Osteoprotegerin and osteocalcin are associated with atherosclerosis in patients with rheumatoid arthritis: a prospective cohort study.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aim of this study was to examine the associations between subclinical atherosclerosis, assessed by intima-media thickness (IMT), and regulators of bone formation, markers of bone turnover and bone mineral density (BMD) in patients with RA. METHODS: Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were consecutively included in a study of development of atherosclerosis. Ultrasound measurement of IMT of the common carotid artery was undertaken at inclusion (T0) and after 11 years (T11) (n=54). Bone turnover biomarkers were examined in samples collected at T0 and T11. BMD was assessed at T11. RESULTS: In patients with RA, osteocalcin (OCN) and osteoprotegerin (OPG) measured at T11 were significantly associated with IMT at T11, adjusted for systolic blood pressure (SBP) and age. BMD at T11 and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and carboxy-terminal crosslinked C-terminal telopeptide (CTX) were not associated with IMT. OPG, OCN and sclerostin at T0 were significantly associated with IMT at T11, and OPG and OCN at T0 were associated with change in IMT from T0 to T11. The associations between IMT and bone biomarkers were stronger in patients with joint erosions at onset of RA, than in patients with non-erosive disease. CONCLUSIONS: Atherosclerosis in patients with RA is associated with OPG and OCN, but not with BMD or markers reflecting ongoing bone turnover, indicating that atherosclerosis is not associated with bone turnover per se.

Smoking cessation is associated with lower disease activity and predicts cardiovascular risk reduction in rheumatoid arthritis patients.

OBJECTIVES: Smoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients. METHODS: Disease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status. RESULTS: Of the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5-6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P < 0.001 for both). There was a gradient of worsening CVD risk factor profiles (lipoproteins and blood pressure) from never to former to current smokers. Furthermore, former and never smokers had significantly lower CVD event rates compared with current smokers [hazard ratio 0.70 (95% CI 0.51, 0.95), P = 0.02 and 0.48 (0.34, 0.69), P < 0.001, respectively]. The CVD event rates for former and never smokers were comparable. CONCLUSION: Smoking cessation in patients with RA was associated with lower disease activity and improved lipid profiles and was a predictor of reduced rates of CVD events.

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

Co-morbidity in patients with early rheumatoid arthritis - inflammation matters.

BACKGROUND: Patients with rheumatoid arthritis (RA) suffer from co-morbidities that contribute to a shortened lifespan. Inflammation is important for the development of cardiovascular disease, but little is known on its relationship with other co-morbidities. We investigated the role of inflammation for the development of new comorbidities in early RA. METHODS: Since 1995, all patients with early RA in Northern Sweden are included in a prospective study on co-morbidities, with a total of 950 patients being included. At the time for this study, 726 had been ill for ≥5 years. Data on co-morbidities, clinical and laboratory disease activity and pharmacological therapy were collected from patient records and further validated using a questionnaire at RA onset (T0) and after 5 years (T5). RESULTS: Of the patients, 53.2 % of the patients had one or more co-morbidity at onset, the commonest being: hypertension (27.3 %), obstructive pulmonary disease (13.9 %), diabetes (8.0 %), hypothyroidism (6.3 %) and malignancy (5.0 %). After 5 years, 41.0 % had developed at least one new co-morbidity, the most common being: hypertension (15.1 %), malignancy (7.6 %), stroke/transient ischemic accident (5.1 %), myocardial infarction (4.3 %) and osteoporosis (3.7 %). Age at disease onset, a raised erythrocyte sedimentation rate (ESR) at inclusion, previous treatment with glucocorticoids (GC; p < 0.001 for all), extra-articular RA (Ex-RA; p < 0.01), DAS28 (area under the curve) at 24 months (p < 0.05), previous smoking at inclusion (p = 0.058) and male gender (p < 0.01) were associated with a new co-morbidity overall at T5. Treatment with biologics (p < 0.05) reduced the risk. In multiple logistic regression modelling, ESR (p = 0.036) at inclusion was associated with a new co-morbidity after 5 years, adjusted for age, sex, smoking and GC treatment. In a similar model, Ex-RA (p < 0.05) was associated with a new co-morbidity at T5. In a third model, adjusted for age and sex, a new pulmonary co-morbidity was associated with a smoking history at inclusion (p < 0.01), but not with ESR. CONCLUSION: There was substantial co-morbidity among early RA patients already at disease onset, with considerable new co-morbidity being added during the first five years. Measures of disease activity were associated with the occurrence of a new co-morbidity indicating that the inflammation is of importance in this context.

Is Lipoprotein-Associated Phospholipase A2 a Link between Inflammation and Subclinical Atherosclerosis in Rheumatoid Arthritis?

OBJECTIVE: Lipoprotein-associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation, is associated with cardiovascular disease. This prospective study of an inception cohort aimed to investigate whether the level of Lp-PLA2 is associated with subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Patients from northern Sweden diagnosed with early RA were consecutively recruited into an ongoing prospective study. From these, all patients ≤60 years (n = 71) were included for measurements of subclinical atherosclerosis at inclusion (T0) and five years later (T5). Forty age- and sex-matched controls were included. The patients were clinically assessed, SCORE, Reynolds Risk Score, and Larsen score were calculated, and blood samples were drawn from all individuals at T0 and T5. RESULTS: There was no significant difference in the level of Lp-PLA2 between patients with RA and controls (p > 0.05). In simple linear regression models among patients with RA, Lp-PLA2 at T0 was significantly associated with intima media thickness (IMT) at T0 and T5, flow mediated dilation (FMD) at T0 and T5, ever smoking, male sex, HDL-cholesterol (inversely), non-HDL-cholesterol, SCORE, Reynolds Risk Score, and Larsen score (p < 0.05). CONCLUSION. In this cohort of patients with early RA, the concentration of Lp-PLA2 was associated with both subclinical atherosclerosis and disease severity.

The Extent of Subclinical Atherosclerosis Is Partially Predicted by the Inflammatory Load: A Prospective Study over 5 Years in Patients with Rheumatoid Arthritis and Matched Controls.

OBJECTIVE: This prospective followup study investigated subclinical atherosclerosis in relation to traditional cardiovascular disease (CVD) risk factors and inflammation in patients with rheumatoid arthritis (RA) recruited at diagnosis compared with controls. METHODS: Patients diagnosed with early RA were consecutively recruited into a prospective study. From these, a subgroup aged ≤ 60 years (n = 71) was consecutively included for ultrasound measurement of intima-media thickness (IMT) and flow-mediated dilation (FMD) at inclusion (T0) and after 5 years (T5). Age- and sex-matched controls (n = 40) were also included. RESULTS: In the Wilcoxon signed-rank test, both IMT and FMD were significantly aggravated at T5 compared to baseline in patients with RA, whereas only IMT was significantly increased in controls. In univariate linear regression analyses among patients with RA, the IMT at T5 was significantly associated with age, systolic blood pressure (BP), cholesterol, triglycerides, Systematic Coronary Risk Evaluation (SCORE), and Reynolds Risk Score at baseline (p < 0.05). Similarly, FMD at T5 was significantly inversely associated with age, smoking, systolic BP, SCORE, and Reynolds Risk Score (p < 0.05). A model with standardized predictive value from multiple linear regression models including age, smoking, BP, and blood lipids at baseline significantly predicted the observed value of IMT after 5 years. When also including the area under the curve for the 28-joint Disease Activity Score over 5 years, the observed value of IMT was predicted to a large extent. CONCLUSION: This prospective study identified an increased subclinical atherosclerosis in patients with RA. In the patients with RA, several traditional CVD risk factors at baseline significantly predicted the extent of subclinical atherosclerosis 5 years later. The inflammatory load over time augmented this prediction.

Modifiable cardiovascular risk factors in patients with ankylosing spondylitis.

The aim of this study was to evaluate whether modifiable cardiovascular disease (CVD) risk factors, e.g. atherogenic blood lipids, hypertension and lifestyle-related factors such as smoking, diet and physical inactivity, differ among patients with ankylosing spondylitis (AS) in comparison to the general population. Eighty-eight patients diagnosed with AS were identified by analysis of the databases of a previous community intervention programme, the Västerbotten intervention programme. The patients were compared with 351 controls matched for age, sex and study period. These databases include the results of blood samples analysed for cholesterol, triglycerides and plasma glucose, as well as data on hypertension, height, weight, smoking and dietary habits and physical activity. No significant differences were found between patients and controls regarding hypertension, body mass index, physical activity, diet or smoking. Levels of serum triglycerides (p < 0.01) and cholesterol (p < 0.01) were significantly lower in the patient group. Among the patients, the level of triglycerides correlated inversely with the intake of total fat (r s = -0.25, p < 0.05), monounsaturated fats (r s = -0.29, p < 0.05) and positively correlated to the intake of carbohydrates (r s = 0.26, p < 0.05). These associations were not apparent among the controls. In the cohort of AS patients studied, no differences were found regarding the modifiable risk factors for CVD compared with the general population. Hence, the increased presence of CVD in patients with AS may be caused by other factors such as differences in metabolism and medication such as NSAID or the chronic low-grade inflammation present in the disease.

Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study.

INTRODUCTION: Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first five years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the five-year follow-up period and the modulatory effect of pharmacological treatment. METHODS: All patients from the four northern-most counties of Sweden with early RA are, since December 1995, consecutively recruited at diagnosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the five-year follow-up (T5). RESULTS: Among the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% (P < 0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5% (P < 0.01) whilst smoking decreased from 29.8 to 22.4% (P < 0.001) and the BMI from 26.3 to 25.8 (P < 0.05), respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (area under the curve (AUC) disease activity score (DAS28)), extra-articular disease, corticosteroid use, shorter duration of treatment with disease modifying anti-rheumatic drugs (DMARDs) and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised erythrocyte sedimentation rate (ESR) at inclusion and AUC DAS28 at six months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors. CONCLUSIONS: The occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.

Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis.

OBJECTIVE: To measure markers of atherogenesis and thrombogenesis in patients with rheumatoid arthritis (RA) and in matched controls, and to relate these variables to markers of inflammation and endothelial activation, and to the presence of atherosclerosis. METHODS: Thirty-nine patients with RA with disease onset between 1974 and 1978, who were younger than 65 years at the present study in 1997, were investigated together with 39 age and sex matched controls. IgG, IgA, and IgM antibodies against oxidized low density lipoprotein (oxLDL ab), malondialdehyde LDL (MDA-LDL ab) and cardiolipin (aCL) were measured by ELISA, circulating immune complexes (CIC) were isolated by precipitation, and homocysteine was measured with HPLC. Hemostatic factors of endothelial origin, i.e., plasminogen activator inhibitor-1 (PAI-1 mass), von Willebrand Factor (vWF), and D-dimer were analyzed by ELISA, and tissue plasminogen activator (tPA) activity was analyzed by a chromogen method. The products analyzed in the RA group correlated with soluble adhesion molecules (sICAM-1, sE-selectin), acute phase reactants, interleukin 6 (IL-6), and IL-2sR alpha, all measured by ELISA, and with accumulated disease activity. The factors were also related to the presence of plaque measured by duplex scanning. Factor analysis was performed to subgroup data in order to find latent variables. RESULTS: Patients with RA had significantly higher levels of oxLDL ab (IgM), MDA-LDL ab (IgA, IgM classes), aCL (IgG, IgA, IgM classes), CIC, homocysteine, PAI-1 mass, and D-dimer than controls. Patients also had significantly higher levels of sICAM-1, sE-selectin, IL-6, and IL-2sR alpha. PAI-1 mass, D-dimer, vWF, CIC, and aCL (IgM, IgA) correlated with erythrocyte sedimentation rate (ESR), and, with the exception of vWF, to accumulated disease activity. CIC correlated significantly with IgM antibodies against oxLDL and aCL. ESR, IL-2sR alpha, PAI-1, tPA activity, vWF, D-dimer, homocysteine, aCL (IgA), and MDA-LDL ab (IgA) correlated with sICAM-1. ESR, haptoglobin, IL-2sR alpha, PAI-1 mass, D-dimer, aCL (IgM), and MDA-LDL ab (IgM) correlated with sE-selectin. sICAM-1 was significantly higher in patients with plaque. In factor analysis, presence of atherosclerotic plaque had loadings of one latent variable together with adhesion molecules and IL-2sR alpha and together with antibodies of, in particular, IgM type of another one. CONCLUSION: Several different etiopathogenic mechanisms for increased cardiovascular mortality in RA are implicated. Continuous endothelial activation is suggested by increased levels of adhesion molecules sICAM-1 and sE-selectin, which correlate with hemostatic factors of endothelial origin and with T cell activation as measured by IL2sR alpha. That factor analysis showed loadings of one variable on antilipid antibodies and plaque and another on T cell activation and plaque indicates that the immune system is involved in the development of atherosclerosis in RA.

Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1beta, and IL-1Ra genes.

OBJECTIVE: To analyze the association of genetic polymorphisms of pro-inflammatory cytokines with rheumatoid arthritis (RA) in comparison with healthy controls from Northern Sweden and the potential contribution of these genetic variants for disease severity and development of cardiovascular complications. METHODS: Polymerase chain reaction amplification was used for analysis of TaqI restriction fragment length polymorphism (RFLP) of interleukin-1 beta (IL-1beta), variable tandem repeat polymorphism of IL-I receptor antagonist (IL-1Ra) gene and NcoI RFLP at position -308 of tumor necrosis factor-alpha (TNF-alpha) gene. One hundred and fifty-four patients with RA, 42 men and 112 women, were consecutively recruited into the study through the Department of Rheumatology. RESULTS: The allele A1 of TNF-alpha was more common in the patient group (p < 0.01; OR = 1.62). Patients having the genotype A1A2 seemed to develop more severe disease compared with patients with A1A1 genotype: they were younger at disease onset (p < 0.05), had a higher accumulated disease activity (p < 0.05) and worse functional class (p < 0.05). Patients with genotype A2A2 of IL- 1beta had higher accumulated disease activity score than patients with A1A1 and A1A2 (p < 0.05). The allelic combination Al IL-1beta/A2 IL-1Ra was less prevalent in RA patients who developed cardiovascular complications (p < 0.005; OR = 0.20). CONCLUSIONS: The Al allele of TNF-alpha associates with RA. Genotypes A1A2 of TNF-alpha and A2A2 of IL-1beta are associated with more severe disease. The allelic combination A1IL-1beta/A2 IL-1Ra is less often present in RA patients who developed cardiovascular complications.