BACKGROUND Juvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. The Mendelian autoinflammatory interferonopathies, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) and STING-Associated Vasculopathy with onset in Infancy (SAVI), are caused by genetic mutations and have extremely elevated IFN signatures thought to drive pathology. The phenotypic overlap of some clinical features of CANDLE and SAVI with JDM led to the comparison of a standardized interferon-regulated gene score (IRG-S) in JDM and myositis-specific autoantibody (MSA) JDM subgroups, with CANDLE and SAVI. METHODS A peripheral 28-component IRG-S assessed by NanoString™ in 57 JDM patients subtyped by MSA was compared with IRG-S in healthy controls (HC) and CANDLE/SAVI patients. Principal component analysis (PCA) was performed, and individual genes were evaluated for their contribution to the score. IRG-S were correlated with disease assessments and patient characteristics. RESULTS IRG-S in JDM patients were significantly higher than in HC but lower than in CANDLE or SAVI. JDM IRG-S overlapped more with SAVI than CANDLE by PCA. Among MSA groups, anti-MDA5 autoantibody-positive patients' IRG-S overlapped most with SAVI. The IFI27 proportion was significantly higher in SAVI and CANDLE than JDM, but IFIT1 contributed more to IRG-S in JDM. Overall, the contribution of individual interferon-regulated genes (IRG) in JDM was more similar to SAVI. IRG-S correlated moderately with JDM disease activity measures (rs = 0.33-0.47) and more strongly with skin activity (rs = 0.58-0.79) in anti-TIF1 autoantibody-positive patients. Weakness and joint disease activity (multinomial OR 0.91 and 3.3) were the best predictors of high IRG-S. CONCLUSIONS Our findings demonstrate peripheral IRG expression in JDM overlaps with monogenic interferonopathies, particularly SAVI, and correlates with disease activity. Anti-MDA5 autoantibody-positive JDM IRG-S were notably more similar to SAVI. This may reflect both a shared IFN signature, which is driven by IFN-β and STING pathways in SAVI, as well as the shared phenotype of vasculopathy in SAVI and JDM, particularly in anti-MDA5 autoantibody-positive JDM, and indicate potential therapeutic targets for JDM.

中文翻译：

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干扰素调节基因在少年皮肌炎与孟德尔自发性炎性干扰素病中的表达。

背景技术青少年皮肌炎（JDM）是具有显着干扰素（IFN）标志的系统性自身免疫疾病，但是JDM的发病机制及其IFN标志的病因仍未知。孟德尔自发炎性干扰素病，慢性非典型性中性粒细胞增生伴脂肪营养不良和体温升高（CANDLE）和STING相关性血管病在婴儿期发作（SAVI）是由基因突变引起的，并具有极高的IFN标记，被认为可驱动病理。CANDLE和SAVI与JDM的某些临床特征在表型上的重叠导致对JDM和肌炎特异性自身抗体（MSA）JDM亚组与CANDLE和SAVI的标准干扰素调节基因评分（IRG-S）进行比较。方法在健康对照（HC）和CANDLE / SAVI患者中，通过NanoString™对57名MSA亚型JDM患者的外围28组分IRG-S与IRG-S进行了比较。进行主成分分析（PCA），并评估各个基因对得分的贡献。IRG-S与疾病评估和患者特征相关。结果JDM患者的IRG-S显着高于HC，但低于CANDLE或SAVI。与PCA的CANDLE相比，JDM IRG-S与SAVI的重叠更多。在MSA组中，抗MDA5自身抗体阳性患者的IRG-S与SAVI重叠最多。SAVI和CANDLE中的IFI27比例明显高于JDM，但IFIT1对JDM中的IRG-S贡献更大。总体而言，JDM中单个干扰素调节基因（IRG）的贡献与SAVI更为相似。在抗TIF1自身抗体阳性的患者中，IRG-S与JDM疾病活动性指标（rs = 0.33-0.47）呈中度相关，与皮肤活动性（rs = 0.58-0.79）更为相关。虚弱和关节疾病活动（多项式OR 0.91和3.3）是高IRG-S的最佳预测指标。结论我们的研究结果表明JDM中外周IRG表达与单基因干扰素病（尤其是SAVI）重叠，并且与疾病活动相关。抗MDA5自身抗体阳性的JDM IRG-S与SAVI更为相似。这可能既反映了由SAVI中的IFN-β和STING途径驱动的共享IFN信号，也反映了SAVI和JDM（尤其是抗MDA5自身抗体阳性JDM）中血管病变的共享表型，并表明了潜在的治疗靶点对于JDM。