György Kerekes

Accelerated Atherosclerosis in Rheumatoid Arthritis

Abstract:  Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. Both traditional, Framingham risk factors and inflammation‐associated factors are involved in RA‐associated atherosclerosis. Among imaging techniques, the early determination of common carotid intima‐media thickness (ccIMT), flow‐mediated vasodilation (FMD), and nitroglycerine‐mediated vasodilation (NMD) may be useful to determine atherosclerosis and endothelial dysfunction. We and others found increased ccIMT and impaired FMD in RA patients. Among immunological and metabolic laboratory markers, anticyclic citrullinated peptide (anti‐CCP) antibodies, IgM rheumatoid factor, circulating immune complexes, pro‐inflammatory cytokines including tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), Th0/Th1 T cells, homocysteine, dyslipidemia, decreased folate and vitamin B12 production, and impaired paraoxonase activity may all be involved in the development of vascular disease in RA. The early diagnosis of endothelial dysfunction and atherosclerosis, active immunosuppressive treatment, the use of drugs that control atherosclerosis, changes in sedentary lifestyle, and the close follow‐up of RA patients may help to minimize cardiovascular risk in these individuals.

Validated methods for assessment of subclinical atherosclerosis in rheumatology.

Rheumatoid arthritis, as well as other types of arthritides and connective tissue diseases, is associated with accelerated atherosclerosis, and increased cardiovascular morbidity and mortality. The early signs of cardiovascular disease therefore need to be recognized in patients with these conditions so that effective cardiovascular protection can be introduced. This Review provides an overview of validated techniques that are currently available to determine subclinical atherosclerosis in patients with rheumatic conditions. Techniques for early assessment of endothelial dysfunction include brachial artery flow-mediated vasodilation and laser Doppler flowmetry. Coronary circulation can be assessed by measuring coronary flow reserve using CT, MRI or PET based techniques. The standard indicators of arterial stiffness are pulse-wave velocity and the augmentation index. Carotid atherosclerosis is determined by the common carotid intima–media thickness (ccIMT) measurement or by the assessment of plaques and plaque areas. The combination of ccIMT with plaque assessment is likely to increase the predictive value of this approach. The potential use of a multimarker approach to increase the diagnostic and prognostic value of these clinical assessments is also discussed.

Comparative assessment of vascular function in autoimmune rheumatic diseases: considerations of prevention and treatment.

Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to increased cardio- and cerebrovascular disease risk. Traditional risk factors, as well as the role of systemic inflammation including cytokines, chemokines, proteases, autoantibodies, adhesion receptors and others have been implicated in the development of these vascular pathologies. The characteristics of vasculopathies may significantly differ depending on the underlying disease. While classical accelerated atherosclerosis has been associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or spondyloarthropathies (SpA), obliterative vasculopathy may rather be characteristic for systemic sclerosis (SSc) or mixed connective tissue disease (MCTD). Antiphospholipid antibodies have been implicated in vasculopathies underlying SLE, antiphospholipid syndrome (APS), RA and MCTD. There is also heterogeneity with respect to inflammatory risk factors. Cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) and immune complexes are primarily involved in arthritides, such as RA, SpA, as well as in SLE. On the other hand, autoantibodies including anti-oxLDL anti-cardiolipin and anti-β2GPI are rather involved in SLE- and APS-associated vasculopathies. Regarding the non-invasive assessment of vascular function, endothelial dysfunction, overt atherosclerosis and vascular stiffness may be indicated by brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and aortic pulse-wave velocity (PWV), respectively. These abnormalities have been described in most inflammatory rheumatic diseases. While ccIMT and stiffness are relatively stable, FMD may be influenced by many confounding factors. In addition to traditional vasculoprotection, immunosuppressive agents including corticosteroids, traditional and biologic DMARDs may have significant vascular and metabolic effects. The official EULAR recommendations on the assessment and management of cardiovascular disease in arthritides have just been published, and similar recommendations in connective tissue diseases are to be developed soon.

Assessment of Subclinical Vascular Disease Associated with Ankylosing Spondylitis

Objective. Studies indicate that ankylosing spondylitis (AS), as well as rheumatoid arthritis, may be associated with accelerated atherosclerosis and vascular disease. We assessed endothelial dysfunction, carotid atherosclerosis, and aortic stiffness in AS in context with clinical and laboratory measurements. Methods. Forty-three patients with AS and 40 matched healthy controls were studied. We assessed common carotid intima-media thickness (ccIMT), flow-mediated vasodilation (FMD), and pulse-wave velocity (PWV) in association with age, disease duration, smoking habits, body mass index, patient’s assessment of pain and disease activity, Bath AS Disease Activity Index, Bath AS Functional Index (BASFI), metric measurements, erythrocyte sedimentation rate, C-reactive protein, and HLA-B27 status. Results. We found impaired FMD (6.85 ± 2.98% vs 8.30 ± 3.96%; p = 0.005), increased ccIMT (0.65 ± 0.15 vs 0.54 ± 0.15 mm; p = 0.01), and higher PWV (8.64 ± 2.44 vs 8.00 ± 1.46 m/s; p = 0.03) in patients with AS compared to controls, respectively. We also found that ccIMT negatively correlated with FMD (r = −0.563; p = 0.0001) and positively correlated with PWV (r = 0.374; p = 0.018). Both ccIMT and PWV correlated with disease duration (r = 0.559; p = 0.013 and r = 0.520; p = 0.022, respectively), BASFI (r = 0.691; p = 0.003 and r = 0.654; p = 0.006), decreased lumbar spine mobility (r = −0.656; p = 0.006 and r = −0.604; p = 0.013), chest expansion (r = −0.502; p = 0.047 and r = −0.613; p = 0.012), and increased wall-occiput distance (r = 0.509; p = 0.044 and r = 0.614; p = 0.011). Conclusion. In this well characterized AS population, impaired FMD and increased ccIMT and PWV indicate abnormal endothelial function and increased atherosclerosis and aortic stiffness, respectively. The value of noninvasive diagnostic tools needs to be further characterized.

Impaired endothelial function and increased carotid intima-media thickness in association with elevated von Willebrand antigen level in primary antiphospholipid syndrome

Primary antiphospholipid syndrome (APS) is characterized by venous or arterial thrombotic events and/or recurrent abortions, fetal death, preeclasmpsia, eclampsia in the presence of anticardiolipin antibodies or lupus anticoagulant, in the absence of accompanying diseases. Antiphospholipid antibodies can activate endothelial cells, and were recently implicated in atherosclerosis. To assess potential endothelial impairment and early signs of atherosclerosis, flow-mediated (endothelium-dependent) and nitrate-mediated (endothelium independent) vasodilation, as well as von Willebrand factor antigen level and carotid artery intima-media thickness (IMT) were measured in patients with primary antiphospholipid syndrome and in healthy controls. Flow-mediated vasodilation in patients with primary APS was significantly lower than that of controls (3.43 ± 2.86% versus 7.96 ± 3.57%; P < 0.0001). We also found significantly higher von Willebrand antigen levels in patients with primary APS than in the control group (157.91 ± 52.45% versus 125.87 ± 32.8%; P = 0.012). Moreover, carotid artery IMT was significantly larger in the primary APS group compared to controls (0.714 ± 0.2 mm versus 0.58 ± 0.085 mm; P = 0.0037). Our results reflect ongoing endothelial damage and accelerated atherosclerosis in patients with primary APS, and suggest that vasoprotective therapy may be beneficial in the treatment of these patients. Lupus (2007) 16, 497—503.

Rheumatoid arthritis and metabolic syndrome

Rheumatoid arthritis (RA), especially active disease, is associated with considerable changes in body composition, lipids, adipokines and insulin sensitivity. Metabolic changes, such as increased total cholesterol, LDL cholesterol and triglyceride levels, occur even in preclinical RA. Active RA is associated with decreased lipid levels, BMI, fat and muscle mass, as well as altered lipid profiles. Some of these changes are also seen in metabolic syndrome, and could increase cardiovascular mortality. Importantly, the systemic inflammation underlying RA is an independent risk factor for cardiovascular disease. This Perspectives article summarizes data on the associations of various components of metabolic syndrome with RA, and discusses the effects of biologic therapy on these factors. The authors propose that components of metabolic syndrome should be monitored in patients with RA throughout the disease course, and argue that optimal disease control using biologic agents might attenuate several adverse effects of metabolic syndrome in these patients.

Vascular effects of biologic agents in RA and spondyloarthropathies

Endothelial dysfunction and accelerated atherosclerosis lead to increased cardiovascular morbidity and mortality in patients with rheumatoid arthritis and other inflammatory rheumatic diseases. Sustained inflammation is a major risk factor for cardiovascular disease. Apart from traditional vasculoprotective agents, biologic agents may also exert favorable effects on the vasculature. Indeed, agents that inhibit tumor necrosis factor (TNF) seem to transiently improve endothelial function. Data regarding the effects of biologic agents on atherosclerosis and arterial stiffness are inconsistent. The effects of the various TNF blockers on dyslipidemia might differ: long-term infliximab therapy could be pro-atherogenic, whereas some studies suggest that etanercept and adalimumab may exert beneficial effects on the lipid profile. TNF blockers have been shown to decrease the incidence of cardiovascular events in patients with rheumatoid arthritis. Preliminary data suggest that rituximab also improves endothelial function and dyslipidemia. Further studies are needed to determine the net effects of biologic agents on the vasculature.

Effects of Biologics on Vascular Function and Atherosclerosis Associated with Rheumatoid Arthritis

Endothelial dysfunction and accelerated atherosclerosis lead to increased cardiovascular morbidity and mortality in rheumatoid arthritis (RA). Sustained inflammation is a major risk factor. Apart from traditional vasculoprotective agents, biologics may also exert favorable effects on the vasculature. Indeed, tumor necrosis factor‐α (TNF‐α) inhibitors agents may transiently improve endothelial function. There are conflicting data regarding the effects of biologics on atherosclerosis and arterial stiffness. Infliximab stimulates the number and differentiation of endothelial progenitor cells that lead to vascular repair. There may be differences in the effects of TNF blockers on dyslipidemia, as long‐term infliximab therapy may be proatherogenic, while some studies suggest that etanercept and adalimumab may exert beneficial effects on lipids. TNF blockers may decrease the incidence of cardiovascular events in RA. Preliminary data suggest that rituximab may also improve endothelial function and dyslipidemia. Further studies are needed to determine the net effects of biologics on the vasculature.

Rosuvastatin improves impaired endothelial function, lowers high sensitivity CRP, complement and immuncomplex production in patients with systemic sclerosis - a prospective case-series study

IntroductionWe studied the effect of rosuvastatin on endothelial and macrovascular function, cardiovascular risk factors and the complement pathway in patients with systemic sclerosis (SSc).MethodsAltogether 28 patients with SSc underwent laboratory and complex vascular assessments before and after six months of 20 mg rosuvastatin treatment. Flow-mediated dilation (FMD) of the brachial artery, as well as carotid artery intima-media thickness (ccIMT), carotid-femoral and aorto-femoral pulse wave-velocity (PWV) were analyzed by ECG-synchronized ultrasound. Ankle-brachial index (ABI) was determined by Doppler, and forearm skin microcirculation was assessed by Laser Doppler perfusion monitoring.ResultsBrachial artery FMD significantly improved upon rosuvastatin therapy (2.2% ± 3.3% before versus 5.7% ± 3.9% after treatment, P = 0.0002). With regard to patient subsets, FMD significantly improved in the 21 lcSSc patients (from 2.1% to 5.6%, P = 0.001). In the seven dcSSc patients, we observed a tendency of improvement in FMD (from 3% to 6%, P = 0.25). Changes in PWV, ccIMT and ABI were not significant. Mean triglyceride (1.7 ± 0.97 versus 1.3 ± 0.46 mmol/l, P = 0.0004), total cholesterol (5.3 ± 1.6 mmol/l versus 4.2 ± 1.3 mmol/l, P = 0.0003), low density lipoprotein cholesterol (3.0 ± 1.3 versus 2.2 ± 1.0 mmol/l, P = 0.005) and C-reactive protein levels (CRP) (5.1 ± 5.2 versus 3.4 ± 2.7, P = 0.01) levels significantly decreased after rosuvastatin treatment. Mean C3, C4 and IC levels also decreased significantly as compared to pretreatment values.ConclusionsSix-month rosuvastatin therapy improves endothelial function and lowers CRP, C3, C4 and IC levels indicating possible favourable effects of this statin on the cardiovascular and immune system in SSc.

Increased production of asymmetric dimethylarginine (ADMA) in ankylosing spondylitis: Association with other clinical and laboratory parameters

OBJECTIVE Asymmetric dimethylarginine (ADMA) has been associated with atherosclerosis, vascular diseases and, recently, also with arthritis including rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS Serum ADMA, arginine and symmetric dimethylarginine (SDMA) levels were assessed by liquid chromatography in 61 AS and 26 osteoarthritis (OA) patients with no known cardiovascular disease. RESULTS Serum ADMA levels were significantly increased in AS compared to OA patients (0.95 ± 0.17 μM versus 0.70 ± 0.25 μM; p < 0.001). There were no differences in serum arginine and SDMA levels. Serum ADMA levels also positively correlated with age (R = 0.258; p = 0.043), body mass index (R = 0.368; p = 0.003), erythrocyte sedimentation rate (R = 0.329; p = 0.009) and ADMA levels negative correlated with chest expansion (R = -0.251; p = 0.04). No correlations were found between ADMA levels and disease duration, pain intensity, BASDAI, BASFI, BASMI, quality of life, CRP, HLA-B27 positivity, endothelial dysfunction or carotid atherosclerosis. CONCLUSION ADMA may serve as a marker of systemic inflammation and may reflect functional immobility in AS. Further studies are needed to assess the possible role of ADMA in AS and AS-related vascular disease.