Patrick H. Dessein

Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study

OBJECTIVES Insulin resistance (IR) has been increasingly implicated in the pathogenesis of gout. The lipoprotein abnormalities described in hyperuricaemic subjects are similar to those associated with IR, and insulin influences renal urate excretion. In this study it was investigated whether dietary measures, reported to be beneficial in IR, have serum uric acid (SU) and lipid lowering effects in gout. METHODS Thirteen non-diabetic men (median age 50, range 38–62) were enrolled. Each patient had had at least two gouty attacks during the four months before enrolment. Dietary recommendations consisted of calorie restriction to 6690 kJ (1600 kcal) a day with 40% derived from carbohydrate, 30% from protein, and 30% from fat; replacement of refined carbohydrates with complex ones and saturated fats with mono- and polyunsaturated ones. At onset and after 16 weeks, fasting blood samples were taken for determination of SU, serum cholesterol (C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Results were expressed as median (SD). RESULTS At onset, the body mass index (BMI) was 30.5 (8.1) kg/m2. Dietary measures resulted in weight loss of 7.7 (5.4) kg (p=0.002) and a decrease in the frequency of monthly attacks from 2.1 (0.8) to 0.6 (0.7) (p=0.002). The SU decreased from 0.57 (0.10) to 0.47 (0.09) mmol/l (p=0.001) and normalised in 7 (58%) of the 12 patients with an initially raised level. Serum cholesterol decreased from 6.0 (1.7) to 4.7 (0.9) mmol/l (p=0.002), LDL-C from 3.5 (1.2) to 2.7 (0.8) mmol/l (p=0.004), TGs from 4.7 (4.2) to 1.9 (1.0) mmol/l (p=0.001), and C:HDL-C ratios from 6.7 (1.7) to 5.2 (1.0) (p=0.002). HDL-C levels increased insignificantly. High baseline SU, frequency of attacks, total cholesterol, LDL-C and TG levels, and total C:HDL-C ratios correlated with higher decreases in the respective variables upon dietary intervention (p<0.05). CONCLUSION The results suggest that weight reduction associated with a change in proportional macronutrient intake, as recently recommended in IR, is beneficial, reducing the SU levels and dyslipidaemia in gout. Current dietary recommendations for gout may need re-evaluation.

Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis

Cardiovascular event rates are markedly increased in rheumatoid arthritis (RA), and RA atherogenesis remains poorly understood. The relative contributions of traditional and nontraditional risk factors to cardiovascular disease in RA await elucidation. The present study comprises three components. First, we compared biomarkers of endothelial dysfunction (vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule [ICAM]-1 and endothelial leucocyte adhesion molecule [ELAM]-1) in 74 RA patients and 80 healthy control individuals before and after controlling for traditional and nontraditional cardiovascular risk factors, including high-sensitivity C-reactive protein (hs-CRP), IL-1, IL-6 and tumor necrosis factor-α. Second, we investigated the potential role of an extensive range of patient characteristics in endothelial dysfunction in the 74 RA patients. Finally, we assessed associations between biomarkers of endothelial dysfunction and ultrasonographically determined common carotid artery intima–media thickness and plaque in RA. The three biomarkers of endothelial dysfunction, as well as hs-CRP, IL-1, IL-6 and tumor necrosis factor-α, were higher in patients than in control individuals (P < 0.0001). Patients were also older, exercised less and had a greater waist circumference, blood pressure and triglyceride levels (P ≤ 0.04). Five patients had diabetes. Differences in endothelial function were no longer significant between patients and controls (P = 0.08) only after both traditional and nontraditional cardiovascular risk factors were controlled for. In the 74 RA patients, IL-6 predicted levels of all three biomarkers (P ≤ 0.03), and rheumatoid factor titres and low glomerular filtration rate (GFR) both predicted levels of VCAM-1 and ICAM-1, independent of traditional cardiovascular risk factors (P ≤ 0.02). VCAM-1 was associated with common carotid artery intima–media thickness (P = 0.02) and plaque (P = 0.04) in RA. Patients had impaired endothelial function, less favourable traditional cardiovascular risk factor profiles, and higher circulating concentrations of hs-CRP and cytokines compared with healthy control individuals. Both traditional and nontraditional cardiovascular risk factors contributed to the differences in endothelial function between RA patients and healthy control individuals. IL-6, rheumatoid factor titres and low GFR were independently predictive of endothelial dysfunction in RA. Disease-modifying agents that effectively suppress both cytokine and rheumatoid factor production, and interventions aimed at preserving renal function may attenuate cardiovascular risk in RA.

Cardiovascular risk in rheumatoid arthritis versus osteoarthritis: acute phase response related decreased insulin sensitivity and high-density lipoprotein cholesterol as well as clustering of metabolic syndrome features in rheumatoid arthritis

Rheumatoid arthritis (RA) patients experience a markedly increased frequency of cardiovascular disease. We evaluated cardiovascular risk profiles in 79 RA patients and in 39 age-matched and sex-matched osteoarthritis (OA) patients. Laboratory tests comprised ultrasensitive C-reactive protein (CRP) and fasting lipids. Insulin sensitivity (IS) was determined by the Quantitative Insulin Sensitivity Check Index (QUICKI) in all OA patients and in 39 of the RA patients. Ten RA patients were on glucocorticoids. RA patients exercised more frequently than OA patients (χ2 = 3.9, P < 0.05). Nine RA patients and one OA patient had diabetes (χ2 = 4.5, P < 0.05). The median CRP, the mean QUICKI and the mean high-density lipoprotein (HDL) cholesterol were 9 mg/l (range, 0.5–395 mg/l), 0.344 (95% confidence interval [CI], 0.332–0.355) and 1.40 mmol/l (95% CI, 1.30–1.49 mmol/l) in RA patients, respectively, as compared with 2.7 mg/l (range, 0.3–15.9 mg/l), 0.369 (95% CI, 0.356–0.383) and 1.68 mmol/l (95% CI, 1.50–1.85 mmol/l) in OA patients. Each of these differences was significant (P < 0.05). After controlling for the CRP, the QUICKI was similar in RA and OA patients (P = 0.07), while the differences in HDL cholesterol were attenuated but still significant (P = 0.03). The CRP correlated with IS, while IS was associated with high HDL cholesterol and low triglycerides in RA patients and not in OA patients. A high CRP (≥ 8 mg/l) was associated with hypertension (χ2 = 7.4, P < 0.05) in RA patients. RA glucocorticoid and nonglucocorticoid users did not differ in IS and lipids (P > 0.05). Excess cardiovascular risk in RA patients as compared with OA patients includes the presence of decreased IS and HDL cholesterol in RA patients. The latter is only partially attributable to the acute phase response. The CRP, IS, HDL cholesterol, triglycerides and hypertension are inter-related in RA patients, whereas none of these relationships were found in OA patients.

Autonomic dysfunction in systemic sclerosis: Sympathetic overactivity and instability

PURPOSE This study was designed to assess the prevalence and nature of autonomic dysfunction (AD) in 34 patients with systemic sclerosis (SSc). PATIENTS AND METHODS Patients were questioned for current symptoms possibly related to AD. Five noninvasive cardiovascular autonomic function tests and sequential plasma catecholamine estimations at rest, during standing, and during sustained handgrip were performed. Seven patients with manometrically documented esophageal involvement and high resting plasma adrenaline levels were treated with clonidine (75 to 375 micrograms/d). One month later, resting plasma catecholamine estimations and esophageal motility studies were repeated. RESULTS Autonomic testing revealed AD in each patient, while symptoms were experienced by 33 of them. Findings on two of the three heart rate tests and both blood pressure tests were significantly impaired as compared with those in 25 matched control subjects. Mean resting plasma adrenaline levels were 18 times higher than in 10 matched controls (p less than 0.001). Plasma catecholamine (adrenaline, noradrenaline, and dopamine) concentrations and mean arterial blood pressures fluctuated inappropriately during standing and sustained handgrip in 28 (82%) of the patients. The presence of headaches correlated significantly with sympathetic overactivity and instability (p less than 0.05). Resting plasma adrenaline concentrations correlated inversely with disease duration (p less than 0.05). Significant suppression of sympathetic overactivity and increases in resting lower esophageal sphincter pressures were observed in the seven patients treated with clonidine. CONCLUSION AD is extremely common in SSc. It is characterized by parasympathetic impairment and marked sympathetic overactivity, particularly in early disease. The potential role of AD in the pathogenesis of SSc deserves further study.

Nurse-recorded auscultatory blood pressure at a single visit predicts target organ changes as well as ambulatory blood pressure

Aim To determine whether high-quality nurse-recorded auscultatory blood pressure (BP) values obtained at a single visit predict cardiovascular target organ changes as closely as ambulatory BP measurements. Methods In a randomly selected population sample (n = 458, 21% receiving antihypertensive treatment; approximately 40% hypertensive), we compared high-quality single visit nurse-recorded auscultatory BP values to same-day 24-h ambulatory BP in their ability to predict multiple target organ changes [left ventricular mass index (LVMI), left ventricle (LV) mean wall thickness (MWT), early-to-late transmitral velocity ratios (E/A), (echocardiography); log of urinary albumin-to-creatinine ratios (log ACR) (24-h urine samples); large artery dysfunction [carotid-femoral pulse wave velocity (PWV) and central augmentation index (Alc) (applanation tonometry)]. Results Nurse-recorded systolic BP (SBP) measurements obtained at a single visit were as closely associated with LVMI (r = 0.44), LV MWT (r = 0.44), E/A (r = −0.55), log ACR (r = 0.20), PWV (r = 0.62) and AIc (r = 0.41) (P < 0.0001 for all relations) as was 24-h SBP (LVMI; r = 0.33, LV MWT; r = 0.37, E/A; r = −0.35, log ACR; r = 0.24, PWV; r = 0.41, and AIc; r = 0.18, P < 0.001 for all relations) and either day or night SBP. On multivariate regression analysis with both nurse-recorded SBP and 24-h SBP in the same model, nurse-recorded SBP was independently associated with LVMI (P = 0.006), LV MWT (P = 0.03), E/A (P < 0.02), PWV (P < 0.0001) and AIc (P = 0.0002), and 24-h SBP was independently and positively associated with log ACR (P < 0.005), and PWV (P = 0.01). Conclusion One or more, high-quality single visit nurse-recorded auscultatory BP measurements may be equally as effective as ambulatory BP in predicting target organ damage in a population sample of African ancestry.

Subclinical Hypothyroidism is Associated with Insulin Resistance in Rheumatoid Arthritis

We investigated the prevalence of subclinical hypothyroidism and its association with insulin resistance and other cardiovascular (CV) risk factors in rheumatoid arthritis (RA). We recorded thyroid function tests, insulin resistance markers comprising the Homeostasis Model Assessment for insulin resistance (HOMA-IR), the Quantitative Insulin Sensitivity Check Index (QUICKI) and triglycerides/high-density lipoprotein (HDL) cholesterol ratios, and other CV risk factors in 126 patients with RA. Fifteen (12%) were taking thyroxine for hypothyroidism and 14 (11%) had subclinical hypothyroidism (thyrotropin > 4 mU/L and normal free thyroxine levels). Compared to the 97 euthyroid patients, the QUICKI was lower and the HOMA-IR higher in treated (p = 0.031 for both) and subclinical (p = 0.004 for both) hypothyroid cases while the triglycerides/HDL cholesterol ratios were higher in subclinical (p = 0.039) but not in treated hypothyroid (p = 0.365) cases. Treated hypothyroid patients were more often hypertensive (n = 11 [75%]) than euthyroid patients (n = 36 [37%]) (p = 0.008). No other differences in characteristics were found among the three groups. After controlling for potentially confounding variables, subclinical hypothyroidism remained independently predictive of the HOMA-IR and QUICKI (p <or= 0.06) while treated hypothyroidism did not (p = 0.2). Subclinical hypothyroidism was commonly encountered and associated with insulin resistance and its related dyslipidemia in RA. Evaluation of thyroid function should be considered in future studies aimed at delineating CV risk in RA.

Is prehypertension an independent predictor of target organ changes in young-to-middle-aged persons of African descent?

Aim We sought to determine whether prehypertension (BP = 120–139/80–89 mmHg) is associated with target organ changes independent of confounders. Methods In 771 participants from a population sample of African ancestry, approximately 46% of whom had hypertension, and approximately 30% prehypertension, organ damage was assessed from echocardiography (left ventricular mass indexed to height2.7, the mean of posterior and septal wall thickness and early-to-late transmitral velocity), 24-h urine samples (urinary albumin-to-creatinine ratio), serum creatinine concentrations, and carotid–femoral pulse wave velocity. Ambulatory blood pressure values that met with prespecified quality control criteria were available in 539 participants. Results A greater proportion of hypertensives (P < 0.0001) but not prehypertensives had elevated 24-h blood pressure values as compared with participants with optimal blood pressure values. Before adjustment for confounders, hypertension was associated with all target organ changes (P < 0.0001), and after adjustment, an independent association was noted between hypertension and all target organ changes (P < 0.05–0.005) except albumin-to-creatinine ratio or serum creatinine concentrations. Before adjustment, prehypertension was associated with left ventricular mass indexed to height2.7, mean wall thickness, pulse wave velocity, and early-to-late transmitral velocity (P < 0.05–0.001), but not with other target organ changes. After adjustment, however, prehypertension was not independently associated with target organ changes. Other factors independently associated with target organ changes were age (all target organs), waist circumference (left ventricular mass indexed to height2.7 and early-to-late transmitral velocity) and diabetes mellitus (albumin-to-creatinine ratio and pulse wave velocity). Interactions between prehypertension and any of the alternative risk factors were not independent predictors of target organ changes. Conclusion Although associated with it, prehypertension is not an independent predictor of organ damage in young-to-middle-aged persons of African ancestry.

Cardiovascular magnetic resonance in rheumatology: Current status and recommendations for use.

Targeted therapies in connective tissue diseases (CTDs) have led to improvements of disease-associated outcomes, but life expectancy remains lower compared to general population due to emerging co-morbidities, particularly due to excess cardiovascular risk. Cardiovascular magnetic resonance (CMR) is a noninvasive imaging technique which can provide detailed information about multiple cardiovascular pathologies without using ionizing radiation. CMR is considered the reference standard for quantitative evaluation of left and right ventricular volumes, mass and function, cardiac tissue characterization and assessment of thoracic vessels; it may also be used for the quantitative assessment of myocardial blood flow with high spatial resolution and for the evaluation of the proximal coronary arteries. These applications are of particular interest in CTDs, because of the potential of serious and variable involvement of the cardiovascular system during their course. The International Consensus Group on CMR in Rheumatology was formed in January 2012 aiming to achieve consensus among CMR and rheumatology experts in developing initial recommendations on the current state-of-the-art use of CMR in CTDs. The present report outlines the recommendations of the participating CMR and rheumatology experts with regards to: (a) indications for use of CMR in rheumatoid arthritis, the spondyloarthropathies, systemic lupus erythematosus, vasculitis of small, medium and large vessels, myositis, sarcoidosis (SRC), and scleroderma (SSc); (b) CMR protocols, terminology for reporting CMR and diagnostic CMR criteria for assessment and quantification of cardiovascular involvement in CTDs; and (c) a research agenda for the further development of this evolving field.

Could cardiovascular disease risk stratification and management in rheumatoid arthritis be enhanced

The markedly enhanced risk of atherosclerotic cardiovascular disease (CVD) in rheumatoid arthritis (RA) is well documented.1 ,2 This prompted a European League Against Rheumatism (EULAR) task force to make a commendable effort in producing recommendations for cardiovascular risk management in patients with inflammatory arthritis.3 These included the application of the systematic coronary risk evaluation score (SCORE), a multiple major traditional risk factor assessment equation. In addition, the EULAR task force recommended applying a multiplier of 1.5 in patients with RA that met 2 of 3 criteria consisting of (1) a disease duration >10 years, (2) rheumatoid factor or anticyclic citrullinated peptide positivity and (3) the presence of extra-articular manifestation, thereby creating the modified (m) SCORE. Risk factor assessment algorithms, including the SCORE and the Framingham risk equation, are recommended worldwide as part of CVD risk management in the population at large.4 ,5 These equations allow for stratifying subjects into low, intermediate, high and very high risk groups. With regard to CVD risk management, lifestyle factors should be addressed in all individuals. The use of cardiovascular drugs, particularly antihypertensive and lipid-lowering agents should be considered in those at high or very high risk as these interventions markedly reduce CVD event rates in such persons. Patients with established CVD, diabetes and chronic kidney disease are at high or very high risk and hence, risk factor equation application is not indicated. Nonetheless, approximately a third of CVD events are not attributable to major CVD risk factors.6 Congruent with this, although multiple risk factor equations are useful in determining the overall CVD risk among different populations, they often underestimate the actual risk in individual subjects. This is particularly evident in those who are at moderate risk according to major risk factor assessment equations.4 ,5 Consequently, based on …

Circulating Concentrations of the Novel Adipokine Chemerin Are Associated with Cardiovascular Disease Risk in Rheumatoid Arthritis

Objective. Depending on physiological context, the adipokine chemerin can reduce or enhance cardiovascular risk. We investigated whether chemerin concentrations represent cardiovascular disease risk in rheumatoid arthritis (RA). Methods. We assessed ELISA-determined chemerin concentrations and those of 4 early endothelial activation molecules as well as angiopoietin 2, which mediates angiogenesis and thereby contributes to advanced atherosclerosis, the common carotid artery intima-media thickness (cIMT), and carotid artery plaque by ultrasound in 236 patients (114 black and 122 white) with RA. Relationships were identified in potential confounder and mediator-adjusted mixed regression models. Results. Mean (SD) chemerin and median (interquartile range) angiopoietin 2 concentrations were 114 (35) ng/ml and 2560 (2044–3341) pg/ml, respectively; the mean (SD) cIMT was 0.708 (0.110) mm, and 40.3% of patients had plaque. Chemerin concentrations were not related to those of early endothelial activation molecules, but associated with those of angiopoietin 2 [β SE = 0.002 (0.0004), p < 0.0001] and plaque [OR 1.006 (95% CI 1.00–1.013), p = 0.05] in all patients. The presence of major conventional cardiovascular risk factors, generalized and abdominal obesity, and RA severity markers modified the independent chemerin-cardiovascular risk relations (interaction p < 0.05). Consequently, chemerin concentrations were associated with cIMT in those with but not without overweight or generalized obesity and abdominal obesity [β SE = 0.001 (0.0003), p = 0.005 and 0.001 (0.0001), p = 0.001 vs −0.001 (0.0004), p = 0.2 and −0.0002 (0.0004), p = 0.6, respectively], and with plaque in those without but not with generalized obesity [OR 1.008 (95% CI) 1.000–1.016, p = 0.03 vs 1.003 (0.990–1.017), p = 0.6, respectively]. The β (SE) for the chemerin-intima-media thickness relations in patients with overweight or generalized obesity and abdominal obesity were larger than in those without these characteristics (p < 0.0001 and = 0.04, respectively). Conclusion. Chemerin is associated with endothelial activation and atherosclerosis in RA. Adiposity influences the chemerin-atherosclerotic phenotype relations in RA.