Effects of 12 months of treatment with disease-modifying anti-rheumatic drugs on low and high density lipoprotein subclass distribution in patients with early rheumatoid arthritis: a pilot study.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have increased cardiovascular risk. The aim of the present study was the assessment of low density lipoprotein (LDL) and high density lipoprotein (HDL) subclass distribution in patients with early RA (ERA, n = 30) compared with age- and sex-matched healthy subjects (n = 30), as well the effect of treatment for 12 months with the disease-modifying anti-rheumatic drugs (DMARDs) methotrexate and prednisone in this distribution. METHOD: LDL and HDL subclass distribution was determined using a polyacrylamide gel-tube electrophoresis method. RESULTS: ERA patients exhibited increased levels of inflammatory markers and high disease activity score. ERA patients had higher serum levels of total cholesterol (TC), LDL cholesterol (LDL-C), and triglycerides (TG) whereas their serum HDL cholesterol (HDL-C) levels were significantly lower compared with controls. ERA patients exhibited significantly higher plasma levels of small dense LDL-C (sdLDL-C), leading to a significantly decreased mean LDL diameter. ERA patients had significantly decreased small HDL particles (HDL-3) concentration whereas serum levels of large HDL particles (HDL-2) did not differ compared with controls. Treatment with DMARDs resulted in a significant decrease in inflammatory markers and disease activity, along with a significant increase in HDL-C serum levels. The concentration of sdLDL-C did not change significantly during treatment. We observed a significant increase in the levels of large HDL-2 whereas the concentration of small HDL-3 did not significantly change. CONCLUSIONS: Patients with ERA have increased sdLDL-C levels and decreased HDL-C levels because of decreased concentration of the small HDL-3 subclass. The administration of DMARDs induced a significant increase in HDL-C levels, which was attributed to the increase in large HDL-2 serum concentration.

Increased plasma visfatin concentration is a marker of an atherogenic metabolic profile.

BACKGROUND AND AIMS: Visfatin is associated with atherosclerosis-related diseases. We assessed in non-diabetic individuals the association of plasma visfatin levels with cardiovascular disease (CVD) risk and the atherosclerosis-related metabolic variables. METHODS AND RESULTS: When study population (n = 179, age 49 ± 11 years) was divided according to visfatin tertiles, the 10-year CVD Framingham risk scores were significantly increased in the top visfatin tertile. We observed a positive association between visfatin tertiles with waist circumference and blood pressure, as well as with total cholesterol and triglyceride levels, but not with apolipoprotein C-III, fibrinogen or pre-beta1 high density lipoprotein (HDL). The percentage of large HDL subclasses was significantly lower and the percentage of small HDL subclasses over the HDL-C concentration was significantly higher in the top visfatin tertile compared with the other tertiles. The atherogenic small dense low density lipoprotein subclasses (sdLDL-C) were significantly increased in the top visfatin tertile compared with the lower tertiles. High sensitivity C-reactive protein (hsCRP) concentration was significantly increased in the top visfatin tertile compared with the lower tertiles. Although age and sex distribution did not differ between visfatin tertiles, the simultaneous adjustment for these parameters attenuated the significance of the differences observed in sdLDL-C and hsCRP levels. Similarly, after adjustment for hsCRP or waist circumference, only triglycerides and blood pressure levels, as well as the distribution of HDL subclasses, remained significantly different between visfatin tertiles. CONCLUSIONS: Our results support a role for visfatin in the detection of subjects with many metabolic abnormalities, which result in increased CVD risk.

Obesity, adipose tissue and rheumatoid arthritis: coincidence or more complex relationship?

In the last two decades we have witnessed a boost in scientific interest and knowledge of adipose tissue biology to such an extent that it was promoted to an active endocrine organ. Adipose tissue is not just related to body weight and appetite regulation. It is also implicated in obesity, a low-grade inflammatory state, as well as inflammatory conditions including rheumatoid arthritis (RA), an autoimmune disease where anti- and pro-inflammatory cytokine balance is critical. All major adipose derived products, simply termed adipokines, like leptin, adiponectin, visfatin and resistin, reportedly participate in inflammation and immunity. In this review we explore in depth the relationship between adipose tissue and RA, with focus on possible mechanisms, beyond observations about circulating or synovial levels, and special reference to future perspectives and clinical implications.

Leptin and adiponectin levels in patients with ankylosing spondylitis. The effect of infliximab treatment.

BACKGROUND: Adipose tissue-derived leptin and adiponectin control hunger, energy expenditure, insulin sensitivity, endothelial function, reproduction and immunity and are thought to play a role in autoimmune diseases. However, their role in ankylosing spondylitis (AS) is not clearly defined. Tumour necrosis factor ΤNF-α is a potential modulator of adipocytokines. The effect of longterm anti-TNF-α treatment on plasma levels of leptin and adiponectin has not been assessed so far. OBJECTIVES: To assess the effect of a 6-month anti-TNF-α treatment on serum leptin and adiponectin levels in AS patients. METHODS: Thirty men with AS were included in the study. Thirty age- and weight-matched men served as controls. Clinical and biochemical parameters were assessed and serum levels of leptin and adiponectin were measured with enzyme immunoassay methods prior to and after the 6-month treatment with infliximab. RESULTS: Mean age and disease duration of AS patients were 40.6±13.7 and 13.4±8.4 years, respectively. At baseline, AS patients exhibited significantly higher adiponectin (15.4±8.3 vs. 8.6±4.2 µg/ml, p<0.05), but no difference in leptin levels (7.2±2.9 vs. 8.9±6.4 ng/ml, p=NS). Adipocytokines did not correlate with any disease parameter. Body weight of the patients did not change significantly over the 6-month period. Serum levels of leptin and adiponectin did not change significantly after the 6-month treatment. CONCLUSIONS: Adiponectin levels were significantly higher in AS patients compared with controls. Infliximab treatment did not change serum levels of leptin and adiponectin suggesting that the anti-TNF-α treatment may not modulate significantly their levels.

Combination of fenofibrate with non-statin drug regimens.

OBJECTIVE: We present the available data on the effects of combined therapy of fenofibrate with drugs affecting lipid metabolism other than statins. METHODS: We consider studies evaluating the effects of combined therapy of fenofibrate with bile acid sequestrants (BAS), ezetimibe, niacin, n-3 fatty acids, plant sterols, orlistat, rimonabant, metformin and glitazones. RESULTS: Combination of BAS (especially colesevelam) with fenofibrate had additional effects on metabolic parameters in patients with mixed hyperlipidemia. Combination of ezetimibe with fenofibrate may be a useful approach to improve the overall lipid profile of patients with mixed hyperlipidemia. There is a further reduction in triglyceride levels when n-3 fatty acids are administered with fenofibrate in patients with severe hypertriglyceridemia. Combined fenofibrate and orlistat treatment further improves metabolic parameters in overweight/obese patients with metabolic syndrome. The fenofibrate/thiazolidinedione combination is an alternative for diabetic patients intolerant to statins, though differences exist between pioglitazone and rosiglitazone. CONCLUSIONS: For patients who cannot tolerate statins there are useful combinations of fenofibrate with other drugs affecting lipid metabolism. These combinations improve several metabolic parameters, but more trials should be carried out to reach more robust conclusions about their effects on cardiovascular events.

The effects of ezetimibe and orlistat, alone or in combination, on high-density lipoprotein (HDL) subclasses and HDL-associated enzyme activities in overweight and obese patients with hyperlipidaemia.

BACKGROUND: High-density lipoprotein (HDL) includes discrete subfractions. HDL exhibits anti-atherogenic properties, which have been partly linked to the activity of HDL-associated enzymes, such as the lipoprotein associated phospholipase A(2) (HDL-LpPLA(2)) and paraoxonase-1 (PON1). OBJECTIVE: We assessed in an open-label randomised study the effect of orlistat and ezetimibe, alone or in combination, on plasma HDL subclasses and HDL-associated enzyme activities in overweight and obese subjects (body mass index > 28 kg/m(2)) with hypercholesterolemia [total cholesterol > 200 mg/100 ml (5.2 mmol/l)]. METHODS: Eighty-six people were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg, three times daily (O group), ezetimibe 10 mg/day (E group) or both (OE group) for 6 months. HDL subfractions were determined using a polyacrylamide gel-tube electrophoresis method. RESULTS: Levels of HDL cholesterol (HDL-C) and apolipoprotein AI did not change significantly in any group. In group O the cholesterol concentration of HDL-2 subclass increased significantly, while the cholesterol of HDL-3 subclass decreased significantly. In groups E and OE HDL-2 subclass did not significantly change, while the cholesterol concentration of HDL-3 subclass decreased significantly. We observed a non-significant decrease in the HDL-LpPLA(2) and PON1 activity in all groups. However, the ratios of both enzyme activities to low-density lipoprotein cholesterol (LDL-C) levels (an index of atherogenicity) significantly increased in all groups. CONCLUSION: Although HDL-C levels did not change after treatment with orlistat and ezetimibe, alone or in combination, there were alterations of the HDL-2 and HDL-3 subclasses. The activity of HDL-LpPLA(2) and PON1 per mg LDL-C increased significantly in all groups.

Excess body weight and risk of first-ever acute ischaemic non-embolic stroke in elderly subjects.

In a population-based case-control study we assessed the association between obesity and acute ischaemic/non-embolic stroke. A total of 163 patients aged older than 70 years (88 men and 75 women) admitted due to a first-ever-in-a-lifetime acute ischaemic/non-embolic stroke and 166 volunteers (87 men and 79 women) without a history of cardiovascular disease were included. The association of stroke with body mass index (BMI) or waist circumference (WC) was determined by multivariate logistic regression modelling after adjusting for potential confounding factors. Overweight and obesity were more prevalent amongst stroke patients compared to controls. Subjects with a BMI > or = 30 kg/m2 had 2.5-times higher odds to suffer an acute ischaemic/non-embolic stroke compared to subjects within the lowest BMI category of 18.5-20.9 kg/m2. Analysis of interaction showed that in the presence of overweight and/or obesity (classified as a BMI > or = 25 kg/m2 and/or a WC > 102 cm in men and > 88 cm in women) the inverse relationship between HDL cholesterol and ischaemic/non-embolic stroke was negated. Excess weight is associated with an increased risk of acute ischaemic/non-embolic stroke in elderly individuals independently of concurrent metabolic derangements. Moreover, in the presence of obesity, HDL cholesterol loses its protective effect against ischaemic stroke.

Increased plasma levels of visfatin/pre-B cell colony-enhancing factor in obese and overweight patients with metabolic syndrome.

BACKGROUND: Visfatin [pre-B cell colony- enhancing factor (PBEF)] is a cytokine highly expressed in visceral fat that exhibits insulin-mimetic properties. However, its role in insulin-resistant states, such as in metabolic syndrome (MetS), remains largely unknown. OBJECTIVE: To investigate the possible differences of plasma visfatin levels between obese and overweight subjects with and without MetS. DESIGN AND PATIENTS: Plasma visfatin concentrations were measured with enzyme-linked immunosorbent assay (ELISA) in 28 overweight and obese [body mass index (BMI)>28 kg/m2] subjects with Mets and 28 age- and sex-matched overweight and obese (BMI>28 kg/m2) individuals without MetS (control group). RESULTS: Patients with MetS exhibited significantly elevated waist circumference (WCR ) values, higher blood pressure readings, higher fasting glucose and triglyceride concentrations as well as lower levels of HDL cholesterol (HDL-C) compared with controls. Total and LDL cholesterol (LDL-C) concentrations did not differ significantly between the two groups. Plasma visfatin concentrations were significantly higher in subjects with MetS compared with controls [27 (16- 65) ng/ml vs 19 (10-47) ng/ml, p<0.05]. The same results were observed even after adjustment for age, sex and BMI. Plasma visfatin levels were positively correlated with age (r=0.32, p<0.05), WCR (r=0.31, p<0.05), triglyceride (r=0.59, p<0.01) and glucose (r=0.33, p<0.05) levels and were negatively correlated with HDL-C levels (r=-0.38, p<0.05). Multiple linear regression analysis revealed similar results. CONCLUSION: Plasma visfatin levels are increased in overweight and obese subjects with MetS compared with those individuals who do not fulfil the criteria for the diagnosis of MetS.