4.1. Chronic inflammation
RA has a complex etiology that involves a combination of genetic susceptibility and environmental triggers. The most prominent genetic risk is the presence of the human leukocyte antigen (HLA) - DRB1*04:01 gene, which encodes a 5-amino acid sequence known as a shared epitope that induces the binding of post-translationally modified (citrullinated) proteins. Another genetic risk factor is PTPN22, which increases citrullination [
38]. The major environmental risk factors include tobacco smoking, female sex, advanced age, and certain foods [
38,
39,
40]. Autoimmune processes include the recognition of synovial tissue self-antigens such as type II collagen, proteoglycans, and cartilage protein gp39 [
41,
42,
43]. The activation and combination of these two major mechanisms are crucial for joint destruction and bone erosion in RA. First, the joint intimal lining expands, causing synoviocyte activation and proliferation, which then begins to secrete pro-inflammtory cytokines such as Tumor necrosis factor (TNF), Interleukin-1 (IL-1), Interleukin-6 IL-6), metalloproteinases, prostaglandins, and leukotrienes. Synovial invasion into the adjacent articular structures damages the cartilage and bone, manifesting as joint swelling. Second, synovial layer proliferation contributes to the activation of neutrophils and T- and B-lymphocytes, which infiltrate the joints and secrete cytokines and proteinases that further damage the extracellular matrix. Effector CD4+ T cells play a crucial role in disease progression and are characterized by an imbalance between Th1/Th17 and regulatory T cells [
44,
45]. As the pathogenic processes of atherosclerosis and synovial inflammation in RA share a common pathway, the understanding of these processes represents a cornerstone of CV risk management in patients with RA. Sustained synovial secretion of inflammatory mediators leads to chronic low-grade activation and dysfunction of the vascular endothelium, promoting accelerated development of atherosclerosis in RA [
46].
Citrullinated synovial proteins induce the production of autoantibodies (anti-CCP) specific mostly for RA and are associated with more severe forms of RA [
47,
48], as well as are the subject of many CV risk studies. According to López-Longo et al., anti-CCP antibodies titer levels of > 25 units/mL carried a higher risk of ischemic heart disease (6.5 vs. 2.6%, odds ratio [OR]: 2.58, 95% CI: 1.17–5.65) without affecting mortality [
49]. Previous studies clarified the association of citrullinated proteins and anti-CCP antibodies with early subclinical atherosclerosis and atherosclerotic plaque promotion by targeting citrullinated fibrinogen in plaques with anti-CCP antibodies to induce inflammation and heart failure independent of coronary artery disease by targeting citrullinated sarcomeric proteins, namely, fibrinogen and vimentin [
50,
51,
52]; however, these studies had important limitations, such as the inability to demonstrate a direct anti-CCP complex in plaque [
50] and many false positive fluorodeoxyglucose (FDG) uptake results [
51]. Several studies addressing anti-CCP positivity reported that it was associated with higher total mortality and increased fatal CV outcomes, but not with heart failure or recurrent ischemia [
52,
53,
54,
55]; limitations are listed is
Table S1 (Supplementary Materials). However, other large studies did not find a significant association between anti-CCP and rheumatoid factor (RF) positivity and CV morbidity and mortality [
56,
57], which we consider to have greater relevance. In addition, other antibodies present in RA are possibly associated with CVD risk, including antibodies against carbamylated proteins (anti-CarP) and malondialdehyde-acetaldehyde adducts [
53]. Genetic susceptibility and environmental triggers also lead to constant activation and clonal expansion of specific CD4 + CD28null T cell subsets, which play a crucial role in the pathogenesis of RA, especially the loss of CD28, a co-stimulatory molecule required for normal T cell activation, correlate with seropositivity and extra-articular RA manifestations [
58]. Increased expression of perforin and killer cell immunoglobulin-like receptors in these cells, with potential direct cytotoxic effects on endothelial cells and their dysfunction, can cause early atherosclerosis, plaque rupture, and thrombosis [
59,
60,
61]. This expression strongly stimulates the activity and recruitment of macrophages and T cells to the plaque, contributing to reactive oxygen species production, inhibiting collagen production, stimulating matrix metalloproteinases, and inducing tissue factor expression [
62]. According to Liuzzo et al. [
63], the level of CD4 + CD28null T-cells in patients’ blood was an independent predictor of future acute coronary events in patients with RA (OR: 3.01, 95% CI: 1.1–8.25, p = 0.023). The activated endothelium promotes the binding of neutrophils, monocytes, and platelets, which is further potentiated by neutrophils, IL-8, and monocyte CCL2 chemokines. Adherent neutrophils and monocytes promote further activation of the vascular endothelium by PAR-1, creating a vicious cycle that leads to endothelial dysfunction. Neutrophils exposed to activated platelets form intravascular neutrophil extracellular traps which by expression of endothelium-activating proteases, histones, and tissue factor promote the creation of intravascular pro-inflammatory and pro-thrombotic milieus [
14]. This finding is supported by the findings of numerous published studies and reviews.
Many studies have focused on the role of inflammatory cytokines in atherogenesis and CV disease development as well as their use for risk stratification. Newer studies reported that C-reactive protein (CRP) and fibrinogen are less likely to be causally associated with atherogenesis, but pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) could be directly etiologically associated with atherogenesis by regulation of inflammatory cascades [
64,
65]. In a prospective study with 1.514 participants and a meta-analysis of 29 studies with approximately 17.000 participants, Kaptoge et al. [
66], studied the roles of six pro-inflammatory cytokines, IL-6 and IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and TNF-α in coronary heart disease and concluded that higher baseline levels of IL-6, IL-18, and TNF-α were associated with a 10–25% higher risk of non-fatal myocardial infarction and CV death, while sCD40L and MMP-9 were not.
Chronic inflammation also has pro-coagulant effects mediated by several mechanisms, including increased expression of adhesion molecules for tissue factors, reduced synthesis of nitrogen oxide and thrombomodulin, and increased pro-coagulant properties of the endothelium [
67]. Endothelial dysfunction is further mediated by the induction of NADPH oxidases and dysfunction of antioxidant systems [
68]. Significantly increased levels of tissue factor, fibrinogen, von Willebrand factor, factor (F) VIII, activated FXIIa, and markers of thrombin synthesis have been observed in patients with RA having high inflammatory activity [
67,
69]. Platelets activated by cytokine-sensitized endothelial neutrophils or monocytes or by anti-CCP antibody exposure are key elements in the development of acute cardiovascular syndromes, as well as in atherosclerotic plaque formation, recruiting leukocytes to the sites of endothelial damage and inflammation, activating complement and other inflammatory receptors, and releasing cytokines and chemokines [
70]. Together, these mechanisms shift the hemostatic balance to a prothrombotic state in RA [
52]. A meta-analysis by Zhou et al. [
71] confirmed that platelet counts are elevated in patients with RA and could serve to assess disease activity. CV risk estimation in the general population is based on different risk that underestimates CV risk in patients with RA. It is hypothesized that chronic inflammation is the key determinant to explain those underestimations, Framingham score, or SCORE system and supported by several studies like HOOM and CARRÉ study [
72]; however these studies have certain limitations in terms of methods used to estimate CV risk.
IL-6 and TNF-are independently associated with a higher coronary calcium score and increased CV risk, favoring the hypothesis that RA-related increased CV risk is associated with higher levels of inflammatory cytokines and their deleterious effects on endothelial cells [
52,
73,
74]. This finding is supported by several published studies. The effect begins very early in RA, mostly affects the carotid and coronary arteries, and is associated with a significant proportion of acute CV events [
75]. High-grade inflammation is associated with increased CV morbidity and mortality, with CRP level and ESR as independent markers, reported in a population-based study during 20 years of follow-up, which is in concordance with several older studies [
57,
76,
77,
78]. The use of CRP, or highly sensitive CRP as a predictor of CV risk in modified CV risk calculators, was not adopted in standard cardiology practice [
79].
Endothelial dysfunction in RA is the result of complex interactions among modifiable CV risk factors, genetic predisposition, chronic inflammation, pro-oxidative stress, prothrombotic status, and metabolic abnormalities (insulin resistance and dyslipidemia) [
79,
80]. It is present in very early RA, even before or within one year of the clinical onset of RA, as well as in arterial wall atherosclerosis with an increased risk of coronary heart disease and myocardial infarction [
81,
82]. According to Gonzalez-Gay et al. [
82], endothelial dysfunction is worsened by long-standing RA > 20 years compared with RA < 7 years; however, the success of inflammation control has not been investigated. Endothelial dysfunction in RA can be assessed by measuring circulating soluble adhesive molecules such as E-selectin, P-selectin, intracellular adhesion molecule-1 (ICAM-1), vascular cell type 1 adhesion molecule (VCAM-1), and flow-mediated arterial dilatation, all of which are suggested to be used in CV risk assessment, supported by a meta-analysis of 20 studies including 852 patients with RA [
83].
Duplex atherosclerosis screening is most commonly used for detecting atherosclerotic plaques that are predictive of CV disease [
84]. Although for assessing cardiovascular burden in RA, carotid intima media thickness (cIMT) measurements were used in previous investigations; it is no longer recommended according to ESC guidelines [
17,
27], but detection of carotid plaque formation has a predictive value with a pronounced effect in early RA and in male gender with a higher inflammation burden [
17,
84].
Flow-mediated dilatation, augmentation index, pulse wave velocity, coronary artery calcification score (CAC), SPECT/CT, PET / CT, and PET/MR are also used to assess the atherosclerotic burden; however, non-imaging methods have many limitations and confounding factors [
85]. CAC, a measure of coronary artery calcification and subclinical atherosclerosis, is closely related to the degree of atherosclerotic plaque burden and is a strong predictor of CV events [
85]. Paccou et al. [
86] compared coronary artery calcification and abdominal aorta calcification between asymptomatic patients with RA and healthy controls, and reported that both were more prevalent and severe in patients with RA. Coronary artery calcification was independently associated with older age and hypertension, whereas abdominal aorta calcification was independently associated with older age and erosive arthritis. However, there are some reservations about this method; for example, non-calcified plaques cannot be detected. Accelerated atherosclerosis in RA, in addition to epicardial artery disease, can also cause microvascular dysfunction, which is crucial for the regulation of myocardial perfusion, and further accelerates CV disease development (
Figure 2).