Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Int J Environ Res Public Health. 2021 Aug 30;18(17):9149. doi: 10.3390/ijerph18179149.
Tocilizumab is an anti-IL-6 therapy widely adopted in the management of the so-called "cytokine storm" related to SARS-CoV-2 virus infection, but its effectiveness, use in relation to concomitant corticosteroid therapy and safety were unproven despite widespread use in numerous studies, mostly open label at the start of the pandemic.
We performed a systematic review and meta-analysis of case-control studies utilising tocilizumab in COVID-19 on different databases (PubMed/MEDLINE/Scopus) and preprint servers (medRxiv and SSRN) from inception until 20 July 2020 (PROSPERO CRD42020195690). Subgroup analyses and meta-regressions were performed. The impact of tocilizumab and concomitant corticosteroid therapy or tocilizumab alone versus standard of care (SOC) on the death rate, need for mechanical ventilation, ICU admission and bacterial infections were assessed.
Thirty-nine studies with 15,531 patients (3657 cases versus 11,874 controls) were identified. Unadjusted estimates ( = 28) failed to demonstrate a protective effect of tocilizumab on survival (OR 0.74 ([95%CI 0.55-1.01], = 0.057), mechanical ventilation prevention (OR 2.21 [95%CI 0.53-9.23], = 0.277) or prevention of ICU admission (OR 3.79 [95%CI 0.38-37.34], = 0.254). Considering studies with adjusted, estimated, tocilizumab use was associated with mortality rate reduction (HR 0.50 ([95%CI 0.38-0.64], < 0.001) and prevention of ICU admission (OR 0.16 ([95%CI 0.06-0.43], < 0.001). Tocilizumab with concomitant steroid use versus SOC was protective with an OR of 0.49 ([95%CI 0.36-0.65], < 0.05) as was tocilizumab alone versus SOC with an OR of 0.59 ([95%CI 0.34-1.00], < 0.001). Risk of infection increased (2.36 [95%CI 1.001-5.54], = 0.050; based on unadjusted estimates).
Despite the heterogeneity of included studies and large number of preprint articles, our findings from the first eight of the pandemic in over 15,000 COVID-19 cases suggested an incremental efficacy of tocilizumab in severe COVID-19 that were confirmed by subsequent meta-analyses of large randomized trials of tocilizumab. This suggests that analysis of case-control studies and pre-print server data in the early stages of a pandemic appeared robust for supporting incremental benefits and lack of major therapeutic toxicity of tocilizumab for severe COVID-19.
托珠单抗是一种抗白细胞介素 6 治疗药物，广泛用于治疗与 SARS-CoV-2 病毒感染相关的所谓“细胞因子风暴”，但在疫情开始时，尽管在许多研究中广泛使用，但它的有效性、与同时使用皮质类固醇治疗的关系和安全性仍未得到证实，这些研究大多是开放标签的。
我们对不同数据库（PubMed/MEDLINE/Scopus）和预印本服务器（medRxiv 和 SSRN）上的 COVID-19 托珠单抗治疗的病例对照研究进行了系统评价和荟萃分析，时间范围为研究开始至 2020 年 7 月 20 日（PROSPERO CRD42020195690）。进行了亚组分析和荟萃回归分析。评估了托珠单抗和同时使用皮质类固醇治疗或托珠单抗单独与标准治疗（SOC）对死亡率、机械通气需求、入住 ICU 和细菌感染的影响。
在纳入的 39 项研究中，共有 15531 名患者（3657 例病例和 11874 例对照）。未调整的估计值（ = 28）未能表明托珠单抗对生存率（OR 0.74 [95%CI 0.55-1.01]， = 0.057）、预防机械通气（OR 2.21 [95%CI 0.53-9.23]， = 0.277）或预防 ICU 入住（OR 3.79 [95%CI 0.38-37.34]， = 0.254）有保护作用。考虑到有调整、估计的托珠单抗使用的研究，托珠单抗与死亡率降低相关（HR 0.50 [95%CI 0.38-0.64]， < 0.001）和预防 ICU 入住（OR 0.16 [95%CI 0.06-0.43]， < 0.001）。托珠单抗与同时使用皮质类固醇治疗与 SOC 相比具有保护作用，OR 为 0.49 [95%CI 0.36-0.65]， < 0.05），托珠单抗单独与 SOC 相比也具有保护作用，OR 为 0.59 [95%CI 0.34-1.00]， < 0.001）。感染风险增加（2.36 [95%CI 1.001-5.54]， = 0.050；基于未调整的估计值）。
尽管纳入的研究存在异质性，并且预印本文章数量众多，但在疫情的头 8 周内对超过 15000 例 COVID-19 病例的研究结果表明，托珠单抗对重症 COVID-19 具有额外的疗效，随后对托珠单抗的大型随机试验进行的荟萃分析也证实了这一点。这表明，在大流行的早期阶段，对病例对照研究和预印本服务器数据的分析似乎能够有力地支持托珠单抗治疗重症 COVID-19 的增量效益，并且没有明显的治疗毒性。
