目的:临床观察表明,在系统性硬化症(SSc)中,血管活化和自身免疫先于细胞外基质(ECM)的重塑。我们通过假设在临床上尚未检测到纤维化的非常早期SSc(veSSc)患者中ECM生物标志物已经受到干扰来挑战这种范例。
方法:42例veSSc患者,定义为存在雷诺现象和至少一个浮肿的手指,抗核抗体阳性或病理性甲褶毛细血管镜检查,不符合2013年美国风湿病学会/欧洲风湿病学协会联盟对SSc的分类标准,与健康对照组(HC,n=29)。ECM降解(BGM,C3M,使用ELISA在血清中测量C4M和C6M)和ECM形成生物标志物(PRO-C3,PRO-C4和PRO-C5)。进行基线处的横截面分析和纵向分析。
结果:与HC相比,veSSc患者表现出III型和IV型胶原蛋白的强烈调节异常(较高的C3M,C4M,p<0.0001和PRO-C3,p=0.004,较低的周转率PRO-C3/C3M和PRO-C4/C4M,两者p<0.0001)。veSSc中的双聚糖降解生物标志物BGM高于HC(p=0.006),而VI型胶原的降解生物标志物,C6M,较低(p=0.002)。在ROC分析中,III型和IV型胶原的生物标志物在veSSc和HC之间有很好的区别:C3M,AUC=0.95,p<0.0001;C4M,AUC=0.97,p<0.0001;周转率PRO-C3/C3M,AUC=0.80,p<0.0001;PRO-C4/C4M,AUC=0.97;p<0.0001。
结论:这些研究结果表明,ECM重塑是一种非常早期的SSc现象,与微血管和自身免疫变化并行发生。区分veSSc患者和HC的III型和IV型胶原的生物标志物,表明它们是检测veSSc的潜在生物标志物。
OBJECTIVE: Clinical observation suggests that vascular activation and autoimmunity precede remodelling of the extracellular matrix (ECM) in systemic sclerosis (SSc). We challenge this paradigm by hypothesising that ECM biomarkers are already disturbed in patients with very early SSc (veSSc) when fibrosis is not yet clinically detectable.
METHODS: 42 patients with veSSc, defined as the presence of Raynaud\'s phenomenon and at least one of puffy fingers, positive antinuclear antibodies or pathological nailfold capillaroscopy, not meeting the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc, were compared with healthy controls (HCs, n=29). ECM degradation (BGM, C3M, C4M and C6M) and ECM formation biomarkers (PRO-C3, PRO-C4 and PRO-C5) were measured in serum using ELISAs. A cross-sectional analysis at baseline and a longitudinal analysis was performed.
RESULTS: Compared with HC, veSSc patients showed a strongly dysregulated turnover of type III and IV collagens (higher C3M, C4M, both p<0.0001 and PRO-C3, p=0.004, lower turnover ratios PRO-C3/C3M and PRO-C4/C4M, both p<0.0001). The biglycan degradation biomarker BGM was higher in veSSc than in HC (p=0.006), whereas the degradation biomarker for type VI collagen, C6M, was lower (p=0.002). In an ROC analysis, biomarkers of type III and IV collagen excellently distinguished between veSSc and HC: C3M, AUC=0.95, p<0.0001; C4M, AUC=0.97, p<0.0001; turnover ratios PRO-C3/C3M, AUC=0.80, p<0.0001; PRO-C4/C4M, AUC=0.97; p<0.0001.
CONCLUSIONS: These findings indicate ECM remodelling as a very early phenomenon of SSc occurring in parallel with microvascular and autoimmune changes. Biomarkers of type III and IV collagens distinguished between veSSc patients and HC, indicating them as potential biomarkers for the detection of veSSc.