Joanna Sulicka

Differential associations of inflammatory and endothelial biomarkers with disease activity in rheumatoid arthritis of short duration.

Objectives. To estimate endothelial dysfunction in patients with rheumatoid arthritis (RA) of short duration in relation to disease activity based on the assessment of 28 joints (DAS28). Methods. We studied 29 patients (22 women, mean age 41 (SD, 9) years) with RA of short duration and 29 healthy controls. The RA subjects were divided into those with low (DAS28: 2.6–5.1, n = 18) or high (DAS28 > 5.1, n = 11) disease activity. Exclusion criteria included clinically overt atherosclerosis and other coexistent diseases. Biochemical markers of inflammatory activation and endothelial dysfunction were measured. Results. There were no significant intergroup differences in the majority of classical cardiovascular risk factors. High-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin-6 were increased in RA subjects. Compared to the controls, levels of soluble vascular cell adhesion molecule-1, von Willebrand factor, and pentraxin-3 were significantly elevated in RA subjects with low disease activity, exhibiting no further significant rises in those with high disease activity. Asymmetric dimethyl-L-arginine, soluble E-selectin, monocyte chemotactic protein-1, and osteoprotegerin were increased only in RA patients with high disease activity. Conclusions. Our findings might suggest a dissociation of pathways governing generalized and joint-specific inflammatory reactions from those involved in endothelial activation and inflammation within the vascular wall.

Elevated markers of inflammation and endothelial activation and increased counts of intermediate monocytes in adult survivors of childhood acute lymphoblastic leukemia

BACKGROUND Adult survivors of childhood malignancy are prone to accelerated atherogenesis and late cardiovascular complications. Plaque formation is initiated by recruitment of monocytes and T-cells into the intima, mediated by adhesion molecules and chemokines expressed by activated endothelial cells. AIM To assess markers of inflammatory activity, endothelial activation as well as monocyte heterogeneity in adult survivors of childhood acute lymphoblastic leukemia (ALL) who had been treated with chemotherapy without cranial irradiation. METHODS AND RESULTS We studied 27 (age: 18-28 years) healthy survivors of childhood ALL and 20 controls (age: 20-31 years). Flow cytometry was used to identify monocyte subsets: classical CD14(++)CD16(-), intermediate CD14(++)CD16(+) and nonclassical CD14(+)CD16(++) monocytes which were further characterized by their expression of HLA-DR and β2-integrins CD11b/CD18 and CD11c/CD18. In ALL survivors we found increased levels of pentraxin-3 (median [interquartile range]: 0.63 [0.36-0.94] vs. 0.40 [0.32-0.57] ng/ml; p = 0.03), soluble vascular cell adhesion molecule-1 (687 [597-761] vs. 558 [534-702]ng/ml; p = 0.02), osteoprotegerin (mean ± SD: 5.24 ± 1.00 vs. 4.42 ± 1.34 pmol/l; p = 0.02) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (107.0 ± 23.6 vs. 89.5 ± 18.9 pg/ml; p = 0.01), whereas C-reactive protein, interleukin 6 and 18, TNF-α, monocyte chemotactic protein-1 and soluble intercellular adhesion molecule-1 were unchanged. Former ALL patients exhibited elevated counts of intermediate monocytes (6.3 ± 4.0 vs. 4.3 ± 1.5% of blood monocytes; p = 0.03). CD11b/CD18 and CD11c/CD18 expression on intermediate monocytes tended to be higher in ALL survivors (1917 ± 993 vs. 1396 ± 673 MFI [median fluorescence intensity]; p = 0.06 and 3883 ± 1445 vs. 3185 ± 645 MFI; p = 0.05, respectively). CONCLUSION Our findings suggest chronic inflammatory activation and immune dysregulation in adult survivors of childhood ALL, which can translate into late cardiovascular morbidity.

Blood monocyte heterogeneity and markers of endothelial activation in ankylosing spondylitis.

Objective. Ankylosing spondylitis (AS) is associated with excessive cardiovascular (CV) morbidity. Interactions between activated endothelium and monocytes precede atherosclerotic plaques. Our aim was to quantify blood monocyte subsets in relation to endothelial activation and inflammatory activity in subjects with AS who were free of clinical atherosclerotic CV disease. Methods. Markers of inflammation and endothelial activation were measured in 47 patients with AS receiving no disease-modifying antirheumatic drugs, and 22 healthy controls. Exclusion criteria included atherosclerotic CV disease and traditional risk factors. Flow cytometry was used to identify monocyte subsets: classical CD14++CD16−, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes and to evaluate their expression of CD11b and CD11c. Results. Traditional risk factors were comparable among the groups, except for lower high-density lipoprotein cholesterol in AS (p = 0.007). Relative to controls, in subjects with AS counts of classical monocytes were higher (84.3 ± 5.4 vs 78.9 ± 5.3% of blood monocytes, p < 0.001) and nonclassical monocytes lower (2.9 ± 2.2 vs 5.5 ± 2.3%, p < 0.001). In AS we observed increased soluble intercellular adhesion molecule-1 [251 (224–293) vs 202 (187–230) ng/ml, p = 0.002], an endothelial ligand for monocytic β2-integrin CD11b/CD18. CD11b expression on all 3 monocyte subsets was elevated in 21 AS subjects with a Bath Ankylosing Spondylitis Disease Activity Index score ≥ 4 versus the remaining patients (p = 0.005–0.03). C-reactive protein, interleukin 6 (IL-6), and pentraxin-3 were increased in AS, in contrast to tumor necrosis factor-α and IL-18. IL-6 correlated with classical monocytes numbers in AS (r = 0.56, p < 0.0001) but not in the controls (r = 0.10, p = 0.65). Conclusion. Our findings suggest a contribution of immune dysregulation to enhanced monocyte-endothelial interactions in AS, especially in patients with active disease, which possibly can accelerate atherogenesis on a longterm basis.

Blood Monocyte Subsets and Selected Cardiovascular Risk Markers in Rheumatoid Arthritis of Short Duration in relation to Disease Activity

Objectives. To evaluate blood monocyte subsets and functional monocyte properties in patients with rheumatoid arthritis (RA) of short duration in the context of cardiovascular (CV) risk and disease activity. Methods. We studied conventional markers of CV risk, intima media thickness (IMT), and blood monocyte subsets in 27 patients aged 41 ± 10 years with RA of short duration (median 12 months) and 22 healthy controls. The RA subjects were divided into low (DAS28: 2.6–5.1) and high (DAS28 > 5.1) disease activity. Results. RA patients exhibited increased levels of intermediate (CD14++CD16+) monocytes with decreased CD45RA expression compared to controls, increased counts of classical (CD14++CD16−) monocytes, and decreased percentages of nonclassical (CD14+CD16++) monocytes. Patients with high disease activity had lower HLA DR expression on classical monocytes compared to low disease activity patients. There were no differences in monocyte subsets between subjects with DAS > 5.1 and DAS ≤ 5.1. There were no significant intergroup differences in IMT and the majority of classical CV risk factors. Conclusions. Patients with RA of short duration show alteration in peripheral blood monocyte subsets despite the fact that there is no evidence of subclinical atherosclerosis. Disease activity assessed with DAS28 was associated with impaired functional properties but not with a shift in monocyte subpopulations.

Elevated Asymmetric Dimethylarginine in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Preliminary Report

Background: Adult survivors of childhood malignancy are predisposed to late cardiovascular (CV) complications. Our aim was to estimate plasma levels of the endogenous nitric oxide formation inhibitor asymmetric dimethylarginine (ADMA), in long-term survivors of childhood acute lymphoblastic leukemia (ALL) treated with only chemotherapy. Methods: ADMA and its isomer symmetric dimethylarginine (SDMA) were measured in 25 former ALL patients (aged 18–28 years) who had survived without recurrent disease ≥ 5 years from completing chemotherapy without cranial irradiation, and in 20 healthy controls (aged 20–31 years). Results: Characteristics of the both groups were similar, except for lower high-density lipoproteins-cholesterol (HDL-C) in ALL survivors. Compared to controls, the former ALL patients exhibited significant, albeit small, rises in levels of ADMA (0.63 ± 0.09 [SD] vs. 0.57 ± 0.07 μmol/L; p = 0.016), but not SDMA, with a consequently increased ADMA to SDMA ratio (1.08 ± 0.22 vs. 0.91 ± 0.16; p = 0.004). The effect of former ALL on ADMA was attenuated (intergroup p = 0.10 [ANCOVA]) upon adjustment for HDL-C (ADMA vs. HDL-C regression coefficient: −0.065 ± 0.030 [SEM]; p = 0.03). Conclusions: ADMA is elevated in adult childhood ALL survivors, which can reflect late detrimental chemotherapy effects, partially related to minor lipid profile changes. Whether these subtle ADMA elevations might herald future CV morbidity, remains to be elucidated.

Women with prehypertension in primary care - Risk profile on the basis of selected cardiovascular risk factors.

Abstract Background. Demographic, social and economic trends will serve to increase the importance of women as healthcare consumers. Design. The aim of the study was to assess cardiovascular (CV) risk in the normotensive female patients during single visit to primary care (PC) offices. Methods. Demographic data, history of coronary heart disease (CHD), diabetes (DM), smoking habit and family history of CV diseases were obtained from women who visited general practitioners. Moreover, blood pressure (BP), pulse rate, weight and height used to calculation body mass index (BMI) and waist circumference (WC) were performed. Prehypertension was defined as a systolic BP (SBP) of 120–139 mmHg, and/or a diastolic BP (DBP) of 80–89mmHg. Results. Prehypertension was observed in 21.5% of the whole group of female PC patients. SBP, DBP, BMI and WC revealed significant trends towards increase with age among both prehypertensives (p<0.001) and normotensives (SBP, BMI, WC: p<0.001; DBP: p<0.05) and in the whole group (p<0.001). Nevertheless, heart rate (HR) significantly increased with age only among prehypertensive women (p<0.05). The CV risk of the studied adult women increased progressively with presence of overweight, obesity and visceral obesity. The CV risk of the youngest groups was associated mainly with high prevalence of smoking, and with high prevalence of CHD and DM among the oldest female patients. Conclusions. The prevalence of majority of CV risk factors increase with age among both prehypertensive and normotensive women, which should stimulate PC practitioners to identify and modify them.

Dimethylated L-arginine analogues versus autoantibodies in early rheumatoid arthritis.

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide formation, is associated with cardiovascular (CV) risk factors, endothelial dysfunction, and adverse CV outcomes (1). Elevated plasma ADMA levels have also been reported in rheumatoid arthritis (RA) patients free of clinically evident atherosclerotic CV disease or traditional risk factors, with active disease despite disease-modifying anti-rheumatic drug (DMARD) therapy (2). In these RA patients, ADMA was related to subclinical carotid atherosclerosis (2) and anti-cyclic citrullinated peptide antibody (anti-CCP) titres (3). Turiel et al (4) have described increased ADMA in DMARD-naïve subjects with early RA without clinical CV disease or risk factors, linking raised ADMA to a depressed coronary flow reserve and higher anti-CCP. These observations suggest that anti-CCP might contribute to excessive ADMA accumulation and thus to CV pathology. In RA, the positivity for anti-CCP increased the future risk of developing clinically manifest ischaemic heart disease independently of traditional risk factors (5). Furthermore, another autoantibody, rheumatoid factor (RF), predicts CV mortality in RA (6) and in non-arthritic individuals (7). Therefore, in this study our aim was to investigate relationships between ADMA, anti-CCP, and RF isotypes in early RA. We studied 25 new-onset RA patients (17 women and eight men; mean age 44 13 years) fulfilling the revised 1987 American College of Rheumatology criteria, without overt CV disease before commencing DMARDs. Enzyme-linked immunosorbent assays (ELISAs) were used to measure plasma ADMA and its structural isomer, symmetric dimethylarginine (SDMA, DLD Diagnostika GmbH, Hamburg, Germany), secondand third-generation anti-CCP [immunoglobulin (Ig)G-anti-CCP2 and IgG/IgAanti-CCP3, respectively], and RF IgG, IgM, and IgA isotypes (INOVA Diagnostics, Inc, San Diego, CA, USA) (Table 1). The ADMA ELISA had previously been validated against high-performance liquid chromatography coupled to mass spectrometry, the golden standard for the determination of ADMA levels (8). According to the manufacturer, the lower detection limits were 0.05 μmol/L for ADMA and SDMA, and the intraand inter-assay coefficients of variation averaged 5.7% and 10.3% for ADMA and 6.1% and 9.8% for SDMA, respectively. Cross-reactivity with L-arginine and other methylarginines was < 0.01–0.02% (SDMA or ADMA vs. L-arginine), 0.44–1.2% (ADMA vs. SDMA), and 0.7–1.0% (SDMA or ADMA vs. N-monomethyl-L-arginine). Ethical approval was granted by the Bioethical Committee of our university and written consent was obtained from each participant. A positive correlation between IgG-RF levels and the ADMA/SDMA ratio was found, mainly driven by a tendency to higher ADMA concentrations at increased IgG-RF titres (Table 2). Clinical, radiological, and biochemical features (including anti-CCP and systemic inflammatory markers) were unrelated to plasma ADMA (0.94 0.23 μmol/L), SDMA (0.57 0.12 μmol/L), or the ADMA/SDMA ratio (1.69 0.36) (p > 0.1). To allow for the possibility of spurious correlations due to multiple testing, multivariate analysis was performed with ADMA or SDMA levels as dependent variables. Multiple linear regression identified IgG-RF (β 1⁄4 0.52 0.24, p 1⁄4 0.04) and age (β 1⁄4 0.43 0.21,