Longitudinal relationships between rheumatoid factor and cytokine expression by immunostimulated peripheral blood lymphocytes from patients with rheumatoid arthritis: New insights into B-cell activation.

To identify associations between immunostimulated cytokine production and disease characteristics, peripheral blood lymphocytes were collected from 155 adult patients with rheumatoid arthritis (RA) before and after a 5-year interval. The lymphocytes were activated in vitro with T-cell stimulants, cytosine-phosphate-guanine (CpG) oligonucleotide, and medium alone (negative control). Expression of 17 cytokines was evaluated with immunoassays, and factor analysis was used to reduce data complexity and identify cytokine combinations indicative of cell types preferentially activated by each immunostimulant. The findings showed that the highest numbers of correlations were between cytokine levels and rheumatoid factor (RF) positivity and between cytokine levels and disease duration. Scores for cytokines driven by CpG and medium alone were negatively associated with RF positivity and disease duration at baseline but positively associated with both at 5 years. Our findings suggest that RF expression sustained over time increases activation of B cells and monocytes without requirements for T-cell functions.

Secular trends in the incidence and prevalence of rheumatoid arthritis within members of an integrated health care delivery system.

The study objective was to estimate secular trends in the overall incidence rate (IR) and prevalence rate (PR) of rheumatoid arthritis (RA); and subgroup-specific IR and PR by race, ethnicity, and sex in a multi-ethnic population of a large integrated health care delivery system. An ecological study was conducted within the adult population of Kaiser Permanente Southern California health plan. From January 1995 up to and including December 2014, annual IR and PR were calculated separately by race, ethnicity, sex and pooled overall. Depending on the stationarity of each ecological series, annual percentage change in IR and PR was evaluated using auto-regressive integrated moving average models. Average overall IR was 53 [95% confidence interval (CI) 46, 61] per 100,000 person-years. The overall as well as subgroup-specific annual IR of RA were unchanged from 1995 to 2014. In 1995, the overall PR of RA was 59 (44, 74) per 100,000 person-years which increased by 14% (7%, 21%) annually thereafter. The increase in PR in Caucasians was lower as compared to African American, Asian and other race (13% vs 15%, 15%, and 18%, respectively). Compared to non-Hispanic ethnicity, the increase in PR among Hispanic was higher (17% vs 14%). Over the past 2 decades, while the incidence of RA was unchanged, the prevalence had increased significantly overall as well as within every subgroup of race, ethnicity, and sex.

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis.

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.

Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries.

Objectives: Cardiovascular disease (CVD) risk calculators developed for the general population do not accurately predict CVD events in patients with RA. We sought to externally validate risk calculators recommended for use in patients with RA including the EULAR 1.5 multiplier, the Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) and QRISK2. Methods: Seven RA cohorts from UK, Norway, Netherlands, USA, South Africa, Canada and Mexico were combined. Data on baseline CVD risk factors, RA characteristics and CVD outcomes (including myocardial infarction, ischaemic stroke and cardiovascular death) were collected using standardized definitions. Performance of QRISK2, EULAR multiplier and ERS-RA was compared with other risk calculators [American College of Cardiology/American Heart Association (ACC/AHA), Framingham Adult Treatment Panel III Framingham risk score-Adult Treatment Panel (FRS-ATP) and Reynolds Risk Score] using c-statistics and net reclassification index. Results: Among 1796 RA patients without prior CVD [mean ( s . d .) age: 54.0 (14.0) years, 74% female], 100 developed CVD events during a mean follow-up of 6.9 years (12430 person-years). Estimated CVD risk by ERS-RA [mean ( s . d .) 8.8% (9.8%)] was comparable to FRS-ATP [mean ( s . d .) 9.1% (8.3%)] and Reynolds [mean ( s . d .) 9.2% (12.2%)], but lower than ACC/AHA [mean ( s . d .) 9.8% (12.1%)]. QRISK2 substantially overestimated risk [mean ( s . d .) 15.5% (13.9%)]. Discrimination was not improved for ERS-RA (c-statistic = 0.69), QRISK2 or EULAR multiplier applied to ACC/AHA compared with ACC/AHA (c-statistic = 0.72 for all) or for FRS-ATP (c-statistic = 0.75). The net reclassification index for ERS-RA was low (-0.8% vs ACC/AHA and 2.3% vs FRS-ATP). Conclusion: The QRISK2, EULAR multiplier and ERS-RA algorithms did not predict CVD risk more accurately in patients with RA than CVD risk calculators developed for the general population.

Predictors of Dissection in Aortic Aneurysms From Giant Cell Arteritis.

BACKGROUND: Factors associated with dissection from inflammatory aortic aneurysms may be different from those in the general population. OBJECTIVE: The aim of this study was to evaluate the risk factors for aortic dissection/rupture in patients with giant cell arteritis (GCA) and aortic aneurysms. METHODS: A population-based incident cohort of patients with a diagnosis of GCA from 1950 to 2004 was used. All patients with aortic aneurysms diagnosed 1 year prior to GCA diagnosis or any time thereafter were included. Cox proportional hazard models were used to evaluate risk factors for aortic dissection/rupture. RESULTS: The study included 33 patients (91% women) with GCA and aortic aneurysms. Mean age at diagnosis of aortic aneurysm was 83.6 years. There were 27 thoracic aneurysms and 19 abdominal aneurysms. Eight patients developed aortic dissection/rupture (both thoracic and abdominal aorta in 5 cases, thoracic aorta only in 2 cases, and isolated abdominal aorta in 1 case).Older age (hazard ratio [HR], 0.27 per 10 years; 95% confidence interval [CI], 0.09-0.86) and later calendar year at diagnosis of aortic aneurysm (HR, 0.29 per 10 years; 95% CI, 0.13-0.69) were associated with decreased risk of dissection/rupture. Size of the thoracic aneurysm (HR, 1.17; 95% CI, 0.69-1.99) was not associated with dissection/rupture. Histopathology showed active aortitis in 4 of 7 patients with aortic dissection/rupture compared with 0 of 7 patients with aortic aneurysm without dissection/rupture. CONCLUSIONS: Aneurysm size was not a predictor of aortic dissection/rupture in this cohort of patients with GCA. The higher frequency of active aortitis in patients with dissection suggests that active inflammation may play a role.

Population-based study of QT interval prolongation in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular morbidity and mortality. Heart rate corrected QT interval (QTc) (which is obtained from a 12-lead electrocardiogram (ECG) and reflects ventricular repolarisation duration) is a strong predictor of cardiovascular mortality. Our primary purpose is to determine the impact of QTc prolongation on mortality in RA patients. METHODS: A population-based inception cohort of patients with RA fulfilling the 1987 ACR criteria in 1988-2007 was identified, with an age- and sex-matched comparison cohort and followed until death, migration or until the end of 2008. Data were collected on ECG variables, medications known to prolong QT interval, electrolytes, cardiovascular risk factors and disease status and RA disease characteristics. Cox proportional hazards models were used to examine QTc prolongation as predictor of mortality. RESULTS: QTc prolongation prior to RA incidence/index date was similar in RA (15%) and non-RA (18%) subjects. During follow-up, the cumulative incidence of QTc prolongation was higher among RA (48% at 20 years after RA incidence) than non-RA (38% at 20 years after index date; p=0.004). Idiopathic QTc prolongation (excluding prolongations explained by ECG changes, medications, etc.) was marginally associated with all-cause mortality (HR: 1.28; 95% CI: 0.91-1.81, p=0.16), but was not associated with cardiovascular mortality (HR: 1.10; 95% CI:0.43-2.86, p=0.83) in RA. CONCLUSIONS: RA patients have a significantly elevated risk of developing QTc prolongation. However, idiopathic prolonged QTc was only marginally associated with all-cause mortality in RA patients. The clinical implications of these findings in RA require further study.

Frequency of radiologic procedures in patients with rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) undergo radiologic investigations for disease and comorbidity evaluation. The actual use of radiologic imaging in RA is unknown. METHODS: Using the Rochester Epidemiology Project medical record linkage system, adult patients from previously assembled population-based cohorts of Olmsted County, Minnesota, residents who fulfilled the 1987 American College of Rheumatology criteria for RA in 1988 to 2007 and comparator subjects without RA of similar age and gender were studied. Data on all radiologic procedures performed were collected. RESULTS: The study included 650 patients with RA and 650 patients without RA. Patients with RA had significantly more radiographs of the chest (rate ratio [RR], 1.33; 95% confidence interval [CI], 1.28-31.38), upper extremity (RR, 2.97; 95% CI, 2.80-83.17), lower extremity (RR, 2.05; 95% CI, 1.94-102.16), spine (RR, 1.46; 95% CI, 1.35-41.59), and hip, pelvis, or sacroiliac joints (RR, 1.14; 95% CI, 1.03-11.26), as well as bone radionuclide (RR, 1.90; 95% CI, 1.50-52.44) and dual-energy x-ray absorptiometry imaging (RR, 1.77; 95% CI, 1.59-61.98) compared with patients without RA. Among patients with RA, having a positive rheumatoid factor was associated with an increased likelihood of undergoing radiologic procedures (RR, 1.05; 95% CI, 1.02-11.07). Women with RA underwent more imaging procedures than men (RR, 1.20; 95% CI, 1.16-21.23). CONCLUSIONS: Patients with RA undergo more radiologic procedures than patients without RA. Among patients with RA, women and patients with a positive rheumatoid factor have more radiologic procedures. The utilization of radiography is likely a reflection of overall disease burden. Despite some guidelines, routine hand wrist radiographs were not obtained with regularity; "overuse" is unlikely.

Evaluation of myocardial function in patients with rheumatoid arthritis using strain imaging by speckle-tracking echocardiography.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD), although strategies to detect subclinical CVD are poorly characterised. The purpose of this study was to assess myocardial function by speckle-tracking echocardiography strain imaging in patients with RA without known CVD. METHODS: Eighty-seven patients with RA selected from a population-based sample underwent echocardiography. Left ventricular (LV) and right ventricular (RV) longitudinal peak systolic strain were measured. A subset of 59 patients with RA was compared with 59 age-, gender- and race-matched subjects with normal echocardiography and no CVD or risk factors. RESULTS: The mean ± SD age of the patients with RA and the normal patients was 55.7±12.1 and 54.5±12.2 years (p=0.42), respectively, with 45 (76%) women in each group. Global LV strain (-15.7±3.2% vs -18.1±2.4%, p<0.001) and RV strain (-17.9±4.7% vs -20.7±2.4%, p<0.001) was reduced in patients with RA compared with normal patients. Among all 87 patients with RA the mean disease duration and C-reactive protein at echocardiography were 10.0±6.1 years and 3.5±3.7 mg/L, and 74% were seropositive. Adjusted univariate regression analysis demonstrated a significant correlation between global LV strain and RA Health Assessment Questionnaire disability index (p=0.032), and borderline associations with prior use of oral corticosteroids (p=0.062) and methotrexate (p=0.054) after adjustment for age, gender, blood pressure, body mass index, heart rate and LV mass index. CONCLUSIONS: Global longitudinal LV and RV strain is reduced in patients with RA compared with healthy patients. Strain abnormalities correlate with RA disease severity. Strain imaging by echocardiography may detect early myocardial dysfunction in RA.

Cardiovascular disease assessment in rheumatoid arthritis: a guide to translating knowledge of cardiovascular risk into clinical practice.

As physicians we like to have evidence for making decisions about interventions to improve health. The evidence vacuum in the field of cardiovascular disease (CVD) prevention and clinical outcome in patients with rheumatoid arthritis (RA) has received vigorous attention in the recent literature. There is broad agreement that a patient with RA fulfilling the criteria established for the general population on CVD risk reduction should receive proven interventions, including smoking cessation, weight reduction, blood pressure control and lipid-lowering therapy. In accordance with these recommendations, and despite all the uncertainties about CVD treatment threshold, targets and outcome results in RA, we firmly advocate that CVD risk should be assessed and acted on in patients with RA as recommended for the general population, even while educational CVD-preventive programmes are being developed and hard CVD end point studies are undertaken in this patient population. The initial strategies for implementing CVD risk evaluation will necessarily be modest at first. There are several possible strategies for collection of data that can be incorporated into the daily routine during rheumatology consultations at outpatient clinics. We recommend starting with these simple procedures: 1. CVD risk factor recording and evaluation using risk calculators available for the general population 2. Referral of patients with high CVD risk to a primary care physician or a cardiologist skilled in this subject for follow-up 3. Providing information about excess CVD risk and how to modify it to the patients as major stakeholders.

Development of reduced kidney function in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with a variety of kidney disorders. However, it is unclear whether the development of reduced kidney function is higher in patients with RA compared to the general population. STUDY DESIGN: Retrospective review. SETTING & PARTICIPANTS: Incident adult-onset RA cases (813) and a comparison cohort of non-RA individuals (813) in Olmsted County, MN, in 1980-2007. PREDICTOR: Baseline demographic and clinical variables. OUTCOMES: Reduced kidney function: (1) estimated glomerular filtration rate (eGFR)<60mL/min/1.73m(2) and (2) eGFR<45mL/min/1.73m(2) on 2 consecutive occasions at least 90 days apart; cardiovascular disease (CVD); and death. MEASUREMENTS: The cumulative incidence of reduced kidney function was estimated adjusting for the competing risk of death. RESULTS: Of 813 patients with RA and 813 non-RA individuals, mean age was 56±16 (SD) years, 68% were women, and 9% had reduced kidney function at baseline. The 20-year cumulative incidence of reduced kidney function was higher in patients with RA compared with non-RA participants for eGFR < 60mL/min/1.73m(2) (25% vs 20%; P=0.03), but not eGFR<45mL/min/1.73m(2) (9% vs 10%; P=0.8). The presence of CVD at baseline (HR, 1.77; 95% CI, 1.14-2.73; P=0.01) and elevated erythrocyte sedimentation rate in patients with RA (HR per 10-mm/h increase, 1.08; 95% CI, 1.00-1.16; P=0.04) was associated with increased risk of eGFR<60mL/min/1.73m(2). eGFR<60mL/min/1.73m(2) was not associated with increased risk of CVD development in patients with RA (HR, 0.99; 95% CI, 0.63-1.57; P=0.9), however, a greater reduction in GFR (eGFR<45mL/min/1.73m(2)) was associated with increased risk of CVD (HR, 1.93; CI, 1.04-3.58; P=0.04). LIMITATIONS: Reduced kidney function was defined by estimating equations for kidney function. We are limited to deriving associations from our findings. CONCLUSIONS: Patients with RA were more likely to develop reduced kidney function over time. CVD and associated factors appear to play a role. The presence of RA in individuals with reduced kidney function may lead to an increase in morbidity from CVD development, for which awareness may provide a means for optimizing care.

Brief report: accelerated aging influences cardiovascular disease risk in rheumatoid arthritis.

OBJECTIVE: To determine whether the impact of aging on cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA) differs from that in the general population (as estimated by the Framingham Risk Score [FRS]). METHODS: A population-based inception cohort of Olmsted County, Minnesota residents ages≥30 years who fulfilled the American College of Rheumatology 1987 criteria for RA in 1988-2008 was assembled and followed up until death, migration, or July 1, 2012. Data on CVD events were collected by medical records 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. RESULTS: The study included 563 patients with RA without prior CVD (mean age 55 years, 72% women, and 69% seropositive [i.e., rheumatoid factor and/or anti-citrullinated protein antibody positive]). During a mean followup of 8.2 years, 98 patients developed CVD (74 seropositive and 24 seronegative), but the 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 effect of age 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). CONCLUSION: Our findings indicate that 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.

Brief report: rheumatoid arthritis is associated with left ventricular concentric remodeling: results of a population-based cross-sectional study.

OBJECTIVE: To study left ventricular (LV) geometry in patients with rheumatoid arthritis (RA) and no history of heart failure compared with that in subjects with neither RA nor a history of heart failure, and to determine the impact of RA on LV remodeling. METHODS: A cross-sectional, community-based study was conducted among adult (age ≥50 years) patients with RA and age- and sex-matched subjects with neither RA nor a history of heart failure. All participants underwent standard 2-dimensional Doppler echocardiography. LV geometry was classified into the following 4 categories based on relative wall thickness and sex-specific cutoffs for the LV mass index: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, or normal geometry. RESULTS: Among 200 patients with RA and 600 age- and sex-matched subjects without RA, the mean age was 65 years, and 74% of the individuals in both cohorts were female. Compared with subjects without RA, patients with RA were significantly more likely to have abnormal LV geometry (odds ratio [OR] 1.44, 95% confidence interval [95% CI] 1.03-2.00), even after adjusting for cardiovascular risk factors and comorbidities. Among subjects with abnormal LV geometry, the odds of concentric LV remodeling were significantly increased in patients with RA (OR 4.73, 95% CI 2.85-7.83). In linear regression analyses, the LV mass index appeared to be lower in patients with RA who were currently receiving corticosteroids (ß ± SE -0.082 ± 0.027, P = 0.002), even after adjusting for cardiovascular risk factors and comorbidities. CONCLUSION: RA was strongly associated with abnormal LV remodeling (particularly concentric LV remodeling) among RA patients without heart failure. This association remained significant after adjustment for cardiovascular risk factors and comorbidities. RA disease-related factors may promote changes in LV geometry. The biologic mechanisms underlying LV remodeling warrant further investigation.

Cardiovascular comorbidity in rheumatic diseases: a focus on heart failure.

Rheumatic diseases are associated with an increased risk of cardiovascular (CV) mortality attributed to a higher incidence of heart failure (HF) and ischemic heart disease. Although traditional CV risk factors contribute to the increased incidence seen in this population, by themselves they do not account for the increased risk; in fact, obesity and hyperlipidemia may play a paradoxic role. Immune-mediated mechanisms and chronic inflammation likely play a role in the pathogenesis of CV disease in patients with rheumatic diseases. The usual clinical features of ischemic heart disease and HF are less likely to be seen in this patient population.

Rheumatoid arthritis and cardiovascular disease.

BACKGROUND: 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. METHODS: A review of current literature on heart disease and RA was conducted. RESULTS: 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. CONCLUSIONS: 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.

Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis.

OBJECTIVES: To evaluate incidence-trends and timing of large-vessel (LV) manifestations in patients with giant cell arteritis (GCA), and to examine the influence of LV manifestations on survival. METHODS: A population-based incident cohort of patients diagnosed with GCA between 1950 and 2004 was used. LV involvement was defined as large-artery stenosis or aortic aneurysm/dissection that developed in the 1 year before GCA diagnosis or at any time thereafter. Patients were followed up until death or 31 December 2009. RESULTS: The study included 204 patients, 80% women, mean age at diagnosis of GCA 76.0 years (±8.2 years). Median length of follow-up was 8.8 years. The cumulative incidence of any LV manifestation at 10 years was 24.9% for patients diagnosed with GCA between 1980 and 2004 compared with 8.3% for patients diagnosed with GCA between 1950 and 1979. The incidence of any LV event was high within the first year of GCA diagnosis. The incidence of aortic aneurysm/dissection increased 5 years after GCA diagnosis. Compared with the general population, survival was decreased in patients with an aortic aneurysm/dissection (standardized mortality ratio (SMR) 2.63; 95% CI 1.78 to 3.73) but not in patients with large-artery stenosis (SMR 1.44; 95% CI 0.87 to 2.25). Patients with GCA and aortic manifestations had a higher than expected number of deaths from cardiovascular and pulmonary causes than the general population. Among patients with GCA, aortic manifestations were associated with increased mortality (HR=3.4; 95% CI 2.2 to 5.4). CONCLUSIONS: Vigilance and screening for aortic aneurysms should be considered in all patients 5 years after the incidence of GCA. Aortic aneurysm/dissection is associated with increased mortality in GCA.

Noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events?

OBJECTIVE: To investigate the incidence of noncardiac vascular disease in a community-based incidence cohort of patients with rheumatoid arthritis (RA) and compare it to that in the general population and to investigate trends in the incidence of noncardiac vascular disease in patients with RA. METHODS: A population-based inception cohort of patients with incident RA between January 1, 1980 and December 31, 2007 in Olmsted County, Minnesota and a cohort of non-RA subjects from the same population base was assembled and followed up until December 31, 2008. Venous thromboembolic, cerebrovascular, and peripheral arterial events were ascertained by medical record review. RESULTS: The study population included 813 patients with RA with a mean±SD age of 55.9±15.7 years (68% women) and an average length of followup of 9.6±6.9 years. Compared to non-RA subjects of similar age and sex, patients diagnosed as having RA between 1995 and 2007 had a higher incidence (%) of venous thromboembolism (cumulative incidence±SE 6.7±1.7 versus 2.8±1.1, respectively; P=0.005) but similar rates of cerebrovascular and peripheral arterial events. Among patients with RA, the incidence of venous thromboembolic, cerebrovascular, and peripheral arterial events was similar in the 1995-2007 time period compared to the 1980-1994 time period. CONCLUSION: Our findings indicate that the incidence of venous thromboembolism is increased in patients with RA compared to non-RA subjects. The incidence of cerebrovascular events and peripheral vascular disease events is 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.

Risk factors for cardiovascular disease in rheumatoid arthritis.

PURPOSE OF REVIEW: To highlight recent evidence regarding the contribution of traditional and nontraditional [e.g. inflammatory markers, rheumatoid arthritis (RA) features] risk factors toward the excess cardiovascular risk in RA. RECENT FINDINGS: The impact of traditional risk factors on the development of cardiovascular disease in persons with RA is an area of active research. Some are more prevalent among people with RA (e.g. smoking); others appear to have paradoxical relationships (e.g. body mass index), and findings remain inconsistent with others (e.g. dyslipidemia). Collectively the data suggest that cardiovascular risk factors behave differently in RA. Thus, risk scores developed for the general population based on traditional cardiovascular risk factors alone are unlikely to accurately estimate cardiovascular risk in RA, highlighting the need for RA-specific risk prediction tools.Nontraditional risk factors, in particular RA disease activity/severity measures, including inflammatory markers, disease activity scores, seropositivity, physical disability, destructive changes on joint radiographs, extra-articular manifestations, and corticosteroid use, have repeatedly shown significant associations with increased cardiovascular risk. Medications used to treat RA may also affect cardiovascular risk. A recent meta-analysis suggests that all nonsteroidal anti-inflammatory drugs confer some cardiovascular risk. The cardiovascular risks/benefits associated with use of disease-modifying antirheumatic drugs and/or biologics remain controversial, as does the role of statins in RA. SUMMARY: Cardiovascular disease remains a major problem for people with RA. Future work should focus on further delineating the underlying biological mechanisms involved, developing and evaluating risk assessment tools and biomarkers, as well as prevention/treatment strategies specific to the RA population.

The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases.

OBJECTIVE: Understanding of the personal risks for rheumatoid arthritis (RA) and other rheumatic diseases remains poor, despite advances in knowledge with regard to their pathogenesis, therapeutics, and clinical impact, in part because the personal lifetime risk of developing these diseases is unknown. This study was undertaken 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 of developing inflammatory autoimmune rheumatic disease over a lifetime. METHODS: 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 the sex-specific lifetime risk of rheumatic disease. RESULTS: The lifetime risk of RA developing in US adults was 3.6% for women and 1.7% for men, and the lifetime risk of rheumatoid factor-positive RA was 2.4% for women and 1.1% for men. The second most common inflammatory autoimmune rheumatic disease was PMR, with a lifetime risk of 2.4% for women and 1.7% for men. The overall lifetime risk of inflammatory autoimmune rheumatic disease was 8.4% for women and 5.1% for men. CONCLUSION: One in 12 women and 1 in 20 men will develop an 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 regarding disease awareness campaigns.

A signature of aberrant immune responsiveness identifies myocardial dysfunction in rheumatoid arthritis.

OBJECTIVE: Heart failure is an important cause of death in patients with rheumatoid arthritis (RA). Evidence suggests that immune mechanisms contribute to myocardial injury and fibrosis, leading to left ventricular diastolic dysfunction (LVDD). The purpose of this study was 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. METHODS: RA patients (n=212) enrolled prospectively in a population-based cohort underwent echocardiography, and LV 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 multiplex immunoassays. Logistic regression models were used to test for associations between a multicytokine immune response score and LVDD, after adjusting for clinical covariates. RESULTS: An 11-cytokine profile effectively differentiated patients 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 interleukin-6 levels, brain natriuretic peptide values, and glucocorticoid use, as well as other RA characteristics and LVDD risk factors. CONCLUSION: The major finding of this study was that aberrant systemic immune responsiveness is associated with advanced myocardial dysfunction in patients with RA. The unique information added by the immune response score concerning the likelihood of LVDD warrants future longitudinal studies of its value in predicting future deterioration in myocardial function.

Analysis of complex biomarkers for human immune-mediated disorders based on cytokine responsiveness of peripheral blood cells.

The advent of improved biomarkers promises to enhance the clinical care for patients with rheumatoid arthritis (RA) and other immune-mediated disorders. We have developed an innovative approach to broadly assess the cytokine responsiveness of human PBMCs using a multistimulant panel and multiplexed immunoassays. The objective of this study was to demonstrate this concept by determining whether cytokine profiles could discriminate RA patients according to disease stage (early versus late) or severity. A 10-cytokine profile, consisting of IL-12, CCL4, TNF-alpha, IL-4, and IL-10 release in response to stimulation with anti-CD3/anti-CD28, CXCL8 and IL-6 in response to CMV and EBV lysate, and IL-17A, GM-CSF, and CCL2 in response to human heat shock protein 60, easily discriminated the early RA group from controls. These data were used to create an immune response score, which performed well in distinguishing the early RA patients from controls and also correlated with several markers of disease severity among the patients with late RA. In contrast, the same 10-cytokine profile assessed in serum was far less effective in discriminating the groups. Thus, our approach lays the foundation for the development of immunologic "signatures" that could be useful in predicting disease course and monitoring the outcomes of therapy among patients with immune-mediated diseases.