ERJ：将 IL-6 作为 PAH 药物靶点的孟德尔随机化和实验医学方法

2021-10-02 刘少飞 MedSci原创

肺动脉高压 (PAH) 是一种罕见且通常致命的疾病，其特征是小肺动脉的深刻重塑导致肺血管阻力 (PVR) 增加和右心衰竭。尽管有现有的治疗方法，但死亡率仍然很高，而且在确定新疗法方面存在重大未满足的

肺动脉高压 (PAH) 是一种罕见且通常致命的疾病，其特征是小肺动脉的深刻重塑导致肺血管阻力 (PVR) 增加和右心衰竭。尽管有现有的治疗方法，但死亡率仍然很高，而且在确定新疗法方面存在重大未满足的医疗需求。很多兴趣集中在PAH与失调的免疫、感染和炎症的关联上。自身免疫性疾病是PAH的病因，最常见的是硬皮病和系统性红斑狼疮。此外，炎症/感染过程如HIV感染和血吸虫病与PAH相关。特发性和遗传性PAH也与自身免疫性甲状腺疾病、HLA亚型有关，并且在高达93%的患者中发现存在自身抗体。事实上，有人提出特发性PAH可能是一种自身免疫性疾病。

炎症和免疫失调在肺动脉高压的发展中很重要。令人信服的临床前数据支持对白细胞介素 6 信号传导进行治疗性阻断。

该研究对第 1 组肺动脉高压患者进行了一项为期 6 个月的静脉托珠单抗 (8 mg·kg) 的开放标签 II 期研究。共同主要终点是安全性，定义为不良事件的发生率和严重程度，以及肺血管阻力的变化。另外，对 11,744 名具有欧洲血统的个体进行了孟德尔随机化研究，其中包括 2085 名患有 IL6R 变异（rs7529229）的特发性/遗传性疾病患者，已知与循环 IL6R 水平相关。 29 名患者（男性10/女性19；平均年龄 54.9[SD11.4]) 被招募。 19 名患有遗传性/特发性和 10 名结缔组织病相关的肺动脉高压。 23 名患者接受了至少一剂托珠单抗。 4 名患者因严重不良事件停用托珠单抗。尽管有证据表明目标参与血浆白细胞介素 6 和 C 反应蛋白水平，但意向治疗和改良意向治疗分析均表明肺血管阻力没有变化。炎症标志物不能预测治疗反应。孟德尔随机化不支持先导变异对肺动脉高压风险的影响（OR 0.99，p=0.88）。不良事件与托珠单抗的已知安全性一致。托珠单抗没有表现出任何一致的治疗效果。

原文出处：

Toshner M. Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH. Eur Respir J. 2021 Sep 29:2002463. doi: 10.1183/13993003.02463-2020. Epub ahead of print. PMID: 34588193.

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2021-10-04 仁心济世

#IL-6#

51 0
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2021-10-04 xugc

#药物靶点#

37 0
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2021-10-04 hb2010ye

#PAH#

49 0
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2021-10-03 病毒猎手

#孟德尔随机#

102 0
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2021-10-03 病毒猎手

#孟德尔随机化#

72 0

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