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1.  Rheumatoid Arthritis and Cardiovascular Disease 
American heart journal  2013;166(4):622-628.e1.
Rheumatic disease and heart disease share common underpinnings involving inflammation. The high levels of inflammation that characterize rheumatic diseases provide a “natural experiment” to help elucidate the mechanisms by which inflammation accelerates heart disease. Rheumatoid arthritis (RA) is the most common of the rheumatic diseases and has the best studied relationships with heart disease.
Review of current literature on heart disease and rheumatoid arthritis
Patients with RA have an increased risk of developing heart disease that is not fully explained by traditional cardiovascular risk factors. Therapies used to treat RA may also affect the development of heart disease; by suppressing inflammation, they may also reduce the risk of heart disease. However, their other effects, as in the case of steroids, may increase heart disease risk.
Investigations of the innate and adaptive immune responses occurring in RA may delineate novel mechanisms in the pathogenesis of heart disease, and help identify novel therapeutic targets for the prevention and treatment of heart disease.
PMCID: PMC3890244  PMID: 24093840
2.  Accelerated Aging Influences Cardiovascular Disease Risk in Rheumatoid Arthritis 
Arthritis and rheumatism  2013;65(10):2562-2566.
To determine whether the impact of aging on cardiovascular disease (CVD) risk in the general population (as estimated by the Framingham risk score [FRS]) differs in patients with rheumatoid arthritis (RA).
A population-based inception cohort of Olmsted County, Minnesota residents aged ≥30 years who fulfilled 1987 ACR criteria for RA in 1988–2008 was assembled and followed until death, migration, or 7-1-2012. Data on CVD events were collected by medical record review. The 10-year FRS for CVD was calculated. Cox models adjusted for FRS were used to examine the influence of age on CVD risk.
The study included 563 patients with RA without prior CVD (mean age: 55 years, 72% women; 69% seropositive [i.e., rheumatoid factor and/or anti-citrullinated protein antibody positive]). During a mean follow-up of 8.2 years, 98 patients developed CVD (74 seropositive and 24 seronegative), but FRS predicted only 59.7 events (35.4 seropositive and 24.3 seronegative). The gap between observed and predicted CVD risk increased exponentially across age, and the age effect on CVD risk in seropositive RA was nearly double its effect in the general population with additional log(age) coefficients of 2.91 for women (p=0.002) and 2.06 for men (p=0.027).
Age exerts an exponentially increasing effect on CVD risk in seropositive RA, but no increased effect among seronegative patients. The causes of accelerated aging in patients with seropositive RA deserve further investigation.
PMCID: PMC3966134  PMID: 23818136
accelerated aging; rheumatoid arthritis; cardiovascular disease
3.  Rheumatoid Arthritis is Associated with Left Ventricular Concentric Remodeling: Results of a Population-based Cross-sectional Study 
Arthritis and rheumatism  2013;65(7):1713-1718.
To study left ventricular (LV) geometry in patients with rheumatoid arthritis (RA) who have no heart failure (HF) versus subjects without either RA or HF, and to determine the impact of RA on LV remodeling.
A cross-sectional, community-based study was conducted among adult (≥50 years) RA patients and age- and sex-matched non-RA subjects without a history of HF. All participants underwent a standard 2D/Doppler echocardiography. LV geometry was classified into four categories based on relative wall thickness and sex-specific cut-offs for LV mass index: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, or normal geometry.
The study included 200 RA patients and 600 matched non-RA subjects (mean age 65; 74% female in both cohorts). RA patients were significantly more likely to have abnormal LV geometry than non-RA subjects (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.03, 2.00), adjusting for cardiovascular risk factors and comorbidities. Among those with abnormal LV geometry, RA patients had significantly increased odds of concentric LV remodeling (OR 4.73; 95% CI 2.85, 7.83). In linear regression analyses, LV mass index appeared to be lower in RA patients currently using corticosteroids (Beta +/− standard error: −0.082 +/− 0.027; p=0.002), adjusting for cardiovascular risk factors and comorbidities.
RA was strongly associated with abnormal LV remodeling, particularly, with concentric LV remodeling, among patients without HF. This association was significant beyond adjustment for cardiovascular risk factors and comorbidities. RA disease related factors may promote changes in LV geometry. The biological mechanisms underlying LV remodeling warrant further investigation.
PMCID: PMC3914147  PMID: 23553738
rheumatoid arthritis; left ventricular remodeling; risk factors
4.  Long-Term Outcomes and Treatment After Myocardial Infarction in Patients with Rheumatoid Arthritis 
The Journal of rheumatology  2013;40(5):605-610.
To investigate the risk profiles, treatment utilization, and outcomes of myocardial infarction (MI) patients with rheumatoid arthritis (RA) and matched MI patients without RA.
We utilized a population-based cohort of Olmsted County, Minnesota, residents with MI from 1979–2009. Among these, we identified 77 patients who fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA and 154 age, sex, and calendar year matched MI patients without RA. Data collection from medical records included RA and MI characteristics, antirheumatic and cardioprotective medications, and reperfusion therapy as well as outcomes (mortality, heart failure, and recurrent ischemia).
The mean age at MI was 72.4 and 55% were female in both cohorts. Cardiovascular risk factor profiles, MI characteristics, and treatment with reperfusion therapy or cardioprotective medications were similar in MI patients with and without RA. However, patients with RA experienced poorer long-term outcomes compared to patients without RA (for mortality: hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.04, 2.08, and for recurrent ischemia: HR: 1.51; 95% CI: 1.04, 2.18).
MI patients with RA receive similar treatment with reperfusion therapy and cardioprotective medications, and have similar short-term outcomes compared to patients without RA. However, patients with RA have poorer long-term outcomes. Thus, despite similar treatment, MI patients with RA have worse long-term outcomes than MI patients without RA.
PMCID: PMC3895921  PMID: 23418388
Rheumatoid arthritis; myocardial infarction
5.  Towards Improving Cardiovascular Risk Management in Patients with Rheumatoid Arthritis: the Need for Accurate Risk Assessment 
Annals of the rheumatic diseases  2011;70(5):719-721.
PMCID: PMC3907170  PMID: 21345812
rheumatoid arthritis; cardiovascular disease
6.  Contribution of Obesity to the Rise in Incidence of Rheumatoid Arthritis 
Arthritis care & research  2013;65(1):71-77.
To determine whether the “obesity epidemic” could explain the recent rise in the incidence of RA.
Obesity is an under-recognized risk factor for RA. In recent years both the prevalence of obesity and the incidence of RA have been rising.
An inception cohort of Olmsted County, Minnesota residents who fulfilled 1987 American College of Rheumatology criteria for RA in 1980–2007 was compared to population-based controls (matched on age, sex and calendar year). Heights, weights and smoking status were collected from medical records. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2. Conditional logistic regression was used to assess the influence of obesity on developing RA. Population attributable risk was used to estimate the incidence of RA in the absence of obesity.
The study included 813 patients with RA and 813 controls. Both groups had extensive medical history available prior to incidence/index date (mean 32.2 years), and approximately 30% of each group were obese at incidence/index date. The history of obesity was a significantly associated with developing RA (OR:1.24; 95 % CI: 1.01, 1.53 adjusted for smoking status). In 1985–2007 the incidence of RA rose by an increment of 9.2 per 100,000 among women. Obesity accounted for 4.8 per 100,000 (or 52%) of this increase.
Obesity is associated with a modest risk for developing RA. Given the rapidly increasing prevalence of obesity, this has had a significant impact on RA incidence and may account for much of the recent increase in incidence of RA.
PMCID: PMC3707391  PMID: 22514156
rheumatoid arthritis; obesity; incidence; population attributable risk; body mass index
7.  Hypothyroidism as a risk factor for development of cardiovascular disease in patients with rheumatoid arthritis 
The Journal of rheumatology  2012;39(5):954-958.
To determine the frequency of hypothyroidism in patients with rheumatoid arthritis (RA), and to elucidate the association of hypothyroidism and development of cardiovascular disease in these patients.
A retrospective medical record review was performed using all incident cases of adult onset RA from a defined geographic population base that fulfilled criteria for RA in the years 1988–2007. Patients with and without thyroid disease were followed longitudinally for the development of cardiovascular disease (CVD).
A cohort of 650 patients with RA and an age and sex matched comparison cohort of 650 patients without RA was assembled (both cohorts mean age 55.8; 69% female). There was no significant difference between cohorts in the presence of hypothyroid disease or subclinical hypothyroidism at time of RA diagnosis. No significant difference was found in the cumulative incidence of hypothyroid disease between the two cohorts. Hypothyroid disease was found to be significantly associated with CVD in patients with RA (hazard ratio 2; 95% confidence interval 1.1,3.6). This difference remained significant and unchanged after adjustment for traditional cardiovascular risk factors (HR: 2.0; 95% CI: 1.1, 3.6).
No significant difference was found in either incidence or prevalence of hypothyroidism between patients with or without RA. Hypothyroid disease was significantly associated with CVD in patients with RA, even after adjustment for other traditional cardiovascular risk factors.
PMCID: PMC3518421  PMID: 22337246
Rheumatoid arthritis; Hypothyroidism; Cardiovascular Disease
8.  Noncardiac vascular disease in Rheumatoid Arthritis: Increase in Venous Thromboembolic Events? 
Arthritis and rheumatism  2012;64(1):53-61.
To investigate the incidence of noncardiac vascular disease in a community-based incidence cohort of patients with rheumatoid arthritis (RA) and compare to that in the general population. To investigate trends in incidence of noncardiac vascular disease in patients with RA.
A population-based inception cohort of patients with RA in Olmsted County, Minnesota with incident RA between 1/1/1980 and 12/31/2007 and a cohort of non-RA subjects from the same population base was assembled and followed until 12/31/2008. Venous thromboembolic events (VTE), cerebrovascular events, and peripheral arterial events were ascertained by medical record review.
The study population included 813 patients with RA (mean age [SD] 55.9 [15.7] years, 68% women), with average length of follow-up of 9.6 years [SD 6.9]. Compared to non-RA subjects of similar age and sex, patients diagnosed with RA between 1995 and 2007 had a higher incidence (%) of VTE compared to non-RA subjects (cumulative incidence [±SE] 6.7 ± 1.7 vs 2.8 ± 1.1, respectively; p=0.005), but similar rates of cerebrovascular and peripheral arterial events. Among patients with RA, the incidence of VTE, cerebrovascular events, and peripheral arterial events was similar in the 1995–2007 time period compared to the 1980–1994 time period.
The incidence of VTE appears to be increased in patients with RA compared to non-RA subjects. The incidence of cerebrovascular events and peripheral vascular disease events was similar in patients with RA compared to non-RA subjects. Among patients with RA, the incidence of noncardiac vascular disease has remained stable in recent decades.
PMCID: PMC3474372  PMID: 21905005
9.  The Impact of Rheumatoid Arthritis Disease Characteristics on Heart Failure 
The Journal of Rheumatology  2011;38(8):1601-1606.
To examine the impact of rheumatoid arthritis (RA) characteristics and antirheumatic medications on the risk of heart failure (HF) in RA.
A population-based incidence cohort of RA patients aged ≥18 (1987 ACR criteria first met between 1/1/1980 and 1/1/2008) without a history of HF was followed until HF onset (defined by Framingham criteria), death, or 1/1/2008. We collected data on RA characteristics, antirheumatic medications and cardiovascular (CV) risk factors. Cox models adjusting for age, sex and calendar year were used to analyze the data.
The study included 795 RA patients (mean age 55.3 years, 69% females, 66% rheumatoid factor [RF] positive). During the mean follow-up of 9.7 years, 92 patients developed HF. The risk of HF was associated with RF positivity (HR 1.6, 95%CI 1.0, 2.5), erythrocyte sedimentation rate (ESR) at RA incidence (HR 1.6, 95%CI 1.2, 2.0), repeatedly high ESR (HR 2.1, 95%CI 1.2, 3.5), severe extra-articular manifestations (HR 3.1, 95%CI 1.9, 5.1) and corticosteroid use (HR 2.0, 95%CI 1.3, 3.2), adjusting for CV risk factors and coronary heart disease (CHD). Methotrexate users were half as likely to have HF as non-users (HR 0.5, 95%CI 0.3, 0.9).
Several RA characteristics and the use of corticosteroids were associated with HF adjusting for CV risk factors and CHD. Methotrexate use appeared to be protective against HF. These findings suggest an independent impact of RA on HF which may be further modified by antirheumatic treatment.
PMCID: PMC3337549  PMID: 21572155
rheumatoid arthritis; heart failure; determinants
10.  A Signature of Aberrant Immune Responsiveness Identifies Myocardial Dysfunction in Rheumatoid Arthritis 
Arthritis and rheumatism  2011;63(6):1497-1506.
Heart failure is an important cause of mortality in patients with rheumatoid arthritis (RA). Evidence suggests that immune mechanisms contribute to myocardial injury and fibrosis, leading to left ventricular diastolic dysfunction (LVDD). In this study, we sought to identify a signature of LVDD in patients with RA by analyzing the responsiveness of the innate and adaptive immune systems to stimulation ex vivo.
Subjects (n=212) enrolled prospectively from a population-based cohort underwent echocardiography, and left ventricular function was classified as normal, mild LVDD, or moderate-to-severe LVDD. The release of 17 cytokines by blood mononuclear cells in response to stimulation with a panel of 7 stimuli or in media alone was analyzed using multiplexed immunoassays. Logistic regression models were used to test for associations between a multi-cytokine immune response score and LVDD after adjusting for clinical covariates.
An 11-cytokine profile effectively differentiated subjects with moderate-to-severe LVDD from those with normal LV function. An immune response score (range 0 – 100) was strongly associated with moderate-to-severe LVDD (odds ratio per 10 units: 1.5; 95% confidence interval: 1.2, 2.1) after adjusting for serum IL-6, brain natriuretic peptide, and glucocorticoid use, as well as other RA characteristics and LVDD risk factors.
The major finding of this study is that aberrant systemic immune responsiveness is associated with advanced myocardial dysfunction in patients with RA. The unique information added by the immune response score on the likelihood of LVDD warrants future longitudinal studies of its value in predicting future deterioration in myocardial function.
PMCID: PMC3106129  PMID: 21384332
11.  B-Type Natriuretic Peptide is a Poor Screening Tool for Left Ventricular Diastolic Dysfunction in Rheumatoid Arthritis Patients without Clinical Cardiovascular Disease 
Arthritis care & research  2011;63(5):729-734.
Patients with rheumatoid arthritis (RA) are at increased risk for heart failure and left ventricular diastolic dysfunction (LVDD). BNP may be useful to screen for LVDD in the general population.
We compared the effectiveness of B-type natriuretic peptide (BNP) as a screening tool for LVDD in RA and non-RA subjects without cardiovascular disease (CVD).
Study subjects were recruited from population-based samples with and without RA, excluding subjects with CVD. LVDD was assessed by 2D/Doppler echocardiography and categorized as none, mild, moderate/severe or indeterminate. Linear regression and proportional odds models evaluated the association between LVDD and BNP adjusting for age, sex, and body mass index.
Among 231 RA and 1730 non-RA subjects without CVD, BNP was significantly higher in subjects with moderate/severe LVDD compared to those with no or mild LVDD (p= 0.02 for RA and p<0.001 for non-RA subjects). More RA subjects had elevated BNP than non-RA subjects (16% vs. 9%, p<0.001). Positive predictive value (25% in RA and 18% in non-RA) and sensitivity (40% in RA and 26% in non-RA) were similarly low in both cohorts, but specificity was significantly lower in RA than in non-RA (89% vs. 94%, p=0.02).
While RA subjects were more likely to have elevated BNP, few RA patients with elevated BNP actually have LVDD. Also, normal BNP levels are less likely to rule out LVDD in RA than in non-RA subjects. Thus, BNP may be less effective for screening in RA subjects compared to the general population.
PMCID: PMC3091972  PMID: 21225672
Annals of the rheumatic diseases  2011;70(3):482-487.
To examine the impact of systemic inflammation and serum lipids on cardiovascular disease (CVD) in rheumatoid arthritis (RA).
In a population-based RA incident cohort (1987 ACR criteria first met between 1988 and 2007), we collected serum lipid measures, erythrocyte sedimentation rates (ESR), C-reactive protein (CRP) measures and cardiovascular events including ischemic heart disease, and heart failure. Cox models were used to examine the association of lipids and inflammation with the risk of CVD and mortality adjusting for age, sex and year of RA incidence.
The study included 651 RA patients (mean age 55.8 years, 69% female); 67% were rheumatoid factor positive. ESR was associated with the risk of CVD (hazard ratio [HR] 1.2 per 10 mm/hr increase, 95% confidence interval [CI] 1.1, 1.3). Similar findings, although not statistically significant, were seen with CRP (p=0.07). We found a significant nonlinear association for total cholesterol (TCh) on risk of CVD, with 3.3-fold increased risk for TCh<4 mmol/L (95%CI 1.5, 7.2) and no increased risk of CVD for TCh≥4 mmol/L (p=0.57). Low low-density cholesterol (LDL<2 mmol/L) was associated with marginally increased risk of CVD (p=0.10); there was no increased risk for LDL≥2 mmol/L (p=0.76).
Inflammatory measures (particularly, ESR) are significantly associated with the risk of CVD in RA. Lipids may have paradoxical associations with the risk of CVD in RA, whereby lower TCh and LDL levels are associated with increased cardiovascular risk.
PMCID: PMC3058921  PMID: 21216812
rheumatoid arthritis; inflammation; lipid paradox; cardiovascular outcomes; ESR; CRP; lipids
13.  The Lifetime Risk of Adult-Onset Rheumatoid Arthritis and Other Inflammatory Autoimmune Rheumatic Diseases 
Arthritis and rheumatism  2011;63(3):633-639.
Understanding of the personal risks for rheumatoid arthritis (RA) and other rheumatic diseases remains poor, despite advances in knowledge of their pathogenesis, therapeutics, and clinical impact, in part because the personal lifetime risk of developing these diseases is unknown.
To estimate the lifetime risk of RA, as well as other inflammatory autoimmune rheumatic diseases, including systemic lupus erythematosus, psoriatic arthritis, polymyalgia rheumatica (PMR), giant cell arteritis, ankylosing spondylitis, and Sjögren’s syndrome, and to provide an overall estimate of the risk for developing inflammatory autoimmune rheumatic disease over a lifetime.
Using the incidence rates obtained from our population-based studies of rheumatic diseases among residents of Olmsted County, Minnesota, and mortality rates from life tables for the general population, we estimated sex-specific lifetime risk of rheumatic disease.
The lifetime risk of RA developing in US adults is 3.6% for women and 1.7% for men, and the lifetime risk of rheumatoid factor positive RA is 2.4% for women and 1.1% for men. The second most common inflammatory autoimmune rheumatic disease is PMR with a lifetime risk of 2.4% for women and 1.7% among men. The overall lifetime risk of inflammatory autoimmune rheumatic disease was 8.4% for women and 5.1% for men.
One in 12 women and 1 in 20 men will develop inflammatory autoimmune rheumatic disease during their lifetime. These results can serve as useful guides in counseling patients regarding their lifetime risk of these conditions and have important implications for disease awareness campaigns.
PMCID: PMC3078757  PMID: 21360492
14.  Increased Prevalence of Metabolic Syndrome Associated with Rheumatoid Arthritis in Patients Without Clinical Cardiovascular Disease 
The Journal of rheumatology  2010;38(1):29-35.
The purpose of our study was to examine whether rheumatoid arthritis (RA) patients with no overt cardiovascular disease (CVD) have a higher prevalence of metabolic syndrome (MetS) than subjects without RA or CVD. We also examined whether RA disease characteristics are associated with the presence of MetS in RA patients without CVD.
Subjects from a population-based cohort of patients who fulfilled 1987 ACR criteria for RA between 1/1/1980 and 12/31/2007 were compared to non-RA subjects from the same population. All subjects with any history of CVD were excluded. Waist circumference, body mass index (BMI), and blood pressure were measured during the study visit. Data on CVD, lipids and glucose measures were ascertained from medical records. MetS was defined using NCEP/ATP III criteria. Differences between the 2 cohorts were examined using logistic regression models adjusted for age and sex.
The study included 232 RA subjects without CVD and 1241 non-RA subjects without CVD. RA patients were significantly more likely to have an elevated waist circumference and elevated blood pressure than non-RA subjects, even though BMI was similar in both groups. Significantly more RA patients were classified as having MetS. In RA patients, MetS was associated with Health Assessment Questionnaire disability index, large joint swelling and uric acid levels, but not with C-reactive protein or RA therapies.
Among subjects without a history of CVD, RA patients are more likely to have MetS than non-RA subjects. MetS in RA patients was associated some measures of disease activity.
PMCID: PMC3014403  PMID: 20952464
15.  Total Cholesterol and LDL levels decrease before rheumatoid arthritis 
Annals of the rheumatic diseases  2009;69(7):1310-1314.
To compare lipid profiles in patients with rheumatoid arthritis (RA) and non-RA subjects during the 5 years before and 5 years after RA incidence/index date.
Lipid measures were abstracted in a population-based incident cohort of RA patients (1987 ACR criteria) first diagnosed between 1/1/1988 and 1/1/2008 and in non-RA subjects. Random effects models adjusting for age, sex and calendar year were used to examine trends in lipid profiles, accounting for multiple measurements per subject.
Study population included a cohort of 577 RA patients (a total of 3,088 lipid measurements) and 540 non-RA subjects (a total of 3,048 lipid measurements). There were significant decreases in total [TCh] and low-density cholesterol [LDL] levels in the RA cohort during the 5 years before RA, compared to the non-RA cohort (p<0.001). Trends in other lipid measures (triglycerides and high-density cholesterol) were similar in RA and non-RA cohorts during the 5 years before and 5 years after RA incidence/index date. During the 5 years before RA incidence/index date, the proportion of RA patients with elevated TCh or LDL measures, but not with abnormal HDL and TG measures, significantly decreased compared to non-RA subjects. Lipid-lowering drugs (statins in particular) were less often (p=0.02) prescribed to RA patients than to non-RA subjects.
TCh and LDL levels and the prevalence of abnormal TCh or LDL measures decreased significantly during the 5 years before RA incidence/index date in RA patients as compared to non-RA cohort. These trends in lipid profile in RA are unlikely to be solely due to lipid-lowering therapy.
PMCID: PMC2890039  PMID: 19854708
rheumatoid arthritis; lipid profiles; longitudinal lipid trends
16.  Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007 
Arthritis and rheumatism  2010;62(6):1576-1582.
To examine the trends in incidence and prevalence of rheumatoid arthritis (RA) from 1995 to 2007.
To augment our preexisting inception cohort of RA patients (1955-1994), we assembled a population-based incidence cohort of individuals aged ≥18 years who first fulfilled ACR 1987 criteria for RA between 1/1/1995 and 12/31/2007 and a cohort of patients with prevalent RA on 1/1/2005. Incidence and prevalence rates were estimated and were age- and sex-adjusted to the 2000 US whites. Trends in incidence rates were examined using Poisson regression methods.
The 1995-2007 incidence cohort comprised 466 patients (mean age 55.6 years; 66% female; 69% rheumatoid factor positive). The overall age- and sex-adjusted annual RA incidence was 40.9/100,000 population. The age-adjusted incidence in women was 53.1/100,000 population,(in men: 27.7/100,000 population). During 1995-2007 there was a moderate increase in RA incidence in women (p=0.02), but not in men (p=0.74). The increase was similar among all age groups. The overall age- and sex-adjusted prevalence on 1/1/2005 was 0.72% (95% CI 0.66–0.77) up from 0.62% (95% CI 0.55–0.69) in 1995 (p<0.001). Applying the 1/1/2005 prevalence to the US 2005 population, an estimated 1.5 million US adults are affected by RA. This is up from the 1.3 million reported previously.
The incidence of RA appears to be rising in women during 1995-2007 period. The reasons for this recent increase in incidence are unknown, but environmental factors may play a role. A corresponding increase in prevalence of RA was also found.
PMCID: PMC2929692  PMID: 20191579
rheumatoid arthritis; incidence; longitudinal trends
17.  Could Accelerated Aging Explain the Excess Mortality in Seropositive Rheumatoid Arthritis Patients? 
Arthritis and rheumatism  2010;62(2):378-382.
To determine whether the mortality pattern in seropositive RA patients is consistent with the concept of accelerated aging by comparing the observed mortality rates in RA to age accelerated mortality rates from the general population using statistical models.
A population-based inception cohort of seropositive RA patients (1987 ACR criteria) was assembled and followed for vital status until July 1, 2008. Expected mortality was obtained by applying the death rates of the general population to the age, sex and calendar year distribution of the RA population. Observed mortality was estimated using Kaplan-Meier methods. Acceleration factors were estimated for expected mortality using accelerated failure time models.
A total of 755 seropositive RA patients (mean age of 55.6 years, 69% women) had a mean follow-up of 12.5 years during which 315 patients died. The expected median survival was age 82.4 years, whereas the median survival for the RA patients was age 76.7 years. The models suggest that, in terms of mortality rates, RA patients are effectively 2 years older at RA incidence, and thereafter age 11.4 effective years for each 10 years of calendar time.
The overall observed mortality experience of seropositive RA patients is consistent with the hypothesis of accelerated aging. The causes of accelerated aging in RA deserve further investigation.
PMCID: PMC2929694  PMID: 20112366
Rheumatoid arthritis; accelerated aging; mortality
18.  Do Rheumatoid Arthritis Patients Have a Higher Risk for Sleep Apnea? 
The Journal of rheumatology  2009;36(9):1869-1872.
Patients with rheumatoid arthritis (RA) have an increased risk for developing cardiovascular disease (CVD) compared to subjects in the general population. The development of CVD has also been linked to chronic sleep apnea. The purpose of this study was to examine the risk for sleep apnea in patients with RA compared to subjects without RA.
This study recruited RA patients and non-RA subjects who were age and sex matched from the same population. These persons completed the Berlin Sleep Questionnaire, which evaluated their level of risk (high or low) for sleep apnea. In addition, there were three subscales evaluating snoring, fatigue, and relevant comorbidities (i.e. high blood pressure and obesity (body mass index (BMI) ≥ 30 kg/m2)). Chi-square tests were used for comparisons.
The study population consisted of 164 patients with RA and 328 patients without RA. Age, sex and BMI were similar for both groups. There was no difference in snoring (p = 0.31) or in the comorbidities subscale (p = 0.37). However, RA patients reported more fatigue (38%) than subjects without RA (13%; p < 0.001). Overall, the risk for sleep apnea was significantly higher for the RA patients (50%) than the non-RA subjects (31%; p < 0.001).
RA patients may be at a higher risk for sleep apnea compared to non-RA subjects. This apparent risk difference may be attributed to the reports of fatigue in the RA patients, which may be associated with sleep apnea or the RA disease itself.
PMCID: PMC2834190  PMID: 19648298
Sleep Apnea; Rheumatoid Arthritis; Cardiovascular Disease
19.  Increased Prevalence of Diastolic Dysfunction in Rheumatoid Arthritis 
Annals of the rheumatic diseases  2010;69(9):1665-1670.
To compare the prevalence of left ventricular (LV) diastolic dysfunction in subjects with and without rheumatoid arthritis (RA), among those with no history of heart failure (HF), and to determine risk factors for diastolic dysfunction in RA.
We conducted a cross-sectional, community-based study comparing cohorts of adult RA and non-RA subjects without a history of HF. Standard 2D/Doppler echocardiography was performed in all participants. Diastolic dysfunction was defined as impaired relaxation (with or without increased filling pressures) or advanced reduction in compliance or reversible or fixed restrictive filling.
The study included 244 RA subjects and 1448 non-RA subjects. Mean age was 60.5 years in the RA cohort (71% female) and 64.9 years (50% female) in the non-RA cohort. The vast majority (>98%) of both cohorts had preserved ejection fraction (EF≥50%). Diastolic dysfunction was more common in RA subjects at 31% compared to 26% (age and sex adjusted) in non-RA subjects (OR 1.6; 95% CI 1.2, 2.4). RA subjects had significantly lower LV mass, higher pulmonary arterial pressure, and higher left atrial volume index than non-RA subjects. RA duration and IL-6 level were independently associated with diastolic dysfunction in RA even after adjustment for cardiovascular risk factors.
Subjects with RA have a higher prevalence of diastolic dysfunction than those without RA. RA duration and IL-6 are independently associated with diastolic dysfunction suggesting the impact of chronic autoimmune inflammation on myocardial function in RA. Clinical implications of these findings require further investigation.
PMCID: PMC2920362  PMID: 20498217
20.  High 10-year risk of cardiovascular disease in newly diagnosed Rheumatoid Arthritis (RA) patients 
Arthritis and rheumatism  2008;58(8):2268-2274.
The purpose of this study was to estimate the 10-year absolute risk of CV events in newly diagnosed RA subjects and the potential contribution of CV risk factors to absolute risk assessment.
A population-based incidence cohort of RA subjects (ascertained according to ACR criteria) was assembled and compared to an age and sex-matched cohort of non-RA subjects. Data were collected on CV risk factors and CV events. Cox regression models were used to estimate the 10-year risk of a combined CV endpoint, adjusting for CV risk factors. Subjects were classified into 5 risk categories based on their 10-year absolute risk.
The absolute CV risk in RA subjects was similar to that of non-RA subjects who were 5-10 years older. The absolute risk varied substantially according to presence of CV risk factors. The 10-year absolute CV risk among 60-69 year old RA subjects with no risk factors was 16.8% but rose to 60.4% in the presence of smoking, hypertension, dyslipidemia, diabetes and obesity. Among RA subjects with low, as compared to normal or high BMI, in addition to the above risk factors, the 10-year absolute CV risk rose to 86.2%.
More than half of 50-59 year old newly diagnosed RA subjects and all of those >60 years of age had a 10% or greater risk of CV disease within the next 10 years and should be targeted for specific CV risk reduction strategies tailored to their personal risk profiles.
PMCID: PMC2929699  PMID: 18668561
Mortality; Rheumatoid Arthritis; Cardiovascular disease; absolute risk
21.  Cardiovascular Morbidity and Mortality in Rheumatoid Arthritis 
The American journal of medicine  2008;121(10 Suppl 1):S9-14.
Patients with rheumatoid arthritis (RA) are at increased risk of mortality compared with the general population. Evidence suggests that this increased mortality can largely be attributed to increased cardiovascular (CV) death. In a retrospective study of an inception cohort of RA patients in Rochester, MN, we found that patients with RA were at increased risk of CV death, ischemic heart disease, and heart failure compared with age- and sex-matched community controls. In addition, when we examined coronary artery tissue from autopsied RA patients, we observed increased evidence of inflammation and an increased proportion of unstable plaques. We also investigated the contribution of traditional and RA-specific risk factors to this increased risk of CV morbidity and mortality. Although traditional CV disease risk factors were found to contribute to the increased risk of mortality in RA patients, they did not fully explain the increased CV mortality observed in RA. Instead, increased inflammation associated with RA appears to contribute substantially to the increased CV mortality. Together with other studies that have demonstrated similar associations between RA and CV mortality, these data suggest that more aggressive management of inflammation in RA may lead to significant improvements in outcomes for patients with RA.
PMCID: PMC2858687  PMID: 18926169
Rheumatoid arthritis; ischemic heart disease; congestive heart failure; epidemiology; cardiovascular mortality
22.  Autoantibodies and the Risk of Cardiovascular Events 
The Journal of rheumatology  2009;36(11):2462-2469.
Inflammation and autoimmunity are associated with increased cardiovascular (CV) risk in rheumatoid arthritis patients. This association may also be present in those without rheumatic diseases. The purpose of this study was to determine whether rheumatoid factor (RF), antinuclear antibody (ANA), and cyclic citrullinated peptide antibody (CCP) positivity are associated with increased risk of CV events and overall mortality in both those with and without rheumatic diseases.
We performed a population-based cohort study of all subjects who had a RF and/or ANA test performed between 1/1/1990 and 1/1/2000, and/or CCP test performed between 9/1/2003 and 1/1/2005, with follow-up until 4/1/2007. Outcomes were ascertained using diagnostic indices from complete medical records, including: CV events [myocardial infarction (MI), heart failure (HF), and peripheral vascular disease (PVD)], and mortality. Cox models were used to analyze the data.
There were 6783 subjects with RF, 7852 with ANA, and 299 with CCP testing. Of these, 10.4%, 23.9% and 14.7% were positive for RF, ANA and CCP, respectively. Adjusting for age, sex, calendar year, comorbidity and rheumatic disease, RF and ANA positivity were significant predictors of CV events (HR 1.24 & 1.26) and death (HR 1.43 & 1.18). Adjusting for age, CCP positivity was associated with CV events but this association was not statistically significant (HR 3.1; 95% CI 0.8, 12.3).
RF and ANA positivity are significant predictors of CV events and mortality in both those with and without rheumatic diseases. These results support the role of immune dysregulation in the etiology of CV disease.
PMCID: PMC2837072  PMID: 19833748
Autoantibodies; cardiovascular diseases; rheumatoid factor; antibodies; antinuclear; mortality
23.  Mortality Trends in Rheumatoid Arthritis: The role of Rheumatoid Factor 
The Journal of rheumatology  2008;35(6):1009-1014.
We have previously demonstrated a widening in the mortality gap between rheumatoid arthritis (RA) subjects and the general population. To further understand this widening in mortality gap, we examined the contribution of rheumatoid factor (RF) positivity on overall mortality trends and cause specific mortality.
A population-based RA incidence cohort (1955–1995, and aged ≥18 years) was followed longitudinally until death or 1/1/2006. The underlying cause of death as coded from national mortality statistics and grouped according to ICD-9/10 chapters was used to define cause specific mortality. Expected cause-specific mortality rates were estimated by applying the age-, sex- and calendar year-specific mortality rates from the general population to the RA cohort. Poisson regression was used to model the observed overall and cause specific mortality rates according to RF status, accounting for age, sex, disease duration, and calendar year.
A cohort of 603 subjects (73% female; mean age 58 years) with RA were followed for a mean of 16 years, during which 398 died. Estimated survival at 30 years after RA incidence was 26.0% in RF(+) RA subjects compared to 36.0% expected (p<0.001), while in RF(−) RA subjects, estimated survival was 29.1% compared to 28.3% expected (p=0.9). The difference between the observed and the expected mortality in the RF(+) RA subjects increased over time, resulting in a widening of the mortality gap, while among RF(−) RA subjects, observed mortality was very similar to the expected mortality over the entire time period. Among RF(+) RA subjects, cause specific mortality was higher than expected for cardiovascular (relative risk [RR] 1.50; 95% confidence interval [CI] 1.22, 1.83) and respiratory diseases (RR 3.49; 95% CI 2.51, 4.72). Among RF(−) RA subjects, no significant differences were found between observed and expected cause specific mortality.
The widening in the mortality gap between RA subjects and the general population is confined to RF(+) RA subjects and largely driven by cardiovascular and respiratory deaths.
PMCID: PMC2834198  PMID: 18412312
Survival; Rheumatoid Factor; Rheumatoid Arthritis; Epidemiology; Trends
24.  Systemic Lupus Erythematosus Features in Rheumatoid Arthritis and Their Impact on Overall Mortality 
The Journal of rheumatology  2009;36(1):50-57.
Systemic lupus erythematosus (SLE) features are commonly observed in patients with rheumatoid arthritis (RA). However, their frequency and clinical significance are uncertain. We examined the frequency of SLE features in RA and their impact on overall mortality.
We assembled a population-based incidence cohort of subjects aged ≥18 years first diagnosed with RA (1987 American College of Rheumatology [ACR] criteria) between 1955–95. Information regarding disease characteristics, therapy, comorbidities and SLE features (1982 ACR criteria) were collected from the complete inpatient and outpatient medical records. Cox regression models were used to estimate the mortality risk associated with lupus features.
The study population comprised 603 incident RA subjects (mean age 58 years, 73% female) with a mean follow-up time of 15 years. By 25 years after RA incidence, ≥4 SLE features were observed in 15.5% of the RA subjects. After adjustment for age and sex, occurrence of ≥4 SLE features was associated with increased overall mortality (hazard ratio [HR] 5.54, 95% confidence interval [CI] 3.59–8.53). With further adjustment for RA characteristics, therapy and comorbidities, the association weakened but remained statistically significant (HR: 2.56, 95% CI 1.60–4.08). After adjustment for age, sex, RA characteristics, therapy and comorbidities, thrombocytopenia (2.0, 95% CI: 1.2, 3.1) and proteinuria (1.8, 95% CI: 1.3, 2.6) were significantly associated with mortality.
SLE features were common in RA, given sufficient observation time. Subjects with RA who developed ≥4 SLE features had an increased risk of death. Proteinuria and thrombocytopenia were individually associated with an increased mortality risk.
PMCID: PMC2836232  PMID: 19004043
Rheumatoid arthritis; systemic lupus erythematosus; mortality
25.  Why do persons with rheumatoid arthritis still die prematurely? 
Annals of the rheumatic diseases  2008;67(Suppl 3):iii30-iii34.
PMCID: PMC2830861  PMID: 19022810
Rheumatoid arthritis; mortality; cardiovascular disease

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