Angelina S Hwang, Jacob A Kechter, Tran H Do, Alysia N Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M Brumfiel, Meera H Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L Yousif, Alyssa L Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J Michelle Kahlenberg, Allison C Billi, Olesya Plazyo, Lam C Tsoi, Mark R Pittelkow, Johann E Gudjonsson, Aaron R Mangold
{"title":"扁平苔藓对巴利替尼的快速反应与细胞毒性 CXCL13+ CD8+ T 细胞的抑制有关。","authors":"Angelina S Hwang, Jacob A Kechter, Tran H Do, Alysia N Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M Brumfiel, Meera H Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L Yousif, Alyssa L Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J Michelle Kahlenberg, Allison C Billi, Olesya Plazyo, Lam C Tsoi, Mark R Pittelkow, Johann E Gudjonsson, Aaron R Mangold","doi":"10.1172/JCI179436","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon gamma (IFN)-γ, a cytokine implicated in the pathogenesis of LP.</p><p><strong>Methods: </strong>In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and post-treatment samples.</p><p><strong>Results: </strong>An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis.</p><p><strong>Conclusion: </strong>This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP.</p><p><strong>Trial registration: </strong>NCT05188521.ROLE OF FUNDING SOURCE. Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3000,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13+ CD8+ T-cells.\",\"authors\":\"Angelina S Hwang, Jacob A Kechter, Tran H Do, Alysia N Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M Brumfiel, Meera H Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L Yousif, Alyssa L Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J Michelle Kahlenberg, Allison C Billi, Olesya Plazyo, Lam C Tsoi, Mark R Pittelkow, Johann E Gudjonsson, Aaron R Mangold\",\"doi\":\"10.1172/JCI179436\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon gamma (IFN)-γ, a cytokine implicated in the pathogenesis of LP.</p><p><strong>Methods: </strong>In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and post-treatment samples.</p><p><strong>Results: </strong>An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis.</p><p><strong>Conclusion: </strong>This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP.</p><p><strong>Trial registration: </strong>NCT05188521.ROLE OF FUNDING SOURCE. Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.</p>\",\"PeriodicalId\":15469,\"journal\":{\"name\":\"Journal of Clinical Investigation\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2024-11-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Investigation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1172/JCI179436\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Investigation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/JCI179436","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
背景：皮肤扁平苔藓（LP）是一种顽固的、难以治疗的炎症性皮肤病，其特征是皮肤上出现瘙痒的、平顶的、剧烈的丘疹。巴利昔尼是一种口服 Janus 激酶（JAK）1/2 抑制剂，可干扰γ干扰素（IFN）-γ 的信号通路，而γ干扰素是一种细胞因子，与 LP 的发病机制有关：在这项II期试验中，12名皮肤型红斑狼疮患者每天接受2毫克巴利替尼治疗，为期16周，同时对治疗前后的样本进行了深入的空间、单细胞和大体转录组学分析：患者出现了早期和持续的临床反应，83.3%的患者在第16周时出现反应。我们的分子数据确定了 LP 皮肤中独特的寡克隆 IFN-γ、CD8+、CXCL13+ 细胞毒性 T 细胞群，并证明在治疗 2 周内 IFN 特征迅速下降，在表皮基底层最为显著：这项研究证明了 JAK 抑制剂对 LP 的疗效和分子机制：NCT05188521.role of funding source.Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.
Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13+ CD8+ T-cells.
Background: Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon gamma (IFN)-γ, a cytokine implicated in the pathogenesis of LP.
Methods: In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and post-treatment samples.
Results: An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis.
Conclusion: This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP.
Trial registration: NCT05188521.ROLE OF FUNDING SOURCE. Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.
期刊介绍：
The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science.
The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others.
The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
