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1.
Eur Respir J ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008934

RESUMO

This phase 2, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of lebrikizumab, an interleukin-13 monoclonal antibody, alone or with background pirfenidone therapy, in patients with idiopathic pulmonary fibrosis (IPF).Patients with IPF aged ≥40 years with % predicted forced vital capacity (%FVC) 40%-100% and diffusing capacity for carbon monoxide 25%-90% and who were treatment-naive (Cohort A) or receiving pirfenidone (2403 mg·day-1; Cohort B) were randomised 1:1 to receive lebrikizumab 250 mg or placebo subcutaneously every 4 weeks. The primary endpoint was annualised rate of %FVC decline over 52 weeks.In Cohort A, 154 patients were randomised to receive lebrikizumab (n=78) or placebo (n=76). In Cohort B, 351 patients receiving pirfenidone were randomised to receive lebrikizumab (n=174) or placebo (n=177). Baseline demographics were balanced across treatment arms in both cohorts. The primary endpoint (annualised rate of %FVC decline) was not met in Cohort A (lebrikizumab versus placebo, -5.2% versus -6.2%; p=0.456) or Cohort B (lebrikizumab versus placebo, -5.5% versus -6.0%; p=0.557). In Cohort B, a non-statistically significant imbalance in mortality favouring combination therapy was observed (hazard ratio, 0.42 [95% CI, 0.17-1.04]). Pharmacodynamic biomarkers indicated lebrikizumab activity. The safety profile was consistent with that in previous studies of lebrikizumab and pirfenidone as monotherapies.Lebrikizumab alone or with pirfenidone was not associated with reduced %FVC decline over 52 weeks despite evidence of pharmacodynamic activity. Lebrikizumab was well tolerated with a favourable safety profile. These findings suggest that blocking IL-13 may not be sufficient to achieve a lung function benefit in patients with IPF.

2.
Sci Immunol ; 5(52)2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097591

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1-/- mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1-/- tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

4.
Nat Commun ; 11(1): 4659, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938936

RESUMO

The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.


Assuntos
Butiratos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Administração por Inalação , Animais , Antígenos de Neoplasias/metabolismo , Bleomicina/toxicidade , Butiratos/administração & dosagem , Butiratos/metabolismo , Butiratos/farmacocinética , Colágeno/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Integrinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Naftiridinas/administração & dosagem , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Fator de Crescimento Transformador beta/metabolismo , Pesquisa Médica Translacional
6.
Ann Rheum Dis ; 79(11): 1478-1484, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32759258

RESUMO

OBJECTIVES: To characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks. RESULTS: A total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments. CONCLUSIONS: The adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy.

8.
Respir Res ; 21(1): 197, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703199

RESUMO

Systemic sclerosis (SSc) is a multi-organ autoimmune disease with complex interactions between immune-mediated inflammatory processes and vascular pathology leading to small vessel obliteration, promoting uncontrolled fibrosis of skin and internal organs. Interstitial lung disease (ILD) is a common but highly variable manifestation of SSc and is associated with high morbidity and mortality. Treatment approaches have focused on immunosuppressive therapies, which have shown some efficacy on lung function. Recently, a large phase 3 trial showed that treatment with nintedanib was associated with a reduction in lung function decline. None of the conducted randomized clinical trials have so far shown convincing efficacy on other outcome measures including quality of life determined by patient reported outcomes. Little evidence is available for non-pharmacological treatment and supportive care specifically for SSc-ILD patients, including pulmonary rehabilitation, supplemental oxygen, symptom relief and adequate information. Improved management of SSc-ILD patients based on a holistic approach is necessary to support patients in maintaining as much quality of life as possible throughout the disease course and to improve long-term outcomes.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32692582

RESUMO

RATIONALE: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises following repeated exposure and sensitisation to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease but to date, no study has investigated the composition of microbial communities in the lower airways in CHP. OBJECTIVE: To characterise and compare the airway microbiome in subjects with CHP, idiopathic pulmonary fibrosis (IPF) and controls. METHODS: We prospectively recruited individuals diagnosed with CHP (n=110), IPF (n=45) and controls (n=28). Subjects underwent bronchoalveolar lavage and bacterial DNA was isolated, quantified by qPCR and the 16S rRNA gene was sequenced to characterise the bacterial communities in the lower airways. MAIN MEASUREMENTS AND RESULTS: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both IPF and CHP subjects included Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. However, in IPF, Firmicutes dominated while the percentage of reads assigned to Proteobacteria in the same group was significantly lower compared to CHP subjects. At the genus level, Staphylococcus was increased in CHP and Actinomyces and Veillonella in IPF. The lower airway bacterial burden in CHP subjects was higher than controls but lower than those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. CONCLUSIONS: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF and, notably, bacterial burden in individuals with CHP fails to predict survival. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

10.
Expert Opin Investig Drugs ; 29(8): 797-808, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32538186

RESUMO

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an age-related disease of unknown cause. The disease is characterized by relentless scarring of the lung parenchyma resulting in respiratory failure and death. Two antifibrotic drugs (pirfenidone and nintedanib) are approved for the treatment of IPF worldwide, but they do not offer a cure and are associated with tolerability issues. Owing to its high unmet medical need, IPF is an area of dynamic research activity. AREAS COVERED: There is a growing portfolio of novel therapies that target different pathways involved in the complex pathogenesis of IPF. In this review, we discuss the mechanisms of action and available data for compounds in the most advanced stages of clinical development. We searched PubMed for articles on this topic published from 1 January 2000, to 6 June 2020. EXPERT OPINION: The approval of pirfenidone and nintedanib has fueled IPF drug discovery and development. New drugs are likely to reach the clinic in the near future. However, numerous challenges remain; the lack of animal models that reproduce the complexity of human disease and the poor translation of preclinical and early-phase positive effects to late stage clinical trials must be tackled.

11.
Chest ; 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32534908

RESUMO

BACKGROUND: In cohort studies of pulmonary sarcoidosis, abnormal ventilatory patterns have generally been subdivided into restrictive and obstructive defects. Mixed ventilatory defects have largely been overlooked in pulmonary sarcoidosis, as total lung capacity has seldom been taken into account in historical series. RESEARCH QUESTION: This study evaluated the prevalence of mixed disease in pulmonary sarcoidosis and its clinical associations. STUDY DESIGN AND METHODS: In patients with pulmonary sarcoidosis (N = 1,110), mixed defects were defined according to American Thoracic Society/European Respiratory Society criteria. Clinical data, pulmonary function variables, and vital status were abstracted from clinical records. Chest radiographs were evaluated independently by two experienced radiologists. RESULTS: The prevalence of a mixed ventilatory defect was 10.4% in the whole cohort, rising to 25.9% in patients with airflow obstruction. Compared with isolated airflow obstruction, mixed defects were associated with lower diffusing lung capacity for carbon monoxide levels (50.7 ± 16.3 vs 70.8 ± 18.1; P < .0001), a higher prevalence of chest radiographic stage IV disease (63.5% vs 38.3%; P < .0001), and higher mortality (hazard ratio, 2.36; 95% CI, 1.34-4.15; P = .003). These findings were reproduced in all patient subgroup analyses, including patients with a histologic diagnosis, a clinical diagnosis, incident disease, and prevalent disease. INTERPRETATION: Mixed disease is present in approximately 25% of patients with pulmonary sarcoidosis and airflow obstruction and is associated with lower diffusing lung capacity for carbon monoxide levels, a higher prevalence of stage IV disease, and higher mortality than seen in a pure obstructive defect. These observations identify a distinct phenotype associated with a mixed ventilatory defect, justifying future studies of its clinical and pathogenetic significance.

12.
Thorax ; 75(10): 901-903, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32580994

RESUMO

The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF.

14.
Respirology ; 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32390252

RESUMO

BACKGROUND AND OBJECTIVE: Temporal trends of healthcare use in the period before a diagnosis of pulmonary fibrosis are poorly understood. We investigated trends in respiratory symptoms and LR HRU in the 10 years prior to diagnosis. METHODS: We analysed a primary care clinical cohort database (UK OPCRD) and assessed patients aged ≥40 years who had an electronically coded diagnosis of pulmonary fibrosis between 2005 and 2015 and a minimum 2 years of continuous medical records prior to diagnosis. Exclusion criteria consisted of electronic codes for recognized causes of pulmonary fibrosis such as CTD, sarcoidosis or EAA. RESULTS: Data for 2223 patients were assessed. Over the 10 years prior to diagnosis of pulmonary fibrosis, there was a progressive increase in HRU across multiple LR-related domains. Five years before diagnosis, 18% of patients had multiple healthcare contacts for LR complaints; this increased to 79% in the year before diagnosis, with 38% of patients having five or more healthcare contacts. CONCLUSION: There are opportunities to diagnose pulmonary fibrosis at an earlier stage; research into case-finding algorithms and strategies to educate primary care physicians is required.

15.
Adv Ther ; 37(7): 3292-3298, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451950

RESUMO

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is the classic progressive fibrosing interstitial lung disease (ILD), but some patients with ILDs other than IPF also develop a progressive fibrosing phenotype (PF-ILD). Information on use and cost of healthcare resources in patients with PF-ILD is limited. METHODS: We used USA-based medical insurance claims (2014-2016) to assess use and cost of healthcare resources in PF-ILD. Patients with at least two ILD claims and at least one pulmonologist visit were considered to have ILD. Pulmonologist visit frequency was used as a proxy to identify PF-ILD (at least four visits in 2016, or at least three more visits in 2016 vs. 2014). RESULTS: Of 2517 patients with non-IPF ILD, 15% (n = 373) had PF-ILD. Mean annual medical costs associated with ILD claims were $35,364 in patients with non-IPF PF-ILD versus $20,211 in the non-IPF ILD population. In 2016, patients with non-IPF PF-ILD made more hospital ILD claims than patients with non-IPF ILD (10.5 vs. 4.7). CONCLUSIONS: These findings suggest higher disease severity and overall healthcare use for patients with a non-IPF ILD manifesting a progressive fibrosing phenotype (non-IPF PF-ILD).

17.
Eur Respir J ; 56(1)2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32299855

RESUMO

Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a major cause of morbidity and mortality, mostly presenting as non-specific interstitial pneumonia. Little is known about the prevalence of pleuroparenchymal fibroelastosis (PPFE), a specific entity affecting the visceral pleura and subpleural parenchyma. We set out to estimate PPFE prevalence in two large cohorts of SSc patients and to assess its impact on survival and functional decline.A total of 359 SSc patients, derived from two referral centres in two different countries (UK and Italy), were included. The first available high-resolution computed tomography scan was independently evaluated by two radiologists blind to clinical information, to quantify ILD extent, freestanding bronchial abnormalities, and lobar percentage involvement of PPFE on a four-point categorical scale. Discordant scores were adjudicated by a third scorer. PPFE extent was further classified as limited (≤2/18) or extensive (>2/18). Results were evaluated against functional decline and mortality.The overall prevalence of PPFE in the combined SSc population was 18% (11% with extensive PPFE), with no substantial difference between the two cohorts. PPFE was significantly linked to free-standing bronchial abnormalities (61% versus 25% in PPFE versus no PPFE; p<0.0001) and to worse survival, independently of ILD severity or short-term lung function changes (HR 1.89, 95% CI 1.10-3.25; p=0.005).In the current study, we provide an exhaustive description of PPFE prevalence and clinical impact in the largest cohort of SSc subjects published so far. PPFE presence should be carefully considered, due to its significant prognostic implications.

18.
Chest ; 158(2): 646-659, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32268131

RESUMO

Biomarkers have the potential to become central to the clinical evaluation and monitoring of patients with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype. Here we summarize the current understanding of putative serum, BAL fluid, and genetic biomarkers in this setting, according to their hypothesized pathobiologic mechanisms: evidence of epithelial cell dysfunction (eg, Krebs von den Lungen-6 antigen), fibroblast proliferation and extracellular matrix production or turnover (eg, matrix metalloproteinase-1), or immune dysregulation (eg, CC chemokine ligand 18). While most of the available data come from idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrosing ILD, data are available in the broader patient population of chronic fibrosing ILDs. A number of these biomarkers show promise, however, none have been validated. In this review article, we assess both the status of proposed biomarkers for chronic fibrosing lung diseases with a progressive phenotype in predicting disease risk or predisposition, diagnosis, prognosis, and treatment response and provide a direct comparison between IPF and other chronic fibrotic ILDs. We also reflect on the current clinical usefulness and future direction of research for biomarkers in the setting of chronic fibrosing ILDs with a progressive phenotype.

19.
Adv Ther ; 37(5): 2460-2476, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32319038

RESUMO

INTRODUCTION: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) places a substantial burden on patients and healthcare systems. The objectives of this study were to describe clinical characteristics and assess healthcare resource utilization and costs of patients with SSc-ILD in England, compared with patients with non-pulmonary organ involvement related to SSc (SSc-OOI). METHODS: This population-based retrospective study used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. Data were extracted from medical records dated January 1, 2005 to March 31, 2016. Patients with SSc were identified and placed in subgroups based on organ involvement: SSc-ILD, SSc-OOI, and both (SSc-ILD-OOI). Patients with SSc-ILD-OOI were included in both the SSc-ILD and SSc-OOI subgroups. All-cause healthcare costs, excluding medication costs, were calculated to 2016 British pounds sterling (£). RESULTS: This study included 675 patients with SSc: 174 (26%) had neither ILD nor other organ involvement (OOI); 127 (19%) had SSc-ILD; 477 (71%) had SSc-OOI; 103 (15%) had SSc-ILD-OOI. Age-weighted median [interquartile range (IQR)] annual healthcare costs per patient were: £1496 (£664-£2817) in SSc only; £6375 (£3451-£15,041) in SSc-ILD; £4084 (£1454-£10,105) in SSc-OOI; £6632 (£4023-£17,009) in SSc-ILD-OOI. In multivariate analysis, older age at diagnosis, diagnosis of anemia, and number of comorbid diseases were associated with higher yearly healthcare costs. CONCLUSION: The annual healthcare cost for patients with SSc-ILD is substantial, and higher than that of patients with SSc-OOI or SSc only. These results quantify the economic burden of SSc-ILD in a real-world setting, and highlight the need for treatment of this disease.

20.
Respir Res ; 21(1): 75, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216814

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.


Assuntos
Butiratos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/uso terapêutico , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Volume de Ventilação Pulmonar/efeitos dos fármacos , Administração por Inalação , Idoso , Antígenos de Neoplasias , Teorema de Bayes , Butiratos/administração & dosagem , Butiratos/farmacocinética , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Nebulizadores e Vaporizadores , Tomografia por Emissão de Pósitrons , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Resultado do Tratamento
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