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We aimed to examine the performance of the expanded cardiovascular (CV) risk prediction score for rheumatoid arthritis (ERS-RA), the Framingham CV risk score and the carotid intima-media thickness (IMT) as predictors of CV mortality in patients with rheumatoid arthritis (RA). We studied 1194 patients with RA who had an ultrasound measurement of the carotid IMT and who had clinical information to calculate the ERS-RA and the Framingham score. Deaths were confirmed by death certificate and attributed to a CV cause if the immediate or underlying cause of death was due to ICDM-9 codes 390-459. We compared areas under receiver operator characteristic curves (ROC AUC) and examined reclassification tables for the performance of each scale to correctly predict CV deaths. Patients were observed for 10,063 person-years, during which 271 patients died (22.6%), for an overall mortality rate of 2.7 deaths per 100 person-years (95% CI 2.4, 3.0). A CV cause of death was identified in 139 patients (11.6%), for a CV mortality rate of 1.4 per 100 person-years (1.2, 1.6). ROC AUCs were 0.72 (95% CI 0.68, 0.76) for the Framingham scale, 0.76 (95% CI 0.72, 0.81) for the carotid IMT and 0.84 (95% CI 0.81, 0.88) for the ERS-RA. Compared to the Framingham scale the ERS-RA correctly reclassified 6% of patients (p=0.02), while the carotid IMT correctly reclassified 5% (p=0.003). The ERS-RA was superior to the Framingham scale in the prediction of CV mortality in patients with RA.

Objective To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA). Methods We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use. Results Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression. Conclusions Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.

Objective: To delineate daily and cumulative glucocorticoid dose thresholds associated with increased mortality rates in rheumatoid arthritis (RA).Methods: We studied RA patients recruited from rheumatology clinics. Annually, we assessed the glucocorticoid dose, demographic, socioeconomic, clinical, and laboratory features of RA, cardiovascular (CV) risk factors, and vital status. We used Cox proportional hazards regression to assess associations between the daily or cumulative glucocorticoid dose and death, adjusting for potential confounders and for the propensity to receive glucocorticoids. We tested strata of the glucocorticoid dose to delineate the threshold associated with death.Results: We studied 779 RA patients with a total of 7,203 person‐years of observation, during which 237 of them died, yielding a mortality rate of 3.2 per 100 person‐years (95% confidence interval [95% CI] 2.8–3.7). One hundred twenty of the deaths were due to CV causes, yielding a CV mortality rate of 1.8 (95% CI 1.5–2.1). Exposure to glucocorticoids was associated with a dose‐dependent increase in death from all causes, with a ratio (HR) of 1.07 per mg of prednisone per day (95% CI 1.05–1.08). Compared to patients who were not receiving corticosteroids, the minimum daily prednisone dose threshold associated with an increase in all‐cause mortality was 8–15 mg, with an adjusted HR of 1.78 (95% CI 1.22–2.60). For the cumulative dose of glucocorticoids, the minimum dosage associated with all‐cause mortality was 40 gm (HR 1.74 [95% CI 1.25–2.44]).Conclusion: Glucocorticoid use in RA is associated with a dose‐dependent increase in mortality rates, with a daily threshold dose of 8 mg, at which the number of deaths increased in a dose‐dependent manner. These findings may assist clinicians in selecting the appropriate glucocorticoid dosage for RA patients who require these agents.

Objective: The role of atherosclerosis in the acute coronary syndromes (ACS) that occur in patients with rheumatoid arthritis (RA) has not been quantified in detail. We undertook this study to determine the extent to which ACS are associated with carotid atherosclerosis in RA.Methods: We prospectively ascertained ACS, defined as myocardial infarction, unstable angina, cardiac arrest, or death due to ischemic heart disease, in an RA cohort. We measured carotid atherosclerosis using high‐resolution ultrasound. We used Cox proportional hazards models to estimate the association between ACS and atherosclerosis, adjusting for demographic features, cardiovascular (CV) risk factors, and RA manifestations.Results: We performed carotid ultrasound on 636 patients whom we followed up for 3,402 person‐years. During this time, 84 patients experienced 121 new or recurrent ACS events, a rate of 3.5 ACS events per 100 patient‐years (95% confidence interval [95% CI] 3.0–4.3). Among the 599 patients without a history of ACS, 66 incident ACS events occurred over 3,085 person‐years, an incidence of 2.1 ACS events per 100 person‐years (95% CI 1.7–2.7). The incidence of new ACS events per 100 patient‐years was 1.1 (95% CI 0.6–1.7) among patients without plaque, 2.5 (95% CI 1.7–3.8) among patients with unilateral plaque, and 4.3 (95% CI 2.9–6.3) among patients with bilateral plaque. Covariates associated with incident ACS events independent of atherosclerosis included male sex, diabetes mellitus, and a cumulative glucocorticoid dose of ≥20 gm.Conclusion: Atherosclerosis is strongly associated with ACS in RA. RA patients with carotid plaque, multiple CV risk factors (particularly diabetes mellitus or hypertension), many swollen joints, and a high cumulative dose of glucocorticoids, as well as RA patients who are men, are at high risk of ACS.

While genetic and environmental factors and their interactions influence susceptibility to rheumatoid arthritis (RA), causative genetic variants have not been identified. The purpose of the present study was to assess the effects of covariates and genotype × sex interactions on the genome-wide association analysis (GWAA) of RA using Genetic Analysis Workshop 16 Problem 1 data and a logistic regression approach as implemented in PLINK. After accounting for the effects of population stratification, effects of covariates and genotype × sex interactions on the GWAA of RA were assessed by conducting association and interaction analyses. We found significant allelic associations, covariate, and genotype × sex interaction effects on RA. Several top single-nucleotide polymorphisms (SNPs) (~22 SNPs) showed significant associations with strong p-values (p < 1 × 10^-4 - p < 1 × 10^-24). Only three SNPs on chromosomes 4, 13, and 20 were significant after Bonferroni correction, and none of these three SNPs showed significant genotype × sex interactions. Of the 30 top SNPs with significant (p < 1 × 10^-4 - p < 1 × 10^-6) interactions, ~23 SNPs showed additive interactions and ~5 SNPs showed only dominance interactions. Those SNPs showing significant associations in the regular logistic regression failed to show significant interactions. In contrast, the SNPs that showed significant interactions failed to show significant associations in models that did not incorporate interactions. It is important to consider interactions of genotype × sex in addition to associations in a GWAA of RA. Furthermore, the association between SNPs and RA susceptibility varies significantly between men and women.

Objective: To evaluate the association between peripheral arterial function and cortical bone thickness in rheumatoid arthritis (RA).Methods: In a cross‐sectional study, we measured the combined cortical thickness (CCT) of the second metacarpal bone from hand radiographs, and the ankle‐to‐arm systolic blood pressure ratio, also known as ankle–brachial index (ABI), in RA patients. We evaluated the association between the 2 using multinomial logistic regression.Results: We obtained CCT and ABI measurements in 588 RA patients. The mean ± SD CCT was 3.62 ± 1.16 mm. The proportion of patients with ≥1 ABI value ≤0.9, indicating obstructed lower limb arteries, increased from 18 (9.2%) of 191 patients in the highest CCT tertile to 25 (12.5%) of 200 in the middle CCT tertile to 38 (19.2%) of 198 in the lowest CCT tertile (P for trend 0.005). We noted a similar pattern for ABI values >1.3, indicative of arterial incompressibility (frequencies in high, middle, and low CCT tertiles were 4.7%, 9.5%, and 19.9%, respectively; P for trend ≤0.001). These trends remained significant after multivariable adjustment for potential confounders. After adjustment for the manifestations of RA and cumulative glucocorticoid dose, the association between CCT and arterial obstruction remained significant, but that with arterial incompressibility weakened considerably.Conclusion: There is an association between metacarpal cortical bone thinning and obstruction or incompressibility of the peripheral arteries in RA. The association with incompressibility may be mediated by systemic inflammation and/or glucocorticoids, but that with obstruction is independent of a wide array of potential confounders. Clinicians should be alert to the possibility of impaired arterial function RA patients with thinned metacarpal cortical bone.

Objective: To estimate the contribution of cardiovascular (CV) risk factors and rheumatoid arthritis (RA) disease manifestations to atherosclerosis in RA.Methods: We used high‐resolution carotid ultrasound to measure the carotid intima‐media thickness (IMT) and plaque in 631 RA patients. Using R² measures from multivariable models, we estimated the contribution of demographic characteristics (age, sex, and ethnic group), CV risk factors (diabetes mellitus, hypercholesterolemia, cigarette smoking, hypertension, and body mass index, and RA manifestations (joint tenderness, swelling, and deformity, nodules, erythrocyte sedimentation rate [ESR], C‐reactive protein, rheumatoid factor, the HLA–DRB1 shared epitope, and cumulative glucocorticoid dose) to each of the outcomes. Estimates were obtained in the full sample, and within strata defined by age, sex, and ethnic group. We tested for interaction between CV risk factors and RA manifestations.Results: The contribution of demographic factors, CV risk factors, and RA manifestations to IMT and plaque R² varied depending on the patients' age stratum. Demographic features explained 11–16% of IMT variance, CV risk factors explained 4%–12%, and RA manifestations explained 1–6%. The greatest contribution of RA manifestations occurred in the youngest age group, while that of CV risk factors occurred in the older age groups. Results for carotid plaque were similar. There was a significant interaction between the number of CV risk factors present and the ESR, suggesting that the ESR's effect on IMT varied according to the number of CV risk factors.Conclusion: Both established CV risk factors and manifestations of RA inflammation contribute significantly to carotid atherosclerosis in RA, and may modify one another's effects. These findings may have implications regarding the prevention of atherosclerosis in RA.