Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study
Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study
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DOI：
10.3171/2016.9.jns16615
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发表时间：
2018-02-01
影响因子：
4.1
通讯作者：
Tyrrell, Pippa
中科院分区：
文献类型：
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作者：
Galea, James;Ogungbenro, Kayode;Tyrrell, Pippa
目的动脉瘤性蛛网膜下腔出血（aSAH）是一种具有长期发病率和死亡率的严重脑血管事件。在最初出血后存活的患者可能会遭受由过多病理过程引起的进一步早期脑损伤。这些可能导致约25%的患者结局恶化或死亡，并可能导致幸存者的长期认知功能障碍。由细胞因子白细胞介素-1（IL-1）介导的炎症是多种形式脑损伤（包括aSAH）后脑缺血的重要促成因素。其作用可被其天然存在的拮抗剂IL-1受体拮抗剂（IL-1 Ra [阿那白滞素]）减弱。作者假设，额外的皮下IL-1 Ra给药将减少炎症和与aSAH.METHODS后不良结局相关的相关血浆标志物，这是一项随机、开放标签、单盲研究，100 mg皮下IL-1 Ra，每天两次给药于aSAH患者，在发作后3天内开始，持续至发作后21天或从神经外科中心出院，两者以较早者为准。在入院时（基线）和发作后第3-8、14和21天采集血样，用于测量炎症标志物。主要结果是血浆IL-6的差异，测量为第3天和第8天之间的曲线下面积，校正基线值。次要结果测量包括其他炎症标志物的曲线下面积分析、IL-1 Ra的血浆药代动力学和6个月时的临床结果。在研究的活性组中纤维蛋白原水平也降低（p < 0.002）。皮下注射IL-1 Ra是安全的，耐受性良好，并具有可预测的血浆药代动力学特征。虽然这项研究没有权力调查的临床效果，评分的格拉斯哥结局量表扩展在6个月更好的积极group. However，这种结果并没有达到统计学意义。结论皮下IL-1 Ra是安全的，耐受性良好的aSAH。它能有效减轻外周炎症。这些数据支持一项III期研究，该研究调查了IL-1 Ra对aSAH后结局的影响。
OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event with long-term morbidity and mortality. Patients who survive the initial bleeding are likely to suffer further early brain injury arising from a plethora of pathological processes. These may result in a worsening of outcome or death in approximately 25% of patients and may contribute to longer-term cognitive dysfunction in survivors. Inflammation, mediated by the cytokine interleukin-1 (IL-1), is an important contributor to cerebral ischemia after diverse forms of brain injury, including aSAH. Its effects are attenuated by its naturally occurring antagonist, IL-1 receptor antagonist (IL-1Ra [ anakinra]). The authors hypothesized that administration of additional subcutaneous IL-1Ra would reduce inflammation and associated plasma markers associated with poor outcome following aSAH.METHODS This was a randomized, open-label, single-blinded study of 100 mg subcutaneous IL-1Ra, administered twice daily in patients with aSAH, starting within 3 days of ictus and continuing until 21 days postictus or discharge from the neurosurgical center, whichever was earlier. Blood samples were taken at admission (baseline) and at Days 3-8, 14, and 21 postictus for measurement of inflammatory markers. The primary outcome was difference in plasma IL-6 measured as area under the curve between Days 3 and 8, corrected for baseline value. Secondary outcome measures included similar area under the curve analyses for other inflammatory markers, plasma pharmacokinetics for IL-1Ra, and clinical outcome at 6 months.RESULTS Interleukin-1Ra significantly reduced levels of IL-6 and C-reactive protein (p < 0.001). Fibrinogen levels were also reduced in the active arm of the study (p < 0.002). Subcutaneous IL-1Ra was safe, well tolerated, and had a predictable plasma pharmacokinetic profile. Although the study was not powered to investigate clinical effect, scores of the Glasgow Outcome Scale-extended at 6 months were better in the active group; however, this outcome did not reach statistical significance.CONCLUSIONS Subcutaneous IL-1Ra is safe and well tolerated in aSAH. It is effective in reducing peripheral inflammation. These data support a Phase III study investigating the effect of IL-1Ra on outcome following aSAH.