Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies.

IF 7.2 2区 医学 Q1 IMMUNOLOGY Journal of Clinical Immunology Pub Date : 2024-10-23 DOI:10.1007/s10875-024-01826-2
Genia Kretzschmar, Laura Piñero Páez, Ziyang Tan, Jun Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Yang Chen, Jaromír Mikeš, Tadepally Lakshmikanth, Anna James, Raphaela Goldbach-Mansky, Marie Fischer, Karin Palmblad, Sara Alehashemi, AnnaCarin Horne, Petter Brodin
{"title":"Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies.","authors":"Genia Kretzschmar, Laura Piñero Páez, Ziyang Tan, Jun Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Yang Chen, Jaromír Mikeš, Tadepally Lakshmikanth, Anna James, Raphaela Goldbach-Mansky, Marie Fischer, Karin Palmblad, Sara Alehashemi, AnnaCarin Horne, Petter Brodin","doi":"10.1007/s10875-024-01826-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>A causal role of type-I interferons (IFN-I) in autoinflammatory type-I interferonopathies such as SAVI (STING-associated vasculopathy with onset in infancy) and CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) is suggested by elevated expression of IFN-I stimulated genes (ISGs). Hitherto, the lack of specific inhibitors of IFN-I signaling has prevented the verification of a causal role for IFN-I in these conditions. Commonly used inhibitors of the JAK/STAT pathway exert broad effects on multiple signaling pathways leading to more general immunosuppression beyond IFN-I signaling.</p><p><strong>Methods: </strong>Here we show in four patients with SAVI and one patient with CANDLE syndrome that blockade of the IFNAR1 receptor (Anifrolumab) exerts an additive effect over JAK-inhibitor alone. In two patients with SAVI, monotherapy with Anifrolumab is sufficient to retain a suppressed IFN-I signature and clinical improvement.</p><p><strong>Results: </strong>Anifrolumab normalizes IFN-I signature genes and relieves symptoms beyond what is typically achieved by a JAK-inhibitor (Baricitinib) alone in patients with type-I interferonopathies. In two patients Anifrolumab was used successfully as monotherapy. Addition of Anifrolumab enabled steroid tapering and cessation with reduced overall immunosuppression and lower risks of opportunistic infections and improved metabolic states and growth which is highly beneficial in these young patients.</p><p><strong>Conclusion: </strong>These results verify a causal role of IFN-I signaling in type-I Interferonopathies SAVI and CANDLE and suggests Anifrolumab as an important new treatment option in autoinflammatory diseases with elevated IFN-I induced gene expression. Genia Kretzschmar, Laura Piñero Páez, and Ziyang Tan are shared-first authors. Sara Alehashemi, AnnaCarin Horne, and Petter Brodin are co-senior author.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":7.2000,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499543/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10875-024-01826-2","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Purpose: A causal role of type-I interferons (IFN-I) in autoinflammatory type-I interferonopathies such as SAVI (STING-associated vasculopathy with onset in infancy) and CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) is suggested by elevated expression of IFN-I stimulated genes (ISGs). Hitherto, the lack of specific inhibitors of IFN-I signaling has prevented the verification of a causal role for IFN-I in these conditions. Commonly used inhibitors of the JAK/STAT pathway exert broad effects on multiple signaling pathways leading to more general immunosuppression beyond IFN-I signaling.

Methods: Here we show in four patients with SAVI and one patient with CANDLE syndrome that blockade of the IFNAR1 receptor (Anifrolumab) exerts an additive effect over JAK-inhibitor alone. In two patients with SAVI, monotherapy with Anifrolumab is sufficient to retain a suppressed IFN-I signature and clinical improvement.

Results: Anifrolumab normalizes IFN-I signature genes and relieves symptoms beyond what is typically achieved by a JAK-inhibitor (Baricitinib) alone in patients with type-I interferonopathies. In two patients Anifrolumab was used successfully as monotherapy. Addition of Anifrolumab enabled steroid tapering and cessation with reduced overall immunosuppression and lower risks of opportunistic infections and improved metabolic states and growth which is highly beneficial in these young patients.

Conclusion: These results verify a causal role of IFN-I signaling in type-I Interferonopathies SAVI and CANDLE and suggests Anifrolumab as an important new treatment option in autoinflammatory diseases with elevated IFN-I induced gene expression. Genia Kretzschmar, Laura Piñero Páez, and Ziyang Tan are shared-first authors. Sara Alehashemi, AnnaCarin Horne, and Petter Brodin are co-senior author.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
I 型干扰素病患者的干扰素特征趋于正常,IFNAR1 阻断抗体(阿尼单抗)的临床效果得到改善。
目的:IFN-I 刺激基因(ISGs)表达的升高表明,I 型干扰素(IFN-I)在 SAVI(婴儿期发病的 STING 相关性血管病变)和 CANDLE(慢性非典型嗜中性粒细胞皮肤病伴脂肪营养不良和体温升高)等自身炎症性 I 型干扰素病中起着因果作用。迄今为止,由于缺乏 IFN-I 信号传导的特异性抑制剂,无法证实 IFN-I 在这些病症中的因果作用。常用的 JAK/STAT 通路抑制剂会对多种信号通路产生广泛影响,从而导致 IFN-I 信号转导之外的更普遍的免疫抑制。在两名SAVI患者中,阿尼单抗的单药治疗足以保持受抑制的IFN-I特征和临床改善:结果:在I型干扰素病患者中,阿尼单抗能使IFN-I特征基因正常化,缓解症状的效果超过了单用JAK抑制剂(巴利昔尼)的效果。在两名患者中,阿尼单抗作为单一疗法取得了成功。加入阿尼单抗后,类固醇的减量和停用可减少总体免疫抑制,降低机会性感染的风险,改善代谢状态和生长,这对这些年轻患者非常有益:这些结果验证了IFN-I信号传导在I型干扰素病SAVI和CANDLE中的因果作用,并提示阿尼洛单抗是治疗IFN-I诱导基因表达升高的自身炎症性疾病的重要新选择。Genia Kretzschmar、Laura Piñero Páez和谭子阳为共同第一作者。Sara Alehashemi、AnnaCarin Horne和Petter Brodin为共同第一作者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
12.20
自引率
9.90%
发文量
218
审稿时长
2 months
期刊介绍: The Journal of Clinical Immunology publishes impactful papers in the realm of human immunology, delving into the diagnosis, pathogenesis, prognosis, or treatment of human diseases. The journal places particular emphasis on primary immunodeficiencies and related diseases, encompassing inborn errors of immunity in a broad sense, their underlying genotypes, and diverse phenotypes. These phenotypes include infection, malignancy, allergy, auto-inflammation, and autoimmunity. We welcome a broad spectrum of studies in this domain, spanning genetic discovery, clinical description, immunologic assessment, diagnostic approaches, prognosis evaluation, and treatment interventions. Case reports are considered if they are genuinely original and accompanied by a concise review of the relevant medical literature, illustrating how the novel case study advances the field. The instructions to authors provide detailed guidance on the four categories of papers accepted by the journal.
期刊最新文献
A large cohort from an immunology reference center and an algorithm for the follow-up of chronic neutropenia. Endophilin A2 Deficiency Impairs Antibody Production in Humans. Polysaccharide, Conjugate, and mRNA-based Vaccines are Immunogenic in Patients with Netherton Syndrome. Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party. Cancer Trends in Inborn Errors of Immunity: A Systematic Review and Meta-Analysis.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1