Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus
Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus
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DOI：
10.1002/art.41518
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发表时间：
2021-02-15
影响因子：
13.3
通讯作者：
White, Wendy, I
中科院分区：
文献类型：
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作者：
Casey, Kerry A.;Smith, Michael A.;White, Wendy, I
目的系统性红斑狼疮（SLE）患者的早发性心血管疾病是导致其死亡的主要原因之一，而I型干扰素（IFN）轴和神经功能失调是其发病的重要因素。在本研究中，我们评估了anifrolumab（一种I型IFN受体阻断抗体）与安慰剂相比减少中性粒细胞胞外陷阱（NET）形成和调节心脏代谢疾病标志物的能力。（一项评价MEDI-546在系统性红斑狼疮受试者中的疗效和安全性的II期随机研究），健康个体作为对照。在开始治疗（基线）之前从SLE患者（n = 305）和健康对照（n = 10-20）收集血液样品，并且在SLE患者已经用300 mg阿尼福鲁单抗（n = 99）或安慰剂（n = 102）治疗之后从SLE患者收集血液样品。确定基线IFN基因签名测试状态，并随时间监测IFN基因签名（21个基因组）。血清蛋白测定采用多重免疫分析法或超灵敏Simoa法。NET复合物，胆固醇流出能力（CEC），糖蛋白乙酰化（GlycA）和其他脂质参数进行了评估plasma.Results NET复合物的形成和肿瘤坏死因子（TNF）和白细胞介素-10（IL-10）的水平与I型IFN途径活性的程度相关。与健康对照组相比，SLE患者的NET复合物和IL-10水平显著升高（P < 0.008）。SLE患者的心血管代谢疾病标志物CEC和GlycA也出现异常（与健康对照组相比P < 0.001）。与基线相比，用阿尼福单抗抑制I型IFN受体显著降低了NET复合物和GlycA，并改善了CEC（P < 0.05），而用安慰剂未观察到改善。结论I型干扰素在调节SLE血管病变的因素中起重要作用，抑制I型干扰素通路可降低SLE患者心血管疾病的危险性。
Objective Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo.Methods Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma.Results Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05).Conclusion These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.