Abstract:
Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. Although antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objectives: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery (n = 875) and validation (n = 347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naive to antifibrotic therapy at the time of biomarker measurement (n = 555). Measurements and Main Results: LCA independently identified two latent classes in both cohorts (P < 0.0001). WFDC2 (WAP four-disulfide core domain protein 2) was the most important determinant of class membership across cohorts. Membership in class 2 was characterized by higher biomarker concentrations and a higher risk of death or transplant (discovery, hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.64-2.48; P < 0.001; validation, HR, 1.95; 95% CI, 1.34-2.82; P < 0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (P = 0.030 for interaction), with a favorable antifibrotic response in class 2 (HR, 0.64; 95% CI, 0.45-0.93; P = 0.018) but not in class 1 (HR, 1.19; 95% CI, 0.77-1.84; P = 0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and responses to antifibrotic therapy. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials.
摘要:
原理:特发性肺纤维化(IPF)导致肺实质不可逆的纤维化。虽然抗纤维化治疗可以减缓IPF的进展,治疗反应是可变的。迫切需要开发一种针对IPF的精准医学方法。目的:鉴定和验证IPF的生物学驱动分子内生型。方法:在前瞻性招募的发现(n=875)和验证(n=347)队列中独立进行潜在类别分析(LCA)。与纤维发生相关的二十五个血浆生物标志物用作类别定义变量。使用校正基线混杂因素的多变量Cox回归测试分子内型与4年无移植生存期之间的关联。然后,在生物标志物测量时(n=555),在未接受抗纤维化治疗的患者的合并队列中评估对未来抗纤维化暴露的内毒素型依赖性差异治疗反应。结果:LCA在两个队列中独立识别出两个潜在类别(p<0.0001)。WAP四二硫键核心结构域蛋白2(WFDC2)是队列中最重要的类别成员资格决定因素。第2类成员的特征是更高的生物标志物浓度和更高的死亡或移植风险(发现:HR2.02[95%CI1.64-2.48];p<0.001;验证:HR1.95[1.34-2.82];p<0.001)。在汇总分析中,在治疗效果的显著异质性观察到在内生型之间(p相互作用=0.030),在第2类(HR0.64[0.45-0.93];p=0.018)中具有良好的抗纤维化反应,但在第1类(HR1.19[0.77-1.84];p=0.422)中没有。结论:在这项多队列研究中,我们确定了两种新的IPF分子内型,其临床结局和对抗纤维化药物的反应不同.待进一步验证,这些内异型可以为未来的IPF临床试验提供精准医学方法.