RESUMO
OBJECTIVES: Peripheral muscle involvement in SSc may comprise myositis or a non-inflammatory myopathy. There is little understanding of the nature of SSc myopathy. This pilot study aimed to evaluate the presence of diffuse fibrosis in the peripheral muscle of patients with SSc by determining extracellular volume (ECV) MRI measurement. METHODS: SSc patients, with either suspected myopathy or no muscle involvement, and healthy controls (HCs) had native T1 and ECV MRI quantification of the thigh and creatine-kinase (CK) measured. Suspected myopathy was defined as current / history of minimally raised CK (>320; <600 IU/l) ± presence of clinical signs/symptoms (including proximal lower-limb muscle weakness and/or myalgia) ± a Manual Muscle Testing (MMT) 8 score of <5 in the thighs. RESULTS: Twelve SSc patients and 10 HCs were recruited. Of the 12 patients, 9 had limited cutaneous SSc, 4 had interstitial lung disease, and 7 had suspected myopathy. The higher skeletal muscle ECV was recorded for SSc patients compared with HCs [mean (s.d.) 23 (11)%, vs 11 (4)%, P = 0.04]. Peripheral muscle ECV was associated with CK (rho = 0.554, P = 0.061) and was higher in SSc patients with myopathy than in those with no myopathy [mean (s.d.) 28 (10) vs 15 (5), P = 0.023]. It was determined that an ECV of 22% best identified myopathy (with a sensitivity of 71% and a specificity of 80%). CONCLUSION: This hypothesis-generating study showed higher ECV in SSc patients compared with HCs, as well as association of ECV with suspected myopathy, suggesting the presence of diffuse fibrosis in the peripheral muscle of SSc patients. Further studies are needed to understand the nature of SSc myopathy.
Assuntos
Doenças Musculares , Miosite , Escleroderma Sistêmico , Creatina Quinase , Fibrose , Humanos , Imageamento por Ressonância Magnética , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Doenças Musculares/complicações , Miosite/complicações , Projetos Piloto , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagem , Escleroderma Sistêmico/patologiaRESUMO
OBJECTIVES: SSc primary heart involvement (SSc-pHI) is a significant cause of mortality. We aimed to characterize and identify predictors of subclinical SSc-pHI using cardiovascular MRI. METHODS: A total of 83 SSc patients with no history of cardiovascular disease or pulmonary arterial hypertension and 44 healthy controls (HCs) underwent 3 Tesla contrast-enhanced cardiovascular MRI, including T1 mapping and quantitative stress perfusion. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide were also measured. RESULTS: Cardiovascular MRI revealed a lower myocardial perfusion reserve in the SSc patients compared with HCs {median (interquartile range (IQR)] 1.9 (1.6-2.4) vs 3 (2-3.6), P < 0.001}. Late gadolinium enhancement, indicating focal fibrosis, was observed in 17/83 patients but in none of the HCs, with significantly higher extracellular volume (ECV), suggestive of diffuse fibrosis, in SSc vs HC [mean (s.d.) 31 (4) vs 25 (2), P < 0.001]. Presence of late gadolinium enhancement and higher ECV was associated with skin score [odds ratio (OR) = 1.115, P = 0.048; R2 = 0.353, P = 0.004], and ECV and myocardial perfusion reserve was associated with the presence of digital ulcers at multivariate analysis (R2 = 0.353, P < 0.001; R2 = 0.238, P = 0.011). High-sensitivity troponin I was significantly higher in patients with late gadolinium enhancement, and N-terminal pro-brain natriuretic peptide was associated with ECV (P < 0.05). CONCLUSION: Subclinical SSc-pHI is characterized by myocardial microvasculopathy, diffuse and focal myocardial fibrosis but preserved myocardial contractile function. This subclinical phenotype of SSc-pHI was associated with high-sensitivity troponin I, N-terminal pro-brain natriuretic peptide, SSc disease severity and complicated peripheral vasculopathy. These data provide information regarding the underlying pathophysiological processes and provide a basis for identifying individuals at risk of SSc-pHI.
Assuntos
Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/etiologia , Escleroderma Sistêmico/complicações , Adulto , Biomarcadores/sangue , Feminino , Fibrose , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVES: To determine whether patients with early rheumatoid arthritis (ERA) have cardiovascular disease (CVD) that is modifiable with disease-modifying antirheumatic drug (DMARD) therapy, comparing first-line etanercept (ETN) + methotrexate (MTX) with MTX strategy. METHODS: Patients from a phase IV ERA trial randomised to ETN+MTX or MTX strategy±month 6 escalation to ETN+MTX, and with no CVD and maximum one traditional risk factor underwent cardiovascular magnetic resonance (CMR) at baseline, years 1 and 2. Thirty matched controls underwent CMR. Primary outcome measure was aortic distensibility (AD) between controls and ERA, and baseline to year 1 AD change in ERA. Secondary analyses between and within ERA groups performed. Additional outcome measures included left ventricular (LV) mass and myocardial extracellular volume (ECV). RESULTS: Eighty-one patients recruited. In ERA versus controls, respectively, baseline (geometric mean, 95% CI) AD was significantly lower (3.0×10-3 mm Hg-1 (2.7-3.3) vs 4.4×10-3 mm Hg-1 (3.7-5.2), p<0.001); LV mass significantly lower (78.2 g (74.0-82.7), n=81 vs 92.9 g (84.8-101.7), n=30, p<0.01); and ECV increased (27.1% (26.4-27.9), n=78 vs 24.9% (23.8-26.1), n=30, p<0.01). Across all patients, AD improved significantly from baseline to year 1 (3.0×10-3 mm Hg-1 (2.7-3.4) to 3.6×10-3 mm Hg-1 (3.1-4.1), respectively, p<0.01), maintained at year 2. The improvement in AD did not differ between the two treatment arms and disease activity state (Disease Activity Score with 28 joint count)-erythrocyte sedimentation rate-defined responders versus non-responders. CONCLUSION: We report the first evidence of vascular and myocardial abnormalities in an ERA randomised controlled trial cohort and show improvement with DMARD therapy. The type of DMARD (first-line tumour necrosis factor-inhibitors or MTX) and clinical response to therapy did not affect CVD markers. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN89222125; ClinicalTrials.gov: NCT01295151.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Etanercepte/uso terapêutico , Metotrexato/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacosRESUMO
OBJECTIVES: We sought to confirm in very early rheumatoid arthritis (ERA) a much greater superiority (30%) of first-line etanercept+methotrexate (ETN+MTX) over treat-to-target MTX (MTX-TT) than previously reported in ERA (14%); and explore whether ETN following initial MTX secures a comparable response to first-line ETN+MTX. METHODS: Pragmatic, open-label, randomised controlled trial of treatment-naïve ERA (≤12 months symptom), Disease Activity Score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2, rheumatoid factor (RF)+/-anticitrullinated peptide antibody (ACPA) positive or ultrasound power Doppler (PD) if RF and ACPA negative. Subjects were randomised 1:1 to ETN+MTX; or MTX-TT, escalated to ETN if week 24 DAS28-ESR ≥2.6 and intramuscular corticosteroid at protocolised time points. Primary endpoint of week 48 DAS28ESR remission with clinical and imaging secondary endpoints. RESULTS: We randomised 120 patients, 60 to each arm (71% female, 73% RF/84% ACPA positive, median (IQR) symptom duration 20.3 (13.1, 30.8) weeks; mean (SD) DAS28 5.1 (1.1)). Remission rates with ETN+MTX and MTX-TT, respectively, were 38% vs 33% at week 24; 52% vs 38% at week 48 (ORs 1.6, 95% CI 0.8 to 3.5, p=0.211). Greater, sustained DAS28-ESR remission observed with ETN+MTX versus MTX-TT (42% and 27%, respectively; p=0.035). PD was fully suppressed by week 48 in over 90% in each arm. Planned exploratory analysis revealed OR 2.84, 95% CI 0.8 to 9.6) of achieving remission after 24 weeks of ETN administered first line compared with administered post-MTX. CONCLUSIONS: Compared with remission rates typically reported with first-line tumour necrosis factor inhabitor+MTX versus MTX-TT, we did not demonstrate a larger effect in very ERA. Neither strategy conferred remission in the majority of patients although ultrasound confirmed local inflammation suppression. Poorer ETN response following failure of MTX-TT is also suggested. Trial registration number NCT02433184.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Etanercepte/uso terapêutico , Metotrexato/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Artrite Reumatoide/fisiopatologia , Quimioterapia Combinada , Intervenção Médica Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
Human embryonic stem (hES) cells activate a rapid apoptotic response after DNA damage but the underlying mechanisms are unknown. A critical mediator of apoptosis is Bax, which is reported to become active and translocate to the mitochondria only after apoptotic stimuli. Here we show that undifferentiated hES cells constitutively maintain Bax in its active conformation. Surprisingly, active Bax was maintained at the Golgi rather than at the mitochondria, thus allowing hES cells to effectively minimize the risks associated with having preactivated Bax. After DNA damage, active Bax rapidly translocated to the mitochondria by a p53-dependent mechanism. Interestingly, upon differentiation, Bax was no longer active, and cells were not acutely sensitive to DNA damage. Thus, maintenance of Bax in its active form is a unique mechanism that can prime hES cells for rapid death, likely to prevent the propagation of mutations during the early critical stages of embryonic development.
Assuntos
Apoptose , Células-Tronco Embrionárias/metabolismo , Complexo de Golgi/metabolismo , Proteína X Associada a bcl-2/metabolismo , Acetilação , Antígenos Nucleares/metabolismo , Transporte Biológico , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/citologia , Inativação Gênica , Genes bcl-2 , Humanos , Autoantígeno Ku , Mitocôndrias/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Proteína X Associada a bcl-2/análiseRESUMO
It is well known that clonal cells can make different fate decisions, but it is unclear whether these decisions are determined during, or before, a cell's own lifetime. Here, we engineered an endogenous fluorescent reporter for the pluripotency factor OCT4 to study the timing of differentiation decisions in human embryonic stem cells. By tracking single-cell OCT4 levels over multiple cell cycle generations, we found that the decision to differentiate is largely determined before the differentiation stimulus is presented and can be predicted by a cell's preexisting OCT4 signaling patterns. We further quantified how maternal OCT4 levels were transmitted to, and distributed between, daughter cells. As mother cells underwent division, newly established OCT4 levels in daughter cells rapidly became more predictive of final OCT4 expression status. These results imply that the choice between developmental cell fates can be largely predetermined at the time of cell birth through inheritance of a pluripotency factor.
Assuntos
Diferenciação Celular/genética , Rastreamento de Células/métodos , Células-Tronco Embrionárias Humanas/metabolismo , Padrões de Herança , Fator 3 de Transcrição de Octâmero/genética , Células-Tronco Pluripotentes/metabolismo , Proteína Morfogenética Óssea 4/farmacologia , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Sistemas CRISPR-Cas , Ciclo Celular/genética , Regulação da Expressão Gênica , Genes Reporter , Células-Tronco Embrionárias Humanas/citologia , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco Pluripotentes/citologia , Engenharia de Proteínas/métodos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Proteína Vermelha FluorescenteRESUMO
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/sangueRESUMO
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.
Assuntos
Arritmias Cardíacas/etiologia , Miocárdio/patologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Esclerodermia Difusa/complicações , Troponina I/sangue , Adulto , Idoso , Arritmias Cardíacas/diagnóstico , Biomarcadores/sangue , Eletrocardiografia Ambulatorial/métodos , Feminino , Fibrose , Coração/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Prospectivos , Esclerodermia Difusa/sangueRESUMO
OBJECTIVES: To compare the effect of non-surgical periodontal therapy on clinical and inflammatory parameters in patients with moderate to severe chronic periodontitis (CP) and rheumatoid arthritis (RA) (RA-CP) with that in CP patients without RA. MATERIAL AND METHODS: Eighteen patients with RA-CP and 18 systemically healthy patients with CP were treated with scaling and root planing (SRP) within 24 h. At baseline, and at 3 and 6 months after SRP, clinical periodontal parameters, inflammatory markers, and microorganisms in subgingival biofilm were assessed. In addition, disease activity markers of RA (DAS28, CRP, ESR) and specific antibodies (RF) were monitored in the RA-CP group. RESULTS: In both groups, non-surgical therapy yielded to statistically significant improvements in all investigated clinical periodontal variables; in RA patients, a statistically significant decrease in serum-CRP was seen at 3 months. At all time-points, levels of inflammatory markers in GCF were higher in RA-CP than in CP patients. Counts of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola decreased statistically significantly in CP but not in the RA-CP group. Changes of DAS28 correlated positively with those of P. gingivalis and negatively with the plaque index. CONCLUSIONS: Within their limits, the present data suggest that (a) non-surgical periodontal therapy improves periodontal conditions in CP patients with and without RA and (b) in patients with RA, eradication of P. gingivalis in conjunction with a high level oral hygiene may transiently decrease disease activity of RA. CLINICAL RELEVANCE: In patients with RA and CP, non-surgical periodontal therapy is a relevant modality not only to improve the periodontal condition but also to decrease RA activity.
Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/terapia , Periodontite Crônica/complicações , Periodontite Crônica/terapia , Adulto , Biomarcadores/análise , Proteína C-Reativa/análise , Estudos de Casos e Controles , Periodontite Crônica/microbiologia , Raspagem Dentária , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice Periodontal , Estudos Prospectivos , Aplainamento Radicular , Resultado do TratamentoRESUMO
PURPOSE: To determine the impact of oral health related quality of life (OHRQoL) on general health in patients suffering from rheumatoid arthritis (RA). MATERIALS AND METHODS: Ninety-one patients with RA (mean age 52.82 ± 11 years, 75.82% female, 20.87% smokers) and 30 systemically healthy patients (control) were evaluated for their OHRQoL by means of the Geriatric Oral Health Assessment Index (GOHAI) and the Oral Health Impact Profile (OHIP)-14 questionnaires. Self-perceived RA status was assessed using the Routine Assessment of Patient Index Data 3 (RAPID3). RESULTS: The mean SC-GOHAI score was 3.69 ± 2.47 for RA subjects and 1.36 ± 2.69 in the control group. Statistically significant differences were seen between RA and control groups (p < 0.05). RA patients with and without periodontitis (PA) exhibited similar SC-GOHAI (Simple Count GOHAI) scores (p = 0.980). No statistically significant differences were observed between any of the groups, either for the OHIP 14-extent or for the OHIP 14-prevalence. RAPID3 scores showed that the majority of the RA patients (65.93%) had high disease severity (RAPID3 >12, mean RAPID3 score 14.39 ± 5.14). Statistically significantly higher values were recorded for general health assessment (PTGE, p = 0.009) and fatigue (FT, p = 0.004) in RA with PA as compared to those without. SC-GOHAI with values between 5 and 8 was statistically significantly associated with high severity health impairment (RAPID3 >12, p = 0.014, OR: 8.64). CONCLUSION: Within their limits, the present findings indicate that: a) moderate OHRQoL as assessed by GOHAI may contribute to high severity impairment of health in RA patients, and b) the GOHAI questionnaire may represent a more adequate tool than OHIP-14 for assessing OHRQoL in patients suffering from RA.
Assuntos
Artrite Reumatoide/epidemiologia , Saúde Bucal , Qualidade de Vida , Estudos de Casos e Controles , Fadiga/epidemiologia , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Romênia/epidemiologia , Inquéritos e QuestionáriosRESUMO
Objective: Cardiac disease in SSc can manifest in various ways and is associated with a poor prognosis. There is little evidence on how best to detect and manage cardiac disease in SSc. Our objective was to produce an expert consensus best practice pathway for the management of cardiac disease in SSc. Methods: The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including cardiac disease. A multidisciplinary task force was convened. The guidelines were partly informed by a comprehensive literature review. Results: A best practice pathway for cardiac disease (with a focus on primary cardiac disease) in SSc is presented, including approaches for early detection and standard pharmacological and device therapies. Due to the benefits, shared care and a multidisciplinary approach are recommended. A future research agenda has been formulated in response to the relative lack of understanding of the natural history of primary cardiac disease that was highlighted by the initiative. Conclusion: The physician should be alert to the possibility of cardiac disease in SSc; it is best managed within a multidisciplinary team including both rheumatologists and cardiologists. This pathway provides a reference for all physicians managing patients with SSc.
Assuntos
Cardiomiopatias/terapia , Escleroderma Sistêmico/terapia , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/terapia , Biomarcadores/sangue , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Fármacos Cardiovasculares/efeitos adversos , Eletrocardiografia , Medicina Baseada em Evidências , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Humanos , Angiografia por Ressonância Magnética , Anamnese/métodos , Monitorização Ambulatorial/métodos , Equipe de Assistência ao Paciente/organização & administração , Pericardite/diagnóstico , Pericardite/etiologia , Pericardite/terapia , Exame Físico/métodos , Fatores de Risco , Escleroderma Sistêmico/diagnósticoRESUMO
BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis, with significant impact on quality of life and functional status. Whilst biologic disease modifying anti-rheumatic drugs (bDMARD) such as tumour necrosis factor-inhibitor (TNFi) agents have revolutionised outcomes in RA, early diagnosis with immediate conventional therapy, titrated in a treat to target approach is also associated with high remission rates. The main aim of the VEDERA study (Very Early versus Delayed Etanercept in Rheumatoid Arthritis) is to assess the depth of remission, sustainability of remission and immunological normalisation induced by very early TNFi with etanercept (ETN) or standard of care +/- delayed ETN. METHODS/DESIGN: VEDERA is a pragmatic, phase IV single-centre open-label randomised superiority trial of 120 patients with early, treatment-naive RA. Patients will be randomised 1:1 to first-line ETN and methotrexate (MTX) or MTX with additional synthetic disease modifying anti-rheumatic drugs (sDMARDs) according to a treat to target (TT) protocol with further step up to ETN and MTX after 24 weeks if remission is not achieved. Participants will have regular disease activity assessments and imaging evaluation including musculoskeletal ultrasound and MRI. The main objective of this study is to assess the proportion of patients with early RA that achieve clinical remission at 48 weeks, following either treatment strategy. In addition, the participants are invited to take part in a cardio-vascular sub-study (Coronary Artery Disease in RA, CADERA), which aims to identify the incidence of cardiovascular abnormalities in early RA. DISCUSSION: The hypothesis underlining this study is that very early treatment with first-line ETN increases the proportion of patients with rheumatoid arthritis achieving clinical remission, in comparison to conventional therapy. TRIAL REGISTRATION: NCT02433184 , 23/04/2015.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Etanercepte/administração & dosagem , Artrite Reumatoide/diagnóstico , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Indução de Remissão/métodos , Resultado do TratamentoAssuntos
Arritmias Cardíacas/epidemiologia , Doenças do Sistema Nervoso Autônomo/epidemiologia , Escleroderma Sistêmico/epidemiologia , Adulto , Idoso , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Eletrocardiografia , Eletrocardiografia Ambulatorial , Técnicas Eletrofisiológicas Cardíacas , Feminino , Bloqueio Cardíaco/epidemiologia , Bloqueio Cardíaco/etiologia , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Medição de Risco , Escleroderma Sistêmico/complicações , Taquicardia Ventricular/epidemiologia , Taquicardia Ventricular/etiologiaRESUMO
Embryonic stem cell (ESC) identity and self-renewal is maintained by extrinsic signaling pathways and intrinsic gene regulatory networks. Here, we show that three members of the Ccr4-Not complex, Cnot1, Cnot2, and Cnot3, play critical roles in maintaining mouse and human ESC identity as a protein complex and inhibit differentiation into the extraembryonic lineages. Enriched in the inner cell mass of blastocysts, these Cnot genes are highly expressed in ESC and downregulated during differentiation. In mouse ESCs, Cnot1, Cnot2, and Cnot3 are important for maintenance in both normal conditions and the 2i/LIF medium that supports the ground state pluripotency. Genetic analysis indicated that they do not act through known self-renewal pathways or core transcription factors. Instead, they repress the expression of early trophectoderm (TE) transcription factors such as Cdx2. Importantly, these Cnot genes are also necessary for the maintenance of human ESCs, and silencing them mainly lead to TE and primitive endoderm differentiation. Together, our results indicate that Cnot1, Cnot2, and Cnot3 represent a novel component of the core self-renewal and pluripotency circuitry conserved in mouse and human ESCs.
Assuntos
Células-Tronco Embrionárias/metabolismo , Inativação Gênica/fisiologia , Células-Tronco Pluripotentes/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/genética , Linhagem Celular , Células-Tronco Embrionárias/citologia , Humanos , Camundongos , Camundongos Knockout , Células-Tronco Pluripotentes/citologia , Proteínas Repressoras/genética , Fatores de Transcrição/genéticaRESUMO
OBJECTIVE: Subclinical systemic sclerosis (SSc) primary heart involvement is commonly described. Whether these findings progress over time is not clear. The study aimed to investigate cardiovascular magnetic resonance (CMR) interval change of subclinical SSc primary heart involvement. METHODS: Patients with SSc with no cardiovascular disease underwent two CMR scans that included T1 mapping and quantitative stress perfusion. The CMR change (mean difference) and association between CMR measures and clinical phenotype were assessed. The study had a prospective design. RESULTS: Thirty-one patients with SSc participated, with a median (interquartile range) follow-up of 33 (17-37) months (10 [32%] in the diffuse subset, 16 [52%] with interstitial lung disease [ILD], and 11 [29%] who were Scl-70+). Four of thirty-one patients had focal late gadolinium enhancement (LGE) at visit 1; one of four had an increase in LGE scar mass between visits. Two patients showed new focal LGE at visit 2. No change in other CMR indices was noted. The three patients with SSc with increased or new LGE at visit 2 had diffuse cutaneous SSc with ILD, and two were Scl-70+. A reduction in forced vital capacity and total lung capacity was associated with a reduction in left ventricular ejection fraction (ρ = 0.413, P = 0.021; ρ = 0.335, P = 0.07) and myocardial perfusion reserve (MPR) (ρ = 0.543, P = 0.007; ρ = 0.627, P = 0.002). An increase in the N-terminal pro-brain natriuretic peptide level was associated with a reduction in MPR (ρ = -0.448, P = 0.042). Patients on disease-modifying antirheumatic drugs (DMARDs) had an increase in native T1 (mean [SD] 1208 [65] vs. 1265 [56] milliseconds, P = 0.008). No other clinically meaningful CMR change in patients receiving DMARDs or vasodilators was noted. CONCLUSION: Serial CMR detects interval subclinical SSc primary heart involvement progression; however, this study suggests abnormalities remain largely stable with follow-up.
RESUMO
Introduction: Heart involvement is a common problem in systemic sclerosis. Recently, a definition of systemic sclerosis primary heart involvement had been proposed. Our aim was to establish consensus guidance on the screening, diagnosis and follow-up of systemic sclerosis primary heart involvement patients. Methods: A systematic literature review was performed to investigate the tests used to evaluate heart involvement in systemic sclerosis. The extracted data were categorized into relevant domains (conventional radiology, electrocardiography, echocardiography, cardiac magnetic resonance imaging, laboratory, and others) and presented to experts and one patient research partner, who discussed the data and added their opinion. This led to the formulation of overarching principles and guidance statements, then reviewed and voted on for agreement. Consensus was attained when the mean agreement was ⩾7/10 and of ⩾70% of voters. Results: Among 2650 publications, 168 met eligibility criteria; the data extracted were discussed over three meetings. Seven overarching principles and 10 guidance points were created, revised and voted on. The consensus highlighted the importance of patient counseling, differential diagnosis and multidisciplinary team management, as well as defining screening and diagnostic approaches. The initial core evaluation should integrate history, physical examination, rest electrocardiography, trans-thoracic echocardiography and standard serum cardiac biomarkers. Further investigations should be individually tailored and decided through a multidisciplinary management. The overall mean agreement was 9.1/10, with mean 93% of experts voting above 7/10. Conclusion: This consensus-based guidance on screening, diagnosis and follow-up of systemic sclerosis primary heart involvement provides a foundation for standard of care and future feasibility studies that are ongoing to support its application in clinical practice.
RESUMO
Introduction: Primary heart involvement in systemic sclerosis may cause morpho-functional and electrical cardiac abnormalities and is a common cause of death. The absence of a clear definition of primary heart involvement in systemic sclerosis limits our understanding and ability to focus on clinical research. We aimed to create an expert consensus definition for primary heart involvement in systemic sclerosis. Methods: A systematic literature review of cardiac involvement and manifestations in systemic sclerosis was conducted to inform an international and multi-disciplinary task force. In addition, the nominal group technique was used to derive a definition that was then subject to voting. A total of 16 clinical cases were evaluated to test face validity, feasibility, reliability and criterion validity of the newly created definition. Results: In total, 171 publications met eligibility criteria. Using the nominal group technique, experts added their opinion, provided statements to consider and ranked them to create the consensus definition, which received 100% agreement on face validity. A median 60(5-300) seconds was taken for the feasibility on a single case. Inter-rater agreement was moderate (mKappa (95% CI) = 0.56 (0.46-1.00) for the first round and 0.55 (0.44-1.00) for the second round) and intra-rater agreement was good (mKappa (95% CI) = 0.77 (0.47-1.00)). Criterion validity showed a 78 (73-84)% correctness versus gold standard. Conclusion: A preliminary primary heart involvement in systemic sclerosis consensus-based definition was created and partially validated, for use in future clinical research.
RESUMO
The prevalence of undiagnosed cardiac involvement in granulomatosis with polyangiitis (GPA) is unknown. In this prospective study we investigated the utility of cardiovascular magnetic resonance (CMR) to identify myocardial abnormalities in GPA and their correlation with disease phenotype. Twenty-six patients with GPA and no cardiovascular disease or diabetes mellitus underwent contrast-enhanced CMR, including late gadolinium-enhancement (LGE), T1-mapping for native T1 and extra-cellular volume (ECV) quantification for assessment of myocardial fibrosis, cine imaging and tissue tagging for assessment of left ventricular (LV) function. Twenty-five healthy volunteers (HV) with comparable age, sex, BMI and arterial blood pressure served as controls. Patients with GPA had similar cardiovascular risk profile to HV. A focal, non-ischaemic LGE pattern of fibrosis was detected in 24% of patients and no controls (p = 0.010). Patients with myocardial LGE were less frequently PR3 ANCA (7% vs 93%, p = 0.007), and had involvement of the lower respiratory tract and skin. LGE scar mass was higher in patients presenting with renal involvement. Native T1 and ECV were higher in patients with GPA than HV; ECV was higher in those with relapsing disease, and native T1 was inversely associated with PR3 ANCA (ß = - 0.664, p = 0.001). Peak systolic strain was slightly reduced in GPA compared to controls; LV ejection function was inversely correlated with disease duration (ß = - 0.454, p = 0.026). Patients with GPA have significant myocardial abnormalities on CMR. ANCA, systemic involvement and disease severity were associated with myocardial fibrosis. CMR could be a useful tool for risk stratification of myocardial involvement in GPA.
Assuntos
Cardiomiopatias/diagnóstico por imagem , Granulomatose com Poliangiite/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Miocárdio/patologia , Função Ventricular Esquerda , Remodelação Ventricular , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Meios de Contraste , Estudos Transversais , Feminino , Fibrose , Granulomatose com Poliangiite/patologia , Granulomatose com Poliangiite/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Índice de Gravidade de Doença , Volume SistólicoRESUMO
OBJECTIVES: To explore the prognostic value of subclinical cardiovascular (CV) imaging measures and serum cardiac biomarkers in systemic sclerosis (SSc) for the development of CV outcomes of primary heart involvement (pHI). METHODS: Patients with SSc with no clinical SSc-pHI and no history of heart disease underwent cardiovascular magnetic resonance (CMR) imaging, and measurement of serum high-sensitivity-troponin I (hs-TnI) and N-terminal-pro-brain natriuretic peptide (NT-proBNP). Follow-up clinical and CV outcome data were recorded. CV outcomes were defined as myocarditis, arrhythmia and/or echocardiographic functional impairment including systolic dysfunction and/or diastolic dysfunction. RESULTS: Seventy-four patients with a median (IQR) age of 57 (49, 63) years, 32% diffuse cutaneous SSc, 39% interstitial lung disease, 30% Scl70+ were followed up for median (IQR) 22 (15, 54) months. Ten patients developed CV outcomes, comprising one patient with myocarditis and systolic dysfunction and nine arrhythmias: three non-sustained ventricular tachycardia and six supraventricular arrhythmias. The probability of CV outcomes was considerably higher in those with NT-proBNP >125 pg/mL versus normal NT-proBNP (X2=4.47, p=0.035). Trend for poorer time-to-event was noted in those with higher extracellular volume (ECV; indicating diffuse fibrosis) and hs-TnI levels versus those with normal values (X2=2.659, p=0.103; X2=2.530, p=0.112, respectively). In a predictive model, NT-proBNP >125 pg/mL associated with CV outcomes (OR=5.335, p=0.040), with a trend observed for ECV >29% (OR=4.347, p=0.073). CONCLUSION: These data indicate standard serum cardiac biomarkers (notably NT-proBNP) and CMR indices of myocardial fibrosis associate with adverse CV outcomes in SSc. This forms the basis to develop a prognostic model in larger, longitudinal studies.
Assuntos
Escleroderma Sistêmico , Biomarcadores , Fibrose , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Estudos Prospectivos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagemRESUMO
The perovskite-type lanthanum ferrite, LaFeO3, has been prepared by thermal decomposition of in situ obtained lanthanum ferrioxalate compound precursor, LaFe(C2O4)3·3H2O. The oxalate precursor was synthesized through the redox reaction between 1,2-ethanediol and nitrate ion and characterized by chemical analysis, infrared spectroscopy, and thermal analysis. LaFeO3 obtained after the calcination of the precursor for at least 550-800 °C/1 h have been investigated by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and high-resolution transmission electron microscopy (HRTEM). A boron-doped diamond electrode (BDD) modified with LaFeO3 ceramic powders at 550 °C (LaFeO3/BDD) by simple immersion was characterized by cyclic voltammetry and tested for the voltammetric and amperometric detection of capecitabine (CCB), which is a cytostatic drug considered as an emerging pollutant in water. The modified electrode exhibited a complex electrochemical behaviour by several redox systems in direct relation to the electrode potential range. The results obtained by cyclic voltammetry (CV), differential-pulsed voltammetry (DPV), and multiple-pulsed amperometry proved the electrocatalytic effect to capecitabine oxidation and reduction and allowed its electrochemical detection in alkaline aqueous solution.