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基于分子特征定义的独特干燥综合征患者亚群。

Unique Sjögren's syndrome patient subsets defined by molecular features.

机构信息

Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Department of Medicine.

出版信息

Rheumatology (Oxford). 2020 Apr 1;59(4):860-868. doi: 10.1093/rheumatology/kez335.

DOI:10.1093/rheumatology/kez335
PMID:31497844
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7188221/
Abstract

OBJECTIVE

To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes.

METHODS

pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200.

RESULTS

Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters.

CONCLUSION

Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

摘要

目的

通过对患者的分子表型进行特征描述和聚类，解决原发性干燥综合征（pSS）临床试验、研究和治疗中存在的异质性问题。

方法

pSS 患者符合美国-欧洲共识组分类标准，且至少存在一种全身表现和刺激唾液流量 ⩾0.1ml/min。从血液（n=47 例有适当样本）的基因表达微阵列数据中得出相关转录模块。使用无偏随机森林建模方法基于该分子信息对患者进行聚类。此外，还使用多重、基于珠的测定法和 ELISA 来评估 30 种血清细胞因子、趋化因子和可溶性受体。11 种自身抗体，包括抗 Ro/SSA 和抗 La/SSB，通过 Bio-Rad Bioplex 2200 进行测量。

结果

转录模块区分了 pSS 患者的三个聚类。第 1 组未显示 IFN 或炎症模块的显著升高。第 2 组显示出强烈的 IFN 和炎症模块网络特征，以及 IP-10/CXCL10、MIG/CXCL9、BLyS（BAFF）和 LIGHT 的血浆蛋白水平较高。第 3 组样本表现出中度升高的 IFN 模块，但炎症模块受到抑制，IP-10/CXCL10 和 B 细胞吸引趋化因子 1/CXCL13 增加，并且 MIG/CXCL9、IL-1α 和 IL-21 呈增加趋势。所有三个聚类中均存在抗 Ro/SSA 和抗 La/SSB。

结论

涵盖 IFN、炎症和其他特征的分子谱可用于将 pSS 患者分为不同的聚类。在未来，这些图谱可能有助于为临床试验选择患者，并指导治疗决策。