Introduction

Treatment strategies and outcome of inflammatory rheumatic diseases (IRD) have considerably changed since the application of tight control of the disease and advent of biologic therapies, which are always adjusted to specific therapeutic targets. Presently, patients with chronic IRD die more frequently because of infectious complications and certain comorbidities than because of the disease itself. Within the general comorbidity of IRD, cardiovascular (CV) disease (CVD) is the most relevant.

In this chapter, we will focus on the CV morbidity of the most prevalent IRD: rheumatoid arthritis (RA) and spondyloarthritis, particularly on ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Other diseases included in the group of spondyloarthritis, such as undifferentiated spondyloarthritis and nonradiographic axial spondyloarthritis, are not discussed in this review because of the lack of consistent data on the CV comorbidities in these entities.

The current knowledge on CVD in patients with IRD has been updated. Therefore, a PubMed search of the most relevant literature was performed, particularly studies published in English over the last 10 years.

Epidemiology of cardiovascular disease in inflammatory rheumatic diseases

Standardized mortality ratios (SMRs) in patients with IRD are higher than those in the general population (1.3–2.3 in RA, 1.6–1.9 in AS, and 0.8–1.6 in PsA, respectively). This increased and often premature mortality is mainly due to CV events . A recent cross-sectional study on individuals periodically followed-up at rheumatology outpatient clinics has shown that despite having low disease activity, the prevalence of CVD in patients with IRD remains elevated compared with individuals without IRD . Another recent population-based study has confirmed that CV mortality among patients with RA in the past 15 years was higher than that in the general population . In this regard, a meta-analysis showed that CV mortality in RA was 50% higher than that in the general population , with a 59% increase due to ischemic heart disease (IHD) and a 52% increase due to cerebrovascular accidents (CVA) . The risk of myocardial infarction (MI) and CVA was increased by 68% and 41%, respectively, in patients with RA compared to the general population . Moreover, the risk of MI in RA corresponds to the overall risk of MI observed in non-RA subjects who are on average 10 years older . Interestingly, this increased risk of CVD in RA is comparable to that observed in type 2 diabetes mellitus (DM) .

Importantly, the presentation of cardiac symptoms in RA is often different from that seen in the general population. It is not uncommon to see RA patients with unrecognized coronary symptoms that are misdiagnosed as mechanical or atypical chest pain that later develops into heart failure more frequently than the general population . This is the result of a process of accelerated atherogenesis that represents the common pathogenic link between CV comorbidity and IRD .

In addition to higher mortality ratios than the general population, AS and PsA patients also have an increased rate of CV mortality . Several studies have shown that IHD, CVA, and peripheral arterial disease (PAD) are more common in patients with AS or PsA than in the general population . Dutch investigators confirmed that the prevalence of MI was more in patients with AS than in the general population . With respect to this, a meta-analysis of seven longitudinal studies revealed a significant increase in MI [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.32–1.93] in AS patients compared to the general population . A significantly increased incidence of stroke was also found (OR 1.50, 95% CI 1.39–1.62) .

Estimation of the CV risk attributed to PsA is more difficult because of the potential CV burden that skin disease itself confers to patients with PsA . Indeed, patients with severe psoriasis have greater global and CV mortality than the general population with a SMR of 1.52 (95% CI 1.44–1.60) . In a population-based cohort study comparing patients with psoriasis, PsA, and RA, after adjustment for traditional CV risk factors (CVRFs), the number of major adverse CV events was more in PsA patients not receiving any disease-modifying antirheumatic drug (DMARD) [hazard ratio (HR) 1.24, 95% CI 1.03–1.49], patients with RA (non-DMARD users: HR 1.39, 95% CI 1.28–1.50; DMARD users: HR 1.58, 95% CI 1.46–1.70), patients with psoriasis not using DMARDs (HR 1.08, 95% CI 1.02–1.15), and patients with severe psoriasis using DMARDs (HR 1.42, 95% CI 1.17–1.73) .

A Danish nationwide cohort study reported a significantly increased overall mortality in patients with psoriasis [risk ratio (RR) 1.74, 95% CI 1.32–2.30], particularly arising from CVD (RR 1.84, 95% CI 1.11–3.06) . In addition, in a study conducted by Han et al., PsA patients showed greater CV morbidity than controls . It was applicable to all types of CV events, including PAD .

CV risk in PsA is comparable to that of DM or RA . In a cross-sectional study that compared PsA with RA in terms of nonfatal CVD, the prevalence of CV events was very similar in both conditions: 10% in PsA versus 12.4% in RA . Moreover, as observed in RA, the increased CV risk in PsA occurs from the onset of the disease. In a population-based cohort study involving a majority of newly diagnosed PsA patients, the CVD risk was higher than expected, and it was underestimated when the Framingham risk score (FRS) was applied .

Epidemiology of cardiovascular disease in inflammatory rheumatic diseases

Standardized mortality ratios (SMRs) in patients with IRD are higher than those in the general population (1.3–2.3 in RA, 1.6–1.9 in AS, and 0.8–1.6 in PsA, respectively). This increased and often premature mortality is mainly due to CV events . A recent cross-sectional study on individuals periodically followed-up at rheumatology outpatient clinics has shown that despite having low disease activity, the prevalence of CVD in patients with IRD remains elevated compared with individuals without IRD . Another recent population-based study has confirmed that CV mortality among patients with RA in the past 15 years was higher than that in the general population . In this regard, a meta-analysis showed that CV mortality in RA was 50% higher than that in the general population , with a 59% increase due to ischemic heart disease (IHD) and a 52% increase due to cerebrovascular accidents (CVA) . The risk of myocardial infarction (MI) and CVA was increased by 68% and 41%, respectively, in patients with RA compared to the general population . Moreover, the risk of MI in RA corresponds to the overall risk of MI observed in non-RA subjects who are on average 10 years older . Interestingly, this increased risk of CVD in RA is comparable to that observed in type 2 diabetes mellitus (DM) .

Importantly, the presentation of cardiac symptoms in RA is often different from that seen in the general population. It is not uncommon to see RA patients with unrecognized coronary symptoms that are misdiagnosed as mechanical or atypical chest pain that later develops into heart failure more frequently than the general population . This is the result of a process of accelerated atherogenesis that represents the common pathogenic link between CV comorbidity and IRD .

In addition to higher mortality ratios than the general population, AS and PsA patients also have an increased rate of CV mortality . Several studies have shown that IHD, CVA, and peripheral arterial disease (PAD) are more common in patients with AS or PsA than in the general population . Dutch investigators confirmed that the prevalence of MI was more in patients with AS than in the general population . With respect to this, a meta-analysis of seven longitudinal studies revealed a significant increase in MI [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.32–1.93] in AS patients compared to the general population . A significantly increased incidence of stroke was also found (OR 1.50, 95% CI 1.39–1.62) .

Estimation of the CV risk attributed to PsA is more difficult because of the potential CV burden that skin disease itself confers to patients with PsA . Indeed, patients with severe psoriasis have greater global and CV mortality than the general population with a SMR of 1.52 (95% CI 1.44–1.60) . In a population-based cohort study comparing patients with psoriasis, PsA, and RA, after adjustment for traditional CV risk factors (CVRFs), the number of major adverse CV events was more in PsA patients not receiving any disease-modifying antirheumatic drug (DMARD) [hazard ratio (HR) 1.24, 95% CI 1.03–1.49], patients with RA (non-DMARD users: HR 1.39, 95% CI 1.28–1.50; DMARD users: HR 1.58, 95% CI 1.46–1.70), patients with psoriasis not using DMARDs (HR 1.08, 95% CI 1.02–1.15), and patients with severe psoriasis using DMARDs (HR 1.42, 95% CI 1.17–1.73) .

A Danish nationwide cohort study reported a significantly increased overall mortality in patients with psoriasis [risk ratio (RR) 1.74, 95% CI 1.32–2.30], particularly arising from CVD (RR 1.84, 95% CI 1.11–3.06) . In addition, in a study conducted by Han et al., PsA patients showed greater CV morbidity than controls . It was applicable to all types of CV events, including PAD .

CV risk in PsA is comparable to that of DM or RA . In a cross-sectional study that compared PsA with RA in terms of nonfatal CVD, the prevalence of CV events was very similar in both conditions: 10% in PsA versus 12.4% in RA . Moreover, as observed in RA, the increased CV risk in PsA occurs from the onset of the disease. In a population-based cohort study involving a majority of newly diagnosed PsA patients, the CVD risk was higher than expected, and it was underestimated when the Framingham risk score (FRS) was applied .

Presence of subclinical atherosclerotic disease in patients with inflammatory rheumatic diseases

Several noninvasive methods are available to determine the presence of subclinical atherosclerosis in patients with IRD . Endothelial dysfunction (ED) is as an early step in the development of atherosclerosis. It can be defined by the presence of impaired ability of the artery to dilate in response to physical and chemical stimuli because of decreased release or increased breakdown of nitric oxide. This process can be noninvasively assessed by flow-mediated endothelium-dependent vasodilatation (FMD) using high-sensitivity brachial ultrasonography. ED was observed in both long-standing RA and young RA patients with low disease activity and without traditional CVRFs . It was also found in patients with AS and PsA patients without classic CVRF .

Persistent ED predisposes the vascular wall to structural damage. It can be detected as an increased carotid artery intima-media wall thickness (cIMT) by carotid ultrasound (US). A good correlation between the presence of ED assessed by FMD and an abnormally increased cIMT was observed in RA patients with long disease duration . In addition, abnormally high cIMT and carotid plaques determined by carotid US were found to be good predictors of CV events in patients with RA . A systematic literature search and meta-analysis confirmed cIMT differences between RA and controls . These findings were also supported by another more recent systematic review with meta-analysis of literature studies that included a total of 59 studies (4317 RA patients and 3606 controls). In this new meta-analysis, patients with RA exhibited higher cIMT (mean difference: 0.10 mm; 95% CI 0.07–0.12; p < 0.00001) and also an increased prevalence of carotid plaques (OR 3.61, 95% CI 2.65–4.93; p < 0.00001) compared with controls . Subanalysis of studies on early RA showed that the difference in cIMT between RA patients and controls was even higher (mean difference: 0.21 mm; 95% CI 0.06–0.35; p = 0.006). The meta-regression models showed that male gender and a more severe inflammatory status significantly affected the cIMT . This is in line with a former study that unveiled a correlation between the mean C-reactive protein (CRP) levels in long-standing RA patients and cIMT . Interestingly, an abnormally high incidence of carotid plaques by carotid US was found in patients with RA that had been categorized as having moderate CV risk when CV risk charts were applied . It has been proposed that RA patients with detectable circulating anti-cyclic-citrullinated peptide (CCP) antibodies may have thicker cIMT of the internal carotid artery wall than patients without evidence of these antibodies .

Similar to that observed in RA, patients with AS were also found to have abnormal carotid US findings, such as higher cIMT, that were associated with accelerated subclinical atherosclerosis and higher frequency of plaques than matched controls . Similarly, patients with PsA had higher cIMT than matched controls .

Abnormal results of other noninvasive surrogate markers of subclinical atherosclerotic disease, such as the pulse wave velocity and the aortic augmentation index, have also been reported in patients with chronic IRD .

Traditional cardiovascular risk factors

Traditional CVRFs, such as smoking, DM, obesity, hypertension, and dyslipidemia, are independently associated with subclinical atherosclerosis, CV events, and increased risk of CV mortality in patients with chronic IRD .

Smoking is known to be a risk factor for the development of RA, particularly in rheumatoid factor (RF) and anti-CCP-positive RA . A recent meta-analysis showed an increased prevalence of cigarette smoking in patients with RA (OR 1.56, 95% CI 1.34, 1.80) . Other studies also found a higher prevalence of current and past smokers among patients with RA that among controls .

Although the literature is not uniform, DM appears to be more common in RA patients than in controls . Insulin resistance (IR) and metabolic syndrome (MetS) were found to be increased in patients with PsA and RA , and the homeostatic model assessment (HOMA)-IR index is increased in RA subjects . Interestingly, some antirheumatic medications such as the antitumor necrosis factor (TNF)-α monoclonal antibody infliximab exert a positive effect on IR in patients with RA and AS with active disease . Similarly, the use of anti-interleukin (IL)-6 tocilizumab was also associated with a significant reduction in HOMA-IR in patients with RA . Conventional DMARDs, such as hydroxychloroquine and methotrexate (MTX), may also decrease the risk of DM in patients with RA.

Obesity itself contributes to a low-grade inflammation status as adipose tissue is a major producer of pro-inflammatory cytokines such as IL-6 and adiponectin . In the general population, a higher body mass index (BMI) is associated with elevated CRP levels and increased risk of CVD . In RA and particularly PsA, abnormal body fat composition is also associated with higher CRP levels and more severe disease . However, a low BMI was associated with increased mortality in RA because low BMI may be an indicator of uncontrolled active systemic inflammation and cachexia (“rheumatoid cachexia”) . Thus, a good control of weight (“normo weight status”) is the ideal situation for patients with RA.

Obesity and hyperuricemia are also more prevalent in PsA patients . With regard to these observations, a recent cross-sectional study on Spanish individuals with IRD showed that PsA patients had more classic CVRF and MetS features than those with RA and AS and controls .

Hypertension has frequently been found in patients with RA . However, it remains unclear whether it is more common than in the general population. Although some studies highlight that hypertension is an important risk factor for CVD in RA patients , a recent meta-analysis of 15 case-control studies found that the prevalence of hypertension in RA was the same as that in controls (OR 1.09, 95% CI 0.91–1.31) . However, hypertension is frequently underdiagnosed in young people with IRD or undertreated in elderly patients . In PsA, hypertension was found in 30% of patients . In a study, blood pressure remained significantly higher in PsA patients than in controls after adjustment for blood pressure-lowering agents .

Interestingly, the effect of traditional CVRFs on the vascular tree may be more deleterious in patients with IRD than the general population because these factors intensify the harmful impact that chronic inflammation induces on the arterial wall. In patients with chronic IRD, the levels of blood lipids behave differently when inflammation persists. The activity of the inflammatory process leads to a decrease in the levels of total cholesterol (Tchol) and its main fractions. HDL-cholesterol (HDL-chol) levels are disproportionately decreased during the activity phases compared with the Tchol levels. This situation leads to an increase in the Tchol/HDL-chol ratio known as “atherogenic index.” LDL-cholesterol levels also decrease because of inflammation. Thus, in contrast to the linear logarithmic association seen in individuals without inflammatory diseases, CVD risk in relation to Tchol and LDL-chol levels could be potentially represented by a U-shaped curve in patients with RA. This pattern explains the increased CV risk observed in patients with RA with active disease despite the reduced serum cholesterol levels compared to the general population . All these modifications, commonly named as “lipid paradox,” are possibly induced by the presence of chronic active inflammation .

Abnormality in the lipid profile can appear early in the course of disease, even before the diagnosis can be made. In a longitudinal population-based study that compared the lipid profiles of patients with RA with those of controls, there was a significant decline in the LDL and Tchol levels in patients with RA that was observed 5 years before disease diagnosis, whereas there were no changes in the control group. Five years after disease diagnosis, patients with RA showed similar levels of LDL and Tchol to those of the control group . Moreover, chronic inflammation leads to oxidative changes that alter the HDL structure and reduce apolipoprotein-AI in patients with active RA . The levels of paraoxonase-1, an antioxidant enzyme associated with HDL, are lower in patients with RA than in controls . Therefore, because of inflammation, there is an impairment of the normal anti-inflammatory, antioxidative, and cardioprotective functions of HDL-cholesterol, which turns out to be proinflammatory and deleterious for the arteries. Other qualitative abnormalities including small dense LDL molecules, which are considered even more atherogenic than LDL, are seen in patients with RA . Lipoprotein A [Lp(a)], which increases the CVD risk, was found increased in patients with RA.

Lipid abnormalities are also frequent in PsA with lower serum levels of HDL-cholesterol and higher serum levels of triglycerides . Dyslipidemia is more prominent in PsA patients with active disease, suggesting a link between the degree of inflammation and the lipid profile . Low Tchol levels have also been reported in AS . One study showed that in patients with AS and high CRP levels, HDL-cholesterol particles contain less apolipoprotein A1, the component responsible for the anti-inflammatory effects, and more proportion of serum amyloid A .

TNF-α blockers increase Tchol and HDL-cholesterol levels with little effect on LDL levels , leading to stabilized atherogenic profile (T-chol/HDL-cholesterol ratio). Changes in lipid profiles mainly occur in RA treatment responders, with minimal changes in nonresponders, suggesting that reduced inflammation, and not a specific treatment, mediates these changes. The humanized anti-IL6 receptor monoclonal antibody tocilizumab elevates LDL and Tchol levels . However, the actual impact of these changes on CVD risk is unclear. The Janus Kinase inhibitor tofacitinib also increases both LDL and HDL levels . The varied effects of the different biologic agents on blood lipids may reflect the influence of individual cytokines on lipid metabolism.

The effects of conventional DMARDs on lipid profiles in RA have been less deeply studied. Despite having an effect on the control of inflammation, MTX does not appear to alter lipid profiles, whereas hydroxychloroquine improves the atherogenic profile in patients with RA . Some statins such as atorvastatin and rosuvastatin have anti-inflammatory effects in IRD. In fact, they have been found to be useful in patients with IRD .

Risk factors related to the disease itself

Several studies on RA indicate that CV risk is increased from the early phases of the disease , and this increase continues throughout its evolution. CV mortality in established disease is known to increase in proportion to disease duration . RF and antinuclear antibodies are considered risk factors for MI, congestive heart failure (CHF), and PAD even in patients without RA . RF and anti-CCP-positive RA patients tend to have more severe joint damage, more extra-articular manifestations, and increased mortality. Goodson et al. reported that patients with RF-positive polyarthritis have a higher risk of death from CVD than RF-negative patients . Aging seems to increase the risk of CV events in the subgroup of seropositive patients with RA but not in the seronegative ones .

Inflammation is involved in the pathogenesis of atherosclerosis. Increased baseline CRP levels have been linked to an increased risk of death from CV causes . High CRP levels conferred risk of CVD even in RA patients in whom the disease was clinically quiescent. A baseline disease activity score 28 of ≥5.1, which indicates high disease activity, was shown to be a predictor of CV events in RA . As discussed before, CRP levels were found to correlate with thicker cIMT in a study involving 47 patients with RA without traditional CVRFs at the time of the carotid US assessment , and in another study, the annual mean CRP level was associated with the risk of CV events and CV mortality in long-standing RA patients .

Serum uric acid elevation, which is common in psoriasis, is also an independent risk factor for CV morbidity and mortality. A study in PsA patients disclosed an association between the levels of serum uric acid and cIMT values . Serum uric acid is also associated with hypertension and end organ damage in RA . A cross-sectional study showed an independent association of serum uric acid with CVD in RA patients .

Effect of nonsteroidal anti-inflammatory drugs and corticosteroids

Nonsteroidal anti-inflammatory drugs (NSAIDs, including coxibs) are commonly used in IRD. They have been associated with an increased risk of death of CV origin . Nevertheless, a longitudinal cohort study of 17,320 patients with RA followed up for an average of 5 years showed a modest increase in CV risk, which was smaller than the risk observed in the general population . A Cox regression analysis stratified by RA status disclosed that NSAID exposure was associated with a 22% risk increase in patients with RA compared with a 51% increase in non-RA patients . A possible explanation for this finding may be that in patients with IRD, the anti-inflammatory effect of NSAIDs may compensate for the potential increased CV risk associated with the use of these drugs. Moreover, these drugs, particularly in inflammatory arthritis patients, improve mobility that in turn may have favorable effects on the CV risk.

The effect of corticosteroids on the vascular system is also complex. Low doses and use for short period of time do not seem to be harmful and may have some beneficial effects on the vascular system by reducing inflammation and also improving patient mobility, whereas high doses, particularly maintained over long periods of time, seem to have a detrimental effect that favors the development of atherosclerosis and increasing the CV risk.

Multivariable models disclosed that the current use of corticosteroids was associated with a 68% more risk of MI in a study that included 298 cases with MI from a series of 8384 patients with RA. Separate multivariable models showed that current daily dose, cumulative duration of use, and total cumulative dose were all associated with a significant increased risk of MI . Nevertheless, in another study on 7051 RA patients that were followed up over a median of 6 years, the use of corticosteroids was not associated with an increase in the risk of CVA . A population-based cohort study showed that unlike RF-positive RA patients in whom high cumulative exposure to corticosteroids had a three-fold increased risk of CV events, RF-negative RA patients treated with corticosteroids did not show an increased risk of CV events, regardless of the dosage or total amount of corticosteroids administered .

There is a general agreement on the fact that both conventional synthetic DMARDs and biologic therapies aimed to reduce and control disease activity can attenuate atherosclerosis by reducing the systemic inflammatory burden . Adequate control of the underlying disease will allow the clinicians to reduce the consumption of NSAIDs and corticosteroids, which may help to reduce the occurrence of CV events.

Genetics and cardiovascular risk

A genetic component may influence the risk of CVD in patients with IRD. Most studies on this issue have been conducted using the candidate gene strategy in which a specific polymorphism or a set of genetic variants within certain loci have been genotyped. Such polymorphisms were selected according to their potential biological function or the location in a region previously reported to be associated with disease susceptibility or severity. Overall, the results of these studies indicate that the genetic involvement in the development of CVD in IRD is complex; it possibly is the result of gene–gene interactions modulated by environmental factors in which the specific role of a single gene is small .

The number of genes studied, particularly in RA, is truly extensive, and a thorough discussion of this topic is beyond the scope of this review. The human leukocyte antigen (HLA) region seems to confer the strongest risk for CVD in RA. It includes a group of genes located on chromosome 6 (6p21) that encode the most polymorphic human proteins, the class I and class II antigen-presenting molecules. HLA is also the main genetic factor implicated in inflammatory immune-mediated pathologies and associated with more diseases than any other region of the human genome . HLA–DRB1 shared epitope (SE) alleles are risk factors for disease susceptibility and the development of CVD in RA . Individuals with RA carrying two copies of the SE exhibit approximately two-fold increase in mortality due to CV events . This fact is even more pronounced in smokers and anti-CCP-positive patients. In this context, HLA–DRB1*0404 SE allele was strongly associated with ED , presence of carotid plaques , CV events, and CV mortality .

Other genetic polymorphisms belonging to genes implicated in the different inflammatory and metabolic pathways, located inside and outside the HLA region, such as the 308 variant (G > A, rs1800629) of the TNFA locus , the rs1801131 polymorphism (A > C; position + 1298) of the methylene tetrahydrofolate reductase (MTHFR) locus , a vitamin D receptor GAT haplotype , polymorphisms in the interferon regulatory factor (IRF) 5 that is a regulator of type I interferon induction , and the NFKB1-94ATTG ins/del polymorphism seem to be associated with increased risk of CVD in patients with RA. However, an association between polymorphisms that exert an influence on the elevated CRP serum levels in nonrheumatic Caucasians and the risk of CVD and subclinical atherosclerosis in RA was not found in a recent report .

Although there are some studies focused on the genetic influence over the CV risk in AS and PsA, the results found up to now are less conclusive.

A summary of the main genes presently known to be involved in the risk of subclinical atherosclerosis and CV disease in RA is given in Table 1 .

Inflammation and cardiovascular disease

A broad body of evidence indicates that inflammation is implicated in the pathogenesis of atherosclerosis and CVD in the general population . A great number of proinflammatory molecules such as CRP, fibrinogen, and diverse cytokines are involved in this process . Proinflammatory cytokines such as TNF, IL-6, and IL-1 play a key role in the development of atherosclerosis in patients with IRD. The levels of these molecules increased in patients with RA and other IRD, which in turn promotes ED and vessel structural damage . Several studies have confirmed the association between inflammation and the risk of CVD in these conditions .

Inflammation contributes to all stages of atherosclerosis, from plaque formation to instability and eventual plaque rupture . Atherosclerosis and RA share many common inflammatory pathways, and the mechanisms leading to synovial inflammation are comparable to those found in unstable atherosclerotic plaques . Acute-phase reactants have been found to be associated with subclinical atherosclerosis, which is expressed by an increased cIMT , and greater CV morbidity and mortality in patients with RA . Similarly, CRP level is an independent predictor of CV risk, particularly of MI, in the general population . Notably, higher IL-6 levels are also associated with increased mortality in patients with acute coronary syndromes and an increased risk of MI in healthy men .

As discussed before, chronic inflammation causes an alteration in the lipid profile of patients with IRD, with a decrease in the serum levels of Tchol and LDL and HDL fractions. There is a decrease in the levels of the three types of cholesterol (“paradoxical inversion”) in individuals with inflammatory conditions, with more pronounced decrease in the HDL levels, which increases the atherogenic index secondarily . Moreover, there are some conformational changes in HDL, which transform it into a proinflammatory and proatherogenic molecule, eliminating its beneficial antioxidative and antiatherogenic properties.

The mechanisms responsible for these changes are not well understood. It has been proposed that because of a high inflammatory burden, excessive production of acute-phase reactants may impair the trafficking of cholesterol in the liver or impede normal cholesterol production. Moreover, CRP mediates the uptake of LDL by macrophages, inducing LDL deposition and increasing LDL uptake by hepatocytes . Other possible mechanisms whereby high levels of systemic inflammation contribute to accelerated atherogenesis in IRD include the development of ED, the activation of the coagulation cascade, the induction of secondary dyslipidemia, an increased atheromatous plaque vulnerability, and an increased extent of coronary artery calcification .

ED has been linked to systemic inflammation and the development of early atherosclerosis. In a recent study, Sidibe et al. demonstrated that vascular endothelial (VE)-cadherin, an important endothelium-specific adhesion molecule for endothelium integrity, was lysed by the stimulation of endothelial cells with TNF-α . In a cohort of 63 patients with early RA, the circulating levels of the extracellular domain of VE-cadherin (VE-90) positively correlated with RA disease activity at baseline and after a 1-year follow-up, suggesting another potential mechanism through which active RA may induce endothelial damage and predispose to atherosclerosis .

Other disorders related to lipid and inflammation include those associated with Lp(a). Lp(a) is a proatherogenic lipoprotein that consists of an LDL-like particle and the specific apolipoprotein(a) [apo(a)]. Lp(a) can become oxidized and provoke an immune response similar to that of oxidized LDL. Apo(a) promotes thrombosis and inhibits fibrinolysis because of its homology with plasminogen . An increase in Lp(a) has been associated with inflammation, but the data are inconsistent . Lp(a) is an independent risk factor for CVD that may be disproportionally increased in RA .

A crucial aspect with major clinical relevance in patients with high inflammatory burden is the augmented risk of vulnerability and rupture of the atherosclerotic plaque. In a postmortem study, 48% of the plaques in the left anterior descending coronary artery of patients with RA were classified as unstable by histologic criteria compared with 22% in non-RA controls. Furthermore, medial and adventitial inflammation was more prominent in subjects with RA than in controls . In another recent study that assessed carotid plaque structure by carotid US in patients with active and inactive RA and non-RA controls, patients with active RA had gray-scale lower values, a characteristic ascribed to vulnerability and rupture of plaques and a cause of thrombosis . In addition, patients with RA with active disease had higher vulnerability to carotid plaques than those in clinical remission .

Similar to in RA, inflammation in spondyloarthritis plays a pivotal role in all phases of atheroma development, from plaque formation to thrombosis, thus intensifying the effects of conventional risk factors. Moreover, adipocytokine production plays a key role in the inflammation and development of atherosclerosis in spondyloarthritis, particularly in PsA . As previously discussed, an increase in the prevalence of MetS has been documented in patients with IRD, particularly those with PsA .

Taken together, inflammation has an important contribution to the development of CVD in patients with IRD. Using heart failure as a model, it has been calculated that classic CVRFs explain up to 80% of the risk of heart failure in non-RA subjects but only 40% of risk among RA patients, suggesting that mechanisms associated with inflammation are of major importance in these patients . Fig. 1 displays the complex interactions between inflammation and other factors associated with the increased risk of CVD in patients with IRD.

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