Aortic valve sclerosis adds to prediction of short-term mortality in patients with documented coronary atherosclerosis

Aims: Aortic valve sclerosis (AVSc), a non-uniform thickening of leaflets with an unrestricted opening, is characterized by inflammation, lipoprotein deposition, and matrix degradation. In the general population, AVSc predicts long-term cardiovascular mortality (+50%) even after adjustment for vascular risk factors and clinical atherosclerosis. We have hypothesized that AVSc is a risk-multiplier able to predict even short-term mortality. To address this issue, we retrospectively analyzed 90-day mortality of all patients who underwent isolated coronary artery bypass grafting (CABG) at Centro Cardiologico Monzino over a ten-year period (2006\u20132016). Methods: We analyzed 2246 patients and 90-day all-cause mortality was 1.5% (31 deaths). We selected only patients deceased from cardiac causes (n = 29) and compared to alive patients (n = 2215). A cardiologist classified the aortic valve as no-AVSc (n = 1352) or AVSc (n = 892). Cox linear regression and integrated discrimination improvement (IDI) analyses were used to evaluate AVSc in predicting 90-day mortality. Results: AVSc 90-day survival (97.6%) was lower than in no-AVSc (99.4%; p < 0.0001) with a hazard ratio (HR) of 4.0 (95%CI: 1.78, 9.05; p < 0.0001). The HR for AVSc, adjusted for propensity score, was 2.7 (95%CI: 1.17, 6.23; p = 0.02) and IDI statistics confirmed that AVSc significantly adds (p < 0.001) to the identification of high-risk patients than EuroSCORE II alone. Conclusion: Our data supports the hypothesis that a risk stratification strategy based on AVSc, added to ESII, may allow better recognition of patients at high-risk of short-term mortality after isolated surgical myocardial revascularization. Results from this study warrant further confirmation

What is the future of targeted therapy in rheumatology: biologics or small molecules?

Background: Until late in the 20th century, the therapy of rheumatic diseases relied on the use of drugs that had been developed through empirical approaches without detailed understanding of the molecular mechanisms involved. That approach changed with the introduction of biologic therapeutics at the end of the 20th century and by the recent development of small-molecule inhibitors of intracellular signal transduction pathways. Here we compare and discuss the advantages and disadvantages of those two groups of targeted anti-inflammatory therapeutics.Discussion: TNF-blocking biologic agents were introduced into the therapy of rheumatoid arthritis and other autoimmune and inflammatory diseases in the late 1990s. Further biologic agents targeting cytokine networks or specific lymphocyte subsets have since been added to the armamentarium of anti-rheumatic therapy. During the last few years, another wave of novel discoveries led to the development of a new class of small molecule anti-inflammatory compounds targeting intracellular signal transduction molecules, such as tyrosine kinases. In all those cases, the specific targets of the drugs are well defined and significant knowledge about their role in the disease pathomechanism is available, qualifying them for being targeted therapeutics for inflammatory rheumatic diseases. While both groups of targeted therapeutics offer significant clinical benefit, they clearly differ in several aspects, such as the localization of their targets, their route of administration and target specificity, as well as technical details such as manufacturing procedures and cost basis. In this debate paper, we compare the advantages and disadvantages of the two different approaches, aiming to shed light on the possible future of targeted therapies.Summary: Biologic therapeutics and small-molecule inhibitors both have significant advantages and disadvantages in the therapy of rheumatic diseases. The future of targeted therapies is one of the most exciting questions of current rheumatology research and therapy. © 2014 Mócsai et al.; licensee BioMed Central Ltd

Points to consider in cardiovascular disease risk management among patients with rheumatoid arthritis living in South Africa, an unequal middle income country

ABSTRACT: Background: It is plausible that optimal cardiovascular disease (CVD) risk management differs in patients with rheumatoid arthritis (RA) from low or middle income compared to high income populations. This study aimed at producing evidence-based points to consider for CVD prevention in South African RA patients. Methods: Five rheumatologists, one cardiologist and one epidemiologist with experience in CVD risk management in RA patients, as well as two patient representatives, two health professionals and one radiologist, one rheumatology fellow and 11 rheumatologists that treat RA patients regularly contributed. Systematic literature searches were performed and the level of evidence was determined according to standard guidelines. Results: Eighteen points to consider were formulated. These were grouped into 6 categories that comprised overall CVD risk assessment and management (n=4), and specific interventions aimed at reducing CVD risk including RA control with disease modifying anti-rheumatic drugs, glucocorticoids and non-steroidal anti-inflammatory drugs (n=3), lipid lowering agents (n=8), antihypertensive drugs (n=1), low dose aspirin (n=1) and lifestyle modification (n=1). Each point to consider differs partially or completely from recommendations previously reported for CVD risk management in RA patients from high income populations. Currently recommended CVD risk calculators do not reliably identify South African black RA patients with very high-risk atherosclerosis as represented by carotid artery plaque presence on ultrasound. Conclusions: Our findings indicate that optimal cardiovascular risk management likely differs substantially in RA patients from low or middle income compared to high income populations. There is an urgent need for future multicentre longitudinal studies on CVD risk in black African patients with RA.The first meeting held amongst local Rheumatologists was funded by the South African Arthritis and Rheumatology Association. The studies by Professor González-Gay have been supported by grants from “Fondo de Investigaciones Sanitarias” PI06/0024, PS09/00748, PI12/00060, PI15/00525, PI18/00043, and RD12/0009/0013 and RD16/0012 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain), co-funded by FEDER funds

Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our  understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA

Imaging atherosclerosis in rheumatoid arthritis: evidence for increased prevalence, altered phenotype and a link between systemic and localised plaque inflammation.

In rheumatoid arthritis (RA), chronic inflammation is thought to drive increased cardiovascular risk through accelerated atherosclerosis. It may also lead to a more high-risk plaque phenotype. We sought to investigate carotid plaque phenotype in RA patients using Dynamic Contrast-Enhanced MRI (DCE-MRI) and Fludeoxyglucose Positron Emission Tomography(FDG-PET). In this pilot study, RA patients and age/sex-matched controls were evaluated for cardiovascular risk factors and carotid plaque on ultrasound. Subjects with plaque >2 mm thick underwent DCE-MRI, and a subgroup of patients had FDG-PET. Comparison of MRI findings between groups and correlation between clinical, serological markers and imaging findings was undertaken. 130 patients and 62 controls were recruited. Plaque was more prevalent in the RA group (53.1% vs 37.0%, p = 0.038) and was independently associated with IL6 levels (HR[95%CI]: 2.03 [1.26, 3.26] per quartile). DCE-MRI data were available in 15 patients and 5 controls. Higher prevalence of plaque calcification was noted in RA, despite similar plaque size (73.3% vs 20%, p = 0.04). FDG-PET detected plaque inflammation in 12/13 patients scanned and degree of inflammation correlated with hs-CRP (r = 0.58, p = 0.04). This study confirms increased prevalence of atherosclerosis in RA and provides data to support the hypothesis that patients have a high-risk plaque phenotype

The Cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

The mechanisms controlling CD4+ T cell switching from an effector to an anti-inflammatory (IL-10+) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ+ to IL-10+ shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4+ T cells

Impact of Systemic Inflammation and Autoimmune Diseases on apoA-I and HDL Plasma Levels and Functions

The cholesterol of high-density lipoproteins (HDLs) and its major proteic component, apoA-I, have been widely investigated as potential predictors of acute cardiovascular (CV) events. In particular, HDL cholesterol levels were shown to be inversely and independently associated with the risk of acute CV diseases in different patient populations, including autoimmune and chronic inflammatory disorders. Some relevant and direct anti-inflammatory activities of HDL have been also recently identified targeting both immune and vascular cell subsets. These studies recently highlighted the improvement of HDL function (instead of circulating levels) as a promising treatment strategy to reduce inflammation and associated CV risk in several diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In these diseases, anti-inflammatory treatments targeting HDL function might improve both disease activity and CV risk. In this narrative review, we will focus on the pathophysiological relevance of HDL and apoA-I levels/functions in different acute and chronic inflammatory pathophysiological conditions