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Introduction: Hydroxychloroquine (HCQ) exerts a large reduction of cardiovascular risk in patients with inflammatory diseases, but the mechanisms are not fully known. The aim of this study was to study potential mechanisms for this.

Methods: This interventional study (EudraCT 2014-005418-45) in 30 patients (23 with rheumatoid arthritis, 7 with systemic lupus erythematosus) investigates the effects of HCQ on cardiovascular risk factors and arterial stiffness in patients with inflammatory disease. Blood lipids, blood pressure, blood glucose, glycated haemoglobin (HbA1c) and arterial stiffness was assessed at initiation, after four weeks of treatment and after eight weeks of treatment with 200 mg HCQ daily.

Results: After four weeks of treatment with HCQ, total cholesterol had decreased from 5.4 mmol/L to 5.1 mmol/L (p<0.001), low-density lipoproteins from 3,0 mmol/L to 2.7 mmol/L (p<0.001) and apolipoprotein B from 0.96 g/L to 0.90 g/L (p<0.01). Those levels remained unchanged after eight weeks of treatment with HCQ. Levels of triglycerides, high-density lipoproteins and apolipoprotein A1 remained unchanged during the study. HbA1c decreased in most patients, especially in patients with high levels at start of HCQ, but increased HbA1c was seen in patients with low levels at start of treatment with HCQ. No significant effect was seen on blood pressure or any measure of arterial stiffness.

Conclusion: This study does not identify the mechanisms of cardiovascular risk reduction from HCQ. Arterial stiffness is not affected by HCQ. The impact of HCQ on HbA1c and blood lipids is rapid, but of modest magnitude, and these effects do not fully explain the reduced risk of cardiovascular disease seen in observational studies. The mechanisms of cardiovascular risk reduction from HCQ are yet not completely known.

Objectives: Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aims of this study were to study the associations between subsets of T-cells, subclinical atherosclerosis assessed by intima-media thickness (IMT) and serological status for CMV in patients with RA.

Methods: Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were included in a prospective study of atherosclerosis. Controls matched for age and sex were also included (n=44). Ultrasound measurement of IMT in the common carotid artery was undertaken at inclusion (T0), after 1.5 years (T1.5) and after 11 years (T11). At T11, flow-cytometry analysis was undertaken to investigate subsets of T-cells. Serological analysis for CMV was undertaken from samples collected at T0.

Results: At T0, 66% of the patients and controls were CMV immunoglobulin G-positive. CMV-IgG positive patients had a significantly more rapid increase in IMT at T1.5, compared with controls and CMV-IgG negative patients. CMV-IgG positive patients had a significantly higher percentage of T-cells lacking CD28 (both CD4+CD28null and CD8+CD28null T-cells) than CMV-IgG negative patients. Increased levels of CD4+CD28null and CD8+CD28null T-cells were significantly associated with IMT at T11, adjusted for systolic blood pressure. CX3CR1 was expressed in CD4+ and CD8+ CD28null T-cells, but CX3CR1 per se was not associated with increased IMT.

Conclusions: Presence of CMV IgG-antibodies in patients with RA is associated with altered T-cell-populations and an increased burden of atherosclerosis. A possible protective effect of antiviral treatment in CMV-positive patients with new-onset RA should be considered.

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.

Objectives: The aim of this study was to investigate aerobic capacity and its associations with disease activity and risk factors for cardiovascular disease (CVD) in early rheumatoid arthritis (RA).

Methods: This cross‐sectional study included 67 patients with early RA. Aerobic capacity was estimated with the Åstrand submaximal test adjusted according to the Nord‐Tröndelag Health Study formula. The following were also assessed: subclinical atherosclerosis by carotid intima‐media thickness and pulse wave analysis; body composition by dual X‐ray absorptiometry; estimated CVD mortality risk by the Systematic Coronary Risk Evaluation; disease activity by the Disease Activity Score 28, C‐reactive protein and erythrocyte sedimentation rate; blood lipids by total cholesterol, low‐density lipoproteins, high‐density lipoproteins, and triglycerides; and functional ability by the Stanford health assessment questionnaire. Univariate and multiple linear regression analyses were performed to explore the associations between variables.

Results: The mean (SD) aerobic capacity was 31.6 (8.7) ml O₂⁻¹ kg min⁻¹. Disease activity and risk factors for CVD were more favourable for patients with aerobic capacity above the median value. Aerobic capacity was associated with ESR and several CVD risk factors, independent of age and sex. In a multiple regression model that was adjusted for age and sex, aerobic capacity was significantly associated with per cent body fat (β = −0.502, 95% CI [−0.671, −0.333]) and triglycerides (β = −2.365, 95% CI [−4.252, −0.479]).

Conclusions: Disease activity and risk factors for CVD were in favour for patients with a higher aerobic capacity. Aerobic capacity was associated with disease activity and several risk factors for CVD, independent of age and sex. In RA, these findings may provide insights into the benefits of using aerobic capacity as a marker to prevent CVD.

Objective: To evaluate the course of impaired spinal mobility in patients with long‐standing well‐defined ankylosing spondylitis (AS ).

Methods: Data from 232 patients with AS (186 men, 46 women) and 3,849 clinical measurements performed between February 1980 and June 2016 were analyzed. Lateral spinal flexion (LSF ), the 10‐cm Schober test, chest expansion (CE ), and cervical rotation measurements were stratified by disease duration at 10‐year intervals and compared with published age‐ and height‐adjusted spinal mobility reference intervals as well as with fixed reference values commonly used in clinical practice.

Results: After 10 years of AS , most patients exhibited at least 1 measurement, most commonly LSF , that was under the 2.5th percentile of the adjusted reference interval (53% of men, 65% of women). In all measurements except CE , there were significant linear increases in the proportion of patients during 40 years of disease duration who exhibited impaired mobility. Measured LSF values <2.5th percentile (mean 14.8 cm) after 10 years were associated with further spinal mobility impairments later in the disease course. Fixed reference values yielded higher proportions of patients with impaired mobility compared with adjusted reference intervals.

Conclusion: Impaired spinal mobility in AS is common after a 10‐year disease duration. LSF below the 2.5th percentile at 10 years appeared to be associated with a worse prognosis. Fixed reference values overestimated spinal mobility impairments in AS and should be avoided.

Objective: To investigate associations between physical activity and risk factors for cardiovascular disease (CVD), subclinical atherosclerosis, and disease activity in patients with early and long-standing rheumatoid arthritis (RA).

Method: This cross-sectional study included 84 patients with early and 37 with long-standing RA (disease duration, mean ± sd: 1.4 ± 0.4 and 16.3 ± 2.3 years, respectively). Physical activity was measured using a combined accelerometer and heart-rate monitor. Further assessments were disease activity (erythrocyte sedimentation rate, Disease Activity Score in 28 joints), functional ability (Health Assessment Questionnaire), risk factors for CVD (blood lipids, i.e. triglycerides, high-density lipoprotein, low-density lipoprotein; blood glucose, blood pressure, sleeping heart rate, waist circumference, body mass index, and body fat), and subclinical atherosclerosis (pulse-wave velocity, augmentation index, and carotid intima–media thickness).

Results: Physical activity variables did not differ between patients with early and long-standing RA. However, 37% of the patients with early and 43% of those with long-standing RA did not reach the World Health Organization’s recommended levels of moderate to vigorous physical activity (MVPA). In a final multiple regression model, adjusted for age, gender, disease duration, and activity monitor wear time, higher total physical activity was associated with lower body fat and higher functional ability. With the same adjustments, more time spent in MVPA was associated with lower high-density lipoprotein and lower sleeping heart rate.

Conclusions: Physical activity was associated with more favourable risk factors for CVD. However, many patients were physically inactive, stressing the importance of promoting physical activity in RA.

Background: In younger individuals, low absolute risk of cardiovascular disease (CVD) may conceal an increased risk age and relative risk of CVD. Calculation of risk age is proposed as an adjuvant to absolute CVD risk estimation in European guidelines. We aimed to compare the discriminative ability of available risk age models in prediction of CVD in rheumatoid arthritis (RA). Secondly, we also evaluated the performance of risk age models in subgroups based on RA disease characteristics.

Methods: RA patients aged 30–70 years were included from an international consortium named A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Prior CVD and diabetes mellitus were exclusion criteria. The discriminatory ability of specific risk age models was evaluated using c-statistics and their standard errors after calculating time until fatal or non-fatal CVD or last follow-up.

Results: A total of 1974 patients were included in the main analyses, and 144 events were observed during follow-up, the median follow-up being 5.0 years. The risk age models gave highly correlated results, demonstrating R2 values ranging from 0.87 to 0.97. However, risk age estimations differed > 5 years in 15–32% of patients. C-statistics ranged 0.68–0.72 with standard errors of approximately 0.03. Despite certain RA characteristics being associated with low c-indices, standard errors were high. Restricting analysis to European RA patients yielded similar results.

Conclusions: The cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive.

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.

Aims: Rheumatoid arthritis may influence the outcome after an acute myocardial infarction. We aimed to compare trends in one-year mortality, co-morbidities and treatments after a first acute myocardial infarction in patients with rheumatoid arthritis versus non-rheumatoid arthritis patients during 1998-2013. Furthermore, we wanted to identify characteristics associated with mortality.

Methods and results: Data for 245,377 patients with a first acute myocardial infarction were drawn from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions for 1998-2013. In total, 4268 patients were diagnosed with rheumatoid arthritis. Kaplan-Meier analysis was used to study mortality trends over time and multivariable Cox regression analysis was used to identify variables associated with mortality. The one-year mortality in rheumatoid arthritis patients was initially lower compared to non-rheumatoid arthritis patients (14.7% versus 19.7%) but thereafter increased above that in non-rheumatoid arthritis patients (17.1% versus 13.5%). In rheumatoid arthritis patients the mean age at admission and the prevalence of atrial fibrillation increased over time. Congestive heart failure decreased more in non-rheumatoid arthritis than in rheumatoid arthritis patients. Congestive heart failure, atrial fibrillation, kidney failure, rheumatoid arthritis, prior diabetes mellitus and hypertension were associated with significantly higher one-year mortality during the study period 1998-2013.

Conclusions: The decrease in one-year mortality after acute myocardial infarction in non-rheumatoid arthritis patients was not applicable to rheumatoid arthritis patients. This could partly be explained by an increased age at acute myocardial infarction onset and unfavourable trends with increased atrial fibrillation and congestive heart failure in rheumatoid arthritis. Rheumatoid arthritis per se was associated with a significantly worse prognosis.

Objectives: Patients with rheumatoid arthritis (RA) have an increased mortality and morbidity due to cardiovascular disease (CVD). In this prospective 5-year follow up of patients with RA, we analysed several biomarkers, known to be associated with atherosclerosis and/or inflammation in the general population. The aim of this study was to find out whether the RA-disease per se affect these biomarkers and if those could be associated with the progression of atherosclerosis, as measured by intima media thickness (IMT) among patients with early RA.

Methods: Patients from northern Sweden diagnosed with early RA, are consecutively recruited into an ongoing prospective study on CVD comorbidity. A subgroup of patients, aged ≤60 years (n = 71) was included for ultrasound measurements of IMT at inclusion (T0) and after 5 years (T5) together with age-sex-matched controls (n = 40). The patients were clinically assessed. Blood was analysed for lipids, ESR and CRP and several biomarkers known to be associated with atherosclerosis in the general population.

Results: At T0, the patients with RA had significantly lower levels of MIF and significantly higher levels of interleukin (IL)-18 and MIC-1 compared with controls. At T5, the patients with RA had significantly higher levels of pentraxin3, MIC-1, TNF-R2, ICAM-1, VCAM-1 and endostatin compared with controls. At T0 the levels of MPO correlated with DAS28, sCD40L with CRP and IL-18 with systolic blood pressure and Reynolds risk score. Using PLSR on a CVD-panel analysed with multiplex immunoassay, the patients with RA could be correctly classified into those who had a worsening in their IMT over the five years or not. Here, MMP3 was identified as influential.

Conclusions: This study indicates that the RA disease itself could affect several of the biomarkers in this study, and possibly also the processes involved in the development of atherosclerosis.