Determinants of outcome in patients with chronic ischemic left ventricular dysfunction undergone percutaneous coronary interventions.

BACKGROUND: Percutaneous coronary interventions (PCI) in patients with ischemic systolic left ventricular dysfunction (SLVD) are routinely performed although their impact on prognosis remains unclear. METHODS: We retrospectively evaluated 385 consecutive patients (76 % male, 66 ± 9 years) with SLVD (left ventricular ejection fraction [LVEF] ≤40 %) due to chronic coronary artery disease, who underwent PCI between 1999 and 2009, and explored clinical factors associated with higher risk of death or of a composite of death and hospitalization for acute decompensated heart failure (ADHF). RESULTS: The median follow-up was 28 months (inter-quartile range 14-46 months). Death and the composite outcome of death and hospitalization for ADHF occurred in 80 (21 %) and 109 (28 %) patients respectively (8.4 and 11.5 per 100 patient-years of follow-up). Insulin-dependent diabetes mellitus (IDDM), multivessel disease, LVEF < 35 %, symptoms of heart failure (HF) emerged both as independent predictors of death (adjusted hazard ratios [HR] 2.64; 1.92, 1.88 and 1.67 respectively) and composite outcome of death and hospitalization for ADHF (adjusted HR 2.22, 1.92, 1.79 and 1.94 respectively). Furthermore advanced age (HR = 1.03) emerged as independent predictors of death and having performed a stress test before PCI correlated with reduced number of deaths and ADHF hospitalizations (HR = 0.60). Of note, PCI significantly reduced the symptom of angina from 63.2 % at baseline to 16.3 % at the last follow up (p < 0.0001). CONCLUSIONS: IDDM, symptoms of HF, multivessel disease and LVEF < 35 % appear to be associated with worse outcome patients with ischemic SLVD undergoing PCI, and may be taken into account for optimal risk stratification. On the other hand, performing a stress testing before PCI seems to be associated with a more favorable outcome.

Does Pizza Consumption Favor an Improved Disease Activity in Rheumatoid Arthritis?

To our knowledge, no studies so far have investigated the role of pizza and its ingredients in modulating disease activity in rheumatoid arthritis (RA). We assessed this question via a recent cross-sectional study including 365 participants from Italy, the birthplace of pizza. Multiple robust linear and logistic regression models were fitted with the tertile consumption categories of each available pizza-related food item/group (i.e., pizza, refined grains, mozzarella cheese, and olive oil) as independent variables, and each available RA activity measure (i.e., the Disease Activity Score on 28 joints with C-reactive protein (DAS28-CRP), and the Simplified Disease Activity Index (SDAI)) as the dependent variable. Stratified analyses were carried out according to the disease severity or duration. Participants eating half a pizza >1 time/week (vs. ≤2 times/month) reported beneficial effects on disease activity, with the significant reductions of ~70% (overall analysis), and 80% (the more severe stratum), and the significant beta coefficients of -0.70 for the DAS28-CRP, and -3.6 for the SDAI (overall analysis) and of -1.10 and -5.30 (in long-standing and more severe RA, respectively). Among the pizza-related food items/groups, mozzarella cheese and olive oil showed beneficial effects, especially in the more severe stratum. Future cohort studies are needed to confirm this beneficial effect of pizza and related food items/groups on RA disease activity.

Efficacy and Safety of Anti-SARS-CoV-2 Antiviral Agents and Monoclonal Antibodies in Patients with SLE: A Case-Control Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19) has spread pandemically with high rates of morbidity and mortality. COVID-19 has also posed unprecedented challenges in terms of rapid development of pharmacological countermeasures to prevent or contrast SARS-CoV-2 pathogenicity. Anti-SARS-CoV-2 antiviral agents and monoclonal antibodies have been specifically designed to attenuate COVID-19 morbidity and prevent mortality in vulnerable subjects, such as patients with immune-mediated diseases, but evidence for the safe and effective use of these drugs in this latter population group is scarce. Therefore, we designed a retrospective, multicentre, observational, case-control study to analyse the impact of these treatments in COVID-19 patients with systemic lupus erythematosus (SLE), a paradigmatic, multi-organ autoimmune disease. We identified 21 subjects treated with antivirals and/or monoclonal antibodies who were matched with 42 untreated patients by age, sex, SLE extension and duration. Treated patients had higher baseline SLE disease activity index 2000 scores [SLEDAI-2K median (interquartile range) = 4 (1-5) vs. 0 (0-2); p = 0.009], higher prednisone doses [5 (0-10) mg vs. 0 (0-3) mg; p = 0.002], and more severe COVID-19 symptoms by a five-point World Health Organisation-endorsed analogue scale [1 (0-1) vs. 0 (0-1); p < 0.010] compared to untreated patients. There was no difference between groups in terms of COVID-19 outcomes and sequelae, nor in terms of post-COVID-19 SLE exacerbations. Three subjects reported mild adverse events (two with monoclonal antibodies, one with nirmatrelvir/ritonavir). These data suggest that anti-SARS-CoV-2 antivirals and monoclonal antibodies might be safely and effectively used in patients with SLE, especially with active disease and more severe COVID-19 symptoms at presentation.

The Crucial Questions on Synovial Biopsy: When, Why, Who, What, Where, and How?

In the majority of joint diseases, changes in the organization of the synovial architecture appear early. Synovial tissue analysis might provide useful information for the diagnosis, especially in atypical and rare joint disorders, and might have a value in case of undifferentiated inflammatory arthritis, by improving disease classification. After patient selection, it is crucial to address the dialogue between the clinician and the pathologist for adequately handling the sample, allowing identifying histological patterns depending on the clinical suspicion. Moreover, synovial tissue analysis gives insight into disease progression helping patient stratification, by working as an actionable and mechanistic biomarker. Finally, it contributes to an understanding of joint disease pathogenesis holding promise for identifying new synovial biomarkers and developing new therapeutic strategies. All of the indications mentioned above are not so far from being investigated in everyday clinical practice in tertiary referral hospitals, thanks to the great feasibility and safety of old and more recent techniques such as ultrasound-guided needle biopsy and needle arthroscopy. Thus, even in rheumatology clinical practice, pathobiology might be a key component in the management and treatment decision-making process. This review aims to examine some essential and crucial points regarding why, when, where, and how to perform a synovial biopsy in clinical practice and research settings and what information you might expect after a proper patient selection.

Multicentric study comparing cyclosporine, mycophenolate mofetil and azathioprine in the maintenance therapy of lupus nephritis: 8 years follow up.

BACKGROUND: The ideal long-term maintenance therapy of Lupus Nephritis (LN) is still a matter of debate. The present study was aimed at comparing the efficacy/safety profile of cyclosporine (CsA), mycophenolate mofetil (MMF) and azathioprine (AZA) in long-term maintenance therapy of LN. METHODS: We performed a retrospective study of patients with biopsy-proven active LN. After induction therapy, all patients received maintenance therapy with CsA, MMF or AZA based on medical decision. Primary endpoint was complete renal remission (CRR) after 8 years (defined as proteinuria < 0.5 g/24 h, eGFR > 60 ml/min/1.73 mq); secondary endpoints were: CRR after 1 year, renal and extrarenal flares, progression of chronic kidney disease (CKD stage 3 or above) and side-effects. RESULTS: Out of 106 patients, 34 received CsA, 36 MMF and 36 AZA. Clinical and histological characteristics at start of induction therapy were comparable among groups. At start of maintenance therapy, CsA patients had significantly higher proteinuria (P = 0.004) or nephrotic syndrome (P = 0.024) and significantly lower CRR (23.5% vs 55.5% on MMF and 41.7% on AZA, P = 0.024). At one year, CRR was similar in the three groups (79.4% on CsA, 63.8% on MMF, 58.3% on AZA, P = 0.2). At 8 years, the primary endpoint was achieved by 79.4% of CsA vs 83.3% of MMF and 77.8% of AZA patients (P = 0.83); 24 h proteinuria, serum creatinine, eGFR were similar. CKD stage 3 or above developed in 8.8% of CsA, in 8.3% of MMF and in 8.3% of AZA patients (P = 0.92). Flares-free survival curves and incidence of side-effects were not different. CONCLUSIONS: This is the first study comparing CsA, MMF and AZA on long-term LN maintenance therapy. All treatments had similar efficacy in achieving and maintaining CRR, despite more severe baseline clinical features in patients treated with CsA.

Adherence to Mediterranean diet and patient perception of rheumatoid arthritis.

OBJECTIVE: To evaluate the association between the adherence to Mediterranean diet (MD) and disease impact, activity, and comorbidities in patients with rheumatoid arthritis (RA). DESIGN: Consecutive patients with RA were enrolled in this cross-sectional study. For each patient, Disease Activity Score on 28 joints (DAS28), Simple Disease Activity Index (SDAI), RA Impact of Disease (RAID), Health Assessment Questionnaire (HAQ), patient global assessment (PGA) and general health (GH) and a self-reported questionnaire called MD score were recorded. RESULTS: 205 RA patients (median age 53 years, female 80.49 %) were enrolled. An association between MD score and HAQ (p-value = 0.033), PGA and GH (p-value 0.023 both) was observed. RAID total score had a statistically significant negative relationship with MD score (p-value = 0.016). A statistically significant negative association was found for pain (p-value = 0.025), functional disability (p-value<0.001), sleep (p-value = 0.041), physical well-being (p-value = 0.027) and coping (p-value = 0.008). Multiple regression analysis to evaluate the relationship between significant RAID items and MD score did not show any statistical significance as all items are strongly related to each other. A negative trend, although not statistically significant was found for DAS28 and SDAI. The only comorbidity associated with MD score was arterial hypertension (OR = 0.94). CONCLUSIONS: In this Italian RA cohort, the adherence to MD was significantly associated with a better RAID, PGA and GH, but higher MD score was not significantly associated with lower disease activity. Our study suggests an overall potential beneficial effect of MD in RA patients.

A Posteriori Dietary Patterns and Rheumatoid Arthritis Disease Activity: A Beneficial Role of Vegetable and Animal Unsaturated Fatty Acids.

To our knowledge, no studies have investigated the relationship between a posteriori dietary patterns (DPs)-representing current dietary behavior-and disease activity in patients with rheumatoid arthritis (RA). We analyzed data from a recent Italian cross-sectional study including 365 RA patients (median age: 58.46 years, 78.63% females). Prevalent DPs were identified through principal component factor analysis on 33 nutrients. RA activity was measured according to the Disease Activity Score on 28 joints (DAS28) and the Simplified Disease Activity Index (SDAI). Single DPs were related to disease activity through linear and logistic regression models, adjusted for the remaining DPs and confounders. We identified five DPs (~80% variance explained). Among them, Vegetable unsaturated fatty acids (VUFA) and Animal unsaturated fatty acids (AUFA) DPs were inversely related to DAS28 in the overall analysis, and in the more severe or long-standing RA subgroups; the highest score reductions (VUFA: 0.81, AUFA: 0.71) were reached for the long-standing RA. The SDAI was inversely related with these DPs in subgroups only. This Italian study shows that scoring high on DPs based on unsaturated fats from either source provides independent beneficial effects of clinical relevance on RA disease activity, thus strengthening evidence on the topic.

Extent and characteristics of carotid plaques and brain parenchymal loss in asymptomatic patients with no indication for revascularization.

BACKGROUND AND AIMS: Extent of subclinical atherosclerosis has been associated with brain parenchymal loss in community-dwelling aged subjects. Identification of patient-related and plaque-related markers could identify subjects at higher risk of brain atrophy, independent of cerebrovascular accidents. Aim of the study was to investigate the relation between extent and characteristics of carotid plaques and brain atrophy in asymptomatic patients with no indication for revascularization. METHODS AND RESULTS: Sixty-four patients (aged 69 ± 8 years, 45% females) with carotid stenosis <70% based on Doppler flow velocity were enrolled in the study. Potential causes of cerebral damage other than atherosclerosis, including history of atrial fibrillation, heart failure, previous cardiac or neurosurgery and neurological disorders were excluded. All subjects underwent carotid computed tomography angiography, contrast enhanced ultrasound for assessment of plaque neovascularization and brain magnetic resonance imaging for measuring brain volumes. On multivariate regression analysis, age and fibrocalcific plaques were independently associated with lower total brain volumes (ß = -3.13 and ß = -30.7, both p < 0.05). Fibrocalcific plaques were also independently associated with lower gray matter (GM) volumes (ß = -28.6, p = 0.003). On the other hand, age and extent of carotid atherosclerosis were independent predictors of lower white matter (WM) volumes. CONCLUSIONS: WM and GM have different susceptibility to processes involved in parenchymal loss. Contrary to common belief, our results show that presence of fibrocalcific plaques is associated with brain atrophy.

Progression of brain white matter hyperintensities in asymptomatic patients with carotid atherosclerotic plaques and no indication for revascularization.

BACKGROUND AND AIMS: Brain white matter hyperintensities (WMHs) have been associated with an increased risk of ischemic stroke and considered as markers of brain ischemia. Progression of WMHs in asymptomatic patients with non-hemodynamically significant carotid plaque could represent a putative marker of plaque vulnerability. We prospectively evaluate progression and determinants of WMHs in this population. METHODS: This prospective study included 51 asymptomatic patients with carotid stenosis <70% that underwent brain magnetic resonance imaging scans at baseline and after a median follow up of 595 days (interquartile range 553-641 days). Patients (mean age of 69 years and 45% females) underwent baseline carotid computed tomography angiography, contrast-enhanced ultrasound for carotid plaque characterization and analysis of subsets of circulating lymphocytes and monocytes by flow cytometry. RESULTS: Seventeen subjects (33.3%) had carotid stenoses of 50-70% (Doppler flow velocity) while the rest had stenoses of <50%. In 25 (49.0%) patients, new WMHs, with 5 new lesions on average and a median volume of 134 mm3, were detected at follow-up. None of the plaque characteristics or of the circulating cellular biomarkers investigated were associated with the global and ipsilateral occurrence of new WMHs whereas, at multivariate analysis, female sex, hypercholesterolemia, and lower glomerular filtration rate (GFR) emerged as independent variables associated with new WMHs. CONCLUSIONS: Half of the patients with carotid plaques of intermediate severity had evidence of WMH progression at follow up. Female gender and systemic factors such as hypercholesterolemia, and lower GFR, but not plaque characteristics or circulating cellular biomarkers, are associated with WMH progression.

Carotid artery plaque uptake of 11C-PK11195 inversely correlates with circulating monocytes and classical CD14++CD16- monocytes expressing HLA-DR.

BACKGROUND: We explored the relation between blood concentrations of monocyte/lymphocyte subsets and carotid artery plaque macrophage content, measured by positron emission tomography (PET) with 11C-PK11195. METHODS AND RESULTS: In 9 patients with carotid plaques we performed 11C-PK11195-PET/computed tomography angiography imaging and measurement of absolute concentrations and frequencies of circulating monocytes and T-cell subsets. Plaque standardized uptake value (SUV) for 11C-PK11195 was negatively correlated with concentrations of total monocytes (r = -0.58, p = 0.05) and CD14++CD16-HLA-DR+ classical subset (r = -0.82, p = 0.005). These correlations hold true also in relation to plaque target to background ratio. No correlation was observed between plaque SUV and CD3+T lymphocytes, CD4+T lymphocytes nor with activated CD3+CD4+T cells expressing HLA-DR. CONCLUSIONS: We first demonstrated a reduction in the absolute concentration of monocytes and particularly in classical monocytes expressing HLA-DR in the presence of an increased uptake of 11C-PK11195 in carotid plaques. The present work, despite being a pilot study comprising only a small number of subjects provides new insights in the search for specific cellular biomarkers with potential diagnostic and prognostic value in patients with a known carotid plaque.

Relation between characteristics of carotid atherosclerotic plaques and brain white matter hyperintensities in asymptomatic patients.

White matter hyperintensities (WMH) can be incidentally found in patients with carotid atherosclerosis on brain magnetic resonance imaging (MRI). We investigated the relationship between WMH and characteristics of carotid plaques in asymptomatic patients without indication for carotid revascularization. We prospectively screened 235 consecutive patients with carotid stenosis <70%. After excluding patients with confounding causes of cerebral damage, 67 asymptomatic patients underwent carotid computed tomography angiography (CTA), contrast-enhanced ultrasound and brain MRI. Number and quantitative measurement of volume of WMH were associated with history of resistant hypertension, degree of stenosis (Doppler) and presence of an ulcerated plaque at CTA (p < 0.05). At multivariate regression analysis, resistant hypertension was independently associated with both number and volume of WMH, presence of an ulcer with number of WMH and degree of stenosis with WMH volume (p < 0.05), although WMH were equally distributed in both hemispheres irrespectively of plaque side. In conclusion, in asymptomatic patients with carotid plaques <70%, a higher burden of WMHs is associated with history of resistant hypertension that could be the expression of microvascular damage. Stenosis severity and presence of plaque ulceration are also associated with WMH burden although their causative relation is not supported by the bilateral distribution of WMH.

Circulating CD14+ and CD14highCD16- classical monocytes are reduced in patients with signs of plaque neovascularization in the carotid artery.

BACKGROUND AND AIMS: Monocytes are known to play a key role in the initiation and progression of atherosclerosis and contribute to plaque destabilization through the generation of signals that promote inflammation and neoangiogenesis. In humans, studies investigating the features of circulating monocytes in advanced atherosclerotic lesions are lacking. METHODS: Patients (mean age 69 years, 56% males) with intermediate asymptomatic carotid stenosis (40-70% in diameter) were evaluated for maximal stenosis in common carotid artery, carotid bulb and internal carotid artery, overall disease burden as estimated with total plaque area (TPA), greyscale and neovascularization in 244 advanced carotid plaques. Absolute counts of circulating CD14+ monocytes, of classical (CD14highCD16-), intermediate (CD14highCD16+) and non-classical (CD14lowCD16+) monocytes and HLA-DR+ median fluorescence intensity for each subset were evaluated with flow cytometry. RESULTS: No correlation was found between monocytes and overall atherosclerotic burden, nor with high sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6). In contrast, plaque signs of neovascularization were associated with significantly lower counts of circulating CD14+ monocytes (297 versus 350 cells/mm3, p = 0.039) and of classical monocytes (255 versus 310 cells/mm3, p = 0.029). CONCLUSIONS: Neovascularized atherosclerotic lesions selectively associate with lower blood levels of CD14+ and CD14highCD16- monocytes independently of systemic inflammatory activity, as indicated by normal hsCRP levels. Whether the reduction of circulating CD14+ and CD14highCD16- monocytes is due to a potential redistribution of these cell types into active lesions remains to be explored.

Non-invasive imaging of vascular inflammation.

In large-vessel vasculitides, inflammatory infiltrates may cause thickening of the involved arterial vessel wall leading to progressive stenosis and occlusion. Dilatation, aneurysm formation, and thrombosis may also ensue. Activated macrophages and T lymphocytes are fundamental elements in vascular inflammation. The amount and density of the inflammatory infiltrate is directly linked to local disease activity. Additionally, patients with autoimmune disorders have an increased cardiovascular (CV) risk compared with age-matched healthy individuals as a consequence of accelerated atherosclerosis. Molecular imaging techniques targeting activated macrophages, neovascularization, or increased cellular metabolic activity can represent effective means of non-invasive detection of vascular inflammation. In the present review, novel non-invasive imaging tools that have been successfully tested in humans will be presented. These include contrast-enhanced ultrasonography, which allows detection of neovessels within the wall of inflamed arteries; contrast-enhanced CV magnetic resonance that can detect increased thickness of the arterial wall, usually associated with edema, or mural enhancement using T2 and post-contrast T1-weighted sequences, respectively; and positron emission tomography associated with radio-tracers such as [(18)F]-fluorodeoxyglucose and the new [(11)C]-PK11195 in combination with computed tomography angiography to detect activated macrophages within the vessel wall. Imaging techniques are useful in the diagnostic work-up of large- and medium-vessel vasculitides, to monitor disease activity and the response to treatments. Finally, molecular imaging targets can provide new clues about the pathogenesis and evolution of immune-mediated disorders involving arterial vessels.