Baricitinib restrains the immune dysregulation in patients with severe COVID-19
Baricitinib restrains the immune dysregulation in patients with severe COVID-19
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DOI：
10.1172/jci141772
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发表时间：
2020-12-01
影响因子：
15.9
通讯作者：
Olivieri, Oliviero
中科院分区：
文献类型：
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作者：
Bronte, Vincenzo;Ugel, Stefano;Olivieri, Oliviero
背景2019年冠状病毒病（COVID-19）患者发生肺炎，通常与淋巴细胞减少症和由于细胞因子释放不受控制而引起的严重炎症反应相关。这些介导物受JAK/STAT信号通路的转录调控，而这些介导物可被小分子抑制。我们治疗了一组患者（n = 20）与baricitinib根据标签外使用的药物。该研究设计为观察性纵向试验，并获得当地伦理委员会的批准。患者接受4 mg baricitinib治疗，每日两次，持续2天，然后每天4 mg，持续7天。评估了免疫表型和血细胞中磷酸化STAT 3（p-STAT 3）表达的变化，并将其与血清来源的细胞因子水平和抗严重急性呼吸综合征-冠状病毒2（抗SARS-CoV-2）的抗体相关联。在一个单一的治疗患者，我们还评估了髓系细胞功能活性的改变。我们提供的证据表明，接受巴瑞替尼治疗的患者血清IL-6、IL-1 β和TNF-α水平显着降低，循环T和B细胞频率快速恢复，并且针对SARS-CoV-2刺突蛋白的抗体产生增加，所有这些在临床上都与氧气治疗需求的减少和P/F的逐渐增加相关（PaO 2，氧分压/FiO（2），吸入氧分数）比值。这些数据表明，baricitinib通过调节患者的免疫状况，阻止了病毒性疾病向严重、极端形式的进展，这些变化与COVID-19肺炎患者更安全、更有利的临床结局相关。
BACKGROUND. Patients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK/STAT signaling pathways, which can be disabled by small molecules.METHODS. We treated a group of patients (n = 20) with baricitinib according to an off-label use of the drug. The study was designed as an observational, longitudinal trial and approved by the local ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTS. We provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1 beta, and TNF-alpha, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO(2), fraction of inspired oxygen) ratio.CONCLUSION. These data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.