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
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
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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.

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。
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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.
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