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Pulmonary hypertension (PH) complicates the treatment of interstitial lung disease (ILD) patients resulting in poor functional status and worse outcomes. Early recognition of PH in ILD is important for initiating therapy and considering lung transplantation. However, no standard exists regarding which patients to screen for PH‐ILD or the optimal method to do so. The aim of this study was to create a risk assessment tool that could reliably predict PH in ILD patients. We developed a PH‐ILD Detection tool that incorporated history, exam, 6‐min walk distance, diffusion capacity for carbon monoxide, chest imaging, and cardiac biomarkers to create an eight‐component score. This tool was analyzed retrospectively in 154 ILD patients where each patient was given a score ranging from 0 to 12. The sensitivity (SN) and specificity (SP) of the PH‐ILD Detection tool and an area‐under‐the‐curve (AUC) were calculated. In this cohort, 74 patients (48.1%) had PH‐ILD. A score of ≥6 on the PH‐ILD Detection tool was associated with a diagnosis of PH‐ILD (SN: 86.5%; SP: 86.3%; area‐under‐the‐curve: 0.920, p < 0.001). The PH‐ILD Detection tool provides high SN and SP for detecting PH in ILD patients. With confirmation in larger cohorts, this tool could improve the diagnosis of PH in ILD and may suggest further testing with right heart catheterization and earlier intervention with inhaled treprostinil and/or lung transplant evaluation.

Patients with PAH still experience disease progression and increased rates of hospitalizations; moreover, hospitalization is a harbinger of disease progression and early mortality (2, 3). [...]along with improving PAH treatment options, developing appropriate and accurate risk prediction is essential to make rational and individualized treatment decisions and, as such, improve outcomes in PAH. [...]most clinicians feel they are better decision-makers than they actually demonstrate in clinical practice. For these reasons, scoring systems are valuable additions to our clinical gestalt. [...]most surrogates we have used to define clinical status are not sufficiently accurate singly, nor has any grouping been studied in a robust, prospective manner. In all likelihood, this will mean using parameters from several different risk calculators to satisfy the requirements noted here. [...]we do not know whether certain parameters might differ depending on ethnicity or geographical region.

Inhaled treprostinil is approved for the treatment of pulmonary hypertension-associated interstitial lung disease (PH-ILD); however, it has not shown significant benefit in patients with a pulmonary vascular resistance (PVR) < 4 WU. As such, treatment for non-severe PH-ILD remains controversial. A total of 16 patients with non-severe PH-ILD were divided into two groups based on changes in PVR during exercise: a dynamic PVR group (n = 10), characterized by an increase in PVR with exertion, and a static PVR group (n = 6), with no increase in PVR with exercise. The dynamic PVR group received inhaled treprostinil, while the static PVR group was monitored off therapy. Baseline and 16-week follow-up values were compared within each group. At 16 weeks, the dynamic PVR group demonstrated significant improvements in mean 6 min walk distance (6MWD) (+32.5 m, p < 0.05), resting PVR (−1.04 WU, p < 0.05), resting mean pulmonary arterial pressure (mPAP) (−5.8 mmHg, p < 0.05), exercise PVR (−1.7 WU, p < 0.05), exercise mPAP (−13 mmHg, p < 0.05), and estimated right ventricular systolic pressure (−9.2 mmHg, p < 0.05). In contrast, the static PVR group remained clinically stable. These observations suggest that an exercise-induced increase in PVR, identified through Level 3 CPET, may help select patients with non-severe PH-ILD who are more likely to benefit from early initiation of inhaled treprostinil.

Pulmonary arterial hypertension (PAH) is a common complication for individuals with limited systemic sclerosis (lSSc). The identification and characterization of biomarkers for lSSc-PAH should lead to less invasive screening, a better understanding of pathogenesis, and improved treatment. Forty-nine PBMC samples were obtained from 21 lSSc subjects without PAH (lSSc-noPAH), 15 lSSc subjects with PAH (lSSc-PAH), and 10 healthy controls; three subjects provided PBMCs one year later. Genome-wide gene expression was measured for each sample. The levels of 89 cytokines were measured in serum from a subset of subjects by Multi-Analyte Profiling (MAP) immunoassays. Gene expression clearly distinguished lSSc samples from healthy controls, and separated lSSc-PAH from lSSc-NoPAH patients. Real-time quantitative PCR confirmed increased expression of 9 genes (ICAM1, IFNGR1, IL1B, IL13Ra1, JAK2, AIF1, CCR1, ALAS2, TIMP2) in lSSc-PAH patients. Increased circulating cytokine levels of inflammatory mediators such as TNF-alpha, IL1-beta, ICAM-1, and IL-6, and markers of vascular injury such as VCAM-1, VEGF, and von Willebrand Factor were found in lSSc-PAH subjects. The gene expression and cytokine profiles of lSSc-PAH patients suggest the presence of activated monocytes, and show markers of vascular injury and inflammation. These genes and factors could serve as biomarkers of PAH involvement in lSSc.

Background Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. Methods We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. Results We identified a common pathogenic gene expression signature—an immune–fibrotic axis—indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an “inflammatory” SSc gene expression signature. Conclusions Our results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.

ABSTRACT Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, proliferation, fibrosis, and microthrombosis of the pulmonary vasculature, which causes elevated pulmonary arterial pressure and vascular resistance leading to right ventricular failure and death. Previous treatments targeted three known pathways involved in the development of PAH: endothelin, nitric oxide, and prostacyclin. Dysfunctional signaling of the transforming growth factor‐beta (TGF‐β) family, via bone morphogenetic protein (BMP) receptor 2 and activin signaling, has also been implicated in PAH leading to the development of a new class of therapies. Sotatercept, the first medication in this class, has shown significant promise as an add‐on therapy. Another drug in the class, cibotercept, is under investigation; however, the clinical trial has been suspended because of the development of pericardial effusions in some patients. In light of this new finding, we investigated whether our patients treated with sotatercept also experienced this possible side effect.

Pulmonary hypertension (PH) results in increased morbidity and mortality in patients with interstitial lung disease (ILD). Early recognition of PH in this population is essential for planning diagnostic testing, initiating therapy, and evaluating for lung transplantation. The previously developed PH‐ILD Detection tool has significant potential in the evaluation and treatment of ILD patients; the aim of this study was to validate the tool in an independent, multicenter cohort of patients. We conducted a retrospective review of prospectively collected data from 161 ILD patients. Patients were stratified into low‐ ( n  = 78, 48.4%), intermediate‐ ( n  = 54, 33.5%), and high‐risk ( n  = 29, 18.0%) groups based on the score obtained with the tool. Intermediate‐ and high‐risk patients underwent follow‐up echocardiogram (TTE); 49.4% ( n  = 41) had an abnormal TTE suggestive of underlying PH. These patients underwent right heart catheterization; PH‐ILD was diagnosed in 73.2% ( n  = 30) of these cases. The PH‐ILD Detection tool has a sensitivity of 93.3%, specificity of 90.9%, and area‐under‐the‐curve of 0.921 for diagnosing PH in ILD patients, validating the findings from the original study and establishing the tool as a fundamental resource for early recognition of PH in ILD patients.