V P van Halm

Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRÉ Investigation

Objectives: Patients with rheumatoid arthritis (RA) have an increased cardiovascular risk, but the magnitude of this risk is not known precisely. A study was undertaken to investigate the associations between RA and type 2 diabetes (DM2), a well-established cardiovascular risk factor, on the one hand, and cardiovascular disease (CVD) on the other. Methods: The prevalence of CVD (coronary, cerebral and peripheral arterial disease) was determined in 353 randomly selected outpatients with RA (diagnosed between 1989 and 2001, aged 50–75 years; the CARRÉ study) and in participants of a population-based cohort study on diabetes and CVD (the Hoorn study). Patients with RA with normal fasting glucose levels from the CARRÉ study (RA, n = 294) were compared with individuals from the Hoorn study with normal glucose metabolism (non-diabetic, n = 258) and individuals with DM2 (DM2, n = 194). Results: The prevalence of CVD was 5.0% (95% CI 2.3% to 7.7%) in the non-diabetic group, 12.4% (95% CI 7.5% to 17.3%) in the DM2 group and 12.9% (95% CI 8.8% to 17.0%) in those with RA. With non-diabetic individuals as the reference category, the age- and gender-adjusted prevalence odds ratio (OR) for CVD was 2.3 (95% CI 1.1 to 4.7) for individuals with DM2 and 3.1 (95% CI 1.6 to 6.1) for those with RA. There was an attenuation of the prevalences after adjustment for conventional cardiovascular risk factors (OR 2.0 (95% CI 0.9 to 4.5) and 2.7 (95% CI 1.2 to 5.9), respectively). Conclusions: The prevalence of CVD in RA is increased to an extent that is at least comparable to that of DM2. This should have implications for primary cardiovascular prevention strategies in RA.

Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis.

Background: Rheumatoid arthritis is characterised by inflammation and an increased cardiovascular risk. It was recently shown that active early rheumatoid arthritis is associated with dyslipidaemia, which may partially explain the enhanced cardiovascular risk. However, it is unknown when this dyslipidaemia starts. Objective: To investigate the progression of the lipid profile over time and the influence of inflammatory parameters on this lipid profile, in people who later developed rheumatoid arthritis. Methods: Levels of total cholesterol, high-density lipoprotein cholesterol (HDLc), triglycerides, apolipoprotein AI (apo AI), apolipoprotein B (apo B) and lipoprotein(a) (Lp(a)) were determined in 1078 stored, deep-frozen, serial blood bank samples, collected between 1984 and 1999, of 79 blood donors who later developed rheumatoid arthritis. These samples were compared with 1071 control samples of unselected blood donors, matched for age, sex and storage time. Results: Samples of patients who later developed rheumatoid arthritis showed, on average, 4% higher total cholesterol, 9% lower HDLc, 17% higher triglyceride and 6% higher apo B levels than matched controls (p⩽0.05). The magnitude of the differences in lipid levels between groups, explained by C reactive protein (CRP), was limited. For example, only 3.6% of the difference in HDLc levels between the groups was explained by the CRP concentrations. Conclusion: Patients who later develop rheumatoid arthritis have a considerably more atherogenic lipid profile than matched blood donors at least 10 years before onset of symptoms. As inflammation only marginally explains the differences between the two groups, a modulating effect of lipids on inflammatory processes is hypothesised.

Changes in lipid profile during infliximab and corticosteroid treatment in rheumatoid arthritis

Objective: To evaluate the effects of infliximab and corticosteroid treatment on the lipid profile in patients with active rheumatoid arthritis (RA). Methods: Infliximab infusions were given at weeks 0, 2, 6 and then every 8 weeks. Before each infusion, disease activity parameters (Disease Activity Index 28-Joint Score (DAS28)) C reactive protein (CRP) and lipid levels (total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, apolipoprotein A1 (apo A1) and apolipoprotein B) were measured in 80 consecutive patients with RA, who completed the study period of 48 weeks. Longitudinal analyses were used to investigate (1) the course of lipid levels over a period of time and (2) the relationship between lipids, prednisone dose and disease activity. Results: Infliximab treatment causes a significant reduction in disease activity and a concomitant decrease in prednisone dose. Although they initially improved significantly, all lipid levels had returned to baseline levels after 48 weeks, except for apo A1. Longitudinal analyses revealed significant yet opposite associations between lipid levels and disease activity and between lipid levels and prednisone dose. DAS28 improvement by 1 point was associated with an increase of 0.016 mmol/l (0.618 mg/dl) total cholesterol and 0.045 mmol/l (1.737 mg/dl) HDL-cholesterol. Reduction of 10 mg prednisone was associated with a decrease of 0.04 mmol/l (1.544 mg/dl) total cholesterol and 0.16 mmol/l (6.177 mg/dl) HDL-cholesterol. Conclusion: Overall, no changes in serum lipid levels were observed after 48 weeks of infliximab treatment. The initial beneficial effects of infliximab on the lipid profile, by means of a reduction of disease activity, are attenuated by a concomitant decrease in prednisone dose.

Increased disease activity is associated with a deteriorated lipid profile in patients with ankylosing spondylitis.

Background: Cardiovascular mortality is increased in patients with ankylosing spondylitis. A possible explanation might be a more prevalent atherogenic lipid profile in patients with ankylosing spondylitis than in the general population. It has been postulated that inflammation deteriorates the lipid profile, thereby increasing cardiovascular risk. Objective: To explore the association between disease activity and lipid profile in patients with ankylosing spondylitis. Methods: Disease activity parameters for ankylosing spondylitis and lipid levels (total cholesterol, high-density lipoprotein cholesterol (HDLc) and triglycerides) were measured in 45 patients with ankylosing spondylitis for 6 months after starting treatment with leflunomide or placebo. Findings in this treatment group were compared with those in 10 patients with ankylosing spondylitis treated with etanercept. A specialised regression model, adjusting for repeated measurements, age and sex, was used to assess the influence of the disease activity variables on the lipid levels. Results: Multilevel regression analyses showed significant associations between disease activity parameters and lipid levels—for instance, an increase of 30 mm at the end of the first hour in erythrocyte sedimentation rate was associated with a decrease of about 6% in total cholesterol level and a decrease of about 11% in HDLc levels. Similar significant associations were found between other disease activity parameters and lipid levels. Conclusion: Increase in disease activity was associated with decreases in lipid levels. The decrease in HDLc levels tended to be almost twice as large as the decrease in total cholesterol levels, resulting in a more atherogenic lipid profile. Hence, effective treatment of disease activity in patients with ankylosing spondylitis may lower the cardiovascular risk by improving the lipid profile.

Rheumatoid arthritis is associated with a high prevalence of hypothyroidism that amplifies its cardiovascular risk

Objective: Rheumatoid arthritis (RA) patients have an increased risk of developing cardiovascular diseases (CVD). Other autoimmune diseases such as hypothyroidism are also associated with an enhanced risk for CVD. Our objective was to determine first, the prevalence of hypothyroid disorders in RA patients, and second, the risk of CVD in RA patients with hypothyroid abnormalities. Methods: Subjects were RA patients who participated in an ongoing prospective cohort study of cardiovascular mortality and morbidity (n = 358) in which hypothyroid abnormalities were assessed. CVD was defined as a verified medical history of coronary, cerebral or peripheral arterial disease. Results: Clinical hypothyroidism was observed in 16 of 236 female RA patients (6.8%), which is significantly higher than in the general population of The Netherlands. Subclinical hypothyroidism was detected in 6 out of 236 RA women (2.5%). In female RA patients, CVD was present in 6 out of 16 (37.5%) of all hypothyroid women. The odds ratio for CVD comparing female hypothyroid RA patients with female euthyroid RA patients was 4.1 (95% CI 1.2–14.3) after adjustment for sex, age, diabetes, smoking (ever), hypertension and statin use. Conclusions: Clinical hypothyroidism was observed three times more often in female RA patients than females in the general population. In female RA patients, clinical hypothyroidism was associated with a fourfold higher risk of CVD in comparison with euthyroid female RA patients independently of the traditional risk factors.

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 CARRÉ 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.

Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRÉ Study

Background Patients with rheumatoid arthritis (RA) have double the risk of cardiovascular (CV) disease, largely independently of traditional CV risk factors. Renal dysfunction is associated with CV morbidity and mortality in the general population, but data on this association in RA are lacking. Objective To investigate the association between renal function and CV events in RA. Methods The CARRÉ Study is an ongoing prospective cohort study of Dutch patients with RA, which records CV events. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease formula. Logistic regression determined the association between estimated GFR and the occurrence of CV events. Results 353 patients were followed for 3 years, and 23 (7%) had a CV event. Patients who had an event had a significantly lower baseline GFR than those who did not (59 vs 79 ml/min, p=0.001). This association remained significant after adjustment for traditional risk factors: in this analysis, a decrease in GFR of 5 ml/min was associated with a 30% (95% CI 7% to 59%) increase in the occurrence of CV events. During follow-up, an unfavourable change in GFR was noted in patients who later had a CV event compared with those who did not. Conclusion These data confirm that, in RA, renal dysfunction is associated with a higher risk of CV disease independently of traditional CV risk factors.

SAT0415 Diastolic Left Ventricular Dysfunction in Ankylosing Spondylitis Improves during Tumor Necrosis Factor Alpha Blocking Therapy

Background Ankylosing spondylitis (AS) is associated with concomitant cardiac pathology, such as diastolic left ventricular (LV) dysfunction (1), valvular dysfunction, and aortic disease (2), all presumably caused by inflammation. The precise prevalence of diastolic left ventricular (LV) dysfunction and the effects of anti-inflammatory treatment thereon are currently unknown. Objectives To investigate the prevalence of diastolic LV dysfunction compared to controls and the effects of tumor necrosis factor (TNF) -α blocking therapy on ventricular function in AS patients. Methods Forty consecutive AS patients were included and treated for one year with TNF-α blocking therapy. Transthoracic echocardiography was performed at baseline and at one year. Forty age and gender matched asymptomatic random controls were included from an established echocardiographic cohort. Diastolic LV function (normal, dysfunction grade I, II, or III) and systolic LV function (ejection fraction, EF) were assessed. Valvular and aortic pathology was documented. Disease activity was measured with C-reactive protein (CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score–CRP (ASDAS). Results At baseline, diastolic LV dysfunction (all grades) was present in nine patients (23%) vs one (3%) control (p=0.011). Systolic LV dysfunction was present in 0 (0%) patients vs one (3%) control (p=0.625). In total, 13 (33%) AS patients and six (15%) controls (p=0.066) had some form of cardiac pathology (i.e. one or more of the following: diastolic and/or systolic LV dysfunction, aortic valve dysfunction, aortic dilatation; one AS patient and one control had two disorders). Treatment with TNF-α blocking therapy had no effect on systolic LV function, but diastolic LV dysfunction (n=3 grade I, n=1 grade II) improved to normal in four patients (p=0.125), and neither worsened nor developed in the other patients. After the start of TNF-α blocking therapy CRP decreased from 4.0 (1.3–12.0) mg/l to 2.0 (1.9–3.2) mg/l (p<0.001), BASDAI decreased from 5.2±1.6 to 3.7±2.0 (p=0.001) and ASDAS decreased from 3.1±1.2 to 2.0±1.0 (p<0.001). Conclusions AS patients had a significantly increased prevalence of diastolic LV dysfunction compared to controls which improved during treatment with TNF-α blocking therapy. This appears to be related to the anti-inflammatory effects of TNF-blocking therapy. References Heslinga SC, Van Dongen CJ, Konings TC, Peters MJ, van der Horst-Bruinsma IE, Smulders YM, et al. Diastolic left ventricular dysfunction in ankylosing spondylitis–a systematic review and meta-analysis. Semin Arthritis Rheum 2014 Aug;44(1):14–9. Nurmohamed MT, van der Horst-Bruinsma I, Maksymowych WP. Cardiovascular and cerebrovascular diseases in ankylosing spondylitis: current insights. Curr Rheumatol Rep 2012 Oct;14(5):415–21. Acknowledgement This is an investigator initiated study partially supported by an unrestricted grant from MSD, The Netherlands Disclosure of Interest None declared

THU0044 Different type of carotid arterial wall remodeling in rheumatoid arthritis as compared to healthy subjects

Background Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, but mechanisms explaining this increased risk have not been fully elucidated. Arteries react on hemodynamic changes by arterial remodeling. Objectives We investigated whether arterial remodeling is different in RA as compared to control subjects. Methods 96 RA-patients and 274 healthy subjects were investigated cross-sectionally in two cohorts. B-mode carotid ultrasonography was used to investigate arterial wall parameters, including carotid intima-media thickness (cIMT), inter-adventitial diameter (IAD) and lumen diameter (LD), calculated as IAD – (2 × cIMT). Using linear regression, the association between presence of RA and arterial wall parameters was assessed. Results RA was associated with a 0.57 mm (9.3%) greater LD. IAD was 0.61 mm (7.8%) higher in RA. cIMT did not differ between RA patients and healthy subjects, resulting in a 4.4% greater wall-to-lumen ratio (ratio of IAD to cIMT, an indicator of outward remodeling) in RA. Associations remained similar after exclusion of patients with prior CV disease and after adjustment for demographic factors and CV risk factors. In RA, disability index and current use of prednisone were significantly associated with a greater wall-to-lumen ratio. Conclusions RA is associated with outward arterial remodelling, which is relevant because this is associated with plaque instability and rupture. Disclosure of Interest None Declared

FRI0100 Sustained development of cardiovascular disease in rheumatoid arthritis despite cardioprotective treatment: The 7-year prospective carre-study

Background Rheumatoid arthritis (RA) is a chronic inflammatory joint disease which is associated with an increased cardiovascular (CV) risk. Still unknown is whether CV risk factors or the underlying inflammatory process in RA renders these patients more at risk of CV disease (CVD). An increment in these factors over several years might explain this predisposition. Objectives The present study compared changes in these factors over time in RA-patients who did and did not develop CVD during follow-up. Methods 7-year incidence rate of CVD was determined in a prospective cohort of 353 RA-patients. CV risk factors, RA-related factors and medication use were assessed at baseline, at 3-years and at 7-years of follow-up. Associations between the changes in investigated factors and development of CVD were assessed using generalized estimating equation (GEE) analyses. Results After 7 years, there were 62 events over 2361 patientyears of follow-up, incidence rate (IR) of 26.3/1.000 patientyears. This was similar to the IR after 3-years of follow-up. GEE analyses showed that, during follow-up, changes in disease activity score of 28 joints (DAS28) and overall 10-year CV risk estimation (as calculated by SCORE) were associated with incident CVD. Use of biologics increased significantly in patients who did not develop incident CVD vs. those who did (26% vs. 6%), while use of statins increased significantly in patients who did develop incident CVD vs. those who did not (43% vs. 14%). Conclusions An increased risk of incident CVD persists in patients with RA. Changes in both DAS-28 as well as 10-year CV risk estimation (SCORE) were associated with the 7-year CVD incidence. Cardioprotective treatment did not seem to extenuate this association. A more aggressive cardioprotective and anti-inflammatory treatment of RA might mitigate the burden of CVD in RA. Disclosure of Interest None Declared