Open access peer-reviewed chapter

Atherosclerosis in Rheumatology: Old and New Insights

Written By

Sabina Oreska and Michal Tomcik

Submitted: 01 May 2019 Reviewed: 15 July 2019 Published: 14 August 2019

DOI: 10.5772/intechopen.88605

From the Edited Volume

Atherosclerosis, Arteriosclerosis and Arteriolosclerosis

Edited by Luigi Gianturco

Chapter metrics overview

875 Chapter Downloads

View Full Metrics


Cardiovascular diseases are the leading cause of morbidity and mortality in general population worldwide. There is an increasing significance of cardiovascular risk in the field of rheumatology, and accordingly, the evidence on the relation between immune system disorders and atherosclerosis has been substantially growing especially in last decades. Since novel immune and metabolic factors are considered to participate in pathogenesis of atherosclerosis and increased cardiovascular risk in rheumatic patients, they are getting to the forefront of the research. Since novel therapeutic approaches have improved survival of rheumatic patients, and decreased morbidity caused by rheumatic disease activity and damage, the significance of other comorbidities leading to premature mortality has arisen. Nevertheless, appropriate recommendations for the management of cardiovascular risk are still lacking. Recently, European League Against Rheumatism (EULAR) recommendations for management of the cardiovascular risk and comorbidities in patients with inflammatory arthropathies have been published. However, the cardiovascular management of these patients is still suboptimal. In addition, the situation in other orphan diseases such as idiopathic inflammatory myopathies, systemic sclerosis and others is even more uncertain and strongly requires further research. This chapter provides an overview of epidemiology, pathogenesis, clinical manifestations, screening and management of atherosclerosis in patients with rheumatic diseases.


  • atherosclerosis
  • rheumatic diseases
  • metabolic risk factors
  • management
  • therapy

1. Introduction

Cardiovascular diseases (CVDs) are estimated to be the leading cause of mortality and morbidity worldwide and are responsible for one-third of world’s population mortality [1]. Atherosclerosis (ATS), as the main cause of CVD, starts to develop early in the life and presents later with clinical manifestations depending on other circumstances. ATS is a multifactorial disease, in which the immune system and impairment of vascular system play a significant role. Inflammation, which can be triggered by infectious agents or by autoimmune reaction, worsens and promotes atherogenesis by several mechanisms [2]. In addition to the immune system, other factors significantly participate in atherogenesis by facilitating the vascular damage, initiating the formation, progression and the rupture of atherosclerotic plaques leading to consequent clinical manifestation of ATS. So-called traditional risk factors include dysregulation of lipid and glucose metabolism, arterial hypertension, and degeneration of vascular tissue caused by aging, smoking and hormonal factors [3].

It is well known that autoimmune diseases are accompanied by increased CV morbidity and mortality, caused by exacerbation of atherogenesis [2]. Traditional risk factors of ATS in general population such as dyslipidemia, glucose intolerance, arterial hypertension, etc. can explain only about 75% of CV manifestations in rheumatic patients [4]. In these patients, non-traditional risk factors associated with the systemic inflammatory disease apply [5].

Despite the significant improvement of the therapy of rheumatic diseases, the incidence of CVD in rheumatic patients remains increased compared to that in general population [6]. Both the CV risk and CVD manifestations differ among rheumatic diseases according to the characteristic pathogenetic mechanism, inflammation activity and other specific features of the rheumatic diseases [7]. CV risk in the more prevalent rheumatic diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) is relatively best described. On the other hand, the situation is less clear in orphan connective tissue diseases such as systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), primary Sjögren’s syndrome (pSS) and others.

The aim of this review chapter is to provide an overview and sum up the current knowledge on CV risk factors and the treatment options of ATS-related comorbidities in rheumatic diseases.


2. Cardiovascular risks in rheumatic diseases

Traditional CV risk factors play two roles in rheumatic patients: the first one as a trigger, the second as a consequence of the rheumatic disease activity [3]. Non-traditional risk factors are given by genetic and epigenetic factors, concurrent autoimmune inflammatory disorder and the specific features of each particular rheumatic disease (age of onset, duration, activity and the type of the disease) and other comorbidities, among others depression [8, 9, 10].

2.1 Metabolic syndrome and its association with immune disorders

Metabolic syndrome (MetS) is defined as a cluster of comorbidities and risk factors leading to CVDs and increasing the CV mortality and morbidity. MetS includes obesity and visceral adiposity, diabetes and insulin resistance (IR), arterial hypertension (AH) and dyslipidemia [11]. The matter of mutual interactions and cross-talk of immune and metabolic system has become the object of many studies in recent years. Immune-metabolic interactions are regulated by genetic factors, nutritional status and by intestinal microbiome. The imbalance of the immune and metabolic interactions contributes to the occurrence and manifestation of rheumatic diseases [12].

The prevalence of MetS in general population is estimated to be 24–44% depending on the exact definition of the MetS and the studied population [11, 13], and increases in rheumatic patients and gout to as much as 36–42%, as was reported in studies comparing rheumatic patients to the healthy control population [13].

Different immune mechanisms have been reported to be implemented in the pathogenesis of MetS, including pro-inflammatory cytokines, namely interleukin (IL)-1 and IL-12 family. These cytokines are included in the regulation of immune response and atherogenic damage, and in the differentiation of T helper cells (Th), which participate in the pathogenesis of both autoimmune disorders and CVDs [14, 15]. Cytokines of IL-23/IL-17 signaling pathway are increased in rheumatic diseases, and significantly participate in atherogenesis [16]. MetS is associated with increased oxidative stress, which, among others, leads to the formation of oxidized phospholipids (oxPL) and contributes to pathogenesis of autoimmune disorders [13].

IR is not only closely related to MetS, but is also considered to act as a key pathogenic factor in MetS [13]. The definition describes IR as a decreased sensitivity and responsiveness of target organs to the action of insulin resulting in hyperinsulinemia [17]. As consequence, this metabolic disorder leads to glucotoxicity, lipotoxicity and inflammation, all of which participate in endothelial damage and dysfunction [18]. The visceral fat tissue is considered to be the major locus of these unfavorable changes. Of note, CVDs, MetS and autoimmune disorders share common pathogenic mechanisms and mediators of inflammation and activity [13].

In recent years, study of microbiome has come to the forefront of interest. An imbalance of intestinal microbiota (dysbiosis) is characterized by a decrease of the number of beneficial intestinal bacteria and the overgrowth of potentially pathogenic bacteria. This phenomenon accompanies metabolic disorders and contributes to the emergence of MetS, obesity and type 2 diabetes mellitus (T2DM) [19]. Impaired balance of the intestinal flora may also contribute to the development of autoimmune disorders. Several studies have demonstrated onset of inflammation induced by alterations in the gut microbiome. This could explain the relationship between the microbiome and systemic inflammatory response [20].

2.2 Obesity as an active contributor to inflammation

The definition of obesity is mostly based on the body mass index (BMI—values higher than 30 kg/m2). Obesity, as well as MetS, is a global health problem especially in developed countries. The prevalence has been constantly growing over the years and to date, it is estimated to be almost 40% in the general population [21, 22]. Nevertheless, the association of obesity and CVDs in the general population is not clear [23]. Some evidence even suggests better prognosis for people with higher value of BMI [24]. However, there is a well-known correlation of obesity and increased risk of T2DM and coronary arterial disease (CAD), as well as a negative impact of obesity on other comorbidities including rheumatic diseases [23]. The immunomodulatory potential of adipose tissue and its ability to create an inflammatory environment of moderate activity could explain the effect of obesity as a risk factor for the development of some autoimmune diseases [22, 25].

Adipose tissue not only consists of adipocytes and connective tissue cells, but also contains immune cells as well (T cells, eosinophils, B regulatory cells and macrophages) [26, 27, 28]. In individuals with normal BMI, the immune cells interact with adipocytes and maintain a non-inflammatory environment by production of anti-inflammatory cytokines (IL-10, IL-4, IL-13) [27]. On the contrary, predominance of pro-inflammatory T helper (Th) type 1 and 17 cells and pro-inflammatory type of macrophages has been found in increased adipose tissue mass of obese individuals [27, 29, 30]. These changes result in the production of pro-inflammatory molecules such as tumor necrosis factor (TNF) and IL-6, which are one of the crucial cytokines involved in the pathogenesis of several rheumatic diseases. Moreover, obesity leads to an altered expression of adipokines, multifunctional molecules produced by white adipose tissue cells and involved in the regulation of inflammatory and autoimmune processes [31, 32]. The MetS and secretion of pro-inflammatory adipokines can be associated with CVDs and autoimmune disorders [13].

Thus, obesity is not only a passive comorbidity, but can actively participate in the inflammatory process. According to the current evidence, obesity can negatively affect the course of most rheumatic diseases, functional disability, quality of life and the overall prognosis [21, 22].

2.3 Dyslipidemia in autoimmune disorders

Dyslipidemia is one of the most common forms of metabolic disease in the general population and also a significant risk factor for atherogenic CVD. In the general population, dyslipidemia is characterized by an increased level of total cholesterol (TC), low-density lipoproteins (LDLs), triglycerides (TGs) and a decreased level of high-density lipoproteins (HDLs) [33]. Under normal circumstances, HDL (in normal serum levels) exerts an anti-atherogenic effect: it removes cholesterol particles from cells (especially macrophages in the artery wall) and from circulation; inhibits the migration of macrophages and the binding of monocytes to the endothelium, oxidation of LDL; promotes endothelial repair and improves endothelial function, and also exerts anti-inflammatory and anti-apoptotic effects [34, 35, 36]. In systemic inflammation, HDL is converted into a dysfunctional form due to loss of anti-inflammatory and anti-oxidative proteins. The modification of apolipoprotein A1 (apo-A1) results in the inability of HDL to uptake LDL from macrophages and in the activation of pro-inflammatory pathways leading to increased risk of coronary artery involvement [35, 37].

Moreover, quantitative changes of lipidogram related to disease activity are often seen in rheumatic diseases. In RA patients, the levels of TC and LDL are lower than in general population. This so-called lipid paradox, best described in RA, is associated with an increased CV risk [37]. Decrease in levels of TC and LDL has been found to precede clinical manifestation of RA. Later, TC and LDL levels tend to increase after the initiation of immunosuppressive therapy and on the contrary, decline during the relapse of RA [38]. Therefore, the low levels of TC and LDL can be misinterpreted as a low CV risk factor when evaluated according to the scoring tools (e.g., Framingham risk score, Reynolds risk score, Systemic Coronary Risk Evaluation—SCORE) [39, 40, 41].

A small study in early RA patients reported non-significant, beneficial effect of methotrexate similar to that of tumor necrosis factor inhibitors (anti-TNF) on lipidogram [42]. On the other hand, higher levels of TC, LDL and TG were described in patients with ankylosing spondylitis (AS) treated by anti-TNF compared to AS patients on nonsteroidal anti-inflammatory drug (NSAID) therapy. Nevertheless, results reported in a cross-sectional study do not allow for a generalized assessment of the influence of long-term anti-TNF therapy on lipidogram in AS [43].

Dyslipidemia is found in almost half of SLE patients, characterized by elevated levels of very-low density lipoprotein (VLDL) and TG. Increased levels of TC and TG are associated with two times increased risk of CVD [44]. In SSc, dyslipidemia is characterized by increased levels of lipoprotein A (LpA) and LDL and decreased levels of HDL and TC [45].

2.4 Role of immune system and autoantibodies in atherogenesis

The presence of immune cells in atherosclerotic plaques proves the participation of immune system in atherogenesis [46, 47]. These infiltrating immune cells are responsible for the promotion and exacerbation of ATS [48]. All the components of immune system are included in atherogenesis, while TNF and IL-1β are the most significant pro-inflammatory cytokines and mediators [1].

Damage of endothelium is the first step in atherogenesis. Particles circulating in the blood penetrate the damaged endothelial barrier into subendothelial layer via the interaction with adhesion molecules on the surface of endothelium. These reactions lead to activation of endothelium and attraction of immune cells [1]. Penetrating particles consist mainly of LDL, which are one of the targets of oxidation and form oxLDL (oxidized LDL). oxLDLs are taken up by macrophages, which subsequently transform into the foam cells. Specific autoantibodies against oxLDL (anti-oxLDL) were detected in the sera of individuals from the general population as well as in rheumatic patients [49]. Furthermore, in rheumatic patients, the levels of anti-oxLDL are increased compared to those in the general population [49, 50]. The presence of these antibodies can predict the peripheral vascular involvement and even the severity of ATS [51]. On the other hand, increased levels of anti-oxLDL antibodies in patients with pSS were paradoxically associated with decreased occurrence of plaques (unlike in RA or SLE), which suggests a possible protective role of anti-oxLDL antibodies in pSS [52].

Many autoantibodies have been described to have a relation to higher risk of ATS and its clinical manifestations [2]. These include the antibodies against heat shock proteins (HSPs), which are expressed on the surface of endothelial cells exposed to stress, and to β-2-glycoprotein I (β2GPI), which are abundantly expressed within the subendothelial layer and intima-media borders of plaques [46, 53]. Furthermore, antinuclear antibodies (ANAs) are more frequently detected in patients with symptomatic angina pectoris and the three-vessel disease compared to individuals without coronary artery involvement [54]. Moreover, ANA positivity is associated with an increased risk of myocardial infarction (MI) in non-rheumatic individuals [55]. Specific anti-endothelial cell antibodies (AECAs) are associated with subclinical or manifested ATS in non-rheumatic population, as well [56].

2.5 Immunosuppressive therapy and its effect on CV risk

Immunosuppressive therapy of rheumatic diseases has a potential effect on CV morbidity and mortality in two ways: on the one hand, it suppresses the inflammatory activity and thus decreases the CV risk; on the other hand, the adverse effect of some drugs can worsen the CV risk [9, 57]. NSAIDs and coxibs (selective blockers of cyclooxygenase-2) mostly used in inflammatory arthropathies exert pro-thrombotic effect and have a negative impact on the CV risk. Due to this fact, benefit-risk ratio should be evaluated individually in every case. Naproxen is considered as the relatively safest drug from this group [58].

Corticosteroids (CSs) suppress the inflammatory activity, hence dampen the CV risk [59, 60]. On the other hand, CSs cause or worsen the traditional CV risk factors [61]. Meta-analysis evaluating CS therapy in RA reported that a long-term therapy with prednisone or prednisone-equivalents in high doses (above 7.5 mg per day) is associated with an increased risk of CV mortality [62]. The effect of lower doses (7.5–10 mg a day) is uncertain [63]. Duration and the cumulative dose of CS are considered as CV risk factors in SLE. Nevertheless, current evidence regarding the CS therapy in SLE is not conclusive [44]. European League Against Rheumatism (EULAR) recommends, especially in inflammatory arthropathies, to keep the glucocorticoid dosage to a minimum and to taper glucocorticoids in case of remission or low disease activity and to regularly check the reasons to continue glucocorticoid therapy [59].

The group of disease-modifying anti-rheumatic drugs (DMARDs) is a heterogeneous entity of medicaments with immunosuppressive effects of various specificity: less specific conventional synthetic DMARDs (csDMARD), or more specific biologic (bDMARDs), biosimilar (bsDMARDs) or targeted synthetic molecules (tsDMARDs). The side effects differ within the whole group. csDMARDs have a potential to reduce atherogenesis and progression of ATS [64]. Thus, the early initiation of therapy with scDMARDs can prevent development of CVDs [65].

Antimalarial drugs have been reported to act favorably on lipid and glucose metabolism, and in SLE patients, they have been described to reduce hypercholesterolemia, ATS and the risk of thrombosis [44, 66, 67]. In addition, hydroxychloroquine (HCQ) influences the production of cytokines, activation of T cells and monocytes via interaction with Toll-like receptor (TLR) signaling pathway, and attenuates the oxidative stress and endothelial dysfunction [68].

The effects of methotrexate (MTX) on the CV risk have been best studied in RA, in which the potential to reduce the risk of heart failure by half was demonstrated [69]. Moreover, MTX can decrease the mortality of RA patients caused by CVDs by 30% [70]. The data suggest that MTX should be considered cardioprotective in rheumatic diseases, although the exact mechanism of this effect is not known yet [71]. A possible link with anti-inflammatory effect has been proposed [72]. On the other hand, according to the results of a recent randomized controlled trial in patients with carotid artery disease or history of MI and concurrent T2DM or MetS, no protective effect of MTX in low doses (15–20 mg weekly) on future risk of CVD was described [73]. Data in other DMARDs are insufficient and, therefore, the effect on CV risk is not clear.

bDMARDs are targeting selectively specific pro-inflammatory molecules, which significantly participate in both pathogenesis of inflammatory diseases and atherogenesis (e.g., TNF, IL-1r, IL-6 and others) [74]. In this group, TNF inhibitors (anti-TNFs) are the best-studied drugs regarding the possible effect on the CV risk. On the one hand, they exert anti-inflammatory and anti-atherogenic effect; on the other hand, they have been demonstrated to worsen the cardiac insufficiency in a couple of first published studies [3, 8]. Their benefit was proven in several randomized controlled trials (RCTs) with more or less significantly beneficial effect when compared to MTX [72, 75, 76, 77]. Anti-TNFa influences particularly the level of HDL and restores its anti-atherogenic potential [78]. The results of RCTs in RA, PsA and psoriasis show a beneficial effect of anti-TNF therapy on glucose metabolism and MetS [79]. Anti-TNFs also reduce the risk of T2DM manifestation and prevent endothelial damage due to specific inhibition of TNF [74, 80]. Overall, current data support the beneficial effect of anti-TNF therapy on CV risk and CVD incidence that is probably related to the attenuation of inflammation and thus also of atherogenesis rather than to the effect on lipidogram (which can change as a consequence of changes in disease activity as well). Published studies have reported the potential of anti-TNF to reduce intima-media thickness and the number of unstable plaques [81]. Nevertheless, anti-TNF therapy is not recommended in patients with congestive heart failure [82]. Not only no positive effect, but even a negative effect of anti-TNF on chronic heart failure has been described. Experts therefore suggest performing a baseline echocardiography examination in patients at risk before the commencement of anti-TNF therapy [81].

Higher IL-6 levels are associated with an increased CV risk, therefore therapeutic blockade of tocilizumab (inhibitor of IL-6 receptor) has a protective potential [83]. Recently published RCT with tocilizumab and etanercept (anti-TNF) reported very similar effect of both drugs on CV risk [84]. Inhibition of the IL-6 receptor by tocilizumab is assumed to influence lipid metabolism in a favorable manner due to blockade of the mobilization of fatty acids to peripheral tissues mediated by IL-6 [84]. On the contrary, anti-IL-6r therapy is known to cause a significant increase in the levels of HDL, TC, LDL and TG [85].

Rituximab (RTX, anti-CD20) is supposed to have a beneficial effect on CV risk due to inhibition of B cells and release of (auto)antibodies, which participate in the vasoconstriction, activation of thrombocytes and promote rupture of atherosclerotic plaques [74]. In SLE patients, the RTX therapy was associated with improvement of lipidogram [86]. The overall effect of RTX on CV risk is not clear, due to limited data and lack of SLE patients treated by RTX [44]. To date, studies with RTX have not shown any long-term adverse cardiovascular effects or cardiotoxicity [74, 87].

The recent study CANTOS (Canacinumab Antiinflammatory Thrombosis Outcome Study) has proven the ability of anti-IL-1b (canacinumab) to reduce the CV events and stroke in non-rheumatic patients with history of MI [88]. The effect of bDMARDs, including the latest bsDMARDs and tsDMARDs, on the CV risk needs to be closely monitored and evaluated in long-term studies with sufficiently large cohorts of rheumatic patients.


3. Atherosclerosis and its manifestation in rheumatic diseases

3.1 Rheumatoid arthritis

RA is relatively the most common autoimmune disease with prevalence of 1%, which primarily affects joints and can also manifest by extra-articular involvement. The most frequent occurrence of RA is in middle-aged women. It can shorten the life expectancy by up to 2.5 years [89, 90]. In addition, there is up to three times higher mortality in RA patients compared to the general population [91]. CV involvement and complications, including asymptomatic heart failure or silent MI and sudden death, are the leading death causes in RA patients and occur in RA patients 1.5 times more often than in the general population [2, 92]. CV risk in RA is comparable to the risk in diabetes [93].

The underlying mechanism of increased CV mortality in RA is not completely understood [94]. The main cause of death in RA is ischemic heart disease (IHD), often asymptomatic and underdiagnosed [91, 95, 96]. Up to three times increased risk of IHD in RA patients with positivity of anti-cyclic citrullinated peptide (aCCP) antibodies and rheumatoid factor (RF) has been reported [69, 97].

In fact, RA itself can act as an independent risk factor for development of CVD [98]. The relation between an increase in the CV risk and the disease duration of RA patients is partly attributable to a higher prevalence of hypertension and smoking [99]. In RA, CV risk is also significantly related to traditional risk factors [100]. Smoking has a negative impact on the course of RA and stimulates the production of RF and aCCP nevertheless, the direct role in the increase of CV risk was not proved [98, 101].

Systemic inflammation accompanying the activity of RA significantly contributes to the atherogenesis and CV mortality [102]. The reduction of CV risk was observed during the DMARD therapy (namely HCQ , MTX, anti-TNFs). According to available studies and their meta-analysis, CV risk is most increased by CS therapy (up to 47%) and NSAIDs, in particular by coxibs (by 36%), and, on the contrary, is decreased by MTX (by 28%) or anti-TNF therapy (by about 30%) [72].

3.2 Ankylosing spondylitis

AS is a chronic inflammatory disease, which primarily affects the joints in the site of enthesis. It belongs to the group of diagnostic entity called spondyloarthropathies, which typically manifest in HLA-B27 positive patients. Similar to RA, AS can also manifest with extra-articular manifestations, such as gastrointestinal, ocular and cardiac involvement. The prevalence of AS in the population is about 0.1% (the overall prevalence of spondyloarthritis is around 1%) and, unlike most rheumatic diseases, occurs more frequently in men (up to three times) [103].

Similar to RA, an increased CV risk has been reported in AS patients [104, 105]. However, views on the close association of ATS and AS are divergent, in particular, due to the small evidence and conflicting results of studies [106]. Regarding the evidence on CV events in AS, the situation is similarly unsatisfactory and inconclusive [107, 108, 109]. Recently published meta-analysis has reported an increased risk of MI (RR = 1.6) and cerebrovascular events (RR = 1.5) compared to the general population [110].

There are several risk factors in AS, which participate in CV comorbidities. Since laboratory markers of inflammation are not elevated in many patients, CV risk is likely related to the risk profile of a typical patient with AS: a smoker with arterial hypertension and dyslipidemia, in whom low levels of HDL and TC accompany the disease activity [105, 110]. In addition, extra-articular cardiac manifestations of AS (e.g., conduction disorders, aortic valve insufficiency, left ventricular dysfunction) contribute to CV morbidity and mortality [105]. Levels of C-reactive protein (CRP), therapy with NSAIDs and work disability are considered significant predictive factors of CV mortality in AS [111, 112]. NSAIDs as the first-line therapy with the highest safety profile should be prescribed for the shortest time period possible [110]. On the other hand, anti-TNFs have a favorable effect on the endothelial function and a decrease of the CV risk [105, 113].

3.3 Psoriatic arthritis

PsA is a systemic inflammatory disease from the spondyloarthritis spectrum, associated with psoriasis [114]. The prevalence is 0.05–0.25% in the general population, but rises to 15–30% in patients with psoriasis [115]. The relative risk of CV involvement in psoriasis is reported to be 1.4, but the relative risk in PsA is less studied and the data are conflicting [116, 117, 118, 119]. Meta-analysis demonstrated a 1.43 fold higher CV risk in PsA patients compared to the general population. The incidence of MI, cerebrovascular events and heart failure has been reported to be increased (1.68, 1.22 and 1.31, respectively) [120].

According to the current evidence, various manifestations of ATS in PsA have been described, from subclinical involvement to symptomatic manifestations [121, 122, 123, 124, 125]. PsA is considered to be an additional independent CV risk factor, as proved by findings of more severe subclinical ATS compared to the general population and the association of plaque development with the inflammatory activity of PsA [120].

PsA is typically associated with high prevalence of MetS, which is two or three times more common than in other rheumatic diseases and the general population [126]. During the active inflammatory phase, there are characteristic alterations of lipidogram with a decrease of HDL and LDL, which consequently rises in remission of the disease [9]. The suggested mechanism, which causes changes of HDL levels, is the uptake of apoA-1 in the tissue affected by inflammation: particles of HDL penetrate from the circulation due to increased endothelial permeability. The consequent decline of serum HDL concentrations increases the CV risk in PsA in a similar manner as in RA [127].

The presence of subclinical ATS and its correlation with inflammatory markers and the effect of immunosuppressive therapy are questionable [9, 128]. Anti-TFN therapy seems to have a beneficial effect on CV risk in PsA, as well as in AS [129].

3.4 Systemic lupus erythematosus

SLE is characterized by a wide spectrum of clinical manifestations and involvement of different organs. The prevalence is 0.03% in Caucasian population, while SLE affects predominantly women in reproductive years, in whom the clinically significant ATS is not usually found under normal circumstances [130]. Although the survival of SLE has significantly improved, thanks to new therapeutic options, it still remains 5–10 years shorter compared to the general population [131]. The rate of SLE-associated mortality has declined, but the rate of CV complications, which are considered to be the leading cause of mortality in SLE nowadays and are responsible for 30% of deaths, has risen [131]. The bimodal mortality pattern describes two peaks of mortality in SLE population: the first peak represents death early in the course of the disease related to the disease activity and infectious complications, and the second peak refers to late death from the CV manifestations [132].

The prevalence of traditional risk factors is higher in SLE compared to the general population [133]. In addition, SLE-related risk factors, including renal involvement, apply in CV morbidity. The presence of SLE itself increases the risk of heart failure up to three times [134]. The clinical manifestation of ATS in SLE is predicted particularly by higher age at the onset of SLE, presence of arterial hypertension and hypercholesterolemia. Among others, the cumulative dose and the duration of CS therapy, long duration of SLE, and activity of immune system including autoantibodies play significant role in ATS [2].

Due to their pathophysiologic mechanism both SLE and vasculitis predispose to the atherosclerotic involvement of coronary circulation [135]. Coronary artery disease affects 6–10% of SLE patients and the incidence is four to eight times higher than in the general population [136, 137].

Risk of heart failure in SLE significantly rises immediately after the first manifestation of the autoimmune disorder, mostly at a young age. The relative risk of heart failure is therefore most increased in young patients in the age between 20 and 30 years, and decreases with a higher age. However, the incidence of CV diseases and heart failure is continually increasing in positive correlation with the increasing age of patients [134]. SLE patients are at 5–10 times higher risk, and young SLE women at age around 40 years are even at 50 times higher risk of MI compared to the general population [138].

Concerning the risk of a stroke in SLE, the ischemic stroke is estimated to be two times, hemorrhagic stroke three times and subarachnoid hemorrhage four times more common in SLE than in the general population [139]. In case of a stroke, young patients are more threatened due to accelerated ATS during the high activity of inflammation. The relation between disease activity and the risk of a stroke was described also in other diseases. Immunosuppressive therapy and other comorbidities (e.g., vasculitis, antiphospholipid syndrome, arterial hypertension) take part in this increased risk, as well [139]. Accompanying factors such as antiphospholipid syndrome, Liebman-Sacks endocarditis and formation of immune complexes of antibodies with antigens predispose patients to thrombotic complications and ischemic stroke, while endothelial dysfunction and interrupted endothelial layer integrity can lead to hemorrhagic stroke. Subarachnoid hemorrhage in SLE probably results from intracerebral vasculitis and concurrent arterial hypertension [139].

Atherosclerotic plaques have been detected in 17–65% of SLE patients using ultrasound examination. The age seems to play a major role in prediction of atherosclerosis and its manifestations in SLE. Some experts suggest a role of consequences of the disease activity and side effects of therapy in older patients with SLE [2].

3.5 Systemic sclerosis

SSc belongs to orphan connective tissue diseases with the prevalence of 0.003–0.06%, and is less understood, concerning the CV risk. The key pathologies leading to CV involvement are vasculopathy, inflammation and tissue fibrosis, which can also affect the heart. In addition to pathognomic microvasculopathy, macrovascular involvement is getting more attention in the last years [45].

To date, the relative risk of CV diseases in SSc in not known. Survival of SSc patients is about 16–34 years shorter compared to the general population with about 3.5 times higher mortality [140]. Due to advances in therapy of scleroderma renal crisis (SRC) and pulmonary arterial hypertension (PAH), new causes of death have got to the front, and the prevalence of ATS in SSc has risen [141]. Cardiac causes account for a quarter of the overall mortality in SSc patients [142]. The prevalence of traditional CV risk does not seem to differ from the general population. SSc-associated factors, which participate in endothelial damage, include inflammation and ischemia-reperfusion injury caused by impaired vasodilation [45]. The level of inflammation in SSc is lower than in RA or SLE, which indicates lower rate of acceleration of ATS. Impaired vasodilation characteristic for both SSc and ATS precedes the clinical manifestation of SSc. It is accompanied by the mechanisms typical for both of these pathologies: imbalance between vasodilators (e.g., nitric oxide, NO) and vasoconstrictors (e.g., endothelin), defective angiogenesis caused by the increased expression of VEGF, the presence of AECA and others. The main clinical manifestations of microvascular impairment, Raynaud’s phenomenon, PAH and SRC, probably predict macrovascular impairment in SSc [45].

Reports on the prevalence of ATS and its clinical manifestations in SSc differ in various studies. Among others, the reason is asymptomatic subclinical cardiac involvement. Increased risk of CV events is attributed both to ATS and the pathogenesis of SSc and its consequences (impaired microcirculation, myocardial fibrosis, arrhythmia, etc.), and last but not least, secondary deterioration of cardiac function due to renal vasculopathy, interstitial lung disease (ILD) and PAH [143].

The risk of MI is almost 2.5 times higher compared to the general population, while the impact of SSc itself outweighs the effect of hypertension or diabetes on the risk of MI. Ischemic injury of myocardium can be caused by occlusive vasculopathy and intermittent vasospasm (so-called myocardial Raynaud’s phenomenon) [144].

It is not clear whether the prevalence of subclinical ATS in SSc is higher compared to the general population. Nussinovitch and Shoenfeld reported carotid involvement in more than 60% of SSc patients, where the findings were described to be more frequent and more severe than in a control group from the general population [143].

Cerebrovascular involvement in SSc patients is 1.3 times more common than in the general population. SSc as an independent risk factor increases the risk of ischemic stroke by up to 43%. There are several pathologic mechanisms in SSc playing a role in the manifestation of a stroke, including vasospasm of cerebral arteries corresponding to the Raynaud’s phenomenon, which can manifest as a transient ischemic attack or a focal neurologic deficit [145].

3.6 Idiopathic inflammatory myopathies

IIM is a heterogeneous group of diseases, which primary affect the skeletal muscles as the common pathologic mechanism. The most prevalent subtypes are dermatomyositis (DM) and polymyositis (PM) [146, 147]. IIM belongs to orphan rheumatologic diseases and occurs in approximately 0.02% of population [148]. The mortality in IIM is almost four times higher than in the general population, with CV involvement as the leading cause [149]. The main pathology responsible for the cardiac involvement in IIM is myocarditis and accelerated ATS in coronary arteries [150]. Other mechanisms have not been sufficiently studied. Resulting structural alterations in myocardium can lead to disturbed function, arrhythmia and other, mostly asymptomatic, rarely fatal manifestations [151].

Data on cardiovascular disability in IIM are insufficient. Meta-analysis of studies in IIM reported 2.24 times higher CV risk compared to the general population [152]. With regard to the prevalence of MI in IIM, there are only limited data. A retrospective study by Rai et al. in more than 700 IIM patients described an increased risk of MI, but not of a stroke. The risk of MI has been increased in PM almost four times and in DM three times compared to the general population. Patients were most threatened by these complications during the first years after the onset of IIM [153].

Traditional risk factors in IIM are specifically related to the specific features of the disease, particularly muscle involvement resulting in impaired physical activity and CS therapy. The prevailing effect of CS in IIM, whether anti-inflammatory or pro-atherogenic, is not clear and has yet to be elucidated [152].

3.7 Primary Sjögren’s syndrome

Primary Sjögren’s syndrome is another relatively rare rheumatic disease with a prevalence of 0.06%. It is characterized by lymphocytic infiltration of exocrine glands (especially lacrimal and salivary) leading to dryness of the mucous membranes (sicca syndrome) and hyperactivity of B lymphocytes. pSS affects preferentially females at the age of 40–60 years [154].

The situation in terms of the CV risk in pSS is similarly unclear as in the above-mentioned rare systemic connective tissue diseases [155]. There is a lack of studies concerning the CV risk in pSS, moreover, the results are conflicting. CVD-associated mortality accounts for 30% of deaths. According to the recent meta-analysis including 14 studies in pSS, the CV risk is significantly increased compared to the general population: the relative risk of coronary artery disease is 1.34, cerebrovascular events 1.46, heart failure 2.54 and thromboembolism 1.78. This meta-analysis has not demonstrated a significantly increased risk of mortality due to CV causes (RR = 1.48) [155].

Similar results have been reported in a population study that also described higher prevalence of arterial hypertension and hypercholesterolemia in pSS patients, and, in addition, suggested pSS as an independent CV risk factor [156]. On the other hand, some studies did not confirm the increased CV risk in pSS [157, 158]. One study has reported subclinical atherosclerotic involvement in pSS patients detected by coronary flow reserve (CFR) and pulse wave velocity (PWV), while the echocardiography showed no pathology [159]. Impaired PWV is thus suggested as a marker of endothelial dysfunction even in patients with normal CFR [160].

Available data rather suggest higher CV risk in pSS patients compared to the general population, and the need of preventive screening and appropriate management, eventually including consultation and monitoring by a cardiologist [155].


4. Examination and estimation of the CV risk

Chronic inflammatory condition can skew the results of the examination, which have otherwise good reliability in the general population [3]. For example, ultrasound imaging of clinically insignificant atherosclerotic lesions or plaques cannot reveal the higher susceptibility to the progression and rupture of plaques in the inflammatory environment [5]. Several scoring systems were developed to facilitate the estimation of the CV risk in the general population. These scoring systems include particularly the traditional risk factors. The most used and widespread systems are Framingham Risk Score (FRS), Systemic Coronary Risk Evaluation (SCORE), QResearch Risk Score (QRISK2, or rather its updated version QRISK 3), Reynolds Risk Score and many others [161, 162]. FRS was the first developed scoring system and served as a default model for creating newer scoring systems. Nowadays, SCORE is probably the most used and widespread scoring system, especially in Europe [163]. Above-mentioned classic scoring systems underestimate the CV risk in rheumatic patients and therefore are not suitable for estimating the CV risk in these patients. A certain compromise was made by developing the Reynolds Risk Score by inclusion of CRP value as a marker of inflammation, and QRISK2 by inclusion the presence of RA as an independent risk factor [161]. Based on the recent EULAR recommendations for management of the CV risk in inflammatory arthropathies published in 2016, a modified SCORE system (mSCORE) should be used for evaluation of the CV risk in RA patients, which is calculated by multiplying the standard calculated value by a coefficient of 1.5 in all RA patients [58]. Despite this modification, mSCORE is not completely reliable in estimation of the CV risk, as was shown in studies describing findings of subclinical ATS in rheumatic patients classified in the low-risk category according to the mSCORE, and the evidence of higher tendency to formation of ATS plaques and instability of these plaques in RA. Due to these reasons, EULAR proposed simultaneous regular non-invasive examination by ultrasound of carotids and/or measuring the ankle-brachial index (ABI) for detection of subclinical ATS in asymptomatic patients in a low-risk category (SCORE 1–4%) [58, 82].

The CV risk should be assessed at least every 5 years in patients with low disease activity and should be reconsidered after major changes in therapy or progression of the disease [58, 59, 82]. In common practise, this assessment means regular examination of blood pressure and lipidogram during the outpatient control and in case of pathologic findings, early consultation by a preventive cardiologist and an adequate therapeutic intervention [62, 164].


5. Therapy

Preventive measures are the first-line therapy recommended in the general population to manage the CV risk. In rheumatic patients, these measures may be complicated due to a chronic disease. Therefore, the pharmacological treatment is needed [62, 82].

Metformin is recommended as the first line for the treatment of the MetS. It has a beneficial effect not only on improvement of insulin sensitivity, but also reduces the levels of LDL and TC and has a beneficial effect on the vascular function, as well as statins. Similar beneficial effect on glucose metabolism is related to administration of antimalarial drugs, which are often used in the treatment of SLE, pSS and also RA. HCQ exerts immunomodulatory and anti-inflammatory effect, and, in addition, induces an increase in insulin activity and serum levels of glucagon and improves the glucose tolerance. Moreover, HCQ reduces plasma glucose levels even in the general population and is therefore suitable as a part of MetS therapy [82]. Other drugs for glucose metabolism control include pioglitazone (a nuclear peroxisome proliferator-activated receptor-γ agonist), and liraglutide (glucagon-like peptide-1 analog), which has a beneficial effect in obese patients [13].

When managing and treating dyslipidemia, the recommended target levels of LDL (especially for RA) are lower than for the general population (LDL < 2.6 mmol/L; in individuals at higher risk, even <1.8 mmol/L). At the same time, preventive antiplatelet therapy should be considered [62]. Statins have been extensively discussed, especially in rheumatology. Via competitive inhibition of HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzym A) reductase, they inhibit the intermediate step in the synthesis of cholesterol. Despite the concerns of potential side effects as induction of immune-mediated necrotizing myopathy (IMNM), the use of statins in IIM patients does not seem to be more risky than in the general population [165]. Several studies demonstrated a beneficial potential of statins to reduce the CV risk via attenuation of the oxidative stress and improvement of endothelial function. Due to their anti-inflammatory potential, statins are preferentially recommended in the therapy of rheumatic patients according to the EULAR recommendations [62]. For example, atorvastatin, when administrated to RA patients, not only reduces the levels of TC and LDL, but apparently also inhibits the inflammation activity [166]. This favorable effect was confirmed in TRACE-RA study [167]. Rosuvastatin exerts a similar beneficial effect in inflammatory joint diseases [168]. Another therapeutic option for dyslipidemia treatment is fenofibrate, which increases the HDL levels, and niacin [13].

Regarding the management of arterial hypertension, targeting the optimal blood pressure is more important than considering the type of drug used in therapy [58]. ACE inhibitors or blockers of AT1 receptor for angiotensin II exert a potential anti-inflammatory effect similar to statins, and therefore are preferentially recommended for treatment of arterial hypertension [62]. There is an exception in SSc patients. ACE inhibitors are recommended in the treatment of manifested SRC, but not as a prevention of SRC. Thus, other antihypertensive drugs should be prescribed (if SRC is not present), especially calcium channel blockers due to their beneficial effect on Raynaud’s phenomenon [169].

Among other drugs with beneficial effect, vitamin D should not be forgotten. It was demonstrated that vitamin D acts as an immunomodulator and probably plays a protective role in the development of CV diseases, insulin resistance and obesity, and has anti-inflammatory effect and can potentially prevent from the development of MetS in RA patients. Also, probiotics are worth mentioning. Based on the results of studies showing that adverse changes of gut microbiome can induce autoimmune disorders, administration of probiotics may be profitable, as this could prevent the development of autoimmune disease or mitigate the consequences of already present pathological metabolic changes. However, further studies are needed to confirm these hypotheses [13].

Finally, the other side of this issue must not be forgotten, that is, adequate anti-inflammatory therapy of rheumatic diseases using DMARDs (especially MTX and TNF inhibitors in RA). Such therapy leads to mitigation of inflammatory activity and also improvement of quality of life and fitness of patients. Better fitness enables physical activity and thus facilitates the elimination of traditional risk factors and thereby reduces the CV risk [13].


6. Conclusion

Rheumatic patients are significantly more at risk of atherosclerosis and its complications than individuals from the general population. Traditional risk factors are in rheumatic patients more frequent. Moreover, these risk factors are often hard to manage by modification of life style. Nowadays, a wide range of therapeutic options is available for elimination of traditional risk factors and reduction of the cardiovascular risk. The appropriate anti-inflammatory therapy represents the golden standard. Despite the growing evidence on the cardiovascular risk in rheumatic patents, the adequate recommendations for management of these patients and early detection of a higher risk are still lacking. The task for the future is to create an examination algorithm to prevent underestimation and negligence of risk in rheumatic patients and also to extend the knowledge on the cardiovascular risk in rare rheumatic diseases.



This study was supported by AZV NV18-01-00161 A, MHCR 023728, and GAUK 312218.


  1. 1. Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: From mice to humans. Immunity. 2013;38(6):1092-1104
  2. 2. Sanjadi M et al. Atherosclerosis and autoimmunity: A growing relationship. International Journal of Rheumatic Diseases. 2018;21(5):908-921
  3. 3. Catapano AL et al. ESC/EAS guidelines for the management of dyslipidaemias the task force for the management of dyslipidaemias of the European society of cardiology (ESC) and the European atherosclerosis society (EAS). Atherosclerosis. 2011;217(1):3-46
  4. 4. Anderson KM et al. Cardiovascular disease risk profiles. American Heart Journal. 1991;121(1 Pt 2):293-298
  5. 5. Kerekes G et al. Validated methods for assessment of subclinical atherosclerosis in rheumatology. Nature Reviews Rheumatology. 2012;8(4):224-234
  6. 6. Castaneda S et al. Cardiovascular morbidity and associated risk factors in Spanish patients with chronic inflammatory rheumatic diseases attending rheumatology clinics: Baseline data of the CARMA project. Seminars in Arthritis and Rheumatism. 2015;44(6):618-626
  7. 7. Amaya-Amaya J, Montoya-Sanchez L, Rojas-Villarraga A. Cardiovascular involvement in autoimmune diseases. BioMed Research International. 2014;2014:367359
  8. 8. Libby P et al. Inflammation in atherosclerosis: From pathophysiology to practice. Journal of the American College of Cardiology. 2009;54(23):2129-2138
  9. 9. Ramonda R et al. Atherosclerosis in psoriatic arthritis. Autoimmunity Reviews. 2011;10(12):773-778
  10. 10. Sarmiento-Monroy JC et al. Cardiovascular disease in rheumatoid arthritis: A systematic literature review in latin america. Art. 2012;2012:371909
  11. 11. Hess PL et al. The metabolic syndrome and risk of sudden cardiac death: The atherosclerosis risk in communities study. Journal of the American Heart Association. 2017;6(8):e006103
  12. 12. Zmora N et al. The role of the immune system in metabolic health and disease. Cell Metabolism. 2017;25(3):506-521
  13. 13. Medina G et al. Metabolic syndrome, autoimmunity and rheumatic diseases. Pharmacological Research. 2018;133:277-288
  14. 14. Pfeiler S et al. IL-1 family cytokines in cardiovascular disease. Cytokine. 30 Nov 2017. pii: S1043-4666(17)30351-4. DOI: 10.1016/j.cyto.2017.11.009 [Epub ahead of print]
  15. 15. van der Heijden T, Bot I, Kuiper J. The IL-12 cytokine family in cardiovascular diseases. Cytokine. 23 Oct 2017. pii: S1043-4666(17)30315-0. DOI: 10.1016/j.cyto.2017.10.010 [Epub ahead of print]
  16. 16. Popovic-Kuzmanovic D et al. Increased activity of interleukin-23/interleukin-17 cytokine axis in primary antiphospholipid syndrome. Immunobiology. 2013;218(2):186-191
  17. 17. Muniyappa R, Iantorno M, Quon MJ. An integrated view of insulin resistance and endothelial dysfunction. Endocrinology and Metabolism Clinics of North America. 2008;37(3):685-711, ix-x
  18. 18. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. The Journal of Clinical Investigation. 2006;116(7):1793-1801
  19. 19. Federico A et al. Gut microbiota, obesity and metabolic disorders. Minerva Gastroenterologica e Dietologica. 2017;63(4):337-344
  20. 20. Abdollahi-Roodsaz S, Abramson SB, Scher JU. The metabolic role of the gut microbiota in health and rheumatic disease: Mechanisms and interventions. Nature Reviews Rheumatology. 2016;12(8):446-455
  21. 21. Teh P, Zakhary B, Sandhu VK. The impact of obesity on SLE disease activity: Findings from the Southern California lupus registry (SCOLR). Clinical Rheumatology. 2019;38(2):597-600
  22. 22. Nikiphorou E, Fragoulis GE. Inflammation, obesity and rheumatic disease: Common mechanistic links. A narrative review. Therapeutic Advances in Musculoskeletal Disease. 2018;10(8):157-167
  23. 23. Riaz H et al. Association between obesity and cardiovascular outcomes: A systematic review and meta-analysis of mendelian randomization studies. JAMA Network Open. 2018;1(7):e183788
  24. 24. Curtis JP et al. The obesity paradox: Body mass index and outcomes in patients with heart failure. Archives of Internal Medicine. 2005;165(1):55-61
  25. 25. Cottam DR et al. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: Implications and effects of weight loss. Obesity Surgery. 2004;14(5):589-600
  26. 26. Nishimura S et al. Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell Metabolism. 2013;18:759-766
  27. 27. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nature Medicine. 2012;18(3):363-374
  28. 28. Rakhshandehroo M, Kalkhoven E, Boes M. Invariant natural killer T cells in adipose tissue: Novel regulators of immune-mediated metabolic disease. Cellular and Molecular Life Sciences. 2013;70(24):4711-4727
  29. 29. Gremese E et al. Obesity as a risk and severity factor in rheumatic diseases (autoimmune chronic inflammatory diseases). Frontiers in Immunology. 2014;5:576
  30. 30. Lumeng CN et al. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes. 2008;57(12):3239-3246
  31. 31. Versini M et al. Obesity in autoimmune diseases: Not a passive bystander. Autoimmunity Reviews. 2014;13(9):981-1000
  32. 32. Sawicka K, Krasowska D. Adipokines in connective tissue diseases. Clinical and Experimental Rheumatology. 2016;34(6):1101-1112
  33. 33. Feng W et al. Wendan decoction for dyslipidemia: Protocol for a systematic review and meta-analysis. Medicine. 2019;98(3):e14159
  34. 34. Ganjali S et al. Monocyte-to-HDL-cholesterol ratio as a prognostic marker in cardiovascular diseases. Journal of Cellular Physiology. 2018;233(12):9237-9246
  35. 35. Rosenson RS et al. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nature Reviews Cardiology. 2016;13(1):48-60
  36. 36. Rye KA et al. The metabolism and anti-atherogenic properties of HDL. Journal of Lipid Research. 2009;50(Suppl):S195-S200
  37. 37. Liao KP et al. Lipid and lipoprotein levels and trend in rheumatoid arthritis compared to the general population. Arthritis Care and Research. 2013;65(12):2046-2050
  38. 38. Myasoedova E et al. Total cholesterol and LDL levels decrease before rheumatoid arthritis. Annals of the Rheumatic Diseases. 2010;69(7):1310-1314
  39. 39. Crowson CS et al. Usefulness of risk scores to estimate the risk of cardiovascular disease in patients with rheumatoid arthritis. The American Journal of Cardiology. 2012;110(3):420-424
  40. 40. Arts EE et al. Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis. Annals of the Rheumatic Diseases. 2015;74(4):668-674
  41. 41. Kawai VK et al. The ability of the 2013 American College of Cardiology/American Heart Association cardiovascular risk score to identify rheumatoid arthritis patients with high coronary artery calcification scores. Arthritis & Rhematology. 2015;67(2):381-385
  42. 42. Turiel M et al. Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis. Cardiovascular Therapeutics. 2010;28(5):e53-e64
  43. 43. Kadayifci FZ, Karadag MG. The relationship of serum endocan levels and anti-TNF-alpha therapy in patients with ankylosing spondylitis. European Journal of Rheumatology. 2018;5(1):1-4
  44. 44. Dhakal BP et al. Heart failure in systemic lupus erythematosus. Trends in Cardiovascular Medicine. 2018;28(3):187-197
  45. 45. Cannarile F et al. Cardiovascular disease in systemic sclerosis. Annals of Translational Medicine. 2015;3(1):8
  46. 46. Shoenfeld Y, Sherer Y, Harats D. Artherosclerosis as an infectious, inflammatory and autoimmune disease. Trends in Immunology. 2001;22(6):293-295
  47. 47. Prasad A et al. Predisposition to atherosclerosis by infections: Role of endothelial dysfunction. Circulation. 2002;106(2):184-190
  48. 48. Zhou X et al. Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation. 2000;102(24):2919-2922
  49. 49. Wu R, Lefvert AK. Autoantibodies against oxidized low density lipoproteins (oxLDL): Characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL. Clinical and Experimental Immunology. 1995;102(1):174-180
  50. 50. Wu R et al. Antibodies against lysophosphatidylcholine and oxidized LDL in patients with SLE. Lupus. 1999;8(2):142-150
  51. 51. Bergmark C et al. Patients with early-onset peripheral vascular disease have increased levels of autoantibodies against oxidized LDL. Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15(4):441-445
  52. 52. Cinoku I et al. Autoantibodies to ox-LDL in Sjogren’s syndrome: Are they atheroprotective? Clinical and Experimental Rheumatology. 2018;36(Suppl 112(3)):61-67
  53. 53. George J et al. Immunolocalization of beta2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: Potential implications for lesion progression. Circulation. 1999;99(17):2227-2230
  54. 54. Grainger DJ, Bethell HW. High titres of serum antinuclear antibodies, mostly directed against nucleolar antigens, are associated with the presence of coronary atherosclerosis. Annals of the Rheumatic Diseases. 2002;61(2):110-114
  55. 55. Liang KP et al. Autoantibodies and the risk of cardiovascular events. The Journal of Rheumatology. 2009;36(11):2462-2469
  56. 56. Majka DS, Chang RW. Is preclinical autoimmunity benign?: The case of cardiovascular disease. Rheumatic Diseases Clinics of North America. 2014;40(4):659-668
  57. 57. Husni ME. Comorbidities in psoriatic arthritis. Rheumatic Diseases Clinics of North America. 2015;41(4):677-698
  58. 58. Agca R et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Annals of the Rheumatic Diseases. 2017;76(1):17-28
  59. 59. Peters MJ et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Annals of the Rheumatic Diseases. 2010;69(2):325-331
  60. 60. Hallgren R, Berne C. Glucose intolerance in patients with chronic inflammatory diseases is normalized by glucocorticoids. Acta Medica Scandinavica. 1983;213(5):351-355
  61. 61. Panoulas VF et al. Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis. Rheumatology. 2008;47(1):72-75
  62. 62. Nurmohamed MT, Heslinga M, Kitas GD. Cardiovascular comorbidity in rheumatic diseases. Nature Reviews Rheumatology. 2015;11(12):693-704
  63. 63. Ruyssen-Witrand A et al. Cardiovascular risk induced by low-dose corticosteroids in rheumatoid arthritis: A systematic literature review. Joint, Bone, Spine. 2011;78(1):23-30
  64. 64. Gargiulo P et al. Ischemic heart disease in systemic inflammatory diseases. An appraisal. International Journal of Cardiology. 2014;170(3):286-290
  65. 65. Prasad M et al. Cardiorheumatology: Cardiac involvement in systemic rheumatic disease. Nature Reviews Cardiology. 2015;12(3):168-176
  66. 66. Mercer E et al. Hydroxychloroquine improves insulin sensitivity in obese non-diabetic individuals. Arthritis Research & Therapy. 2012;14(3):R135
  67. 67. Cairoli E et al. Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: A longitudinal evaluation of the lipid-lowering effect. Lupus. 2012;21(11):1178-1182
  68. 68. Floris A et al. Protective effects of hydroxychloroquine against accelerated atherosclerosis in systemic lupus erythematosus. Mediators of Inflammation. 2018;2018:3424136
  69. 69. Myasoedova E et al. The influence of rheumatoid arthritis disease characteristics on heart failure. The Journal of Rheumatology. 2011;38(8):1601-1606
  70. 70. Choi HK et al. Methotrexate and mortality in patients with rheumatoid arthritis: A prospective study. Lancet. 2002;359(9313):1173-1177
  71. 71. Wright K, Crowson CS, Gabriel SE. Cardiovascular comorbidity in rheumatic diseases: A focus on heart failure. Heart Failure Clinics. 2014;10(2):339-352
  72. 72. Roubille C et al. 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. Annals of the Rheumatic Diseases. 2015;74(3):480-489
  73. 73. Ridker PM et al. Low-dose methotrexate for the prevention of atherosclerotic events. The New England Journal of Medicine. 2019;380(8):752-762
  74. 74. Roubille C et al. Biologics and the cardiovascular system: A double-edged sword. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry. 2013;12(1):68-82
  75. 75. Micha R et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. The American Journal of Cardiology. 2011;108(9):1362-1370
  76. 76. Westlake SL et al. Tumour necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: A systematic literature review. Rheumatology. 2011;50(3):518-531
  77. 77. Dixon WG et al. 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 and Rheumatism. 2007;56(9):2905-2912
  78. 78. Daien CI et al. Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: A systematic review with meta-analysis. Annals of the Rheumatic Diseases. 2012;71(6):862-868
  79. 79. Channual J, Wu JJ, Dann FJ. Effects of tumor necrosis factor-alpha blockade on metabolic syndrome components in psoriasis and psoriatic arthritis and additional lessons learned from rheumatoid arthritis. Dermatologic Therapy. 2009;22(1):61-73
  80. 80. Antohe JL et al. Diabetes mellitus risk in rheumatoid arthritis: Reduced incidence with anti-tumor necrosis factor alpha therapy. Arthritis Care and Research. 2012;64(2):215-221
  81. 81. Atzeni F et al. Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: Cause for concern? Immunotherapy. 2015;7(4):353-361
  82. 82. Martin-Martinez MA et al. Recommendations for the management of cardiovascular risk in patients with rheumatoid arthritis: Scientific evidence and expert opinion. Seminars in Arthritis and Rheumatism. 2014;44(1):1-8
  83. 83. Interleukin-6 Receptor Mendelian Randomisation Analysis, C et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis. Lancet. 2012;379(9822):1214-1224
  84. 84. Kim SC et al. Cardiovascular safety of tocilizumab versus tumor necrosis factor inhibitors in patients with rheumatoid arthritis: A multi-database cohort study. Arthritis & Rhematology. 2017;69(6):1154-1164
  85. 85. Kawashiri SY et al. Effects of the anti-interleukin-6 receptor antibody, tocilizumab, on serum lipid levels in patients with rheumatoid arthritis. Rheumatology International. 2011;31(4):451-456
  86. 86. Pego-Reigosa JM et al. Long-term improvement of lipid profile in patients with refractory systemic lupus erythematosus treated with B-cell depletion therapy: A retrospective observational study. Rheumatology. 2010;49(4):691-696
  87. 87. Kilickap S et al. Addition of rituximab to chop does not increase the risk of cardiotoxicity in patients with non-Hodgkin’s lymphoma. Medical Oncology. 2008;25(4):437-442
  88. 88. Ridker PM et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. The New England Journal of Medicine. 2017;377(12):1119-1131
  89. 89. Kaneko Y, Takeuchi T. A paradigm shift in rheumatoid arthritis over the past decade. Internal Medicine. 2014;53(17):1895-1903
  90. 90. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356-361
  91. 91. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis: An extraarticular feature of rheumatoid arthritis? Arthritis and Rheumatism. 2002;46(4):862-873
  92. 92. Mackey RH, Kuller LH, Moreland LW. Update on cardiovascular disease risk in patients with rheumatic diseases. Rheumatic Diseases Clinics of North America. 2018;44(3):475-487
  93. 93. van Halm VP et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: A cross-sectional study, the CARRE Investigation. Annals of the Rheumatic Diseases. 2009;68(9):1395-1400
  94. 94. Solomon DH et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107(9):1303-1307
  95. 95. Kaplan MJ, McCune WJ. New evidence for vascular disease in patients with early rheumatoid arthritis. Lancet. 2003;361(9363):1068-1069
  96. 96. Zinger H, Sherer Y, Shoenfeld Y. Atherosclerosis in autoimmune rheumatic diseases-mechanisms and clinical findings. Clinical Reviews in Allergy and Immunology. 2009;37(1):20-28
  97. 97. Lopez-Longo FJ et al. Association between anti-cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis. Arthritis and Rheumatism. 2009;61(4):419-424
  98. 98. del Rincon ID et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis and Rheumatism. 2001;44(12):2737-2745
  99. 99. Chung CP et al. Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis. Arthritis Research & Therapy. 2006;8(6):R186
  100. 100. Boyer JF et al. Traditional cardiovascular risk factors in rheumatoid arthritis: A meta-analysis. Joint, Bone, Spine. 2011;78(2):179-183
  101. 101. Shoenfeld Y et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation. 2005;112(21):3337-3347
  102. 102. Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: Moving upstream to identify novel targets for atheroprotection. Circulation Research. 2016;118(1):145-156
  103. 103. Stolwijk C et al. Epidemiology of spondyloarthritis. Rheumatic Diseases Clinics of North America. 2012;38(3):441-476
  104. 104. Papagoras C, Voulgari PV, Drosos AA. Atherosclerosis and cardiovascular disease in the spondyloarthritides, particularly ankylosing spondylitis and psoriatic arthritis. Clinical and Experimental Rheumatology. 2013;31(4):612-620
  105. 105. Nurmohamed MT, van der Horst-Bruinsma I, Maksymowych WP. Cardiovascular and cerebrovascular diseases in ankylosing spondylitis: Current insights. Current Rheumatology Reports. 2012;14(5):415-421
  106. 106. Peters MJ et al. Ankylosing spondylitis: A risk factor for myocardial infarction? Annals of the Rheumatic Diseases. 2010;69(3):579-581
  107. 107. Mathieu S et al. Cardiovascular profile in ankylosing spondylitis: A systematic review and meta-analysis. Arthritis Care and Research. 2011;63(4):557-563
  108. 108. Brophy S et al. No increased rate of acute myocardial infarction or stroke among patients with ankylosing spondylitis-a retrospective cohort study using routine data. Seminars in Arthritis and Rheumatism. 2012;42(2):140-145
  109. 109. Chou CH et al. A nationwide population-based retrospective cohort study: Increased risk of acute coronary syndrome in patients with ankylosing spondylitis. Scandinavian Journal of Rheumatology. 2014;43(2):132-136
  110. 110. Mathieu S, Pereira B, Soubrier M. Cardiovascular events in ankylosing spondylitis: An updated meta-analysis. Seminars in Arthritis and Rheumatism. 2015;44(5):551-555
  111. 111. Bakland G, Gran JT, Nossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Annals of the Rheumatic Diseases. 2011;70(11):1921-1925
  112. 112. Mok CC et al. Life expectancy, standardized mortality ratios, and causes of death in six rheumatic diseases in Hong Kong, China. Arthritis and Rheumatism. 2011;63(5):1182-1189
  113. 113. Genre F et al. Anti-TNF-alpha therapy reduces endothelial cell activation in non-diabetic ankylosing spondylitis patients. Rheumatology International. 2015;35(12):2069-2078
  114. 114. Braun J et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Annals of the Rheumatic Diseases. 2011;70(6):896-904
  115. 115. Gladman DD et al. Psoriatic arthritis: Epidemiology, clinical features, course, and outcome. Annals of the Rheumatic Diseases. 2005;64(Suppl. 2):ii14-ii17
  116. 116. Ahlehoff O et al. Psoriasis is associated with clinically significant cardiovascular risk: A Danish nationwide cohort study. Journal of Internal Medicine. 2011;270(2):147-157
  117. 117. Kondratiouk S, Udaltsova N, Klatsky AL. Associations of psoriatic arthritis and cardiovascular conditions in a large population. The Permanente Journal. 2008;12(4):4-8
  118. 118. Gladman DD et al. Cardiovascular morbidity in psoriatic arthritis. Annals of the Rheumatic Diseases. 2009;68(7):1131-1135
  119. 119. Han C et al. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The Journal of Rheumatology. 2006;33(11):2167-2172
  120. 120. Polachek A et al. Risk of cardiovascular morbidity in patients with psoriatic arthritis: A meta-analysis of observational studies. Arthritis Care & Research. 2017;69(1):67-74
  121. 121. Eder L et al. Subclinical atherosclerosis in psoriatic arthritis: A case-control study. The Journal of Rheumatology. 2008;35(5):877-882
  122. 122. Gonzalez-Juanatey C et al. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis and Rheumatism. 2007;57(6):1074-1080
  123. 123. Gonzalez-Juanatey C et al. Endothelial dysfunction in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis and Rheumatism. 2007;57(2):287-293
  124. 124. Tam LS et al. Subclinical carotid atherosclerosis in patients with psoriatic arthritis. Arthritis and Rheumatism. 2008;59(9):1322-1331
  125. 125. Rose S et al. Psoriatic arthritis and sacroiliitis are associated with increased vascular inflammation by 18-fluorodeoxyglucose positron emission tomography computed tomography: Baseline report from the psoriasis atherosclerosis and cardiometabolic disease initiative. Arthritis Research & Therapy. 2014;16(4):R161
  126. 126. Mok CC et al. Prevalence of atherosclerotic risk factors and the metabolic syndrome in patients with chronic inflammatory arthritis. Arthritis Care and Research. 2011;63(2):195-202
  127. 127. Oliviero F et al. Apolipoprotein A-I and cholesterol in synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Clinical and Experimental Rheumatology. 2009;27(1):79-83
  128. 128. Kimhi O et al. Prevalence and risk factors of atherosclerosis in patients with psoriatic arthritis. Seminars in Arthritis and Rheumatism. 2007;36(4):203-209
  129. 129. Angel K et al. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: A controlled study. Hypertension. 2010;55(2):333-338
  130. 130. Cervera R et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine. 2003;82(5):299-308
  131. 131. Wigren M, Nilsson J, Kaplan MJ. Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: Common mechanisms and possible targets for intervention. Journal of Internal Medicine. 2015;278(5):494-506
  132. 132. Urowitz MB et al. The bimodal mortality pattern of systemic lupus erythematosus. The American Journal of Medicine. 1976;60(2):221-225
  133. 133. Petri M et al. Coronary artery disease risk factors in the Johns Hopkins lupus cohort: Prevalence, recognition by patients, and preventive practices. Medicine. 1992;71(5):291-302
  134. 134. Kim CH et al. Incidence and risk of heart failure in systemic lupus erythematosus. Heart. 2017;103(3):227-233
  135. 135. Mason JC, Libby P. Cardiovascular disease in patients with chronic inflammation: Mechanisms underlying premature cardiovascular events in rheumatologic conditions. European Heart Journal. 2015;36(8):482-489c
  136. 136. Petri M et al. Risk factors for coronary artery disease in patients with systemic lupus erythematosus. The American Journal of Medicine. 1992;93(5):513-519
  137. 137. Manzi S et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: Comparison with the Framingham study. American Journal of Epidemiology. 1997;145(5):408-415
  138. 138. Schoenfeld SR, Kasturi S, Costenbader KH. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: A systematic review. Seminars in Arthritis and Rheumatism. 2013;43(1):77-95
  139. 139. Holmqvist M et al. Stroke in systemic lupus erythematosus: A meta-analysis of population-based cohort studies. RMD Open. 2015;1(1):e000168
  140. 140. Psarras A et al. A critical view on cardiovascular risk in systemic sclerosis. Rheumatology International. 2017;37(1):85-95
  141. 141. Soriano A, Afeltra A, Shoenfeld Y. Is atherosclerosis accelerated in systemic sclerosis? Novel insights. Current Opinion in Rheumatology. 2014;26(6):653-657
  142. 142. Rubio-Rivas M et al. Mortality and survival in systemic sclerosis: Systematic review and meta-analysis. Seminars in Arthritis and Rheumatism. 2014;44(2):208-219
  143. 143. Nussinovitch U, Shoenfeld Y. Atherosclerosis and macrovascular involvement in systemic sclerosis: Myth or reality. Autoimmunity Reviews. 2011;10(5):259-266
  144. 144. Man A et al. The risk of cardiovascular disease in systemic sclerosis: A population-based cohort study. Annals of the Rheumatic Diseases. 2013;72(7):1188-1193
  145. 145. Chu SY et al. Increased risk of acute myocardial infarction in systemic sclerosis: A nationwide population-based study. The American Journal of Medicine. 2013;126(11):982-988
  146. 146. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). The New England Journal of Medicine. 1975;292(7):344-347
  147. 147. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). The New England Journal of Medicine. 1975;292(8):403-407
  148. 148. Findlay AR, Goyal NA, Mozaffar T. An overview of polymyositis and dermatomyositis. Muscle & Nerve. 2015;51(5):638-656
  149. 149. Dobloug GC et al. Mortality in idiopathic inflammatory myopathy: Results from a Swedish nationwide population-based cohort study. Annals of the Rheumatic Diseases. 2018;77(1):40-47
  150. 150. Schwartz T et al. Cardiac involvement in adult and juvenile idiopathic inflammatory myopathies. RMD Open. 2016;2(2):e000291
  151. 151. Diederichsen LP. Cardiovascular involvement in myositis. Current Opinion in Rheumatology. 2017;29(6):598-603
  152. 152. Ungprasert P et al. Risk of coronary artery disease in patients with idiopathic inflammatory myopathies: A systematic review and meta-analysis of observational studies. Seminars in Arthritis and Rheumatism. 2014;44(1):63-67
  153. 153. Rai SK et al. Risk of myocardial infarction and ischaemic stroke in adults with polymyositis and dermatomyositis: A general population-based study. Rheumatology. 2016;55(3):461-469
  154. 154. Qin B et al. Epidemiology of primary Sjogren’s syndrome: A systematic review and meta-analysis. Annals of the Rheumatic Diseases. 2015;74(11):1983-1989
  155. 155. Beltai A et al. Cardiovascular morbidity and mortality in primary Sjogren syndrome: A systematic review and meta-analysis. Arthritis Care and Research (Hoboken). 20 Dec 2018. DOI: 10.1002/acr.23821 [Epub ahead of print]
  156. 156. Bartoloni E et al. Cardiovascular disease risk burden in primary Sjogren’s syndrome: Results of a population-based multicentre cohort study. Journal of Internal Medicine. 2015;278(2):185-192
  157. 157. Chiang CH et al. Primary Sjogren’s syndrome and the risk of acute myocardial infarction: A Nationwide study. Acta Cardiologica Sinica. 2013;29(2):124-131
  158. 158. Chiang CH et al. Primary Sjogren’s syndrome and risk of ischemic stroke: A nationwide study. Clinical Rheumatology. 2014;33(7):931-937
  159. 159. Atzeni F et al. Can speckle tracking echocardiography detect subclinical left ventricular dysfunction in patients with primary Sjogren’s syndrome? Clinical and Experimental Rheumatology. 2017;35(1):173
  160. 160. Atzeni F et al. New parameters for identifying subclinical atherosclerosis in patients with primary Sjogren’s syndrome: A pilot study. Clinical and Experimental Rheumatology. 2014;32(3):361-368
  161. 161. Payne RA. Cardiovascular risk. British Journal of Clinical Pharmacology. 2012;74(3):396-410
  162. 162. Hippisley-Cox J, Coupland C, Brindle P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: Prospective cohort study. BMJ. 2017;357:j2099
  163. 163. Conroy RM et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: The SCORE project. European Heart Journal. 2003;24(11):987-1003
  164. 164. Piepoli MF et al. European Guidelines on cardiovascular disease prevention in clinical practice: The sixth joint task force of the european society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European association for cardiovascular prevention & rehabilitation (EACPR). European Heart Journal. 2016;2016, 37(29):2315-2381
  165. 165. Charles-Schoeman C et al. Treatment of dyslipidemia in idiopathic inflammatory myositis: Results of the International Myositis Assessment and Clinical Studies Group survey. Clinical Rheumatology. 2012;31:1163-1168, 1168
  166. 166. McCarey DW et al. Trial of atorvastatin in rheumatoid arthritis (TARA): Double-blind, randomised placebo-controlled trial. Lancet. 2004;363(9426):2015-2021
  167. 167. Kitas GD et al. Trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis (TRACE RA): A multicenter, randomized, placebo controlled trial. Arthritis & Rheumatology. 15 Apr 2019. pp. 1-13. DOI: 10.1002/art.40892 [Epub ahead of print]
  168. 168. Rollefstad S et al. Rosuvastatin-induced carotid plaque regression in patients with inflammatory joint diseases: The rosuvastatin in rheumatoid arthritis, ankylosing spondylitis and other inflammatory joint diseases study. Arthritis & Rheumatology. 2015;67(7):1718-1728
  169. 169. Kowal-Bielecka O et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Annals of the Rheumatic Diseases. 2017;76(8):1327-1339

Written By

Sabina Oreska and Michal Tomcik

Submitted: 01 May 2019 Reviewed: 15 July 2019 Published: 14 August 2019