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Objective Patients with rheumatoid arthritis (RA) are at increased risk of coronary artery disease (CAD) and seem to develop more severe acute coronary syndromes (ACS) than the general population. Because few studies have investigated the CAD distribution in the context of acute or stable CAD in RA, the objective was to investigate whether this risk is due to a different distribution and severity of coronary stenoses (versus non-RA), resulting in clinical manifestation of CAD. Methods We performed a population-based study using linkages of nationwide clinical, health, and demographics registers. We compared 1 cohort of patients with RA, and 1 matched cohort of patients without RA, undergoing a first coronary angiography from 2006 through 2015. Cardiovascular (CV) characteristics and the presence and distribution of clinically significant stenoses were compared (through odds ratios [ORs]), stratified by indication (stable CAD, ST-elevation myocardial infarction [STEMI], and non–ST-elevation ACS [NSTACS]), using logistic regression. Results We identified 2,985 patients with RA and 10,290 patients without RA who underwent a first coronary angiography. A higher proportion of patients with RA (75% versus 69%) had STEMI and NSTACS as indication for angiography. We found no difference in the presence and distribution of clinically significant coronary stenoses in RA compared with the patients without RA, regardless of the CAD type (for having any significant stenosis in stable CAD OR 0.9, STEMI OR 0.8, and NSTACS OR 1.1), stratification by RA duration, sex, or burden of concomitant CV risk factors. Conclusion Although RA may accelerate the development of clinical CAD events, the underlying angiographic characteristics are similar to those in patients without RA.

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., Previously included in thesis in manuscript form.

First published in thesis in manuscript form with title: "Aerobic capacity is associated with cardiovascular risk factors and disease activity in early rheumatoid arthritis : a cross sectional study"

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.

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.

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.

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.

OBJECTIVE: Cardiovascular (CV) risk estimation calculators for the general population do not perform well in patients with rheumatoid arthritis (RA). An RA-specific risk calculator has been developed, but did not perform better than a risk calculator for the general population when validated in a heterogeneous multinational cohort. METHODS: In a cohort of patients with new-onset RA from northern Sweden (n = 665), the risk of CV disease was estimated by the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA) and the American College of Cardiology/American Heart Association algorithm (ACC/AHA). The ACC/AHA estimation was analyzed, both as crude data and when adjusted according to the recommendations by the European League Against Rheumatism (ACC/AHA × 1.5). ERS-RA was calculated using 2 variants: 1 from patient and physician reports of hypertension (HTN) and hyperlipidemia [ERS-RA (reported)] and 1 from assessments of blood pressure (BP) and blood lipids [ERS-RA (measured)]. The estimations were compared with observed CV events. RESULTS: All variants of risk calculators underestimated the CV risk. Discrimination was good for all risk calculators studied. Performance of all risk calculators was poorer in patients with a high grade of inflammation, whereas ACC/AHA × 1.5 performed best in the high-inflammatory patients. In those patients with an estimated risk of 5-15%, no risk calculator performed well. CONCLUSION: ERS-RA underestimated the risk of a CV event in our cohort of patients, especially when risk estimations were based on patient or physician reports of HTN and hyperlipidemia instead of assessment of BP and blood lipids. The performance of ERS-RA was no better than that of ACC/AHA × 1.5, and neither performed well in high-inflammatory patients.

An unexpected human outbreak of the mosquitoborne Sindbis virus occurred in a previously nonendemic area of Sweden. At follow-up, 6-8 months after infection, 39% of patients had chronic arthralgia that affected their daily activities. Vectorborne infections may disseminate rapidly into new areas and cause acute and chronic disease.

Supplement: 2Meeting Abstract: FRI0625

Supplement: 2Meeting Abstract: AB1301

Supplement: 129Meeting Abstract: PP15

Supplement: 129Meeting Abstract: PP28

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.

Abstractnummer: 27The authors have chosen not to publish the abstract

Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared with the general population. In 2009, the European League Against Rheumatism (EULAR) taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorised according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk for CVD in patients with RA, and this may also apply to ankylosing spondylitis and psoriatic arthritis. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of non-steroidal anti-inflammatory drugs and corticosteroids should be in accordance with treatment-specific recommendations from EULAR and Assessment of Spondyloarthritis International Society. Ten recommendations were defined, of which one is new and six were changed compared with the 2009 recommendations. Each designated an appropriate evidence support level. The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence.

Background/Purpose: Rheumatoid arthritis (RA) patients are at high risk of cardiovascular disease (CVD). Risk algorithms for the general population lack precision when applied to RA patients and validated RA-specific CVD prediction models are missing. Risk age estimations are recommended as adjuncts to assessment of absolute 10-year risk of fatal CVD events. Two risk age models based on the Systematic Coronary Risk Evaluation (SCORE) algorithm have been developed; the cardiovascular risk age and the vascular age. However, the performance of these models has not been compared. Using longitudinal data on CVD events in RA patients, we aimed to compare the discriminative ability of cardiovascular risk age and vascular age among RA patients and in subgroups of RA patients based on disease characteristics. Methods: Patients with RA were included from an international consortium, aged 30-70 years at baseline. Those with prior CVD, diabetes and/or users of lipid-lowering and/or antihypertensive therapy at baseline were excluded. Cardiovascular risk age was estimated based on chronologic age, smoking status, total cholesterol and systolic blood pressure at baseline. Vascular age was derived from the 10-year risk of CVD according to the SCORE algorithm, with or without high density lipoprotein cholesterol, using the equations for low and high risk countries. Performance of each risk age model in predicting CVD events was assessed using the concordance index. Results: Among the1867 RA patients included, 74% were female, median (inter-quartile range) age and disease duration were 52.0 (44.0, 59.9) and 0.6 (0.1, 6.4) years, 72.5% were rheumatoid factor positive, 24.7% were using glucocorticoids and 10.3% were using biologics at baseline. Overall, 144 CVD events occurred and median follow-up time was 5.0 (2.6, 9.3) years. Median difference between estimated risk age and chronologic age was 4.0 to 6.7 years, depending on the specific risk age model applied. Overall, the C-index ac, Supplement: 10Meeting Abstract: 147

Supplement 2Meeting abstract FRI0652HPR

Objective. A long-term follow-up of patients with rheumatoid arthritis (RA) to evaluate factors related to coronary artery calcification (CAC). Methods. All 22 eligible patients (4 males/18 females, mean age 65 years, and RA-duration 30-36 years) from the original (baseline; n = 39) study of atherosclerosis were included. Inflammation, cardiovascular risk factors, and biomarkers were measured at baseline. At follow-up 13 years later, CAC was assessed by computed tomography (CT) and the grade of inflammation was measured. Multivariate analysis of differences between patients with low (0-10) and high CAC (>10) was done by orthogonal projection to latent structures (OPLS). Results. Ten patients had CAC 0-10 and 12 had >10 (range 18-1700). Patients with high CAC had significantly higher ESR (24.3 versus 9.9 mm/h) and swollen joint count (2 versus 0). The OPLS models discriminated between patients having high or low CAC. With only baseline variables, the sensitivity was 73% and the specificity 82%. The model that also included inflammatory variables from follow-up had a sensitivity of 89% and a specificity of 85%. Exclusion of baseline intima media thickness and plaque from the latter model modestly reduced the accuracy (sensitivity 80% and specificity 83%). Conclusions. CAC is related to inflammation in patients with RA.

We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.