The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease

ObjectiveTo examine the role of rheumatoid arthritis (RA) flare, remission and RA severity burden in cardiovascular disease (CVD).MethodsIn a population-based cohort of patients with RA without CVD (age ≥30 years; 1987 American College of Rheumatology criteria met in 1988–2007), we performed medical record review at each clinical visit to estimate flare/remission status. The previously validated RA medical Records-Based Index of Severity (RARBIS) and Claims-Based Index of RA Severity (CIRAS) were applied. Age- and sex-matched non-RA subjects without CVD comprised the comparison cohort. Cox models were used to assess the association of RA activity/severity with CVD, adjusting for age, sex, calendar year of RA, CVD risk factors and antirheumatic medications.ResultsStudy included 525 patients with RA and 524 non-RA subjects. There was a significant increase in CVD risk in RA per time spent in each acute flare versus remission (HR 1.07 per 6-week flare, 95% CI 1.01 to 1.15). The CVD risk for patients with RA in remission was similar to the non-RA subjects (HR 0.90, 95% CI 0.51 to 1.59). Increased cumulative moving average of daily RARBIS (HR 1.16, 95% CI 1.03 to 1.30) and CIRAS (HR 1.38, 95% CI 1.12 to 1.70) was associated with CVD. CVD risk was higher in patients with RA who spent more time in medium (HR 1.08, 95% CI 0.98 to 1.20) and high CIRAS tertiles (HR 1.18, 95% CI 1.06 to 1.31) versus lower tertile.ConclusionsOur findings show substantial detrimental role of exposure to RA flare and cumulative burden of RA disease severity in CVD risk in RA, suggesting important cardiovascular benefits associated with tight inflammation control and improved flare management in patients with RA.

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Improved Incidence of Cardiovascular Disease in Patients with Incident Rheumatoid Arthritis in the 2000s: a Population-Based Cohort Study

The Journal of Rheumatology ◽

10.3899/jrheum.200842 ◽

2021 ◽

pp. jrheum.200842 ◽

Cited By ~ 1

Author(s):

Elena Myasoedova ◽

John M. Davis ◽

Veronique L. Roger ◽

Sara J. Achenbach ◽

Cynthia S. Crowson

Keyword(s):

Rheumatoid Arthritis ◽

Cardiovascular Disease ◽

Population Based ◽

Source Population ◽

Cvd Risk Factors ◽

Stroke Patients ◽

Cvd Risk ◽

Cox Models ◽

Risk Of Death ◽

Strength Of Association

Objective To assess trends in incidence of cardiovascular disease (CVD) and mortality following incident CVD events in patients with rheumatoid arthritis (RA) onset in 1980- 2009 versus non-RA subjects. Methods We studied Olmsted County, Minnesota residents with incident RA (age ≥ 18 years, 1987 ACR criteria met in 1980-2009) and non-RA subjects from the same source population with similar age, sex and calendar year of index. All subjects were followed until death, migration, or 12/31/2016. Incident CVD events included myocardial infarction and stroke. Patients with CVD before RA incidence/index date were excluded. Cox models were used to compare incident CVD events by decade, adjusting for age, sex and CVD risk factors. Results The study included 905 patients with RA and 904 non-RA subjects. Cumulative incidence of any CVD event was lower in patients with incident RA in 2000s versus 1980s. Hazard Ratio [HR] for any incident CVD 2000s versus 1980s: 0.53; 95% confidence interval (CI): 0.31-0.93. The strength of association attenuated after adjustment for anti-rheumatic medication use: HR 0.64, 95%CI 0.34-1.22. Patients with RA in 2000s had no excess in CVD over non-RA subjects (HR: 0.71, 95%CI:0.42-1.19). Risk of death after a CVD event was somewhat lower in patients with RA after 1980s: HR: 0.54, 95%CI:0.33-0.90 in 1990s and HR: 0.68, 95%CI:0.33-1.41 in 2000s versus 1980s. Conclusion Incidence of major CVD events in RA has declined in recent decades. The gap in CVD occurrence between RA patients and the general population is closing. Mortality after CVD events in RA may be improving.

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Fragility Fractures Are Associated with an Increased Risk for Cardiovascular Events in Women and Men with Rheumatoid Arthritis: A Population-based Study

The Journal of Rheumatology ◽

10.3899/jrheum.160651 ◽

2017 ◽

Vol 44 (5) ◽

pp. 558-564 ◽

Cited By ~ 6

Author(s):

Orla Ni Mhuircheartaigh ◽

Cynthia S. Crowson ◽

Sherine E. Gabriel ◽

Veronique L. Roger ◽

L. Joseph Melton ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Fragility Fracture ◽

Fragility Fractures ◽

Population Based ◽

Cvd Risk ◽

Cox Models ◽

Excess Morbidity ◽

Increased Risk ◽

Time Dependent Covariates

Objective.Women and men with rheumatoid arthritis (RA) have an increased risk for fragility fractures and cardiovascular disease (CVD), each of which has been reported to contribute to excess morbidity and mortality in these patients. Fragility fractures share similar risk factors for CVD but may occur at relatively younger ages in patients with RA. We aimed to determine whether a fragility fracture predicts the development of CVD in women and men with RA.Methods.We studied a population-based cohort with incident RA from 1955 to 2007 and compared it with age- and sex-matched non-RA subjects. We identified fragility fractures and CVD events following the RA incidence/index date, along with relevant risk factors. We used Cox models to examine the association between fractures and the development of CVD, in which fractures and CVD risk factors were modeled as time-dependent covariates.Results.There were 1171 subjects (822 women; 349 men) in each of the RA and non-RA cohorts. Over followup, there were 406 and 346 fragility fractures and 286 and 225 CVD events, respectively. The overall CVD risk was increased significantly for RA subjects following a fragility fracture (HR 1.81, 95% CI 1.38–2.37) but not for non-RA subjects (HR 1.18, 95% CI 0.85–1.63). Results were similar for women and men with RA.Conclusion.Fragility fractures in both women and men with RA are associated with an increased risk for CVD events and should raise an alert to clinicians to target these individuals for further screening and preventive strategies for CVD.

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The Influence of Rheumatoid Arthritis Disease Characteristics on Heart Failure

The Journal of Rheumatology ◽

10.3899/jrheum.100979 ◽

2011 ◽

Vol 38 (8) ◽

pp. 1601-1606 ◽

Cited By ~ 66

Author(s):

ELENA MYASOEDOVA ◽

CYNTHIA S. CROWSON ◽

PAULO J. NICOLA ◽

HILAL MARADIT-KREMERS ◽

JOHN M. DAVIS ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Heart Failure ◽

Population Based ◽

Independent Effect ◽

Cox Models ◽

American College Of Rheumatology ◽

Disease Characteristics ◽

Rheumatoid Arthritis Disease ◽

History Of

Objective.To examine the influence of rheumatoid arthritis (RA) characteristics and antirheumatic medications on the risk of heart failure (HF) in patients with RA.Methods.A population-based incidence cohort of RA patients aged ≥ 18 years (1987 American College of Rheumatology criteria first met between January 1, 1980, and January 1, 2008) with no history of HF was followed until onset of HF (defined by Framingham criteria), death, or January 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.Results.The study included 795 RA patients [mean age 55.3 yrs, 69% women, 66% rheumatoid factor (RF)-positive]. During the mean followup 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 extraarticular 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 nonusers (HR 0.5, 95% CI 0.3, 0.9).Conclusion.Several RA characteristics and the use of corticosteroids were associated with HF, with adjustment for CV risk factors and CHD. Methotrexate use appeared to be protective against HF. These findings suggest an independent effect of RA on HF that may be further modified by antirheumatic treatment.

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Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-204960 ◽

2014 ◽

Vol 74 (6) ◽

pp. 1212-1217 ◽

Cited By ~ 46

Author(s):

Elizabeth V Arkema ◽

Jerker Jonsson ◽

Eva Baecklund ◽

Judith Bruchfeld ◽

Nils Feltelius ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

General Population ◽

Population Based ◽

Calendar Time ◽

Cox Models ◽

Increased Risk ◽

National Cohort ◽

Biologics Register

ObjectiveTo estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therapies.MethodsData from the Swedish National Population Registers, Tuberculosis Register and the Swedish Biologics Register were used to conduct a prospective population-based national cohort study (2002–2011). We estimated the rate of incident TB in the general population and in a cohort of biological-naïve and biological-exposed patients diagnosed with RA. Cox models were used to estimate HRs with particular attention to risks by calendar and follow-up time and individual biologics.ResultsCompared to the general population, RA patients not exposed to biologicals had a fourfold increased risk of TB (HR 4.2; 95% CI 2.7 to 6.7), which did not decline over calendar time. In contrast, the risk of TB in the biological-exposed RA population decreased since 2002 compared with biological-naïve; from HR=7.9 (95% CI 3.3 to 18.9) in 2002–2006 to HR=2.4 (95% CI 0.9 to 6.1) in 2007–2011. The HRs for most recent exposure to adalimumab and infliximab compared with etanercept were 3.1 (95% CI 0.8 to 12.5) and 2.7 (95% CI 0.7 to 10.9), respectively, and the HR for etanercept compared with biological-naïve RA was 1.7 (95% CI 0.6 to 4.6).ConclusionsIn the past decade, the risk of TB has decreased among biological-exposed RA patients but remains higher than in biological-naïve RA patients. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients.

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Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.135871 ◽

2011 ◽

Vol 70 (3) ◽

pp. 482-487 ◽

Cited By ~ 254

Author(s):

Elena Myasoedova ◽

Cynthia S Crowson ◽

Hilal Maradit Kremers ◽

Veronique L Roger ◽

Patrick D Fitz-Gibbon ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cardiovascular Disease ◽

Systemic Inflammation ◽

Serum Lipid ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Population Based ◽

Cox Models ◽

Increased Risk ◽

The Impact

ObjectiveTo examine the impact of systemic inflammation and serum lipids on cardiovascular disease (CVD) in rheumatoid arthritis (RA).MethodsIn a population-based RA incident cohort (1987 American College of Rheumatology criteria first met between 1988 and 2007), details were collected of serum lipid measures, erythrocyte sedimentation rates (ESRs), C-reactive protein (CRP) measures and cardiovascular events, including ischaemic 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.ResultsThe study included 651 patients with RA (mean age 55.8 years, 69% female); 67% were rheumatoid factor positive. ESR was associated with the risk of CVD (HR=1.2 per 10 mm/h increase, 95% CI 1.1 to 1.3). Similar findings, although not statistically significant, were seen with CRP (p=0.07). A significant non-linear association for total cholesterol (TCh) with risk of CVD was found, with 3.3-fold increased risk for TCh <4 mmol/l (95% CI 1.5 to 7.2) and no increased risk of CVD for TCh ≥4 mmol/l (p=0.57). Low low-density lipoprotein 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).ConclusionInflammatory 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.

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Cardiovascular Disease in Rheumatoid Arthritis: Risk Factors, Autoantibodies, and the Effect of Antirheumatic Therapies

Clinical Medicine Insights Arthritis and Musculoskeletal Disorders ◽

10.1177/11795441211028751 ◽

2021 ◽

Vol 14 ◽

pp. 117954412110287

Author(s):

Mir Sohail Fazeli ◽

Vadim Khaychuk ◽

Keith Wittstock ◽

Boris Breznen ◽

Grace Crocket ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Cardiovascular Disease ◽

Literature Review ◽

Rheumatoid Factor ◽

Qualitative Evidence Synthesis ◽

Cvd Risk ◽

Rheumatoid Arthritis Risk ◽

Published Evidence ◽

Increased Risk

Objective: To scope the current published evidence on cardiovascular risk factors in rheumatoid arthritis (RA) focusing on the role of autoantibodies and the effect of antirheumatic agents. Methods: Two reviews were conducted in parallel: A targeted literature review (TLR) describing the risk factors associated with cardiovascular disease (CVD) in RA patients; and a systematic literature review (SLR) identifying and characterizing the association between autoantibody status and CVD risk in RA. A narrative synthesis of the evidence was carried out. Results: A total of 69 publications (49 in the TLR and 20 in the SLR) were included in the qualitative evidence synthesis. The most prevalent topic related to CVD risks in RA was inflammation as a shared mechanism behind both RA morbidity and atherosclerotic processes. Published evidence indicated that most of RA patients already had significant CV pathologies at the time of diagnosis, suggesting subclinical CVD may be developing before patients become symptomatic. Four types of autoantibodies (rheumatoid factor, anti-citrullinated peptide antibodies, anti-phospholipid autoantibodies, anti-lipoprotein autoantibodies) showed increased risk of specific cardiovascular events, such as higher risk of cardiovascular death in rheumatoid factor positive patients and higher risk of thrombosis in anti-phospholipid autoantibody positive patients. Conclusion: Autoantibodies appear to increase CVD risk; however, the magnitude of the increase and the types of CVD outcomes affected are still unclear. Prospective studies with larger populations are required to further understand and quantify the association, including the causal pathway, between specific risk factors and CVD outcomes in RA patients.

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The epigenetic etiology of cardiovascular disease in a longitudinal Swedish twin study

Clinical Epigenetics ◽

10.1186/s13148-021-01113-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Xueying Qin ◽

Ida K. Karlsson ◽

Yunzhang Wang ◽

Xia Li ◽

Nancy Pedersen ◽

...

Keyword(s):

Cardiovascular Disease ◽

Dna Methylation ◽

Cvd Risk ◽

Significance Level ◽

Latent Trajectory ◽

Lagged Effects ◽

The Cross ◽

Level 2 ◽

Cardiometabolic Traits

Abstract Background Studies on DNA methylation have the potential to discover mechanisms of cardiovascular disease (CVD) risk. However, the role of DNA methylation in CVD etiology remains unclear. Results We performed an epigenome-wide association study (EWAS) on CVD in a longitudinal sample of Swedish twins (535 individuals). We selected CpGs reaching the Bonferroni-corrected significance level (2 $$\times$$ × 10–7) or the top-ranked 20 CpGs with the lowest P values if they did not reach this significance level in EWAS analysis associated with non-stroke CVD, overall stroke, and ischemic stroke, respectively. We further applied a bivariate autoregressive latent trajectory model with structured residuals (ALT-SR) to evaluate the cross-lagged effect between DNA methylation of these CpGs and cardiometabolic traits (blood lipids, blood pressure, and body mass index). Furthermore, mediation analysis was performed to evaluate whether the cross-lagged effects had causal impacts on CVD. In the EWAS models, none of the CpGs we selected reached the Bonferroni-corrected significance level. The ALT-SR model showed that DNA methylation levels were more likely to predict the subsequent level of cardiometabolic traits rather than the other way around (numbers of significant cross-lagged paths of methylation → trait/trait → methylation were 84/4, 45/6, 66/1 for the identified three CpG sets, respectively). Finally, we demonstrated significant indirect effects from DNA methylation on CVD mediated by cardiometabolic traits. Conclusions We present evidence for a directional association from DNA methylation on cardiometabolic traits and CVD, rather than the opposite, highlighting the role of epigenetics in CVD development.

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Plasma Branched-Chain Amino Acids and Incident Cardiovascular Disease in the PREDIMED Trial

Clinical Chemistry ◽

10.1373/clinchem.2015.251710 ◽

2016 ◽

Vol 62 (4) ◽

pp. 582-592 ◽

Cited By ~ 91

Author(s):

Miguel Ruiz-Canela ◽

Estefania Toledo ◽

Clary B Clish ◽

Adela Hruby ◽

Liming Liang ◽

...

Keyword(s):

Cardiovascular Disease ◽

Amino Acids ◽

Cardiovascular Death ◽

Branched Chain Amino Acids ◽

Control Group ◽

Cvd Risk ◽

Hazard Ratios ◽

Increased Risk ◽

Branched Chain

Abstract BACKGROUND The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect. METHODS We developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death. RESULTS After adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05–2.76) and 2.09 (1.27–3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed. CONCLUSIONS Higher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.

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Abstract P156: Assessing the Effect of the Heart of New Ulm Project: a Population-Based Program to Reduce Cardiovascular Disease

Circulation ◽

10.1161/circ.135.suppl_1.p156 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Abbey C Sidebottom ◽

Arthur Sillah ◽

David M Vock ◽

Michael M Miedema ◽

Raquel Pereira ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Health System ◽

Matched Control ◽

Population Based ◽

Control Population ◽

Cvd Risk Factors ◽

Cvd Risk ◽

Matched Control Population

Background: Despite a highly recognized priority for public health and healthcare to implement population-level strategies to reduce the burden of cardiovascular disease (CVD), limited evidence exists on the most effective strategies. Data collection and evaluation of large scale, community based-prevention programs can be challenging and costly to achieve. The Heart of New Ulm (HONU) Project, begun in 2009, is a population-based initiative with healthcare, community, and workplace interventions addressing multiple levels of the social-ecological model designed to reduce modifiable CVD risk factors in rural New Ulm, MN. The community is served by one health system, enabling the use of electronic health record (EHR) data for surveillance. Objective: To assess trends for CVD risk factors, events, and healthcare utilization for New Ulm residents compared to a matched control population. Methods: We matched New Ulm residents (n = 4,077) with controls (n = 4,077) from a regional community served by the same health system using refined covariate balance techniques to match on baseline demographics, CVD risk factors, and health care utilization. Mixed effects longitudinal models with adjustment for age and gender, and an interaction for time by community, were run. Model based estimates were constructed for the entire cohort at each time period. Results: Over the first 6 years of the HONU Project,blood pressure, LDL, total cholesterol, and triglycerides were managed better in New Ulm than the matched comparison community. The proportion of New Ulm residents with controlled blood pressure increased by 6.2 percentage points while the control group increased by 2 points. 10-year ASCVD risk scores showed less decline for New Ulm residents than controls (16 vs. 18.4). The intervention and control groups did not differ with regard to inpatient stays, CVD events, smoking, or glucose. Conclusions: Compared to a matched control population, we found improved control of CVD risk factors in the New Ulm Population exposed to the HONU Project.

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Differences in estimates for ten-year risk of cardiovascular disease in Black versus white persons with identical risk factor profiles using pooled cohort equations

10.1101/2021.04.18.21255704 ◽

2021 ◽

Author(s):

Ramachandran S. Vasan ◽

Edwin van den Heuvel

Keyword(s):

Cardiovascular Disease ◽

Black Women ◽

White Women ◽

Absolute Risk ◽

Density Lipoprotein ◽

Clinical Decision ◽

Population Based ◽

Decision Threshold ◽

Cvd Risk ◽

Risk Profiles

AbstractBackgroundSex- and race-specific pooled cohort equations (PCE) are recommended for estimating the 10-year risk of cardiovascular disease (CVD), with an absolute risk >7.5% indicating a clinical decision threshold.MethodsWe generated in silico 30,565 risk profiles in men and 29,515 in women by combining numerical (age, total and high-density lipoprotein cholesterol, systolic blood pressure) and binary risk factors (smoking, diabetes, antihypertensive treatment). We compared PCE-estimated 10-year CVD risk in Black versus white individuals with identical risk profiles. We performed similar comparisons in participants in the Framingham Third Generation cohort and the National Health and Nutrition Examination Survey 2017-2018.ResultsThere were 6357 risk profiles associated with 10-year CVD risk >7.5% for Black but not for white men (median risk difference [RD] 6.25%, range 0.15-22.8%; median relative risk [RR] 2.40, range 1.02-12.6). There were 391 profiles with 10-year CVD risk >7.5% for white but not for Black men (median RD 2.68%, range 0.07-16.9%; median RR 1.42, range 1.01-3.57). There were 6543 risk profiles associated with 10-year estimated CVD risk >7.5% for Black but not for white women (median RD 6.14%, range 0.35-26.8%; median RR 2.29, range 1.05-12.6). There were 318 profiles with 10-year CVD risk >7.5% for white but not for Black women (median RD 3.71%, range 0.22-20.1%; median RR 1.66, range 1.03-5.46). The population-based samples demonstrated similar risk differences.ConclusionsThe PCE may generate substantially divergent CVD risk estimates for Black versus white individuals with identical risk profiles, which could introduce race-related variations in clinical recommendations for CVD prevention.

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