背景:系统性硬化症(SSc)的血清纤维化标志物仍然有限。增强的肝纤维化(ELF)评分是由III型前胶原氨基末端前肽(PIIINP)组成的胶原标记集,金属蛋白酶组织抑制剂1(TIMP-1),和透明质酸(HA)。这项纵向研究旨在检查ELF评分及其单一分析物作为SSc纤维化替代结果指标的性能。方法:纳入85例符合2013年ACR/EULAR标准且无慢性肝病的SSc患者。血清PIIINP,TIMP-1,HA,测量ELF评分并与临床变量相关,包括改良的Rodnan皮肤评分(mRSS)和间质性肺病(ILD)。在使用免疫抑制剂和/或抗纤维化药物治疗期间,对20例SSc患者进行了后续血清学测试和mRSS评估。结果:血清PIIINP,SSc患者的TIMP-1和ELF评分明显高于健康对照组[PIIINP:10.31(7.83-14.10)与5.61(4.69-6.30),p<.001;TIMP-1:110.73(66.21-192.45)与61.81(48.86-85.24),p<.001;ELF:10.34(9.91-10.86)vs.9.68(9.38-9.99),p<.001]。甚至更高水平的PIIINP,弥漫性皮肤SSc患者的TIMP-1和ELF评分高于局限性皮肤SSc患者。在基线,PIIINP和ELF评分均与mRSS具有良好的相关性(PIIINP:r=.586,p<.001;ELF:r=.482,p<.001)。纵向分析表明,PIIINP的变化与mRSS的变化呈正相关(r=0.701,p=0.001),虽然ELF评分的变化不相关,在统计背景下,mRSS的变化(ELF:r=.140,p=.555)。SSc合并ILD患者血清TIMP-1明显增高,与无ILD患者的匹配组相比[109.45(93.05-200.09)vs.65.50(40.57-110.73),p=0.007]。结论:在SSc患者中,ELF评分与皮肤纤维化程度密切相关,而血清PIIINP是皮肤纤维化纵向变化的敏感标志物。在未来,循环胶原代谢产物可能用于评估抗纤维化治疗对该疾病的治疗效果.
Background: Serum fibrosis markers for systemic sclerosis (SSc) remain limited. The Enhanced Liver Fibrosis (ELF) score is a collagen marker set consisting of procollagen type III amino terminal propeptide (PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1), and hyaluronic acid (HA). This longitudinal study aimed to examine the performance of the ELF score and its single analytes as surrogate outcome measures of fibrosis in SSc. Methods: Eighty-five SSc patients fulfilling the 2013 ACR/EULAR criteria with the absence of chronic liver diseases were enrolled. Serum PIIINP, TIMP-1, HA, and the ELF score were measured and correlated with clinical variables including the modified Rodnan skin score (mRSS) and interstitial lung disease (ILD). Twenty SSc patients underwent a follow-up serological testing and mRSS evaluation during treatment with immunosuppressants and/or anti-fibrotic drugs. Results: Serum PIIINP, TIMP-1, and ELF score were significantly higher in patients with SSc than in healthy controls [PIIINP: 10.31 (7.83-14.10) vs. 5.61 (4.69-6.30), p < .001; TIMP-1: 110.73 (66.21-192.45) vs. 61.81 (48.86-85.24), p < .001; ELF: 10.34 (9.91-10.86) vs. 9.68 (9.38-9.99), p < .001]. Even higher levels of PIIINP, TIMP-1, and ELF score were found in patients with diffuse cutaneous SSc than those with limited cutaneous SSc. At baseline, both PIIINP and ELF score showed good correlation with mRSS (PIIINP: r = .586, p < .001; ELF: r = .482, p < .001). Longitudinal analysis showed that change in PIIINP positively correlated with change in mRSS (r = 0.701, p = .001), while change in ELF score were not related, in a statistical context, to the change in mRSS (ELF: r = .140, p = .555). Serum TIMP-1 was significantly higher in SSc patients with ILD, compared to the matched group of patients without ILD [109.45 (93.05-200.09) vs. 65.50 (40.57-110.73), p = 0.007]. Conclusion: In patients with SSc, the ELF score well correlates with the extent of skin fibrosis, while serum PIIINP is a sensitive marker for longitudinal changes of skin fibrosis. In the future, circulating collagen metabolites may potentially be used to evaluate therapeutic effects of anti-fibrotic treatments in the disease.