INSERM U1016, UMR8104, Cochin Institute, Paris Descartes University, and Cochin Hospital, Paris Descartes University, Paris, France.
Oslo University Hospital, Oslo and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Arthritis Rheumatol. 2019 Jun;71(6):972-982. doi: 10.1002/art.40815. Epub 2019 Apr 26.
Interstitial lung disease (ILD) in systemic sclerosis (SSc) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and prognostic performance of 4 candidate serum biomarkers for SSc-associated ILD.
Serum samples from a combined cohort of SSc patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme-linked immunosorbent assay for concentrations of lung epithelial-derived surfactant protein D (SP-D), Krebs von den Lungen 6 glycoprotein (KL-6), CCL18, and OX40 ligand (OX40L). Lung fibrosis was measured by high-resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow-up 3.2 ± 4.4 years) were investigated.
In SSc patients at baseline, serum levels of KL-6 correlated with the forced vital capacity (FVC) (r = -0.317, P < 0.001), diffusing capacity for carbon monoxide (r = -0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL-6 and SP-D, but not CCL18 and OX40L, were associated with lung fibrosis (odds ratio [OR] 2.41, 95% confidence interval [95% CI] 1.43-4.07 [P = 0.001] and OR 3.15, 95% CI 1.81-5.48 [P < 0.001], respectively). In SSc patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio [HR] 2.90, 95% CI 1.25-6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02-13.52; P = 0.048). Matrix-based logistic regression models for the diagnosis and prognosis of SSc-associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP-D (for diagnosis) and serum levels of CCL18 (for progression of disease).
These results show that SP-D is a relevant diagnostic biomarker for SSc-associated ILD, whereas KL-6 could be used to assess the severity of lung fibrosis. CCL18 appears to be a potential predictive marker for progression of ILD in SSc.
系统性硬化症（SSc）相关的间质性肺病（ILD）具有高度可变的病程，因此非常需要预测工具。本研究旨在评估 4 种候选血清生物标志物在 SSc 相关 ILD 中的诊断和预后性能。
通过酶联免疫吸附试验，对来自法国巴黎和挪威奥斯陆的 SSc 患者（n=427）的混合队列的血清样本进行肺上皮衍生表面活性剂蛋白 D（SP-D）、Krebs von den Lungen 6 糖蛋白（KL-6）、CCL18 和 OX40 配体（OX40L）浓度分析。通过高分辨率计算机断层扫描和肺功能测试测量肺纤维化。研究了这些候选生物标志物与基线疾病受累的相关性，并预测随时间推移的疾病进展（平均±SD 随访 3.2±4.4 年）。
在 SSc 患者的基线时，KL-6 血清水平与用力肺活量（FVC）（r=-0.317，P<0.001）、一氧化碳弥散量（r=-0.335，P<0.001）和肺纤维化程度（r=0.551，P<0.001）相关。在多变量分析中，KL-6 和 SP-D 血清水平与肺纤维化相关（比值比[OR]2.41，95%置信区间[95%CI]1.43-4.07[P=0.001]和 OR 3.15，95%CI 1.81-5.48[P<0.001]），但 CCL18 和 OX40L 血清水平与肺纤维化无关。在 SSc 患者中，基线时存在 ILD，纵向、多变量分析表明 CCL18 血清水平是 FVC 下降>10%的独立预测因子（危险比[HR]2.90，95%CI 1.25-6.73；P=0.014）和新发广泛疾病（HR 3.71，95%CI 1.02-13.52；P=0.048）。构建了用于诊断和预测 SSc 相关 ILD 的基于矩阵的逻辑回归模型，根据 SP-D（用于诊断）和 CCL18（用于疾病进展）的血清水平，这些模型将 SSc 相关 ILD 的诊断或肺纤维化恶化的风险（轻度、中度或重度）分为 3 组。
这些结果表明 SP-D 是 SSc 相关 ILD 的一个有意义的诊断生物标志物，而 KL-6 可用于评估肺纤维化的严重程度。CCL18 似乎是 SSc 中 ILD 进展的一个潜在预测标志物。
