担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jid.2024.08.028

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jdermsci.2024.10.001

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue^1–3. 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 TEN^4–6. 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 proteomics^7,8. 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.

DOI： 10.1038/s41586-024-08061-0

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その他リンク： https://www.nature.com/articles/s41586-024-08061-0

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE OF REVIEW: Recent studies have been clarifying the pathogenesis and early diagnostic markers of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Additionally, the efficacy of tumor necrosis factor alpha inhibitors is attracting attention. This review provides) recent evidence for the diagnosis and management of SJS/TEN. RECENT FINDINGS: Risk factors for the development of SJS/TEN have been identified, particularly the association between HLA and the onset of SJS/TEN with specific drugs, which has been intensively studied. Research on the pathogenesis of keratinocyte cell death in SJS/TEN has also progressed, revealing the involvement of necroptosis, an inflammatory cell death, in addition to apoptosis. Diagnostic biomarkers associated with these studies have also been identified. SUMMARY: The pathogenesis of SJS/TEN remains unclear and effective therapeutic agents have not yet been established. As the involvement of innate immunity, such as monocytes and neutrophils, in addition to T cells, has become clear, a more complex pathogenesis is predicted. Further elucidation of the pathogenesis of SJS/TEN is expected to lead to the development of new diagnostic and therapeutic agents.

DOI： 10.1097/ACI.0000000000000914

PubMed

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記述言語：英語  

DOI： 10.1111/1346-8138.15800

PubMed

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2018&ichushi_jid=J01174&link_issn=&doc_id=20180502370003&doc_link_id=10.14924%2Fdermatol.128.581&url=https%3A%2F%2Fdoi.org%2F10.14924%2Fdermatol.128.581&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

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