Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial.
Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial.
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DOI：
10.1182/bloodadvances.2023011578
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发表时间：
2023-12-26
期刊：
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
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作者：
与仅CH突变或无CH突变相比，CH突变和贫血丰富了与炎症相关的蛋白质组学特征。Canakinumab治疗与并发贫血和CH突变患者的血红蛋白反应改善相关。Canakinumab是一种靶向促炎细胞因子白介素-1β (IL-1β)的单克隆抗体，在Canakinumab抗炎血栓结局研究（CANTOS）中，可改善血红蛋白水平，同时预防复发性心血管事件。在与克隆造血（CH）相关的TET2突变患者中，这种心血管（CV）预防效果更大。目前的蛋白质基因组学分析旨在了解canakinumab在CH和贫血背景下的临床反应和潜在的蛋白质组学特征。该分析包括来自CANTOS研究的4595名患者，他们接受了canakinumab或安慰剂，并使用SomaScan和靶向CH突变深度测序评估了多重蛋白质组学（4785个蛋白质）。偶发性贫血在CH突变的情况下更为常见，但通过canakinumab治疗可以减少。与无贫血或无CH突变的CH突变患者相比，Canakinumab治疗与并发CH突变和贫血患者较高的血红蛋白增量显著相关。与没有CH突变的患者相比，CH突变的存在与炎症和感染防御反应的蛋白质组学特征以及高危CV疾病的标志物相关，而贫血的存在进一步增强了这一特征。在CH突变和贫血患者中，Canakinumab抑制hepcidin、促炎细胞因子、髓样活化和补体途径，并在更大程度上逆转病理性失调的途径。这些分子研究结果为IL-1β阻断的临床应用提供了证据，并支持进一步研究canakinumab用于并发贫血和CH突变患者。本研究在www.clinicaltrials.gov注册，编号为#NCT01327846。
CH mutations and anemia enrich proteomic signatures associated with inflammation compared with only CH mutations or no CH mutations. Canakinumab treatment is associated with improved hemoglobin response in patients with concurrent anemia and CH mutations. Canakinumab, a monoclonal antibody targeting proinflammatory cytokine interleukin-1β (IL-1β), improved hemoglobin levels while preventing recurrent cardiovascular events in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). This cardiovascular (CV) preventive effect was greater in patients with TET2 mutations associated with clonal hematopoiesis (CH). The current proteogenomic analysis aimed to understand the clinical response to canakinumab and underlying proteomic profiles in the context of CH and anemia. The analysis included 4595 patients from the CANTOS study who received either canakinumab or placebo and evaluated multiplexed proteomics (4785 proteins) using SomaScan and targeted deep sequencing for CH mutations. Incident anemia was more common in the presence of CH mutations but reduced by canakinumab treatment. Canakinumab treatment was significantly associated with higher hemoglobin increment in patients with concurrent CH mutations and anemia than patients with CH mutations without anemia or without CH mutations. Compared with those without CH mutations, the presence of CH mutations was associated with proteomic signatures of inflammation and defense response to infection, as well as markers of high-risk CV disease which was further enhanced by the presence of anemia. Canakinumab suppressed hepcidin, proinflammatory cytokines, myeloid activation, and complement pathways, and reversed pathologically deregulated pathways to a greater extent in patients with CH mutations and anemia. These molecular findings provide evidence of the clinical use of IL-1β blockade and support further study of canakinumab for patients with concurrent anemia and CH mutations. This study was registered at www.clinicaltrials.gov as #NCT01327846.
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DOI：
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发表时间：
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期刊：
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影响因子：
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