Role of immunosuppressive therapy in rheumatic diseases concurrent with COVID-19
Role of immunosuppressive therapy in rheumatic diseases concurrent with COVID-19
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DOI：
10.1136/annrheumdis-2020-217460
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发表时间：
2020-06-01
影响因子：
27.4
通讯作者：
Liu, Yi
中科院分区：
文献类型：
--
作者：
Lu, Chenyang;Li, Shasha;Liu, Yi
图1 糖皮质激素和一些DMARD在患者、小鼠模型和人类细胞中严重COVID-19中细胞因子谱上的表达谱。(A) 热图显示托珠单抗和甲氨蝶呤均诱导基因显着下调，包括IL-2、CSF3、IL-10、IL-7、CCL2、TNF、FTH1、CXCL10、CCL3和IL-6 （GSE45867）。每列都是一个病人；数据由 z 分数表示。使用 GeneChip 人类基因组 U133 plus 2.0 阵列测量早期 RA 患者在开始托珠单抗 (n= 12) 或甲氨蝶呤 (n= 7) 治疗之前和之后 12 周获得的配对滑膜活检样本的表达水平；(B) 热图显示 HCQ 下调了由风湿性热灭活 A 组诱导的三名健康参与者的 PBMC 中靶向细胞因子的表达链球菌 (GSE74235)；每列都是 PBMC 样本（HCQ 处理前或 24 小时后）；采用Illumina HiSeq 2000的RNA-seq测定各基因的表达水平；数据以z分数和log2（倍数变化）表示。（C）托法替尼（GSE69300）、金硫苹果酸钠、硫唑嘌呤、甲氨蝶呤、泼尼松龙、甲泼尼龙（GSE12860）下调靶向细胞因子的基因；左：C57/B6 雌性小鼠经媒介物 (n = 2) 或托法替尼 (n = 3) 治疗 4 天后的整个皮肤用于计算倍数变化；通过Affymetrix小鼠基因组430 2.0阵列测量表达；右图：用类风湿性关节炎滑膜成纤维细胞 (RASF) 上清液刺激人类软骨细胞，这些细胞已经用类固醇、DMARD 或什么都不处理；通过 Affymetrix 人类基因组 U133A 阵列测量 RASF 上清液刺激的软骨细胞中细胞因子的表达水平，并显示倍数变化；(D) 与未处理相比，Auronfin、地塞米松、双氯芬酸（一种 NSAID）、GW 627368X（一种 EP4 受体拮抗剂）、aIL6 和柳氮磺吡啶处理的细胞显示这些基因的表达较低（GSE95588）；通过 Illumina HiSeq 测量经过 TNF 处理的 CD14+ MCSF 分化巨噬细胞样本的表达水平，无论是否经过药物处理；每列都是一个复制品。 Z 分数：所有样本中基因的相对表达水平，倍数变化 (log2)：药物治疗与未治疗。蓝色细胞：下调；红细胞：上调。 DMARDs，缓解疾病的抗风湿药； HCQ，羟氯喹； IL，白细胞介素； MCSF，巨噬细胞集落刺激因子； NSAID，非甾体类抗炎药； PBMC，外周血单个核细胞； RA，类风湿性关节炎； SF，滑膜成纤维细胞； TNF，肿瘤坏死因子。自 2020 年 3 月 11 日起，世界卫生组织已宣布 COVID-19 为大流行病。1 欧盟和美国的 COVID-19 病例累计发病率显示出相似的趋势，英国证实，虽然各国处于不同的阶段，但 COVID-19 大流行在所有国家都在迅速进展。 2 截至 2020 年 4 月 10 日，全球已有 1521,252 人确诊新型冠状病毒肺炎 (COVID-19)，死亡率约为
Figure 1 Expression profiling of glucocorticoids and some DMARDs on the cytokine profile represented in severe COVID-19 in patients, mouse models and human cells.(A) Heatmap showing both tocilizumab and methotrexate induced a significant downregulation of genes including IL-2, CSF3, IL-10, IL-7, CCL2, TNF, FTH1, CXCL10, CCL3 and IL-6 (GSE45867). Each column is a patient; data were represented by z-score. The expression level of paired synovial biopsy samples obtained from the affected knees of patients with early RA before and 12 weeks after initiation of tocilizumab (n= 12) or methotrexate (n= 7) therapy were measured using GeneChip human genome U133 plus 2.0 arrays;(B) heatmap showing that HCQ downregulated the expression of targeted cytokines in PBMC of three healthy participants induced by rheumatogenic, heat-killed group A Streptococcus (GSE74235); each column is a PBMC sample (before or 24 hours after HCQ treatment); the expression level of each gene was measured by RNA-seq of Illumina HiSeq 2000; data were represented by z-score and the log2 (fold change).(C) Tofacitinib (GSE69300), sodium aurothiomalate, azathioprine, methotrexate, prednisolone, methylprednisolone (GSE12860) downregulated genes of targeted cytokines; left: whole skin from C57/B6 female mice after 4 days of treatment of vehicle (n= 2) or tofacitinib (n= 3) were used to calculate the fold change; expression was measured by Affymetrix mouse genome 430 2.0 array; right: human chondrocytes were stimulated with supernatant of rheumatoid arthritis synovial fibroblast (RASF), which have been treated with steroids, DMARDs or nothing; expression level of cytokines in RASF supernatant-stimulated chondrocytes were measured by Affymetrix human genome U133A array and fold change was represented;(D) compared with no treatment, Auronfin, dexamethasone, diclofenac (an NSAID), GW 627368X (an EP4 receptor antagonist), aIL6 and sulfasalazine treated cells showed lower expression of these genes (GSE95588); expression level of samples from TNF treated CD14+ MCSF-differentiated macrophages with or without drug treatment were measured by Illumina HiSeq; each column is a replicate. Z-score: relative expression level of a gene in all samples, fold change (log2): drug treated versus untreated. blue cells: downregulated; red cells: upregulated. DMARDs, disease-modifying anti-rheumatic drugs; HCQ, hydroxychloroquine; IL, interleukin; MCSF, macrophage colony-stimulating factor; NSAID, non-steroidal antiinflammatory drugs; PBMC, peripheral blood mononuclear cells; RA, rheumatoid arthritis; SF, synovial fibroblasts; TNF, tumour necrosis factor.The COVID-19 has been declared a pandemic by WHO since 11 March 2020. 1 The cumulative incidence of COVID-19 cases is showing similar trends in European Union and USA, and the UK confirmed that, while at a different stage depending on the country, the COVID-19 pandemic is progressing rapidly in all countries. 2 As of 10 April 2020, COVID-19 has been confirmed in 1521252 people worldwide, carrying a mortality of approximately