Giorgos S. Metsios

Hypertension in rheumatoid arthritis

RA associates with an increased burden of cardiovascular disease, which is at least partially attributed to classical risk factors such as hypertension (HT) and dyslipidaemia. HT is highly prevalent, and seems to be under-diagnosed and under-treated among patients with RA. In this review, we discuss the mechanisms that may lead to increased blood pressure in such patients, paying particular attention to commonly used drugs for the treatment of RA. We also suggest screening strategies and management algorithms for HT, specific to the RA population, although it is clear that these need to be formally assessed in prospective randomized controlled trials designed specifically for the purpose, which, unfortunately, are currently lacking.

Association of physical inactivity with increased cardiovascular risk in patients with rheumatoid arthritis.

Objective Patients with rheumatoid arthritis (RA) are characterized by reduced physical activity and increased morbidity and mortality from cardiovascular disease (CVD). The aim of this study was to investigate associations between levels of physical activity and CVD risk profile in RA patients. Methods Levels of physical activity were assessed in 65 RA patients (43 females). Using the International Physical Activity Questionnaire, patients were allocated into three groups: active, moderately active and inactive. Anthropometric characteristics, RA activity/severity, multiple classical and novel CVD risk factors and 10-year CVD event probability were assessed and compared among the three groups. Results Significant differences were detected among groups in systolic blood pressure (P = 0.006), cholesterol (P < 0.001), low-density lipoprotein (P = 0.01), homeostasis model assessment (P = 0.001), type-1 plasminogen activator inhibitor antigen (P < 0.001), tissue-type plasminogen activator antigen (P = 0.019), homocysteine (P = 0.027), fibrinogen (P = 0.001), apolipoprotein B (P = 0.002) and von Willebrand Factor (P = 0.001), with a consistent deterioration from the physically active to the physically inactive group. Multivariate analysis of variance revealed that levels of physical activity were significantly associated with the differences in all of the above variables (P < 0.05) after adjustment for age, weight, sex, smoking status, as well as RA disease activity and severity. Conclusion This cross-sectional study suggests that physically inactive RA patients have significantly worse CVD risk profile compared with physically active patients. The possible beneficial impact of increased physical activity, including structured exercise, to the CVD risk of RA patients needs to be accurately assessed in prospective studies. Eur J Cardiovasc Prev Rehabil 16:188-194

Obesity in rheumatoid arthritis

Obesity is a major threat for public health and its study has attracted significant attention in the general population, predominantly due to its association with significant metabolic and cardiovascular complications. In RA research, BMI is frequently reported as a demographical variable, but obesity, as such, has received little interest. This is surprising, in view of the clear associations of obesity with other arthritides, particularly OA, but also in view of the now-clear association of RA with increased cardiovascular morbidity and mortality. In this review, we summarize the studies that have looked into obesity in the RA population, evaluate their findings, identify knowledge gaps and propose directions for future research. We also pose a question of high clinical and research significance: is the use of BMI still a valid way of assessing obesity in RA?

Acute and Short-term Effects of Secondhand Smoke on Lung Function and Cytokine Production

RATIONALE The acute effect of secondhand smoke (SHS) on lung function and the duration of system disruption remain unknown. OBJECTIVES To assess the SHS effects and their duration on lung function and inflammatory markers. METHODS In a randomized single-blind crossover experiment data were obtained from 16 (8 women) nonsmoking adults at baseline and at 0, 1, and 3 hours after a 1-hour SHS exposure set at bar/restaurant SHS levels. MEASUREMENTS AND MAIN RESULTS Serum and urine cotinine, lung function, and cytokines IL-4, IL-5, IL-6, tumor necrosis factor (TNF)-alpha, and IFN-gamma. At 0 hours most lung function parameters were significantly reduced (indicative: FEV(1), 4.3 +/- 0.4 vs. 3.8 +/- 0.3 L; FEV(1)/FVC, 0.9 +/- 0.1 vs. 0.8 +/- 0.1; P < 0.05) but at 3 hours they were at baseline levels. In contrast, cotinine (serum, 8.9 +/- 3.2 vs. 35.5 +/- 10.2 ng x ml(-1)), IL-4 (41.3 +/- 5.8 vs. 44.2 +/- 4.5 pg x ml(-1)), IL-5 (36.1 +/- 3.2 vs. 60.1 +/- 7.0 pg x ml(-1)), IL-6 (2.5 +/- 0.3 vs. 7.6 +/- 1.4 pg x ml(-1)) and IFN-gamma (0.3 +/- 0.2 vs. 0.6 +/- 0.2 IU x ml(-1)) at 3 hours were higher than at baseline (P < 0.05). IL-4 and TNF-alpha increased only in men, whereas IL-5, IL-6, and IFN-gamma were different between sexes after exposure (P < 0.05). Regression analyses revealed inverse associations of FEV(1) and FEV(1)/FVC ratio with IL-5 (P < 0.05) in men and with IL-5 (P = 0.01), IL-6 (P < 0.001), IFN-gamma (P = 0.034) and serum cotinine (P < 0.001) in women. CONCLUSIONS We conclude that 1 hour of SHS exposure at bar/restaurant levels is accompanied by significant decrements on lung function and marked increases in inflammatory cytokines, particularly in men. More importantly, whereas most smoke-induced effects on lung function appear to recede within 60 minutes, inflammatory cytokines remain elevated for at least 3 hours after exposure to SHS.

Individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis

Background and objectives Low cardiorespiratory fitness (CRF) is a significant predictor of cardiovascular disease (CVD), and interventions aiming at increasing CRF are known to reduce CVD risk. The effects of such interventions on CVD risk have not been studied in patients with rheumatoid arthritis (RA). Methods 40 age, gender, body mass index (BMI) and disease duration matched RA patients were allocated to either an exercise (receiving 6 months individualised aerobic and resistance high intensity exercise intervention, three times per week), or control (receiving advice on exercise benefits and lifestyle changes) arm. Participants were assessed at baseline, 3 and 6 months for aerobic capacity (VO2max), individual CVD risk factors (blood pressure, lipids, insulin resistance, body composition), 10-year CVD event probability and RA characteristics (C-reactive protein (CRP), Disease Activity Score 28 (DAS28) and Health Assessment Questionnaire (HAQ)). Results There were no differences between groups at baseline in any of the assessed variables. VO2max (p=0.001), blood pressure (systolic: p<0.001; diastolic: p=0.003), triglycerides (p=0.030), high density lipoprotein (HDL; p=0.042), total cholesterol:HDL ratio (p=0.005), BMI (p=0.001), body fat (p=0.026), 10-year CVD event probability (p=0.012), CRP (p=0.042), DAS28 (p=0.008) and HAQ (p=0.003) were all significantly improved in the exercise versus the control group. The change in VO2max was the strongest predictor for the observed improvements in all of the assessed CVD risk factors and disease characteristics. Conclusions Individualised aerobic and resistance exercise intervention can lead to significantly improved CRF, individual CVD risk factors, composite CVD risk, and disease activity and severity in RA patients.

Association of interleukin-6 (IL-6)-174G/C gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis: The role of obesity and smoking

BACKGROUND Cardiovascular morbidity and mortality are increased in rheumatoid arthritis (RA). Interleukin-6 (IL-6) is high in RA and, together with smoking and obesity, an important contributor to the development of cardiovascular disease (CVD). The present study examined the potential association of IL-6-174 G/C polymorphism, together with obesity and smoking, with the presence of CVD in RA patients. METHODS AND RESULTS DNA samples were collected from 383 RA patients (who also had extensive clinical and laboratory evaluations). IL-6-174 G/C was identified using real time PCR and melting curve analysis. Serum IL-6 levels were measured in a subgroup of 135 RA patients to examine the functionality of the polymorphism. Carriers of the IL6-174C-allele demonstrated increased prevalence of CVD (26.2% vs. 17.0%, p=0.041). There was a significant association with CVD, even after adjustment for traditional CVD risk factors (OR=1.92, 95%CI: 1.03 to 3.58, p=0.041). IL-6 levels were significantly increased in C-allele carriers [14.02 (3.21-38.81) vs. 4.48 (2.25-16.5), p=0.028]. No significant interactions were observed between adiposity and IL6-174G/C genotypes. There was only a trend for an interaction between ever smoking and IL6 C-allele carriers on CVD. CONCLUSION The IL-6-174C-allele may associate with CVD in RA patients and possibly exerts its effect via increased inflammation. This finding, if confirmed in future studies, may be used as a part of a genetic screening tool for RA patients at high CVD risk.

Associations of obesity with modifiable risk factors for the development of cardiovascular disease in patients with rheumatoid arthritis

Objectives: To assess the association of body mass index (BMI) with modifiable cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA). Methods: BMI, disease activity, selected CVD risk factors and CVD medication were assessed in 378 (276 women) patients with RA. Patients exceeding accepted thresholds in ⩾3 CVD risk factors were classified as having the metabolic syndrome (MetS). Results: BMI independently associated with hypertension (OR = 1.28 (95% CI = 1.22 to 1.34); p = 0.001), high-density lipoprotein (OR = 1.10 (95% CI = 1.06 to 1.15); p = 0.025), insulin resistance (OR = 1.13 (95% CI = 1.08 to 1.18); p = 0.000) and MetS (OR = 1.15 (95% CI = 1.08 to 1.21); p = 0.000). In multivariable analyses, BMI had the strongest associations with CVD risk factors (F1–354 = 8.663, p = 0.000), and this was followed by lipid-lowering treatment (F1–354 = 7.651, p = 0.000), age (F1–354 = 7.541, p = 0.000), antihypertensive treatment (F1–354 = 4.997, p = 0.000) and gender (F1–354 = 4.707, p = 0.000). Prevalence of hypertension (p = 0.004), insulin resistance (p = 0.005) and MetS (p = 0.000) was significantly different between patients with RA who were normal, overweight and obese, and BMI differed significantly according to the number of risk factors present (p = 0.000). Conclusions: Increasing BMI associates with increased CVD risk independently of many confounders. RA-specific BMI cut-off points better identify patients with RA at increased CVD risk. Weight-loss regimens should be developed and applied in order to reduce CVD in patients with RA.

Biological evidence for the acute health effects of secondhand smoke exposure

A vast number of studies on the unfavorable effects of secondhand smoke (SHS) exist within the international literature, the majority of which evaluate longitudinal epidemiological data. Although limited, the experimental studies that assess the acute and short-term effects of exposure to SHS are also increasing in number. They include cellular, animal, and human studies that indicate a number of pathophysiological mechanisms through which the deleterious effects of SHS may arise. This current review evaluates the existing biological evidence regarding the acute health effects of SHS exposure. Analyses on the inhaled toxicants and the carcinogenicity of SHS are included as well as in-depth discussions on the evidence for acute SHS-induced respiratory, cardiovascular, metabolic, endocrine and immune effects, and SHS-induced influences on oxygen delivery and exercise. The influence of the length of exposure and the duration of the observed effects is also described. Moreover, recent findings regarding the underlying pathophysiological mechanisms related to SHS are depicted so as to generate models that describe the SHS-induced effects on different systems within the human body. Based on the presented biological evidence, it is concluded that brief, acute, transient exposures to SHS may cause significant adverse effects on several systems of the human body and represent a significant and acute health hazard. Future research directions in this area include research on the concentrations of tobacco smoke constituents in the alveolar milieu following SHS exposure, individual susceptibility to SHS, as well as the effects of SHS on neurobehavioral activity, brain cell development, synaptic development, and function.

Rheumatoid arthritis susceptibility genes associate with lipid levels in patients with rheumatoid arthritis

Introduction Rheumatoid arthritis (RA), a systemic inflammatory disease with complex genetic aetiology, associates with excess cardiovascular morbidity and mortality. Dyslipidaemia, a major cardiovascular risk factor has been reported to predate the onset of RA, thus suggesting a potential genetic link between the two conditions. The authors assessed whether RA susceptibility genes associate with the presence of dyslipidaemia in RA patients. Methods 400 well-characterised RA patients were included in this cross-sectional study. Fasting lipid profile (total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides, apolipoproteins (ApoA and ApoB) and lipoprotein (a)) and four RA susceptibility genes (PTPN22, TRAF1/C5, STAT4 and human leucocyte antigen shared epitope (HLA-SE)) were assessed and associations were sought in both univariate and multivariate analyses. Results Following adjustment for age, sex and erythrocyte sedimentation rate, the G allele of TRAF1/C5 associated with lower total cholesterol (p=0.010), LDL (p=0.022) and ApoB (p=0.014); one or more copies of the shared epitope associated with lower ApoA (p=0.035) and higher ApoB:ApoA ratio (p=0.047); while STAT4 TT homozygotes had higher lipoprotein (a) (p=0.004). Conclusions RA susceptibility genes (TRAF1/C5, STAT4 and HLA-DRB1-SE) may be involved in the regulation of lipid metabolism in RA patients, thus contributing to cardiovascular disease (CVD) risk and adverse outcome. If these findings are replicated, such genotyping could be used to identify and target for prevention those RA patients most at risk of CVD. It will also be interesting to study the association of these genes with lipid levels in the general population and identify mechanisms to explain the link.

Cigarette smoking significantly increases basal metabolic rate in patients with rheumatoid arthritis

Objective: Basal metabolic rate (BMR) is the most important indicator of human metabolism and its abnormalities have been linked to undesirable health outcomes. Cigarette smoking associates with increased BMR in healthy individuals; it is also related with worse disease outcomes in patients with rheumatoid arthritis (RA), in whom BMR is high due to hypercatabolism caused by systemic inflammation. We aimed to investigate whether smokers with RA demonstrated higher BMR levels than their non-smoking counterparts. Methods: A total of 53 patients with RA (36 female, 17 male, 20 current smokers) were assessed for: BMR (indirect calorimetry), anthropometrical data, fat-free mass (bioelectrical impedance), physical function (health assessment questionnaire; HAQ) and disease activity (disease activity score DAS28 and C reactive protein). Results: RA smokers and non-smokers were not significantly different for age, height, weight, body mass index and fat-free mass. Compared to non-smokers, smokers with RA demonstrated significantly higher BMR (mean (SD) 1513.9 (263.3) vs 1718.1 (209.2) kcal/day; p<0.001) and worse HAQ (1.0 (0.8) vs 1.7 (0.8); p = 0.01). The BMR difference was significantly predicted by the interaction smoking/gender (p = 0.04). BMR was incrementally higher in light, moderate and heavy smokers (p = 0.018), and correlated with the daily number of cigarettes smoked (r = 0.68, p = 0.04). Conclusion: Current cigarette smoking further increases BMR in patients with RA and has a negative impact on patients’ self-reported functional status. Education regarding smoking cessation is needed for the RA population.