2. Cardiovascular risk in patients with RA

#### 2.1. Cardiovascular burden in RA

Patients with systemic autoimmune conditions especially inflammatory joint disorders such as RA are at increased risk to develop cardiovascular comorbidity, in particular subclinical or clinically significant atherosclerotic coronary heart disease [1–5, 8].

Compared to general population, patients with RA experience excessive cardiovascular morbidity and, even, mortality, with an increased risk of about 50% [1, 2, 8, 9]. The rate of global cardiovascular as well as individual events comprising fatal and nonfatal myocardial infarction, congestive heart failure, stroke, and major adverse cardiac events (MACE) is increased in RA, the magnitude of cardiovascular risk in such patient being comparable with that related to diabetes [1, 2, 8].

A comprehensive overview of cardiovascular complications and safety issues indicates that RA develops twice myocardial infarction and features an increased risk (up to 87%) of heart failure as compared to general, non-RA population [1–3, 8–11]. Moreover, congestive heart failure in different RA subtypes has a worsen prognosis compared to non-RA patients; more than half of patients known with RA are prone to undergo diastolic heart failure, while diastolic ventricular failure and pulmonary arterial hypertension are broadly reported in long-standing RA [2, 8–11]. Myocarditis typically associates with active disease subtypes and is rare, clinically non-symptomatic, without influence on cardiac mortality [1, 2]. Conversely, atherothrombosis and clinically significant coronary heart disease are highly expressed (65% increase in cardiovascular risk) and account for premature death [2]. Finally, valvular disease, especially mitral regurgitation, is frequent (80%) but usually asymptomatic, while valve nodules, conduction anomalies, and arrhythmias are uncommon in such patients [2].

Both early RA and established or long-standing RA are characterized by augmented CV risk, with a special emphasis on active status, irrespective of disease duration [1, 2, 4, 11].

Cardiovascular comorbidities of autoimmune disorders are the result of different contributing factors and their synergistic effects [1, 2, 4, 5, 8, 9, 11]. Although the prevalence and influence of traditional risk factors in RA is high, the excess of cardiovascular burden is only partially clarified [1–4, 6, 8, 9, 11]. A wide spectrum of nontraditional meaning RA-associated factors is already considered, including disease activity, severity, as well as antirheumatic drugs [1, 2, 4, 6, 8, 11–13].

### 2.2. Factors involved in cardiovascular risk in RA

Furthermore, the complex and dynamic interrelation between traditional CV risk factors (such as hypertension, diabetes, obesity, abnormal lipid metabolism), chronic systemic inflammation, early accelerated atherosclerosis, and RA-related factors (e.g., C-reactive protein level, CRP, disease activity and severity, medication) taken together in a genetically predisposed

European League Against Rheumatism (EULAR) 2015/2016 recommendations for cardiovascular disease management have recently highlighted three key trends in cardiovascular risk assessment and management in patients with RA and spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis) including optimal disease control (early diagnosis, treat-totarget strategy with the dynamic use of antirheumatic synthetic and biologic drugs) and non-

The present chapter will emphasize excessive cardiovascular morbidity in RA, the optimal strategy to identify and stratify the cardiovascular risk profile in different RA settings, the prime selection of medication from the whole spectrum of non-biologic (methotrexate and non-methotrexate drugs) and biologic (TNF and non-TNF) antirheumatic drugs according to

Patients with systemic autoimmune conditions especially inflammatory joint disorders such as RA are at increased risk to develop cardiovascular comorbidity, in particular subclinical or

Compared to general population, patients with RA experience excessive cardiovascular morbidity and, even, mortality, with an increased risk of about 50% [1, 2, 8, 9]. The rate of global cardiovascular as well as individual events comprising fatal and nonfatal myocardial infarction, congestive heart failure, stroke, and major adverse cardiac events (MACE) is increased in RA, the magnitude of cardiovascular risk in such patient being comparable with that related to

A comprehensive overview of cardiovascular complications and safety issues indicates that RA develops twice myocardial infarction and features an increased risk (up to 87%) of heart failure as compared to general, non-RA population [1–3, 8–11]. Moreover, congestive heart failure in different RA subtypes has a worsen prognosis compared to non-RA patients; more than half of patients known with RA are prone to undergo diastolic heart failure, while diastolic ventricular failure and pulmonary arterial hypertension are broadly reported in long-standing RA [2, 8–11]. Myocarditis typically associates with active disease subtypes and is rare, clinically non-symptomatic, without influence on cardiac mortality [1, 2]. Conversely, atherothrombosis and clinically significant coronary heart disease are highly expressed (65% increase in cardiovascular risk) and account for premature death [2]. Finally, valvular disease, especially mitral regurgitation, is frequent (80%) but usually asymptomatic, while valve nod-

ules, conduction anomalies, and arrhythmias are uncommon in such patients [2].

pharmacological as well as pharmacological management of risk factors [6, 7].

background remains a challenge in routine practice [1–5].

2. Cardiovascular risk in patients with RA

clinically significant atherosclerotic coronary heart disease [1–5, 8].

2.1. Cardiovascular burden in RA

their cardiotoxicity.

86 Newest Updates in Rheumatology

diabetes [1, 2, 8].

The dynamic link between chronic systemic inflammation and atherosclerosis remains a key point in the pathobiology of cardiovascular involvement in various systemic autoimmune conditions, including inflammatory rheumatic disorders [1, 2, 10–13].

Cardiovascular risk in RA is multifactorial; since traditional risk factors fairly explain, specific issues related to disease activity and medication endorses the cardiovascular disease in RA [1–4, 10–13].

Smoking, diabetes, obesity, hypertension, as well as abnormal lipid pattern (dyslipidemia) are major metabolic risk factors for cardiovascular disease, while seropositivity (rheumatoid factor, RF, and anti-cyclic citrullinated peptide antibodies (ACPA)), systemic extra-articular features, anti-inflammatory (nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids), and disease-modifying antirheumatic drugs (DMARDs) are specific aspects with precise relevance for cardiovascular outcomes in RA patients (Figure 1) [1, 2, 4–6, 10–13].

Figure 1. Traditional and non-traditional cardiovascular risk factors in RA (adapted from 8).

Furthermore, it is well established that chronic inflammation represents an independent risk factor for premature atherosclerosis, irrespective of other traditional factors [1, 3, 4], supporting severe, either subclinical or clinical coronary, and carotid disease in patients with RA [10–13].

Inflammation may alter the effect of existing risk or protective factors for cardiovascular disease, leading to an altered cardiovascular profile [1, 2, 6, 10–13].

Potent pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 and their signaling pathways play a fundamental role in persistent systemic inflammation and are the main determinants of cardiovascular risk in RA [1–4, 6]; in addition, they may interfere with classic factors resulting in altered endothelial function, insulin resistance, modified lipid spectrum, and the obesity paradox in RA [1, 2, 10–14].

There is a body of evidence showing the proatherogenic role of TNF-α and IL-1 as well as potential dual effect of IL-6 on atherogenesis [2, 3].

Thus, targeting inflammation to reduce the cardiovascular disease risk in inflammatory conditions seems to be a realistic project; additionally, an optimal control of rheumatoid inflammation through specific synthetic and/or biologic antirheumatic drugs always underwrites the decline of cardiovascular comorbidity [1–3, 6, 7].

The exclusive relationship of inflammation, endothelial dysfunction, and surrogate biomarkers of atherosclerosis with risks to cardiovascular disease among RA patients was extensively addressed [1–3, 10–13]. The pathophysiology of endothelial dysfunction is multifactorial, a complex network of interacting factors and mechanisms being emphasized. Not only different metabolic (dyslipidemia, hyperglycemia), non-metabolic (hypertension, smoking, oxidative stress) but also RA-specific factors (systemic inflammation) are associated with vascular dysfunction [1, 2, 9, 15–21].

Early intervention of irreversible vascular damage is strictly related to abnormal vascular tone, upregulation of fibrinolysis, and coagulation systems with subsequent procoagulant imbalance, subclinical and clinical atherosclerosis, and supporting cardiovascular disease development in RA (Figure 2) [1, 2, 6, 9–13].

responses and apoptosis, cytokine imbalance, DNA damage), to alter endothelial cells (e.g., overexpression of adhesion molecule, endothelial dysfunction), and to promote a procoagulant

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Figure 2. Inflammation, endothelial dysfunction, and atherosclerosis in cardiovascular disease.

Smoking has a high prevalence in patients with RA and is classically associated with different predictive factors of the cardiovascular outcomes including seropositivity (for both RF and ACPA), disease severity, disability, and articular damage (erosions) [1, 2, 15]. Various studies have suggested that smoking and second-hand (passive) smoking may limit the therapeutic response in RA, promoting and perpetuating inflammatory aggressive effects on cardiovascu-

Among classical risk factors, hypertension is an important predictor of cardiovascular events not only in general population but also in patients with systemic autoimmune conditions, with

Since the pathobiology of increased blood pressure is multifactorial, blood pressure control in inflammatory autoimmune settings is largely related to chronic inflammation and immunemediated mechanisms, along with classic mechanical injury of the arterial wall. Strong evidence

the highest morbidity in RA (up to 40% in CORRONA) [1, 9, 16].

and inflammatory environment [1, 3, 15].

lar risk [1–3, 6, 15].

2.2.1.2. Hypertension

#### 2.2.1. Traditional risk factors

Although the relation between traditional cardiovascular risk factors and RA was largely addressed in the last decade, conflicting effects are still open [1–3, 9]. Obviously, classic factors mapping cardiovascular outcomes are more common among patients with autoimmune disorders [1, 2, 9].

A closer look to various traditional risk factors for cardiovascular disease in RA, their prevalence, and relations with disease activity and severity revealed the following aspects (Table 1).

#### 2.2.1.1. Smoking

Recognized as a risk factor of both autoimmune diseases and accelerated atherosclerosis [1, 2, 15], tobacco smoking is able to modulate the immune system (e.g., induction of the inflammatory

Cardiovascular Safety of Anti-TNF and Non-TNF Biological Therapy in Patients with Rheumatoid Arthritis http://dx.doi.org/10.5772/intechopen.76684 89

Figure 2. Inflammation, endothelial dysfunction, and atherosclerosis in cardiovascular disease.

responses and apoptosis, cytokine imbalance, DNA damage), to alter endothelial cells (e.g., overexpression of adhesion molecule, endothelial dysfunction), and to promote a procoagulant and inflammatory environment [1, 3, 15].

Smoking has a high prevalence in patients with RA and is classically associated with different predictive factors of the cardiovascular outcomes including seropositivity (for both RF and ACPA), disease severity, disability, and articular damage (erosions) [1, 2, 15]. Various studies have suggested that smoking and second-hand (passive) smoking may limit the therapeutic response in RA, promoting and perpetuating inflammatory aggressive effects on cardiovascular risk [1–3, 6, 15].

#### 2.2.1.2. Hypertension

Furthermore, it is well established that chronic inflammation represents an independent risk factor for premature atherosclerosis, irrespective of other traditional factors [1, 3, 4], supporting severe, either subclinical or clinical coronary, and carotid disease in patients with RA [10–13].

Inflammation may alter the effect of existing risk or protective factors for cardiovascular

Potent pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 and their signaling pathways play a fundamental role in persistent systemic inflammation and are the main determinants of cardiovascular risk in RA [1–4, 6]; in addition, they may interfere with classic factors resulting in altered endothelial function, insulin resistance, mod-

There is a body of evidence showing the proatherogenic role of TNF-α and IL-1 as well as

Thus, targeting inflammation to reduce the cardiovascular disease risk in inflammatory conditions seems to be a realistic project; additionally, an optimal control of rheumatoid inflammation through specific synthetic and/or biologic antirheumatic drugs always underwrites the

The exclusive relationship of inflammation, endothelial dysfunction, and surrogate biomarkers of atherosclerosis with risks to cardiovascular disease among RA patients was extensively addressed [1–3, 10–13]. The pathophysiology of endothelial dysfunction is multifactorial, a complex network of interacting factors and mechanisms being emphasized. Not only different metabolic (dyslipidemia, hyperglycemia), non-metabolic (hypertension, smoking, oxidative stress) but also RA-specific factors (systemic inflammation) are associated with vascular dys-

Early intervention of irreversible vascular damage is strictly related to abnormal vascular tone, upregulation of fibrinolysis, and coagulation systems with subsequent procoagulant imbalance, subclinical and clinical atherosclerosis, and supporting cardiovascular disease develop-

Although the relation between traditional cardiovascular risk factors and RA was largely addressed in the last decade, conflicting effects are still open [1–3, 9]. Obviously, classic factors mapping cardiovascular outcomes are more common among patients with autoimmune dis-

A closer look to various traditional risk factors for cardiovascular disease in RA, their prevalence, and relations with disease activity and severity revealed the following aspects (Table 1).

Recognized as a risk factor of both autoimmune diseases and accelerated atherosclerosis [1, 2, 15], tobacco smoking is able to modulate the immune system (e.g., induction of the inflammatory

disease, leading to an altered cardiovascular profile [1, 2, 6, 10–13].

ified lipid spectrum, and the obesity paradox in RA [1, 2, 10–14].

potential dual effect of IL-6 on atherogenesis [2, 3].

decline of cardiovascular comorbidity [1–3, 6, 7].

function [1, 2, 9, 15–21].

88 Newest Updates in Rheumatology

2.2.1. Traditional risk factors

orders [1, 2, 9].

2.2.1.1. Smoking

ment in RA (Figure 2) [1, 2, 6, 9–13].

Among classical risk factors, hypertension is an important predictor of cardiovascular events not only in general population but also in patients with systemic autoimmune conditions, with the highest morbidity in RA (up to 40% in CORRONA) [1, 9, 16].

Since the pathobiology of increased blood pressure is multifactorial, blood pressure control in inflammatory autoimmune settings is largely related to chronic inflammation and immunemediated mechanisms, along with classic mechanical injury of the arterial wall. Strong evidence


controls [1, 13, 18–20]. In addition, the link between diabetes and chronic low-grade inflammation [1–3] is well known, supporting the hypothesis of the interaction between traditional CV risk factors and inflammatory burden in determining diabetes in RA [1, 2, 13, 18–20]. Furthermore, both classic risk factors (e.g., high blood pressure, high body mass index, high total cholesterol, metabolic syndrome) and novel cardiovascular risk factors (RA duration, exposure to glucocorticoids, radiographic damage, CRP levels) significantly correlated with glucose metabolism abnor-

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While in general, non-RA population, body mass index is recognized as an independent predictor for cardiovascular disease, patients with RA are characterized by the paradoxical relation obesity (cardiovascular risk): low body mass index correlates with high cardiovascular events, unrelated to disease activity [1, 2, 6]. Moreover, the relation obesity-inflammation via

Abnormal serum lipid pattern remains one of the main risk factors for cardiovascular morbidity and mortality in general population [1]; overall, modifications in high-density lipoprotein (HDL)-cholesterol as well as total/ HDL-cholesterol and triglyceride/HDL-cholesterol ratios

Up to 65% of RA patients display an altered lipid profile [1, 2, 11, 12, 20], comprising modifications in absolute circulating lipid levels that widely reflect the interconnection between

The well-known lipid paradox, meaning low serum concentration of lipids associated with high cardiovascular burden in autoimmune inflammatory conditions, accounts for a negative correlation between total cholesterol, high-density and low-density lipoprotein (LDL)-choles-

Additionally, chronic inflammation is characterized by excessive consumption and deleterious synthesis of lipoproteins associated with structural (e.g., HDL associated with increased serum amyloid A with a potentially proatherogenic phenotype) as well as functional modifications

Generally, both HDL-cholesterol and LDL-cholesterol are decreased in active RA and may increase with efficient control of inflammation with to non-biologic and biologic drugs [1, 2, 6, 20]. Moreover, small-dense LDL particles, known as more atherogenic than larger particles,

Interestingly, preclinical phase of RA accounts for raised inflammatory biomarkers (CRP) and dyslipidemia, with a negative correlation between the increased inflammation and decreased serum lipids [1, 2, 20]. This paradigm is applicable not only for chronic systemic autoimmune joint pathology but also in cardiovascular disease, postsurgery, or related to antineoplastic

malities and diabetes [1, 2, 13, 18–20].

2.2.1.4. Body mass index and obesity

2.2.1.5. Dyslipidemia and lipid paradox in RA

inflammatory and metabolic pathways [1, 2, 20].

terol fractions, and inflammatory biomarkers.

(e.g., altered HDL phenotype) [1, 20].

therapy [1, 2, 6, 20].

adipose tissue metabolism is largely applicable in RA patients.

are associated with adverse cardiovascular disease risk [1, 20].

are raised not only in metabolic disorders but also in RA [1, 20].

Table 1. Traditional cardiovascular risk factors in RA.

indicates the direct association between inflammation and hypertension; TNF-α can exert vascular endothelial damage and oxidative stress, while IL-6 enhances the arterial tonus. Not only blood pressure itself but also arterial inflammation is more prevalent in patients with RA and independently associated with both traditional cardiovascular risk factors and rheumatoid arthritis disease characteristics [1, 16].

There is no clear data suggesting the relation between hypertension and RA activity. However, the deleterious role of NSAIDs and glucocorticoids on hypertension is well established [1, 16].

#### 2.2.1.3. Insulin resistance

Although underdiagnosed, especially in RA with longer disease duration, the prevalence of impaired fasting glucose, type 2 diabetes, as well as abnormal insulin resistance is largely increased among patients with autoimmune joint conditions compared to age- and gender-matched controls [1, 13, 18–20]. In addition, the link between diabetes and chronic low-grade inflammation [1–3] is well known, supporting the hypothesis of the interaction between traditional CV risk factors and inflammatory burden in determining diabetes in RA [1, 2, 13, 18–20]. Furthermore, both classic risk factors (e.g., high blood pressure, high body mass index, high total cholesterol, metabolic syndrome) and novel cardiovascular risk factors (RA duration, exposure to glucocorticoids, radiographic damage, CRP levels) significantly correlated with glucose metabolism abnormalities and diabetes [1, 2, 13, 18–20].

#### 2.2.1.4. Body mass index and obesity

While in general, non-RA population, body mass index is recognized as an independent predictor for cardiovascular disease, patients with RA are characterized by the paradoxical relation obesity (cardiovascular risk): low body mass index correlates with high cardiovascular events, unrelated to disease activity [1, 2, 6]. Moreover, the relation obesity-inflammation via adipose tissue metabolism is largely applicable in RA patients.

### 2.2.1.5. Dyslipidemia and lipid paradox in RA

indicates the direct association between inflammation and hypertension; TNF-α can exert vascular endothelial damage and oxidative stress, while IL-6 enhances the arterial tonus. Not only blood pressure itself but also arterial inflammation is more prevalent in patients with RA and independently associated with both traditional cardiovascular risk factors and rheumatoid

CV risk factors Prevalence and particularities in RA Relation with RA activity

May impair therapeutic response, modulating

inflammation effects on CV risk

Adversely impact with NSAIDs and

Without evidence

Irrespective of RA activity

Irrespective of RA activity

biologic DMARDs

HDL cholesterol and atherogenic index improvement following non-biologic and

glucocorticoids

Tobacco smoking High prevalence in RA population

90 Newest Updates in Rheumatology

Direct link with

• disability • articular damage

Hypertension High prevalence (COMORA 40%)

Insulin resistance High prevalence in RA

metabolism

(altered HDL)

Table 1. Traditional cardiovascular risk factors in RA.

Body mass index &

obesity

String association with CV outcome

Associated with NSAIDs and DMARDs increased vascular peripheral resistance interplay between inflammation and hypertension • TNFα results in endothelial vascular damage

Promote low-grade chronic inflammation

Paradoxical relation in RA: low body mass index

Body mass index—independent CV risk predictor Relation obesity—inflammation via adipose tissue

LDL-, HDL-, total cholesterol negatively correlates

• seropositivity (ACPA, RF) • RA severity and activity

& oxidative stress • IL-6 alter the arterial tonus

associated with high CA risk

Dyslipidemia Not only the quantity but also the quality, structure, and function of lipids

associated with high CV risk)

with inflammatory biomarkers Inflammation = consumption + decreased lipoprotein synthesis + defect of lipoprotein synthesis + structural and functional changes

55–65% cases—abnormal lipid profile Lipid paradox (low lipids in inflammation

There is no clear data suggesting the relation between hypertension and RA activity. However, the deleterious role of NSAIDs and glucocorticoids on hypertension is well established [1, 16].

Although underdiagnosed, especially in RA with longer disease duration, the prevalence of impaired fasting glucose, type 2 diabetes, as well as abnormal insulin resistance is largely increased among patients with autoimmune joint conditions compared to age- and gender-matched

arthritis disease characteristics [1, 16].

2.2.1.3. Insulin resistance

Abnormal serum lipid pattern remains one of the main risk factors for cardiovascular morbidity and mortality in general population [1]; overall, modifications in high-density lipoprotein (HDL)-cholesterol as well as total/ HDL-cholesterol and triglyceride/HDL-cholesterol ratios are associated with adverse cardiovascular disease risk [1, 20].

Up to 65% of RA patients display an altered lipid profile [1, 2, 11, 12, 20], comprising modifications in absolute circulating lipid levels that widely reflect the interconnection between inflammatory and metabolic pathways [1, 2, 20].

The well-known lipid paradox, meaning low serum concentration of lipids associated with high cardiovascular burden in autoimmune inflammatory conditions, accounts for a negative correlation between total cholesterol, high-density and low-density lipoprotein (LDL)-cholesterol fractions, and inflammatory biomarkers.

Additionally, chronic inflammation is characterized by excessive consumption and deleterious synthesis of lipoproteins associated with structural (e.g., HDL associated with increased serum amyloid A with a potentially proatherogenic phenotype) as well as functional modifications (e.g., altered HDL phenotype) [1, 20].

Generally, both HDL-cholesterol and LDL-cholesterol are decreased in active RA and may increase with efficient control of inflammation with to non-biologic and biologic drugs [1, 2, 6, 20]. Moreover, small-dense LDL particles, known as more atherogenic than larger particles, are raised not only in metabolic disorders but also in RA [1, 20].

Interestingly, preclinical phase of RA accounts for raised inflammatory biomarkers (CRP) and dyslipidemia, with a negative correlation between the increased inflammation and decreased serum lipids [1, 2, 20]. This paradigm is applicable not only for chronic systemic autoimmune joint pathology but also in cardiovascular disease, postsurgery, or related to antineoplastic therapy [1, 2, 6, 20].

Tight control of inflammation in RA by non-biologic and/or biologic antirheumatic medication usually accounts for the improved lipid level [1, 2, 6, 7].
