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

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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.