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RationaleThe Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) trial demonstrated that sirolimus stabilized lung function and improved measures of functional performance and quality of life in patients with lymphangioleiomyomatosis. The physiologic mechanisms of these beneficial actions of sirolimus are incompletely understood.ObjectivesTo prospectively determine the longitudinal computed tomographic lung imaging correlates of lung function change in MILES patients treated with placebo or sirolimus.MethodsWe determined the baseline to 12-month change in computed tomographic image-derived lung volumes and the volume of the lung occupied by cysts in the 31 MILES participants (17 in sirolimus group, 14 in placebo group) with baseline and 12-month scans.Measurements and main resultsThere was a trend toward an increase in median expiratory cyst volume percentage in the placebo group and a reduction in the sirolimus group (+2.68% vs. +0.97%, respectively; P = 0.10). The computed tomographic image-derived residual volume and the ratio of residual volume to total lung capacity increased more in the placebo group than in the sirolimus group (+214.4 ml vs. +2.9 ml [P = 0.054] and +0.05 ml vs. -0.01 ml [P = 0.0498], respectively). A Markov transition chain analysis of respiratory cycle cyst volume changes revealed greater dynamic variation in the sirolimus group than in the placebo group at the 12-month time point.ConclusionsCollectively, these data suggest that sirolimus attenuates progressive gas trapping in lymphangioleiomyomatosis, consistent with a beneficial effect of the drug on airflow obstruction. We speculate that a reduction in lymphangioleiomyomatosis cell burden around small airways and cyst walls alleviates progressive airflow limitation and facilitates cyst emptying.

Author(s): Noah C. Schoenberg [sup.1] , Rahul G. Argula [sup.2] , Elizabeth S. Klings [sup.3] , Kevin C. Wilson [sup.3] [sup.4] , Harrison W. Farber [sup.5] Author Affiliations: (1) grid.239395.7, [...], Introduction Pulmonary hypertension (PH) in the setting of end-stage renal disease (ESRD) has important prognostic and therapeutic consequences. We estimated the prevalence of PH among patients with ESRD and compared mortality between ESRD patients with and without PH. Methods Two independent reviewers searched three databases using a search strategy built around the medical subject headings of "hypertension, pulmonary" and "kidney failure, chronic." Keywords and synonyms were also used. Study selection criteria included (1) Enrollment of patients with ESRD undergoing hemodialysis or peritoneal dialysis, (2) Assessment for the presence of PH using transthoracic echocardiography, and (3) Determination of PH prevalence or associated mortality. The primary outcomes were prevalence of PH or associated mortality. The Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence. Results The initial search identified 1046 publications, from which 41 studies were selected. The median prevalence of PH identified by echocardiographic criteria among patients with ESRD was 38% (range 8% to 70%), and was significantly increased in patients undergoing hemodialysis (HD) (median 40%, range 16-70%) as compared with peritoneal dialysis (PD) (median 19%, range 8-37%). Meta-analysis demonstrated that overall mortality was higher among ESRD patients with echocardiographic evidence of PH than ESRD patients without echocardiographic evidence of PH (RR 2.02; 95% CI 1.70-2.40). Conclusions Echocardiographic evidence of PH is common among ESRD patients undergoing dialysis and associated with increased mortality. Identification of those patients with evidence of pulmonary hypertension on transthoracic echocardiography may warrant further evaluation and treatment.

Systemic sclerosis (SSc) is a disease state characterized by a significant lifetime risk for the development of pulmonary hypertension (PH). SSc-associated PH is comprised of a heterogenous array of phenotypes. SSc patients are at risk for both precapillary and postcapillary PH conditions. These include pulmonary arterial hypertension (PAH), PH secondary to interstitial lung disease (ILD-PH), and left heart disease associated PH. SSc-PAH is a vasculopathy that is distinct from idiopathic PAH and probably PAH associated with other connective tissue diseases. This concise review provides an overview of the various forms of SSc-PH, as well as advances in the screening, therapeutic management, and risk stratification strategies for the various types of SSc-PH. As the same SSc patient often displays multiple overlapping PH groups, treatment decisions are complex and often need to be individualized. This review also attempts to provide a rational framework for the management of SSc-PH patients with overlapping disease phenotypes. [ABSTRACT FROM AUTHOR]

Advances in pulmonary arterial hypertension therapies have led to improvements in the quality of life and survival for patients with idiopathic pulmonary arterial hypertension, but these trends have not uniformly translated to patients with systemic sclerosis-associated pulmonary arterial hypertension. In order to better understand the heterogeneity in treatment response and survival, we aimed to examine the histological and immunophenotypic differences between the systemic sclerosis-associated pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension pulmonary vasculopathies. We performed a semi-quantitative lung morphometry-based analysis comparing sections obtained from systemic sclerosis-associated pulmonary arterial hypertension (n = 24), idiopathic pulmonary arterial hypertension (n = 9), and control (n = 13) bio-banked lung tissue specimens. H&E (Hematoxylin and Eosin) and VVG (Verhoeff-Van Gieson)-stained lung sections were analyzed for interstitial and vascular pathology. Immunohistochemistry was used to stain for an array of inflammatory and fibrosis mediators. Baseline demographic and hemodynamic data for each patient were collected via chart review at the time of lung explantation. Plexiform lesions were present in 5/9 (55%) of idiopathic pulmonary arterial hypertension samples, but absent in all systemic sclerosis-associated pulmonary arterial hypertension samples (0/24). Systemic sclerosis-associated pulmonary arterial hypertension lungs demonstrated significantly worse interstitial fibrosis (p = 0.0001) and interstitial cellularity (p = 0.0002) compared to idiopathic pulmonary arterial hypertension lungs. The degree of smooth muscle hypertrophy and pulmonary artery intimal proliferation were not different between systemic sclerosis-associated pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension lungs. Immunohistochemistry analysis revealed that systemic sclerosis-associated pulmonary arterial hypertension lungs exhibited increased interstitial infiltration of CD3 T-cells (p = 0.009), CD20 B-cells (p = 0.01), and CD163 macrophages (p = 0.048) when compared to idiopathic pulmonary arterial hypertension and control lungs. Systemic sclerosis-associated pulmonary arterial hypertension lungs display a distinct pulmonary vascular pathology as well as significant interstitial fibrosis when compared to idiopathic pulmonary arterial hypertension lungs., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Introduction: The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD., Methods: Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded., Results: At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and -19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL -1 at RCT baseline to 359 pg·mL -1 at week 64; and the absolute (% predicted) mean forced vital capacity change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinil versus placebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio 0.69 (95% CI 0.49-0.97); p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients., Conclusions: These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT., Competing Interests: Conflict of interest: A. Waxman reports that the present manuscript was funded by United Therapeutics; and reports grants or contracts with payments to his institution from United Therapeutics, Gossamer, Acceleron/Merck, ARIA CV and NIH/NHLBI, patents with Johnson & Johnson, and participation on a data safety monitoring board or advisory board for INSMED. R. Restrepo-Jaramillo reports research grants from Merck, United Therapeutics, Bayer and J&J Actelion, payment of honoraria for speakers bureaus from United Therapeutics, Bayer and J&J Actelion, and participation on advisory boards for Merck, United Therapeutics and Bayer. T. Thenappan reports grants for clinical research studies from United Therapeutics, Tenax Therapeutics, Aria CV and Merck, and consulting fees from United Therapeutics and Acceleron Pharma. P. Engel reports no disclosures. A. Bajwa reports a grant from United Therapeutics for study procedures, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics, Bayer, Johnson & Johnson, Boehringer Ingelheim, and Intuitive. A. Ravichandran reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics, Bayer, Abbott, Medtronic and Janssen. J. Feldman reports consulting fees from United Therapeutics, Aerovate, Altavant and Liquidia, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen and United Therapeutics, and participation on a data safety monitoring board or advisory board for Liquidia, Altavant and Aerovate. A. Hajari Case reports that the present manuscript is funded by United Therapeutics; and reports clinical research contracts to institution from United Therapeutics, and serving as Senior Medical Advisor for the Pulmonary Fibrosis Foundation. R.G. Argula reports consulting fees from Liquidia Corporation, United Therapeutics, Merck Pharma Inc., Janssen Inc. and CVS Health, and payment or honoraria for lectures and educational events from United Therapeutics. V. Tapson reports research grants paid to institution from Boston Scientific Corporation, Bristol Myers Squibb and Genentech, speaker and consulting fees from Janssen, fees from Boston Scientific Corporation for participating in an executive committee for a clinical trial, that he serves as President for PE Response Team Consortium (unpaid), owns stock in Thrombolex and Inari Medical, and that he is employed as VP of Medical Affairs at Inari Medical. P. Smith reports that he is an employee of the study sponsor, United Therapeutics. C. Deng and E. Shen report that they are employees of and hold stock in United Therapeutics, the study sponsor. S.D. Nathan reports that the present manuscript is funded by United Therapeutics; and reports consulting fees from United Therapeutics, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics., (Copyright ©The authors 2023.)