The effect of anti-TNF treatment on body composition and insulin resistance in patients with rheumatoid arthritis.

Given the link between systemic inflammation, body composition and insulin resistance (IR), anti-inflammatory therapy may improve IR and body composition in inflammatory joint diseases. This study assesses the IR and beta cell function in rheumatoid arthritis (RA) patients with active disease compared to osteoarthritis (OA) patients and investigates the effect of anti-TNF treatment on IR, beta cell function and body composition in RA. 28 Consecutive RA patients starting anti-TNF treatment (adalimumab), and 28 age, and sex-matched patients with OA were followed for 6 months. Exclusion criteria were use of statins, corticosteroids, and cardiovascular or endocrine co-morbidity. Pancreatic beta cell function and IR, using the homeostasis model assessment (HOMA2), and body composition, using dual-energy X-ray absorptiometry (DXA) were measured at baseline and 6 months. At baseline, IR [1.5 (1.1-1.8) vs. 0.7 (0.6-0.9), 100/%S] and beta cell function (133% vs. 102%) were significantly (p < 0.05) higher in RA patients with active disease as compared to OA patients. After 6 months of anti-TNF treatment, IR [1.5 (1.1-1.8) to 1.4 (1.1-1.7), p = 0.17] slightly improved and beta cell function [133% (115-151) to 118% (109-130), p <0.05] significantly improved. Improvement in IR and beta cell function was most pronounced in RA patients with highest decrease in CRP and ESR. Our observations indicate that IR and increased beta cell function are more common in RA patients with active disease. Anti-TNF reduced IR and beta cell function especially in RA patients with highest decrease in systemic inflammation and this effect was not explained by changes in body composition.

Circulating microparticles remain associated with complement activation despite intensive anti-inflammatory therapy in early rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterised by synovitis and joint destruction. The pathogenesis of RA is not clear, but is considered to be an immune-mediated inflammatory disorder, in which the complement system plays an important role. Although cell-derived microparticles (MPs) have been associated with inflammation and complement activation, it is unknown whether MPs are either cause or consequence. Therefore, we investigated whether circulating MPs differ between patients with very early as yet untreated arthritis and healthy controls, and whether intensive anti-inflammatory treatment of such patients affects circulating MPs. METHODS: Patients with RA (n=24) and controls (n=15) were included. Nine patients with RA were re-evaluated after 8 weeks of intensive treatment with a combination of drugs ('COmBination therapy in Rheumatoid Arthritis' (COBRA) scheme). Disease activity was measured by erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and Disease Activity Score for 28 joints (DAS28). Flow cytometry was used to study MPs and exposure of complement activator molecules and complement components. RESULTS: At baseline, concentrations of MPs exposing C1q, CRP or serum amyloid-P (SAP)were all significantly elevated in patients with early RA compared to controls (p=0.003, p=0.002 and p=0.003, respectively). Upon treatment, DAS28 score, ESR and CRP levels significantly decreased (p=0.008, p=0.008 and p=0.012), but the concentrations of circulating MPs and MPs exposing complement components or activator molecules were unaffected. CONCLUSION: Circulating MPs exposing complement components or activator molecules are elevated in early RA. Since a strong anti-inflammatory therapy suppressed inflammation in patients with early RA but not levels of circulating MPs, it is unlikely that inflammation is the main underlying cause of MP release in these patients.

The metabolic syndrome is amplified in hypothyroid rheumatoid arthritis patients: a cross-sectional study.

OBJECTIVES: Rheumatoid arthritis (RA) patients are at increased risk of cardiovascular disease (CVD), which is even more pronounced in hypothyroid RA patients. An unfavourable cardiovascular risk profile conferred by a higher prevalence of the metabolic syndrome (MetS) and a higher Framingham risk score might explain this amplified cardiovascular morbidity. This study compared first, MetS (features) and second, the Framingham 10-year CVD risk in RA patients with hypothyroidism compared with euthyroid RA patients. METHODS: RA patients participating in the CARRE investigation were divided into two groups: hypothyroid and euthyroid RA patients. MetS according to the National Cholesterol Education Program Third Adult Treatment Panel criteria and the Framingham risk score was compared between hypothyroid and non-hypothyroid CVD event-free RA patients. RESULTS: In total, 257 RA patients were included: 236 with RA (91.8%) and 21 with hypothyroid RA (8.2%), respectively. The prevalence of the MetS was significantly higher in hypothyroid RA patients (43%) compared with RA patients (20%). Moreover, female hypothyroid RA patients had a higher Framingham risk score compared with euthyroid RA patients. With RA patients as the reference category, the age and gender-adjusted prevalence odds ratio for the MetS was 3.5 (95% CI 1.3 to 9.1) in hypothyroid RA. CONCLUSIONS: Hypothyroid RA patients, particularly female patients, have a more unfavourable cardiovascular risk profile, reflected by an increased prevalence of the MetS and higher Framingham score, than euthyroid RA patients, suggesting a greater need for cardiovascular risk management in these patients to prevent future CVD events.

Improvement of lipid profile is accompanied by atheroprotective alterations in high-density lipoprotein composition upon tumor necrosis factor blockade: a prospective cohort study in ankylosing spondylitis.

OBJECTIVE: Cardiovascular mortality is increased in ankylosing spondylitis (AS), and inflammation plays an important role. Inflammation deteriorates the lipid profile and alters high-density lipoprotein cholesterol (HDL-c) composition, reflected by increased concentrations of serum amyloid A (SAA) within the particle. Anti-tumor necrosis factor (anti-TNF) treatment may improve these parameters. We therefore undertook the present study to investigate the effects of etanercept on lipid profile and HDL composition in AS. METHODS: In 92 AS patients, lipid levels and their association with the inflammation markers C-reactive protein (CRP), erythrocyte sedimentation rate, and SAA were evaluated serially during 3 months of etanercept treatment. HDL composition and its relationship to inflammation markers was determined in a subgroup of patients, using surface-enhanced laser desorption/ionization time-of-flight analysis. RESULTS: With anti-TNF treatment, levels of all parameters of inflammation decreased significantly, whereas total cholesterol, HDL-c, and apolipoprotein A-I (Apo A-I) levels increased significantly. This resulted in a better total cholesterol:HDL-c ratio (from 3.9 to 3.7) (although the difference was not statistically significant), and an improved Apo B:Apo A-I ratio, which decreased by 7.5% over time (P=0.008). In general, increases in levels of all lipid parameters were associated with reductions in inflammatory activity. In addition, SAA was present at high levels within HDL particles from AS patients with increased CRP levels and disappeared during treatment, in parallel with declining plasma levels of SAA. CONCLUSION: Our results show for the first time that during anti-TNF therapy for AS, along with favorable changes in the lipid profile, HDL composition is actually altered whereby SAA disappears from the HDL particle, increasing its atheroprotective ability. These findings demonstrate the importance of understanding the role of functional characteristics of HDL-c in cardiovascular diseases related to chronic inflammatory conditions.

Microvascular function is impaired in ankylosing spondylitis and improves after tumour necrosis factor alpha blockade.

OBJECTIVES: Ankylosing spondylitis (AS) is associated with increased cardiovascular morbidity and mortality. Microvascular function has been linked to several risk factors for cardiovascular disease. Inflammation in AS may cause microvascular dysfunction. To test this, we assessed microvascular function in (a) patients with AS compared to healthy controls and (b) patients with AS before and after 1 month of anti-tumour necrosis factor (TNF)alpha treatment with etanercept. METHODS: A total of 15 consecutive patients with AS, who were scheduled for etanercept treatment according to the Assessment in Ankylosing Spondylitis (ASAS) group guidelines, and 12 healthy controls matched for age and sex, were recruited. Endothelium-dependent and independent vasodilatation in skin were evaluated with laser Doppler fluxmetry after iontophoresis of acetylcholine and sodium nitroprusside, respectively. Videomicroscopy was used to measure recruitment of skin capillaries after arterial occlusion. RESULTS: Compared to healthy controls, patients with AS had impaired endothelium-dependent vasodilatation and capillary recruitment. Following anti-TNFalpha treatment, microvascular function improved significantly for endothelium-dependent vasodilatation (p = 0.03) and capillary recruitment (p = 0.006). A significant correlation was observed between changes in endothelium-dependent vasodilatation and changes in erythrocyte sedimentation rate (ESR) (r = -0.56; p = 0.03). CONCLUSION: Microvascular dysfunction is present in patients with AS with active disease, but improves as inflammation regresses after TNFalpha blockade.

Decrease of fructosamine levels during treatment with adalimumab in patients with both diabetes and rheumatoid arthritis.

Tumour necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine which has been closely linked to obesity and insulin resistance. We present two cases of patients with rheumatoid arthritis (RA) and concomitant diabetes mellitus, who showed a marked decrease of fructosamine levels after initiating therapy with adalimumab, a TNFalpha-blocking agent, for active RA. This finding may implicate that TNFalpha blockade causes better glycaemic control in RA patients with concomitant diabetes, possibly by improving insulin resistance.