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Objective: To assess the relationship between serum concentrations of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) and the therapeutic response to disease-modifying antirheumatic drugs (DMARD) in patients with early rheumatoid arthritis (RA)., Methods: Circulating levels of TRAIL and its soluble receptor OPG were measured by ELISA in paired serum samples obtained from 66 patients with early RA at their first visit (baseline) and after 1 year of therapy. Levels of TRAIL and OPG were analyzed in relation to the clinical response, defined by the 28-joint count Disease Activity Score (DAS28)., Results: Both serum TRAIL and OPG increased after DMARD therapy. Baseline levels of TRAIL, but not OPG, were significantly higher (p < 0.05) in the patients that achieved a clinical response by DAS28 after 1 year of therapy, versus patients without clinical response to DMARD. Baseline serum levels of TRAIL were higher (p < 0.01) in rheumatoid factor-negative patients., Conclusion: Our data suggest that the basal level of circulating TRAIL is an important determinant in the therapeutic response to DMARD in patients with early RA.

In order to identify rate and stability of remission induced by low-dose prednisone comedication in early rheumatoid arthritis (RA), we evaluated patients with early RA (<1 year) who were randomized to receive (P) or not (non-P) low-dose prednisone in association with step-up disease-modifying antirheumatic drug therapy over 2 years. Prevalence and duration of clinical remission were evaluated in the first and second year. Each treatment group included 105 patients; no significant differences were found at baseline. During the first year, P patients achieved higher rates of clinical remission with a time-averaged odds ratio (OR) of 1.965 (CI 95% 1.214-3.182, P= 0.006). Moreover, they showed a higher probability of sustained remission during the second year (OR 4.480, CI 95% 1.354-14.817, P= 0.014). In conclusion, we found as in early RA low-dose prednisone comedication is associated with higher rate of clinical remission, earlier disease activity control and more stable remission over time.

Hospitalization for acute heart failure (AHF) is one of the burdensome aspects of 21st century medicine, leading to significant debilitating symptoms, high morbidity and mortality and consuming significant portion of the health care budget. Management of AHF is thought-provoking given the heterogeneity of the patient population, absence of a universally accepted definition, incomplete understanding of the pathophysiology and the beneficial and adverse effects of currently used therapies and lack of robust evidence-based guidelines. The article will discuss the clinical approach to the patients admitted with AHF, reviewing types of intervention (both approved and investigational) and will delineate their role and timing in specific AHF presentations. One of the challenges of AHF management is to effectively treat the subsets of patients with slow improvement or those with refractory AHF or early recurrence (worsening HF) during their initial admission. Unfortunately, the majority of these patients are at increased risk for subsequent complications and adverse outcomes. Therefore, considerable efforts in AHF management should be directed towards this population. Regretfully, to date no specific targeted therapy was proven beneficial for these patients, being one of the leading reasons for the lack of improvement in AHF outcomes over the last 30 years.

The role of heart rate (HR) as an independent predictor of cardiovascular morbidity and mortality remains controversial. Direct evidence supporting a causal association between HR and prognosis is still lacking even if such relation appears plausible and may be inferred from epidemiological studies and clinical trials with HR lowering agents. The introduction of If current blocking agents, namely ivabradine, has offered the novel and unique opportunity to directly and exclusively interfere with HR and, thus, to validate the presence of a causal relationship between HR and prognosis. The BEAUTIFUL trial has recently confirmed that HR is a powerful negative prognostic predictor in patients with coronary artery disease and left ventricular systolic dysfunction. Particularly, subjects with a resting HR >70 b/min showed an increased risk of major adverse cardiovascular events. In these patients, HR reduction with ivabradine was associated with a reduction in major cardiac ischemic events, though not mortality. Further data will become available with the SHIFT trial in which patients with heart failure and HR > or =70 b/min are included and reduction in cardiovascular mortality and heart failure hospitalizations is the primary endpoint.

Background: Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration., Methods and Results: We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF) < or = 0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0 +/- 12.2% versus +7.1 +/- 8.1% in the Gln27Gln homozygotes, and 8.3 +/- 11.4% units in the Gln27Glu heterozygotes; p = 0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered., Conclusion: Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.

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.

B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). Rituximab is a chimeric monoclonal antibody that depletes B-cells by binding to the CD20 surface antigen that has been approved for the treatment of RA. Its efficacy has been clearly demonstrated by different clinical trials and, recently, in long-term observational studies. The use of rituximab in clinical practice has highlighted its efficacy and safety over more than 5 years of treatment, as well as to try to understand the timing for retreatment of patients relapsing after a good initial response.

Background: Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF)., Methods and Results: We analysed the clinical significance of WRF in 318 consecutive patients admitted at our institute for AHF. WRF was defined as the occurrence, at any time during the hospitalisation, of both a > or =25% and a > or =0.3 mg/dL increase in serum creatinine (s-Cr) from admission (WRF-Abs-%)., Results: Patients were followed for 480+/-363 days. Fifty-three patients (17%) died and 132 (41%) were rehospitalised for HF. WRF-Abs-% occurred in 107 (34%) patients. At multivariable survival analysis, WRF-Abs-% was an independent predictor of death or HF rehospitalisation (adjusted HR, 1.47; 95%CI, 1.13-1.81; p=0.024). The independent predictors of WRF-Abs-%, evaluated using multivariable logistic regression, were history of chronic kidney disease (p=0.002), LV ejection fraction (p=0.012), furosemide daily dose (p=0.03) and NYHA class (p=0.05) on admission., Conclusion: WRF is a frequent finding in patients hospitalised for AHF and is associated with a poor prognosis. Severity of HF and daily furosemide dose are the most important predictors of the occurrence of WRF.

Though its etiology remains unknown thus far, the role that autoimmune processes play in rheumatoid arthritis (RA) pathogenesis has been widely proven. Given the easier accessibility of humoral components, the first feature of this contribution to be recognized has been the occurrence of the so-called rheumatoid factor in a large proportion of RA patients. This antibody recognizes the Fc portion of human IgG. By investigating RA pathologic processes and also through experimental models where immune complexes play a fundamental role, many other autoantibodies have then come to our knowledge to be associated with the disease. Their presence and persistence implies that clones of autoreactive B cells survive and proliferate in RA patients under a continuous stimulation. Whether this is a mechanism of disease initiation or just an epiphenomenon is still unclear but no doubt exists that autoantibodies represent a very useful tool in both diagnostic and prognostic terms. Being much more than simple autoantibody producers, B cells are able to secrete many important cytokines and to efficiently present antigens to T lymphocytes in the synovial environment. All of these functions are essential in the development of RA, and lately have claimed attention as B cell depletion has become a common and effective strategy of treatment in RA.

CCL21 is a homeostatic lymphoid chemokine instrumental in the recruitment and organization of T cells and dendritic cells into lymphoid T areas. In human secondary lymphoid organs (SLOs), CCL21 is produced by cells distributed throughout the T zone, whereas high endothelial venules (HEVs) lack CCL21 mRNA. A critical question remains whether the development of ectopic lymphoid tissue (ELT) in chronic inflammation recapitulates the features of SLOs. Thus, we systematically investigated in situ the cellular sources of CCL21 in SLOs and ELTs in several human diseases characterized by lymphoid neogenesis. By in situ hybridization and the use of combinatorial cell markers, we show that CCL21-producing vessels in inflamed tissues systematically display typical markers of lymphatic vessels, whereas, as in SLOs, ectopic HEVs do not synthesize detectable levels of CCL21. We also provide first-time evidence that a common pattern of CCL21 expression by CD45-negative myofibroblast-like cells localized in extra-HEV position and organized in a fibroblastic reticular network similarly characterizes human SLOs and organized ELTs. Altogether, our results demonstrate that in humans the pattern of CCL21 production in SLOs is maintained during inflammation and that the phenotypic and functional properties of stromal cells, found in SLO T-cell areas, are reproduced at ectopic sites.

Clinical trials have consistently shown the benefits of beta-blocker treatment in patients with chronic heart failure (HF). As a result, bisoprolol, carvedilol, and metoprolol succinate are now indicated for the treatment of all patients with chronic HF who do not have major contraindications. Bisoprolol is the first beta-blocker shown to improve survival in an outcome trial. In the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), all-cause mortality and sudden death were reduced in patients treated with bisoprolol compared with those on placebo (11.8% vs 17.3%; p < 0.0001 and 3.6% vs 6.3%, p < 0.002; respectively) regardless of age, NYHA functional class, and co-morbidities. Further studies have shown both the efficacy of bisoprolol on secondary endpoints and patients subgroups as well its high cost effectiveness. More recently, CIBIS-III has shown similar efficacy and safety of the initiation of HF treatment with either bisoprolol or enalapril, with a tendency to a survival advantage with bisoprolol. Nowadays, the role of bisoprolol, as well as that of carvedilol and metoprolol succinate, in HF treatment is firmly established and research is mainly focused on implementation of treatment and better dosing. This article will summarize evidence for the efficacy of bisoprolol in the treatment of HF.

Anemia is one of the most frequent co-morbidities in the patients with heart failure. Its prevalence increases from 4-7% in the subjects with asymptomatic left ventricular dysfunction to >30% in the patients with severe heart failure. Renal insufficiency, activation of inflammatory mediators, and treatment with renin-angiotensin antagonists seem to be its main determinants. The results of many studies agree in showing that anemia is a powerful independent determinant of survival in patients with heart failure. However, the mechanisms of this relation are still incompletely understood. Moreover a favourable effect on prognosis of the correction of anemia has not been shown, yet, and also controlled studies assessing its effects on exercise tolerance have yielded controversial results.

Objective: To evaluate the presence and immunohistochemical characteristics of subchondral bone marrow inflammatory infiltrate in rheumatoid arthritis (RA) and to determine the in situ relationship between marrow inflammation and osteoclast recruitment., Methods: Bone samples and paired synovia from 8 RA patients undergoing joint surgery were analyzed by immunohistochemistry and in situ hybridization for specific lymphoid neogenetic features, such as T and B cell composition, follicular dendritic cell (FDC) networks, peripheral lymph node addressin (PNAd)-positive high endothelial venules, and lymphoid chemokine expression. Osteoclasts were identified as multinucleated tartrate-resistant acid phosphatase (TRAP)-positive and cathepsin K-positive cells adherent to the bone surface., Results: An inflammatory infiltrate with perivascular aggregates of variable size was detected in 7 (87.5%) of 8 synovial samples and in paired bone samples. Lymphoid neogenetic features typical of rheumatoid synovium were also recognized in the bone marrow. PNAd+ blood vessels were found in 4 of 8 patients, CD21+ FDC networks in 2 patients, CXCL13+ cells in 5 patients, and CCL21+ cells in 6 patients. TRAP-positive and cathepsin K-positive osteoclasts were identified on both the synovial and marrow sides of the bone surface. Bone marrow samples showing a higher degree of inflammation were characterized by a significantly increased number of osteoclasts adherent to the subchondral bone., Conclusion: Our data demonstrate that lymphoid aggregates with lymphoid neogenetic features are detectable on the subchondral side of the joint in established RA. Moreover, the local inflammation/aggregation process appears to be related to osteoclast differentiation on the marrow side of subchondral bone, supporting a functional role of the bone compartment in local damage.

Systemic lupus erythematosus (SLE) is characterized by an increased incidence of vascular disease which is only partially explained by traditional risk factors. Previous reports suggested that the level of lipoprotein(a) [Lp(a)], a particle linked to atherothrombotic disorders, is increased in patients with SLE. However, whether there are any differences in the distribution of apolipoprotein(a) [apo(a)] phenotypes between SLE patients and healthy controls remain to be determined. To address this issue, Lp(a) levels and apo(a) isoform size were analyzed in a total of 54 patients with SLE and in 108 age- and gender-matched healthy controls. SLE patients showed Lp(a) levels [median (interquartile range): 25.3 (6.5-51.0) vs. 9.5 (4.6-25.9) mg/dl, P=0.0109)] and a percentage of subjects with at least one small-sized apo(a) isoform (< or =25 K-IV repeats) significantly higher than controls (44.44% vs. 25.92%, P=0.0277). Multiple regression analysis adjusting for age, gender, disease duration, kidney involvement, the presence of active disease, as well as the carriage of at least one small apo(a) isoform revealed that only small apo(a) phenotypes were significant predictors of Lp(a) levels in SLE patients (P=0.0001). We conclude that genetic factors related to apo(a) size are a major determinant of elevated Lp(a) levels in patients with SLE. As small apo(a) phenotypes have been related to adverse vascular effects, it is feasible that small apo(a) isoforms may be a useful biological marker in the assessment of vascular risk in patients with SLE.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are among the most abundant proteins in the eukaryotic cell nucleus and play a direct role in several aspects of the RNA life including splicing, export of the mature RNAs and translation. To date, approximately 30 proteins have been identified. A growing body of evidence points to hnRNPs as an important target of the autoimmune response in rheumatic diseases. Autoantibodies to A and B proteins of the hnRNP complex have been detected in late 1980s in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Beyond their role as diagnostic test in clinical practice, these autoantibodies are starting to be regarded as important tools to obtain deeper insight into the pathogenesis of autoimmune rheumatic diseases. Furthermore, new anti-hnRNP antibodies have been recognized in the last ten years extending the spectrum of anti-hnRNP reactivity in different autoimmune disorders.

Objectives: To investigate the clinical, serologic, radiologic and immunogenetic characteristics of rheumatoid arthritis (RA) occurring in patients with beta-thalassemic trait as compared with RA in control patients from the same geographical area., Materials and Methods: Twenty-eight patients with beta-thalassemic trait fulfilling the American College of Rheumatology (ACR) criteria for RA were compared with a control group of twenty-eight RA patients matched for age, sex, disease duration and place of birth. Clinical and routine laboratory assessment, including anti-keratin antibodies and anti-citrullinated peptide antibodies, was carried out in the two groups. The patients were also evaluated for HLADRB1 alleles and radiologic damage., Results: No differences were found with regard to clinical indexes of disease activity, laboratory parameters, and joint erosions. The immunogenetic analysis did not show any significant difference, the percentage of patients with alleles encoding for the shared epitope being similar in the two groups (61% vs. 57%). As for the extra-articular features, we found a trend for a lower prevalence of sicca syndrome in the beta-thalassemic group (14% vs. 39%; P = 0.06). Rheumatoid nodules were not found in beta-thalassemic patients while they were present in two RA patients in the control group., Conclusions: The chronic polyarthritis occurring in beta-thalassemic trait carriers can be regarded as a true RA similar to that found in Mediterranean countries, possibly characterized by a low prevalence of extra-articular features.

The aim of the present study was to investigate the effect of long-term infliximab treatment on various autoantibodies in patients with rheumatoid arthritis. Serum samples from 30 consecutive patients, who were prospectively followed during infliximab and methotrexate therapy for refractory rheumatoid arthritis, were tested at baseline and after 30, 54 and 78 weeks. At these points, median values of the Disease Activity Score were 6.38 (interquartile range 5.30-6.75), 3.69 (2.67-4.62), 2.9 (2.39-4.65) and 3.71 (2.62-5.06), respectively. Various autoantibodies were assessed by standard indirect immunofluorescence and/or ELISA. Initially, 50% of patients were positive for antinuclear antibodies, and this figure increased to 80% after 78 weeks (P = 0.029). A less marked, similar increase was found for IgG and IgM anticardiolipin antibody titre, whereas the frequency of anti-double-stranded DNA antibodies (by ELISA) exhibited a transient rise (up to 16.7%) at 54 weeks and dropped to 0% at 78 weeks. Antibodies to proteinase-3 and myeloperoxidase were not detected. The proportion of patients who were positive for rheumatoid factor (RF) was similar at baseline and at 78 weeks (87% and 80%, respectively). However, the median RF titre exhibited a progressive reduction from 128 IU/ml (interquartile range 47-290 IU/ml) to 53 IU/ml (18-106 IU/ml). Anti-cyclic citrullinated peptide (CCP) antibodies were found in 83% of patients before therapy; anti-CCP antibody titre significantly decreased at 30 weeks but returned to baseline thereafter. In conclusion, the presence of anti-double-stranded DNA antibodies is a transient phenomenon, despite a stable increase in antinuclear and anticardiolipin antibodies. Also, the evolution of RF titres and that of anti-CCP antibody titres differed during long-term infliximab therapy.