390 research outputs found
B cell autoimmunity and bone damage in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic immune-inflammatory disease associated with significant bone damage. Pathological bone remodeling in RA is primarily driven by persistent inflammation. Indeed, pro-inflammatory cytokines stimulate the differentiation of bone-resorbing osteoclasts and, in parallel, suppress osteoblast function, resulting in net loss of bone. Abating disease activity thus remains the major goal of any treatment strategy in patients with RA. Autoantibody-positive patients, however, often show a rapidly progressive destructive course of the disease, disproportionate to the level of inflammation. The epidemiological association between RA-specific autoantibodies, in particular anti-citrullinated protein autoantibodies, and poor structural outcomes has recently found mechanistic explanation in the multiple roles that B cells play in bone remodeling. In this review, we will summarize the substantial progress that has been made in deciphering how B cells and autoantibodies negatively impact on bone in the course of RA, through both inflammation-dependent and independent mechanisms
Histopathology of the synovial tissue : perspectives for biomarker development in chronic inflammatory arthritides
The histopathological and molecular analysis of the synovial tissue has contributed to fundamental advances in our comprehension of arthritis pathogenesis and of the mechanisms of action of currently available treatments. On the other hand, its exploitation in clinical practice for diagnostic or prognostic purposes as well as for the prediction of treatment response to specific disease-modifying anti-rheumatic drugs is still limited. In this review, we present an overview of recent advances in the field of synovial tissue research with specific reference to the methods for synovial tissue collection, approaches to synovial tissue analysis and current perspectives for the exploitation of synovial tissue-derived biomarkers in chronic inflammatory arthritides
New Catalyst for the Synthesis of Poly(butyleneterephthalate) with High Thermo-oxidative Stability
Rheumatoid arthritis treatment : the earlier the better to prevent joint damage
The management of rheumatoid arthritis has undergone major advances in recent years, both in terms of the drugs armamentarium and therapeutic strategy. Treating disease to target, aiming at remission, through a tight control protocol is regarded as the standard of care. Reaching clinical and radiographic disease remission has therefore become an achievable goal. Increasing evidence has demonstrated that early diagnosis, prompt treatment initiation and early achievement of remission are the major predictors of long-term clinical, functional and radiographic outcomes. Concentrating efforts in controlling disease activity in a very early window of opportunity offers unique sustained benefits. In this short review, we analysed the available evidence supporting the value of treating rheumatoid arthritis early and the impact on disease outcomes, with particular focus on radiographic progression
Human metapneumovirus establishes persistent infection in lung microvascular endothelial cells and primes a th2-skewed immune response
Human metapneumovirus (HMPV) is a major cause of lower respiratory tract infections. HMPV infection has been hypothesized to alter dendritic cell (DC) immune response; however, many questions regarding HMPV pathogenesis within the infected lung remain unanswered. Here, we show that HMPV productively infects human lung microvascular endothelial cells (L-HMVECs). The release of infectious virus occurs for up to more than 30 days of culture without producing overt cytopathic effects and medium derived from persistently HMPV-infected L-HMVECs (secretome) induced monocyte-derived DCs to prime naïve CD4 T-cells toward a Th2 phenotype. Moreover, we demonstrated that infected secretomes trigger DCs to up-regulate OX40L expression and OX40L neutralization abolished the pro-Th2 effect that is induced by HMPV-secretome. We clarified secretome from HMPV by size exclusion and ultracentrifugation with the aim to characterize the role of viral particles in the observed pro-Th2 effect. In both cases, the percentage of IL-4-producing cells and expression of OX40L returned at basal levels. Finally, we showed that HMPV, per se, could reproduce the ability of secretome to prime pro-Th2 DCs. These results suggest that HMPV, persistently released by L-HMVECs, might take part in the development of a skewed, pro-Th2 lung microenvironment
Nebivolol: haemodynamic effects and clinical significance of combined beta-blockade and nitric oxide release.
Nebivolol is a third-generation beta-adrenergic receptor antagonist (beta-blocker) with high selectivity for beta(1)-adrenergic receptors. In addition, it causes vasodilatation via interaction with the endothelial L-arginine/nitric oxide (NO) pathway. This dual mechanism of action underlies many of the haemodynamic properties of nebivolol, which include reductions in heart rate and blood pressure (BP), and improvements in systolic and diastolic function. With respect to BP lowering, the NO-mediated effects cause a reduction in peripheral vascular resistance and an increase in stroke volume with preservation of cardiac output. Flow-mediated dilatation and coronary flow reserve are also increased during nebivolol administration. Other haemodynamic effects include beneficial effects on pulmonary artery pressure, pulmonary wedge pressure, exercise capacity and left ventricular ejection fraction. In addition, nebivolol does not appear to have adverse effects on lipid metabolism and insulin sensitivity like traditional beta-blockers. The documented beneficial haemodynamic effects of nebivolol are translated into improved clinical outcomes in patients with hypertension or heart failure. In patients with hypertension, the incidence of bradycardia with nebivolol is often lower than that with other currently available beta-blockers. This, along with peripheral vasodilatation and NO-induced benefits such as antioxidant activity and reversal of endothelial dysfunction, should facilitate better protection from cardiovascular events. In addition, nebivolol has shown an improved tolerability profile, particularly with respect to events commonly associated with beta-blockers, such as fatigue and sexual dysfunction. Data from SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure) showed that significantly fewer nebivolol versus placebo recipients experienced the primary endpoint of all-cause mortality or cardiovascular hospitalization. The benefits of nebivolol therapy were shown to be cost effective. Thus, nebivolol is an effective and well tolerated agent with benefits over and above those of traditional beta-blockade because of its effects on NO release, which give it unique haemodynamic effects, cardioprotective activity and a good tolerability profile
POS1258 MISSING THE WINDOW OF OPPORTUNITY: EARLY ARTHRITIS CLINICS IN TIMES OF COVID-19
Background:The outcomes of patients with chronic inflammatory arthritis (IA), such as rheumatoid arthritis (RA), have dramatically improved over the past 20 years. Earlier identification of IA and prompter treatment institution have been key advancements, promoted by the constitution of Early Arthritis Clinics (EAC) and the development of more sensitive classification criteria for RA. The outbreak of new COronaVIrus Disease 2019 (COVID-19) has quickly become a global health emergency and has forced a rearrangement in the management of other non-COVID-19 diseases. The impact of the lock-down of the healthcare systems on chronic inflammatory diseases such as RA is expected to be significant but is at present unknown.Objectives:To assess the effects of the lock-down imposed by the COVID-19 pandemic on the referral and clinical presentation of patients with new-onset RA.Methods:Data were retrieved from the Pavia EAC inception cohort, established in 2005 for the early identification of patients with new-onset IA. Referral criteria to the EAC include: ≥3 swollen joints (SJ) and/or 30 min. Demographic and clinical characteristics of the patients are assessed at baseline and regularly over follow-up.At 31 Dec 2020, the Pavia EAC collects information on 2.508 patients. For this study, baseline characteristics of the patients referred in the semester following the COVID-19 lock-down (Jul-Dec 2020) were compared with: (i) patients referred in the semester immediately preceding the lock-down (Jul-Dec 2019); (ii) patients referred in the semester following the publication of the 2010 RA classification criteria (Jan-Jun 2011); (iii) patients referred in the semester preceding the publication of the 2010 criteria (Jul-Dec 2009).Results:In the semester following the lock-down imposed by the COVID-19 pandemic, there was a decrease in the referral of patients with new-onset suspected IA compared with previous periods (n=71 vs n=91 in the semester before the lock-down, n=96 in the first semester of 2011, n=101 in the second semester of 2009). Furthermore, fewer of the referred patients fulfilled RA criteria at presentation (36.6% vs 44.3%, 46.5% and 42.9% in the other semesters). Among patients with RA, more were autoantibody-positive (72% vs 50%, 49.1% and 52.2%). There was a trend for increased diagnostic delay in the overall cohort of RA after the COVID-19 lock-down (Figure 1A). The delay was particularly longer in autoantibody-positive patients, returning to the values seen before the introduction of the 2010 RA criteria (Figure 1B). In contrast, the few autoantibody-negative patients were referred earlier (Figure 1C). Disease activity at presentation was significantly higher in RA patients presenting after the lock-down compared with the progressive trend for reduction observed over the previous years, irrespective of the autoantibody status (Figure 1D-F). Such increase was determined by an inversion of the trend towards lower levels of objective parameters of inflammation, such as the swollen joint count (Figure 1G-I) and acute phase reactants, and a further increase in the secular trend towards worsening of patient-derived measures, such as the tender joint count and patient global assessment (Figure 1J-L).Figure 1.Effects of COVID-19 lock-down on new-onset RA at presentation.Conclusion:The COVID-19 pandemic is posing unprecedented challenges in the management of patients suffering from chronic diseases. RA has returned to be diagnosed outside the window of opportunity, with a significantly higher inflammatory burden at presentation. The many benefits of early diagnosis, which have dramatically changed the outcomes of autoantibody-positive RA, are at risk of vanishing in short times. Equally important, autoantibody-negative RA is at risk of further under-diagnosis and under-treatment.Disclosure of Interests:Bernardo D'Onofrio: None declared, Ludovico De Stefano: None declared, Bianca Lucia Palermo: None declared, Blerina Xoxi: None declared, Antonio Manzo: None declared, Carlomaurizio Montecucco Speakers bureau: BMS, Lilly, Sanofi, Pfizer, Galapagos, Roche, Novartis, Serena Bugatti Speakers bureau: BMS, Lilly, Sanofi, Pfizer, Galapago
Fibroblast growth factor 2-antagonist activity of a long-pentraxin 3-derived antiangiogenic pentapeptide.
Fibroblast growth factor-2 (FGF2) plays a major role in angiogenesis. The pattern recognition receptor long-pentraxin 3 (PTX3) inhibits the angiogenic activity of FGF2. To identify novel FGF2-antagonistic peptide(s), four acetylated (Ac) synthetic peptides overlapping the FGF2-binding region PTX3-(97-110) were assessed for their FGF2-binding capacity. Among them, the shortest pentapeptide Ac-ARPCA-NH(2) (PTX3-[100-104]) inhibits the interaction of FGF2 with PTX3 immobilized to a BIAcore sensorchip and suppresses FGF2-dependent proliferation in endothelial cells, without affecting the activity of unrelated mitogens. Also, Ac-ARPCA-NH(2) inhibits angiogenesis triggered by FGF2 or by tumorigenic FGF2-overexpressing murine endothelial cells in chick and zebrafish embryos, respectively. Accordingly, the peptide hampers the binding of FGF2 to Chinese Hamster ovary cells overexpressing the tyrosine-kinase FGF receptor-1 (FGFR1) and to recombinant FGFR1 immobilized to a BIAcore sensorchip without affecting heparin interaction. In all the assays the mutated Ac-ARPSA-NH(2) peptide was ineffective. In keeping with the observation that hydrophobic interactions dominate the interface between FGF2 and the FGF-binding domain of the Ig-like loop D2 of FGFR1, amino acid substitutions in Ac-ARPCA-NH(2) and saturation transfer difference-nuclear magnetic resonance analysis of its mode of interaction with FGF2 implicate the hydrophobic methyl groups of the pentapeptide in FGF2 binding. These results will provide the basis for the design of novel PTX3-derived anti-angiogenic FGF2 antagonists
Can we improve the treatment of congestion in heart failure?
INTRODUCTION: Dyspnoea and peripheral oedema, caused by fluid redistribution to the lungs and/or by fluid overload, are the main causes of hospitalization in patients with heart failure and are associated with poor outcomes. Treatment of fluid overload should relieve symptoms and have a neutral or favorable effect on outcomes. AREAS COVERED: We first consider the results obtained with furosemide administration, which is still the mainstay of treatment of congestion in patients with heart failure. We then discuss important shortcomings of furosemide treatment, including the development of resistance and side effects (electrolyte abnormalities, neurohormonal activation, worsening renal function), as well as the relationship of furosemide - and its doses - with patient prognosis. Finally, the results obtained with potential alternatives to furosemide treatment, including different modalities of loop diuretic administration, combined diuretic therapy, dopamine, inotropic agents, ultrafiltration, natriuretic peptides, vasopressin and adenosine antagonists, are discussed. EXPERT OPINION: Relief of congestion is a major objective of heart failure treatment but therapy remains based on the administration of furosemide, an agent that is often not effective and is associated with poor outcomes. The results of the few controlled studies aimed at the assessment of new treatments to overcome resistance to furosemide and/or to protect the kidney from its untoward effects have been mostly neutral. Better treatment of congestion in heart failure remains a major unmet need
- …