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1.
Ann Rheum Dis ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041748

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3). METHODS: Full-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor. RESULTS: SSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro. CONCLUSIONS: Our data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31680161

RESUMO

OBJECTIVES: Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations. METHODS: SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses. RESULTS: The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]. CONCLUSION: Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality.

3.
Ann Rheum Dis ; 78(11): 1576-1582, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31391176

RESUMO

OBJECTIVES: To investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc). METHODS: 601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5-4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed. RESULTS: During 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05). CONCLUSIONS: The present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA.

4.
Mol Med Rep ; 20(2): 1488-1498, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257535

RESUMO

Fibrosis is characterized by excessive extracellular matrix (ECM) deposition, and is the pathological outcome of tissue injury in a number of disorders. Accumulation of the ECM may disrupt the structure and function of native tissues and organs, including the lungs, heart, liver and skin, resulting in significant morbidity and mortality. On this basis, multiple lines of evidence have focused on the molecular pathways and cellular mechanisms involved in fibrosis, which has led to the development of novel antifibrotic therapies. CD248 is one of several proteins identified to be localized to the stromal compartment in cancers and fibroproliferative disease, and may serve a key role in myofibroblast generation and accumulation. Numerous studies have supported the contribution of CD248 to tumour growth and fibrosis, stimulating interest in this molecule as a therapeutic target. In addition, it has been revealed that CD248 may be involved in pathological angiogenesis. The present review describes the current understanding of the structure and function of CD248 during angiogenesis and fibrosis, supporting the hypothesis that blocking CD248 signalling may prevent both myofibroblast generation and microvascular alterations during tissue fibrosis.


Assuntos
Antígenos CD/genética , Antígenos de Neoplasias/genética , Miofibroblastos/metabolismo , Neoplasias/genética , Neovascularização Patológica/genética , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Ensaios Clínicos como Assunto , Colágeno/genética , Colágeno/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose/prevenção & controle , Regulação da Expressão Gênica , Humanos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Transdução de Sinais
5.
Nature ; 570(7760): 194-199, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31142841

RESUMO

Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (PLP) as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active tetrameric state. SHMT2 also promotes inflammatory cytokine signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC-SHMT2 complex at a resolution of 3.8 Å. BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer-and not the active PLP-bound tetramer-binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.

6.
Sci Rep ; 9(1): 4589, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872612

RESUMO

Systemic sclerosis (SSc) is characterized by microangiopathy with impaired reparative angiogenesis and fibrosis. Epidermal Growth Factor Like-domain 7 (EGFL7), firstly described in endothelial cells plays a pivotal role in angiogenesis. Fibroblasts (FBs) are involved in vascular remodeling, under physiological and pathological conditions. In this study, we investigated: (i) the expression of EGFL7 and its miR-126 in patients affected by diffuse cutaneous SSc (dcSSc); (ii) the ability of Transforming Growth Factor-beta (TGF-ß) to modulate EGFL7 expression; (iii) the ability of EGFL7 to modulate COL1A1 expression and proliferation/migration, and (iv) the functional role of EGFL7 on angiogenesis. Patients were divided in 2 subsets: patients fulfilling the classification criteria in less than one year from Raynaud's Phenomenon onset (Early Onset Subset-EOS), and all the others (Long Standing Subset-LSS). We show that EGFL7 expression is increased in EOS dcSSc skin and cultured FBs. EGFL7 is inducible by TGF-ß on Healthy Controls (HC) FBs but not in SSc-FBs. EGFL7 decreases COL1A1 expression in EOS SSc-FBs while EGFL7 silencing up-regulates COL1A1 expression. EGFL7 promotes migration/invasion of EOS SSc-FBs but not proliferation. Finally, SSc-FBs, partially inhibit angiogenesis in organotypic coculture assays, and this is reversed by treatment with human recombinant (rh)EGFL7. We conclude that EGFL7 and its specific microRNA miR-126 may be involved in the pathogenesis of SSc vasculopathy and fibrosis.

7.
Rheumatology (Oxford) ; 58(7): 1221-1226, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30690570

RESUMO

OBJECTIVES: To screen for significant arrhythmias with an implantable loop recorder (ILR) in patients with SSc and no known cardiovascular disease, and identify associated disease phenotype, blood and cardiovascular magnetic resonance (CMR) biomarkers. METHODS: Twenty patients with SSc with no history of primary SSc heart disease, traditional cardiovascular disease, diabetes or maximum one traditional cardiovascular risk factor underwent clinical assessment, contrast-enhanced CMR and ILR insertion. RESULTS: ILR data were available for 19 patients: 63% female, mean (s.d.) age of 53 (12) years, 32% diffuse SSc. Eight patients had significant arrhythmias over 3 years: one complete heart block, two non-sustained ventricular tachycardia [all three dcSSc, two anti-topoisomerase antibodies (Scl70) positive, three interstitial lung disease and two previous digital ulceration] and five atrial arrhythmias of which four were with limited SSc. These required interventions with one permanent pacemaker implantation, four anti-arrhythmic pharmacotherapy, one anticoagulation.Patients with significant arrhythmia had higher baseline high-sensitivity troponin I and N-terminal pro-brain natriuretic peptide [mean difference (95% CI) 117 (-11, 245) and 92 (-30, 215) ng/l, respectively], and CMR-extracellular volume [mean (s.d.) 32 (2) vs 29 (4)%]. Late gadolinium enhancement was observed in five patients, only one with significant arrhythmia. CONCLUSION: This first ILR study identified potentially life-threatening arrhythmias in asymptomatic SSc patients attributable to a primary SSc heart disease. Disease phenotype, CMR-extracellular volume (indicating diffuse fibrosis) and cardiac biomarkers may identify at-risk patients that would benefit from ILR screening. Future studies can inform a risk model and provide insights into SSc-associated arrhythmia pathogenesis.

8.
Rheumatology (Oxford) ; 58(2): 254-259, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239834

RESUMO

Objectives: To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort. Methods: Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software. Results: Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score. Conclusion: Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.


Assuntos
Cirrose Hepática/etiologia , Escleroderma Sistêmico/complicações , Adulto , Idoso , Bancos de Espécimes Biológicos , Biomarcadores/sangue , Feminino , Fibrose , Humanos , Ácido Hialurônico/sangue , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/etiologia , Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de Doença , Pele/patologia , Inibidor Tecidual de Metaloproteinase-1/sangue
9.
Int J Oncol ; 54(2): 537-549, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30483772

RESUMO

Caveolin­1 (Cav­1) expression has been shown to be associated with tumor growth and resistance to chemotherapy in pancreatic cancer. The primary aim of this study was to explore the significance of Cav­1 expression in pancreatic cancer cells as compared to fibroblasts in relation to cancer cell proliferation and chemoresistance, both in vitro and in vivo, in an immunodeficient mouse model. We also aimed to evaluate the immunohistochemical expression of Cav­1 in the epithelial and stromal component of pancreatic cancer tissue specimens. The immunohistochemical staining of poorly differentiated tissue sections revealed a strong and weak Cav­1 expression in the epithelial tumor cells and stromal fibroblasts, respectively. Conversely, the well­differentiated areas were characterized by a weak epithelial Cav­1 expression. Cav­1 downregulation in cancer cells resulted in an increased proliferation in vitro; however, it had no effect on chemoresistance and growth gain in vivo. By contrast, the decreased expression of Cav­1 in fibroblasts resulted in a growth advantage and the chemoresistance of cancer cells when they were co­injected into immunodeficient mice to develop mixed fibroblast/cancer cell xenografts. On the whole, the findings of this study suggest that the downregulation of Cav­1 in fibroblasts is associated with an increased tumor proliferation rate in vivo and chemoresistance. Further studies are warranted to explore whether the targeting of Cav­1 in the stroma may represent a novel therapeutic approach in pancreatic cancer.


Assuntos
Caveolina 1/genética , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Caveolina 1/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Arthritis Rheumatol ; 70(11): 1829-1834, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29781588

RESUMO

OBJECTIVE: Data on the role of tobacco exposure in systemic sclerosis (SSc; scleroderma) severity and progression are scarce. We aimed to assess the effects of smoking on the evolution of pulmonary and skin manifestations, based on the European Scleroderma Trials and Research group database. METHODS: Adult SSc patients with data on smoking history and a 12-24-month follow-up visit were included. Associations of severity and progression of organ involvement with smoking history and the Comprehensive Smoking Index were assessed using multivariable regression analyses. RESULTS: A total of 3,319 patients were included (mean age 57 years, 85% female); 66% were never smokers, 23% were ex-smokers, and 11% were current smokers. Current smokers had a lower percentage of antitopoisomerase autoantibodies than previous or never smokers (31% versus 40% and 45%, respectively). Never smokers had a higher baseline forced expiratory volume in 1 second/forced vital capacity (FEV1 /FVC) ratio than previous and current smokers (P < 0.001). The FEV1 /FVC ratio declined faster in current smokers than in never smokers (P = 0.05) or ex-smokers (P = 0.01). The baseline modified Rodnan skin thickness score (MRSS) and the MRSS decline were comparable across smoking groups. Although heavy smoking (>25 pack-years) increased the odds of digital ulcers by almost 50%, there was no robust adverse association of smoking with digital ulcer development. CONCLUSION: The known adverse effect of smoking on bronchial airways and alveoli is also observed in SSc patients; however, robust adverse effects of smoking on the progression of SSc-specific pulmonary or cutaneous manifestations were not observed.


Assuntos
Pulmão/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Pele/patologia , Fumar/fisiopatologia , Adulto , Idoso , Autoanticorpos/imunologia , DNA Topoisomerases/imunologia , Progressão da Doença , Ex-Fumantes , Feminino , Volume Expiratório Forçado , Humanos , Modelos Lineares , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , não Fumantes , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Índice de Gravidade de Doença , Fumantes , Fumar/imunologia , Fumar/patologia , Capacidade Vital
12.
Arthritis Res Ther ; 20(1): 17, 2018 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-29382380

RESUMO

BACKGROUND: Interstitial lung disease in systemic sclerosis (SSc-ILD) is a major cause of SSc-related death. Imunosuppressive treatment (IS) is used in patients with SSc for various organ manifestations mainly to ameliorate progression of SSc-ILD. Data on everyday IS prescription patterns and clinical courses of lung function during and after therapy are scarce. METHODS: We analysed patients fulfilling American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2013 criteria for SSc-ILD and at least one report of IS. Types of IS, pulmonary function tests (PFT) and PFT courses during IS treatment were evaluated. RESULTS: EUSTAR contains 3778/11,496 patients with SSc-ILD (33%), with IS in 2681/3,778 (71%). Glucocorticoid (GC) monotherapy was prescribed in 30.6% patients with GC combinations plus cyclophosphamide (CYC) (11.9%), azathioprine (AZA) (9.2%), methotrexate (MTX) (8.7%), or mycophenolate mofetil (MMF) (7.3%). Intensive IS (MMF + GC, CYC or CYC + GC) was started in patients with the worst PFTs and ground glass opacifications on imaging. Patients without IS showed slightly less worsening in forced vital capacity (FVC) when starting with FVC 50-75% or >75%. GC showed negative trends when starting with FVC <50%. Regarding diffusing capacity for carbon monoxide (DLCO), negative DLCO trends were found in patients with MMF. CONCLUSIONS: IS is broadly prescribed in SSc-ILD. Clusters of clinical and functional characteristics guide individualised treatment. Data favour distinguished decision-making, pointing to either watchful waiting and close monitoring in the early stages or start of immunosuppressive treatment in moderately impaired lung function. Advantages of specific IS are difficult to depict due to confounding by indication. Data do not support liberal use of GC in SSc-ILD.


Assuntos
Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pulmão/efeitos dos fármacos , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Medicina de Precisão/métodos , Testes de Função Respiratória , Escleroderma Sistêmico/complicações
13.
Ann Rheum Dis ; 77(7): 1032-1038, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29463517

RESUMO

OBJECTIVES: The aim of this study was to adapt the Systemic Sclerosis Quality of Life Questionnaire (SScQoL) into six European cultures and validate it as a common measure of quality of life in systemic sclerosis (SSc). METHODS: This was a seven-country (Germany, France, Italy, Poland, Spain, Sweden and UK) cross-sectional study. A forward-backward translation process was used to adapt the English SScQoL into target languages. SScQoL was completed by patients with SSc, then data were validated against the Rasch model. To correct local response dependency, items were grouped into the following subscales: function, emotion, sleep, social and pain and reanalysed for fit to the model, unidimensionality and cross-cultural equivalence. RESULTS: The adaptation of the SScQoL was seamless in all countries except Germany. Cross-cultural validation included 1080 patients with a mean age 58.0 years (SD 13.9) and 87% were women. Local dependency was evident in individual country data. Grouping items into testlets corrected the local dependency in most country specific data. Fit to the model, reliability and unidimensionality was achieved in six-country data after cross-cultural adjustment for Italy in the social subscale. The SScQoL was then calibrated into an interval level scale. CONCLUSION: The individual SScQoL items have translated well into five languages and overall, the scale maintained its construct validity, working well as a five-subscale questionnaire. Measures of quality of life in SSc can be directly compared across five countries (France, Poland Spain, Sweden and UK). Data from Italy are also comparable with the other five countries although require an adjustment.


Assuntos
Comparação Transcultural , Qualidade de Vida , Escleroderma Sistêmico/fisiopatologia , Escleroderma Sistêmico/psicologia , Adulto , Fatores Etários , Idoso , Estudos Transversais , Feminino , França , Alemanha , Humanos , Internacionalidade , Itália , Masculino , Pessoa de Meia-Idade , Polônia , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Fatores Sexuais , Perfil de Impacto da Doença , Espanha , Suécia , Reino Unido
14.
Arthritis Rheumatol ; 70(6): 903-911, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29457381

RESUMO

OBJECTIVE: Reliable and objective outcome measures to facilitate clinical trials of novel treatments for systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) are badly needed. Laser speckle contrast imaging (LSCI) and thermography are noninvasive measures of perfusion that have shown excellent potential. This multicenter study was undertaken to determine the reliability and validity of a hand cold challenge protocol using LSCI, standard thermography, and low-cost cell phone/mobile phone thermography (henceforth referred to as mobile thermography) in patients with SSc-related RP. METHODS: Patients with RP secondary to SSc were recruited from 6 UK tertiary care centers. The patients underwent cold challenge on 2 consecutive days. Changes in cutaneous blood flow/skin temperature at each visit were imaged simultaneously using LSCI, standard thermography, and mobile thermography. Measurements included area under the curve (AUC) for reperfusion/rewarming and maximum blood flow rate/skin temperature after rewarming (MAX). Test-retest reliability was assessed using intraclass correlation coefficients (ICCs). Estimated latent correlations (estimated from multilevel models, taking values between -1 and 1; denoted as rho values) were used to assess the convergent validity of LSCI and thermography. RESULTS: In total, 159 patients (77% with limited cutaneous SSc) were recruited (84% female, median age 63.3 years). LSCI and standard thermography both had substantial reliability, with ICCs for the reperfusion/rewarming AUC of 0.67 (95% confidence interval [95% CI] 0.54, 0.76) and 0.68 (95% CI 0.58, 0.80), respectively, and ICCs for the MAX of 0.64 (95% CI 0.52, 0.75) and 0.72 (95% CI 0.64, 0.81), respectively. Very high latent correlations were present for the AUCs of LSCI and thermography (ρ = 0.94; 95% CI 0.87, 1.00) and for the AUCs of standard and mobile thermography (ρ = 0.98; 95% CI 0.94, 1.00). CONCLUSION: This is the first multicenter study to examine the reliability and validity of cold challenge using LSCI and thermography in patients with SSc-related RP. LSCI and thermography both demonstrated good potential as outcome measures. LSCI, standard thermography, and mobile thermography had very high convergent validity.


Assuntos
Técnicas de Diagnóstico Cardiovascular/estatística & dados numéricos , Doença de Raynaud/diagnóstico por imagem , Escleroderma Sistêmico/complicações , Termografia/estatística & dados numéricos , Idoso , Área Sob a Curva , Temperatura Baixa , Meios de Contraste , Estudos de Viabilidade , Feminino , Dedos/irrigação sanguínea , Dedos/diagnóstico por imagem , Mãos/irrigação sanguínea , Mãos/diagnóstico por imagem , Humanos , Lasers , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Doença de Raynaud/etiologia , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Temperatura Cutânea , Estatísticas não Paramétricas , Termografia/métodos
15.
Arthritis Rheumatol ; 70(6): 932-942, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29409120

RESUMO

OBJECTIVE: Aberrant activation of Wnt signaling has been observed in tissues from patients with systemic sclerosis (SSc). This study aimed to determine the role of transforming growth factor ß (TGFß) in driving the increased Wnt signaling, through modulation of axis inhibition protein 2 (Axin-2), a critical regulator of the Wnt canonical pathway. METHODS: Canonical Wnt signaling activation was analyzed by TOPflash T cell factor/lymphoid enhancer factor promoter assays. Axin-2 was evaluated in vitro by analysis of Axin-2 primary/mature transcript expression and decay, TGFß receptor type I (TGFßRI) blockade, small interfering RNA-mediated depletion of tristetraprolin 1, and XAV-939-mediated Axin-2 stabilization. In vivo, Axin-2 messenger RNA (mRNA) and protein expression was determined in skin and lung biopsy samples from mice that express a kinase-deficient TGFßRII specifically on fibroblasts (TßRIIΔk-fib-transgenic mice) and from littermate controls. RESULTS: SSc fibroblasts displayed an increased response to canonical Wnt ligands despite basal levels of Wnt signaling that were comparable to those in healthy control fibroblasts in vitro. Notably, we showed that SSc fibroblasts had reduced basal expression of Axin-2, which was caused by an endogenous TGFß-dependent increase in Axin-2 mRNA decay. Accordingly, we observed that TGFß decreased Axin-2 expression both in vitro in healthy control fibroblasts and in vivo in TßRIIΔk-fib-transgenic mice. Additionally, using Axin-2 gain- and loss-of-function experiments, we demonstrated that the TGFß-induced increased response to Wnt activation characteristic of SSc fibroblasts depended on reduced bioavailability of Axin-2. CONCLUSION: This study highlights the importance of reduced bioavailability of Axin-2 in mediating the increased canonical Wnt response observed in SSc fibroblasts. This novel mechanism extends our understanding of the processes involved in Wnt/ß-catenin-driven pathology and supports the rationale for targeting the TGFß pathway to regulate the aberrant Wnt signaling observed during fibrosis.


Assuntos
Proteína Axina/fisiologia , Fibroblastos/metabolismo , Escleroderma Sistêmico/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Via de Sinalização Wnt/genética , Animais , Regulação para Baixo , Humanos , Pulmão/citologia , Camundongos , Camundongos Transgênicos , Pele/citologia
16.
Ann Rheum Dis ; 77(3): 431-440, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29259049

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-ß) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-ß and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis. METHODS: PEDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast-endothelial cell co-cultures and matrigel assays were employed to assess angiogenesis. RESULTS: PEDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-ß in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-ß receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density. CONCLUSIONS: Our data reveal a new pathway by which TGF-ß suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc.


Assuntos
Caveolina 1/metabolismo , Proteínas do Olho/metabolismo , Fibroblastos/metabolismo , Neovascularização Patológica/metabolismo , Fatores de Crescimento Neural/metabolismo , Escleroderma Sistêmico/patologia , Serpinas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real , Escleroderma Sistêmico/metabolismo , Pele/patologia
17.
Rheumatology (Oxford) ; 57(3): 441-450, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28499034

RESUMO

Objectives: The multisystem manifestations of SSc can greatly impact patients' quality of life. The aim of this study was to identify factors associated with disability in SSc. Methods: SSc patients from the prospective DeSScipher cohort who had completed the scleroderma health assessment questionnaire (SHAQ), a disability score that combines the health assessment questionnaire and five visual analogue scales, were included in this analysis. The effect of factors possibly associated with disability was analysed with multiple linear regressions. Results: The mean SHAQ and HAQ scores of the 944 patients included were 0.87 (s.d. = 0.66) and 0.92 (s.d. = 0.78); 59% of the patients were in the mild to moderate difficulty SHAQ category (0 ⩽ SHAQ < 1), 34% in the moderate to severe disability category (1 ⩽ SHAQ < 2) and 7% in the severe to very severe disability category (2 ⩽ SHAQ ⩽ 3). The means of the visual analogue scales scores were in order of magnitude: overall disease severity (37 mm), RP (31 mm), pulmonary symptoms (24 mm), gastrointestinal symptoms (20 mm) and digital ulcers (19 mm). In multiple regression, the main factors associated with high SHAQ scores were the presence of dyspnoea [modified New York Heart Association (NYHA) class IV (regression coefficient B = 0.62), modified NYHA class III (B = 0.53) and modified NYHA class II (B = 0.21; all vs modified NYHA class I)], FM (B = 0.37), muscle weakness (B = 0.27), digital ulcers (B = 0.20) and gastrointestinal symptoms (oesophageal symptoms, B = 0.16; stomach symptoms, B = 0.15; intestinal symptoms, B = 0.15). Conclusion: SSc patients perceive dyspnoea, pain, digital ulcers, muscle weakness and gastrointestinal symptoms as the main factors driving their level of disability, unlike physicians who emphasize objective measures of disability.


Assuntos
Atividades Cotidianas , Avaliação da Deficiência , Qualidade de Vida , Escleroderma Sistêmico/fisiopatologia , Perfil de Impacto da Doença , Europa (Continente) , Gastroenteropatias/etiologia , Gastroenteropatias/fisiopatologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Estudos Longitudinais , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Medição da Dor , Estudos Prospectivos , Análise de Regressão , Fatores de Risco , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/psicologia , Índice de Gravidade de Doença , Úlcera Cutânea/etiologia , Úlcera Cutânea/fisiopatologia
18.
BMJ Case Rep ; 20172017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29054902

RESUMO

The authors present a case of a 51-year-old woman with clinical diagnosis of mixed connective tissue disease and overlap systemic lupus erythematosus features, with a 6-month history of progressive painless abdominal distension. On examination, evident signs of ascites were present. Both the abdominal-pelvic ultrasound and CT scan confirmed a large amount of ascites. A diagnostic paracentesis was performed, which revealed typical features of chylous ascites (CA). An extensive diagnostic work-up led by a multidisciplinary team was performed, excluding malignancy, cirrhosis, infectious, as well as cardiac and primary lymphatic causes. The patient was kept under surveillance, with dietary therapy and periodic ascitic drainages. The hypothesis of an autoimmune cause for CA was considered by exclusion. Rituximab therapy was initiated and an excellent response was achieved, with reduction of the rate of accumulation of CA and an increase in quality of life of the patient.


Assuntos
Ascite Quilosa/terapia , Fatores Imunológicos/uso terapêutico , Lúpus Eritematoso Sistêmico/diagnóstico , Rituximab/uso terapêutico , Doenças do Tecido Conjuntivo Indiferenciado/diagnóstico , Ascite Quilosa/etiologia , Dieta com Restrição de Gorduras , Dieta Rica em Proteínas , Feminino , Humanos , Lúpus Eritematoso Sistêmico/terapia , Pessoa de Meia-Idade , Paracentese , Doenças do Tecido Conjuntivo Indiferenciado/terapia , Conduta Expectante
19.
Ann Rheum Dis ; 76(8): 1327-1339, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27941129

RESUMO

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.


Assuntos
Gastroenteropatias/terapia , Hipertensão Pulmonar/terapia , Nefropatias/terapia , Doença de Raynaud/terapia , Escleroderma Sistêmico/terapia , Úlcera/terapia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Técnica Delfos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Europa (Continente) , Dedos , Fluoxetina/uso terapêutico , Gastroenteropatias/etiologia , Glucocorticoides/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Hipertensão Pulmonar/etiologia , Nefropatias/etiologia , Pneumopatias/etiologia , Pneumopatias/terapia , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostaglandinas I/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Doença de Raynaud/etiologia , Reumatologia , Escleroderma Sistêmico/complicações , Inibidores de Captação de Serotonina/uso terapêutico , Úlcera/etiologia
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