Anticytokine Agents Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis
Anticytokine Agents Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis
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DOI：
10.1161/circresaha.118.313129
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发表时间：
2019-02-01
影响因子：
20.1
通讯作者：
Ridker, Paul M.
中科院分区：
文献类型：
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作者：
Ridker, Paul M.
认识到动脉粥样硬化是一种复杂的慢性炎症性疾病介导的适应性和先天性免疫导致的假设，抗细胞因子治疗靶向特定的IL（白细胞介素）信号转导通路可以作为强大的手段，以降低血脂在预防和治疗心血管疾病。参与人类动脉粥样硬化的细胞因子可大致分为促炎性和促动脉粥样硬化性（如IL-1、IL-6和TNF [肿瘤坏死因子]）或抗炎性和抗动脉粥样硬化性（如IL-10和IL-1 rA）。最近的CANTOS（Canakinumab抗炎血栓结局研究）表明，特异性靶向IL-1 β可以显著降低心血管事件发生率，而无需降低血脂或血压。在CANTOS中，这种以精氨酸为靶点的动脉粥样硬化治疗方法的获益程度与中枢信号细胞因子IL-6和下游临床生物标志物高敏CRP（C反应蛋白）的降低程度相关。相比之下，在最近的CIRT（心血管炎症减少试验）中，低剂量甲氨蝶呤既没有降低IL-1 β，IL-6或高敏CRP，也没有降低心血管事件发生率。总之，这两项当代试验提供了原则证据，即集中的细胞因子抑制，而不是广谱抗炎治疗，可能是动脉粥样硬化保护的关键。本文综述了动脉粥样硬化中的细胞因子，靶向抗细胞因子治疗的潜在益处和风险，并展望了未来解决残余炎症风险的临床实践。
The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anticytokine therapies targeting specific IL (interleukin) signaling pathways could serve as powerful adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. Cytokines involved in human atherosclerosis can be broadly classified as proinflammatory and proatherogenic (such as IL-1, IL-6, and TNF [tumor necrosis factor]) or as anti-inflammatory and antiatherogenic (such as IL-10 and IL-1rA). The recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) has shown that specific targeting of IL-1 beta can significantly reduce cardiovascular event rates without lipid or blood pressure lowering. In CANTOS, the magnitude of benefit of this cytokine-targeted approach to atherosclerosis treatment was associated to the magnitude of reduction of the central signaling cytokine IL-6 and the downstream clinical biomarker high-sensitivity CRP (C-reactive protein). By contrast, in the recent CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1 beta, IL-6, or high-sensitivity CRP nor lowered cardiovascular event rates. Taken together, these 2 contemporary trials provide proof of principle that focused cytokine inhibition, not broad-spectrum anti-inflammatory therapy, is likely to be crucial for atheroprotection. This review provides an overview of cytokines in atherosclerosis, the potential benefits and risks associated with targeted anticytokine therapies, and a look to the future of clinical practices addressing residual inflammatory risk.