FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2513609898> ?p ?o ?g. }

• W2513609898 endingPage "1386" @default.
• W2513609898 startingPage "1371" @default.
• W2513609898 abstract "Among the interstitial lung diseases (ILDs), idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis, and fibrotic connective tissue disease-related ILD are associated with a worse prognosis, with death occurring as a result of both respiratory failure and serious associated comorbidities. The recent development and approval of the antifibrotic agents nintedanib and pirfenidone, both of which reduced the rate of decline in lung function in patients with IPF in clinical trials, offer hope that it may be possible to alter the increased mortality associated with IPF. Although chronic hypersensitivity pneumonitis and connective tissue disease related-ILD may be associated with an inflammatory component, the evidence for the use of immunosuppressive agents in their treatment is largely limited to retrospective studies. The lack of benefit of immunosuppressive therapy in advanced fibrosis argues for rigorous clinical trials using antifibrotic therapies in these types of ILD as well. Patients with fibrotic ILD may benefit from identification and management of associated comorbid conditions such as pulmonary hypertension, gastroesophageal reflux, and OSA, which may improve the quality of life and, in some cases, survival in affected individuals. Because early assessment may optimize posttransplantation outcomes, lung transplant evaluation should occur early in patients with IPF and those with other forms of fibrotic ILD. Among the interstitial lung diseases (ILDs), idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis, and fibrotic connective tissue disease-related ILD are associated with a worse prognosis, with death occurring as a result of both respiratory failure and serious associated comorbidities. The recent development and approval of the antifibrotic agents nintedanib and pirfenidone, both of which reduced the rate of decline in lung function in patients with IPF in clinical trials, offer hope that it may be possible to alter the increased mortality associated with IPF. Although chronic hypersensitivity pneumonitis and connective tissue disease related-ILD may be associated with an inflammatory component, the evidence for the use of immunosuppressive agents in their treatment is largely limited to retrospective studies. The lack of benefit of immunosuppressive therapy in advanced fibrosis argues for rigorous clinical trials using antifibrotic therapies in these types of ILD as well. Patients with fibrotic ILD may benefit from identification and management of associated comorbid conditions such as pulmonary hypertension, gastroesophageal reflux, and OSA, which may improve the quality of life and, in some cases, survival in affected individuals. Because early assessment may optimize posttransplantation outcomes, lung transplant evaluation should occur early in patients with IPF and those with other forms of fibrotic ILD. Interstitial lung diseases (ILDs) are a diverse group of parenchymal pulmonary disorders characterized by varying degrees of inflammation and fibrosis. When pulmonary fibrosis predominates, ILDs are especially challenging to manage and treat. Idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (cHP), and connective tissue disease-related ILD (CTD-ILD) are associated with significant mortality.1King Jr., T.E. Tooze J.A. Schwarz M.I. Brown K.R. Cherniack R.M. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.Am J Respir Crit Care Med. 2001; 164: 1171-1181Crossref PubMed Google Scholar, 2Mooney J.J. Elicker B.M. Urbania T.H. et al.Radiographic fibrosis score predicts survival in hypersensitivity pneumonitis.Chest. 2013; 144: 586-592Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Kocheril S.V. Appleton B.E. Somers E.C. et al.Comparison of disease progression and mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia.Arthritis Rheum. 2005; 53: 549-557Crossref PubMed Scopus (0) Google Scholar Other less well-characterized types of fibrotic ILD include fibrotic nonspecific interstitial pneumonia and interstitial pneumonia with autoimmune features, with a usual interstitial pneumonia (UIP) pattern. Although a conservative approach to management has been advocated in early or mild ILD, antiinflammatory and immunosuppressive therapies are considered and often prescribed when progression of CTD-ILD and cHP occurs despite the largely unproven efficacy in these disorders. A recently completed trial comparing mycophenolate mofetil with oral cyclophosphamide in systemic sclerosis-associated interstitial lung disease (SSc-ILD) showed noninferiority with mycophenolate mofetil.4Tashkin D.P. Roth M.D. Clements P.J. et al.Sclerodema Lung Study II InvestigatorsMycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Two novel antifibrotic agents, nintedanib and pirfenidone, which slowed lung function decline and disease progression in patients with IPF and mild to moderate lung disease, are now approved for the treatment of IPF, a generally progressive and fatal disorder. No strong recommendations can be made regarding the use of nintedanib or pirfenidone in cHP or fibrotic CTD-ILD until the safety and efficacy of these agents are formally evaluated in such populations. Adjunct therapies for patients with fibrotic ILD include oxygen to correct hypoxemia and the identification and treatment of comorbidities. The present article reviews the most recent advances in the clinical management and medical therapy for the three common fibrotic ILDs: IPF, cHP, and CTD-ILD. IPF, the most prevalent idiopathic interstitial pneumonia, has a median survival of 3 to 5 years from diagnosis.1King Jr., T.E. Tooze J.A. Schwarz M.I. Brown K.R. Cherniack R.M. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.Am J Respir Crit Care Med. 2001; 164: 1171-1181Crossref PubMed Google Scholar, 5Fernandez Perez E.R. Daniels C.E. Schroeder D.R. et al.Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study.Chest. 2010; 137: 129-137Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Raghu G. Idiopathic pulmonary fibrosis: guidelines for diagnosis and clinical management have advanced from consensus-based in 2000 to evidence-based in 2011.Eur Respir J. 2011; 37: 743-746Crossref PubMed Scopus (0) Google Scholar Although its etiology remains unknown, potential risk factors for IPF include cigarette smoking, gastroesophageal reflux, and certain environmental exposures.7Raghu G. Collard H.R. Egan J.J. et al.An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.Am J Respir Crit Care Med. 2011; 183: 788-824Crossref PubMed Scopus (1979) Google Scholar Its pathophysiology is currently believed to involve epithelial injury with abnormal wound healing. The initial conception of the pathogenic process in IPF as partially inflammatory resulted in consideration of broad immunosuppression as a potential therapy. However, the Prednisone, Azathioprine and N-Acetylcysteine: A Study That Evaluates Response in IPF (PANTHER) trial showed that prednisone, azathioprine, and N-acetylcysteine (NAC) resulted in increased mortality compared with placebo.8Raghu G. Anstrom K.J. King Jr., T.E. Lasky J.A. Martinez F.J. Idiopathic Pulmonary Fibrosis Clinical Research NetworkPrednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.N Engl J Med. 2012; 366: 1968-1977Crossref PubMed Scopus (0) Google Scholar In addition, NAC alone was not beneficial in patients with IPF who had mild to moderate impairment of lung function.9Martinez F.J. de Andrade J.A. Anstrom K.J. King Jr., T.E. Raghu G. Idiopathic Pulmonary Fibrosis Clinical Research NetworkRandomized trial of acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2093-2101Crossref PubMed Scopus (0) Google Scholar These studies demonstrated the necessity and ability of well-designed clinical trials to elucidate the safety and efficacy of therapy in IPF. More recently, clinical trials have focused on therapies that attenuate fibrosis. Pirfenidone is an oral agent recently approved by the US Food and Drug Administration (FDA) for the treatment of IPF (Table 1). It is a pyridone analogue with multiple potential mechanisms of action, including the inhibition of cytokines that play key roles in fibrosis and inflammation such as transforming growth factor-β (TGF-β) and tumor necrosis factor-α.10Grattendick K.J. Nakashima J.M. Feng L. Giri S.N. Margolin S.B. Effects of three anti-TNF-alpha drugs: etanercept, infliximab and pirfenidone on release of TNF-alpha in medium and TNF-alpha associated with the cell in vitro.Int Immunopharmacol. 2008; 8: 679-687Crossref PubMed Scopus (43) Google Scholar, 11Oku H. Nakazato H. Horikawa T. Tsuruta Y. Suzuki R. Pirfenidone suppresses tumor necrosis factor-alpha, enhances interleukin-10 and protects mice from endotoxic shock.Eur J Pharmacol. 2002; 446: 167-176Crossref PubMed Scopus (101) Google Scholar, 12Nakayama S. Mukae H. Sakamoto N. et al.Pirfenidone inhibits the expression of HSP47 in TGF-beta1-stimulated human lung fibroblasts.Life Sci. 2008; 82: 210-217Crossref PubMed Scopus (67) Google Scholar, 13Oku H. Shimizu T. Kawabata T. et al.Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis.Eur J Pharmacol. 2008; 590: 400-408Crossref PubMed Scopus (0) Google Scholar Oral administration results in peak serum concentrations at 30 min in fasting older adults or approximately 4 h when taken with food; its mean elimination half-life approaches 2.4 h.14Rubino C.M. Bhavnani S.M. Ambrose P.G. Forrest A. Loutit J.S. Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults.Pulm Pharmacol Ther. 2009; 22: 279-285Crossref PubMed Scopus (39) Google Scholar, 15Costabel U. Bendstrup E. Cottin V. et al.Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events.Adv Ther. 2014; 31: 375-391Crossref PubMed Scopus (31) Google ScholarTable 1Potential Therapies for Fibrotic Interstitial Lung DiseaseDiseaseMedicationDoseMechanism of ActionIdiopathic pulmonary fibrosisNintedanib150 mg bidKinase inhibitor; inhibition of VEGFR 1-3, FGFR 1-3, PDGFR α and βPirfenidone801 mg tidPossible inhibition of transforming growth factor-β and tumor necrosis factor-αChronic hypersensitivity pneumonitisPrednisone0.5-1 mg/kg/d up to 60 mg/d, then tapered to lowest effective doseInhibition of multiple inflammatory cytokinesConnective tissue disease-associatedPrednisone0.5-1 mg/kg/d up to 60 mg/dDoses > 20 mg/d are not advised in SScInhibition of multiple inflammatory cytokinesAzathioprine1.5-2 mg/kg/dPurine antagonist; inhibition of cellular and humoral immunityCyclophosphamide1-2 mg/kg/d po or 500-1,000 mg IV every 4 wkAlkylating agent; crosslinks DNAMycophenolate mofetil1,000 mg bid up to 3,000 mg/dInhibition of B- and T-lymphocyte proliferationRituximab1,000 mg IV, repeat in 2 wkMonoclonal antibody which binds and depletes B-lymphocyte CD20Tacrolimus1 mg bid titrated by 1 mg based on trough levelsCalcineurin inhibitor; inhibits activation of T-lymphocytesAll these medications are given by mouth unless otherwise indicated.FGFR = fibroblast growth factor receptor; PDGFR = platelet-derived growth factor receptor; SSc = systemic sclerosis; VEGFR = vascular endothelial growth factor receptor. Open table in a new tab All these medications are given by mouth unless otherwise indicated. FGFR = fibroblast growth factor receptor; PDGFR = platelet-derived growth factor receptor; SSc = systemic sclerosis; VEGFR = vascular endothelial growth factor receptor. Five randomized, double-blind, placebo-controlled trials have evaluated the clinical efficacy and safety of pirfenidone in patients with IPF. The first such Phase 2 trial showed that patients treated with pirfenidone 1,800 mg/d experienced a significant reduction in the decline of their vital capacity at 9 months and were free of IPF exacerbations.16Azuma A. Nukiwa T. Tsuboi E. et al.Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2005; 171: 1040-1047Crossref PubMed Scopus (0) Google Scholar These findings prompted a Phase 3 clinical trial17Taniguchi H. Ebina M. Kondoh Y. et al.Pirfenidone in idiopathic pulmonary fibrosis.Eur Respiratory J. 2010; 35: 821-829Crossref PubMed Scopus (0) Google Scholar using different doses of pirfenidone that reported a significantly reduced decline in the vital capacity of patients taking the highest dose of pirfenidone compared with placebo. Progression-free survival defined as time until death and/or ≥ 10% decline in vital capacity was greater in the pirfenidone group. These studies led to the approval of pirfenidone for the treatment of IPF in Japan in 2008.18Cottin V. The role of pirfenidone in the treatment of idiopathic pulmonary fibrosis.Respiratory Res. 2013; 14: S5PubMed Google Scholar Two similarly designed international Phase 3 trials (Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes) [CAPACITY] 004 and 006) were conducted in North America, Europe, and Australia (Table 2).19Noble P.W. Albera C. Bradford W.Z. et al.Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials.Lancet. 2011; 377: 1760-1769Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar, 20Loeh B. Drakopanagiotakis F. Bandelli G.P. et al.Intraindividual response to treatment with pirfenidone in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2015; 191: 110-113Crossref PubMed Google Scholar In CAPACITY-004, patients treated with pirfenidone 2,403 mg/d had a significantly reduced decline in percent predicted FVC of –8.0% vs –12.4% in the placebo group at 72 weeks. CAPACITY-006 found no significant difference in change in FVC between these groups. The decline in the 6-min walk test was significantly reduced in patients taking 2,403 mg/d in the pooled analysis of both trials. Assessment of data from both CAPACITY and the Japanese trials led to the approval of pirfenidone in the European Union in 2011.21Kreuter M. Pirfenidone: an update on clinical trial data and insights from everyday practice.Eur Respir Rev. 2014; 23: 111-117Crossref PubMed Scopus (21) Google ScholarTable 2Recent Trials in Fibrotic Interstitial Lung DiseaseDiseaseTrial/MedicationPrimary End Point/ObjectiveOutcomesIdiopathic pulmonary fibrosisCAPACITY-004 (PIPF004)19Noble P.W. Albera C. Bradford W.Z. et al.Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials.Lancet. 2011; 377: 1760-1769Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar[Pirfenidone 2,403 mg/d vs 1,197 mg/d vs placebo]Change in FVC at 72 wkPirfenidone 2,403 mg/d significantly reduced decline in FVCCAPACITY-006 (PIPF006)19Noble P.W. Albera C. Bradford W.Z. et al.Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials.Lancet. 2011; 377: 1760-1769Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar[Pirfenidone 2,403 mg/d vs placebo]Change in FVC at 72 wkNo significant difference between groupsASCEND22King Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (0) Google Scholar[Pirfenidone 2,403 mg/d vs placebo]Change in FVC at 52 wkPirfenidone significantly reduced decline in FVC, significantly improved progression-free survivalRECAP26Costabel U. Albera C. Bradford W.Z. et al.Analysis of lung function and survival in RECAP: an open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis.Sarcoidosis Vasc Diffuse Lung Dis. 2014; 31: 198-205PubMed Google Scholar[Pirfenidone 2,403 mg/d]Long-term safety and tolerabilityPirfenidone was safe and generally well toleratedLoeh et al20Loeh B. Drakopanagiotakis F. Bandelli G.P. et al.Intraindividual response to treatment with pirfenidone in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2015; 191: 110-113Crossref PubMed Google Scholar[Retrospective comparison of pirfenidone vs historical control subjects]Treatment-elicited changes in lung functionReduction in annual decline in FVC after initiation of pirfenidoneTOMORROW32Richeldi L. Costabel U. Selman M. et al.Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.N Engl J Med. 2011; 365: 1079-1087Crossref PubMed Scopus (0) Google Scholar[Nintedanib 50 mg/d vs 50 mg bid vs 100 mg bid vs 150 mg bid vs placebo]Rate of decline in FVC at 12 moTrend toward a reduced decline in lung function and fewer acute exacerbations with 150 mg bidINPULSIS-133Richeldi L. Cottin V. Flaherty K.R. et al.Design of the INPULSIS trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis.Respir Med. 2014; 108: 1023-1030Abstract Full Text Full Text PDF PubMed Google Scholar, 34Richeldi L. du Bois R.M. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (561) Google Scholar[Nintedanib 150 mg bid vs placebo]Rate of decline in FVC at 52 wkReduced FVC decline with nintedanibINPULSIS-233Richeldi L. Cottin V. Flaherty K.R. et al.Design of the INPULSIS trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis.Respir Med. 2014; 108: 1023-1030Abstract Full Text Full Text PDF PubMed Google Scholar, 34Richeldi L. du Bois R.M. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (561) Google Scholar[Nintedanib 150 mg bid vs placebo]Rate of decline in FVC at 52 wkReduced FVC decline; increased time to first acute exacerbationCostabel et al.36Costabel U. Inoue Y. Richeldi L. et al.Efficacy of nintedanib in idiopathic pulmonary fibrosis across prespecified subgroups in INPULSIS.Am J Respir Crit Card Med. 2016; 193: 178-185Crossref PubMed Google Scholar[Prespecified subgroup analyses of pooled data from INPULSIS-1 and -2]Treatment effect of nintedanibNintedanib had a consistent effect on slowing disease progression across several prespecified subgroupsConnective tissue disease-interstitial lung diseaseSLS68Tashkin D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (679) Google Scholar, 69Hoyles R.K. Ellis R.W. Wellsbury J. et al.A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma.Arthritis Rheum. 2006; 54: 3962-3970Crossref PubMed Scopus (0) Google Scholar[Cyclophosphamide ≤ 2 mg/kg/d vs placebo]Percent predicted FVC at 12 mo, after adjusting for baseline FVCModest benefit on FVC, dyspnea, skin thickening, and quality of life with cyclophosphamideEUSTAR Rituximab study76Jordan S. Distler J.H. Maurer B. et al.Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group.Ann Rheum Dis. 2015; 74: 1188-1194Crossref PubMed Scopus (31) Google Scholar[Retrospective comparison of rituximab with control subjects]Change in skin fibrosisRituximab improved skin fibrosis and prevented worsening of lung fibrosisLOTUSS SSc-ILD study72National Institutes of Health Clinical Center. Safety and Tolerability of Pirfenidone in Participants With Systemic Sclerosis–Related Interstitial Lung Disease (SSc-ILD) (LOTUSS) (LOTUSS). NCT01933334. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2007. https://clinicaltrials.gov/ct2/show/NCT01933334. Updated July 6, 2016.Google Scholar, 73Khanna D. Albera C. Fischer A. et al.An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial.J Rheumatol. 2016; 43: 1672-1679Crossref PubMed Google Scholar[Pirfenidone 2,403 mg/d]Evaluation of adverse eventsPirfenidone was safe and generally well toleratedTacrolimus in polymyositis and dermatomyositis84Labirua-Iturburu A. Selva-O'Callaghan A. Martinez-Gomez X. Trallero-Araguas E. Labrador-Horrillo M. Vilardell-Tarres M. Calcineurin inhibitors in a cohort of patients with antisynthetase-associated interstitial lung disease.Clin Exp Rheumatol. 2013; 31: 436-439PubMed Google Scholar, 85Witt L.J. Demchuck C. Curran J.J. Strek M.E. Benefit of adjunctive tacrolimus in connective tissue disease-interstitial lung disease.Pulm Pharmacol Ther. 2016; 36: 46-52Crossref PubMed Google Scholar[Retrospective comparison of tacrolimus vs conventional therapy]Time to relapse or death from respiratory cause or serious adverse eventEvent-free survival and disease-free survival significantly longer with tacrolimusChronic hypersensitivity pneumonitisKeir et al60Keir G.J. Maher T.M. Ming D. et al.Rituximab in severe, treatment-refractory interstitial lung disease.Respirology. 2014; 19: 353-359Crossref PubMed Scopus (0) Google Scholar[Rituximab, pre-to-post]Change in predicted percentage of FVC and DlcoMedian improvement in FVC; stable DlcoASCEND = Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis; CAPACITY = Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes; Dlco = diffusion capacity of the lung for carbon monoxide; EUSTAR = European Scleroderma Trial and Research; LOTUSS = Safety and Tolerability of Pirfenidone in Patients With Systemic Sclerosis−Related Interstitial Lung Disease; SLS = Scleroderma Lung Study; TOMORROW = To Improve Pulmonary Fibrosis With BIBF 1120. Open table in a new tab ASCEND = Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis; CAPACITY = Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes; Dlco = diffusion capacity of the lung for carbon monoxide; EUSTAR = European Scleroderma Trial and Research; LOTUSS = Safety and Tolerability of Pirfenidone in Patients With Systemic Sclerosis−Related Interstitial Lung Disease; SLS = Scleroderma Lung Study; TOMORROW = To Improve Pulmonary Fibrosis With BIBF 1120. The FDA requested an additional study to support the approval of pirfenidone for use in IPF, which led to the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial22King Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (0) Google Scholar (Table 2). This trial used a modified study design with a centralized confirmation of diagnosis that included review of all high-resolution CT (HRCT) scans and a lung biopsy if the CT scan showed possible rather than definite UIP. The eligibility criteria were also modified to enroll patients at a higher risk of disease progression than those in the CAPACITY trials by allowing a lower diffusion capacity of the lung for carbon monoxide (Dlco) of 30% rather than 35% predicted and requiring a FEV1/FVC ratio > 0.80. This study reported a smaller mean decline from baseline in FVC of –235 mL in those receiving pirfenidone compared with –428 mL in the placebo group (P < .001) at 52 weeks. A reduction was noted in the proportion of patients with a ≥ 10% decline in the percent predicted FVC or death in the pirfenidone vs placebo groups. Patients in the pirfenidone group also had a significantly improved progression-free survival (defined as time to first occurrence of a ≥ 10% reduction in the percent predicted FVC, decrease in the 6-min walk test of ≥ 50 m, or occurrence of death) and a significantly smaller decline in their 6-min walk test over the 1-year period compared with placebo. There were no significant differences in dyspnea, all-cause mortality, or IPF-related mortality. Major side effects of pirfenidone compared with placebo included nausea, vomiting, dyspepsia, anorexia, and skin rash. A pooled population of 1,247 patients enrolled in the ASCEND and both CAPACITY trials was analyzed for all-cause mortality by using prespecified criteria. A significant reduction in IPF-related mortality (hazard ratio [HR], 0.35 [95% CI, 0.17 to 0.72]; P = .0029) and all-cause mortality (HR, 0.52 [95% CI, 0.21 to 0.87]; P = .0107) was noted at 52 weeks with the use of pirfenidone compared with placebo.23Nathan S. Albera C. Bradford W. et al.Effect of pirfenidone on IPF-related mortality outcome measures in patients with idiopathic pulmonary fibrosis (IPF): pooled data analysis from the ASCEND and CAPACITY trials.Chest. 2015; 148: 391ACrossref Google Scholar Utilizing data from the same cohort, Nathan et al24Nathan S.D. Albera C. Bradford W.Z. et al.Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis.Thorax. 2016; 71: 429-435Crossref PubMed Scopus (7) Google Scholar evaluated the effect of continued treatment with pirfenidone in those patients who had experienced a ≥ 10% decline in FVC by month 6. Analysis of longitudinal FVC data and mortality during the subsequent 6 months demonstrated that the pirfenidone group had fewer patients with a ≥ 10% decline in FVC or death compared with the placebo group (5.9% vs 27.9%; P = .009; relative difference, 78.9%). Their findings suggest that patients with IPF, who exhibit meaningful disease progression despite treatment, may benefit from continued treatment with pirfenidone. In the PANORAMA study, Behr et al25Behr J. Bendstrup E. Crestani B. et al.Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet Respir Med. 2016; 4: 445-453Abstract Full Text Full Text PDF PubMed Google Scholar assessed the safety and tolerability of combination therapy with pirfenidone and NAC in patients with IPF. This randomized, double-blind, multicenter trial evaluated 123 patients with IPF who were established on pirfenidone therapy and assessed the effect of concomitant therapy with oral NAC or placebo. The investigators found that the occurrence of adverse events related to study treatment, the number of patients experiencing severe adverse events, and the number of life-threatening adverse events or death was similar between patients receiving pirfenidone with NAC and those receiving pirfenidone with placebo. However, exploratory analysis revealed that the addition of NAC to pirfenidone led to a decrease in FVC (−91.3 mL/6 months [95% CI, −174.4 to −8.3]; P = .031). The long-term safety of pirfenidone was evaluated in an open-label extension study (RECAP) of patients who completed either the CAPACITY or ASCEND studies; patients were treated for up to 7.7 years.26Costabel U. Albera C. Bradford W.Z. et al.Analysis of lung function and survival in RECAP: an open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis.Sarcoidosis Vasc Diffuse Lung Dis. 2014; 31: 198-205PubMed Google Scholar Patients starting pirfenidone at 2,403 mg/d in the RECAP trial who had previously been given placebo in the CAPACITY trial reported a mean change of –5.9% in the percent predicted FVC at 60 weeks, similar to results of previous randomized clinical trials.19Noble P.W. Albera C. Bradford W.Z. et al.Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials.Lancet. 2011; 377: 1760-1769Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar Rash and photosensitivity occurred in 16% and 9% of treated patients, respectively. Since drug approval, agranulocytosis and angioedema have been identified as rare drug-related adverse events. Nintedanib ethanesulfonate is an orally available intracellular tyrosine kinase inhibitor that targets several growth factor receptors (Table 1).27Roth G.J. Binder R. Colbatzky F. et al.Nintedanib: from discovery to the clinic.J Med Chem. 2015; 58: 1053-1063Crossref PubMed Scopus (30) Google Scholar Its action on the adenosine 5′-triphosphate-binding site of the vascular endothelial growth factor receptor 2 kinase domain results in the inhibition of vascular endothelial growth factor receptor 1 to 3, fibroblast growth factor receptor 1 to 3, and platelet-derived growth factor receptor-α and -β.28Wollin L. Maillet I. Quesniaux V. Holweg A. Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis.J Pharmacol Exp Ther. 2014; 349: 209-220Crossref PubMed Scopus (74) Google Scholar, 29Kudo K. Arao T. Tanaka K. et al.Antitumor activity of BIBF 1120, a triple angiokinase inhibitor, and use of VEGFR2+pTyr+ peripheral blood leukocytes as a pharmacodynamic biomarker in vivo.Clin Cancer Res. 2011; 17: 1373-1381Crossref PubMed Scopus (21) Google Scholar, 30Hilberg F. Roth G.J. Krssak M. et al.BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor" @default.
• W2513609898 created "2016-09-16" @default.
• W2513609898 creator A5065857269 @default.
• W2513609898 creator A5069296013 @default.
• W2513609898 date "2016-12-01" @default.
• W2513609898 modified "2023-10-14" @default.
• W2513609898 title "Therapeutic Approach to Adult Fibrotic Lung Diseases" @default.
• W2513609898 cites W140484599 @default.
• W2513609898 cites W1516256623 @default.
• W2513609898 cites W1523001731 @default.
• W2513609898 cites W1547683341 @default.
• W2513609898 cites W1548223836 @default.
• W2513609898 cites W1569431722 @default.
• W2513609898 cites W1726813435 @default.
• W2513609898 cites W1757222072 @default.
• W2513609898 cites W1770545381 @default.
• W2513609898 cites W1857071204 @default.
• W2513609898 cites W1860863518 @default.
• W2513609898 cites W1932542775 @default.
• W2513609898 cites W1938547050 @default.
• W2513609898 cites W1939859220 @default.
• W2513609898 cites W1964646819 @default.
• W2513609898 cites W1966466614 @default.
• W2513609898 cites W1973615532 @default.
• W2513609898 cites W1975158384 @default.
• W2513609898 cites W1975807940 @default.
• W2513609898 cites W1988552525 @default.
• W2513609898 cites W1991855818 @default.
• W2513609898 cites W1998253400 @default.
• W2513609898 cites W2002247399 @default.
• W2513609898 cites W2005968813 @default.
• W2513609898 cites W2006282566 @default.
• W2513609898 cites W2014362193 @default.
• W2513609898 cites W2014689880 @default.
• W2513609898 cites W2016517608 @default.
• W2513609898 cites W2016575029 @default.
• W2513609898 cites W2023238496 @default.
• W2513609898 cites W2030067176 @default.
• W2513609898 cites W2036041938 @default.
• W2513609898 cites W2039943389 @default.
• W2513609898 cites W2040357625 @default.
• W2513609898 cites W2042926190 @default.
• W2513609898 cites W2043331041 @default.
• W2513609898 cites W2047310826 @default.
• W2513609898 cites W2049610833 @default.
• W2513609898 cites W2051483231 @default.
• W2513609898 cites W2055740721 @default.
• W2513609898 cites W2056364917 @default.
• W2513609898 cites W2057292199 @default.
• W2513609898 cites W2059895364 @default.
• W2513609898 cites W2060585298 @default.
• W2513609898 cites W2060929392 @default.
• W2513609898 cites W2063946490 @default.
• W2513609898 cites W2064164967 @default.
• W2513609898 cites W2064247359 @default.
• W2513609898 cites W2067514811 @default.
• W2513609898 cites W2069413406 @default.
• W2513609898 cites W2079739884 @default.
• W2513609898 cites W2079960537 @default.
• W2513609898 cites W2083760789 @default.
• W2513609898 cites W2084638872 @default.
• W2513609898 cites W2085604666 @default.
• W2513609898 cites W2086655418 @default.
• W2513609898 cites W2089756110 @default.
• W2513609898 cites W2089858213 @default.
• W2513609898 cites W2095975942 @default.
• W2513609898 cites W2097319008 @default.
• W2513609898 cites W2098305693 @default.
• W2513609898 cites W2098971028 @default.
• W2513609898 cites W2100098412 @default.
• W2513609898 cites W2105914270 @default.
• W2513609898 cites W2111195342 @default.
• W2513609898 cites W2111739981 @default.
• W2513609898 cites W2114549477 @default.
• W2513609898 cites W2116531828 @default.
• W2513609898 cites W2117098575 @default.
• W2513609898 cites W2117663892 @default.
• W2513609898 cites W2122083530 @default.
• W2513609898 cites W2122336434 @default.
• W2513609898 cites W2123700925 @default.
• W2513609898 cites W2125079712 @default.
• W2513609898 cites W2125898678 @default.
• W2513609898 cites W2126884637 @default.
• W2513609898 cites W2130652869 @default.
• W2513609898 cites W2131014787 @default.
• W2513609898 cites W2132946922 @default.
• W2513609898 cites W2134027168 @default.
• W2513609898 cites W2138871107 @default.
• W2513609898 cites W2141623508 @default.
• W2513609898 cites W2142941142 @default.
• W2513609898 cites W2143772891 @default.
• W2513609898 cites W2144111246 @default.
• W2513609898 cites W2144722417 @default.
• W2513609898 cites W2147322791 @default.
• W2513609898 cites W2147543851 @default.
• W2513609898 cites W2148261626 @default.
• W2513609898 cites W2148744507 @default.
• W2513609898 cites W2150115931 @default.

• next