Tocilizumab in COVID-19: some clarity amid controversy.
Tocilizumab in COVID-19: some clarity amid controversy.
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DOI：
10.1016/s0140-6736(21)00712-1
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发表时间：
2021-05-01
期刊：
影响因子：
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通讯作者：
Leaf DE
中科院分区：
文献类型：
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作者：
Gupta S;Leaf DE
免疫反应的过度激活，包括释放促炎细胞因子，如白细胞介素-6（IL-6），可能在COVID-19引起的严重疾病的病理生理学中发挥关键作用。[1]与这一观点相一致，减少COVID-19住院患者死亡率的少数疗法之一是皮质类固醇地塞米松。2因此，人们对研究除类固醇外，是否使用其他更具靶向的抗炎药物进行治疗具有极大的兴趣，Tocilizumab是一种重组人源化单克隆抗体，可抑制IL-6与膜和可溶性IL-6受体的结合。来自中国的早期观察结果表明，接受托珠单抗治疗的COVID-19住院患者的结局有所改善。[3]这些初步报告之后，在COVID-19重症患者中进行了大型观察性研究，表明托珠单抗的死亡率有所改善。4随后的随机临床试验研究托珠单抗报告了相互矛盾的结果，但这些试验在规模，研究设计和入选患者的疾病严重程度方面存在很大差异。例如，几项最初的试验5-7未能显示托珠单抗的死亡率益处，但这些试验每项招募的患者少于300例，因此检测组间死亡差异的能力不足。8早期试验的其他局限性是排除了危重患者5，7以及托珠单抗治疗和托珠单抗未治疗患者之间类固醇使用的不平衡。9 2021年发表的社区获得性肺炎随机、嵌入式、多因素适应性平台试验（REMAP-CAP）研究是迄今为止规模最大的研究托珠单抗治疗COVID-19的试验（n= 803），并显示了生存益处。10然而，由于REMAP-CAP仅限于重症患者，托珠单抗对住院但非重症COVID-19患者的作用仍不清楚。
Hyperactivation of the immune response, including release of pro-inflammatory cytokines such as interleukin-6 (IL-6), might play a key role in the pathophysiology of severe illness from COVID-19. 1 Consistent with this notion, one of the few therapies that reduces mortality in hospitalised patients with COVID-19 is the corticosteroid, dexamethasone. 2 Accordingly, there has been great interest in examining whether treatment with additional, more targeted anti-inflammatory agents beyond steroids could provide further benefit.Tocilizumab is a recombinant humanised monoclonal antibody that inhibits binding of IL-6 to both membrane and soluble IL-6 receptors. Early observations from China suggested improved outcomes in hospitalised patients with COVID-19 who received tocilizumab. 3 These preliminary reports were followed by large observational studies in critically ill patients with COVID-19, which suggested a mortality benefit with tocilizumab. 4 Subsequent randomised clinical trials examining tocilizumab reported conflicting results, but these trials differed considerably in size, study design, and illness severity of the patients enrolled. For instance, several initial trials 5–7 failed to show a mortality benefit for tocilizumab, but these trials enrolled fewer than 300 patients each and were thus underpowered to detect differences in death between groups. 8 Additional limitations of early trials were exclusion of critically ill patients 5, 7 and imbalances in the use of steroids between tocilizumab-treated and tocilizumab-untreated patients. 9 The Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) study published in 2021 was, until now, the largest trial (n= 803) to examine tocilizumab in COVID-19, and showed a survival benefit. 10 However, as REMAP-CAP was limited to critically ill patients, the role of tocilizumab for hospitalised but non-critically ill patients with COVID-19 remained unclear.