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2.
ACR Open Rheumatol ; 1(4): 258-266, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31777802

RESUMO

Objective: Primary cardiac involvement is presumed to account for a substantial part of disease-related mortality in systemic sclerosis (SSc). Still, there are knowledge gaps on the evolution and total burden of systolic dysfunction in SSc. Here we evaluated prospective left ventricular (LV) and right ventricular (RV) systolic function in an unselected SSc cohort and assessed the burden of systolic dysfunction on mortality. Methods: From the Oslo University Hospital cohort, 277 SSc patients were included from 2003-2016 and compared with healthy controls. Serial echocardiographies were reevaluated in order to detect change in systolic function. Right heart catheterization was performed on patients suspected of pulmonary hypertension. Descriptive and regression analyses were conducted. Results: At baseline, LV systolic dysfunction by ejection fraction less than 50%, or a global longitudinal strain greater than -17.0%, was found in 12% and 24%, respectively. RV systolic dysfunction measured by tricuspid annular plane systolic excursion (TAPSE) less than 17 mm was evident in 10%. Follow-up echocardiography was performed after a median of 3.3 years (interquartile range [IQR] 1.5-5.6). At follow-up, LV systolic function remained stable, whereas RV function evaluated by TAPSE deteriorated (mean 23.1 to 21.7 mm, P = 0.005) equaling a 15% prevalence of RV systolic dysfunction. RV systolic function predicted mortality in multivariable models (hazard ratio 0.41, 95% confidence interval [CI] 0.19-0.90, P value 0.027), whereas LV systolic function lost predictive significance when adjusted for TAPSE. Conclusion: In this unselected and prospective study, systolic dysfunction of the LV and RV was a frequent complication of SSc. LV systolic function remained stable across the observation period, whereas RV function deteriorated and predicted mortality.

3.
EBioMedicine ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31732480

RESUMO

BACKGROUND: Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology. METHODS: We collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex. FINDINGS: The concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93·0 pg/ml [±97·2] vs. 37·5 pg/ml [±35·4], p < 0·001; PDGF-BB 102·5 pg/ml [±78·8] vs. 61·9 pg/ml [±47·0], p < 0·001; FGF-2 1442·4 pg/ml [±426·6] vs. 1201·7 pg/ml [±535·2], p = 0·009; VEGF 40·6 pg/ml [±20·1] vs. 24·9 pg/ml [±29·5], p < 0·001; and M-CSF 25526 pg/ml [±24,799] vs. 6120 pg/ml [±7245], p < 0·001). There were no significant differences in these growth factor/angiogenic molecules/cytokine concentrations when segregated by IPF, SSc-ILD and other PF-ILDs. INTERPRETATION: Nintedanib specific targeted molecular pathways are augmented to a similar magnitude in all PF-ILD lung tissue as compared to controls, suggesting that Nintedanib treatment may be efficacious in PF-ILD regardless of aetiology. We speculate that clinical trials using Nintedanib for PF-ILD with or without IPF or SSc-ILD should show a similar relative reduction in FVC decline as seen in IPF and SSc-ILD (∼45-50%). FUNDING: Health Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).

4.
Nat Commun ; 10(1): 4955, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

5.
Expert Rev Clin Immunol ; 15(10): 1009-1017, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31566449

RESUMO

Introduction: Systemic sclerosis (SSc) is a rare and complex connective tissue disease characterized by fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is a common complication of SSc and the leading cause of SSc-related death. No drugs are licensed for the treatment of SSc-ILD. Areas covered: This review provides an overview of the current treatment of SSc-ILD and a perspective on investigational therapies, focusing on those studied in randomized controlled trials. Expert opinion: There is substantial room for improvement in the treatment of SSc-ILD. Current treatment focuses on immunosuppressant therapies, particularly cyclophosphamide and mycophenolate. Hematopoietic stem cell transplantation has been shown to improve long-term outcomes, but the risk of treatment-related mortality restricts its use to select patients at specialized centers. Modifying the course of disease to improve outcomes remains the goal for new therapies. Several drugs are under investigation as potential therapies for SSc-ILD, providing hope that the limited treatment armamentarium for SSc-ILD will be expanded and improved in the near future. Expert consensus is needed on how to screen for and monitor SSc-ILD and on when to initiate and escalate therapy.

7.
Am J Respir Crit Care Med ; 200(10): 1258-1266, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310156

RESUMO

Rationale: Interstitial lung disease (ILD) represents a major challenge in systemic sclerosis (SSc), but there are no precise, population-based data on its overall impact, limiting opportunities for screening and management strategies.Objectives: Evaluate impact of ILD in a unique, nationwide, population-based SSc cohort.Methods: ILD was assessed prospectively in the Norwegian SSc (Nor-SSc) cohort, including all 815 patients with SSc resident in the country from 2000 to 2012. Lung high-resolution computed tomography (HRCT) scans were available for fibrosis quantification at baseline (n = 650, 80%) and follow-up. Pulmonary function tests were assessed at baseline (n = 703, 86%) and follow-up. Vital status and standardized mortality ratios (SMRs) were estimated at study end (2018) in the 630 incident Nor-SSc cases and 15 individually matched control subjects. Cumulative survival rates were computed.Measurements and Main Results: At baseline, 50% of the subjects with SSc (n = 324) had ILD by HRCT and 46% displayed pulmonary function declines consistent with ILD progression. Mortality correlated with extent of lung fibrosis as SMR increased from 2.2 with no fibrosis to 8.0 with greater than 25% fibrosis. SMR was inversely related to baseline FVC% and increased at all FVC levels below 100%. In patients with normal-range baseline FVC (80-100%), the 5- and 10-year survival rates correlated with presence or absence of lung fibrosis, being 83% and 80%, respectively, with no fibrosis and 69% and 56%, respectively, with lung fibrosis (P = 0.03).Conclusions: The mere presence of ILD at baseline appears to affect outcome in SSc, suggesting that all patients with SSc should undergo a baseline pulmonary function test and lung HRCT screening to diagnose ILD early and tailor further management.

8.
Arthritis Rheumatol ; 71(7): 1204-1206, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31082000
9.
RMD Open ; 5(1): e000826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30997150

RESUMO

Background: Systemic sclerosis (SSc) is a severe, progressive multiorgan disease but to date, there are no established standardised international guidelines for follow-up of patients with SSc. The goal of this project was to develop an expert consensus for annual systematic investigations in patients with SSc to enhance their standard-of-care. Material and methods: The Delphi method was applied. All SSc experts from the European Scleroderma Trials and Research group network and the Scleroderma Clinical Trial Consortium were invited to participate. All experts were asked to answer questionnaires in five Delphi steps to determine the domains of interest and tools for each domain for an annual systematic assessment of patients with SSc. Each item was rated on a scale between 0% and 100% (not and very important), and parameters rated >80% by more than 75% of the experts were regarded as acceptable. Results: In total, 157 experts worldwide participated with 71.3% experts seeing >50 patients with SSc annually. In the first round, 23 domains and 204 tools were suggested. After five Delphi steps, experts agreed on 10 domains including (1) Raynaud's phenomenon; (2) Digital ulcers; (3) Skin and mucosa; (4) Lung; (5); Heart; (6) GI domain, (7) Renal; (8) Musculoskeletal; (9) Laboratory and (10) Treatment. Overall, 55 tools were identified including clinical assessments, laboratory measurements and imaging or functional investigations. Conclusion: Through five Delphi steps with world leading experts, a consensus was established on strongly suggested tools for a minimum annual systemic assessment of organ involvement in SSc. This work should enhance the standardisation and homogenisation of the practices.

10.
Ann Rheum Dis ; 78(7): 979-987, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30967395

RESUMO

OBJECTIVE: To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. METHODS: We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. RESULTS: 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55-1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=0.019 as compared with controls vs 3 [0.66-5.35]; p=0.012). CONCLUSION: Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.

11.
J Rheumatol ; 46(10): 1316-1325, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30770517

RESUMO

OBJECTIVE: To compare safety and efficacy outcomes between the cyclophosphamide (CYC) arms of Scleroderma Lung Study (SLS) I and II. METHODS: Participants enrolled in the CYC arms of SLS I (n = 79) and II (n = 69) were included. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (in SLS II, patients received placebo in Year 2). Eligibility criteria for SLS I and II were nearly identical. Outcomes included the forced vital capacity (FVC%)-predicted and DLCO%-predicted (measured every 3 mos) and quantitative radiographic extent of interstitial lung disease (measured at 1 and 2 yrs for SLS I and SLS II, respectively). Joint models were created to evaluate the treatment effect on the course of the FVC/DLCO over 2 years while controlling for baseline disease severity. RESULTS: SLS I and II CYC participants had similar baseline characteristics. After adjusting for baseline disease severity, there was no difference in the course of the FVC%-predicted (p = 0.535) nor the DLCO%-predicted (p = 0.172) between the SLS I and II CYC arms. In both groups, treatment with CYC led to a significant improvement in the FVC%-predicted from 3 to 12 months, but no significant improvement beyond this point. Treatment with CYC had no effect on the DLCO for either group. CONCLUSION: Treatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not sustained following cessation of CYC. These results suggest that increasing the duration of ILD therapy may improve outcomes for patients with systemic sclerosis-ILD.

12.
Arthritis Rheumatol ; 71(4): 655-656, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30663863
13.
Arthritis Rheumatol ; 71(6): 972-982, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30624031

RESUMO

OBJECTIVE: Interstitial lung disease (ILD) in systemic sclerosis (SSc) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and prognostic performance of 4 candidate serum biomarkers for SSc-associated ILD. METHODS: Serum samples from a combined cohort of SSc patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme-linked immunosorbent assay for concentrations of lung epithelial-derived surfactant protein D (SP-D), Krebs von den Lungen 6 glycoprotein (KL-6), CCL18, and OX40 ligand (OX40L). Lung fibrosis was measured by high-resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow-up 3.2 ± 4.4 years) were investigated. RESULTS: In SSc patients at baseline, serum levels of KL-6 correlated with the forced vital capacity (FVC) (r = -0.317, P < 0.001), diffusing capacity for carbon monoxide (r = -0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL-6 and SP-D, but not CCL18 and OX40L, were associated with lung fibrosis (odds ratio [OR] 2.41, 95% confidence interval [95% CI] 1.43-4.07 [P = 0.001] and OR 3.15, 95% CI 1.81-5.48 [P < 0.001], respectively). In SSc patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio [HR] 2.90, 95% CI 1.25-6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02-13.52; P = 0.048). Matrix-based logistic regression models for the diagnosis and prognosis of SSc-associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP-D (for diagnosis) and serum levels of CCL18 (for progression of disease). CONCLUSION: These results show that SP-D is a relevant diagnostic biomarker for SSc-associated ILD, whereas KL-6 could be used to assess the severity of lung fibrosis. CCL18 appears to be a potential predictive marker for progression of ILD in SSc.

14.
Rheumatology (Oxford) ; 58(2): 313-320, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30281089

RESUMO

Objectives: Studies assessing relative mortality risks across the spectrum of systemic inflammatory rheumatic diseases are largely missing. In this study, we wanted to estimate standard mortality ratios (SMRs) and causes of death in an ethnically homogeneous cohort covering all major CTDs and primary systemic vasculitides (PSVs). Methods: We prospectively followed all incident CTD and PSV cases included in the Norwegian CTD and vasculitis registry (NOSVAR) between 1999 and 2015. Fifteen controls for each patient matched for sex and age were randomly drawn from the Norwegian National Population Registry. Causes of death were obtained from the National Cause of Death Register, death certificates and hospital charts. Results: The cohort included 2140 patients (1534 with CTD, 606 with PSV). During a mean follow-up time of 9 years, 279 of the patients (13%) died, compared with 2864 of 32 086 (9%) controls (P < 0.001). Ten years after diagnosis, the lowest survival was 60% in dcSSc, 73% in anti-synthetase syndrome (ASS) and 75% in lcSSc. In the CTD group, the highest SMRs were observed in dcSSc (SMR 5.8) and ASS (SMR 4.1). In the PSV group, Takayasu arteritis (SMR 2.5) and ANCA-associated vasculitis (SMR 1.5) had the highest SMRs. Major causes of death were cardiovascular disease (CTD 27%, PSV 28%), neoplasms (CTD 25%, PSV 27%), chronic respiratory disease (CTD 20%, PSV10%) and infections (CTD 9%, PSV 16%). Conclusion: We observed premature deaths across the spectrum of CTDs and PSVs, with highest SMRs in dcSSc and ASS. The overall mortality was highest in the CTD group.


Assuntos
Doenças do Tecido Conjuntivo/mortalidade , Vasculite Sistêmica/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Estudos de Casos e Controles , Causas de Morte , Doenças do Tecido Conjuntivo/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Infecções Oportunistas/complicações , Infecções Oportunistas/mortalidade , Estudos Prospectivos , Sistema de Registros , Doenças Respiratórias/etiologia , Doenças Respiratórias/mortalidade , Taxa de Sobrevida , Vasculite Sistêmica/complicações , Adulto Jovem
15.
Eur J Rheumatol ; : 1-8, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31922474

RESUMO

Systemic sclerosis (SSc) is a complex autoimmune disease of unknown etiology. Genetic factors are thought to collude with various environmental triggers to induce SSc and subsequently manifest various SSc disease phenotypes. Emerging evidence suggests that the microbiota of the gastrointestinal tract (GIT) may represent a key pathogenic participant in this disease state. Recent studies have demonstrated specific alterations in the GIT microbial composition in SSc patients, and this article reviews studies that have investigated the GIT microbiota in SSc patients. The focus of this article is to highlight the modifications in the GIT microbiota observed in SSc patients belonging to different cohorts and to demonstrate how these alterations may be associated with specific SSc features. This article presents the results of these SSc microbiota studies in the context of findings from microbiotic studies in other autoimmune states to explore similarities and differences across disease states affecting the immune system. Finally, this article provides insights into potential SSc therapies that target the GIT microbiota. Given the complexity and variability of the SSc disease state, any treatment aimed at modulating GIT microbiota will likely need to be coupled with additional interventions that target other SSc disease components.

16.
PLoS One ; 13(11): e0206545, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30457999

RESUMO

BACKGROUND: Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial. METHODS: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed. RESULTS: CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH. CONCLUSION: CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.


Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Pulmão/metabolismo , Escleroderma Sistêmico/metabolismo , Adulto , Biomarcadores/metabolismo , Progressão da Doença , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/cirurgia , Pulmão/patologia , Pulmão/cirurgia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/cirurgia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/cirurgia , Sindecana-1/metabolismo
17.
J Am Coll Cardiol ; 72(15): 1804-1813, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30286924

RESUMO

BACKGROUND: Primary cardiac affection is common and is a major cause of death in systemic sclerosis (SSc), but there are knowledge gaps regarding the effect of cardiac dysfunction on mortality. OBJECTIVES: The purpose of this study was to evaluate diastolic function in a large, unselected SSc cohort and assess the effect of diastolic dysfunction (DD) on mortality. METHODS: SSc patients followed prospectively at the Oslo University Hospital from 2003 to 2016 with available echocardiographies and matched control subjects were included. DD was assessed by echocardiography according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Pulmonary hypertension (PH) was diagnosed by right heart catheterization. Vital status was available for all patients. Cox regression analyses with hazards ratios (HRs) were conducted. RESULTS: Diastolic function was assessed in 275 SSc patients at baseline and in 186 patients at follow-up. At baseline, 46 of the 275 SSc patients (17%) were diagnosed with DD and 195 (71%) had normal diastolic function. After a median follow-up of 3.4 years (interquartile range: 1.6 to 6.2 years), the proportion of DD increased from 17% to 29%. During follow-up, 57% of patients with DD at baseline died, compared with 13% of patients with normal diastolic function. At baseline, 86 patients had performed right heart catheterization, and 43 were diagnosed with PH; of these 60% deceased. In multivariable Cox regression analyses, DD was a stronger predictor of death (HR: 3.7; 95% CI: 1.69 to 8.14; c-index 0.89) than PH (HR: 2.0; 95% CI: 1.1 to 3.9; c-index 0.84). CONCLUSIONS: DD is frequent in SSc, and the presence of DD is associated with high mortality. DD exceeds PH with respect to predicting mortality.


Assuntos
Insuficiência Cardíaca Diastólica , Hipertensão Pulmonar , Escleroderma Sistêmico , Disfunção Ventricular Esquerda , Cateterismo Cardíaco/métodos , Ecocardiografia Doppler/métodos , Feminino , Seguimentos , Insuficiência Cardíaca Diastólica/diagnóstico , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/mortalidade , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Noruega/epidemiologia , Modelos de Riscos Proporcionais , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/mortalidade , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/mortalidade
18.
Arthritis Rheumatol ; 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30281215

RESUMO

We thank Zhou and co-workers for their interest regarding our newly published manuscript on the role of CCL21 in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc). Here, we want to respond to their concerns. Genome-wide association studies (GWASs) have been foreshadowed to be a major advance in biomedical discovery, with many robust associations to complex diseases. However, although there are found polymorphisms with SSc, there are, to date, no existing genetic loci for SSc-PAH. Secondly, despite this success, GWAS studies have met considerable skepticism regarding their clinical applicability; mainly arising from their unclear functional consequences. This article is protected by copyright. All rights reserved.

19.
Ann Rheum Dis ; 77(9): 1326-1332, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29875097

RESUMO

OBJECTIVES: To identify the predictive clinical characteristics and establish a prediction model for the progression of mild interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). METHODS: Patients with SSc from two independent prospective cohorts were included in this observational study. All patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria, had mild ILD at baseline diagnosed by High-Resolution Computed Tomography (HRCT), available baseline and ≥1 annual follow-up pulmonary function tests and no concomitant pulmonary hypertension or airflow obstruction. ILD progression was defined as a relative decrease in forced vital capacity (FVC)%≥15%, or FVC%≥10% combined with diffusing capacity for carbon monoxide %≥15% at 1-year follow-up. Candidate predictors for multivariate logistic regression were selected by expert opinion based on clinical significance. A prediction model for ILD progression was established in the derivation cohort and validated in the multinational validation cohort. RESULTS: A total of 25/98 and 25/117 patients with SSc showed ILD progression in the derivation cohort and the validation cohort, respectively. Lower SpO2 after 6 min walk test (6MWT) and arthritis ever were identified as independent predictors for ILD progression in both cohorts. The optimal cut-off value of SpO2 after 6MWT for predicting ILD progression was determined as 94% by receiver operating characteristic curve analysis. The derived SPAR model combining both predictors (SPO2 and ARthritis) increased the prediction rate from 25.5% to 91.7% with an area under the curve (95% CI) of 0.83 (0.73 to 0.93). CONCLUSIONS: The evidence-based SPAR prediction model developed in our study might be helpful for the risk stratification of patients with mild SSc-ILD in clinical practice and cohort enrichment for future clinical trial design.


Assuntos
Doenças Pulmonares Intersticiais/etiologia , Escleroderma Sistêmico/complicações , Adulto , Idoso , Progressão da Doença , Teste de Esforço/métodos , Feminino , Humanos , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Capacidade de Difusão Pulmonar , Curva ROC , Testes de Função Respiratória , Medição de Risco/métodos , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/fisiopatologia , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X , Capacidade Vital
20.
Arthritis Rheumatol ; 70(10): 1644-1653, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29687634

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles for chemokines CCL19 and CCL21 and their receptor CCR7 in lung inflammation leading to PAH. The objective of this study was to assess the chemokine CCL19-CCL21 axis in patients with SSc-related PAH. METHODS: Serum samples obtained from 2 independent prospective SSc cohorts (n = 326), patients with idiopathic PAH (n = 12), and healthy control subjects (n = 100) were analyzed for CCL19/CCL21 levels, by enzyme-linked immunosorbent assay. The levels were defined as either high or low, using the mean + 2 SD value in controls as the cutoff value. Risk stratification at the time of PAH diagnosis and PAH-related events were performed. Descriptive and Cox regression analyses were conducted. RESULTS: CCL21 levels were higher in patients with SSc compared with controls and were elevated prior to the diagnosis of PAH. PAH was more frequent in patients with high CCL21 levels (≥0.4 ng/ml) than in those with low CCL21 levels (33.3% versus 5.3% [P < 0.001]). In multivariate analyses, CCL21 was associated with PAH (hazard ratio [HR] 5.1, 95% CI 2.39-10.76 [P < 0.001]) and occurrence of PAH-related events (HR 4.7, 95% CI 2.12-10.46, P < 0.001). Risk stratification at the time of PAH diagnosis alone did not predict PAH-related events. However, when risk at diagnosis was combined with high or low CCL21 level, there was a significant predictive effect (HR 1.3, 95% CI 1.03-1.60 [P = 0.027]). A high CCL21 level was associated with decreased survival (P < 0.001). CONCLUSION: CCL21 appears to be a promising marker for predicting the risk of SSc-related PAH and PAH progression. CCL21 may be part of a dysregulated immune pathway linked to the development of lung vascular damage in SSc.


Assuntos
Quimiocina CCL21/sangue , Hipertensão Pulmonar Primária Familiar/sangue , Escleroderma Sistêmico/sangue , Adulto , Idoso , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Hipertensão Pulmonar Primária Familiar/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Valores de Referência , Medição de Risco/métodos , Fatores de Risco , Escleroderma Sistêmico/complicações
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