversial. Several drugs, such as carbamazepine and allopurinol, are reported to have a strong relationship with a specific human leukocyte antigen (HLA) type. This relationship differs between different ethnicities. Recently, the usefulness of HLA screening before administering specific drugs to decrease the incidence of SJS/TEN has been investigated. Skin detachment in SJS/TEN skin lesions is caused by extensive epidermal cell death, which has been considered to be apoptosis via the Fas-FasL pathway or perforin/granzyme pathway. We reported that necroptosis, i.e. programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, and its interaction with the formyl peptide receptor 1 induce necroptosis. Several diagnostic or prognostic biomarkers for SJS/TEN have been reported, such as CCL-27, IL-15, galectin-7, and RIP3. Supportive care is recommended for the treatment of SJS/TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α antagonists are still controversial. Recently, the beneficial effects of cyclosporine and TNF-α antagonists have been explored. In this review, we discuss recent advances in the pathophysiology and management of SJS/TEN.

ImportanceCarriage of HLA-B*58:01 has been shown to be associated with allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in many populations globally; however, there is a critical need to investigate whether this is generalizable to populations of mixed ancestry, such as those in the US.ObjectiveTo assess the association of human leukocyte antigen (HLA) class I and II in a cohort of US patients who received a diagnosis of allopurinol-induced SJS/TEN or DRESS compared with allopurinol-tolerant and population control participants.Design, setting, and participantsThis genetic association study included consenting individuals who had specialist-adjudicated allopurinol-induced SJS/TEN or DRESS (collectively allopurinol-induced severe cutaneous adverse reactions [SCARs]) between January 1, 2015, and December 31, 2024. HLA carriage in these individuals was compared with allopurinol-tolerant and population control participants identified through the Vanderbilt University Medical Center biobank, which includes 94 489 individuals with imputed HLA class I and II typing from genotyping array data. Data were analyzed from January 2025 to August 2025.Main outcomes and measuresThe main outcome measure was the association of HLA class I and II alleles with allopurinol-induced SCARs. HLA class I and II conditional logistic regression case-control analyses were performed between patients with allopurinol-induced SCARs and both population control and allopurinol-tolerant control participants matched on age, sex, and self-identified race. Odds ratios (ORs) and 95% CIs were reported, with Bonferroni-corrected P ResultsThis genetic association study used conditional logistic regression analyses and included 16 patients with allopurinol-induced SCAR (mean [SD] age, 61.1 [12.6] years; 9 female patients [56.25%] and 7 male patients [43.75%]) and 160 allopurinol-tolerant control participants matched 10:1. Two HLA class I alleles were found to be independently associated with increased risk of allopurinol-induced SCAR: HLA-B*58:01 (OR, 28.0 [95% CI, 8.6-100.6]) and HLA-A*34:02 (OR, 20.6 [95% CI, 3.3-131.1]). No HLA class II alleles meeting the Bonferroni-corrected P Conclusions and relevanceThese findings suggest that although HLA-B*58:01 was found to be associated with allopurinol-induced SCARs, generalizing findings from previous studies, the allele was absent in more than one-third of the patient cohort and is therefore an incomplete indicator of risk. Importantly, in the US allopurinol-induced SCAR cohort, HLA-A*34:02 was found to be a second independent genetic risk factor for allopurinol-induced SCARs. These findings underscore the need to conduct population-based studies that both reproduce known and uncover novel HLA associations to reduce harm through contributions to screening, risk stratification, and diagnosis.