Background In contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity. Methods and results CLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure. Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest. Conclusion In patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes. ClinicalTrials identifier ISRCTN43070564

Sarcoidosis is a disorder of unknown etiology characterized by development of necrosis-free epithelioid cell granulomas in various tissues. There are two main phenotypes of pulmonary sarcoidosis (PS): Lofgren’s syndrome (LS) is an acute form with favorable outcome, while non-Lofgren’s syndrome (nLS) is a chronic type of disease that can lead to pulmonary fibrosis in 20% of cases.Our study was aimed at investigating changes in the main cell-surface differentiation antigens on peripheral blood regulatory T cells (Tregs) from the patients with first diagnosed PS without treatment (LS, n = 11) and nLS (n = 46) compared to healthy volunteers (HC, n = 26).These indexes might be used as immunological markers for predicting severity of this disorder. Flow cytometry analysis of peripheral blood cell samples demonstrated that the nLS patients had decreased relative numbers of CD3+ cells vs healthy controls, as well as diminished CD3+CD4+ cells vs HC and LS patients. Furthermore, the relative and absolute Treg numbers were also decreased in nLS group vs HC (2.83% (2.47; 3.36) vs 3.33% (2.79; 3.84), p = 0.021), and 37 (29; 52) cells vs 50 (42; 65), p = 0.004, respectively) per one microliter of peripheral blood. Relative number of CD39-positive Тregs in chronic vs acute sarcoidosis patients was associated with 51.02% (38.20; 61.62) vs 48.64% (41.46; 63.72) that was significantly (p < 0.001 and p = 0.007, respectively) higher than in HC (39.52% (11.55; 46.34). We have found that “naïve” (CD45R0-CD62L+) Тregs did not significantly differ in percentage of CD39- and CD73-positive cells in all the groups tested. Moreover, CD45R0+CD62L+ Тregs in LS and nLS patients contained significantly more CD39-positive cells (69.66% (61.92; 79.34) and 67.62% (61.92; 79.34), respectively, compared to 47.55% (15.74; 65.32) in HC (p < 0.001 and p = 0.004, respectively). In case of CD45R0 + CD62LTregs able to exit from the circulation and migrate to the site of inflammation, an increased percentage of CD39-positive subset was noted only in patients with chronic sarcoidosis and HC (61.79% (55.12; 73.09) and 57.27% (16.03; 66.98), p = 0.006). Enhanced CD39 expression on Tregs seems to be related to chronic immune response, so that antigen elimination becomes impossible due to Treg overactivation, as shown in patients with sarcoidosis and some other chronic autoimmune and infectious disorders.

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Sarcoidosis is an inflammatory disease of unknown etiology with damage to the lungs and other organs characterized by development of necrosis-free epithelioid cell granulomas. Granulomatous inflammation characterized by the activation of different immune systems cells, in particular T lymphocytes, and the cytokines production. Our study was aimed at investigating the characteristics of the cytokine profile of blood plasma in patients with sarcoidosis. We studied peripheral blood plasma samples of patients with sarcoidosis (n = 52). The control blood samples were taken from healthy volunteers (n = 22). The level of 46 cytokines (pg/ml) was determined, as follows: IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL- 6, IL-7, IL-9, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IFNα2, IFNγ, TNFα, TNFβ, IL- 1ra, IL-10, EGF, FGF-2, Flt3 Ligand, G-CSF, GM-CSF, PDGF-AA, PDGF-AB / BB, TGFα, VEGF-A, sCD40L, CCL2, CCL3, CCL4, CCL5, CCL7, CCL11, CCL17, CCL20, CCL22, CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, CXCL13, CX3CL1. Significantly higher levels of interleukins and some proinflammatory cytokines were found in the patients with sarcoidosis, i.e., IL-3, 0.70 vs 0.20, p = 0.003; IL-4, 14.37 vs 3.15, p = 0.009; IL-5, 1.06 vs 0.89, p < 0.001; IL-12 (p70), 1.27 vs 0.56, p = 0.028; IL-17A, 1.48 vs 0.43, p < 0.001; IFNα2, 41.79 vs 25.04, p = 0.003; IFNγ, 4.13 vs 1.14, p < 0.001; TNFα, 21.67 vs 6.70, p < 0.001; anti-inflammatory cytokine IL-10, 1.03 vs 0.45, p = 0.019; growth factors: FGF-2, 40.08 vs 30.58, p = 0.008, G-CSF, 24.18 vs 8.21, p = 0.006, and VEGF-A, 42.52 vs 26.76, p = 0.048; chemokines: CCL3, 3.86 vs 1.33, p < 0,001; CCL17, 78.24 vs 26.24, p < 0.001; CCL20, 7.19 vs 5.64, p = 0.021; CCL22, 660.60 vs 405.00, p < 0,001; CXCL9, 4013 vs 1142, p < 0,001; CXCL10, 565.90 vs 196.60, p < 0.001; CXCL11, 230.20 vs 121.10, p = 0.018; CX3CL1, 56.99 vs 5.16, p < 0.001. Peripheral blood chemokine CCL11 levels were significantly lower in patients compared to the group of healthy volunteers: 77.58 vs 124.70, p = 0.022. The features of the cytokine profile in patients with sarcoidosis may indicate their important role in the processes of formation and outcomes of granulomas. These issues require an additional detailed study, comparison with phenotypes, differential course and outcomes of the disease.

Various immune cells as well as related cytokines are involved in immunopathogenesis of sarcoidosis and mechanisms of granuloma development. Currently, a role for chemokines in sarcoidosis has been extensively investigated, which is paralleled with a search for key molecules necessary for recruiting immune cells to intrusion site and granuloma formation as well as affecting outcome of the latter. Our study was aimed for determining level of plasma CCL17/TARC and CCL22/MDC chemokines in patients with sarcoidosis who received no immunosuppressive therapy is of high priority for clarifying some aspects in underlying immunopathogenesis as well as seeking out for secure clinical and laboratory criteria for assessing activity and disease prognosis. We studied peripheral blood plasma samples of the patients with sarcoidosis (n = 52). In 37% (19/52), they exhibited acute clinical manifestations, and 63% (33/52) had chronic sarcoidosis. The control group included peripheral blood samples from healthy volunteers (n = 22). The chemokine concentrations (pg/ml) were determined by multiplex analysis using xMAP technology (Luminex), and Milliplex MAP test system (Millipore, USA). In the patients with sarcoidosis, significantly higher levels of chemokines were shown relative to healthy volunteers: CCL17 – 78.24 pg/ml vs 26.24 pg/ml, p < 0.001; CCL22 – 660.60 pg/ml vs 405.00 pg/ml, p < 0.001. Evaluation of clinical and laboratory diagnostic characteristics for plasma chemokine levels in sarcoidosis patients allowed to assess their sensitivity and specificity. The respective values were as follows: in acute sarcoidosis: for CCL17 – 63% and 78%, CCL22 – 63% and 91%; in chronic sarcoidosis: CCL17 – 58% and 83%, CCL22 – 67% and 86%, respectively. In chronic sarcoidosis the levels of this chemokine correlated with the activity of angiotensin-converting enzyme (ACE), for CCL17 (r = 0.530; p = 0.003), for CCL22 (r = 0.446; p = 0.014). Patients with systemic lesions vs no systemic lesions (sarcoidosis of the respiratory system only) had significantly elevated CCL17 level: 102.82 pg/ml vs 32.72 pg/ml, p = 0.011. The concentration of chemokine CCL17 was significantly increased in patients with vs without signs of hepatomegaly: 130.73 pg/ml vs 51.60 pg/ml, p = 0.022. Levels of chemokines was significantly increased in patients with vs without ultrasound signs of splenomegaly comprising: for CCL17 – 249.18 pg/ml vs 46.87 pg/ml, p = 0.002; for CCL22 – 1271.40 pg/ml vs 660.63 pg/ml, p = 0.003. Thus, it should be noted that the peripheral blood plasma level of chemokines CCL17 and CCL22 may be used as additional prognostic markers in chronic sarcoidosis with varying scoring of clinical signs including with/without systemic disease manifestations.