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.

中文翻译：

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特发性肺纤维化的分子内型：两个多中心观察队列的潜在类别分析。


基本原理：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 进展，但治疗反应是可变的。迫切需要开发一种针对 IPF 的精准医学方法。目的： 识别和验证 IPF 的生物驱动的分子内型。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）。与纤维化相关的 25 种血浆生物标志物作为类别定义变量。使用针对基线混杂因素进行调整的多变量 Cox 回归来检验分子内型与 4 年无移植生存率之间的关联。然后在生物标志物测量时未接受过抗纤维化治疗的患者的汇总队列中评估内型依赖性差异治疗对未来抗纤维化暴露的差异治疗反应 （n = 555）。测量和主要结果： LCA 独立确定了两个队列中的两个潜在类别 （P < 0.0001）。WFDC2 （WAP 四二硫键核心结构域蛋白 2） 是队列中类成员的最重要决定因素。2 类成员的特点是生物标志物浓度较高，死亡或移植风险较高（发现，风险比 [HR]，2.02;95% 置信区间 [CI]，1.64-2.48;P < 0.001;验证，心率，1.95;95% CI，1.34-2.82;P < 0.001）。在汇总分析中，观察到内型之间的治疗效果存在显著异质性 （相互作用 P = 0.030），2 类抗纤维化反应良好 （HR，0.64;95% CI，0.45-0.93;P = 0.018），但不属于 1 类 （HR，1.19;95% CI，0.77-1.84;P = 0.422）。 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，它们具有不同的临床结果和对抗纤维化治疗的反应。在进一步验证之前，这些内型可以为未来的 IPF 临床试验提供精准医学方法。