Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands; Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands; Department of Dermatology, Radboud University Medical Centre, Nijmegen, the Netherlands.
Department of Dermatology, Radboud University Medical Centre, Nijmegen, the Netherlands; Radboud University, Nijmegen, the Netherlands.
J Autoimmun. 2019 Jul;101:86-93. doi: 10.1016/j.jaut.2019.04.008. Epub 2019 Apr 18.
Localized Scleroderma (LoS) encompasses a group of idiopathic skin conditions characterized by (sub)cutaneous inflammation and subsequent development of fibrosis. Currently, lack of accurate tools enabling disease activity assessment leads to suboptimal treatment approaches.
To investigate serum concentrations of cytokines and chemokines implicated in inflammation and angiogenesis in LoS and explore their potential to be utilized as biomarker of disease activity. Additionally, to investigate the implication of potential biomarkers in disease pathogenesis.
A 39-plex Luminex immuno-assay was performed in serum samples of 74 LoS and 22 Healthy Controls. The relation between a validated clinical measure of disease activity (mLoSSI) and serum analytes was investigated. Additionally, gene and protein expression were investigated in circulating cells and skin biopsies.
From the total of 39, 10 analytes (CCL18, CXCL9, CXCL10, CXCL13, TNFRII, Galectin-9, TIE-1, sVCAM, IL-18, CCL19) were elevated in LoS serum. Cluster analysis of serum samples revealed CCL18 as most important analyte to discriminate between active and inactive disease. At individual patient level, CCL18 serum levels correlated strongest with mLoSSI-scores (r = 0.4604, P < 0.0001) and in longitudinal measures CCL18 concentrations normalised with declining disease activity upon treatment initiation. Additionally, CCL18 was elevated in LoS serum, and not in (juvenile) dermatomyositis or spinal muscular atrophy. Importantly, CCL18 gene and protein expression was increased at the inflammatory border of cutaneous LoS lesions, with normal expression in unaffected skin and circulating immune cells.
CCL18 is specific for disease activity in LoS thereby providing relevance as a biomarker for this debilitating disease.
局限性硬皮病（LoS）包含一组特发性皮肤疾病，其特征为（皮下）炎症和随后的纤维化发展。目前，缺乏能够评估疾病活动的准确工具导致治疗方法不理想。
研究LoS 中涉及炎症和血管生成的细胞因子和趋化因子的血清浓度，并探讨其作为疾病活动生物标志物的潜力。此外，还研究了潜在生物标志物在疾病发病机制中的作用。
对 74 例 LoS 和 22 例健康对照者的血清样本进行了 39 plex Luminex 免疫分析。研究了一种验证的疾病活动临床评估（mLoSSI）与血清分析物之间的关系。此外，还在循环细胞和皮肤活检中研究了基因和蛋白表达。
在总共 39 个分析物中，10 个分析物（CCL18、CXCL9、CXCL10、CXCL13、TNFRII、Galectin-9、TIE-1、sVCAM、IL-18、CCL19）在 LoS 血清中升高。血清样本的聚类分析显示 CCL18 是区分活动期和非活动期疾病的最重要分析物。在个体患者水平上，CCL18 血清水平与 mLoSSI 评分相关性最强（r=0.4604，P<0.0001），并且在纵向测量中，CCL18 浓度在治疗开始时随着疾病活动的下降而正常化。此外，CCL18 在 LoS 血清中升高，而不在（青少年）皮肌炎或脊髓性肌萎缩症中升高。重要的是，CCL18 的基因和蛋白表达在皮肤 LoS 病变的炎症边界处增加，而在未受影响的皮肤和循环免疫细胞中正常表达。
CCL18 是 LoS 疾病活动的特异性标志物，因此作为这种使人衰弱的疾病的生物标志物具有相关性。
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