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

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

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

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

Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function.

BACKGROUND: Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients. METHODS AND RESULTS: We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of ≥1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0-9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24-4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39-3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88-2.2 at multivariable analysis for mortality and rehospitalizations). CONCLUSIONS: WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion

severe drug hypersensitivity syndrome due to sulphasalazine in patient with rheumatoid arthritis

Drug Hypersensitivity Syndrome, also known as Drug Rash with Eosinophilia and Systemic Symptoms is a severe adverse reaction characterized by clinical manifestations including fever, skin eruption, lymphoadenopathy, associated with eosinophilia, leukocytosis and multiple visceral involvement, with 10% of mortality due to development of multiple organ failure. This reaction usually occurs between two and six-eight weeks after the beginning of the treatment and may not resolve with interruption of the suspected drug. Sulfonamides, anticonvulsant, allopurinol are the most frequently involved molecules, but recently cases have been described also with gabapentin and strontium ranelate. In the present report we describe a case of a patient with rheumatoid arthritis who presented severe drug hypersensitivity syndrome, with liver and kidney involvement due to sulphasalazine

Molecular Interaction Studies of HIV-1 Matrix Protein p17 and Heparin: IDENTIFICATION OF THE HEPARIN-BINDING MOTIF OF p17 AS A TARGET FOR THE DEVELOPMENT OF MULTITARGET ANTAGONISTS

Once released by HIV cells, p17 binds heparan sulfate proteoglycans (HSPGs) and CXCR1 on leukocytes causing their dysfunction. By exploiting an approach integrating computational modeling, site-directed mutagenesis of p17, chemical desulfation of heparin, and surface plasmon resonance, we characterized the interaction of p17 with heparin, a HSPG structural analog, and CXCR1. p17 binds to heparin with an affinity (Kd 190 nM) that is similar to those of other heparin-binding viral proteins. Two stretches of basic amino acids (basic motifs) are present in p17 N and C termini. Neutralization (Arg3Ala substitution) of the N-terminal, but not of the C-terminal basic motif, causes the loss of p17 heparin-binding capacity. The N-terminal heparin-binding motif of p17 partially overlaps the CXCR1-binding domain. Accordingly, its neutralization prevents also p17 binding to the chemochine receptor. Competition experiments demonstrated that free heparin and heparan sulfate (HS), but not selectively 2-O-, 6-O-, and N-O desulfated heparins, prevent p17 binding to substrate-immobilized heparin, indicating that the sulfate groups of the glycosaminoglycan mediate p17 interaction. Evaluation of the p17 antagonist activity of a panel of biotechnological heparins derived by chemical sulfation of the Escherichia coli K5 polysaccharide revealed that the highlyN,O-sulfated derivative prevents the binding of p17 to both heparin and CXCR1, thus inhibiting p17-driven chemotactic migration of human monocytes with an efficiency that is higher than those of heparin and HS. Here, we characterized at a molecular level the interaction of p17 with its cellular receptors, laying the basis for the development of heparin-mimicking p17 antagonists

Anti-citrullinated protein antibodies and high levels of rheumatoid factor are associated with systemic bone loss in patients with early untreated rheumatoid arthritis

BACKGROUND: Autoantibodies such as anti-citrullinated protein antibodies (ACPA) are major risk factors for articular bone destruction from the earliest phases of rheumatoid arthritis (RA). The aim of the current study was to determine whether RA-associated autoantibodies also impact on systemic bone loss in patients with early disease. METHODS: Systemic bone mineral density (BMD) was measured in the lumbar spine and the hip in 155 consecutive treatment-na\uefve patients with early RA (median symptom duration 13 weeks). Demographic and disease-specific parameters, including clinical disease activity, ultrasonographic (US) examination of the hands and wrists, radiographic scoring of joint damage, ACPA and rheumatoid factor (RF) levels were recorded from all patients. Reduced BMD was defined as Z score\u2009 64\u2009-1 SD and analysed in relation to disease-related characteristics and autoantibody subgroups. RESULTS: Reduced BMD was found in 25.5 % of the patients in the spine and 19.4 % in the hip. Symptom duration, clinical and US disease activity, functional disability and radiographic damage did not significantly impact on spine and hip BMD loss in regression analyses adjusted for possible confounders (age, gender, menopausal status, current smoking, body mass index). In contrast, ACPA positivity (at any level) negatively affected the spine Z-score (adjusted OR (95 % CI) 2.76 (1.19 to 6.42)); the hip Z score was affected by high titres only (adjusted OR (95 % CI) 2.96 (1.15 to 7.66)). The association of ACPA with reduced BMD in the spine was confirmed even at low levels of RF (adjusted OR (95 % CI) 2.65 (1.01 to 7.24)), but was further increased by concomitant high RF (adjusted OR (95 % CI) 3.38 (1.11 to 10.34)). In contrast, Z scores in the hip were significantly reduced only in association with high ACPA and RF (adjusted OR (95 % CI) 4.96 (1.48 to 16.64)). CONCLUSIONS: Systemic BMD in patients with early RA is reduced in relation with ACPA positivity and high RF levels. This finding supports the notion that RA-associated autoimmunity may have a direct causative role in bone remodeling

Vitamin D 25OH Deficiency and Mortality in Moderate to Severe COVID-19: A Multi-Center Prospective Observational Study

Introduction: Several studies and meta-analyses suggested the role of vitamin D 25OH in preventing severe forms of coronavirus disease 2019 (COVID-19). However, the evidence on the clinical benefits of vitamin D 25OH adequacy in patients hospitalized for COVID-19 remain conflicting and speculative. We aimed to investigate the association between vitamin D 25OH serum levels and mortality in hospitalized patients with moderate to severe COVID-19. Method: This prospective observational multicentre study included 361 consecutive patients with moderate to severe COVID-19 admitted to the Italian hospitals involved in the NUTRI-COVID19 trial from March to August 2020. For each patient, serum vitamin D 25OH levels were assessed 48 h since admission and classified as deficient (<20 ng/mL) or adequate (≥20 ng/mL). We built a propensity score for low/adequate vitamin D 25OH levels to balance the clinical and demographic properties of the cohort, which resulted in 261 patients with good common support used for the survival analysis. Results: Two Hundred-seventy-seven (77%) of the 361 enrolled patients (207 [57%] males, median age 73 ± 15.6 years) had vitamin D 25OH deficiency. Fifty-two (20%) of the 261 matched patients died during the hospital stay, corresponding to a hazard ratio of 1.18 for vitamin D 25OH deficiency (95% confidence interval: 0.86–1.62; p = 0.29). Discussion: The prevalence of vitamin D 25OH deficiency was confirmed to be very high in hospitalized patients with COVID-19. The use of a propensity score demonstrate an absence of significant association between vitamin D deficiency and mortality in hospitalized patients