Background Inflammatory cytokines, such as interleukin (IL)-1β, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1β can reverse these effects is unclear. Objective To determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia. Design Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846). Setting Many clinical sites in 39 countries. Participants 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry. Intervention Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women). Results Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1β inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher. Limitation CANTOS was not designed to assess the cause of anemia in individual trial participants. Conclusion These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1β/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia. Primary Funding Source Novartis Pharmaceuticals.

中文翻译：

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白细胞介素-1β抑制作用对事件性贫血的影响：一项随机试验的探索性分析。

背景炎性细胞因子，例如白介素（IL）-1β，会改变铁稳态和促红细胞生成，导致贫血，但目前尚不清楚抑制IL-1β是否能逆转这些作用。目的确定卡那曲单抗对IL-1β的抑制作用是否能减少普遍贫血患者的贫血事件并改善血红蛋白水平。随机对照试验的设计探索性分析。（ClinicalTrials.gov：NCT01327846）。在39个国家/地区设置许多临床站点。参加者8683 CANTOS（Canakinumab抗炎血栓形成结果研究）参加者在试验入场时无贫血，而1303受试者在试验入场时患有普遍性贫血。干预随机分配，每3个月一次皮下接受安慰剂或canakinumab（50、150或300 mg）。测量主要结果是突发性贫血（男性血红蛋白水平<130 g / L，女性<120 g / L）。结果与安慰剂组相比，接受canakinumab的参与者的贫血发生率随着高敏C反应蛋白（hsCRP）基线水平的升高而增加，并且hsCRP和IL-6均降低。在3.7年的中位随访期间，无基线贫血症的受试者接受任何剂量的canakinumab治疗后的贫血发生率均显着低于接受安慰剂的受试者（危险比，为0.84 [95％CI，0.77至0.93]； P <0.001）。与安慰剂相比，在抗炎反应最强的受试者中观察到IL-1β抑制对贫血的最大益处，这一作用在正式的调解分析中得到了证实。在基线贫血的人群中，与安慰剂相比，canakinumab治疗2年后平均血红蛋白水平增加了11.3 g / L（P <0.001）。卡那基单抗增加了感染的风险，并与轻度血小板减少症和中性粒细胞减少症相关，均未达到3级或更高。局限性CANTOS并非旨在评估个别试验参与者的贫血原因。结论这些对随机试验数据的探索性分析提供了原理上的证明，即至少通过IL-1β/ IL-6信号传导途径抑制炎症，可减少贫血患者的贫血发生率并改善血红蛋白水平。主要资金来源诺华制药。卡那基单抗增加了感染的风险，并与轻度血小板减少症和中性粒细胞减少症相关，均未达到3级或更高。局限性CANTOS并非旨在评估个别试验参与者的贫血原因。结论这些对随机试验数据的探索性分析提供了原理上的证明，即至少通过IL-1β/ IL-6信号传导途径抑制炎症，可减少贫血患者的贫血发生率并改善血红蛋白水平。主要资金来源诺华制药。卡那基单抗增加了感染的风险，并与轻度血小板减少症和中性粒细胞减少症相关，均未达到3级或更高。局限性CANTOS并非旨在评估个别试验参与者的贫血原因。结论这些对随机试验数据的探索性分析提供了原理上的证明，即至少通过IL-1β/ IL-6信号传导途径抑制炎症，可减少贫血患者的贫血发生率并改善血红蛋白水平。主要资金来源诺华制药。至少通过IL-1β/ IL-6信号通路，可减少贫血患者的贫血发生率并改善血红蛋白水平。主要资金来源诺华制药。至少通过IL-1β/ IL-6信号通路，可减少贫血患者的贫血发生率并改善血红蛋白水平。主要资金来源诺华制药。