Distinguishing Phenotypes of Pulmonary Hypertension in Patients with Connective Tissue Disease-related Interstitial Lung Disease

项目摘要 肺动脉高压（PH）是一种病因众多但治疗方法有限的高发病率疾病。好处是- 已知有效的药物仅对具有非常特殊形式的PH的患者是安全和有效的。最近， 一种吸入药物曲前列尼尔被批准用于治疗与间质性肺病相关的PH（PH-I）。 ILD）。大多数PH-ILD研究要么关注特发性肺纤维化患者，要么将ILD作为一种全肺疾病， 包容性诊断然而，各种形式的ILD在其基础病理生理学和AF方面是不同的。 感染的病人群体。结缔组织病相关ILD（CTD-ILD）是ILD的一种未充分研究的形式 这种疾病往往会影响年轻的、种族多样的女性患者。PH和CTD-ILD的交叉点特别重要。 由于PH可能通过肺血管的纤维化诱导消融或 CTD慢性炎症导致的血管内功能障碍。在这个时候，确定哪种机制 个体CTD-ILD患者的PH由临床医生自行决定，临床医生还必须决定 根据他们的决定进行治疗。这些决定通常是由主观评估的指导， 胸部成像中观察到的纤维化程度（例如，计算机断层扫描[CT]），限制性扩张的严重程度 肺功能测试（PFT）和侵入性血流动力学测量期间测量的缺陷。在这 建议，我将使用一个CT和PFT为基础的严重程度分期系统，这是在患者的巩膜， 皮肤ILD，将CTD-ILD和PH患者分类为具有实质或血管表型。 当我将该系统应用于约翰霍普金斯PH中心登记处的20名患者时， 重新分类并接受与其表型不一致的治疗。为了研究这些的含义， 初步研究结果，我将利用约翰霍普金斯PH，ILD和肌炎中心的登记表型 CTD-ILD相关PH（CTD-ILD-PH）患者。我的首要目标是确定CTD-ILD-PH的比例 具有实质和血管表型的患者，并比较表型之间的疾病严重程度 在诊断的时候。为此，我将比较当时收集的各种疾病严重程度指标 目前和前瞻性入组我们登记研究的患者的PH诊断。这些措施将包括 全球和特定人群的生活质量问卷、6分钟步行距离、WHO功能分级，以及 通过超声心动图、血清NT-pro-BNP水平和右心导管检查进行血流动力学评估。 其次，比较接受表型一致性研究的CTD-ILD-PH患者的临床结局。 治疗与那些谁接受表型不一致的治疗，我将比较临床措施， 在PH治疗前后4到6个月，这项研究的结果将为以下方面提供数据： 为将来针对具有CTD-ILD实质和血管表型患者的PH治疗研究提供信息- PH和作为一个强大的基础，为未来的K级奖项。

PROJECT SUMMARY Pulmonary hypertension (PH) is a highly morbid disease with numerous causes but limited therapies. The avail- able medications are only known to be safe and effective for patients with very specific forms of PH. Recently, an inhaled medication, treprostinil, was approved for the treatment of PH related to interstitial lung disease (PH- ILD). Most PH-ILD studies have either focused on patients with idiopathic pulmonary fibrosis or ILD as an all- inclusive diagnosis. However, the various forms of ILD are distinct in their underlying pathophysiology and af- fected patient populations. Connective tissue disease-related ILD (CTD-ILD) is an understudied form of ILD which tends to affect young, ethnically diverse, female patients. The intersection of PH and CTD-ILD is particu- larly challenging as the PH may arise through fibrosis-induced ablation of pulmonary blood vessels or from endovascular dysfunction driven by the chronic inflammation of CTD. At this time, determining which mechanism underlies an individual CTD-ILD patient’s PH is left to the discretion of clinicians who must also decide which treatments to use based on their decision. These decisions are usually guided by subjective assessments of the degree of fibrosis seen on chest imaging (e.g., computed tomography [CT]), the severity of restrictive ventilatory defect measured during pulmonary function testing (PFT), and invasive hemodynamic measurements. In this proposal, I will use a CT- and PFT-based severity staging system which was validated in patients with sclero- derma ILD, to classify patients with CTD-ILD and PH as having either a parenchymal or vascular phenotype. When I applied this system to 20 patients in the Johns Hopkins PH Center Registry, 35% of these patients were reclassified and had received therapies discordant with their phenotype. To investigate the implications of these preliminary findings, I will leverage the Johns Hopkins PH, ILD, and Myositis Centers’ registries to phenotype patients with CTD-ILD-related PH (CTD-ILD-PH). My first aim is to determine the proportion of CTD-ILD-PH patients with parenchymal and vascular phenotypes and compare disease severity between phenotypes at the time of diagnosis. For this aim, I will compare various measures of disease severity collected at the time of PH diagnosis for patients currently and prospectively enrolled in our registries. These measures will include global and symptom-specific quality of life questionnaires, 6-minute walk distances, WHO functional class, and hemodynamic assessments by echocardiography, serum NT-pro-BNP levels, and right heart catheterization. Second, to compare the clinical outcomes of CTD-ILD-PH patients who receive phenotype-concordant therapy with those who receive phenotype-discordant therapy, I will compare the clinical measures de- scribed above before and after four to six months of PH therapy. Results from this study will provide data to inform future studies of PH therapies for patients with the parenchymal and vascular phenotypes of CTD-ILD- PH and serve as a strong foundation for a future K-level award.