nintedanib and Hypertension--Pulmonary

Idiopathic pulmonary fibrosis (IPF) is characterized by relentlessly progressive lung function impairment that is consistently fatal in the absence of lung transplantation, as no curative pharmacological treatment exists. The pace of progression varies across patients, and acute life-threatening exacerbations occur unpredictably, causing further sharp drops in lung function. Recently introduced antifibrotic agents slow the pace of disease progression and may improve survival but fail to stop the fibrotic process. Moreover, the magnitude and kinetics of the response to these drugs cannot be predicted in the individual patient. These characteristics require that lung transplantation be considered early in the course of the disease. However, given the shortage of donor lungs, lung transplantation must be carefully targeted to those patients most likely to benefit. Current guidelines for lung transplantation listing may need reappraisal in the light of recent treatment advances. Patients with IPF often have multiple comorbidities such as coronary heart disease, frailty, and gastro-oesophageal reflux disease (GERD). Consequently, extensive screening for and effective treatment of concomitant conditions is crucial to appropriate candidate selection and outcome optimisation. A multidisciplinary approach is mandatory. Pulmonologists with expertise in IPF must work closely with lung transplant teams. Careful consideration must be given to preoperative optimisation, surgical technique, and pulmonary rehabilitation to produce the best post-transplantation outcomes.

Topics: Age Factors; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Comorbidity; Disease Progression; Frailty; Gastroesophageal Reflux; Humans; Hypertension, Pulmonary; Idiopathic Interstitial Pneumonias; Idiopathic Pulmonary Fibrosis; Indoles; Lung Neoplasms; Lung Transplantation; Prognosis; Pyridones; Telomere Shortening

Pulmonary hypertension (PH) due to chronic lung disease is associated with a poor prognosis, regardless of the underlying respiratory condition. Updated PH guidelines recommend optimal treatment of the underlying lung disease, including long-term oxygen therapy, in patients with chronic hypoxemia despite the lack of randomized controlled clinical trials supporting this statement. So far, randomized controlled trials of drugs approved for pulmonary arterial hypertension have yielded discouraging results in both interstitial lung diseases and COPD with PH. In some cases, the trials were terminated because of an increase in death and other major adverse events in the active treatment arm vs placebo. In cases of PH due to idiopathic pulmonary fibrosis, new therapies under investigation use a combination of novel antifibrotic treatments and other treatments approved for pulmonary arterial hypertension. The choice of robust end points as well as a target group of patients with specific hemodynamic criteria may help in the selection of innovative therapeutic strategies. The aim of this review is to discuss recent studies and clinical trials for the treatment of PH due to the main chronic respiratory diseases and to discuss possible future scenarios for the evaluation of new therapeutic strategies.

Topics: Antihypertensive Agents; Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endpoint Determination; Epoprostenol; Forecasting; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Indoles; Lung Diseases, Interstitial; Phosphodiesterase 5 Inhibitors; Pilot Projects; Protein-Tyrosine Kinases; Pulmonary Disease, Chronic Obstructive; Pyridones

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy, inflammation and fibrosis. These three main disease-determining pathways are the target of the currently available treatments used to possibly modify the progression of disease-related manifestations, although this synergy has not been fully applied on SSc joint, skin or lung involvement yet. Areas covered: we describe the current status of SSc treatment/therapy performing a literature search in MEDLINE/Pubmed and Thomson Reuter's Web of Science for articles published until March 2016. Moreover, ongoing registered clinical trials (RCTs) on SSc were searched through clinicaltrials.gov website. Expert commentary: presently, promising drugs are under evaluation to target the different pathogenic pathways of systemic sclerosis: Tocilizumab and Abatacept for skin and lung fibrosis; Riociguat and Selexipag are approved for pulmonary arterial hypertension but promising anti-fibrotic effects are now being studied. Finally, several anti-fibrotic molecules are currently involved in RCTs, such as Nintedanib, IVA-337, Terguride.

Topics: Abatacept; Acetamides; Antibodies, Monoclonal, Humanized; Biological Products; Clinical Trials as Topic; Fibrinolytic Agents; Fibrosis; Humans; Hypertension, Pulmonary; Indoles; Inflammation; Joints; Lisuride; Lung; PubMed; Pyrazines; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Skin

Maher has received grants, consulting fees, and speaker fees from GlaxoSmithKline and UCB and grants from Novartis. He has also received consulting fees and speaker fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, Lanthio, InterMune International AG (a wholly owned Roche subsidiary since 2014), F. Hoffmann-La Roche, Sanofi-Aventis, and Takeda. Maher is supported by a National Institute for Health Research Clinician Scientist Fellowship (NIHR Ref: CS:-2013-13-017). Dejonckheere is an employee of F. Hoffmann-La Roche. Nathan has received consulting fees from Roche-Genentech and Boehringer Ingelheim. He is also on the speakers bureau for Roche-Genentech and Boehringer Ingelheim and has received research funding from both companies. All authors contributed equally to study concept and design, data collection and analysis, and manuscript preparation.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Indoles; Phosphodiesterase 5 Inhibitors; Pyridones; Survival Rate

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with poor survival. Recent studies have improved understanding of IPF and new discoveries have led to novel treatment options, which now have become available for patients. In face of the newly available therapies we present an update on the pathophysiology and epidemiology of IPF. We discuss the typical clinical findings and elaborate diagnostic procedures according to current guidelines and our daily practice approach. The role of biomarkers will briefly be outlined. Finally, we discuss novel antifibrotic treatment options for IPF (pirfenidone, nintedanib) and the management of patients regarding to comorbidities and complications. Both pirfenidone and nintedanib were shown to reduce the progression of IPF and therefore represent novel therapeutic strategies in this so far untreatable chronic lung disease.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Disease Progression; Enzyme Inhibitors; Gastroesophageal Reflux; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Indoles; Practice Guidelines as Topic; Pyridones

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause that leads to respiratory failure and death within few years of diagnosis. Pulmonary hypertension (PH) is a common complication in IPF, where it is strongly associated with increased morbidity and mortality. Patients with IPF and PH have particularly poor prognosis, despite current best medical therapies and the anti-fibrotic therapy with pirfenidone or nintedanib. The aim of our study was to assess the clinical and prognostic impact of PH in patients affected by IPF, already treated with pirfenidone or nintedanib. Seventy-four consecutive outpatients with a diagnosis of IPF, in therapy with pirfenidone or nintedanib, were prospectively enrolled in the study. All patients underwent pulmonary and cardiology assessment by clinical exam, spirometry, DLCO test, chest CT, 6MWT and echocardiography performed by a cardiologist experienced in PH in an ambulatory setting under resting conditions. GAP index has been determinate for all patients. During follow-up, all patients were evaluated every 6 months, or less if necessary. Data about mortality were then collected in a 3-year follow-up. Of the seventy-four patients enrolled, 38 were treated with pirfenidone and 36 with nintedanib. The two groups were comparable for age, gender, FVC, DLCO and PAPS. The patients were also divided in four groups, based on presence of mild/moderate/severe PH by echocardiography at baseline. Significant differences were found for DLCO and the GAP index. Severity of PH was significantly associated with a reduction of DLCO and with an increased GAP index. Survival was directly correlated with 6MWT (R = 0.48), DLCO (R = 0.29, p < 0.01), and reversely with tGAP index (- 0.31, p < 0.01 in all cases), while no significant correlation was found with PAsP. 36-month survival analysis showed an HR of 4.05 (95% CI 1.07-7.34, p = 0.02) for DLCO < 50% and of 1.56 (95% CI 1.02-2.39, p = 0.03) for GAP index. The development and progression of PH in patients affected by IPF reduce the survival and the severity of PH is associated with a reduction of DLCO value and an increase of the GAP index. Echocardiographic stratification based on PAsP values may be useful in stratifying prognosis in IPF patients and deciding specific PAH drugs.

Topics: Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Indoles; Pyridones; Treatment Outcome

Nintedanib is an inhibitor of receptor tyrosine kinases, including vascular endothelial growth factor receptor, but its effects on pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) patients with chronic hypoxia were unclear.. This study included a nintedanib prospective study and historical control study. In the nintedanib prospective study, pulmonary artery systolic pressure (PASP) measured using transthoracic echocardiography was evaluated at six points during 48 weeks in 16 IPF patients in whom nintedanib was started. In the historical control study, adjusted annual change in PASP was compared between patients treated with (n = 16) and without (n = 15) nintedanib.. In the nintedanib prospective study, the mean PASP at 48 weeks after starting nintedanib was significantly higher compared to that at baseline. When IPF patients were divided into two groups, IPF patients with or without long-term oxygen treatment (LTOT), mean PASP at 48 weeks was significantly higher than that at baseline only in IPF patients receiving LTOT (P = 0.001). In the historical control study, adjusted annual change in PASP in IPF patients treated with nintedanib was significantly lower than that in patients treated with no antifibrotic agents when considering patients without LTOT (0.26 mmHg vs 7.05 mmHg; P = 0.011).. We found differential effects of nintedanib on PH between IPF patients with or without LTOT. Nintedanib may have a disadvantageous effect on PH in IPF patients with LTOT. Conversely, nintedanib treatment may be beneficial to PH in IPF patients without LTOT.

Topics: Aged; Aged, 80 and over; Echocardiography; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Indoles; Male; Middle Aged; Oxygen Inhalation Therapy; Prospective Studies; Protein Kinase Inhibitors; Retrospective Studies; Treatment Outcome

The patient was a 71-year-old man with severe idiopathic pulmonary fibrosis (IPF) and who demonstrated a slow deterioration of his respiratory condition. After nintedanib administration, his forced vital capacity and chest high-resolution computed tomography (HRCT) findings were stable, but his dyspnea on exertion were worsened. He was diagnosed with pulmonary hypertension (PH) by right heart catheterization (mean pulmonary arterial pressure: 30 mmHg). In this case, we suspected that nintedanib caused his PH, as his IPF had not progressed.

Topics: Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Indoles; Male; Tomography, X-Ray Computed; Vital Capacity

Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. We evaluated the inhibitory effects of nintedanib both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and we evaluated pulmonary hemodynamics and PAs pathology. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Endothelial Cells; HEK293 Cells; Humans; Hypertension, Pulmonary; Indoles; Muscle, Smooth; Muscle, Smooth, Vascular; Rats; Vascular Remodeling

Topics: Animals; Humans; Hypertension, Pulmonary; Indoles; Protein-Tyrosine Kinases; Rats, Inbred WKY

Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-related antigen-2 (Fra2) mouse model of systemic sclerosis (SSc).. The effects of nintedanib on pulmonary arterial hypertension with proliferation of pulmonary vascular smooth muscle cells (PVSMCs) and luminal occlusion, on microvascular disease with apoptosis of microvascular endothelial cells (MVECs) and on fibroblast activation with myofibroblast differentiation and accumulation of extracellular matrix were analysed. We also studied the effects of nintedanib on the levels of key mediators involved in the pathogenesis of SSc and on macrophage polarisation.. Nintedanib inhibited proliferation of PVSMCs and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Treatment with nintedanib also inhibited apoptosis of MVECs and blunted the capillary rarefaction in Fra2-transgenic mice. These effects were associated with a normalisation of the serum levels of vascular endothelial growth factor in Fra2 mice on treatment with nintedanib. Nintedanib also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice. The antifibrotic effects of nintedanib were associated with impaired M2 polarisation of monocytes and reduced numbers of M2 macrophages.. Nintedanib targets core features of SSc in Fra2-transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung disease.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Enzyme Inhibitors; Fibrosis; Fos-Related Antigen-2; Hypertension, Pulmonary; Indoles; Macrophage Activation; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Protein-Tyrosine Kinases; Pulmonary Artery; Scleroderma, Systemic; Vascular Endothelial Growth Factor A

Idiopathic pulmonary fibrosis is defined as chronic fibrosing interstitial pneumonia limited to the lung, with poor prognosis. The incidence has been rising in recent years probably due to improved diagnostic methods and increased life expectancy. In 2013, the SEPAR guidelines for the diagnosis and treatment for idiopathic pulmonary fibrosis were published. Since then, clinical trials and meta-analyses have shown strong scientific evidence for the use of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis. In 2015, the international consensus of 2011 was updated and new therapeutic recommendations were established, prompting us to update our recommendation for the medical treatment of idiopathic pulmonary fibrosis accordingly. Diagnostic aspects and non-pharmacological treatment will not be discussed as no relevant developments have emerged since the 2013 guidelines.

Topics: Adrenal Cortex Hormones; Disease Progression; Disease-Free Survival; Evidence-Based Medicine; Gastroesophageal Reflux; Gastrointestinal Diseases; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Indoles; Meta-Analysis as Topic; Pulmonary Emphysema; Pyridones; Randomized Controlled Trials as Topic; Societies, Medical; Spain

Topics: Algorithms; Animals; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Endothelin Receptor Antagonists; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Indoles; Pulmonary Artery; Pyrazoles; Pyridones; Pyrimidines; Rituximab; Scleroderma, Systemic; Sulfonamides

Idiopathic pulmonary fibrosis is defined as a chronic fibrosing interstitial pneumonia limited to the lung, of unknown cause, with poor prognosis and few treatment options. In recent years there has been an increase in their prevalence, probably due to the optimization of diagnostic methods and increased life expectancy. The ATS/ERS Consensus (2000) established the diagnostic criteria and recommendations for the assessment of the disease course and treatment. Later studies have helped to redefine diagnostic criteria and treatment options. In 2011, an international consensus was published, establishing diagnostic criteria and new treatment strategies. These guidelines have been updated with the newest aspects of diagnosis and treatment of idiopathic pulmonary fibrosis. A level of evidence has been identified for the most relevant questions, particularly with regard to treatment options.

Topics: Acetylcysteine; Biopsy; Bronchoalveolar Lavage Fluid; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Contraindications; Diagnostic Imaging; Disease Progression; Evidence-Based Medicine; Gastroesophageal Reflux; Genetic Therapy; Glucocorticoids; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Immunologic Factors; Incidence; Indoles; Lung; Lung Transplantation; Oxygen Inhalation Therapy; Palliative Care; Prevalence; Prognosis; Pulmonary Emphysema; Pyridones; Risk Factors; Spain