背景：无肌病型皮肌炎（Clinical amyopathic dermatomyositis，CADM)）是一组具有皮肌炎特征性皮疹但无肌无力症状的皮肌炎，约占皮肌炎的 5-20%，其诊断常存在困难。2017EULAR/ACR 分类标准在 CADM 人群中的准确性尚不明确。CADM 发病与遗传、免疫、环境等因素相关，皮损中可见炎症细胞浸润，尚无研究分析皮损的免疫浸润（Immune infiltration）的细胞分布情况及致病关键基因。目的：1.对 CADM 患者的临床特征和诊治经验进行总结，并在亚洲人群中对 2017 年EULAR/ACR 炎性肌病分类标准进行验证。2.分析皮损的免疫浸润细胞的分布情况及相关枢纽（hub）基因，并在 CADM 患者中验证。方法：1.纳入北京协和医院皮肤科根据 2002 Sontheimer 标准诊断为 CADM 的 64 例患者，总结临床资料，并检索 PubMed数据库总结既往文献中 CADM 患者的临床资料；应用 2017EULAR/ACR 分类标准对本中心患者评分。2..筛选皮损数据库 GSE142807 的差异表达基因（Differentially expressed genes，DEGs） 。运用基因本体论（Gene Ontology，GO）功能富集分析和京都基因和基因组百科全书 （Kyoto Encyclopedia of Genes and Genomes， KEGG） 通路分析鉴定 DEGs功能。运用 CIBERSORT算法分析皮损中的免疫浸润，运用加权基因共表达网络分析（Weighted correlation network analysis，WGCNA）筛选与免疫浸润相关的模块基因。在 GSE142807 和 GSE46239 中鉴定枢纽（hub）基因的诊断效能，分析 hub 基因与免疫浸润的相关性。 运用基因集富集分析 （Gene Set Enrichment Analysis， GSEA）鉴定单个 hub 基因信号通路。3.实时荧光定量聚合酶链式反应在 CADM 患者外周血中验证 hub 基因 IFI44L。4.免疫组织化学染色在 CADM 患者皮损中验证 hub 基因 CXCL10，并探究IFNγ-CXCL9/10-CXCR3 轴的表达情况。结果：1. 73.4%的 CADM 患者在确诊之前曾被误诊为其他疾病。32.8%的患者未达到2017EULAR/ACR 标准设置的 55%截止概率。2. 72.6%（45/64）的患者接受过羟氯喹治疗，但 68.8%（31/45）的患者对羟氯喹单药治疗反应不理想，需联用免疫抑制剂等。3. 6 例患者在中位随访期 10.5 个月（四分位数：9-13）后出现肌肉无力，病程早期异常升高的炎症指标可能预测肌肉症状发展。4. 免疫浸润分析示 M1 型巨噬细胞、静息肥大细胞和静息 CD4+T 记忆细胞在 DM皮损中显著升高（p＜0.05） ，其中 M1型巨噬细胞占比最高。5. WGCNA 示蓝色模块基因与 M1型巨噬细胞浸润相关性最强， 最终鉴定出 10 个与皮损发生及 M1巨噬细胞浸润相关的 hub 基因：CXCL10、IFI44L、GBP1、IFIT3、STAT2、OAS3、CMPK2、PLSCR1、IFIH1、HERC6。hub 基因的主要生物学功能为参与 I 型干扰素和抗病毒反应信号通路， 所有的 hub 基因具有较高的诊断效能 （曲线下面积＞0.8） 。6. CXCL10 在 CADM 皮损中表达显著上调（p=0.008） ，IFI44L 在 CADM 外周血中表达显著上调（p=0.004） 。7. IFNγ、CXCL9、CXCR3 的免疫组化评分在 CADM 和健康对照组间无显著差异，1 例合并肺癌的 CADM 患者皮损中 IFNγ、CXCL9/10、CXCR3 均表达为阳性。结论：1. 根据 2017EULAR/ACR 分类标准，32.8%的 CADM 患者无法被诊断。2. 68.8%的患者对羟氯喹单药治疗反应不佳，必要时需联用免疫抑制剂。3. 对 CADM 患者应密切监测，特别是病程早期炎症指标升高的患者，需警惕转化为经典型 DM。4. CXCL10、IFI44L、GBP1、IFIT3、STAT2、OAS3、CMPK2、PLSCR1、IFIH1、HERC6等 10 个 hub 基因可能与 DM 皮损发生及 M1 型巨噬细胞浸润相关，可作为未来的机制研究方向。5. IFNγ-CXCL9/10-CXCR3 轴的上调可能提示 CADM 合并癌症。

Background: Clinical amyopathic dermatomyositis (CADM) represents a subtype of 5–20% of patients with dermatomyositis (DM), characterized by typical rash without muscle weakness. 2017 EULAR/ACR criteria for idiopathic inflammatory myositis (IIM) classification had not been verified in Asian patients with CADM. The pathogenesis of CADM is related to genetics, environments, and immune mechanisms. Obvious inflammatory infiltrating cells can be observed in the skin lesions of DM. However, the relationship between differentially expressed genes (DEGs) and immune infiltration was not analyzed yet. Objective: To investigate clinical features, cutaneous findings, diagnostic accuracy, and treatment regimen of CADM patients, and to identify hub genes related to immune infiltration in skin lesions of dermatomyositis. Methods: Sixty-four patients diagnosed with CADM at Peking Union Medical College Hospital by dermatologists were retrospectively analyzed. Published studies were searched on the PubMed database to extract relevant data of CADM patients. The diagnostic value of EULAR/ACR criteria was tested in our patients. Gene expression data of skin lesions in DM was obtained from GSE142807 to identify DEGs. The functional correlation was identified by GO and KEGG pathway enrichment analysis. CIBERSORT algorism was used to evaluate immune cell infiltration in DM skin lesions. Weighted correlation network analysis (WGCNA) was used to identify module genes associated with macrophage infiltration. Receiver operating characteristic analyses （ROC） curved showed the diagnostic value of hub genes in GSE142807 and GSE46239. The correlation between hub genes and differentially expressed immune infiltration groups was investigated. GSEA was performed to discover underlying signaling pathway of hub genes. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical staining (IHC) were used to verify hub genes. The expression profile of the IFNγ-CXCL9/10-CXCR3 axis in skin lesions of CADM was shown by IHC. Results: 73.4% of patients with CADM were misdiagnosed before the ultimate diagnosis. 32.8% of patients were not classified into probable or definite DM using 2017 EULAR/ACR criteria. 68.8% (31 out of 45) of patients receiving hydroxychloroquine required at least one aggressive agent combined with hydroxychloroquine due to insufficient response or side effects. Six patients with normal muscle strength developed muscle weakness after a median of 10.5 months (IQR 9-13), and elevated inflammatory markers at the initial visit might indicate their muscle weakness development. Infiltration of M1 macrophages, resting mast cells, and resting CD4+ memory T cells were significantly greater in skin lesions (p＜0.05), with M1 macrophages being the most abundant infiltrating cells. WGCNA identified module eigengene (ME) blue as key module associated with M1 macrophage infiltration. Ten hub genes were identified ultimately: CXCL10、IFI44L、GBP1、 IFIT3、 STAT2、 OAS3、 CMPK2、 PLSCR1、 IFIH1、 HERC6, which were enriched in type I interferon and virus response pathway. The diagnostic values of all hub genes were sufficient (Area under curve > 0.8). IHC showed that CXCL10 expression was significantly increased in CADM lesions (p=0.008). RT-qPCR showed that the relative expression of IFI44L mRNA was significantly higher in CADM patients with active diseases (p=0.004). IHC showed no significant differences in the expression of IFNγ, CXCL9, and CXCR3 between CADM and healthy controls. Only one patient with concomitant lung cancer exhibited high expression of IFNγ, CXCL9/10, and CXCR3. Conclusions: 32.8% of patients may be overlooked using the three skin variables of the 2017 EULAR/ACR criteria. The response rate to single hydroxychloroquine in our cohort was 68.8%, thus, immunosuppressants should be given in need. Long-term monitoring for the development of myositis in patients with CADM, especially those with elevated inflammatory markers at the initial visit, may be warranted. The CXCL10, IFI44L, GBP1, IFIT3, STAT2, OAS3, CMPK2, PLSCR1, IFIH1, and HERC6 genes may play vital roles in the pathogenesis of DM skin lesions and immune infiltration of M1 macrophages. These genes could be recognized as potential biomarkers and therapeutic targets of DM, which may pave the way for future research. The overexpression of the IFNγ-CXCL9/10-CXCR3 axis might indicate concomitant cancer with CADM.