Topping Joanne, Chang Leon, Nadat Fatima, Poulter James A, Ibbotson Alice, Lara-Reyna Samuel, Watson Christopher M, Carter Clive, Pournara Linda P, Zernicke Jan, Ross Rebecca L, Cargo Catherine, Lyons Paul A, Smith Kenneth G C, Del Galdo Francesco, Rech Jürgen, Fautrel Bruno, Feist Eugen, McDermott Michael F, Savic Sinisa
University of Leeds, Leeds, United Kingdom.
St James's University Hospital, Leeds, United Kingdom.
Arthritis Rheumatol. 2025 May;77(5):582-595. doi: 10.1002/art.43054. Epub 2024 Dec 16.
Adult-onset Still disease (AOSD) is a systemic autoinflammatory disorder (AID) of unknown etiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large cohort with AOSD to investigate the underlying pathology and identify novel targets for potential treatment.
We investigated AOSD cases (n = 60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n = 106) alongside measurements of NLRP3 inflammasome activation using a custom assay and type I interferon (IFN) score using a novel method.
We observed higher than expected frequencies of rare germline variants associated with monogenic AIDs in AOSD cases (AOSD 38.4% vs healthy controls [HCs] 20.4%) and earlier onset of putative somatic variants associated with clonal hematopoiesis of indeterminate potential. Transcriptome profiling revealed a positive correlation between Still Activity Score and gene expression associated with the innate immune system. ASC/NLRP3 specks levels and type I IFN scores were significantly elevated in AOSD cases compared with HCs (P = 0.0001 and 0.0015, respectively), in addition to several cytokines: interleukin (IL)-6 (P < 0.0001), IL-10 (P < 0.0075), IL-12p70 (P = 0.0005), IL-18 (P < 0.0001), IL-23 (P < 0.0001), IFN-α2 (P = 0.0009), and IFNγ (P = 0.0002).
Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC/NLRP3 specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not by themselves be sufficient to cause disease, but may contribute to a polygenic model for AOSD.
成人斯蒂尔病（AOSD）是一种病因不明的系统性自身炎症性疾病（AID）。遗传学研究一直有限。在此，我们对一大群AOSD患者进行了详细的基因和炎症生物标志物分析，以研究其潜在病理并确定潜在治疗的新靶点。
我们使用虚拟基因面板的全外显子组测序研究了60例AOSD病例的罕见种系和体细胞变异。通过全血批量RNA测序研究转录组谱。对一个扩大的患者队列（n = 106）进行细胞因子分析，同时使用定制检测方法测量NLRP3炎性小体激活情况，并使用一种新方法计算I型干扰素（IFN）评分。
我们观察到AOSD病例中与单基因AID相关的罕见种系变异频率高于预期（AOSD为38.4%，而健康对照[HCs]为20.4%），且与不确定潜能的克隆性造血相关的假定体细胞变异发病更早。转录组分析显示斯蒂尔活动评分与先天免疫系统相关基因表达之间呈正相关。与HCs相比，AOSD病例中的ASC/NLRP3斑点水平和I型IFN评分显著升高（分别为P = 0.0001和0.0015），此外还有几种细胞因子：白细胞介素（IL）-6（P < 0.0001）、IL-10（P < 0.0075）、IL-12p70（P = 0.0005）、IL-18（P < 0.0001）、IL-23（P < 0.0001）、IFN-α2（P = 0.0009）和IFNγ（P = 0.0002）。
我们的研究表明AOSD存在相当大的遗传复杂性，并证明了ASC/NLRP3斑点检测在疾病分层和靶向治疗中的潜在效用。所鉴定的丰富遗传变异本身可能不足以导致疾病，但可能有助于AOSD的多基因模型。
