Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL.
Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC.
Chest. 2020 Oct;158(4):1526-1534. doi: 10.1016/j.chest.2020.04.066. Epub 2020 May 22.
A number of circulating plasma biomarkers have been shown to predict survival in patients with idiopathic pulmonary fibrosis (IPF), but most were identified before the use of antifibrotic (AF) therapy in this population. Because pirfenidone and nintedanib have been shown to slow IPF progression and may prolong survival, the role of such biomarkers in AF-treated patients is unclear.
To determine whether plasma concentration of cancer antigen 125 (CA-125), C-X-C motif chemokine 13 (CXCL13), matrix metalloproteinase 7 (MMP7), surfactant protein D (SP-D), chitinase-3-like protein-1 (YKL-40), vascular cell adhesion protein-1 (VCAM-1), and osteopontin (OPN) is associated with differential transplant-free survival (TFS) in AF-exposed and nonexposed patients with IPF.
A pooled, multicenter, propensity-matched analysis of IPF patients with and without AF exposure was performed. Optimal thresholds for biomarker dichotomization were identified in each group using iterative Cox regression. Longitudinal biomarker change was assessed in a subset of patients using linear mixed regression modeling. A clinical-molecular signature of IPF TFS was then derived and validated in an independent IPF cohort.
Three hundred twenty-five patients were assessed, of which 68 AF-exposed and 172 nonexposed patients were included after propensity matching. CA-125, CXCL13, MMP7, YKL-40, and OPN predicted differential TFS in AF-exposed patients but at higher thresholds than in AF-nonexposed individuals. Plasma biomarker level generally increased over time in nonexposed patients but remained unchanged in AF-exposed patients. A clinical-molecular signature predicted decreased TFS in AF-exposed patients (hazard ratio [HR], 5.91; 95% CI, 2.25-15.5; P < .001) and maintained this association in an independent AF-exposed cohort (HR, 3.97; 95% CI, 1.62-9.72; P = .003).
Most plasma biomarkers assessed predicted differential TFS in AF-exposed patients with IPF, but at higher thresholds than in nonexposed patients. A clinical-molecular signature of IPF TFS may provide a reliable predictor of outcome risk in AF-treated patients but requires additional research for optimization and validation.
多项循环血浆生物标志物已被证明可预测特发性肺纤维化（IPF）患者的生存率，但大多数标志物是在该人群中使用抗纤维化（AF）治疗之前确定的。由于吡非尼酮和尼达尼布已被证明可减缓 IPF 进展并可能延长生存时间，因此这些生物标志物在接受 AF 治疗的患者中的作用尚不清楚。
确定血浆癌抗原 125（CA-125）、C-X-C 基序趋化因子 13（CXCL13）、基质金属蛋白酶 7（MMP7）、表面活性剂蛋白 D（SP-D）、几丁质酶 3 样蛋白 1（YKL-40）、血管细胞黏附蛋白 1（VCAM-1）和骨桥蛋白（OPN）的血浆浓度是否与接受和未接受 AF 治疗的 IPF 患者的移植后无生存（TFS）差异相关。
对接受和未接受 AF 暴露的 IPF 患者进行了一项汇集的、多中心、倾向匹配的分析。使用迭代 Cox 回归在每组中确定生物标志物二分法的最佳阈值。使用线性混合回归模型评估了一部分患者的纵向生物标志物变化。然后在独立的 IPF 队列中推导并验证了 IPF TFS 的临床-分子特征。
评估了 325 名患者，其中 68 名接受 AF 暴露和 172 名未接受 AF 暴露的患者在进行倾向匹配后被纳入。CA-125、CXCL13、MMP7、YKL-40 和 OPN 预测了接受 AF 暴露的患者的差异 TFS，但在接受 AF 暴露的患者中的阈值高于未接受 AF 暴露的患者。未接受 AF 暴露的患者的血浆生物标志物水平通常随时间而增加，但接受 AF 暴露的患者的水平保持不变。临床-分子特征预测接受 AF 暴露的患者的 TFS 降低（风险比 [HR]，5.91；95%CI，2.25-15.5；P<.001），并在独立的 AF 暴露队列中维持这种关联（HR，3.97；95%CI，1.62-9.72；P=0.003）。
评估的大多数血浆生物标志物均预测了接受 AF 暴露的 IPF 患者的差异 TFS，但在接受 AF 暴露的患者中的阈值高于未接受 AF 暴露的患者。IPF TFS 的临床-分子特征可能为接受 AF 治疗的患者的预后风险提供可靠的预测指标，但需要进一步的研究以进行优化和验证。
