Pathogenesis Of Stevens-Johnson Syndrome Research Articles

Sensory neuroimmune signaling in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN).

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions often triggered by medications. While the involvement of CD8+ T cells causing keratinocyte death is well recognized, the contribution of neural elements to the persistent skin inflammation has been largely overlooked. To investigate the potential neuroimmune regulation in SJS/TEN. Unbiased single-cell RNA sequencing and flow cytometry were performed using circulating CD8+ T cells from healthy controls and patients with SJS/TEN. ELISA and LEGENDplex assays were respectively used to detect neuropeptides and inflammatory mediators. Skin tissues were examined by immunofluorescence staining for neuropeptide-associated nerves and cytokine receptors. Calcium imaging, Smart-seq, and a 3D skin model were employed for cultured human CD8+ T cells. The unbiased RNA-sequencing revealed an upregulation of the receptor for neuropeptide calcitonin gene-related peptide (CGRP), known as RAMP1, in effector CD8+ T cells in SJS/TEN. Increased CGRP+ nerve fibers and CGRP levels, along with upregulated IL-15R and IL-18R on CD8+ T cells, were displayed in the affected skin of SJS/TEN. The CGRP-RAMP1 axis was necessary and sufficient to enhance receptors for IL-15 and IL-18 and cytotoxic activities in CD8+ T cells, ultimately resulting in keratinocyte apoptosis. Calcium influx was detected in CGRP-stimulated CD8+ T cells. HCN2, a hyperpolarization-activated cation channel, was required for this process and the subsequent cytotoxic effects. Our study highlights the role of neural elements in regulating CD8+ T cell-mediated inflammatory responses and provides new potential translational targets to improve the outcomes of severe cutaneous drug reactions.

A bioinformatic approach to identify pathogenic variants for Stevens-Johnson syndrome.

Stevens-Johnson syndrome (SJS) produces a severe hypersensitivity reaction caused by Herpes simplex virus or mycoplasma infection, vaccination, systemic disease, or other agents. Several studies have investigated the genetic susceptibility involved in SJS. To provide further genetic insights into the pathogenesis of SJS, this study prioritized high-impact, SJS-associated pathogenic variants through integrating bioinformatic and population genetic data. First, we identified SJS-associated single nucleotide polymorphisms from the genome-wide association studies catalog, followed by genome annotation with HaploReg and variant validation with Ensembl. Subsequently, expression quantitative trait locus (eQTL) from GTEx identified human genetic variants with differential gene expression across human tissues. Our results indicate that two variants, namely rs2074494 and rs5010528, which are encoded by the HLA-C (human leukocyte antigen C) gene, were found to be differentially expressed in skin. The allele frequencies for rs2074494 and rs5010528 also appear to significantly differ across continents. We highlight the utility of these population-specific HLA-C genetic variants for genetic association studies, and aid in early prognosis and disease treatment of SJS.

Systemic lupus erythematosus patient on steroid therapy that develop to a Stevens-Johnson syndrome: a case report

Stevens-Johnson syndrome (SJS) is a cutaneous immunity reaction involving the skin and mucosa and is an emergency condition that can be fatal. The incidence of this disease is relatively rare in the range of 1-2 per 1.000.000 population. The pathogenesis of SJS involves the immune system response of antigenic drug to body tissues but it still cannot be fully explained to date. We reported a woman, 35 years old with systemic lupus erythematosus (SLE) who had been on steroid therapy and in the course of treatment developed into SJS after administration of anti-epileptic drug. Steroids have anti-inflammatory effects mainly due to decreased syntheses or suppression of inflammatory mediators. SJS still can develop in patient with SLE who had been on steroid therapy. Giving steroid that indicated for the treatment of a disease including SLE, cannot prevent the occurrence of an allergic event including SJS. The presence of steroid can extend the duration of starting the drug with the occurrence of SJS and reduce the severity of the disease. Steroid still have a role in treatment that can be used both in SJS and SLE.

A multicentric, prospective and retrospective analysis of Stevens–Johnson syndrome, toxic epidermal necrolysis and Stevens–Johnson syndrome/toxic epidermal necrolysis overlap: An Indian perspective

Background: Stevens Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent adverse drug reactions characterized by generalized rash, blisters, epidermal detachment, mucosal and systemic involvement presenting as dermatological emergencies. Drugs are the most common culprits implicated in the pathogenesis of SJS /TEN. The primary step in the management of SJS/TEN is identification and stopping the offending drug. Materials and methods: This was a multi-centric retrospective as well as prospective observational study conducted in 7 tertiary care hospitals including Father Muller Medical College Hospital , Mangalore, India. A detailed evaluation of the hospital in patient record for 10 years retrospective from September 2015 and all new cases of SJS/TEN as well as SJS-TEN overlap presenting to these centres for 1 year prospective was performed. Detailed history was taken and clinical examination was recorded and different modalities of treatment was noted and compared. Results: A total of 152 patients with clinical diagnosis of SJS ,TEN and SJS-TEN overlap were analysed. Males were more commonly affected than females and history of drug intake was present in 118 patients (77.6%). The most common drugs which caused SJS/ TEN in our study were antibiotics in 40 patients (26.3%) followed by anti epileptics in 35 patients (23%) and nevirapine in 10 patients (6.5%). In our study the most common finding on cutaneous examination was maculopapular rash (19.3%). Conclusion: SJS and TEN form part of a spectrum of severe cutaneous drug reactions that can lead to high morbidity which can be reduced by early withdrawal of the offending drug and timely intervention. Individuals with known drug allergies need to be educated and drug allergy card has to be carried.

Striking enhancement at the site of radiation for nivolumab-induced Stevens-Johnson syndrome

Stevens-Johnson syndrome is a rare adverse cutaneous drug reaction characterized by epidermal detachment of <10% body surface area with an average mortality rate of 1-5%. The mechanism of SJS is not fully understood. Nivolumab is a monoclonal antibody directed against programmed cell death-1 protein (PD-1), a receptor with immune checkpoint inhibitory and antineoplastic activities. We present a case of SJS in a patient being treated with anti-PD-1 therapy nivolumab for metastatic squamous cell carcinoma of the oropharynx. This case is unusual because of the severe accentuation with striking enhancement at his prior radiation site and in the cutaneous region with heavier tumor burden from his metastatic disease. This reaction may give insight to the underlying pathophysiology of SJS, suggesting that immune checkpoint inhibitors can activate T-cells to target keratinocytes and that external factors may be involved in creating distinct epitopes for T-cell recognition. We hope this case adds to the body of knowledge in the pathogenesis of Stevens-Johnson syndrome and cutaneous adverse events seen with checkpoint inhibitors.

Ofloxacin-induced toxic epidermal necrolysis.

Sir, Toxic epidermal necrolysis (TEN) is a potentially life-threatening dermatologic disorder characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes, resulting in exfoliation and possible sepsis and/or death. It is also known as Lyell's syndrome. The drugs most commonly involved are antibiotics such as sulfonamides, beta-lactams tetracyclines, and quinolones. Anticonvulsants are such as phenytoin, phenobarbital and carbamazepine. Antiretroviral drugs, nonsteroidal anti-inflammatory drugs, and allopurinol.[1] Mycoplasma pneumoniae, herpes simplex, lupus erythematosus, aplastic anemia after allogeneic hematopoietic stem cell transplantation have also been reported as a cause of nondrug induced TEN.[2] A 42-year-old man presented with rapidly progressive generalized detachment of skin. Patient gave a history of abdominal pain and diarrhea for which he took tablets containing ofloxacin. After 2 days, he developed acute generalized erythematous rashes all over his body including face, trunk, upper, and lower extremities [Figure 1]. He also developed erosive lesions over oral mucosa and congestion of conjuntiva [Figure 2]. Figure 1 Sheet like peeling of skin Figure 2 Crusting and erosive lesions over lip On examination, patient was febrile (39°C) and hypotensive (100/70 mm Hg). Generalized sheet like peeling of the skin involving >90% of body was present. Erosion and crusting over lip was present. Nikolsky sign was positive. There was no hepatosplenomegaly or lymphadenopathy. His total white blood cell count was 5.23 × 109/L. Platelet count was normal. Hemoglobin was 13.5 g/dl. Liver function tests showed mild elevation in aspartate aminotransferase (90 U/L) and alanine aminotransferase (70 U/L). Serum creatinine was 1.1 mg/dl. History and clinical findings were suggestive of TEN secondary to ofloxacin intake. Patient was treated with dexamethasone intravenously and fusidic acid antibiotic cream topically. Fluid management, symptomatic and supportive management had been done. Patient showed significant improvement within 2 week. Lesions totally resolved in a few weeks leaving postinflammatory pigmentation over body. The pathogenesis of Stevens-Johnson syndrome (SJS)/TEN is not fully understood, but is believed to be immune-mediated. The clinical, histopathological, and immunological findings in SJS/TEN support the concept, that SJS and TEN are specific drug hypersensitivity reactions in which cytotoxic T lymphocytes play a role in the initiation phase.[3] The histopathology of SJS/TEN lesions show that keratinocyte apoptosis followed by necrosis is the pathogenic basis of the widespread epidermal detachment observed in SJS/TEN.[2] The risk of death for patients with TEN can be accurately predicted by the TEN-specific severity-of-illness score. We calculated that our patient had a final score of 2 and a mortality risk of 12.1%. The frequency of fluoroquinolone use has been increasing owing to their broad antibacterial spectra and few adverse effects. Until now, these drugs have seldom been implicated in patients with TEN, but the incidence of fluoroquinolone-induced cutaneous reactions may be on the increase.[4] Until date, a total of 31 cases of SJS or TEN in which a fluoroquinolone was the offending agent have been reported. Of these, 26 were associated with ciprofloxacin, whereas only one was associated with ofloxacin.[5] Here, we are reporting a patient with TEN induced by ingestion of oral ofloxacin which is not a common cause of TEN.

Possible role of TH17 cells in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening forms of the same mucocutaneous diseases.1 The pathogenesis of SJS/TEN is still unclear; however, drugs are the most important etiologic agents. SJS/TEN is believed to involve an immune-mediated cytotoxic reaction against keratinocytes, leading to massive apoptosis. Accumulating evidence has shown that the extensive keratinocyte apoptosis might be mediated by granulysin, perforin/granzyme B, and Fas ligand, which can be released by cytotoxic CD8+ T lymphocytes, natural killer T cells, and macrophages.

Intravenous immunoglobulin in the treatment of childhood Stevens Johnson syndrome

A 12-year-old boy of Polynesian background, who had been previously well, presented with swollen blistering lesions involving his lips and oral mucosa which then progressed to involve his limbs and genitalia over 3 days. He was unable to eat and drink and had difficulty passing urine because of pain. A diagnosis of Stevens Johnson syndrome (SJS) was made. The question of whether intravenous immunoglobulin (IVIG) would be effective in treating this condition was raised. SJS is a severe mucocutaneous reaction characterised by destruction of epithelial cells resulting in widespread blisters with involvement of at least two mucosal membranes. It has a clinical course of up to 6 weeks with a high morbidity and mortality of 5–10%. The current management of SJS is primarily supportive. It involves careful wound care, close monitoring of fluid and electrolyte balance, ophthalmological review and eye care, infection control, pain control and nutritional support. Any inciting drug is discontinued, and causative organism is treated – the most common being Mycoplasma pneumoniae. The use of IVIG for SJS has been controversial. IVIG has been used with reported beneficial effects in various case reports in treating SJS. In 1998, Viard et al. reported that IVIG inhibited Fas-mediated keratinocyte apoptosis in vitro – a key mechanism in the pathogenesis of SJS. This added in vitro evidence to clinical experience.

High-Level Human Herpesvirus-6 Viremia Associated With Onset of Stevens-Johnson Syndrome: Report of Two Cases

The pathogenesis of Stevens-Johnson syndrome (SJS) remains obscure, but it has been associated with various infectious agents, including members of the herpesvirus family. We present the first report of high-level human herpesvirus-6 viremia at the onset of SJS, suggesting a possible new association. This finding supports the need for further investigation into the possible relationship between human herpesvirus-6 and SJS, which may illuminate the pathogenesis of SJS and bring us closer to achieving enhanced prevention and treatment of this rare disease.

Progress on the pathogenesis of Stevens-Johnson syndrome

在由药物所引起的皮肤疾病中,Stevens-Johnson综合征(Stevens-Johnson syndrome,SJS)是一种最严重威胁生命的由免疫介导的药物不良反应.SJS的发病率以及引起SJS的常见药物在不同的国家和人群中是不同的.如何通过基因检测来准确地检出SJS的高危人群对于有效地预防此疾病的发生极为重要;同时,也有助于探索其发病机制.该文主要总结关于SJS易患基因的研究,特别是关于人白细胞抗原-B的等位基因1502与SJS的相关性,以及此相关性在不同种族和人群的差异。

An update on Stevens–Johnson syndrome and toxic epidermal necrolysis in children

This study summarizes current research and understanding of the pathogenesis of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and provides an update on the treatment of these conditions in children. The association of specific human leukocyte antigen subtypes with SJS and TEN occurring in certain racial groups to specific drugs has led to recommendations on pretreatment testing. Several pathways have been postulated to lead to keratinocyte apoptosis in SJS and TEN. These include Fas-Fas ligand interaction, cytotoxic T-cell and natural killer-cell damage via perforin/granzyme B/granulysin and tumor necrosis factor-alpha. The use of intravenous immunoglobulins and systemic corticosteroids in TEN is still controversial, and more trials are needed to prove the efficacy of these agents. Newer agents such as cyclosporin, infliximab and plasmapheresis have shown promise in the treatment of SJS and TEN. As the pathogenesis of SJS and TEN is further unraveled, the emergence of newer therapeutic agents with more specific mechanisms of action may lead to improved survival in this oftentimes devastating disease.

Immunohistochemical Expression of Apoptotic Markers in Drug-Induced Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered to be severity variants of the same disease, which is almost always associated with drug intake. In contrast, erythema multiforme (EM) is a disorder regarded as only rarely caused by drugs. Keratinocyte apoptosis has been shown to play an important part in the pathogenesis of SJS and TEN, whilst its role in EM remains controversial. To determine the expression of apoptosis-associated molecules Fas, Fas ligand (FasL), Bcl-2 and Bax in the above disorders, an immunohistochemical analysis was performed. We studied both lesional skin from thirty patients having drug-induced EM and 5 cases classified within the SJS/TEN spec nottrum and normal skin samples. We found a keratinocyte overexpression of Fas antigen, an important molecule mediating apoptosis, not only in SJS and TEN but also in EM. Another noteworthy finding was the strong expression of Bcl-2, a protein known as blocking apoptosis, along the basal layer and in the dermal infiltrate both in SJS/TEN and in EM. Taken together, these findings suggest that Fas-dependent keratinocyte apoptosis may play a part in the pathogenesis of both SJS/TEN and EM. Fas-mediated cell death may be partially suppressed by the Bcl-2 protein.