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Background: The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of poor outcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed to assess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in patients with advanced IPF and at risk of group 3 pulmonary hypertension. Methods: We did a multicentre, international, double-blind, randomised, placebo-controlled, phase 2b study at 56 university clinics, research hospitals, and tertiary sites in Canada, Europe (Belgium, Czech Republic, Germany, Greece, Hungary, Italy, the Netherlands, Spain, and Turkey), Israel, and Africa (Egypt and South Africa). Eligible patients (aged 40–80 years) had advanced IPF (carbon monoxide diffusing capacity ≤40% predicted at screening), and were at risk of group 3 pulmonary hypertension (mean pulmonary artery pressure of ≥20 mm Hg with pulmonary artery wedge pressure of ≤15 mm Hg on previous right-heart catheterisation, or intermediate or high probability of group 3 pulmonary hypertension on echocardiography as defined by the 2015 European Society of Cardiology and European Respiratory Society guidelines). Patients were randomly assigned 1:1 to oral sildenafil tablets (20 mg three times daily) or placebo, both in addition to oral pirfenidone capsules (801 mg three times daily), using a validated interactive voice-based or web-based response system with permuted block randomisation, stratified by previous right-heart catheterisation (yes or no) and forced expiratory volume in 1 s to forced vital capacity ratio (

Background: The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. Methods: The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Findings: Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI −8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [−31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. Interpretation: The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Funding: Boehringer Ingelheim.

Background: Sarcoidosis-related pulmonary hypertension (SRPH) is an entity associated with significant morbidity and mortality irrespective of disease severity, while the pathogenic mechanisms remain poorly understood. Methods: This cross-sectional study included consecutive patients with biopsy-proven sarcoidosis (n = 313) who were followed up in an outpatient setting from October 2002 through June 2010. All patients underwent clinical and cardiopulmonary evaluation, including cardiac MRI, to assess prevalence of SRPH and identify possible underlying pathophysiological mechanisms. Results: By Doppler echocardiographic criteria, 37 (11.8 %) patients were found to have pulmonary arterial systolic pressure (PASP) >40 mmHg. Twelve of the 37 patients agreed to undergo right heart catheterization and SRPH was confirmed in nine patients. Compared to patients without SRPH, those with SRPH were significantly older and had greater lung function impairment; disease duration did not differ between patients with and without SRPH. Multiple logistic regression analysis showed that diffusing capacity for carbon monoxide (DLCO) and age were independent determinants of SRPH. Pulmonary fibrosis and left ventricular diastolic dysfunction due to cardiac sarcoidosis or other comorbidities accounted for SRPH in the majority of patients. In the nonpulmonary fibrosis group, DLCO ≤ 50.65 (% predicted) was associated with SRPH (sensitivity = 77.8 %, specificity = 72.2 %; p = 0.031, AUC = 0.759). Conclusion: In a large cohort of sarcoidosis patients, this study found a prevalence of SRPH of about 12 %. Pulmonary fibrosis and left ventricular diastolic dysfunction due to cardiac sarcoidosis or other comorbidities are frequent pathogenic mechanisms. © 2012 Springer Science+Business Media New York.

Background and aim: Pulmonary fibrosis is a devastating disease with few treatment options. Angiogenesis that leads to aberrant vascular remodeling is regulated by an opposing balance of angiogenic and angiostatic factors. The present study aims to evaluate the role of three angiogenic (IL-8, ENA-78 and GRO-a) and three angiostatic (MIG, IP-10, ITAC) chemokines in bronchoalveolar lavage fluid (BALF), before and after treatment with Interferon gamma-1b (IFN gamma-1b). Patients and methods: We studied prospectively 20 patients (16 males, 4 females) of median age 68 years (range, 40-75) with histologically confirmed IPF/UIP. Patients were assigned to receive IFN gamma-1b 200 μg sc thrice a week. Angiogenic and angiostatic mediators' levels were measured by ELISA kits. Results: The levels of the angiogenic chemokines significantly decreased after 12 months (mo) of IFN-γ-1b treatment (median values in pg/ml, IL-8/CXCL8: 640 vs. 81, p