The atherosclerotic process begins early in life with the accumulation of lipid-laden cells beneath the endothelium – the fatty streak – that includes mainly macrophages and some T cells. The fatty streak can vanish or may progress to atheroma formation. Atheromata consist of cells, connective tissue elements, lipids and debris that together thicken the intima. Inflammatory and immune cells constitute an important part of the atherosclerotic lesions. LDL cholesterol infiltrates the wall of large- and medium-sized arteries where it is responsible for initiating an inflammatory response. LDL oxidation evokes the release of phospholipids that activate the endothelium mainly at sites of hemodynamic strain (high oscillatory, but low average shear stress), which leads to increased expression of adhesion molecules and inflammatory cytokines. Blood platelets adhere to surface molecules of endothelial cells via their glycoproteins IIb/IIIa.

The atheroma possesses a central core with foam cells and extracellular lipid droplets surrounded by a cap of smooth muscle cells and a collagen-rich matrix. Atheroma growing involves infiltration by T cells, macrophages and mast cells; many of them are activated and produce pro-inflammatory cytokines (interleukin-1β, tumour necrosis factor, γ-interferon) that promote the migration and proliferation of smooth muscle cells and the construction of a dense extracellular matrix – the advance atherosclerotic lesion.

The acute coronary syndromes are usually initiated by a rupture of the fibrous cap but in some cases can occur just by endothelial erosion. In one quarter of cases, the endothelium does not rupture, but instead it is replaced for prothrombotic inflammatory cells. Plaque rupture usually occurs in areas of sustained inflammation, macrophage accumulation and apoptosis. Proteolytic enzymes produced by activated macrophages can degrade the collagen of the fibrous cap facilitating its rupture. These enzymes belong to the matrix metalloproteinase (MMP) family. The three MMPs [1, 8, 13] are overproduced by macrophages present in lesions where massive thrombosis has occurred. Furthermore, it seems to be a crosstalk between this immune effector macrophage pathway and adaptive immune cells (T cells) inhibiting the synthesis and augmenting the degradation of interstitial collagen. In fact, it has been demonstrated that T-cell-derived cytokine CD40 ligand (CD154) boosts the production of interstitial collagenase by human macrophages.

The observations above provide a cellular and molecular mechanism linking inflammation to the thinning and weakening of the fibrous cap, which can precipitate plaque rupture, thrombosis and acute CV events. Longitudinal studies have demonstrated that the overall disease activity, a proxy of inflammatory burden, is crucial for cardiovascular outcome of immune-mediated inflammatory rheumatic diseases [14]. Steiman et al. showed in SLE patients the predictive value of disease activity by demonstrating that clinically active lupus patients are at higher CV risk than serologically active clinically quiescent patients. After a 10-year follow-up, 7.3 % of clinically active patients developed new coronary events comparing to 1.8 % of those with clinically quiescent disease [15]. Likewise, in RA patients, systemic inflammation and CV risk factors predict greater IMT progression rate [16]. High levels of inflammatory cytokines generate a spectrum of pro-atherogenic changes that fosters atherosclerosis development and progression. A direct effect on the vasculature can be observed throughout the whole process, that is, from early endothelial dysfunction to plaque rupture and the occurrence of a thrombotic event (Fig. 6.1). Not only endothelial function and repair are negatively affected by increased circulating levels of pro-inflammatory cytokines such as tumour necrosis factor (TNF), interleukin (IL)-Iβ or IL-6 but also high levels of inflammation are associated with plaque instability and rupture.

In addition, systemic inflammation affects several other pathways through which may contribute to accelerated atherogenesis:

The association between inflammatory biomarkers and the risk for future CV events has been recognized in several clinical and epidemiological observations. While high levels of C-reactive protein (CRP) are present in major inflammatory situations, high-sensitivity (hs) CRP elevation coexists with states of low-grade inflammation such as atherosclerosis. CRP has been associated with a number of CV risk factors like obesity, smoking, heart rate, high blood pressure, high serum fibrinogen, hypercholesterolaemia, hypertriglyceridaemia, apolipoprotein B or increased fasting blood glucose. In the general population, hsCRP is an independent predictor of future vascular events at any level of LDL cholesterol and, in association with LDL cholesterol levels, it improves the individual estimation of CV risk.

Nonetheless, in patients with rheumatic diseases, where highly increased CRP is a characteristic, the relationship of this inflammatory biomarker to subsequent clinical events has not been consistently established.

Endothelial cells (EC) are crucial in maintaining blood fluidity and in regulating vascular tonus and permeability. Under normal conditions, EC express molecules that prevent platelet aggregation and clot formation. Inflammatory cytokines modify endothelial homeostasis that results in increased expression of adhesion molecules, loss of antithrombotic properties, increased permeability and reduced ability to produce NO in response to several stimuli. Intercellular adhesion molecules and chemokines mediate leukocyte adhesion to endothelial cells or extracellular matrix, endothelial transmigration and leukocyte activation. Endothelial activation and dysfunction are chief phenomena in early atherogenesis and precedes structural vascular changes. Endothelial dysfunction is potentially reversible with the control of the underlying inflammatory condition.

Along with non-invasive endothelial function testing (e.g. endothelium-dependent flow-mediated dilation, peripheral artery tonometry, pulse wave velocity measurement), circulating biomarkers of endothelial activation have been studied in systemic rheumatic diseases. Increased levels of E-selectin, sICAM-1, VCAM, thrombomodulin (TM) and tissue factor (TF) were identified in relation to disease activity [17].

Another surrogate marker of EC function is the number of circulating endothelial progenitor cells (EPC) and endothelial microparticles. EPC are a heterogeneous cell population derived from the bone marrow involved in angiogenesis and repair of endothelium. Variations in the level of circulating and mature EPC or EPC impaired function have been documented in active RA, SLE and pSS, suggesting compromised endothelial repair [18, 19].

The progression of atherosclerosis and local thrombosis is closely linked phenomena that may culminate in a thrombotic occlusion of the vascular lumen and consequent acute CV event. Alterations of haemostatic and haemorheologic factors contribute to atherogenesis and are related to vascular ischemic events in the general population [20].

In immune-mediated inflammatory rheumatic diseases, both altered blood rheology and high levels of haemostatic biomarkers have been found in association with subclinical atherosclerosis [21]. Serum levels of haemostatic factors, namely, von Willebrand factor (vWF), plasminogen activator inhibitor (PAI)-1, thrombomodulin and tissue factor, are related to inflammatory status. Some of these markers (PAI-1 and vWF) were studied in RA patients and baseline values found to be independent predictors of future CV events.

Patients have reduced erythrocyte deformability and increased erythrocyte aggregation, which may contribute to impaired microcirculation and microvascular dysfunction. The interaction between inflammation and thrombogenesis is not entirely understood. Nevertheless, we and others found disturbed and unfavourable haemorheologic phenotype in association with active RA and active SLE, and this might represent an additional link between inflammation and atherogenesis [21].

The contribution of autoantibodies to atherogenesis remains unclear in the scope of rheumatic diseases, yet the current evidence suggests a relationship between some autoantibodies and subclinical atherosclerosis. Increased production of anti-endothelial cell antibodies, a putative marker of vascular damage, has been reported in SLE, RA, systemic vasculitis and other rheumatic diseases [22]. Oxidation is one of the major aspects involved in atheroma development, and high levels of antibodies against oxidized low-density lipoproteins (ox-LDL), a quantifiable marker of oxidative stress present over a certain time period, are found in a significant proportion of lupus patients [23], although their biological role is not well established.

Antiphospholipid antibodies, a family of autoantibodies directed against phospholipid-binding plasma proteins, are strongly associated with thrombosis and pregnancy morbidity. Anti-cardiolipin (aCl) and anti-β2 glycoprotein I antibodies are the most extensively studied, but other antiphospholipid (aPL) antibodies are implicated in CV events through thrombotic pathways. It has been hypothesized that non-thrombotic mechanisms might also relate aPL and CV events. A possible mechanism linking aPL and atherogenesis is their role in inducing oxidative stress. Moreover, anti-cardiolipin antibodies directly interfere with paraoxonase activity, a high-density lipoprotein-related antioxidant enzyme, adding to the oxidative stress found in these conditions [24]. In fact, some small studies found an association between aPL titres and features of subclinical atherosclerosis (increased IMT and CAC score). Furthermore, low levels of IgM anti-oxidized cardiolipin and anti-oxidized phosphatidylserine were found more frequently in lupus patients with carotid plaques compared to those without plaques [25]. More recently, the presence of aPL was shown to be predictive of CAC score > 0 at 15 and 20 years in the large Coronary Artery Risk Development in Young Adults (CARDIA) cohort [26].

Evidence shows that treatment of inflammation reduces CV burden related to systemic rheumatic diseases. The effective control of disease activity can revert early vascular changes measured by endothelium-dependent flow-mediated dilation (FMD), prevent progression of subclinical atherosclerosis and more importantly reduce incident CV events and CV death. Methotrexate is a disease-modifier antirheumatic drug (DMARD) broadly used for the treatment of chronic inflammatory rheumatic disorders. There is substantial documentation that its use not only controls arthritis and improves disease-specific outcomes but significantly reduces the risk of CV events and death in RA patients [27]. A recent meta-analysis reports a 21 % lower risk for fatal and nonfatal hard CV events in methotrexate users (RA, psoriasis and polyarthritis) after a median follow-up of 5.84 years (relative risk 0.79; 95 % CI 0.73–0.87), and risk reduction was even greater when analysis was adjusted for disease activity [28]. More recently, the introduction of biological therapies revolutionized the control of clinical manifestations and of structural damage progression in an important proportion of patients who failed synthetic DMARDs. Inhibition of TNF, available for the last 15 years, is associated with improvement of endothelial function [29], prevention of atherosclerosis progression [30] and reduction of risk for all cardiovascular events [31]. The impact of biologics with other mode of action remains largely unknown, although improvement of endothelial function was documented in the short term after IL-6 blockade.

Other antirheumatic medications may also have a beneficial effect on atherogenesis, but except for antimalarials, data is limited. The use of hydroxychloroquine is associated with reduced risk of subclinical atherosclerosis, CV events and overall mortality in lupus patients, but the mechanisms underlying this benefit remain largely undetermined.

The debate around the effect of corticosteroids in atherogenesis continues. If on the one hand corticosteroids have a potent anti-inflammatory effect, on the other hand, this group of drugs has a negative impact on CV risk factors, including weight gain, worsening insulin resistance, hypertension and hyperlipidaemia. Thus, the balance between risk and benefit depends on corticosteroid dosage and duration of treatment.