Genome-wide association study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Europe

<p>Abstract</p> <p>Background</p> <p>Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare but extremely severe cutaneous adverse drug reactions in which drug-specific associations with HLA-B alleles were described.</p> <p>Objectives</p> <p>To investigate genetic association at a genome-wide level on a large sample of SJS/TEN patients.</p> <p>Methods</p> <p>We performed a genome wide association study on a sample of 424 European cases and 1,881 controls selected from a Reference Control Panel.</p> <p>Results</p> <p>Six SNPs located in the HLA region showed significant evidence for association (OR range: 1.53-1.74). The haplotype formed by their risk allele was more associated with the disease than any of the single SNPs and was even much stronger in patients exposed to allopurinol (OR_allopurinol= 7.77, 95%CI = [4.66; 12.98]). The associated haplotype is in linkage disequilibrium with the HLA-B*5801 allele known to be associated with allopurinol induced SJS/TEN in Asian populations.</p> <p>Conclusion</p> <p>The involvement of genetic variants located in the HLA region in SJS/TEN is confirmed in European samples, but no other locus reaches genome-wide statistical significance in this sample that is also the largest one collected so far. If some loci outside HLA play a role in SJS/TEN, their effect is thus likely to be very small.</p

Allergologische Diagnostik von Überempfindlichkeitsreaktionen auf Arzneimittel

Überempfindlichkeitsreaktionen auf Arzneimittel müssen ausreichend geklärt werden mit dem Ziel, den Auslöser zu identifizieren. Die Anamnese umfasst neben der allgemeinen Anamnese auch Informationen zu angewandten Arzneimitteln, zur Klassifikation und zu den Umständen der Reaktion. Hauttests erfolgen bei allen Reaktionen mit Symptomen allergischer Überempfindlichkeiten mit geeigneten Testkonzentrationen, möglichst zwischen 4 Wochen und 6 Monate nach Abheilung der Reaktion durch Pricktest, Intrakutantest, Epikutantest oder Photopatchtest. Validierte Tests zum Nachweis spezifischer IgE-Antikörper im Serum sind nur für wenige Arzneistoffe (vor allem Betalaktamantibiotika) verfügbar; andere immunologische Labormethoden, z.B. der Basophilen-Aktivierungstest, werden nur in ausgewählten Fällen angewendet. Provokationstests sind indiziert, wenn der Auslöser durch bisherige Untersuchungen nicht mit Sicherheit identifiziert werden kann. Die Bewertung der Ergebnisse von Provokationstests sollte möglichst anhand objektiver Parameter erfolgen. Das Ergebnis der abschließenden Gesamtbeurteilung wird mit dem Patienten ausführlich besprochen und in einem Allergiepass niedergeleg

Allergologische Diagnostik von Überempfindlichkeitsreaktionen auf Arzneimittel

Drug hypersensitivity reactions have to be tested to identify the culprit substance. The history includes the general information and specific data concerning used drugs, the classification and circumstances of the reaction. Skin tests are performed in all hypersensitivity reactions with allergic symptoms. Tests should be done between four weeks and six months after clearance of the symptoms by performing skin prick test, intradermal test, patch test or photopatch test. Validated tests for the detection of specific IgE antibodies in the serum are available for only few drugs, especially betalactam antibiotics. Other laboratory tests, e.g., the basophil activation test are done only in special cases. Provocation tests are indicated, if the culprit drug cannot be identified by the above mentioned tests. If possible, the evaluation of provocation tests should rely on objective parameters. The concluding assessment will be discussed with the patient and will be documented in an allergy pass

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs

AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production

Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-kappa B activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36 alpha, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.Peer reviewe

Updates in SJS/TEN: collaboration, innovation, and community

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15–20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1–5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28–29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper