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2.
Clin Rheumatol ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31916109

RESUMO

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), pcorr = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), pcorr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), pcorr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), pcorr = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), pcorr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), pcorr = 6.6 × 10-6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), pcorr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.

5.
Chest ; 157(1): 89-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31351047

RESUMO

BACKGROUND: Patients with interstitial lung disease (ILD) may develop pulmonary hypertension (PH), often disproportionate to the severity of the ILD. The right ventricular to left ventricular diameter (RV:LV) ratio measured at CT pulmonary angiogram (CTPA) has been shown to provide valuable information in patients with pulmonary arterial hypertension and to predict death or deterioration in acute pulmonary embolism. METHODS: Demographic characteristics, ILD subtype, echocardiography, and detailed CTPA measurements were collected in consecutive patients undergoing both CTPA and right heart catheterization at the Royal Brompton Hospital between 2005 and 2015. Fibrosis severity was formally scored according to CT criteria. The RV:LV ratio at CTPA was evaluated by using three different methods. Cox proportional hazards analysis was used to assess the relation of CTPA-derived parameters to predict death or lung transplantation. RESULTS: A total of 92 patients were included (64% male; mean age 65 ± 11 years) with an FVC 57 ± 20% predicted, corrected transfer factor of the lung for carbon monoxide 22 ± 8% predicted, and corrected transfer coefficient of the lung for carbon monoxide 51 ± 17% predicted. PH was confirmed at right heart catheterization in 78%. Of all the CTPA-derived measures, an RV:LV ratio ≥ 1.0 strongly predicted mortality or transplantation at univariate analysis (hazard ratio, 3.26; 95% CI, 1.49-7.13; P = .003), whereas invasive hemodynamic data did not. The RV:LV ratio remained an independent predictor at multivariate analysis (hazard ratio, 3.19; 95% CI, 1.44-7.10; P = .004), adjusting for an ILD diagnosis of idiopathic pulmonary fibrosis and CT imaging-derived ILD severity. CONCLUSIONS: An increased RV:LV ratio measured at CTPA provides a simple, noninvasive method of risk stratification in patients with suspected ILD-PH. This should prompt closer follow-up, more aggressive treatment, and consideration of lung transplantation.

6.
Am J Respir Crit Care Med ; 201(6): 650-660, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31841044

RESUMO

Systemic sclerosis (SSc) is a complex, multiorgan, autoimmune disease. Lung fibrosis occurs in ∼80% of patients with SSc; 25% to 30% develop progressive interstitial lung disease (ILD). The pathogenesis of fibrosis in SSc-associated ILD (SSc-ILD) involves cellular injury, activation/differentiation of mesenchymal cells, and morphological/biological changes in epithelial/endothelial cells. Risk factors for progressive SSc-ILD include older age, male sex, degree of lung involvement on baseline high-resolution computed tomography imaging, reduced DlCO, and reduced FVC. SSc-ILD does not share the genetic risk architecture observed in idiopathic pulmonary fibrosis (IPF), with key risk factors yet to be identified. Presence of anti-Scl-70 antibodies and absence of anti-centromere antibodies indicate increased likelihood of progressive ILD. Elevated levels of serum Krebs von den Lungen-6 and C-reactive protein are both associated with SSc-ILD severity and predict SSc-ILD progression. A promising prognostic indicator is serum chemokine (C-C motif) ligand 18. SSc-ILD shares similarities with IPF, although clear differences exist. Histologically, a nonspecific interstitial pneumonia pattern is commonly observed in SSc-ILD, whereas IPF is defined by usual interstitial pneumonia. The course of SSc-ILD is variable, ranging from minor, stable disease to a progressive course, whereas all patients with IPF experience progression of disease. Although appropriately treated patients with SSc-ILD have better chances of stabilization and survival, a relentlessly progressive course, akin to IPF, is seen in a minority. Better understanding of cellular and molecular pathogenesis, genetic risk, and distinctive features of SSc-ILD and identification of robust prognostic biomarkers are needed for optimal disease management.

7.
ERJ Open Res ; 5(4)2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31687368

RESUMO

Our study presents findings on a previously developed standard set of clinical outcome data for pulmonary sarcoidosis patients. We aimed to assess whether changes in outcome varied between the different centres and to evaluate the feasibility of collecting the standard set retrospectively. This retrospective observational comparative benchmark study included six interstitial lung disease expert centres based in the Netherlands, Belgium, the UK and the USA. The standard set of outcome measures included 1) mortality, 2) changes in pulmonary function (forced vital capacity (FVC), forced expiratory volume in 1 s, diffusing capacity of the lung for carbon monoxide), 3) soluble interleukin-2 receptor (sIL-2R) change, 4) weight changes, 5) quality-of-life (QoL) measures, 6) osteoporosis and 7) clinical outcome status (COS). Data collection was considered feasible if the data were collected in ≥80% of all patients. 509 patients were included in the retrospective cohort. In total six patients died, with a mean survival of 38±23.4 months after the diagnosis. Centres varied in mean baseline FVC, ranging from 110 (95% CI 92-124)% predicted to 99 (95% CI 97-123)% pred. Mean baseline body mass index (BMI) of patients in the different centres varied between 27 (95% CI 23.6-29.4) kg·m-2 and 31.8 (95% CI 28.1-35.6) kg·m-2. 310 (60.9%) patients were still on systemic therapy 2 years after the diagnosis. It was feasible to measure mortality, changes in pulmonary function, weight changes and COS. It is not (yet) feasible to retrospectively collect sIL-2R, osteoporosis and QoL data internationally. This study shows that data collection for the standard set of outcome measures for pulmonary sarcoidosis was feasible for four out of seven outcome measures. Trends in pulmonary function and BMI were similar for different hospitals when comparing different practices.

8.
BMC Pulm Med ; 19(1): 185, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651292

RESUMO

BACKGROUND: Diffuse alveolar haemorrhage (DAH) is characterized by the diffuse accumulation of red blood cells within the alveoli, presence of ground glass opacities and/or consolidation on computed tomography (CT). Aside from identifiable non-immune causes, DAH is classically subdivided into idiopathic (idiopathic pulmonary haemosiderosis, IPH) and autoimmune DAH. Here we describe three cases presenting with recurrent pulmonary haemorrhage, initially classified as IPH, who, several years after first presentation, develop anti myeloperoxidase antibodies (MPO) positivity, emphysema on CT and, in one case, renal involvement. CASE PRESENTATION: Patient 1 was diagnosed with IPH aged 14. Her disease remained poorly controlled despite immunosuppression, although ANCA remained negative over the years. Nineteen years from initial presentation, she developed MPO-ANCA positive antibodies and mild renal impairment. She was treated with Rituximab with good response. From first presentation, the chest CT was consistently characterized by diffuse ground-glass opacities and interlobular septal thickening. Ten years later, cystic opacities consistent with emphysema, with a striking peribronchovascular distribution, developed. Patient 2 was diagnosed with IPH aged 32. He was treated with corticosteroids and methotrexate, with fluctuating response. At 11 years from initial presentation, MPO-ANCA positivity was identified, and emphysema with a peribronchovascular distribution was observed on CT, with subsequent significant increase in extent. Patient 3 was diagnosed with IPH at the age of seven, and had recurrent episodes of haemoptysis of varying degree of severity, treated with intermittent courses of corticosteroids until age 11, when he was intubated due to severe DAH. Eight years after the diagnosis emphysematous changes were noted on CT and MPO-ANCA positivity developed for the first time 11 years after initial diagnosis. CONCLUSIONS: We believe these three cases highlight: 1) the possibility of development of ANCA positivity several years down the line from first DAH presentation 2) the possibility that DAH may lead to cystic/emphysematous changes with peribronchovascular distribution on CT. Moreover, the need for ongoing immunosuppressive treatment and the development of emphysema, emphasize a possible role played by autoimmune phenomena, even when DAH is initially diagnosed as "idiopathic". Further studies are required to better understand the relationship between DAH, ANCA positivity and development of emphysema.

9.
ERJ Open Res ; 5(3)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31544111

RESUMO

Domiciliary oxygen therapy is often prescribed for patients with hypoxaemia due to advanced lung disease, most commonly chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Long-term oxygen therapy (LTOT) trials conducted in patients with COPD in the 1980s remain the basis for clinical decisions and guideline recommendations regarding LTOT for patients with non-COPD conditions as there is a lack of high-quality evidence concerning its use in the non-COPD population. There is also a lack of evidence for the use of ambulatory and nocturnal oxygen therapy in patients with isolated exertional and nocturnal hypoxaemia. These deficiencies pose significant challenges in patient care, with consequent discrepancies in guideline recommendations and clinical approaches. In recent years, new studies have been and are currently being conducted to fill the gaps in our understanding and use of domiciliary oxygen therapy for other indications, including ILD. This article provides a comparison of the epidemiology and significance of hypoxaemia in patients with COPD and ILD, with an up-to-date review of current evidence regarding the role of different types of domiciliary oxygen therapy in these conditions.

10.
Ann Am Thorac Soc ; 16(11): 1351-1359, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31425665

RESUMO

Pleuroparenchymal fibroelastosis (PPFE) is an unusual pulmonary disease with unique clinical, radiological, and pathological characteristics. Designated a rare idiopathic interstitial pneumonia in 2013, its name refers to a combination of fibrosis involving the visceral pleura and fibroelastotic changes predominating in the subpleural lung parenchyma. Although a number of disease associations have been described, no single cause of PPFE has been unequivocally identified. A diagnosis of PPFE is most commonly achieved by identifying characteristic abnormalities on computed tomographic scans. The earliest changes are consistently located in the upper lobes close to the lung apices, the same locations where subsequent disease progression is also most conspicuous. When sufficiently severe, the disease leads to progressive volume loss of the upper lobes, which, in combination with decreased body mass, produces platythorax. Once regarded as a slowly progressing entity, it is now acknowledged that some patients with PPFE follow an inexorably progressive course that culminates in irreversible respiratory failure and early death. In the absence of effective medical drug treatment, lung transplant remains the only therapeutic option for this disorder. This review focuses on improving early disease recognition and evaluating its pathophysiological impact and discusses working approaches for its management.

12.
Biomed Res Int ; 2019: 1484736, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119153

RESUMO

Background and Objective: Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-ß (TGF-ß) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods: In TGF-ß-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions: Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-ß increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-ß-mediated NOX4/SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF-ß-induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.


Assuntos
Fibrose Pulmonar Idiopática/genética , NADPH Oxidase 4/genética , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genética , Escleroderma Sistêmico/genética , Fatores de Transcrição/genética , Azepinas/farmacologia , Proteínas de Ciclo Celular , Desdiferenciação Celular/genética , Proliferação de Células/genética , Epigênese Genética , Regulação da Expressão Gênica/genética , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/patologia , Pulmão/metabolismo , Pulmão/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fator 2 Relacionado a NF-E2/genética , Oxirredução , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologia , Superóxido Dismutase/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/farmacologia , Triazóis/farmacologia
13.
Semin Respir Crit Care Med ; 40(2): 208-226, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31137061

RESUMO

Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). SSc-ILD adversely impacts quality of life and is currently the leading cause of death in this multisystem disease. Identifying clinically significant SSc-ILD is critically important. Accurate staging and prognostication remain difficult; however, significant advances have been made in the last decade. Evidence supports the need to treat patients with extensive and/or progressive SSc-ILD, while only a subset of patients with limited ILD may require treatment. Research is urgently required to allow improved prediction of patients at risk of ILD progression at an early point in the disease, and ideally prior to its onset, to allow prevention. The last decade has seen the publication of landmark clinical trials for SSc-ILD. More effective strategies with less toxicity are under investigation. For those with refractory or very advanced disease, studies into disease-specific palliative approaches are in their infancy. Lung transplantation as an option for SSc-ILD remains patient- and center-specific, with data to suggest equivalent outcomes to other fibrotic lung diseases, in carefully selected cases. This review aims to provide a comprehensive overview of all key aspects of SSc-ILD.

16.
BMJ Open Respir Res ; 6(1): e000394, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30956806

RESUMO

Introduction: Routine and international comparison of clinical outcomes enabling identification of best practices for patients with pulmonary sarcoidosis is lacking. The aim of this study was to develop a standard set of outcome measures for pulmonary sarcoidosis, using the value-based healthcare principles. Methods: Six expert clinics for interstitial lung diseases in four countries participated in a consensus-driven RAND-modified Delphi study. A mixed-method approach was applied for the identification of an outcome measures set and initial conditions for patients with pulmonary sarcoidosis. The expert team consisted of multidisciplinary professionals (n=14) from Cleveland Clinic, Cincinnati MC, Erasmus MC, Leuven UZ, Royal Brompton and St. Antonius Hospital. During a ranking process, participants were instructed to rank variables on a scale from 1 to 10 based on whether it has (1) impact of the outcome on quality of life, (2) impact of quality of care on the outcome and (3) the number of patients negatively affected by the outcome. Results: An outcome measures set was defined consisting of seven outcome measures: mortality, pulmonary function, soluble interleukin-2 receptor change as an activity biomarker, weight gain, quality of life, osteoporosis and clinical outcome status. Discussion: Collecting outcomes in pulmonary sarcoidosis internationally and the use of a broadly accepted set can enable international comparison. Differences in outcomes can potentially be used as a starting point for quality improvement initiatives.

18.
ERJ Open Res ; 5(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30792985

RESUMO

This article reviews a selection of the scientific presentations on interstitial lung disease (ILD)/diffuse parenchymal lung disease (DPLD) that were made at the 2018 European Respiratory Society (ERS) International Congress in Paris. A number of advances in the epidemiology, pathogenesis, diagnosis and treatment of these disorders were presented and discussed by clinicians and researchers. The research topics span over all four groups of ERS Assembly 12: Interstitial Lung Diseases (Group 12.01: Idiopathic interstitial pneumonias; Group 12.02: ILD/DPLD of known origin; Group 12.03: Sarcoidosis and other granulomatous ILD/DPLD; Group 12.04: Rare ILD/DPLD).

19.
Eur Respir J ; 53(1)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30487199

RESUMO

The aim of this study was to compare radiology-based prediction models in rheumatoid arthritis-related interstitial lung disease (RAILD) to identify patients with a progressive fibrosis phenotype.RAILD patients had computed tomography (CT) scans scored visually and using CALIPER and forced vital capacity (FVC) measurements. Outcomes were evaluated using three techniques, as follows. 1) Scleroderma system evaluating visual interstitial lung disease extent and FVC values; 2) Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines applied to RAILD; and 3) CALIPER scores of vessel-related structures (VRS). Outcomes were compared to IPF patients.On univariable Cox analysis, all three staging systems strongly predicted outcome (scleroderma system hazard ratio (HR) 3.78, p=9×10-5; Fleischner system HR 1.98, p=2×10-3; and 4.4% VRS threshold HR 3.10, p=4×10-4). When the scleroderma and Fleischner systems were combined, termed the progressive fibrotic system (C-statistic 0.71), they identified a patient subset (n=36) with a progressive fibrotic phenotype and similar 4-year survival to IPF. On multivariable analysis, with adjustment for patient age, sex and smoking status, when analysed alongside the progressive fibrotic system, the VRS threshold of 4.4% independently predicted outcome (model C-statistic 0.77).The combination of two visual CT-based staging systems identified 23% of an RAILD cohort with an IPF-like progressive fibrotic phenotype. The addition of a computer-derived VRS threshold further improved outcome prediction and model fit, beyond that encompassed by RAILD measures of disease severity and extent.

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