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Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease

October 2018

October 2018

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Authors:

Arielle Urman

State University of New York Downstate Medical Center

Nicholas Taklalsingh

Residency Program

Isabel Mcfarlane

State University of New York Downstate Medical Center

Rheumatoid Arthritis (RA), a chronic systemic inflammatory disease which affects approximately 1% of the population, is classically characterized by inflammation and synovitis that leads to cartilage damage and juxta-articular bone destruction. Accumulating evidence indicates that a major cause of death among RA patients is Cardio Vascular Disease (CVD), in excess of that in the general population. In this review, we discuss the epidemiology of CVD in RA populations, the underlying pathophysiologic mechanisms of CVD in RA including the role of chronic inflammation in driving accelerated atherosclerosis, the obesity paradox and altered metabolic pathways leading to pro-inflammatory HDL formation and insulin resistance. We also discuss the pitfalls in the evaluation of CVD utilizing traditional risk scores which tend to underestimate CVD risk in RA population and the efforts directed to find more accurate predictors for early CVD detection. Finally, we will present the latest developments in the evaluation and management of CVD in RA patients, given recent evidence on the role of inflammation and its impact on CVD.

Risk Factors Arrows Represent the Causal Relationship between the Activity of Inflammatory Factors, and the Development of Traditional Risk Factors (Increased Adiposity, Dyslipidemia, Insulin Resistance) and RA-Specific Risk Factors that Reflect Disease Activity. Hs-CRP High Sensitivity C Reactive Protein, ESR Estimated Sedimentation Rate, TNF Tumor Necrosis Factor, IL-6 Interleukin-6, IL-1 Interleukin-1, IL-17 Interleukin-17

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Review Article Open Access

Publishers

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SciFed Journal of Cardiology

Arielle Urman, SF J Cardiol, 2018, 2:3

page 1 of 23

Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular

Disease

Arielle Urman, Nicholas Taklalsingh, Cristina Sorrento, *Isabel M. McFarlane

*Department of Internal Medicine Division of Rheumatology SUNY-Downstate Medical Center Brooklyn, NY 11203, USA

Keywords

Rheumatoid Arthritis; Cardiovascular Risk

Factors; Cardiovascular Disease; Risk Assessment;

Cardiovascular Outcomes; Pathogenesis; Treatment;

Evaluation

Introduction

Rheumatoid Arthritis (RA), a chronic systemic

inflammatory disease which affects approximately

1% of the population, is classically characterized by

inflammation and synovitis that leads to cartilage damage

with joint space narrowing and juxta-articular bone

erosions. CVD risk is increased among RA patients as

demonstrated by numerous epidemiological studies, as the

presence of traditional Cardio Vascular (CV) risk factors

do not explain the higher rate of CV events seen in this

population. The inflammatory milieu of RA, marked

by elevations of serum inflammatory mediators and

endothelial dysfunction, creates an opportune climate for

the development of atherosclerosis and cardio myocyte

dysfunction. Accordingly, CVD in RA is associated

with active RA disease as measured by joint swelling,

extra-articular disease, and elevated serum inflammatory

markers. Clinically, RA patients with CVD present with an

increased rate of silent cardiac disease, atypical symptoms

and diastolic heart failure. Predicting CVD and evaluating

the risk have proven to be difficult in RA, in part due to

the paucity of studies and challenges with risk calculator

models. Imaging techniques and special functional

tests may provide more reliable tools to assess risk and

progression of CVD in this patient population. Optimizing

*Corresponding author: Isabel M. McFarlane, Department of Internal

Medicine Division of Rheumatology SUNY-Downstate Medical Center

Brooklyn, NY 11203, USA. E-mail: Isabel.McFarlane@downstate.edu;

Tel: 718-221-6515

Received September 10, 2018; Accepted September 27, 2018; Published

Citation: Arielle Urman (2018) Inflammation beyond the Joints:

Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

distributed under the terms of the Creative Commons Attribution License,

which permits unrestricted use, distribution, and reproduction in any

medium, provided the original author and source are credited.

Abstract

Rheumatoid Arthritis (RA), a chronic systemic inflammatory disease which affects approximately 1% of the

population, is classically characterized by inflammation and synovitis that leads to cartilage damage and juxta-articular

bone destruction. Accumulating evidence indicates that a major cause of death among RA patients is Cardio Vascular

Disease (CVD), in excess of that in the general population. In this review, we discuss the epidemiology of CVD in RA

populations, the underlying pathophysiologic mechanisms of CVD in RA including the role of chronic inflammation in

driving accelerated atherosclerosis, the obesity paradox and altered metabolic pathways leading to pro-inflammatory

HDL formation and insulin resistance. We also discuss the pitfalls in the evaluation of CVD utilizing traditional

risk scores which tend to underestimate CVD risk in RA population and the efforts directed to find more accurate

predictors for early CVD detection. Finally, we will present the latest developments in the evaluation and management

of CVD in RA patients, given recent evidence on the role of inflammation and its impact on CVD.

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 2 of 23

prevention and management in RA includes a combination

approach that addresses traditional risk factors and

inflammation.

Epidemiology

The recognition that RA carries a heightened CVD

morbidity and mortality derived from a number of reviews

and meta-analysis. In a review that included 91,618

patients, CVD accounted for 39.6% of all deaths [1]. One

meta-analysis comprising 111,758 patients found a 50%

increased risk of CVD death, with Ischemic Heart Disease

(IHD) and Cerebral Vascular Accidents (CVA) accounting

for 59% and 52% increased risks, respectively [2]. Another

meta-analysis of 14 observational studies concluded a

48% increased risk of incident CVD in patients with RA,

with the risk of Myocardial Infarction (MI) and CVA being

increased by 68% and 41%, respectively, with a single

study identifying the risk of Congestive Heart Failure

(CHF) increased by 87% [3]. These statistics are supported

by a recent prospective population-based cohort study of

CVD end-points showing that RA patients had higher

rates, via adjusted incidence ratio (IRR) of MI (IRR: 1.43),

unheralded coronary death (1.60), heart failure (1.61),

cardiac arrest (2.26), peripheral arterial disease (1.36)

and lower rates of stable angina (hazard ratio: 0.83) [4].

Increased incidence of CV events in RA patients have

been linked to that in diabetics, with a two-fold increase

compared to the general population [5].

Most recently, a large population-based study

matched RA patient’s ≥15 years of age to individuals without

RA. The mortality rate for RA patients was 232-compared

to184 in the non-RA population (14% versus 9%).

Overall, RA patients had increased all-cause mortality, but

age specific mortality ratios suggested excess mortality

among patients younger than 45 years due to respiratory

and circulatory diseases [6]. The majority of population-

based studies are derived primarily from European and

North American cohorts. A recent cross-sectional study

of Chinese patients showed an approximately two-fold

increased risk of CVD, IHD and CHF in RA patients

compared to age and sex-matched controls [7]. One South

African study looked at CVD in RA patients belonging to

an African Black population cohort. Their review argues

that CVD in RA occurring in developed population cohorts

cannot be extrapolated to developing countries population

as further research is needed to ascertain the true disease

prevalence given the degree of heterogeneity in ethnicity

and geographic locations [8].

Pathophysiology

The pathophysiology of CVD in RA involves

immune dysregulation and chronic inflammation which

results from the interaction of genetic and environmental

factors [9]. Inflammation favors atherosclerotic CVD,

with inflammatory markers like C Reactive Protein

(CRP) considered independent predictors for coronary

heart disease in the general population [10, 11]. Evidence

supports that inflammation is the major driver of excess

CVD in RA [12, 13].

Systemic Inflammation and Endothelial

Dysfunction

Elevated levels of cytokines such as tumor necrosis

factor-α (TNF-α), interleukin-17 (IL-17), interleukin-6

(IL-6), and interleukin-1β (IL-1β) are found in both RA

and CVD, with higher levels being present in RA [10, 14-

16]. These cytokines have been implicated in endothelial

cell activation, a crucial step for pannus formation in the

synovial tissue and in the pathogenesis of atherosclerotic

CVD [10, 17, 18]. (Figure 1) Endothelial activation induces

cellular expression of chemokines and adhesion molecules

that enable leukocyte migration into the joint space or

vascular intima which favor further neutrophil recruitment,

activation and propagation of the local inflammatory

process [19-21]. IL-17 induces endothelial cells to express

chemokines that promote neutrophil recruitment [22].

Local T1 helper cells release interferon-gamma (IFN-γ)

which, together with TNF-α and IL-17, causes endothelial

cell apoptosis, [23, 24] eliminating the endothelial cells’

anti-thrombotic properties [25]. In the inflammatory milieu

of RA, atherosclerotic plaques are particularly unstable

and vulnerable to rupture [26, 27]. TNF- α and IL-17 also

prevent nitric oxide and thrombomodulin synthesis and,

along with IL-1 increase tissue factor production and

activation [17, 28-31]. Similarly, IL-6 increases levels of

fibrinogen and IL-6 receptor signaling pathways play a

causal role in coronary heart disease [29, 32]. In concert,

these actions create a hypercoagulable environment in the

vascular lumen.

Results of cytokine-targeted therapy studies

provide proof-of-concept in vivo, confirming the role

of the cytokines and inflammation in RA pathogenesis.

For example, TNF-α blockade improves endothelial-

dependent vascular function in RA patients [33]. In patients

with Coronary Artery Disease (CAD), anti-IL-1β therapy

significantly reduced the rate of subsequent CV events,

independent of lipid-lowering [34]. Furthermore, IL-6

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receptor inhibition lessened the inflammatory response

and release of troponin-T after acute MI [35].

In addition to direct pro-atherogenic effects,

TNF-α and IL-17 increase insulin resistance, alter lipid

levels and function, and create oxidative stress. IL-17

also affects cardio myocytes by inducing inflammation

and apoptosis which result in myocardial remodeling

due to increased cardiac fibroblast activity and collagen

production [36-39]. These processes likely contribute to

the development of cardiomyopathy and heart failure [40].

There is also widespread vascular dysfunction with

impaired vasodilation, which positively correlates with

elevated inflammatory markers such as high sensitivity

CRP (hsCRP) [41-43]. Furthermore, Coronary Flow

Reserve (CFR) is decreased and carotid Intima-Media

Thickness (cIMT) is increased in RA population [44].

Deranged Lipids and Atheroma Instability

RA and other systemic inflammatory conditions

are associated with a unique type of dyslipidemia

characterized by high levels of triglycerides and low

levels of Low-Density Lipoproteins (LDL) and High-

Density Lipoproteins (HDL). Although lipoprotein levels

are low, there is a paradoxical increase in CV risk [45].

This “lipid paradox” is explained by the fact that low

lipoprotein levels are associated with inflammatory

states, and inflammation is independently associated with

CV events, and perhaps in a more causal fashion than

cholesterol levels. Low lipoprotein levels are associated

with elevations in ESR and CRP [46]. Furthermore, a

clinically significant portion of HDL is altered in structure

and function so that instead of being anti-inflammatory

and atheroprotective, it enhances LDL-oxidation and foam

cell formation [47-50]. This pro-inflammatory HDL has

an altered proteome and does not bind efficiently with

Lecithin-Cholesterol Acyl Transferase (LCAT) resulting in

inadequate clearance of lipids from developing atheromas,

a decreased efflux capacity. Pro-inflammatory HDL levels

positively correlate with acute phase proteins, including

serum amyloid A and complement factors, as well as RA

disease activity [51, 52].

With increased control of inflammation, LDL

levels rise while HDL production is shifted toward the anti-

inflammatory form [53]. Accordingly, decreasing hsCRP

by at least 10 mg/L over two years is associated with a

rise in LDL and increased HDL cholesterol efflux capacity

[54]. Lipid levels rise with the use of Disease Modifying

Anti-Rheumatic Drugs (DMARDs), anti-TNF, anti-IL-6R,

and Janus kinase inhibitors [53, 55-57].

The altered lipid profile in RA may be responsible

for increased CVD events by causing increased instability

of atherosclerotic plaques. A post-mortem study

demonstrated lower overall grades of stenosis and fewer

vessels with severe-grade stenosis, but significantly more

vulnerable plaques, with increased medial and adventitial

inflammation, in RA subjects compared to controls [27].

On ultrasound examination, RA patients had more carotid

plaques than age and sex matched controls without RA.

Controls were found to have more stable plaques [58].

Although RA patients had fewer atheromas and less

severe stenosis, they had higher frequency of CVD events

when compared to the general population suggesting that

atherosclerotic plaques in RA are more prone to rupture.

Hypercoagulability

There is evidence that RA patients are

hypercoagulable. Some of the related pathophysiology was

discussed above in the context of the effects of cytokines

on endothelial cells. To review, elevated concentrations of

fibrinogen, von Will brand factor, fibrin D-dimer, tissue

plasminogen activator antigen, and platelets are seen

in RA patients [59]. Another pathway that contributes

to hypercoagulability is the CD40-CD40L, which is

upregulated in RA and associated with a genetic variant

of CD40. Studies of this pathway in CVD have shown

that levels of soluble CD40L are predictive of MI and

associated with plaque rupture and thrombosis [60-62].

The Role of T Cells

The major risk allele for RA, HLA DRB1, is

associated with the proliferation of an autoreactive

CD4+CD28- T cell population [9]. These T cells are

senescent meaning that, contrary to what the name

Figure 1: Shared Pathogenesis

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suggests, they are terminal effectors that are highly active

in secreting pro-inflammatory cytokines and resistant

to apoptosis [63]. Significantly, the responsible allele

has also been linked to increased CVD [64]. Expansion

of the CD4+CD28-T cell population is associated with

preclinical cardiovascular disease; these T cells are found

within atherosclerotic plaques [65] where they release

IFN-γ and IL-17, promoting an inflammatory milieu [66].

In one study of RA patients, it was found that patients with

greater expansion of this T cell population had increased

atherosclerosis and endothelial dysfunction, as measured

by carotid IMT and brachial artery Flow Mediated

Vasodilation (FMV), than those with smaller populations

[67]. TNF-α blocking therapy restored CD28 expression

on T cells [68].

It is thought that activation of T cells and

macrophages inside the atheroma by antigens generated

from oxidized LDL may trigger macrophage-mediated

destruction of the fibrous cap with erosion of the overlying

endothelium, bringing thrombogenic particles from

the endothelium into contact with blood, triggering the

coagulation cascade and arterial occlusion, leading to

dreaded cardiovascular events [69].

Risk Factors

CV risk scores valuable for the general population

(Systematic Coronary Risk Evaluation score, Framingham

Risk Score, Reynolds Risk Score) generally underestimate

or overestimate (QRisk II) CV risk in patients with RA

[70]. According to a recent, large, international cohort

study, the Framingham Risk Score in Adult Treatment

Panel (FRS-ATP), RA-related characteristics have been

shown to account for roughly a third of CVD events in

RA patients [71]. There have been many attempts to adjust

pre-existing CVD risk calculators as well as to derive new

risk calculators, but all have resulted in underestimations

[72-74].

In 2015, the Extended Risk Score - Rheumatoid

Arthritis (ERS-RA) was released. The project used data

from the Consortium of Rheumatology Researchers of

North America (CORRONA) cohort, the largest US-based

RA registry to assess newly diagnosed RA patients without

CVD for all possible traditional and RA-related CV risk

factors. Factors such as age, sex, diabetes, hyperlipidemia,

hypertension, and patient-reported tobacco use were

included; in addition to, RA-related factors such as,

level of disease activity, extent of functional disability,

RA duration, presence of subcutaneous nodules, joint

erosions on X-ray, RF or anti-CCP antibody positivity,

any use of corticosteroids or DMARDS, and current use

of methotrexate, NSAIDS, or anti-TNF drugs were also

recorded. Race, education, physical activity, BMI, family

history of early MI, and aspirin use were also considered.

Patients were followed for a mean of 2.9 years. The

researchers concluded that rather than multiplying by

a correction factor [75, 76] or including inflammatory

biomarkers in the calculation, using clinical disease activity

(moderate or high instead of none or low), functional

disability (moderate or high instead of none or low), disease

duration greater than 10 years, and any prednisone use, in

addition to traditional risk factors, resulted in an improved

risk prediction model [77]. However, a later attempt to

externally validate the ERS-RA algorithm found that the

algorithm does not predict CVD in RA more accurately

than risk calculators made for the general population [72].

Other recent efforts that used DAS28, ESR, or health

assessment questionnaires in addition to traditional risk

factors have also failed [73].

Abnormal Body Adiposity

CVD is traditionally associated with abdominal

adiposity and increased BMI. While these associations

hold true in RA patients, there is also an association

between CVD mortality, weight loss and low BMI in RA

[78-82]. One study found that obesity is associated with

decreased mortality in RA patients, however, others have

shown that obesity contributes the same or to a lower

magnitude of CVD risk in RA patients compared to

Figure 2: Risk Factors

Arrows Represent the Causal Relationship between the Activity of

Inflammatory Factors, and the Development of Traditional Risk Factors

(Increased Adiposity, Dyslipidemia, Insulin Resistance) and RA-

Specific Risk Factors that Reflect Disease Activity.

Hs-CRP High Sensitivity C Reactive Protein, ESR Estimated

Sedimentation Rate, TNF Tumor Necrosis Factor, IL-6 Interleukin-6,

IL-1 Interleukin-1, IL-17 Interleukin-17

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controls [83, 84]. The observed “obesity paradox” appears

to be a consequence of the association between catabolic

weight loss and increased inflammation and mortality [81].

Chronic inflammation in RA is associated with loss of lean

body mass and increased fat mass, specifically abdominal

adiposity and visceral fat; it has been termed rheumatoid

cachexia, there is no net weight loss so that BMI is

maintained. Rheumatoid cachexia may affect 10-67% of

RA patients [85, 86]. (Figure 3) Moreover, RA patients

have decreased muscle and fat mass resulting in low BMI.

Among RA patients, classical cachexia with BMI <20 is

associated with increased CVD-related mortality [82]. Any

seemingly protective effect of obesity likely represents the

absence of intense disease activity [87].

Bioelectrical impedance studies have shown

that RA patients may have more fat mass for a given

BMI than controls, suggesting that BMI measurements

may underestimate fat mass and CVD risk in RA [37,

88]. It has been suggested that the BMI cut-off for

overweight and obesity should be 2 kg/m2 lower in RA

patients in order to appropriately estimate the health risks

conferred by being overweight or obese [88]. Increased

BMI in RA is associated with typical CVD risk factors,

hypercholesterolemia, diastolic hypertension, and elevated

CRP [78, 79, 89].

The relationship between BMI and CVD in

RA is U-shaped in that at low BMI, inflammatory and

RA-related factors predominate contributing to CVD

risk whereas at high BMI, traditional CVD risk factors

contribute significantly. This results in decreased CVD risk

in RA patients with higher BMI compared to those with

lower BMIs, supporting the postulate that inflammation

associated with RA is a more powerful risk factor for

CVD than traditional CVD risk factors. Additionally,

hypertension and smoking confer attributable risk for

CVD to RA patients as seen for the general population [73,

84].

Dyslipidemia

In RA, CVD risk is associated with lower than

expected levels of LDL-C and Total-Cholesterol (T-C)

which means that using LDL-C to extrapolate CVD risk in

RA results in an underestimation [90]. Recent studies have

shown that a U-shaped association between cholesterol

levels and CVD risk also exists in non-RA population [90].

Low cholesterol levels may reflect chronic inflammation

and are associated with high levels of triglycerides and

LDL Particles (LDL-P) [54]. LDL-P and ApoB have been

shown to be a better surrogate for estimating CVD risk than

LDL-C when the two measures are discordant [91-95].

HDL-C also presents a challenge in RA patients.

As discussed above, a significant portion of the HDL-C

is pro-inflammatory and dysfunctional. HDL particles

(HDL-P) concentration appears to be inversely related to

carotid-IMT and CHD than HDL-C [96].

That the higher risk of CVD associated with lower

cholesterol levels in RA reflects increased inflammation

is supported by evidence. In patients receiving DMARDs,

decreasing hsCRP correlated with improvements in HDL

efflux capacity and rising LDL [54].

Insulin Resistance

Insulin resistance is more prevalent in RA with

a rate of 54% in RA compared to 40-45% in the general

population [97]. It has been hypothesized that the increased

prevalence of insulin resistance is due to inflammation. In

RA, insulin resistance has been shown to be associated

Figure 3: Inflammation Alters Traditional Risk Factors

Figure 4: The Good, the Bad, and the Neutral – A New Way of Thinking

of Cholesterol

New evidence has shed light on the ambiguity of cholesterol and

suggests that conventional categorizations oversimplify the matter.

HDL-P High Density Lipoprotein-Particles, Apoa1 Apolipoprotein A1,

T-C Total-Cholesterol, LDL-C Low Density Lipoprotein-Cholesterol,

HDL-C High Density Lipoprotein-Cholesterol, LDL-P Low Density

Lipoprotein-Particles, Apo B Apolipoprotein B

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with elevations in TNF-α, IL-6, ESR, and CRP, measures

of RA disease activity and importantly, coronary artery

calcification [97]. One study demonstrated no significant

difference between the CVD risk conferred by diabetes to

RA patients compared to non-RA patients [84].

Smoking

Smoking, a strong predictor of CVD in RA is

also more prevalent in RA than in the general population,

although it only contributes in a smaller magnitude to the

CV risk [73, 84, 98].

Genetic Markers

One study demonstrated an increased risk of CV

mortality in RA patients with HLA-DRB1*04 shared

epitope alleles and the association was even stronger

with HLA-DRB1*0404. The HLA-DRB1*04 allele is

also associated with treatment resistant RA, endothelial

dysfunction and extra-articular RA manifestations [12, 99-

105]. The IL-6-174C allele is associated with increased

CVD in RA patients and this corresponds with elevated

IL-6 levels in the carrier’s serum [106].

Clinical Disease Activity

The CORRONA researchers found that per each

10-point reduction in Clinical Disease Activity Index

(CDAI range 0-76) score there was a 21% reduction in

CVD event risk, with a reduction of 53% between high

disease activity and remission [107]. Similarly, other

studies found Disease Activity Score 28 (DAS28), joint

pain severity, functional disability, severe extra articular

RA and, in some cases, disease duration were independently

associated with increased risk of cardiovascular events

and new onset CAD [108-110]. Absence of joint pain is

associated with decreased cardiac risk [109]. Accordingly,

a study of patients treated with anti-IL-6 therapy found that

decreased risk of cardiovascular events correlated with the

extent of reduction in disease activity measured by DAS28

[111]. There is a small but significant increase in CVD risk

in RA patients for time spent in acute flare compared to

time spent in remission. CVD risk for patients in remission

is similar to the risk in patients without RA [112].

On the other hand, a higher score on the Health

Assessment Questionnaire (score 0-3) at one year after

RA diagnosis is an independent predictor of future CVD-

related and all-cause mortality [113]. The association

between CVD risk in RA and extra-articular disease has

been observed in patients with RA vasculitis, pulmonary

disease, rheumatoid nodules among others, with a hazard

ratio of 2.32 in patients with RA lung disease [45].

Disease severity is also associated with subclinical,

premature atherosclerosis, as measured by Coronary

Artery Calcification (CAC) score and cIMT [114, 115].

The greatest difference in CAC between RA and non-RA

patients occurs in the youngest age group [114].

The “time-to-risk profile” depends on the CVD

phenotype [116]. Risk for certain categories of CVD is

increased even prior to RA diagnosis, while risk for others

is not increased until years after diagnosis. For example,

risks for IHD and venous thromboembolism are not

increased prior to diagnosis but increase rapidly after RA

onset [117-119]. The risk for ACS within the first year

after diagnosis is particularly increased in patients with a

high disease activity score [116, 120]. On the other hand,

risk for ischemic stroke is first detectable at ten years after

RA onset [121].

Corticosteroids

It is unclear how corticosteroid use affects CVD

risk although it appears to be related to pre-existing heart

conditions. Corticosteroid use has been shown to increase

the risk of CVD death in patients with RA without CHD

history, even after adjustments for CV risk factors.

However, in patients with history of CHD, corticosteroid

use actually decreases the risk of death from CVD [45,

122, 123]. Use of corticosteroids has been associated

with an increased risk of CV events, as has use of COX-

2 inhibitors and shorter duration of DMARD use [108].

On the other hand, studies have found no significant

association between corticosteroids and CV events

[124]. Low-dose corticosteroid use had no effect on

atherosclerosis, ventricular function, heart rate variability

or arterial stiffness however, an association with major

CV events, including MI, stroke, and death was found

[125]. Glucocorticoid use was associated with increased

CVD risk and poorer survival for RA patients over age

65 at diagnosis, while methotrexate was associated

with decreased CVD risk [126]. We hypothesize, that

RA patients who required corticosteroid treatment had

more active disease and higher levels of inflammation

which in addition to the effects on insulin sensitivity and

sympathetic tone from glucocorticoids led to an increased

rate of cardiovascular events.

Inflammatory Markers

Inflammation is at the heart of the matter in

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RA patients. (Figure 5) This is reflected by the strong

correlation between disease activity, quantified to some

extent by plasma biomarkers of inflammation, and CVD

risk. Seropositivity for Rheumatoid Factor (RF) and Anti-

Citrullinated Peptide Antibodies (ACPA), along with higher

white blood cell count at diagnosis, and higher cumulative

C-Reactive Protein (CRP), Erythrocyte Sedimentation

Rate (ESR) and pain-visual analog scale scores were

associated with higher CVD risk among patient <65 years

of age at RA diagnosis [126]. Inflammatory markers (ESR,

CRP, WBC, IL-6, TNF-alpha) have a stronger association

with fatal CVD and heart failure than with atherosclerosis

and MI [45, 127].

C Reactive Protein (CRP)/High-Sensitivity CRP

(hsCRP)

Elevated serum CRP levels are associated

with increased CVD risk, including MI, heart failure,

atherosclerosis, and mortality in RA [124, 128]. It is also

an independent predictor of CVD risk, specifically of MI,

in healthy people without RA. The association holds true

even in sub-groups of patients with LDL cholesterol levels

below 130 mg/dl and is a stronger predictor of CVD events

than LDL-cholesterol, atherogenic cholesterol index,

serum amyloid A, IL-6, homocysteine, and Inter Cellular

Adhesion Molecule-1 (ICAM-1) [129]. An hsCRP level

of >5 mg/dL has been shown to be an independent and

statistically significant predictive marker of CV death in

RA patients with a hazard ratio of 3.9 and 4.22 for men and

women, respectively [128]. A CRP > 10 mg/L has been

associated with increased MI with a hazard ratio of 2.12

(95% CI 1.02 to 4.38) [130].

Elevated CRP levels has also been associated

with a significantly increased risk of heart failure and

mortality with hazard ratios 1.25 and 1.08, respectively, in

RA patients [131]. In both RA and the general population,

elevated CRP is associated with number of atherosclerotic

plaques and with increased carotid IMT. A proposed

mechanism for these strong associations is that CRP

promotes atherogenesis by increasing uptake of oxidized

LDL cholesterol by macrophages and inhibiting cholesterol

efflux from foam cells, and also promotes plaque rupture

by promoting the production of matrix metalloproteinases

by macrophages [132, 133].

ESR

Elevated ESR is independently associated

with increased cardiovascular risk [108, 122]. Studies

have shown that ESR > 42 mm/h carries increased MI

and ischemic stroke risks [130] and ESR=50 mm/h is

associated with approximately 10-fold increase in CVD

risk [130, 131]. A 15 year follow-up study found increased

risk for CVD death with a hazard ratio of 2.03 ((95% CI)

1.45-2.83) for patients with at least 3 ESR values of at

least 60 mm/hr [45].

RF Positivity

Many studies have shown that RF positivity (+)

is significantly associated with increased cardiovascular

and all-cause mortality in RA [134, 135]. In fact, the

mortality gap between RF (-) RA patients and the general

population has remained stable in recent years while the

gap for RF (+) patients has increased [136]. Interestingly,

the association between RF (+) and increased CV and all-

cause mortality holds true even in patients without RA

[137]. RF (+) is positively associated with smoking and

diabetes but correlates inversely with cholesterol levels

[138]. Seropositivity confers increased cardiovascular risk

and all-cause mortality, even after adjusting for smoking

and diabetes [139]. RF (+) also strengthens the association

between CRP levels and CV death [128] However, some

more recent studies have not found an association between

RF positivity and CVD risk [77, 120].

ACPA Positivity

Studies evaluating ACPA positivity as a risk

factor for CVD in RA have produced mixed results. ACPA

positivity was shown to be associated with increased risk

of fatal CVD and death but lower or no increased risk

of non-fatal CVD, CHD, or stroke compared to ACPA

negative patients [108, 109, 140, 141]. Other studies

found borderline associations with CVD events without

statistical significance [120, 140]. Studies that looked at

Figure 5: Inflammation is the Hub of the Risk Factor Wheel

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coronary atherosclerosis and ACPA positivity found no

association even though citrullinated proteins were found

within atherosclerotic plaques [142]. However, another

study found that ACPA antibodies are independently

associated with IHD (6.5% versus 2.6%) and higher

mortality rates (11.2% versus 6.8%) compared to ACPA

antibody negative RA patients [143]. Interestingly, an

association between high levels of ACPA and reduced left

ventricular mass, end diastolic volume, and stroke volume,

but not reduced ejection fraction has been described.

Cytokines

Elevated levels of IL-6 are associated with CVD

in RA and in the general population, and IL-6 receptor

signaling pathways are known to have a causal role in the

development of CAD [32]. Elevated levels of IL-6 predict

cardiovascular event risk in healthy men and women.

[129, 144, 145] Among women with RA, IL-6 is strongly

associated with increased cardiovascular and all-cause

mortality rather than non-fatal CVD or CHD [109].

Elevated cytokine concentrations are associated

with subclinical CVD in RA patients. Elevated levels

of inflammatory markers such as IL-6, Serum Amyloid

A (SAA), intercellular adhesion molecule-1 (ICAM-1),

E-selectin, TNF-α, and myeloperoxidase were found in RA,

but only IL-6 and TNF-α concentrations correlated with

high coronary calcium scores, independent of Framingham

risk score and diabetes [146]. Elevated IL-6 is associated

with higher levels of markers of endothelial dysfunction,

ICAM-1 and Vascular Cell Adhesion Molecule-1 (VCAM-

1) [147].

Other biomarkers being investigated are high-

sensitivity cardiac troponin I (hs-cardiac troponin 1) and

N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP).

Hs-cardiac troponin 1 has been shown to be independently

associated with subclinical coronary plaques and a

predictor of CV events in RA patients [148]. NT-proBNP

is an independent predictor of CV mortality and has been

shown to be most useful as a predictor when levels are at

least 100 pg/ml [149-152].

Clinical Manifestations of Cardiovascular Disease

in Rheumatoid Arthritis

Ischemic Heart Disease

RA is associated with an increased risk of IHD.

Prospective cohort studies place the relative risk of MI in

RA between 1.7 and 2.0, and meta-analyses data estimate

a standardized mortality ratio of IHD between 1.59 and

1.77 [2, 153-156]. There is evidence that subclinical

atherosclerotic disease is more common in RA. RA

patients who underwent Computed Tomography (CT)-

angiography for evaluation of coronary plaques had a

significantly higher proportion of plaques when compared

with controls [157]. RA patients were also more likely

to have single, double, and triple-vessel disease, >50%

stenosis, and extensive segmental disease. Moderate RA

disease activity (DAS28 ≥3.2) is most closely associated

with non-calcified coronary plaque [157]. RA patients

who were identified to have unilateral or bilateral carotid

plaques by ultrasound examination were more likely to

have newly incident Acute Coronary Syndrome (ACS)

compared to RA patients without carotid artery plaques

[115]. This may point to carotid artery plaque identification

as a potential predictive tool for estimating CAD and CVD

event risk in RA patients.

Just as higher RA disease activity has been

associated with an increased risk of subclinical

atherosclerotic disease, several studies have demonstrated

that high disease activity is associated with an increased risk

of incident IHD. RA patients with ACS have significantly

higher DAS28 scores [116]. RA patients with IHD have

more tender joints [158]. ACS and IHD are associated with

elevated ESR in RA patients [116, 158]. A 10-point drop in

Clinical Disease Activity Index (CDAI) resulted in a 21%

decrease in composite cardiovascular risk. The effect of

disease activity may be cumulative as increased risk with

extended disease duration is observed; RA patients at >10

years after diagnosis had a significantly increased risk of

MI, while those at <10 years after diagnosis did not have

a significantly increased risk. These findings suggest that

both disease length and severity affect the risk of developing

IHD in RA. Furthermore, it has been demonstrated that the

relative risk of MI, stroke, or CV death in RA patients is

highest among young RA patients and lowest for those >

75 years old. This risk-age discrepancy could be explained

by the fact that high-risk RA patients suffered premature

CV death leaving a relatively healthy older population

[107].

It appears that RA patients experience IHD

differently from the general population. RA patients

are five times more likely to have unrecognized MIs,

identified by characteristic ECG findings in a patient with

no documented history of previous MI) [45]. RA patients

are more likely to suffer from sudden cardiac death and

have increased frequency of ST-segment elevation MI,

higher troponin levels, more inpatient complications, and

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higher short-term mortality after first acute MI or stroke

than non-RA patients [45, 116, 159]. In addition, a review

of Acute Coronary Syndrome (ACS) treatment patterns

and outcomes among RA patients found not only a higher

case fatality rate for MI but also that these patients were

less likely to receive coronary artery bypass grafting,

percutaneous reperfusion, and secondary prevention of

MI including beta-blockers and lipid-lowering agents

[116, 160]. On the other hand, one study that found no

difference in ACS management still found worse mortality

and increased recurrent ischemia in RA compared to non-

RA patients [161].

Congestive Heart Failure

RA has also been associated with an increased

risk of ischemic and non-ischemic CHF, with a more

significantly increased risk for ischemic CHF [162-169].

RA patients have a higher rate of diastolic dysfunction, but

no difference in left ventricular ejection fraction compared

to the general population [137, 166, 170-175].

In non-RA populations, ischemic CHF can be

attributed to hypertension, smoking, high BMI, and

alcohol abuse however, in RA, those traditional risk

factors do not fully explain the occurrence of the disease

prevalence and RA patients are less likely to have obesity

and hypertension [176]. As in IHD, RA patients are more

likely to experience CHF differently from non-RA patients

with greater incidence of sub-clinical disease; they present

with less orthopnea, dyspnea on exertion, and paroxysmal

nocturnal dyspnea compared to controls. This absence of

the cardinal symptoms of CHF could potentially delay

diagnosis and treatment in RA patients [176]. Stroke and

atrial fibrillation have also been found to be more prevalent

in RA patients, with a 40% higher risk of atrial fibrillation

and a 30% increased risk of stroke in RA compared to the

general population [177].

Evaluation and Workup

It is of paramount importance that CV disease be

promptly diagnosed and evaluated in patients with RA

given the heightened risk of mortality [2]. The workup

of CV disease in RA should include history, physical

examination, laboratory tests, electrocardiography

and echocardiography, with a specific focus on IHD,

heart failure, myocarditis, micro-vascular disease and

pulmonary hypertension, conditions more prevalent in

RA [163, 178, 179]. Risk assessment tools, such as the

Systematic Coronary Risk Evaluation (SCORE) index

and Framingham models were developed to estimate

CV risk in the general population [180, 181]. These

tools underestimate the CV risk in RA largely due to the

exclusion of non-traditional risk factors [70, 182]. Studies

have shown that RA patients deemed to have moderate

risk by these models, actually have carotid plaques which

place them at a much higher CV risk [183, 184]. The

QRESEARCH CV Risk Algorithm 2 (QRISK2), a risk

calculator that incorporates RA in its assessment, was

found to be of value in the determination of fatal versus

non-fatal CV risk but appears to overestimate CV events

in RA [70, 76].

The Modified SCORE (mSCORE) index,

developed by the European League Against Rheumatism

(EULAR), has shown a higher 10-year CV risk in patients

with RA. This emphasized the need to include RA disease-

specific factors to the estimation of CV risk in calculation

tools [75, 185, 186]. The 2016 updated EULAR

recommendations advised a multiplication factor of 1.5 for

CV risk assessment calculators when used in patients with

RA [186]. However, current research suggests that many

of these risk assessment tools, including the Expanded

CV Risk Prediction Score for Rheumatoid Arthritis (ERS-

RA), EULAR multiplier and QRISK2, are still not ideal

[72, 77]. Future research is likely to provide a more

accurate CV risk assessment calculator to be used among

RA population.

Figure 6: Elevated Inflammatory Biomarkers Found in Rheumatoid

Arthritis

These markers are being studied for their usefulness in contributing to

cardiovascular disease risk assessment tools in rheumatoid arthritis

patients CRP C-reactive protein, ESR Estimated Sedimentation Rate,

NT-probnp N-terminal pro brain natriuretic peptide, TNF-Α tumor

necrosis factor-alpha, IL-6 interleukin-6, IL-Β interleukin-beta, IL-17

interleukin-17, ICAM-1 Intercellular Adhesion Molecule-1, VCAM-

1 Vascular Cell Adhesion Molecule-, Hs-cardiac troponin 1 high

sensitivity-cardiac troponin 1, RF Rheumatoid Factor, ACPA Anti-

Citrullinated Protein Antibodies

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Serum biomarkers have been studied as surrogate

CV end points in RA [187] (Figure 6). The Reynold’s risk

assessment incorporated hsCRP given its usefulness across

a full range of CV risk profiles. However, the Reynold’s

risk assessment failed to accurately predict CVD in RA

[188-190].

Imaging studies are also useful in determining CV

risk with high sensitivity and specificity. An ideal imaging

tool would be able to provide: accurate prediction of CV

mortality, early subclinical detection of atherosclerosis,

longitudinal evaluation of interval changes in CVD

and detection of impact of atherosclerosis and other

manifestations of CVD [191]. Endothelial dysfunction has

been reliably associated with impending atherosclerotic

disease [192]. (See Figure 1) Flow-mediated dilation

(FMD) and Brachial Artery Reactivity Testing (BART) can

help estimate endothelial function [193, 194]. However,

rigorous research found that of the parameters measured

in BART, only forearm hyperemic flow could estimate

the 10-year CV risk in RA by correlation with AHA/ACC

risk categories [195]. While impaired in RA, FMD did not

show significant correlation with estimated 10-year CV

risk [195, 196]. Utilizing ultrasonography (US), the aortic

Pulse Wave Velocity (aPWV) and augmentation index

(AIx) can provide a measurement of arterial stiffness [193,

194]. A meta-analysis concluded that arterial stiffness was

abnormal in patients with RA [197]. Studies have shown

that although aPWV and AIx can predict CV risk in the

general population, they are not useful to predict CV

events in RA [198].

Carotid plaque and cIMT, as measured by US, have

been independently associated with CV risk determination

in the general population [199]. A 5-year prospective study

of RA patients without CV risk factors showed that cIMT

≥0.90 mm, predicted CV events in >60% of the cohort. A

cIMT ≤0.77 mm was associated with no CV events. cIMT

is useful in estimating CV risk in RA patients who may

be underestimated by conventional risk scoring calculators

[115, 200]. Studies showed that 65% of patients classified

as moderate risk and 85% of those in high or very high-

risk categories have increased cIMT and/or carotid plaque,

signifying its utility in re-estimating CV risk in this

intermediate-risk cohort [183]. Carotid plaques, defined as

a localized intima-media thickening of >1 mm, was shown

to have significant correlation with poor CV survival

and ischemic CV events. These findings are particularly

important in the presence of bilateral carotid plaques,

where the incidence of CV events rises by over a factor

of 4 [115, 201]. The updated EULAR recommendations

suggest that carotid US be used to screen for asymptomatic

atherosclerotic plaques as part of CV disease evaluation in

patients with RA [186].

Cardiac CT and CAC score are useful modern

imaging techniques to quantify risk in RA patients. Similar

to the ultra-sonographic techniques, CAC is well known

to be a useful risk prediction marker of CV events in the

general population [202]. A study of 227 patients showed

that patients with both early and established RA had more

severe CAC scores. Patients with established disease had

an odds ratio of 3.42 for severe CAC when adjusting for

CV risk factors, making cardiac CT a useful discriminator

of CV risk in RA patients [203]. Cardiac MRI (CMR)

can be used to quantify the extent of myocardial damage

in patients with RA [204]. Although limited literature

currently exists on CMR use in RA, patients tend to have

reduced left ventricular mass and ejection fraction [172].

Myocardial strain imaging with the use of

Speckle-Tracking Echocardiography (STE) is a new

technique to evaluate myocardial function that can detect

early myocardial dysfunction in patients with RA [205].

The Mayo Clinic used this modality to detect subclinical

myocardial diastolic dysfunction in a retrospective study

of 87 patients with RA without history of CV disease.

Global left ventricular and right ventricular strain were

reduced in RA patients, with worse strain correlating

with other markers of RA disease severity [205]. An

Italian study examining RA patients free of CV disease

and normal transthoracic echocardiograms, demonstrated

statistically significant reductions in LV end-systolic radial

and longitudinal strains when compared to the general

population controls [206]. Larger prospective trials are

needed to confirm its usefulness as a routine modality

and clinical utility in predicting CV events. Table 1 for a

summary of special tests that may be used to assess CVD

in RA).

Additionally, genetic and serological markers are

being studied to evaluate CV disease in RA patients. Human

leukocyte antigens, cytokines, adipokines, endothelial

cell activation markers, and their related genes all show

a significant correlation with the development of CV risk

in RA patients [206, 207] (See Figure 6). Age-adjustments

should also be considered when evaluating CV risk in RA

patient since younger RA patients tend to have higher rates

of CAD, and dyslipidemia deserves special attention as

previously discussed [208].

An accurate CV risk assessment tool would involve

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a composite score that factors in clinical and demographic

data, carotid US results and serological and genetic serum

markers, providing a more individualized approach to CV

risk for patients with RA [207]. We encourage clinicians

to adopt a cautious approach when investigating patients

with RA and maintain a low threshold for treatment and

start prevention strategies to minimize the burden of CV

disease in patients with RA.

Management

Chronic inflammation is now regarded as the

driver of accelerated atherosclerosis in the RA population

[209, 210]. Effective disease control seems to be pivotal

to preventing atherosclerosis and its consequences. One

of the first studies to show that disease control improved

mortality was a retrospective review of RA patients

receiving intramuscular gold therapy [211]. Disease

Modifying Anti-Rheumatic Drugs (DMARD) and

particularly methotrexate (MTX) soon were also found to

reduce mortality up to 50%. In addition, MTX treatment

reduced ESR and CRP, and raised TC and HDL levels

[212, 213]. Hydroxychloroquine (HCQ) has also been

found to have a favorable effect on lipid profile and has an

additional antithrombotic effect [214]. HCQ reduces total

cholesterol (T-C), LDL-C and increases HDL-C leading to

a favorable atherogenic index [215-217].

The availability of DMARDs and anti-TNF

therapies have been associated with decreases in CV

fatalities in RA [218]. Clinical reports support the

notion that arrhythmic events are significantly reduced

in patients taking anti-TNF therapies or MTX [111, 219,

220]. Elevated levels of hsCRP and IL-6 were found to

be strong and independent predictors of sudden cardiac

death among a healthy cohort reinforcing the idea that

inflammatory cytokines induce structural, chronic cardiac

sympathetic activation, and myoelectrical alteration which

favor arrhythmogenic events in the non-RA population

[221, 222]. Moreover, triple therapy with MTX plus

sulfasalazine and HCQ for 52 weeks was demonstrated

to reduce disease activity and increase HDL-C, lower

LDL-C, and lower the atherogenic index [223].

A five-year study that compared RA patients on

synthetic DMARDs to those on anti-TNF therapy found

that the risk of MI was decreased by 39% in the latter

group. The study also demonstrated that 16 months of anti-

TNF therapy was not only associated with a lower CV risk,

but also influenced disease severity and mortality post MI.

These findings reinforced the concept that a reduction of

vascular inflammation in RA is linked to better outcomes

by decreasing atherosclerosis which entails improved

endothelial function, plaque stabilization and post-MI

remodeling [224, 225]. The randomized control trial

of golimumab in MTX refractory RA patients (GO-

FORWARD) revealed that at 14 weeks, the T-C, LDL-C

and HDL-C, had increased in the MTX-golimumab group

compared to the placebo-MTX control [226, 227]. In

MTX naïve patients (GO-BEFORE), rises in the lipid

parameters at 24 weeks were similar in the golimumab-

MTX and placebo-MTX groups, which supported the

notion that the improvements in lipid profile were due

to MTX effectiveness in naïve patients [228, 229].

Tocilizumab (TCZ)’s effects (IL-6R inhibitor) on lipids

and CV risk was examined in the MEASURE trial. TCZ

resulted in a decrease of HDL-associated serum amyloid

A, phospholipase A2, lipoprotein A, ﬁbrinogen, D-dimer

and elevation of paraoxonase while ApoB/ApoA1 ratio

remained stable. This shows that TCZ induced elevations

in LDL-C but altered HDL particles towards an anti-

inﬂammatory composition, ameliorating many vascular

risk surrogates [53, 229].

The relationship of TCZ and major CV adverse

events (MACE) was studied in about 4000 RA patients

with moderate to severe RA. TCZ’s ability to decrease

disease activity positively correlated with a lower risk

of future MACE. The higher the disease activity despite

TCZ, the higher the risk of future MACE. Moreover, lipid

parameters while on TCZ were not useful as markers of

risk for MACE [111].

JAK inhibitors also increase HLD-C and LDL-C

Table 1: Special Tests

Predictive Requires Further

Testing Not Predictive

Forearm

Hyperemic Flow

[195]

Cardiac MRI [204]

Flow-Mediated

Dilation [195, 196]

Carotid Intima

Media Thickness

[115, 183, 186,

201]

Brachial Artery

Reactivity [195]

Cardiac CT and

Coronary Speckle-Tracking

Echocardiography

[205]

Aortic Pulse Wave

Velocity [198]

Artery

Calcification

Score [203]

Augmentation Index

[198]

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in a similar fashion as seen with tocilizumab, with a

reduction in the CV risk and decreased cIMT despite the

elevation in lipid profile. Pooled analysis found the MACE

events were similar for patients on tofacitinib or placebo

and this risk did not increase over time. However, in 2017

concerns for venous thromboembolic events lead the FDA

to establish mandatory reporting of all MACE for the JAK

inhibitors class. Venous thromboembolism has been seen

as an adverse effect with the entire class, and portal vein

thrombosis was linked to ruxolitinib [230]. This should be

kept in mind as pulmonary embolism appears to be a class-

wide issue for JAK inhibitors.

The anti-inflammatory effect of statins was tested

in the TARA trial (Trial of Atorvastatin in Rheumatoid

Arthritis), in which RA patients ≥ 50 years old without

known CVD or diabetes, who had RA for ≥ 10 years and

were maintained on DMARD therapy, were initiated on

atorvastatin or placebo as adjuvant therapy and followed

for 6 months. Modest but significant improvements were

seen in disease activity index and swollen joint count in

addition to a decrease in ESR and CRP of 28% and 50%,

respectively [231]. Furthermore, a large population-

based study in which non-RA patients on statins were

followed for 12 years looked at the crude incidence of

RA in the population. It found that the high dose statin

group (atorvastatin 20-80 mg, rosuvastatin 5-40 mg, or

simvastatin 80 mg) was associated with a 23% reduction

in the risk of incident RA, compared to the low-dose statin

group, suggesting that statins may reduce inflammation

directly [232]. Statins have also been demonstrated to

improve arterial stiffness and endothelial dysfunction

[233, 234]. Remarkably but not surprisingly, a population

study of RA patients who had their statins discontinued for

more than 3 months revealed a 67% increase in the risk of

MI with a 2% increased risk of acute MI for each month of

discontinuation [235]. The addition of a second non-statin

lipid lowering therapy such as ezetimibe was also studied

in patient with hsCRP >6 mg/dL, leading to significant

reductions in LDL-C, hsCRP and disease severity [236].

A propensity score analysis of RA patients on at least one

DMARD demonstrated that the concomitant use of statins

was associated with a 21% lower risk of all-cause mortality

[237].

The benefits of early therapy in RA were confirmed

by a 20-year follow up study of a cohort of RA patients who

had low disease activity throughout, but in whom disability

was apparent by year seven of disease and continued to

rise regardless of whether they received treatment for their

RA. In this study 44% of patients died, however, patients

who had received DMARD treatment within 6 months

of disease onset tended to have a lower risk of death that

those who did not receive treatment [238]. Early initiation

of statins should also be considered for patients with RA,

even in the absence of dyslipidemia given that this patient

population carries high risk features for CVD and statins

have been demonstrated to have effective preventative and

protective properties in RA patients [239].

A recent large population study encountered that

the risk of ACS was increased 23% in the siblings of RA

patients compared to the general population suggesting

a possible shared susceptibility between RA and ACS.

Therefore, inquiring about family history of RA during

health maintenance visits might help detect and address

subclinical CVD risk in patients otherwise considered low

risk [240]. Rheumatology clinics also failed to discuss

hypertension in 2 out of 3 visits, which represent a huge

missed opportunity since 40% of RA patients met criteria

for uncontrolled hypertension. Better strategies are needed

to address modifiable risk factors such as hypertension,

including prompt referral to primary care and patient

education in order to improve outcomes in this vulnerable

patient population [241].

Conclusion

While RA occurs in about 1% of the general

population, CVD disproportionally affects RA patients

and is currently the major cause of morbidity and mortality

among RA patients. CVD presents much earlier in RA

patients and has been reported even before full clinical

presentation and diagnosis of RA. Among the major CVD

presentations, silent MI, diastolic dysfunction, arrythmias,

stroke and sudden cardiac death appear to be prevalent

and occur at a relatively younger age. Other features of

CVD in RA include the obesity paradox and the lipid

paradox making this disease a particularly interesting

and rather challenging entity to diagnose and manage.

Chronic inflammation appears to be the major underlying

pathogenic factor linking RA and CVD. This is associated

with endothelial dysfunction, lipid abnormalities,

hypercoagulability and early atherosclerosis with unstable

plaque formation. Physicians should be cognizant of RA

disease activity as it correlates with higher CVD risk.

The use of DMARDs and biologics have been shown to

control not only RA but also CVD risk. Early detection

and aggressive management of CVD should be employed

in this high-risk population together with control of the

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traditional CVD risk factors including hypertension,

hyperlipidemia, smoking and diabetes. Further research

is needed to help characterize and establish the ideal

management strategies in this vulnerable population and

inform future guideline development in this field.

Acknowledgment

This work is supported in part by Dr. Moro O.

Salifu's efforts through NIH Grant # S21MD012474

References

1. Sokka T, Abelson B, Pincus T (2008) Mortality in rheumatoid

arthritis: 2008 update. Clin Exp Rheumatol 26: S35-S61.

2. Avina-Zubieta JA, Choi HK, Sadatsafavi M, et al. (2008) Risk

of cardiovascular mortality in patients with rheumatoid arthritis:

a meta-analysis of observational studies. Arthritis Rheum 59:

1690-1697.

3. Avina-Zubieta JA, Thomas J, Sadatsafavi M, et al. (2012) Risk

of incident cardiovascular events in patients with rheumatoid

arthritis: a meta-analysis of observational studies. Ann Rheum

Dis 71: 1524-1529.

4. Pujades-Rodriguez M, Bram Duyx, Sara LT, et al. (2016)

Rheumatoid Arthritis and Incidence of Twelve Initial

Presentations of Cardiovascular Disease: A Population Record-

Linkage Cohort Study in England. PLoS One 11: e0151245.

5. Kang EH, Liao KP, Kim SC (2018) Cardiovascular Safety

of Biologics and JAK Inhibitors in Patients with Rheumatoid

Arthritis. Curr Rheumatol Rep 20: 42.

6. Widdifield JPJ, Huang A, Bernatsky S (2018) Causes of death

in rheumatoid arthritis: How do they compare to the general

population?

7. Zou K, Fu-Kun Xiao, Hong-Ying Li, et al. (2017) Risk of

cardiovascular disease in Chinese patients with rheumatoid

arthritis: A cross-sectional study based on hospital medical

records in 10 years. PLoS One 12: e0180376.

8. Solomon A, Linda Tsang, Angela J. Woodiwiss, et al. (2014)

Cardiovascular disease risk amongst African black patients

with rheumatoid arthritis: the need for population specific

stratification. Biomed Res Int 10.

9. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid

arthritis. N Engl J Med 365: 2205-2219.

10. Libby P, Ridker PM, Maseri A (2002) Inflammation and

atherosclerosis. Circulation 105: 1135-1143.

11. Ridker PM, Rifai N, Rose L, et al. (2002) Comparison of

C-reactive protein and low-density lipoprotein cholesterol levels

in the prediction of first cardiovascular events. N Engl J Med

347: 1557-1565.

12. Gonzalez-Gay MA, Gonzalez-Juanatey C, Lopez-Diaz MJ,

et al. (2007) HLA-DRB1 and persistent chronic inflammation

contribute to cardiovascular events and cardiovascular mortality

in patients with rheumatoid arthritis. Arthritis Rheum 57:

125-132.

13. Sattar N, McInnes IB (2005) Vascular comorbidity in

rheumatoid arthritis: potential mechanisms and solutions. Curr

Opin Rheumatol 17: 286-292.

14. Arend WP (2001) Physiology of cytokine pathways in

rheumatoid arthritis. Arthritis Rheum 45: 101-106.

15. Houssiau FA, Devogelaer JP, Van Damme J, et al. (1988)

Interleukin-6 in synovial fluid and serum of patients with

rheumatoid arthritis and other inflammatory arthritides. Arthritis

Rheum 31: 784-788.

16. Robert M, Miossec P (2017) Effects of Interleukin 17 on the

cardiovascular system. Autoimmun Rev 16: 984-991.

17. Hot A, Lenief V, Miossec P (2012) Combination of IL-17

and TNFalpha induces a pro-inflammatory, pro-coagulant and

pro-thrombotic phenotype in human endothelial cells. Ann

Rheum Dis 71: 768-776.

18. McInnes IB, Schett G (2007) Cytokines in the pathogenesis

of rheumatoid arthritis. Nat Rev Immunol 7: 429-442.

19. Pober JS, Cotran RS (1990) Cytokines and endothelial cell

biology. Physiol Rev 70: 427-451.

20. Fossiez F, Djossou O, Chomarat P, et al. (1996) T cell

interleukin-17 induces stromal cells to produce proinflammatory

and hematopoietic cytokines. J Exp Med 183: 2593-2603.

21. Munro JM, Pober JS, Cotran RS (1989) Tumor necrosis

factor and interferon-gamma induce distinct patterns of

endothelial activation and associated leukocyte accumulation in

skin of Papio anubis. Am J Pathol 135: 121-133.

22. Yuan S, Zhang S, Zhuang Y, et al. (2015) Interleukin-17

Stimulates STAT3-Mediated Endothelial Cell Activation for

Neutrophil Recruitment. Cell Physiol Biochem 36: 2340-2356.

23. Li JH, Pober JS (2005) The cathepsin B death pathway

contributes to TNF plus IFN-gamma-mediated human

endothelial injury. J Immunol 175: 1858-1866.

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 14 of 23

24. Zhu F, Wang Q, Guo C, et al. (2011) IL-17 induces apoptosis

of vascular endothelial cells: a potential mechanism for human

acute coronary syndrome. Clin Immunol 141: 152-160.

25. Bombeli T, Mueller M, Haeberli A (1997) Anticoagulant

properties of the vascular endothelium. Thromb Haemost 77:

408-423.

26. Kitas GD, Gabriel SE (2011) Cardiovascular disease in

rheumatoid arthritis: state of the art and future perspectives. Ann

Rheum Dis 70: 8-14.

27. Aubry MC, Maradit-Kremers H, Reinalda MS, et al. (2007)

Differences in atherosclerotic coronary heart disease between

subjects with and without rheumatoid arthritis. J Rheumatol 34:

937-942.

28. Bevilacqua MP, J S Pober, G R Majeau, et al. (1986)

Recombinant tumor necrosis factor induces procoagulant activity

in cultured human vascular endothelium: characterization and

comparison with the actions of interleukin 1. Proc Natl Acad Sci

USA 83: 4533-4537.

29. Grignani G, Maiolo A (2000) Cytokines and hemostasis.

Haematologica 85: 967-972.

30. Yoshizumi M, Perrella MA, Lee ME, et al. (1993) Tumor

necrosis factor downregulates an endothelial nitric oxide

synthase mRNA by shortening its half-life. Circ Res 73: 205-209.

31. Sohn RH, Deming CB, Johns DC, et al. (2005) Regulation

of endothelial thrombomodulin expression by inflammatory

cytokines is mediated by activation of nuclear factor-kappa B.

Blood 105: 3910-3917.

32. Go AS, Assimes TL, Quertermous T, et al. (2012) Interleukin-6

receptor pathways in coronary heart disease: a collaborative

meta-analysis of 82 studies. Lancet 379: 1205-1213.

33. Hurlimann D, Forster A, Noll G, et al. (2002) Anti-tumor

necrosis factor-alpha treatment improves endothelial function in

patients with rheumatoid arthritis. Circulation 106: 2184-2187.

34. Ridker PM (2017) Canakinumab for Residual Inflammatory

Risk. Eur Heart J 38: 3545-3548.

35. Kleveland O, Kunszt G, Bratlie M, et al. (2016) Effect of a

single dose of the interleukin-6 receptor antagonist tocilizumab

on inflammation and troponin T release in patients with non-

ST-elevation myocardial infarction: a double blind, randomized,

placebo-controlled phase 2 trial. Eur Heart J 37: 2406-2413.

36. Zuniga LA, Shen WJ, Joyce-Shaikh B, et al. (2010) IL-17

regulates adipogenesis, glucose homeostasis, and obesity. J

Immunol 185: 6947-6959.

37. Liao KP, Solomon DH (2013) Traditional cardiovascular

risk factors, inflammation and cardiovascular risk in rheumatoid

arthritis. Rheumatology 52: 45-52.

38. Su SA, Yang D, Zhu W, et al. (2016) Interleukin-17A mediates

cardiomyocyte apoptosis through Stat3-iNOS pathway. Biochim

Biophys Acta 1863: 2784-2794.

39. Zhou SF, Yuan J, Liao MY, et al. (2014) IL-17A promotes

ventricular remodeling after myocardial infarction. J Mol Med

92: 1105-1116.

40. Wu L, SuFey Ong, Monica V. Talor, et al. (2014) Cardiac

fibroblasts mediate IL-17A-driven inflammatory dilated

cardiomyopathy. J Exp Med 211: 1449-1464.

41. Arosio E, De Marchi S, Rigoni A, et al. (2007) Forearm

haemodynamics, arterial stiffness and microcirculatory reactivity

in rheumatoid arthritis. J Hypertens 25: 1273-1278.

42. Datta D, Ferrell WR, Sturrock RD, et al. (2007) Inflammatory

suppression rapidly attenuates microvascular dysfunction in

rheumatoid arthritis. Atherosclerosis 192: 391-395.

43. Galarraga B, Khan F, Kumar P, et al. (2008) C-reactive

protein: the underlying cause of microvascular dysfunction in

rheumatoid arthritis. Rheumatology 47: 1780-1784.

44. Ciftci O, Yilmaz S, Topcu S, et al. (2008) Impaired coronary

microvascular function and increased intima-media thickness in

rheumatoid arthritis. Atherosclerosis 198: 332-337.

45. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. (2005)

Increased unrecognized coronary heart disease and sudden

deaths in rheumatoid arthritis: a population-based cohort study.

Arthritis Rheum 52: 402-411.

46. Lee YH, Choi SJ, Ji JD, et al, (2000) Lipoprotein (a) and

lipids in relation to inflammation in rheumatoid arthritis. Clin

Rheumatol 19: 324-325.

47. Van Lenten BJ, Hama SY, de Beer FC, et al. (1995) Anti-

inflammatory HDL becomes pro-inflammatory during the acute

phase response. J Clin Invest 96: 2758-2767.

48. Navab M, Hama SY, Hough GP, et al. (2001) A cell-free

assay for detecting HDL that is dysfunctional in preventing the

formation of or inactivating oxidized phospholipids. J Lipid Res

42: 1308-1317.

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 15 of 23

49. Navab M, Van Lenten BJ, Srinivasa Reddy T, et al. (2001)

High-density lipoprotein and the dynamics of atherosclerotic

lesions. Circulation 104: 2386-2387.

50. McMahon M, Grossman J, FitzGerald J, et al. (2006)

Proinflammatory high-density lipoprotein as a biomarker for

atherosclerosis in patients with systemic lupus erythematosus

and rheumatoid arthritis. Arthritis Rheum 54: 2541-2549.

51. Watanabe J, Charles-Schoeman C, Miao Y, et al. (2012)

Proteomic profiling following immunoaffinity capture of

high-density lipoprotein: association of acute-phase proteins

and complement factors with proinflammatory high-density

lipoprotein in rheumatoid arthritis. Arthritis Rheum 64:

1828-1837.

52. Charles-Schoeman C, Watanabe J, Lee YY, et al. (2009)

Abnormal function of high-density lipoprotein is associated with

poor disease control and an altered protein cargo in rheumatoid

arthritis. Arthritis Rheum 60: 2870-2879.

53. McInnes IB, Thompson L, Giles JT, et al. (2015) Effect of

interleukin-6 receptor blockade on surrogates of vascular risk

in rheumatoid arthritis: MEASURE, a randomised, placebo-

controlled study. Ann Rheum Dis 74: 694-702.

54. Liao KP, Playford MP, Michelle F, et al. (2015) The

association between reduction in inflammation and changes

in lipoprotein levels and HDL cholesterol efflux capacity in

rheumatoid arthritis. J Am Heart Assoc 4.

55. Navarro-Millan I, Charles-Schoeman C, Yang S, et al.

(2013) Changes in lipoproteins associated with methotrexate or

combination therapy in early rheumatoid arthritis: results from

the treatment of early rheumatoid arthritis trial. Arthritis Rheum

65: 1430-1438.

56. Pollono EN, Lopez-Olivo MA, Lopez JA, et al. (2010) A

systematic review of the effect of TNF-alpha antagonists on lipid

profiles in patients with rheumatoid arthritis. Clin Rheumatol

29: 947-955.

57. Kremer JM, Bloom BJ, Breedveld FC, et al. (2009) The

safety and efficacy of a JAK inhibitor in patients with active

rheumatoid arthritis: Results of a double blind, placebo-

controlled phase IIa trial of three dosage levels of CP-690,550

versus placebo. Arthritis Rheum 60: 1895-1905.

58. Semb AG, Rollefstad S, Provan SA, et al. (2013) Carotid

plaque characteristics and disease activity in rheumatoid

arthritis. J Rheumatol 40: 359-368.

59. McEntegart A, Capell HA, Creran D, et al. (2001)

Cardiovascular risk factors, including thrombotic variables,

in a population with rheumatoid arthritis. Rheumatology 40:

640-644.

60. Schonbeck U, Libby P (2001) CD40 signaling and plaque

instability. Circ Res 89: 1092-1103.

61. Schonbeck U, Varo N, Libby P, et al. (2001) Soluble CD40L

and cardiovascular risk in women. Circulation 104: 2266-2268.

62. Vasan RS (2006) Biomarkers of cardiovascular disease:

molecular basis and practical considerations. Circulation 113:

2335-2362.

63. Vallejo AN (2005) CD28 extinction in human T cells: altered

functions and the program of T-cell senescence. Immunol Rev

205: 158-169.

64. Liuzzo G, Kopecky SL, Frye RL, et al. (1999) Perturbation of

the T-cell repertoire in patients with unstable angina. Circulation

100: 2135-2139.

65. Pasceri V, Yeh ET (1999) A tale of two diseases: atherosclerosis

and rheumatoid arthritis. Circulation 100: 2124-2126.

66. Eid RE, Rao DA, Zhou J, et al. (2009) Interleukin-17 and

interferon-gamma are produced concomitantly by human

coronary artery-infiltrating T cells and act synergistically on

vascular smooth muscle cells. Circulation 119: 1424-1432.

67. El-Menoufy MA, EK, Ahmed, et al. (2018) Unusual

CD4+CD28- T lymphocyte subset is implicated in the

pathogenesis of early atherosclerosis in patients with rheumatoid

arthritis. The Egyptian Rheumatologist.

68. Gerli R, Schillaci G, Giordano A, et al. (2004) CD4+CD28-

T lymphocytes contribute to early atherosclerotic damage in

rheumatoid arthritis patients. Circulation 109: 2744-2748.

69. Pober JS, Sessa WC (2007) Evolving functions of endothelial

cells in inflammation. Nat Rev Immunol 7: 803-815.

70. Arts EE, Popa C, Den Broeder AA, et al. (2015) Performance

of four current risk algorithms in predicting cardiovascular

events in patients with early rheumatoid arthritis. Ann Rheum

Dis 74: 668-674.

71. Crowson CS, Rollefstad S, Ikdahl E, et al. (2018) Impact of

risk factors associated with cardiovascular outcomes in patients

with rheumatoid arthritis. Ann Rheum Dis 7: 48-54.

72. Crowson CS, Gabriel SE, Semb AG, et al. (2017) Rheumatoid

arthritis-specific cardiovascular risk scores are not superior to

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 16 of 23

general risk scores: a validation analysis of patients from seven

countries. Rheumatology 56: 1102-1110.

73. Crowson CS, Rollefstad S, Kitas GD, et al. (2017) Challenges

of developing a cardiovascular risk calculator for patients with

rheumatoid arthritis. PLoS One 12: e0174656.

74. Crowson CS, Rollefstad S, Kitas GD, et al. (2017) Correction:

Challenges of developing a cardiovascular risk calculator for

patients with rheumatoid arthritis. PLoS One 12: e0175605.

75. Peters MJ, Symmons DP, McCarey D, et al. (2010) EULAR

evidence-based recommendations for cardiovascular risk

management in patients with rheumatoid arthritis and other

forms of inflammatory arthritis. Ann Rheum Dis 69: 325-331.

76. Hippisley-Cox J, Vinogradova Y, Minhas R, et al. (2008)

Predicting cardiovascular risk in England and Wales: prospective

derivation and validation of QRISK2. BMJ 336: 1475-1482.

77. Solomon DH, Greenberg J, Curtis JR, et al. (2015) Derivation

and internal validation of an expanded cardiovascular risk

prediction score for rheumatoid arthritis: a Consortium of

Rheumatology Researchers of North America Registry Study.

Arthritis Rheumatol 67: 1995-2003.

78. Stavropoulos-Kalinoglou A, Metsios GS, Panoulas VF, et

al. (2009) Associations of obesity with modifiable risk factors

for the development of cardiovascular disease in patients with

rheumatoid arthritis. Ann Rheum Dis 68: 242-245.

79. Armstrong DJ, McCausland EM, Quinn AD, et al. (2006)

Obesity and cardiovascular risk factors in rheumatoid arthritis.

Rheumatology 45: 782-783.

80. Sparks JA, Chang SC, Nguyen US, et al. (2018) Weight

Change During the Early Rheumatoid Arthritis Period and Risk

of Subsequent Mortality in Women With Rheumatoid Arthritis

and Matched Comparators. Arthritis Rheumatol 70: 18-29.

81. Baker JF, Billig E , Michaud K, et al. (2015) Weight Loss, the

Obesity Paradox, and the Risk of Death in Rheumatoid Arthritis.

Arthritis Rheumatol 67: 1711-1717.

82. Kremers HM, Nicola PJ, Crowson CS, et al. (2004)

Prognostic importance of low body mass index in relation to

cardiovascular mortality in rheumatoid arthritis. Arthritis Rheum

50: 3450-3457.

83. Wolfe F, Michaud k (2012) Effect of body mass index on

mortality and clinical status in rheumatoid arthritis. Arthritis

Care Res 64: 1471-1479.

84. Gonzalez A, Maradit Kremers H, Crowson CS, et al. (2007)

The widening mortality gap between rheumatoid arthritis patients

and the general population. Arthritis Rheum 56: 3583-3587.

85. Roubenoff R, Roubenoff RA, Ward LM, et al. (1992)

Rheumatoid cachexia: depletion of lean body mass in rheumatoid

arthritis. J Rheumatol 19: 1505-1510.

86. Engvall IL, Elkan AC, Tengstrand B, et al. (2008) Cachexia

in rheumatoid arthritis is associated with inflammatory activity,

physical disability, and low bioavailable insulin-like growth

factor. Scand J Rheumatol 37: 321-328.

87. Escalante A, Haas RW, Rincon I del (2005) Paradoxical

effect of body mass index on survival in rheumatoid arthritis:

role of comorbidity and systemic inflammation. Arch Intern

Med 165: 1624-1629.

88. Stavropoulos-Kalinoglou A, Metsios GS, Koutedakis Y,

Nevill AM, et al. (2007) Redefining overweight and obesity in

rheumatoid arthritis patients. Ann Rheum Dis 66: 1316-1321.

89. Dessein PH, Norton GR, Woodiwiss AJ, et al. (2007)

Independent role of conventional cardiovascular risk factors as

predictors of C-reactive protein concentrations in rheumatoid

arthritis. J Rheumatol 34: 681-688.

90. Liao KP, Liu J, Lu B, et al. (2015) Association between lipid

levels and major adverse cardiovascular events in rheumatoid

arthritis compared to non-rheumatoid arthritis patients. Arthritis

Rheumatol 67: 2004-2010.

91. Sniderman AD, Islam S, Yusuf S, et al. (2012) Discordance

analysis of apolipoprotein B and non-high density lipoprotein

cholesterol as markers of cardiovascular risk in the

INTERHEART study. Atherosclerosis 225: 444-449.

92. Pencina MJ, D’Agostino RB, Zdrojewski T, et al. (2015)

Apolipoprotein B improves risk assessment of future coronary

heart disease in the Framingham Heart Study beyond LDL-C

and non-HDL-C. Eur J Prev Cardiol 22: 1321-1327.

93. Lawler PR, Akinkuolie AO, Ridker PM, et al. (2017)

Discordance between Circulating Atherogenic Cholesterol Mass

and Lipoprotein Particle Concentration in Relation to Future

Coronary Events in Women. Clin Chem 63: 870-879.

94. Otvos JD, Mora S, Shalaurova I, et al. (2011) Clinical

implications of discordance between low-density lipoprotein

cholesterol and particle number. J Clin Lipidol 5: 105-113.

95. Mackey RH, Kuller LH, Moreland LW (2018) Update

on Cardiovascular Disease Risk in Patients with Rheumatic

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 17 of 23

Diseases. Rheum Dis Clin North Am 44: 475-487.

96. Mackey RH, Greenland P, Lloyd-Jones D, et al. (2012)

High-density lipoprotein cholesterol and particle concentrations,

carotid atherosclerosis, and coronary events: MESA (multi-

ethnic study of atherosclerosis). J Am Coll Cardiol 60: 508-516.

97. Chung CP, Oeser A, Solus JF, et al. (2008) Inflammation-

associated insulin resistance: differential effects in rheumatoid

arthritis and systemic lupus erythematosus define potential

mechanisms. Arthritis Rheum 58: 2105-2112.

98. Costenbader KH, Feskanich D, Mandl LA, et al. (2006)

Smoking intensity, duration, and cessation, and the risk of

rheumatoid arthritis in women. Am J Med 119: e1-e9.

99. Gonzalez-Gay MA, Garcia-Porrua C, Hajeer AH (2002)

Influence of human leukocyte antigen-DRB1 on the susceptibility

and severity of rheumatoid arthritis. Semin Arthritis Rheum 31:

355-360.

100. Gonzalez-Gay MA, Gonzalez-Juanatey C, Ollier WE

(2004) Endothelial dysfunction in rheumatoid arthritis: influence

of HLA-DRB1 alleles. Autoimmun Rev 3: 301-304.

101. Ollier W, Venables PJ, Mumford PA, et al. (1984) HLA

antigen associations with extra-articular rheumatoid arthritis.

Tissue Antigens 24: 279-291.

102. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, et al.

(2003) HLA-DRB1 status affects endothelial function in treated

patients with rheumatoid arthritis. Am J Med 114: 647-652.

103. Salvarani C, Macchioni P, Mantovani W, et al. (1992)

Extraarticular manifestations of rheumatoid arthritis and HLA

antigens in northern Italy. J Rheumatol 19: 242-246.

104. Weyand CM, Hicok KC, Conn DL, et al. (1992) The

influence of HLA-DRB1 genes on disease severity in rheumatoid

arthritis. Ann Intern Med 117: 801-806.

105. Perdriger A, Chalès G, Semana G, et al. (1997) Role of

HLA-DR-DR and DR-DQ associations in the expression

of extraarticular manifestations and rheumatoid factor in

rheumatoid arthritis. J Rheumatol 24: 1272-1276.

106. Panoulas VF, Stavropoulos-Kalinoglou A, Metsios GS,

et al. (2009) Association of interleukin-6 (IL-6)-174G/C

gene polymorphism with cardiovascular disease in patients

with rheumatoid arthritis: the role of obesity and smoking.

Atherosclerosis 204: 178-183.

107. Solomon DH, Reed GW, Kremer JM, et al. (2015) Disease

activity in rheumatoid arthritis and the risk of cardiovascular

events. Arthritis Rheumatol 67: 1449-1455.

108. Innala L, Bozena Möller, Lotta Ljung, et al. (2011)

Cardiovascular events in early RA are a result of inflammatory

burden and traditional risk factors: a five year prospective study.

Arthritis Res Ther 13: 131.

109. Mackey RH, Kuller LH, Deane KD, et al. (2015) Rheumatoid

Arthritis, Anti-Cyclic Citrullinated Peptide Positivity, and

Cardiovascular Disease Risk in the Women’s Health Initiative.

Arthritis Rheumatol 67: 2311-2322.

110. Turesson C, McClelland RL, Christianson TJ, et al. (2007)

Severe extra-articular disease manifestations are associated with

an increased risk of first ever cardiovascular events in patients

with rheumatoid arthritis. Ann Rheum Dis 66: 70-75.

111. Rao VU, Pavlov A, Klearman M, et al. (2015) An evaluation

of risk factors for major adverse cardiovascular events during

tocilizumab therapy. Arthritis Rheumatol 67: 372-380.

112. Myasoedova E, Chandran A, Ilhan B, et al. (2016) The role

of rheumatoid arthritis (RA) flare and cumulative burden of RA

severity in the risk of cardiovascular disease. Ann Rheum Dis

75: 560-565.

113. Farragher TM, Lunt M, Bunn DK, et al. (2007) Early

functional disability predicts both all-cause and cardiovascular

mortality in people with inflammatory polyarthritis: results from

the Norfolk Arthritis Register. Ann Rheum Dis 66: 486-492.

114. Giles JT, Moyses S, Wendy P, et al. (2009) Coronary arterial

calcification in rheumatoid arthritis: comparison with the Multi-

Ethnic Study of Atherosclerosis. Arthritis Res Ther 11: 36.

115. Evans MR, et al. (2011) Carotid atherosclerosis predicts

incident acute coronary syndromes in rheumatoid arthritis.

Arthritis Rheum 63: 1211-1220.

116. Mantel A, Escalante A, Battafarano DF, et al. (2015)

Rheumatoid arthritis is associated with a more severe

presentation of acute coronary syndrome and worse short-term

outcome. Eur Heart J 36: 3413-3422.

117. Holmqvist ME, Wedrén S, Jacobsson LT, et al. (2009)

No increased occurrence of ischemic heart disease prior to

the onset of rheumatoid arthritis: results from two Swedish

population-based rheumatoid arthritis cohorts. Arthritis Rheum

60: 2861-2869.

118. Holmqvist ME, Neovius M, Eriksson J, et al. (2012) Risk of

venous thromboembolism in patients with rheumatoid arthritis

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 18 of 23

and association with disease duration and hospitalization. JAMA

308: 1350-1356.

119. Holmqvist ME, Wedrén S, Jacobsson LT, et al. (2010)

Rapid increase in myocardial infarction risk following diagnosis

of rheumatoid arthritis amongst patients diagnosed between

1995 and 2006. J Intern Med 268: 578-585.

120. Mantel A, Holmqvist M, Nyberg F, et al. (2015) Risk factors

for the rapid increase in risk of acute coronary events in patients

with new-onset rheumatoid arthritis: a nested case-control study.

Arthritis Rheumatol 67: 2845-2854.

121. Holmqvist M, Gränsmark E, Mantel A, et al. (2013)

Occurrence and relative risk of stroke in incident and prevalent

contemporary rheumatoid arthritis. Ann Rheum Dis 72: 541-546.

122. Wallberg-Jonsson S, Johansson H, Ohman ML, et al.

(1999) Extent of inflammation predicts cardiovascular disease

and overall mortality in seropositive rheumatoid arthritis. J

Rheumatol 26: 2562-2571.

123. Jacobsson LT, Turesson C, Hanson RL, et al. (2001) Joint

swelling as a predictor of death from cardiovascular disease

in a population study of Pima Indians. Arthritis Rheum 44:

1170-1176.

124. Meissner Y, Zink A, Kekow J, et al. (2016) Impact of

disease activity and treatment of comorbidities on the risk of

myocardial infarction in rheumatoid arthritis. Arthritis Res Ther

18: 183.

125. Ruyssen-Witrand A, Bruno F, Alain S et al. (2011)

Cardiovascular risk induced by low-dose corticosteroids in

rheumatoid arthritis: a systematic literature review. Joint Bone

Spine 78: 23-30.

126. Ajeganova S, Andersson ML, Frostegård J, et al. (2013)

Disease factors in early rheumatoid arthritis are associated

with differential risks for cardiovascular events and mortality

depending on age at onset: a 10-year observational cohort study.

J Rheumatol 40: 1958-1966.

127. Maradit-Kremers H, Nicola PJ, Crowson CS, et al. (2007)

Raised erythrocyte sedimentation rate signals heart failure in

patients with rheumatoid arthritis. Ann Rheum Dis 66: 76-80.

128. Goodson NJ, Symmons DP, Scott DG, et al. (2005)

Baseline levels of C-reactive protein and prediction of death

from cardiovascular disease in patients with inflammatory

polyarthritis: a ten-year follow up study of a primary care-based

inception cohort. Arthritis Rheum 52: 2293-2299.

129. Ridker PM, Hennekens CH, Buring JE, et al. (2000)

C-reactive protein and other markers of inflammation in the

prediction of cardiovascular disease in women. N Engl J Med

342: 836-843.

130. Zhang J, Rheum AD, Myasoedova E, et al. (2014)

Republished: The association between inflammatory markers,

serum lipids and the risk of cardiovascular events in patients

with rheumatoid arthritis. Postgrad Med J 90: 722-729.

131. Myasoedova E, Crowson CS, Kremers HM, et al. (2011)

Lipid paradox in rheumatoid arthritis: the impact of serum

lipid measures and systemic inflammation on the risk of

cardiovascular disease. Ann Rheum Dis 70: 482-487.

132. Singh U, Dasu MR, Yancey PG, et al. (2008) Human

C-reactive protein promotes oxidized low density lipoprotein

uptake and matrix metalloproteinase-9 release in Wistar rats. J

Lipid Res 49: 1015-1023.

133. Wang X, Liao D, Bhardwaj U, et al. (2008) C-reactive

protein inhibits cholesterol efflux from human macrophage-

derived foam cells. Arterioscler Thromb Vasc Biol 28: 519-526.

134. Wolfe F, Mitchell DM, Sibley JT, et al. (1994) The mortality

of rheumatoid arthritis. Arthritis Rheum 37: 481-494.

135. Goodson NJ, Wiles NJ, Lunt M, et al. (2002) Mortality

in early inflammatory polyarthritis: cardiovascular mortality

is increased in seropositive patients. Arthritis Rheum 46:

2010-2019.

136. Gonzalez A, Maradit Kremers H, Crowson CS, et al.

(2008) Do cardiovascular risk factors confer the same risk for

cardiovascular outcomes in rheumatoid arthritis patients as in

non-rheumatoid arthritis patients? Ann Rheum Dis 67: 64-69.

137. Liang KP, Myasoedova E, Crowson CS, et al. (2010)

Increased prevalence of diastolic dysfunction in rheumatoid

arthritis. Ann Rheum Dis 69: 1665-1670.

138. Wolfe F (2000) The effect of smoking on clinical, laboratory,

and radiographic status in rheumatoid arthritis. J Rheumatol 27:

630-637.

139. Tomasson G, Aspelund T, Jonsson T, et al. (2010) Effect of

rheumatoid factor on mortality and coronary heart disease. Ann

Rheum Dis 69: 1649-654.

140. Liang KP, Kremers HM, Crowson CS, et al. (2009)

Autoantibodies and the risk of cardiovascular events. J

Rheumatol 36: 2462-2469.

141. Humphreys JH, Van Nies JA, Chipping J, et al. (2014)

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 19 of 23

Rheumatoid factor and anti-citrullinated protein antibody

positivity, but not level, are associated with increased mortality

in patients with rheumatoid arthritis: results from two large

independent cohorts. Arthritis Res Ther 16: 483.

142. Sokolove J, Brennan MJ, Sharpe O, et al. (2013) Brief report:

citrullination within the atherosclerotic plaque: a potential target

for the anti-citrullinated protein antibody response in rheumatoid

arthritis. Arthritis Rheum 65: 1719-1724.

143. Lopez-Longo FJ, Oliver-Miñarro D, Sánchez-Ramón

S, et al. (2009) Association between anti-cyclic citrullinated

peptide antibodies and ischemic heart disease in patients with

rheumatoid arthritis. Arthritis Rheum 61: 419-424.

144. Ridker PM, Rifai N,e Stampfer MJ, et al. (2000) Plasma

concentration of interleukin-6 and the risk of future myocardial

infarction among apparently healthy men. Circulation 101:

1767-1772.

145. Danesh J, Kaptoge S, Mann AG, et al. (2008) Long-term

interleukin-6 levels and subsequent risk of coronary heart

disease: two new prospective studies and a systematic review.

PLoS Med 5: e78.

146. Rho YH, Chung CP, Oeser A, et al. (2009) Inflammatory

mediators and premature coronary atherosclerosis in rheumatoid

arthritis. Arthritis Rheum 61: 1580-1585.

147. Dessein PH, Joffe BI, Singh S (2005) Biomarkers of

endothelial dysfunction, cardiovascular risk factors and

atherosclerosis in rheumatoid arthritis. Arthritis Res Ther 7:

634-643.

148. Karpouzas GA, Estis J, Rezaeian P, et al. (2018) High-

sensitivity cardiac troponin I is a biomarker for occult coronary

plaque burden and cardiovascular events in patients with

rheumatoid arthritis. Rheumatology 57: 1080-1088.

149. Zethelius B, Berglund L, Sundström J, et al. (2008) Use

of multiple biomarkers to improve the prediction of death from

cardiovascular causes. N Engl J Med 358: 2107-2116.

150. Avouac J, Meune C, Chenevier-Gobeaux C, et al. (2014)

Inflammation and disease activity are associated with high

circulating cardiac markers in rheumatoid arthritis independently

of traditional cardiovascular risk factors. J Rheumatol 41:

248-255.

151. Mirjafari H, Welsh P, Verstappen SM, et al. (2014)

N-terminal pro-brain-type natriuretic peptide (NT-pro-BNP)

and mortality risk in early inflammatory polyarthritis: results

from the Norfolk Arthritis Registry (NOAR). Ann Rheum Dis

73: 684-690.

152. Provan S, Angel K, Semb AG, et al. (2010) NT-proBNP

predicts mortality in patients with rheumatoid arthritis: results

from 10-year follow-up of the EURIDISS study. Ann Rheum

Dis 69: 1946-1950.

153. Solomon DH, Goodson NJ, Katz JN, et al. (2006) Patterns

of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis

65: 1608-1612.

154. Lindhardsen J, Ahlehoff O, Gislason GH, et al. (2011) The

risk of myocardial infarction in rheumatoid arthritis and diabetes

mellitus: a Danish nationwide cohort study. Ann Rheum Dis 70:

929-934.

155. Solomon DH, Karlson EW, Rimm EB, et al. (2003)

Cardiovascular morbidity and mortality in women diagnosed

with rheumatoid arthritis. Circulation 107: 1303-1307.

156. Meune C, Touzé E, Trinquart L, et al. (2010) High risk of

clinical cardiovascular events in rheumatoid arthritis: Levels

of associations of myocardial infarction and stroke through a

systematic review and meta-analysis. Arch Cardiovasc Dis 103:

253-261.

157. Karpouzas GA, Malpeso J, Choi TY, et al. (2014) Prevalence,

extent and composition of coronary plaque in patients with

rheumatoid arthritis without symptoms or prior diagnosis of

coronary artery disease. Ann Rheum Dis 73: 1797-1804.

158. Crepaldi G, Alberto Scirè C, Carrara G, et al. (2016)

Cardiovascular Comorbidities Relate More than Others with

Disease Activity in Rheumatoid Arthritis. PLoS One 11:

e0146991.

159. Van Doornum S, Brand C, King B, et al. (2006) Increased

case fatality rates following a first acute cardiovascular event

in patients with rheumatoid arthritis. Arthritis Rheum 54:

2061-2068.

160. Van Doornum S, Caroline B, Sundararajan V, et al. (2010)

Rheumatoid arthritis patients receive less frequent acute

reperfusion and secondary prevention therapy after myocardial

infarction compared with the general population. Arthritis Res

Ther 12: 183.

161. McCoy SS, Crowson CS, Maradit-Kremers H, et al. (2013)

Longterm outcomes and treatment after myocardial infarction

in patients with rheumatoid arthritis. J Rheumatol 40: 605-610.

162. Nicola PJ, Crowson CS, Maradit-Kremers H, et al. (2006)

Contribution of congestive heart failure and ischemic heart

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page 20 of 23

disease to excess mortality in rheumatoid arthritis. Arthritis

Rheum 54: 60-67.

163. Nicola PJ, Maradit-Kremers H, Roger VL, et al. (2005)

The risk of congestive heart failure in rheumatoid arthritis:

a population-based study over 46 years. Arthritis Rheum 52:

412-420.

164. Crowson CS, Nicola PJ, Kremers HM, et al. (2005) How

much of the increased incidence of heart failure in rheumatoid

arthritis is attributable to traditional cardiovascular risk factors

and ischemic heart disease? Arthritis Rheum 52: 3039-3044.

165. Wolfe F, Michaud K (2004) Heart failure in rheumatoid

arthritis: rates, predictors, and the effect of anti-tumor necrosis

factor therapy. Am J Med 116: 305-311.

166. Schau T, Gottwald M, Arbach O, et al. (2015) Increased

Prevalence of Diastolic Heart Failure in Patients with

Rheumatoid Arthritis Correlates with Active Disease, but Not

with Treatment Type. J Rheumatol 42: 2029-2037.

167. Khalid U, Egeberg A, Ahlehoff O, et al. (2018) Incident

Heart Failure in Patients with Rheumatoid Arthritis: A

Nationwide Cohort Study. J Am Heart Assoc 7.

168. Logstrup BB, Ellingsen T, Pedersen AB, et al. (2018)

Development of heart failure in patients with rheumatoid

arthritis: A Danish population-based study. Eur J Clin Invest 48:

e12915.

169. Mantel A, Holmqvist M, Jernberg T, et al. (2017) Long-

term outcomes and secondary prevention after acute coronary

events in patients with rheumatoid arthritis. Ann Rheum Dis 76:

2017-2024.

170. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, et al.

(2004) Echocardiographic and Doppler findings in long-term

treated rheumatoid arthritis patients without clinically evident

cardiovascular disease. Semin Arthritis Rheum 33: 231-238.

171. Myasoedova E, Crowson CS, Roger VL, et al. (2013) Brief

report: rheumatoid arthritis is associated with left ventricular

concentric remodeling: results of a population-based cross-

sectional study. Arthritis Rheum 65: 1713-1718.

172. Giles JT, Malayeri AA, Fernandes V, et al. (2010) Left

ventricular structure and function in patients with rheumatoid

arthritis, as assessed by cardiac magnetic resonance imaging.

Arthritis Rheum 62: 940-951.

173. Midtbo H, Gerdts E, Kvien TK, et al. (2015) Disease

activity and left ventricular structure in patients with rheumatoid

arthritis. Rheumatology 54: 511-519.

174. Midtbo H, Semb AG, Matre K, et al. (2017) Disease activity

is associated with reduced left ventricular systolic myocardial

function in patients with rheumatoid arthritis. Ann Rheum Dis

76: 371-376.

175. Cioffi G, Viapiana O, Ognibeni F, et al. (2016) Combined

Circumferential and Longitudinal Left Ventricular Systolic

Dysfunction in Patients with Rheumatoid Arthritis without

Overt Cardiac Disease. J Am Soc Echocardiogr 29: 689-698.

176. Davis JM, Roger VL, Crowson CS, et al. (2008) The

presentation and outcome of heart failure in patients with

rheumatoid arthritis differs from that in the general population.

Arthritis Rheum 58: 2603-2611.

177. Lindhardsen J, Rintek Madsen O, Torp-Pedersen C, et

al. (2012) Risk of atrial fibrillation and stroke in rheumatoid

arthritis: Danish nationwide cohort study. BMJ 344: e1257.

178. Mavrogeni S, Spargias K, Markussis V, et al. (2009)

Myocardial inflammation in autoimmune diseases: investigation

by cardiovascular magnetic resonance and endomyocardial

biopsy. Inflamm Allergy Drug Targets 8: 390-397.

179. Peters MJ, van Halm VP, Voskuyl AE, et al. (2009) Does

rheumatoid arthritis equal diabetes mellitus as an independent

risk factor for cardiovascular disease? A prospective study.

Arthritis Rheum 61: 1571-1579.

180. Conroy RM, Pyörälä K, Fitzgerald AP, et al. (2003)

Estimation of ten-year risk of fatal cardiovascular disease in

Europe: the SCORE project. Eur Heart J 24: 987-1003.

181. D’Agostino RB, Vasan RS, Pencina MJ, et al. (2008)

General cardiovascular risk profile for use in primary care: the

Framingham Heart Study. Circulation 117: 743-753.

182. Arts EE, Popa CD, Den Broeder AA, et al. (2016) Prediction

of cardiovascular risk in rheumatoid arthritis: performance of

original and adapted SCORE algorithms. Ann Rheum Dis 75:

674-680.

183. Corrales A, González-Juanatey C, Peiró ME, et al.

(2014) Carotid ultrasound is useful for the cardiovascular risk

stratification of patients with rheumatoid arthritis: results of a

population-based study. Ann Rheum Dis 73: 722-727.

184. Corrales A, Parra JA, González-Juanatey C, et al. (2013)

Cardiovascular risk stratification in rheumatic diseases: carotid

ultrasound is more sensitive than Coronary Artery Calcification

Score to detect subclinical atherosclerosis in patients with

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 21 of 23

rheumatoid arthritis. Ann Rheum Dis 72: 1764-1770.

185. de Campos, de Magalhães Souza Fialho SC, Nazário NO,

et al. (2016) Assessment of cardiovascular risk in patients with

rheumatoid arthritis using the SCORE risk index. Rev Bras

Reumatol Engl Ed 5: 138-144.

186. Agca R, Heslinga SC, Rollefstad S, et al. (2017) EULAR

recommendations for cardiovascular disease risk management

in patients with rheumatoid arthritis and other forms of

inflammatory joint disorders: 2015/2016 update. Ann Rheum

Dis 76: 17-28.

187. Kozera L, Andrews J, Morgan AW (2011) Cardiovascular

risk and rheumatoid arthritis the next step: differentiating

true soluble biomarkers of cardiovascular risk from surrogate

measures of inflammation. Rheumatology 50: 1944-1954.

188. Ridker PM, Cook N (2004) Clinical usefulness of very high

and very low levels of C-reactive protein across the full range of

Framingham Risk Scores. Circulation 109: 1955-1959.

189. Ridker PM, Buring JE, Rifai N, et al. (2007) Development

and validation of improved algorithms for the assessment of

global cardiovascular risk in women: the Reynolds Risk Score.

JAMA 297: 611-619.

190. Crowson CS, Matteson EL, Roger VL, et al. (2012)

Usefulness of risk scores to estimate the risk of cardiovascular

disease in patients with rheumatoid arthritis. Am J Cardiol 110:

420-424.

191. Fent GJ, Greenwood JP, Plein S, et al. (2017) The role

of non-invasive cardiovascular imaging in the assessment of

cardiovascular risk in rheumatoid arthritis: where we are and

where we need to be. Ann Rheum Dis 76: 1169-1175.

192. Matsuzawa Y, Lerman A (2014) Endothelial dysfunction

and coronary artery disease: assessment, prognosis, and

treatment. Coron Artery Dis 25: 713-724.

193. Kullo IJ, Malik AR (2007) Arterial ultrasonography and

tonometry as adjuncts to cardiovascular risk stratification. J Am

Coll Cardiol 49: 1413-1426.

194. Kullo IJ, Malik AR, Bielak LF, et al. (2007) Brachial artery

diameter and vasodilator response to nitroglycerine, but not

flow-mediated dilatation, are associated with the presence and

quantity of coronary artery calcium in asymptomatic adults. Clin

Sci 112: 175-182.

195. Scanlon EM, Mankad R, Crowson CS, et al. (2017)

Cardiovascular risk assessment in patients with rheumatoid

arthritis: a correlative study of noninvasive arterial health

testing. Clin Rheumatol 36: 763-771.

196. Di Minno MN, Ambrosino P, Lupoli R, et al. (2015) Clinical

assessment of endothelial function in patients with rheumatoid

arthritis: A meta-analysis of literature studies. Eur J Intern Med

26: 835-842.

197. Ambrosino P, Tasso M, Lupoli R, et al. (2015) Non-invasive

assessment of arterial stiffness in patients with rheumatoid

arthritis: a systematic review and meta-analysis of literature

studies. Ann Med 47: 457-467.

198. Ikdahl E, Rollefstad S, Wibetoe G, et al. (2016)

Predictive Value of Arterial Stiffness and Subclinical Carotid

Atherosclerosis for Cardiovascular Disease in Patients with

Rheumatoid Arthritis. J Rheumatol 43: 1622-1630.

199. Polak JF, Szklo M, Kronmal RA, et al. (2013) The value

of carotid artery plaque and intima-media thickness for incident

cardiovascular disease: the multi-ethnic study of atherosclerosis.

J Am Heart Assoc 2: e000087.

200. Gonzalez-Juanatey C, Llorca J, Martin J, et al. (2009)

Carotid intima-media thickness predicts the development of

cardiovascular events in patients with rheumatoid arthritis.

Semin Arthritis Rheum 38: 366-371.

201. Ajeganova S, de Faire U, Jogestrand T, et al. (2012)

Carotid atherosclerosis, disease measures, oxidized low-

density lipoproteins, and atheroprotective natural antibodies for

cardiovascular disease in early rheumatoid arthritis an inception

cohort study. J Rheumatol 39: 1146-1154.

202. Lehmann N, Erbel R, Mahabadi AA, et al. (2018) Value of

Progression of Coronary Artery Calcification for Risk Prediction

of Coronary and Cardiovascular Events: Result of the HNR

Study (Heinz Nixdorf Recall). Circulation 137: 665-679.

203. Chung CP, Oeser A, Raggi P, et al. (2005) Increased

coronary-artery atherosclerosis in rheumatoid arthritis:

relationship to disease duration and cardiovascular risk factors.

Arthritis Rheum 52: 3045-3053.

204. Kobayashi Y, Giles JT, Hirano M, et al. (2010) Assessment

of myocardial abnormalities in rheumatoid arthritis using a

comprehensive cardiac magnetic resonance approach: a pilot

study. Arthritis Res Ther 12: 171.

205. Fine NM, Crowson CS, Lin G, et al. (2014) Evaluation of

myocardial function in patients with rheumatoid arthritis using

strain imaging by speckle-tracking echocardiography. Ann

Rheum Dis 73: 1833-1839.

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Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 22 of 23

206. Sitia S, Tomasoni L, Cicala S, et al. (2012) Detection of

preclinical impairment of myocardial function in rheumatoid

arthritis patients with short disease duration by speckle tracking

echocardiography. Int J Cardiol 160: 8-14.

207. Lopez-Mejias R, Castañeda S, González-Juanatey C,

et al. (2016) Cardiovascular risk assessment in patients with

rheumatoid arthritis: The relevance of clinical, genetic and

serological markers. Autoimmun Rev 15: 1013-1030.

208. Fransen J, Kazemi-Bajestani SM, Bredie SJ, et al. (2016)

Rheumatoid Arthritis Disadvantages Younger Patients for

Cardiovascular Diseases: A Meta-Analysis. PLoS One 11:

e0157360.

209. Ross R (1999) Atherosclerosis an inflammatory disease. N

Engl J Med 340: 115-126.

210. Sattar N, McCarey DW, Capell H, et al. (2003) Explaining

how high-grade systemic inflammation accelerates vascular risk

in rheumatoid arthritis. Circulation 108: 2957-2963.

211. Lehtinen K, Isomaki H (1991) Intramuscular gold therapy

is associated with long survival in patients with rheumatoid

arthritis. J Rheumatol 18: 524-529.

212. Choi HK, Hernán MA, Seeger JD, et al. (2002) Methotrexate

and mortality in patients with rheumatoid arthritis: a prospective

study. Lancet 359: 1173-1177.

213. Krause D, Schleusser B, Herborn G, et al. (2000) Response

to methotrexate treatment is associated with reduced mortality

in patients with severe rheumatoid arthritis. Arthritis Rheum 43:

14-21.

214. Atzeni F, Turiel M, Caporali R, et al. (2010) The effect

of pharmacological therapy on the cardiovascular system of

patients with systemic rheumatic diseases. Autoimmun Rev 9:

835-839.

215. Kerr G, Aujero M, Richards J, et al. (2014) Associations

of Hydroxychloroquine use with lipid profiles in rheumatoid

arthritis: pharmacologic implications. Arthritis Care Res 66:

1619-1626.

216. Morris SJ, Wasko MC, Antohe JL, et al. (2011)

Hydroxychloroquine use associated with improvement in lipid

profiles in rheumatoid arthritis patients. Arthritis Care Res 63:

530-534.

217. Wallace DJ, Metzger AL, Stecher VJ, et al. (1990)

Cholesterol-lowering effect of Hydroxychloroquine in patients

with rheumatic disease: reversal of deleterious effects of steroids

on lipids. Am J Med 89: 322-326.

218. Jacobsson LT, Turesson C, Gülfe A, et al. (2005) Treatment

with tumor necrosis factor blockers is associated with a

lower incidence of first cardiovascular events in patients with

rheumatoid arthritis. J Rheumatol 32: 1213-1218.

219. Dixon WG, Watson KD, Lunt M, et al. (2007) Reduction

in the incidence of myocardial infarction in patients with

rheumatoid arthritis who respond to anti-tumor necrosis factor

alpha therapy: results from the British Society for Rheumatology

Biologics Register. Arthritis Rheum 56: 2905-2912.

220. Roubille C, Richer V, Starnino T, et al. (2015) The effects

of tumour necrosis factor inhibitors, methotrexate, non-steroidal

anti-inflammatory drugs and corticosteroids on cardiovascular

events in rheumatoid arthritis, psoriasis and psoriatic arthritis:

a systematic review and meta-analysis. Ann Rheum Dis 74:

480-489.

221. Empana JP, Jouven X, Canouï-Poitrine F, et al. (2010)

C-reactive protein, interleukin 6, fibrinogen and risk of sudden

death in European middle-aged men: the PRIME study.

Arterioscler Thromb Vasc Biol 30: 2047-2052.

222. Masoud S, Boon Lim P, Kitas GD, et al. (2017) Sudden

cardiac death in patients with rheumatoid arthritis. World J

Cardiol 9: 562-573.

223. Charles-Schoeman C, Wang X, Lee YY, et al. (2016)

Association of Triple Therapy with Improvement in Cholesterol

Profiles over Two-Year Followup in the Treatment of Early

Aggressive Rheumatoid Arthritis Trial. Arthritis Rheumatol 68:

577-586.

224. Kleinbongard P, Heusch G, Schulz R (2010) TNFalpha

in atherosclerosis, myocardial ischemia/reperfusion and heart

failure. Pharmacol Ther 127: 295-314.

225. Low AS, Symmons DPM, Lunt M, et al. (2017) Relationship

between exposure to tumour necrosis factor inhibitor therapy

and incidence and severity of myocardial infarction in patients

with rheumatoid arthritis. Ann Rheum Dis 76: 654-660.

226. Charles-Schoeman C, Yin Lee Y, Shahbazian A, et al. (2017)

Improvement of High-Density Lipoprotein Function in Patients

With Early Rheumatoid Arthritis Treated With Methotrexate

Monotherapy or Combination Therapies in a Randomized

Controlled Trial. Arthritis Rheumatol 69: 46-57.

227. Popa C, van Tits LJ, Barrera P, et al. (2009) Anti-inflammatory

therapy with tumour necrosis factor alpha inhibitors improves

high-density lipoprotein cholesterol antioxidative capacity in

ISSN:XXXX-XXXX SFJC, an open access journal

Volume 2 · Issue 3 · 1000019SF J Cardiol

Citation: Arielle Urman (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

page 23 of 23

rheumatoid arthritis patients. Ann Rheum Dis 68: 868-872.

228. Keystone EC, Genovese MC, Klareskog L, et al. (2009)

Golimumab, a human antibody to tumour necrosis factor {alpha}

given by monthly subcutaneous injections, in active rheumatoid

arthritis despite methotrexate therapy: the GO-FORWARD

Study. Ann Rheum Dis 68: 789-796.

229. Weinblatt ME, Mease P, Mysler E, et al. (2015) The

efficacy and safety of subcutaneous clazakizumab in patients

with moderate-to-severe rheumatoid arthritis and an inadequate

response to methotrexate: results from a multinational, phase

IIb, randomized, double-blind, placebo/active-controlled, dose-

ranging study. Arthritis Rheumatol 67: 2591-2600.

230. Verden A, Dimbil M, Kyle R, et al. (2018) Analysis of

Spontaneous Postmarket Case Reports Submitted to the FDA

Regarding Thromboembolic Adverse Events and JAK Inhibitors.

Drug Saf 41: 357-361.

231. McCarey DW, McInnes IB, Madhok R, et al. (2004) Trial

of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind,

randomised placebo-controlled trial. Lancet 363: 2015-2021.

232. Tascilar K, Dell’Aniello S, Hudson M, et al. (2016) Statins

and Risk of Rheumatoid Arthritis: A Nested Case-Control Study.

Arthritis Rheumatol 68: 2603-2611.

233. Hermann F, Forster A, Chenevard R, et al. (2005)

Simvastatin improves endothelial function in patients with

rheumatoid arthritis. J Am Coll Cardiol 45: 461-464.

234. Van Doornum S, McColl G, Wicks IP (2004) Atorvastatin

reduces arterial stiffness in patients with rheumatoid arthritis.

Ann Rheum Dis 63: 1571-1575.

235. De Vera, Choi H, Abrahamowicz M, et al. (2011) Statin

discontinuation and risk of acute myocardial infarction in

patients with rheumatoid arthritis: a population-based cohort

study. Ann Rheum Dis 70: 1020-1024.

236. Maki-Petaja KM, BA, Hall FC, et al. (2007) Ezetimibe

and simvastatin reduce inflammation, disease activity, and

aortic stiffness and improve endothelial function in rheumatoid

arthritis. J Am Coll Cardiol 50: 852-858.

237. Schoenfeld SR, Lu L, Rai SK, et al. (2016) Statin use and

mortality in rheumatoid arthritis: a general population-based

cohort study. Ann Rheum Dis 75: 1315-1320.

238. Gwinnutt JM, Symmons DPM, MacGregor AJ, et al.

(2017) Twenty-Year Outcome and Association between Early

Treatment and Mortality and Disability in an Inception Cohort

of Patients with Rheumatoid Arthritis: Results from the Norfolk

Arthritis Register. Arthritis Rheumatol 69: 1566-1575.

239. Whelton SP, VMF, McEvoy JW, et al. (2017) Cardiovascular

Risk Assesment and Allocation of Lipid-Lowering Therapy

in Patients with Chronic Inflammatory Diseases. Am Coll

Cardiology.

240. Westerlind Hea (2018) Siblings of patients with rheumatoid

arthritis share increased risk for acute coronary syndrome.

Amsterdam.

241. Bartels CM, Heather J, Jacobs EA, et al. (2018) Frequency

and Predictors of Communication about High Blood Pressure

in Rheumatoid Arthritis Visits. J Clin Rheumatol 24: 210-217.

Citation: Arielle Urman (2018) Inflammation beyond the Joints:

Rheumatoid Arthritis and Cardiovascular Disease. SF J Cardiol 2:3.

Cardiovascular Risk Factors and Echocardiographic Findings in a Predominantly Black Population with Rheumatoid Arthritis and Heart Failure

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Mar 2024

Purpose: To investigate the risk and safety profile of non-steroidal anti-inflammatory drugs (NSAIDs) for osteoporotic fractures in patients with rheumatoid arthritis (RA). Methods: 298 RA patients admitted to The First People's Hospital of Huzhou, Huzhou, China from August 2020 to September 2022, were investigated. Patients were assigned to groups based on drugs used viz: control group received anti-rheumatic drugs other than NSAIDs; corticosteroid group received dexamethasone, disease-modifying anti-rheumatic drugs (DMARDs) groups received sulfasalazine, NSAID group received either diclofenac or ibuprofen etc. Each group of patients received the respective treatment frequently for at least 3 years. The primary outcome in this study was the incidence of osteoporotic fracture resulting from fragile bone and deterioration of bone mass. Results: The incidence of osteoporotic fracture was highest in NSAID group (11.58 %) when compared to 5.44, 4.96, and 2.36 % in the corticosteroid, DMARD and control groups, respectively (p < 0.05). This shows that users of NSAIDs had a 5-fold higher risk of osteoporotic fracture than patients in control group (OR = 1.26 (95 % CI: 1.22 - 1.81)) and 2-fold possibility of osteoporotic fracture when compared to corticosteroid users ((OR = 1.46 (95 % CI: 1.57 - 2.32)) and DMARD users (1.83 (95 % CI: 1.26 - 1.67)). Conclusion: Rheumatoid arthritis patients on NSAIDs such as celecoxib, diclofenac, ibuprofen, indomethacin, and oxaprozin are at risk of developing osteoporotic fracture. Therefore, NSAIDs must be used with proper counseling in RA patients to minimize the risk of osteoporotic fracture. In future, the study duration will need to be extended to determine the long-term effects and potential changes in bone properties.

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Artificial intelligence-based preventive, personalized and precision medicine for cardiovascular disease/stroke risk assessment in rheumatoid arthritis patients: a narrative review

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RHEUMATOL INT

The challenges associated with diagnosing and treating cardiovascular disease (CVD)/Stroke in Rheumatoid arthritis (RA) arise from the delayed onset of symptoms. Existing clinical risk scores are inadequate in predicting cardiac events, and conventional risk factors alone do not accurately classify many individuals at risk. Several CVD biomarkers consider the multiple pathways involved in the development of atherosclerosis, which is the primary cause of CVD/Stroke in RA. To enhance the accuracy of CVD/Stroke risk assessment in the RA framework, a proposed approach involves combining genomic-based biomarkers (GBBM) derived from plasma and/or serum samples with innovative non-invasive radiomic-based biomarkers (RBBM), such as measurements of synovial fluid, plaque area, and plaque burden. This review presents two hypotheses: (i) RBBM and GBBM biomarkers exhibit a significant correlation and can precisely detect the severity of CVD/Stroke in RA patients. (ii) Artificial Intelligence (AI)-based preventive, precision, and personalized (aiP³) CVD/Stroke risk AtheroEdge™ model (AtheroPoint™, CA, USA) that utilizes deep learning (DL) to accurately classify the risk of CVD/stroke in RA framework. The authors conducted a comprehensive search using the PRISMA technique, identifying 153 studies that assessed the features/biomarkers of RBBM and GBBM for CVD/Stroke. The study demonstrates how DL models can be integrated into the AtheroEdge™–aiP³ framework to determine the risk of CVD/Stroke in RA patients. The findings of this review suggest that the combination of RBBM with GBBM introduces a new dimension to the assessment of CVD/Stroke risk in the RA framework. Synovial fluid levels that are higher than normal lead to an increase in the plaque burden. Additionally, the review provides recommendations for novel, unbiased, and pruned DL algorithms that can predict CVD/Stroke risk within a RA framework that is preventive, precise, and personalized.

Strychni Semen Combined with Atractylodes Macrocephala Koidz Attenuates Rheumatoid Arthritis by Regulating Apoptosis

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Aug 2023
CURR COMPUT-AID DRUG

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint pain and disability, and seriously impact patients' quality of life. Strychni Semen combined with Atractylodes Macrocephala koidz (SA) have pronounced curative effect on RA, and there is no poisoning of Strychni Semen (SS). However, its pharmacological mechanisms are still unclear. Objective: In this study, we aimed to investigate the pharmacological mechanisms of Strychni Semen combined with Atractylodes Macrocephala Koidz (SA) for the treatment of RA. Methods: We used network pharmacology to screen the active components of SA and predict the targets and pathways involved. Results originating from network pharmacology were then verified by animal experiments. Results: Network pharmacology identified 81 active ingredients and 141 targets of SA; 2640 disease-related genes were also identified. The core targets of SA for the treatment of RA included ALB, IL-6, TNF and IL-1β. A total of 354 gene ontology terms were identified by Gene ontology (GO) enrichment analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results showed that SA was closely associated with TNF signaling pathways in the treatment of RA. Furthermore, according to the predicted results of network pharmacology, we established a rat model of Adjuvant arthritis (AA) for in vivo experiments. Analysis showed that each treatment group led to an improvement in paw swelling, immune organ coefficient and synovial tissue morphology in AA rats to different degrees, inhibit the expression levels of IL-1β, TNF-α and IL-6, upregulated the levels of Fas, Bax and Caspase 3, down-regulated the expression levels of Fas-L, Bcl-2 and p53. Conclusion: SA has an anti-RA effect, the mechanism underlying the therapeutic action of SA in AA rats was related to the regulation of apoptosis signaling pathways.

CORRELATION BETWEEN HEPCIDIN AND PROCALCITONIN AND THEIR DIAGNOSTIC ROLE IN PATIENTS WITH COVID-19

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ABSTRACT The aim:The purpose of this study is to find out the association between procalcitonin and hepcidin in patients with COVID-19, in addition to their role as diagnostic markers. Materials and methods: A total of 75 patients infected with coronavirus were included in the current study, their age is ranging between 20 to 78 years. Those patients was hospitalized in Al-Sadr Teaching Hospital in Najaf, in Iraq. This study also included 50 healthy subjects which are volunteers and considered as a (control group). Biomarker (procalcitonin and hepcidin) measurements were achieved by electrochemiluminescent immunoassay (ECLIA) in the Elecsys immunoassay system. Results: The present study showed a significant increase the serum cencentration of hepcidin and procalcitonin in patients with COVID-19 as compared tohealthy subjects. There was a highly significant increasing(p < 0.01) in hepcidin and PCT level in patients with severe infection comparing to other catgaries.The current study also revealed that the sensitivity values of the markers were: 0.88%, 0.85 for procalcitonin and hepcidin respectively, which indicate high diagnostic power. Conclusions: Serum levels of hepcidin and procalcitonin are increased as inflammatory markers in COVID-19 patients with relatively high sensitivity. It seems that these imflammatory markers obviously elevate in the severe cases COVID-19dusease. KEY WORDS: Covid-19, hepcidin, procalcitonin, imflammatory markers

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Jan 2023
Wiad Lek

Objective: The aim: To establish indicators and significance of sonography in the evaluation of muscle necrosis in ischemia of the limb acording to quantitative ultrasonographic indicators and density of collagen by histological method. Patients and methods: Materials and methods: In experiments, rabbits modeled with 6-hour limb ischemia by applying an elastic tourniquet. On days 5, 15, and 30, ultrasound and histological studies of the muscles and correlation analysis were performed between the muscles' entropy and the degree of their damage (atrophy, fibrosis and necrosis). Results: Results: The relative amount of structurally altered tissue was estimated morphometrically and compared with entropy. A high correlation of muscle damage with vertical δ-entropy indicates that sonography is highly likely to detect areas of necrosis and, to a lesser extent, fibrosis in the development of ischemic limb contracture in the early stages. Conclusion: Conclusions: Vertical δ-entropy in sonography is a significant indicator of muscle damage after traumatic ischemia and has strong relationship with muscle fibrosis.

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Jan 2023
Wiad Lek

Objective: The aim: To determine the features of daily shifts in blood pressure (BP), the influence of the presence of rheumatoid arthritis (RA) on BP control and identify factors that affect BP among patients with RA in combination with resistant hypertension (RH). Patients and methods: Materials and methods: All material for writing this scientific work were the results of a comprehensive survey of 201 people with RH and RA, hypertension (H) and RA, RA without H, H without RA and relatively healthy individuals. A laboratory study was performed: rheumatoid factor, C-reactive protein (CRP), K+ serum, and creatinine levels. All patients underwent office BP measurement and ambulatory BP monitoring for 24 hours. Statistical processing of the study results was carried out using "IBM SPSS Statistics 22". Results: Results: Among patients with RA in combination with RH non-dippers (38.7%) are the most common type of BP profile. Patients with RH in combination with RA are characterized by an increase in BP more at night (p <0.003), which corresponds to the high frequency of night-peackers (17.7%). The presence of RA determines worse control of diastolic BP (p <0.01) and more vascular overload on organs and systems during the night (p <0.05). Conclusion: Conclusions: An increase in BP in patients with RA in combination with RH is more significant at night, characterized by poorer BP control and greater vascular load at night indicating the need for tighter control of BP during sleep. Non-dippers are most often detected among patients with RA in combination with RH, which is prognostically unfavorable for the development of nocturnal "vascular accidents".

DESIGN AND IN VITRO EVALUATION OF ACRIVASTINE AS ORODISPERSIBLE TABLET USING DIRECT COMPRESSION METHOD

Article

Jan 2023
Wiad Lek

Objective: The aim: This study aimed to develop mouth-dissolving tablets of Acrivastine, an antihistamine medication, in order to increase its oral bioavailability. Patients and methods: Materials and methods: Different super disintegrants, such as crospovidone, croscarmellose sodium, and sodium starch glycolate, were used to make Acrivastine oral dispersible tablets (ODTs). These super disintegrants were utilized in various concentrations. The formulation (F3) with 6% w/w crospovidone had a fast disintegration time (less than 30 seconds) and practically total drug release within 10 minutes. All of the formulations were made using the direct compression method and proper diluents, binders, and lubricants. Fourier transform infrared spectroscopy (FTIR) tests were used to investigate the drug-ex¬cipient interaction, and all formulations demonstrated improved drug-excipient compatibility. Results: Results: The average weight of all formulations was between 175 and 180 mg. All formulations' hardness and friability were within acceptable ranges. Direct compression tablets had a hardness of 3.2 to 4 kg/cm2. All formulations were determined to have a friability of less than 1.0%. For oral dissolving tablets, the in vitro disintegration time is critical, and this time preferred to be < 60 seconds. The results also showed that crospovidone disintegrated after 24 seconds and sodium starch glycolate disintegrated in 40 seconds in vitro. Conclusion: Conclusions: When compared to croscarmellose sodium and sodium starch glycolate, crospovidone performs better as a super disintegrant. In comparison to other formula, tablets breakdown in the mouth in 30 seconds and have a maximum in vitro drug release time in 1-3 minutes.

Unusual CD4 + CD28 − T lymphocyte subset is implicated in the pathogenesis of early atherosclerosis in patients with rheumatoid arthritis

Article

Full-text available

Jul 2018

Background Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis which is not fully explained by traditional risk factors. Such excess risk appears to be driven by systemic inflammation. Aim of the work Aim of the work was to compare between RA patients with and without CD4⁺CD28⁻ T-cell expansion regarding carotid intima-media thickness (IMT) and brachial artery flow-mediated endothelium-dependent dilatation (FMEDD), as markers of early atherosclerosis. Patients and methods The study was conducted on 39 female patients with no overt cardiovascular disease or risk factor and 28 age matched females as controls. Atherosclerotic changes were assessed through measurement of carotid IMT and FMEDD. CD4⁺CD28⁻ T-cells were assessed by flow cytometry. Results The mean age of the patients was 34.9 ± 5 years and the disease duration of 6.1 ± 2.1 years. Traditional risk factors were comparable between patients and controls. Serum homocysteine level tended to be higher in the patients (11 ± 4.21 μmol/L) compared to the control (9.91 ± 3.61 μmol/L). Patients had significantly higher carotid IMT (0.83 ± 0.24 mm vs 0.6 ± 0.15 mm, p = 0.008) and lower FMEDD (3.27 ± 1.49% vs 6.01 ± 1.79%, p = 0.002). Similarly, patients with CD4⁺CD28⁻ expansion (n = 12) had significantly higher IMT (1 ± 0.23 mm) and lower FMEDD (2.25 ± 1.06%) compared to those without (n = 27) (0.76 ± 0.21 mm and 3.67 ± 1.47%); p = 0.01, p = 0.01 respectively; but not affected by receiving methotrexate or not. Laboratory investigations were comparable in patients with and without expansion. Conclusion CD4⁺CD28⁻ cells may contribute to the development of premature atherosclerosis in RA patients. Further studies are recommended to evaluate the benefit of CD4⁺CD28⁻ T-cell modulation on the future development of atherosclerosis in these patients.

Cardiovascular Safety of Biologics and JAK Inhibitors in Patients with Rheumatoid Arthritis

Article

Full-text available

May 2018
Curr Rheumatol Rep

Purpose of review: Increased cardiovascular (CV) risk and associated mortality in rheumatoid arthritis (RA) are not fully explained by traditional CV risk factors. This review discusses the epidemiology and mechanisms of increased CV risk in RA and treatment effects on CV risk focusing on biologic disease-modifying anti-rheumatic drugs (DMARDs) and JAK inhibitors. Recent findings: Intermediary metabolic changes by inflammatory cytokines are observed in body composition, lipid profile, and insulin sensitivity of RA patients, leading to accelerated atherosclerosis and increased CV risk. Successful treatment with DMARDs has shown beneficial effects on these metabolic changes and ultimately CV outcomes, in proportion to the treatment efficacy in general but also with drug-specific mechanisms. Recent data provide further information on comparative CV safety between biologic DMARDs or JAK inhibitors as well as their safety signals for non-atherosclerotic CV events. CV benefits or safety signals associated with DMARD treatments can differ despite similar drug efficacy against RA, suggesting that both anti-inflammatory and drug-specific mechanisms are involved in altering CV risk.

High-sensitivity cardiac troponin I is a biomarker for occult coronary plaque burden and cardiovascular events in patients with rheumatoid arthritis

Article

Full-text available

Mar 2018

Objectives: Patients with RA display greater occult coronary atherosclerosis burden and experience higher cardiovascular morbidity and mortality compared with controls. We here explored whether pro-inflammatory cytokines and high-sensitivity cardiac troponin I (hs-cTnI), a biomarker of myocardial injury, correlated with plaque burden and cardiovascular events (CVEs) in RA. Methods: We evaluated 150 patients with 64-slice coronary CT angiography. Coronary artery calcium, number of segments with plaque (segment involvement score), stenotic severity and plaque burden were assessed. Lesions were described as non-calcified, mixed or fully calcified. Blood levels of hs-cTnI and pro-inflammatory cytokines were assessed during coronary CT angiography. Subjects were followed over 60 (s.d. 26) months for both ischaemic [cardiac death, non-fatal myocardial infarction (MI), stroke, peripheral arterial ischaemia] and non-ischaemic (new-onset heart failure hospitalization) CVEs. Results: Plasma hs-cTnI correlated with all coronary plaque outcomes (P < 0.01). Elevated hs-cTnI (⩾1.5 pg/ml) further associated with significant calcification, extensive atherosclerosis, obstructive plaque and any advanced mixed or calcified plaques after adjustments for cardiac risk factors or Framingham D'Agostino scores (all P < 0.05). Eleven patients suffered a CVE (1.54/100 patient-years), eight ischaemic and three non-ischaemic. Elevated hs-cTnI predicted all CVE risk independent of demographics, cardiac risk factors and prednisone use (P = 0.03). Conversely, low hs-cTnI presaged a lower risk for both extensive atherosclerosis (P < 0.05) and incident CVEs (P = 0.037). Conclusion: Plasma hs-cTnI independently associated with occult coronary plaque burden, composition and long-term incident CVEs in patients with RA. Low hs-cTnI forecasted a lower risk for both extensive atherosclerosis as well as CVEs. hs-cTnI may therefore optimize cardiovascular risk stratification in RA.

Incident Heart Failure in Patients With Rheumatoid Arthritis: A Nationwide Cohort Study

Article

Full-text available

Jan 2018

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with a wide range of comorbidities, including cardiovascular disease, but its association with heart failure (HF) is not fully clear. We investigated the risk of incident HF in a nationwide cohort of patients with RA. Methods and results: The study comprised the entire Danish population aged ≥18 years followed from January 1, 2008 until first hospitalization for HF, emigration, December 31, 2012, or death. Information on comorbidity, medication, and socioeconomic status was identified by individual-level linkage of administrative registers. Patients with a rheumatologist diagnosis of RA between 1978 and 2008 were included. The primary study outcome was incident HF defined as first hospital admission for HF. Incidence rates of HF per 1000 person-years were calculated and incidence rate ratios adjusted for age, sex, calendar year, comorbidity, medications, socioeconomic status, smoking, and alcohol consumption were estimated. A total of 4 305 225 subjects with no history of HF were eligible for analysis at the study start. Of these subjects, 24 343 developed RA and 50 623 were hospitalized for HF. Overall incidence rates of incident HF were 2.43 and 6.64 for the reference population (n=49 879) and patients with RA (n=744), respectively. Correspondingly, the fully adjusted incidence rate ratio for incident HF was increased in patients with RA with incidence rate ratio 1.30 (95% confidence interval, 1.17-1.45). Conclusions: In this cohort study, RA was associated with an increased hospitalization for HF. These findings add significantly to the existing evidence of RA as a clinically relevant risk factor for HF.

OP0136 Siblings of patients with rheumatoid arthritis are at increased risk of acute coronary syndrome

Conference Paper

Jun 2018

Background Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease such as acute coronary syndromes (ACS), which cannot entirely be explained by traditional cardiovascular risk factors. Studies have shown an association between RA disease severity and risk of ACS, speaking for a contribution of the RA disease per se to the excess ACS risk. In a recent report, however, we demonstrated that despite more efficient control of inflammation in RA during the recent years, the excess risk for ACS among patients with RA compared to the general population remains¹. This finding suggests that besides effects related to the RA disease per se, there may be a shared susceptibility. If the excess risk of ACS in patients with RA were increased due to this, an increased risk of ACS would be observed also in individuals with a similar genetic set-up and background as the patients with RA, such as their siblings. Objectives To investigate any potential shared susceptibility between RA and ACS by estimating the risk of ACS in full siblings of patients with (vs. without) RA. Methods We used the Swedish Rheumatology Quality register (SRQ) to identify an early RA cohort diagnosed between 1996–2015, which was linked to the Swedish Multigeneration Register, Patient Register, the Cause of Death register, and the Total Population Register. Through this, we sampled five general population comparator subjects to each patient with RA, matched by birth year and sex, and identified all full siblings to patients with RA and for their comparator subjects born within five years of their index case. The comparators, and all siblings, were required to be alive and living in Sweden at the time of the index patient’s RA diagnosis (=start of follow-up). All unique individuals were then followed for ACS (defined as first ever hospitalisation for ACS (ICD10: I21 or I20.0) or MI listed as the cause of death), and censored at death, migration, RA diagnosis (for non-RA subjects) or the end of the study (Dec 31 st 2015). We calculated hazard ratios (HR) using a Cox proportional hazards model, adjusting for age, sex and calendar period of diagnosis. Confidence intervals (CI) were estimated using a robust sandwich estimator. Results We identified 7492 patients with RA who had 10 671 full siblings, and 35 120 population comparator subjects with 47 137 full siblings. The HR for ACS was 1.44 (95% CI: 1.25 to 1.66) and 1.23 (95% CI: 1.09 to 1.40) for patients with RA and their siblings, respectively, compared to the comparator subjects. A direct comparison between the RA patients and their RA-free siblings confirmed the familial association between RA and ACS, HR 1.19 (95% CI: 1.02 to 1.38). Conclusions The increased risk of ACS in siblings of patients with RA a) provide evidence of shared susceptibility between RA and ACS, the nature of which needs to be further investigated, and b) suggests that to bring down the CV risk in RA to that in the general population, cardiopreventive measures must go beyond optimised RA disease control. Reference [1] Holmqvist M, Ljung L, Askling J Acute coronary syndrome in new-onset rheumatoid arthritis: a population-based nationwide cohort study of time trends in risks and excess risks, Ann Rheum Dis2017 Disclosure of Interest H. Westerlind: None declared, M. Holmqvist: None declared, L. Ljung: None declared, T. Frisell: None declared, J. Askling Grant/research support from: Johan Askling has or has had research agreements with Abbvie, BMS, MSD, Pfizer, Roche, Astra-Zeneca, Eli Lilly, Samsung Bioepis, and UCB, mainly in the context of safety monitoring of biologics via ARTIS. Karolinska Institutet has received remuneration for JA participating in advisory boards arranged by Pfizer and Eli Lilly.

Update on Cardiovascular Disease Risk in Patients with Rheumatic Diseases

Article

Jun 2018
RHEUM DIS CLIN N AM

Cardiovascular disease (CVD) risk is 1.5-fold higher in rheumatoid arthritis (RA), partly due to subclinical atherosclerosis that develops before the diagnosis of RA. Dyslipidemia in RA is better quantified by lipoproteins and apolipoproteins than by cholesterol levels. Current risk factors likely underestimate CVD risk by underestimating prior risk factor levels. Some of the 2-fold higher risk of heart failure and total mortality in RA may be due to myocardial disease caused by inflammation. Per recent recommendations, to reduce CVD risk in RA, control disease activity, reduce inflammation, and aggressively treat CVD risk factors.

Frequency and Predictors of Communication About High Blood Pressure in Rheumatoid Arthritis Visits

Article

Apr 2018

Background/objective: Given heightened cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) and that higher blood pressure (BP) represents greater CVD risk, we hypothesized that higher BP would predict more BP-related communication in rheumatology visits. We examined predictors of documented BP communication during RA clinic visits. Methods: This was a retrospective cohort study of RA patients identified in electronic health record records with uncontrolled hypertension (HTN) receiving both primary and rheumatology care. Trained abstractors reviewed RA visit notes for "BP communication" using a standardized tool to elicit documentation about BP or HTN beyond recording vital signs. We used multivariate logistic regression to examine the impact of BP category (American Heart Association: ideal normotension, pre-HTN, and stages I and II HTN) on odds ratios (95% confidence intervals) of BP communication. Results: Among 1267 RA patients, 40% experienced BP elevations meeting the definition of uncontrolled HTN. Of 2677 eligible RA visits, 22% contained any documented BP communication. After adjustment, models predicted only 31% of visits with markedly high BPs 160/100 mm Hg or greater would contain BP communication. Compared with stage I, stage II elevation did not significantly increase communication (odds ratio, 2.0 [95% confidence interval, 1.4-2.8] vs. 1.5 [1.2-2.2]), although both groups' odds exceeded pre-HTN and normotension. Less than 10% of eligible visits resulted in documented action steps recommending follow-up of high BP. Conclusions: Regardless of BP magnitude, most RA clinic visits lacked documented communication about BP despite compounded CVD risk. Future work should study how rheumatology clinics can facilitate follow-up of high BPs to address HTN as the most common and reversible CVD risk factor.

Causes of Death in Rheumatoid Arthritis: How Do They Compare to the General Population?

Article

Mar 2018

Objective: To compare mortality rates, underlying causes of death, excess mortality and years of potential life lost (YPLL) among rheumatoid arthritis (RA) patients relative to the general population. Methods: We studied an inception cohort of 87,114 Ontario RA patients and 348,456 age/sex/area-matched general population comparators over 2000 to 2013. All-cause, cause-specific, and excess mortality rates, mortality rate ratios (MRRs), and YPLL were estimated. Results: A total of 11,778 (14% of) RA patients and 32,472 (9% of) comparators died during 508,385 and 1,769,365 person-years (PY) of follow-up, respectively, for corresponding mortality rates of 232 (95% CI 228, 236) and 184 (95% CI 182, 186) per 10,000 PYs. Leading causes of death in both groups were diseases of the circulatory system, cancer, and respiratory conditions. Increased mortality for all-cause and specific causes was observed in RA relative to the general population. MRRs were elevated for most causes of death. Age-specific mortality ratios illustrated a high excess mortality among RA patients under 45 years of age for respiratory disease and circulatory disease. RA patients lost 7,436 potential years of life per 10,000 persons, compared with 4,083 YPLL among those without RA. Conclusion: Mortality rates were increased in RA patients relative to the general population across most causes of death. The potential life years lost (before the age of 75) among RA patients was roughly double that among those without RA, reflecting higher rate ratios for most causes of death and RA patients dying at earlier ages. This article is protected by copyright. All rights reserved.

Development of heart failure in patients with rheumatoid arthritis: A Danish population-based study

Article

Feb 2018

Objectives: To investigate the incidence of heart failure (HF) and ischemic heart disease (IHD) in different time-spans following incident rheumatoid arthritis (RA). Furthermore, to investigate the impact of IHD on the development of HF and the impact of different treatment era's of RA. Methods: This matched cohort study used nationwide, prospectively collected data. From the total Danish population of approximately 5.7 million inhabitants we identified 51,859 patients (between 1995 and July 2016) with incident RA and a sex and age matched cohort from the general population (256,653 persons). Results: The hazard ratio (HR) for HF among RA patients compared with persons from comparison cohort were 2.28 within the first year of index date, 1.39 within1-5 years of index date, and 1.38 within 5-10 after index date. No difference was identified regarding different treatment era's of RA. For IHD the sHR was 1.93 within the first year of index date, 1.26 within 1-5 years of index date, and 1.31 within 5-10 after index date. Coronary revascularization was also more common within the first year after diagnosis of RA. An increased risk of percutaneous coronary intervention and coronary by-pass grafting within 10 years following the RA diagnosis were observed. HR for new onset of HF in RA without IHD was 1.23, while the HR for new onset of HF in patients with RA and IHD was 2.06. Conclusions: RA patients had higher rates of HF and IHD throughout the entire observation period compared to the comparison cohort. RA was associated with a larger risk for developing HF. This article is protected by copyright. All rights reserved.

Cytokines and endothelial cell biology

Article

Apr 1990

Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease

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