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It is assumed that in candidates for TNF-alpha inhibitor (TNFi) treatment, tuberculin skin test (TST) may be unreliable, since BCG vaccination causes false positive and drugs cause false negative results, favoring the use of Quantiferon or T-spot assays. However, these tests may not be readily available in all parts of the world. We aimed to determine the reliability of TST with respect to BCG vaccination and drugs in candidates for TNFi treatment, and how isoniazid is tolerated, assuming that the use of TST would result in increased isoniazid use. We included 1031 adult patients who were prescribed a TNFi for the first time. We analysed the association of BCG and drugs with TST and Quantiferon results, the determinants of a positive TST, and evaluated the tolerability of isoniazid. BCG vaccination and male sex were associated with positive TST (OR 3.56, 95% CI 1.98-6.41 and OR 2.54, 95% CI 1.75-3.68, respectively), while prednisolone and azathioprine were associated with negative TST (OR 0.63, 95% CI 0.43-0.91 and OR 0.40, 95% CI 0.11-0.76). Isoniazid was prescribed to 684 (66.3%) patients and had to be discontinued in 12.2% of these before 9 months, most commonly due to hepatotoxicity (44%). One patient developed tuberculosis despite isoniazid use. BCG vaccination may be associated with false positive TST, despite a long time since vaccination in candidates for TNFi treatment. Prednisolone and azathioprine use were associated with negative TST. Despite the high frequency of isoniazid use associated with using TST instead of QTF, isoniazid was generally well tolerated.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

Objective This study aimed to analyze the role of chronic thromboembolic pulmonary hypertension (CTEPH) in patients with persistent chest symptoms after acute PE. Methods Patients aged between 18 and 80 years who were followed up for acute PE were screened for chest symptoms which persisted after the anticoagulation treatment. Patients suffering other types of pulmonary hypertension (PH) or metastatic malignancies were excluded in this study. Demographic and functional data of patients included this study were collected. The patients underwent transthoracic echocardiography and ventilation/perfusion (VQ) scans. Also, invasive hemodynamic studies were done to patients with intermediate/high probability of VQ scans. Results Of the 140 patients screen for this study, 29 patients (Female/Male=16/13) with mean age of 56.1±11.2 years and follow-up time of 35.1±17.7 months met the inclusion criteria. The mean systolic pulmonary artery blood pressure (sPAP) on transthoracic echocardiography was 28.9±4.9 mm Hg (range=20-40 mm Hg). Furthermore, intermediate or high probability of VQ scans was detected in 2 patients, who were subsequently diagnosed with CTEPH (6.9%) via right heart catheterization. Conclusion CTEPH was diagnosed at a low rate in patients with persistent chest symptoms after the anticoagulation treatment for PE. CTEPH is still an elusive entity, which requires a multidisciplinary and invasive approach.

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, whose build-up scar tissue is induced by several molecules. Gastrin-releasing peptide (GRP) is released from pulmonary neuroendocrine cells, alveolar macrophages, and some nerve endings in the lung. A possible role of GRP in IPF is unclear. We aimed to investigate the fibrotic response to GRP, at the cellular level in MRC5 and A549 cell lines. The proliferative and fibrotic effects of GRP on these cells were evaluated by using BrdU, immunoblotting, immunofluorescence and qRT-PCR for molecules associated with myofibroblast differentiation, TGF-β and Wnt signalling. All doses of GRP increased the amount of BrdU incorporation in A549 cells. In contrast, the amount of BrdU increased in MRC5 cells in the first 24 h, though progressively decreased by 72 h. GRP did not stimulate epithelial-mesenchymal transition in A549 cells, rather, it stimulated the differentiation of MRC5 cells into myofibroblasts. Furthermore, GRP induced gene and protein expressions of p-Smad2/3 and Smad4, and reduced the levels of Smad7 in MRC5 cells. In addition, GRP decreased Wnt5a protein levels and stimulated β-catenin activation by increasing Wnt4, Wnt7a and β-catenin protein levels. GRP caused myofibroblast differentiation by inducing TGF-βand Wnt pathways via paracrine and autocrine signalling in MRC5 cells. In conclusion, GRP may lead to pulmonary fibrosis due to its proliferative and fibrotic effects on lung fibroblasts. The abrogation of GRP-mediated signal activation might be considered as a treatment modality for fibrotic lung diseases., Scientific Research Projects Coordination Unit of Istanbul University

WOS:000526091700006 PubMed ID: 32281955 Objective: Chronic obstructive pulmonary disease (COPD) is associated with atrial fibrillation (AF) and reduced forced expiratory volume (FEV1) is an independent predictor for new onset AF. The aims of this study were (1) to analyze the atrial electromechanical delay (AEMD) and P wave dispersion which are two predictors of AF development in patients with COPD and without any cardiovascular disease, and (2) to assess the relationship of those with pulmonary functions as quantified by FEV1 measurements. Methods: The study included 41 patients with COPD (33 male; mean age: 51 years) and 32 healthy controls. P wave dispersion was calculated as the difference between the maximum and minimum P wave duration in a 12-lead surface electrocardiography (ECG) recording. AEMD, defined as the time interval from the P wave onset on the ECG to the initiation of the late diastolic (Am) wave using a tissue Doppler examination, was measured from the lateral mitral annulus (LAEMD), septal annulus (SAEMD), and tricuspid lateral annulus (TAEMD). Results: P wave dispersion was significantly longer in the COPD group than those in the controls (76 +/- 19 ms vs. 45 +/- 10 ms; p

Pulmonary emphysema leads to a cascade of events starting with enlarged alveoli, loss of alveoli and, subsequently to the damage and disruption of pulmonary epithelium. The integrity of the pulmonary epithelium, which is constituted by pneumocytes linked to each other through E-cadherin proteins, is important for respiration. The aim of the present study was to detect the content and destruction of E-cadherin protein and to investigate the contribution of E-cadherin to pulmonary emphysema pathogenesis. The structural changes, reparative capacity of the pulmonary epithelium, amount of E-cadherin protein and, the immunoreactivity of neural precursor cell expressed developmentally down-regulated protein 9 (NEDD9) were evaluated in emphysematous (n=7) and non-emphysematous (n=6) areas of lung samples taken from patients with chronic obstructive pulmonary disease. Emphysematous areas are characterized by enlarged alveoli, disrupted alveolar walls and epithelium, increased type 2 pneumocytes and NEDD9 immunoreactivity, and reduced E-cadherin proteins. Our data shows that E-cadherin levels are decreased in emphysematous areas due to its degradation by NEDD9. Decreased E-cadherin levels also lead to the disintegration of the pulmonary epithelium by causing the presence of weakness intercellular connections or the absence of intercellular connections. The repair of the pulmonary epithelium could not complete due to the reduced E-cadherin, because type 2 pneumocytes could not differentiate into type 1 pneumocytes. In conclusion, the reduced E-cadherin levels lead to emphysematous alterations in human lungs and contributes to pulmonary emphysema pathogenesis.

Additional file 2: Table S1. The effect of different concentrations of GRP on the viability and proliferation of human lung adenocarcinoma (A549) and human fetal lung fibroblast (MRC5) cells.

Introduction: Pulmonary neuroendocrine cells (PNECs) play important roles in lung biology, such as cell proliferation and differentiation, and the lung development. Their possible roles in pulmonary fibrosis have not been investigated in detail. Gastrin-releasing peptide (GRP) released from PNECs leads to the fibrosis by increased immunoreactivities of pSmad2/3, collagen and alpha-smooth muscle actin (α-SMA) in the mice lungs. However, the molecular mechanism of this effect has not been elucidated in this study. Aims and objectives: We aimed to investigate the fibrotic response of GRP at the molecular level on human lung fibroblasts (MRC5). Methods: MRC5 cells were stimulated for 24, 48 and 72 hours with GRP at a dose range of 10-5-10-7M. The proliferative and fibrotic effects of GRP on the cells were evaluated by proliferation assay, immunoblotting (Smad-TGF-β and Wnt pathways), and qRT-PCR analysis. Results: The protein expressions of α-SMA and fibronectin were increased by GRP (10-5M) as a manner of time-dependent. In addition, GRP induced the gene and protein expressions of p-Smad2/3 and Smad4, and reduced the levels of Smad7 in these cells. And also, GRP treatment increased the protein levels of Wnt4 and Wnt5a as well as β-catenin activation in fibroblasts, while it reduced Dkk1 protein level. The proliferative effect of GRP on fibroblasts was observed in the first 24 hours. Conclusion: GRP induced myofibroblast differentiation, by inducing of Smad-dependent TGF-β and Wnt signaling pathways. GRP may lead to pulmonary fibrosis due to its proliferative and fibrotic effects on fibroblasts. Thus, the prevention of GRP-mediated signal activation can be considered in the treatment of fibrotic lung diseases.

Patients with pulmonary hypertension (PH) show no symptoms at rest, but symptoms are triggered by physical activities.The primary aim of our study was to assess physical activity of patients with PH by using an activity monitor. The secondary aim was to evaluate the correlation between the activity monitor parameters and 6-min walk distance (6MWD), activity of daily living (ADL), quality of life, WHO functional class and PH classification.Thirty-eight patients with pulmonary arterial hypertension (PAH) and seven patients with chronic thromboembolic PH were included in the study. Physical activity was assessed using a SenseWear arm band. A 6-min walk test was performed. Daily living activities were assessed using the 'nottingham extended activity of daily living index' (NEADL). For quality of life assessments, 'Minnesota living with heart failure' (MLHF) and 'Short form-36' (SF-36) surveys were used.Physical activity, exercise capacity, quality of life and contribution to ADL were lower in patients with PH. These data were associated with the 6MWD, quality of life and ADL index scores. We also found weak and moderate correlations between activity monitor data and SF-36 sub-group scores, MLHF and NEADL scores (P 0.05). For the group with PAH, idiopathic PAH patients had more exercise capacity and total energy expenditure compared with patients with scleroderma-associated PAH.Correlation between activity monitor data and 6MWD, most of SF-36 sub-group scores, MLHF scores and NEADL index scores suggest that activity monitor can be used in the evaluation of patients with PH.

Background: TNFα-inhibitor(TNF-αI) treatment increases tuberculosis(Tb) risk.Whenever Tb develops, guidelines recommend to stop TNF-αIs.However, this may result in flare of the underlying disease.There is limited data about the safety of re-administration of biologics. Objective: To determine the safety of re-administration of biologic agents in patients who developed Tb during TNF-αI-treatment. Methods: 21 of 1867 rheumatology patients(11 men, mean age 38.4±13.2 years;mean disease duration 10.6±7.8 years) developed Tb(8 pulmonary, 13 extrapulmonary) under TNF-αI(15 with infliximab,3 adalimumab,3 etanercept).The mean follow-up period was 38.1±28.5 months. Results: Among 21 Tb patients,1 had military-Tb and died during the first month of Tb-treatment.TNF-αI was restarted in 15/20 remaining patients(75%).In 3 patients TNF-αI was restarted while Tb-treatment was ongoing (etanercept in 1 Behcet9s patient at month 3,rituximab in 2 RA patients at month 4),and in 12 patients, median 3.5 months (IQR:0.6-22.2 months) after Tb-treatment was completed.Tb relapsed as pulmonary-Tb in one Behcet patient on 18th month of infliximab. Infliximab was stopped and Tb-retreatment started for 6 months.At the 3rd month of Tb-treatment,etanercept was started due to severe uveitis and switched to canakinumab due to inadequate response after 15 months.After 3rd dose of canakinumab,the patient developed TB-meningitis and received another 9 months of anti-Tb treatment and is currently stable on Interferon-alpha therapy for 16 months. Conclusion: Biologic agents including TNF-αI,can be restarted in patients who had previously developed Tb under anti-TNF treatment.Careful follow-up for TB relapse is required.

Aims: TNF-alpha inhibitors widely used for the treatment of chronic inflammatory diseases in recent years. The increased risk of tuberculosis (TB) is the most important side effects of TNF-alpha inhibitors useage. We want to share the features of 19 patients who developed TB during the treatment of TNF-alpha inhibitors. Findings: The data files of patients who admitted to approval for the TNF-alpfa inhibitors treatment, were retrospectively evaluated between 2002-2014. 19 patients developped TB. 9(%47) patients were female, 10(%53) were male. The average age of patients were 38,4±13,9. 12(%63.2) patients were still smoking (40±11,8 packet-year), 7(%36,8) patients who never smoked. The primary disease for using TNF alpha inhibitors treatment were; 10 patients with ankylosing spondylitis, 4 Rheumatoid Arthritis, 3 patients with Behcet9s disease, 1 Takayasu Arteritis, 1 Psoriatic Arthritis. 9 patients used Infliximab, 6 Adalimumab, 4 Enbrel treatment. The PPD values of the patient;7 patients were 0mm, 11 were ppd ≥5mm, we didnt apply ppd test to 1 patient because of previous history of anti-tuberculosis treatment. 11 (%57,7) patients received INH prophylaxis, 8 (%42.1) patients didn9t. Culture positive pulmonaryTB occurred in 7 patients (%36,8), 12 (63.2%) patients developped extrapulmonary TB (4 miliary TB, 3 tuberculous pleurisy, 2 patients with gastrointestinal TB, 1 tuberculosis lymphadenitis, 1 urogenital TB, 1 ear TB). All patients have completed the tuberculosis treatment. Conclusion: The TB risk is increased in patients who use TNF alpha inhibitor therapy, and majority of them are extrapulmonary tuberculosis. The clinicians must be careful in terms of extrapulmonary tuberculosis in these patients.

Introduction and aim: Progressive systemic sclerosis (pSS) is a multisystemic connective tissue disease characterized by fibrosis of the skin and internal organs including lung. The mechanisms that leads to progressive lung fibrosis in scleroderma remain obscure. In this study, we aimed to investigate the correlation between HRCT findings and patients' clinical and functional status and the degree of alveolitis based on the BAL resultsMaterials and methods: 65 patients with pSS were evaluated. Thoracic HRCT, pulmonary function tests, and dyspnea measurements were applied, and BAL was performed. The parenchymal abnormalities identified on HRCT were coded, and scored according to Warrick et al.Among parameters investigated, a correlation was found between the number of segments with subpleural cysts and the duration of disease. Also there was a correlation between the HRCT score and patient age whereas no correlation was detected between the duration of the disease, manifestation of the symptoms, and the x-ray findings. A correlation was found between the percentage of neutrophils detected in BAL and the extent of the honeycombing on HRCT.This study showed a strong correlation between the extent of x-ray abnormalities and FVC, RV, and DLCO, as well as an increase in the percentage of BAL fluid neutrophils in patients with SSc-PI.

WOS: 000288959600009, PubMed ID: 20946338, Background and objective: Extrapulmonary sarcoidosis is common, and is almost always associated with concomitant thoracic involvement. Extrapulmonary manifestations vary on the basis of gender, age at presentation and ethnicity. The aim of this study was to investigate extrapulmonary involvement in patients with sarcoidosis in Turkey. Methods: This study was conducted by Turkish Thoracic Society Clinical Problems Study Group. New cases of sarcoidosis between 1 June 2004 and 31 May 2006 were recorded on electronic case record forms sent to all potential investigators and information about extrapulmonary involvement was collected. Results: One hundred and nineteen of 293 patients (83 female, 36 male, mean age = 45 +/- 12 years) had extrapulmonary involvement in this study (40.6%). The median time to diagnosis was 6 months and this was longer than patients with just thoracic sarcoidosis (P = 0.001). Extrapulmonary symptoms were present in 181 (61.8%) patients, and skin lesions, arthralgia and back pain were the commonest (33.4%, 20.8% and 16.4%, respectively). Incidence of organ involvement was independent of age with the exception of ocular involvement, which was higher in those under the age of 40 years (P = 0.007). Conclusions: Skin and peripheral lymph node involvement were the most common sites of extrapulmonary involvement and ocular involvement was more common in those under the age of 40 years in patients with sarcoidosis in a Turkish population.