University Medical Center Utrecht, Utrecht, The Netherlands.
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Arthritis Rheumatol. 2017 Dec;69(12):2359-2369. doi: 10.1002/art.40243. Epub 2017 Oct 30.
Patients with definite systemic sclerosis (SSc) who lack fibrotic features can be stratified into an intermediate stage of disease severity between preclinical/early SSc (EaSSc) and fibrotic subsets (limited cutaneous SSc [lcSSc] and diffuse cutaneous SSc [dcSSc]). The aim of the present study was to molecularly characterize nonfibrotic SSc and EaSSc on the basis of a broad panel of serum markers of inflammation and tissue damage, in order to increase the knowledge of the pathophysiologic mechanisms underlying SSc progression before the development of fibrosis.
An 88-plex immunoassay was performed in serum samples from a discovery cohort composed of 21 patients with EaSSc (meeting the LeRoy and Medsger criteria), 15 with nonfibrotic SSc (meeting the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria, without skin or lung fibrosis), and 11 healthy controls. Analyte concentrations that were consistently significantly different at the exploratory P value threshold of 0.1 were selected for replication analysis in a larger group composed of 47 patients with EaSSc, 48 with nonfibrotic SSc, and 43 healthy controls, as well as 51 patients with lcSSc and 35 with dcSSc. The value of the replicated molecules in predicting SSc progression (at a family-wise error rate of 0.05) was tested.
Based on the results of the explorative analysis, 16 molecules were selected for testing in the replication set. The results showed that CXCL10, CXCL11, tumor necrosis factor receptor type II (TNFRII), and chitinase 3-like protein 1 levels were significantly increased in patients with EaSSc and those with nonfibrotic SSc as compared to healthy controls. The disease in patients with high concentrations of CXCL10 and TNFRII was also characterized by a faster rate of progression from EaSSc and from nonfibrotic SSc to worse disease stages.
SSc patients with preclinical/early SSc and those with established, yet nonfibrotic, disease exhibit clear molecular alterations that are associated with faster rates of disease evolution. These data open novel avenues for disease interception in SSc.
缺乏纤维化特征的明确系统性硬化症（SSc）患者可在临床前/早期 SSc（EaSSc）和纤维化亚组（局限性皮肤 SSc [lcSSc]和弥漫性皮肤 SSc [dcSSc]）之间的疾病严重程度的中间阶段进行分层。本研究的目的是基于广泛的炎症和组织损伤的血清标志物，对非纤维化 SSc 和 EaSSc 进行分子表征，以便在纤维化发展之前增加对 SSc 进展潜在病理生理机制的了解。
在由 21 名符合 LeRoy 和 Medsger 标准的 EaSSc 患者（发现队列）、15 名符合美国风湿病学会/欧洲抗风湿病联盟 2013 年分类标准、无皮肤或肺纤维化的非纤维化 SSc 患者和 11 名健康对照者的血清样本中进行了 88 plex 免疫分析。在包含 47 名 EaSSc 患者、48 名非纤维化 SSc 患者和 43 名健康对照者以及 51 名 lcSSc 患者和 35 名 dcSSc 患者的更大组中进行了复制分析，选择了在探索性 P 值阈值为 0.1 时始终有显著差异的分析物浓度。还测试了复制分子在预测 SSc 进展中的价值（在错误发现率为 0.05 的情况下）。
基于探索性分析的结果，选择了 16 种分子进行复制集测试。结果表明，与健康对照组相比，EaSSc 患者和非纤维化 SSc 患者的 CXCL10、CXCL11、肿瘤坏死因子受体 II（TNFRII）和几丁质酶 3 样蛋白 1 水平显着升高。高浓度 CXCL10 和 TNFRII 的疾病患者的疾病进展速度也更快，从 EaSSc 和非纤维化 SSc 发展到更差的疾病阶段。
临床前/早期 SSc 的 SSc 患者和已建立但非纤维化的疾病患者表现出明确的分子改变，这些改变与更快的疾病演变相关。这些数据为 SSc 的疾病干预开辟了新途径。
