Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis
Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis
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DOI：
10.1093/eurheartj/ehz542
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发表时间：
2020-06-14
影响因子：
39.3
通讯作者：
Libby, Peter
中科院分区：
文献类型：
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作者：
Ridker, Paul M.;MacFadyen, Jean G.;Libby, Peter
Canakinumab抗炎性血栓形成结局研究（CANTOS）证实，在对胆固醇无任何有益作用的情况下，靶向炎症的白细胞介素-1 β（IL-1 β）抑制剂可显著降低心血管（CV）事件发生率。然而，接受高强度他汀类药物和卡那单抗治疗的CANTOS参与者仍然存在相当大的复发CV事件风险。白细胞介素-18（IL-18，与IL-1 β一样，需要NLRP 3炎性体激活）和白细胞介素-6（IL-6，IL-1下游的促炎细胞因子）可能导致即使在canakinumab治疗时也会发生的复发事件，方法来自4848例稳定的心肌梗死后患者的血浆样品，这些患者被分配到活性IL-10组，1 β抑制和结果CANTOS中的安慰剂在开始canakinumab之前和之后使用经验证的ELISA测量IL-18和IL-6。所有参与者的复发性主要不良心血管事件（MACE）和全因死亡率的中位随访时间为3.7年（最长5年）。与安慰剂相比，canakinumab以剂量依赖性方式显著降低IL-6水平，在50、150和300 mg剂量下，3个月时IL-6减去安慰剂的中位降低百分比分别为24.8%、36.3%和43.2%（所有P值
Aims The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflamma- tion with interleukin-1 beta (IL-1 beta) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1 beta requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis.Methods Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1 beta inhibition and results or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values