Semin Immunopathol DOI 10.1007/s00281-017-0632-2

REVIEW

Cardiovascular risk in patients with rheumatoid arthritis Kim Lauper 1 & Cem Gabay 1

Received: 24 March 2017 / Accepted: 10 April 2017 # Springer-Verlag Berlin Heidelberg 2017

Abstract Substantial epidemiologic data have shown an increased risk of cardiovascular (CV) disease in rheumatoid arthritis (RA) patients. Traditional CV risk factors may partly contribute to CV disease in RA; however, current evidence underlines the important role of inflammation in the pathogenesis of atherosclerosis and amplification of CV risk. Interplays between inflammation and lipid metabolism in the development of atherosclerosis have been established by recent scientific advances. Atherosclerosis is currently viewed as an inflammatory disease, and modifications of lipoproteins during inflammation accelerate atherogenesis. The role of inflammation in the increased CV risk in RA has been further demonstrated by the CV protective effect of methotrexate and TNF antagonists, particularly in patients responding to these treatments. The management of CV risk in RA should include the use of effective disease-modifying anti-rheumatic drugs to control disease activity and the treatment of traditional CV risk factors.

Keywords Atherosclerosis . Cardiovascular diseases . Inflammation . Lipoproteins . Rheumatoid arthritis . Risk factors

This article is a contribution to the special issue on Immunopathology of Rheumatoid Arthritis – Guest Editors: Cem Gabay and Paul Hasler * Cem Gabay [email protected] 1

Division of Rheumatology, University Hospitals of Geneva, 26 Avenue Beau-Séjour, 1206 Geneva, Switzerland

Introduction Since the 1950s, multiple studies have described an increased mortality and morbidity in patients with rheumatoid arthritis (RA) [1, 2]. The extent of this rise in mortality varies greatly between the reports, depending on the type of cohort and settings with a standardized mortality ratio estimated at 1.27 (95% confidence interval (CI) 1.13–1.41) in a community study [3] and at 2.26 (95% CI 2.16–2.36) in a tertiary care center [2]. RA patients are more predisposed to infections, lymphoproliferative disorders, lung cancer, respiratory disease, and cardiovascular (CV) events than the general population, and a large share of the increased mortality and morbidity of RA is attributable to CV events [2, 4–7].

Cardiovascular morbidity and mortality in RA A meta-analysis in 2008 comprising 111,758 patients with 22,927 CV events found a 50% increase in CV death in RA patients using standardized mortality ratio compared to the general population, with both an increased risk for ischemic heart disease and cerebrovascular accident [8]. However, the patient populations included in these studies were heterogeneous in terms of age, disease duration, settings of care (rheumatology outpatient clinics versus community centers), RA classification, study design, and quality. The quality of the studies included was assessed using a 10-point score determined by the source of study population (community-based, clinic-based, or undefined), the type of cohort (inception versus non-inception), the RA definition (American College of Rheumatology classification criteria for RA, other validated

Semin Immunopathol

criteria, other predefined but non-validated criteria), the ascertainment of CV death outcome (cause of death verified, cause of death not verified, not mentioned), extent of loss of followup, and matching by or adjustment for Framingham risk factors. Of note, the magnitude of the increased CV risk was lower in studies qualified as Bgood^ based on these criteria. In a more recent study of 119,209 women from the Nurses’ Health Study cohort without RA at inclusion and followed from 1976 to 2012, the hazard ratio for CV mortality in RA incident cases was 1.45 (95% CI 1.14–1.83). Most importantly, the increased CV risk appeared early in the course of RA, being high even in newly diagnosed patients [9, 10].

Contributor of CV disease in RA Traditional cardiovascular risk factors Traditional CV risk factors in the general population comprise cigarette smoking, diabetes, hypertension, dyslipidemia, sedentary lifestyle, obesity, and age [11]. Differences have been reported in the prevalence of hypertension, diabetes, smoking, sedentary lifestyle, and dyslipidemia between RA patients and the general population, with some studies suggesting an increase of these risk factors in RA, although the evidence is conflicting [12–16]. Hypertension Elevated CRP levels have been independently associated to hypertension in the general population. High levels may induce the development of high blood pressure by influencing the renin-angiotensin system via the upregulation of the expression of the angiotensin 1 receptor, reducing endothelial nitric oxide. These changes lead to an increased production of endothelin-1, leucocyte adherence, platelet activation, and elevated levels of plasminogen activator inhibitor 1 with subsequent fibrinolysis and atherothrombosis [17]. Conversely, high blood pressure might induce shear stress in the vasculature initiating the expression of adhesion molecules in the endothelium leading to an inflammatory cascade [17]. In any case, the prevalence of hypertension in RA patients is high but varies widely from 4 to 73% between the studies, which is explained by great variations in sample sizes, definition of hypertension, and study population [17]. It is still unclear if there is a greater prevalence of hypertension in the RA population than in the general population [17]. Insulin resistance and diabetes In the general population, elevated levels of interleukin (IL)-6 and CRP increase the risk of developing diabetes [18]. Tumor necrosis factor (TNF) production may induce insulin

resistance by decreasing the tyrosine kinase activity of the insulin receptor, thus hampering the uptake of glucose in the skeletal muscle [19]. In RA patients, insulin resistance correlates with the level of inflammation [20], and TNF antagonists improve insulin resistance in normal-weight patients [21]. Nevertheless, there are still controversies regarding the difference in the prevalence of diabetes between RA patients and the general population [13, 14]. Smoking Smoking is an environmental factor associated with an increased risk of developing RA [22]. Consistently, patients with RA seem to be more frequently smokers than individuals in the general population [13, 15]. However, in a study including only women, the prevalence of past smokers, but not of current smokers, was higher in RA than in the general population [14]. Smoking is also linked to a higher disease activity [23, 24], a poor response to TNF inhibitors [25, 26], rheumatoid factor and anti-citrullinated protein antibody (ACPA) positivity, and rheumatoid nodules [24], which are all associated with worse CV outcomes [27–31]. Hyperhomocysteinemia A high level of homocystein is a modest predictor of CV outcomes in the general population [32]. Individuals with polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, which is involved in folate metabolism and associated to higher homocystein levels, have a greater risk of CV disease [33]. However, folic acid administration does not reduce the risk of MACE in CV patients [34]. In RA patients, methotrexate (MTX) administration leads to an increase in plasma levels of homocystein, which is counterbalanced by supplementation of folic or folinic acid [35] as well as the antiinflammatory effect of MTX. Body weight Overweight and obesity are well-known risk factors of CV disease in the general population [36, 37], but in RA patients, low BMI has been associated with an increased CV mortality [38]. The body composition in RA patients seems to be different than in the general population, with lower muscle mass and higher percentage of fat (Brheumatoid cachexia^), particularly abdominal fat [39]. This central obesity is associated with CV disease in the general population [37] and CV risk factors in the RA population [39]. The mechanism is unclear, but the excessive production of cytokines like TNF, IL-6, and IL-1β in RA may trigger muscle wasting [40, 41] and increase the accumulation of visceral fat by stimulating the migration of mesenchymal cells in adipose tissue and adipocyte differentiation [39].

Semin Immunopathol

Non-steroidal anti-inflammatory drugs and corticosteroids Patients with RA are frequently treated with non-steroidal anti-inflammatory drugs (NSAIDS) and glucocorticoids. While these drugs are known to be associated with an increased CV risk in the general population, the link is not so clear in RA [42–44]. Particularly, glucocorticoids induce hypertension, perturbation of the lipid profile, and insulin resistance, but can also suppress inflammation, and studies are yet inconclusive [44]. Glucocorticoids may have a direct effect on endothelial cells through the glucocorticoid receptor α [44]. Interestingly, animal studies suggest a deleterious effect of glucocorticoids with endothelial dysfunction in non-inflammatory states and a protective effect on endothelial cells during inflammation [44]. In RA patients, confounding by indication makes the net clinical effect of glucocorticoids difficult to assess. However, after having adjusted for potential confounders and for the propensity to receive glucocorticoids, a cohort study of 779 RA patients showed a dose-dependent increased CV risk with the use of glucocorticoids, with a minimum threshold at 8 mg of prednisone per day [45]. The Blipid paradox^ RA patients do not seem to have more hyperlipidemia than individuals in the general population. In fact, low-density lipoproteins (LDLs), high-density lipoproteins (HDLs), and total cholesterol levels are reduced in patients with active disease, consistent with the findings in other inflammatory conditions such as sepsis and cancer [13, 46]. These reduced lipid levels in a condition paradoxically associated with an increased CV risk has been called the lipid paradox. The mechanism is unclear but probably involves a direct effect of cytokines, including IL-6 [47]. Indeed, the injection of IL-6 is associated with a reduction of serum levels of total cholesterol simultaneously with enhanced CRP levels [48]. Accordingly, the administration of the neutralizing anti-IL-6 receptor antibody, tocilizumab, and of the Janus kinase (JAK) inhibitors, tofacitinib and baricitinib, which also suppress IL-6 signaling, are associated with increased cholesterol levels [47, 49].

RA as a CV risk factor RA as an independent risk factor Whether or not traditional CV risk factors are increased in the RA population, they do not fully explain the elevated CV risk in RA patients. In the Nurse’s Health Study, despite the absence of difference in traditional CV risk factors between RA patients and the non-RA individuals, the adjusted relative risk

for myocardial infarction in RA patients was of 2.0 (CI 1.23– 3.29) [7]. In a longitudinal cohort study of 236 RA patients compared to 4635 community-dwelling persons, even after adjusting for cohort membership (RA cohort versus community cohort) and traditional CV risk factors (age, sex, diabetes mellitus, systolic blood pressure, body mass index, cigarette smoking, and hypercholesterolemia), the incidence rate ratio decreased merely from 3.96 (95% CI 1.86–8.43) to 3.17 (95% CI 1.33–6.36) compared to an adjustment for age and sex only [50]. An important limitation of this study were the different enrollment and follow-up procedures between the RA cohort and the comparison group, making it prone to differences in the measure of the outcome and to selection bias with unmeasured confounders altering the results. Nevertheless, in another study of 603 RA subjects compared to 603 age and sexmatched controls, the CV risk conferred by some of the traditional risk factors (male gender, smoking, personal history of CV disease) for the development of CV disease was significantly less in the RA than in the comparison cohort, while other risk factors (family cardiac history, hypertension, dyslipidemia, body mass index, or diabetes mellitus) demonstrated a similar influence in RA subjects compared to non-RA individuals [15]. Considering the fact that CV disease is more prevalent in the RA populations, these results suggest that RA itself may be a risk factor. CRP and CV risk Several lines of evidence indicate that inflammation plays an important role in the occurrence of CV events in RA [51]. The link between inflammation and CV events was first established in the general population, where modestly elevated CRP levels were found to be associated with an increased CV risk [52]. However, the results of a large study using a BMendelian randomization^ approach indicated that CRP is rather a marker than a direct contributor of CV disease. This study included four separate Danish cohorts comprising more than 40,000 participants and examined the association between CRP gene polymorphisms, CRP levels, and the risk for CV disease [53]. First, the investigators analyzed the relationship between CRP levels and the risk of CV events in one of the cohorts and reported an increased relative risk of ischemic heart disease of 2.2 (95% CI 1.6 to 2.9) and of ischemic cerebrovascular disease of 1.6 (95% CI 1.1 to 2.5) in individuals with serum CRP levels above 3 mg/L as compared to those with CRP levels below 1 mg/L. Second, they explored the association between CRP gene polymorphisms and serum CRP levels in another cohort and found a significant increase in CRP levels with four genotypes. Assuming a causal association between elevated CRP and CV disease, genetic polymorphisms associated with elevated CRP levels should confer an increased CV risk. However, there was no association between CV events and the different CRP genotypes including

Semin Immunopathol

analysis of both single and combined polymorphisms. These results do not support a direct role of CRP in the pathogenesis of CV events but rather that CRP elevation reflects low-grade vascular or systemic inflammation. In contrast, the same study showed that apolipoprotein E (ApoE) polymorphisms were associated with elevated cholesterol levels and an increased risk of CV events [53].

Atherosclerosis and inflammation It was previously believed that atherosclerosis was mostly due to the passive accumulation of lipids in arterial walls, but current evidence suggests that inflammation is likely to play an important role [54–57]. In the early stage, the endothelium is activated and increases the expression of adhesion molecules, chemokines, and cytokines [58]. The development of atherosclerotic plaques occurs when inflammatory cells, in particular monocytes and T lymphocytes, migrate, adhere, and infiltrate the arterial wall. These infiltrating immune cells perpetuate the inflammatory process by the secretion of chemokines and cytokines that further promote the proliferation of smooth muscle cells and the uptake of LDL by macrophages forming foam cells, leading to a thicker plaque and the formation of a necrotic core (Fig. 1) [54–57]. Interactions between T cells and macrophages inhibit the synthesis of collagen and increase its degradation with subsequent thinning of the plaque fibrous cap, leading to a heightened risk of plaque rupture and arterial thrombosis by exposure of thrombogenic material to the blood flow [59].

Endothelial activation Preceding the clinically detectable plaque, atherosclerosis begins with the activation of the endothelium [58]. Normally, endothelial cells are relatively inert and do not bind leucocytes. Under the influence of most of the traditional CV risk factors, the endothelial cells shift their relative production of the vasodilatator nitric oxide (NO), generated by the endothelial NO synthase enzyme (eNOS) from L-citrulline and L-arginine, to the production of vasoconstricting factors such as endothelin-1 [58, 60]. NO has other vascular protective effect such as the inhibition of platelet aggregation, proliferation of vascular smooth muscle cells, and leucocyte adhesion [58, 60]. On the other hand, angiotensin-II can upregulate the production of the proinflammatory IL-6, chemokines such as monocyte chemoattractant-1 (MCP-1), and the vascular cell adhesion molecule-1 (VCAM-1) [54]. These processes lead to an imbalance between vasodilating and vasoconstricting factors and a proinflammatory state.

Infiltration of inflammatory cells The production of MCP-1 attracts monocytes, and the expression of VCAM-1 allows the binding of monocytes and T lymphocytes on endothelial cells [54]. Monocytes migrate through the endothelium, differentiating into macrophages. They increase their expression of receptors for modified lipoproteins such as the scavenger receptors and eventually form foam cells by taking up LDL, forming the Bfatty streak^ [57]. In addition, macrophages secrete growth factors and proinflammatory cytokines, intensifying the inflammatory response and the recruitment of inflammatory cells [57]. T cells enter the arterial wall as well and become activated by antigens such as oxidized LDL, producing cytokines that notably induce the production of matrix metalloproteinases, tissue factors, and inflammatory mediators by macrophages [57].

Progression of the atheroma Over the years, the lipid-rich core expands and the fibrous cap thins, eroded by the matrix metalloproteinases [59]. Cytokines such as interferon (IFN)-γ hinder collagen production [59]. The fibrous cap becomes vulnerable and subjected to rupture, the core necrosis with macrophage apoptosis. Eventually, the fatty streak progresses into an advanced plaque during abrupt outbursts interspersed by stagnant phases, first in an centripetal manner and afterward in direction of the lumen [57]. These rapid episodes of growth follow bouts of plaque rupture where tissue factor enters in contact with blood flow, initiating the coagulation cascade and platelet activation. Myocardial infarction occurs if the occlusion of coronary artery from the thrombus is complete; otherwise, a repair process begins with proliferation of smooth muscle cells and production of collagen, expanding the atheroma [57].

RA and atherosclerosis RA and atherosclerosis share similar physiopathological processes. Under the influence of environmental factors, like smoking, predisposed individuals develop an immune dysregulation where the endothelium allows the migration of inflammatory cells in the synovium, predominantly macrophages and T cells [51]. Matrix metalloproteinases and proinflammatory cytokines such as TNF and IL-6 are produced [51]. Atherosclerosis occurs early in the course of RA [64]. It is hypothesized that chronic inflammation, in particular the involvement of TNF and IL-6, accelerates the progression of atherosclerosis [65] (Fig. 1). Furthermore, arterial plaques in RA patients seem to be less stable than in non-RA individuals and even more vulnerable when the disease activity is high [51].

Semin Immunopathol Fig. 1 Pathogenic mechanisms of atherosclerosis in RA. Interactions between environmental and genetic factors may predispose to both rheumatoid arthritis and atherosclerosis. Cytokines are released from inflamed synovial tissue and regulate production of CRP and modification of lipoproteins and body fat composition. The combination of these factors may concur to the activation of the endothelium and the progression of atherosclerosis

Neutrophil extracellular traps Polymorphonuclear neutrophil granulocytes can attack microorganisms via phagocytosis, production of cytoplasmic lytic granules, or by releasing nuclear chromatin and proteins in the form of a reticulated extracellular matrix called neutrophil extracellular traps (NETs) [61]. During this process, the ensuing cellular death is termed NETosis. Neutrophil extracellular traps in RA NETs have been implicated in the pathogenesis of RA [61]. First, the formation of NETs depends on the deimination of histone by the enzyme protein arginine deiminase 4 (PAD4). About 75% of RA patients present anti-citrullinated protein/ peptide antibodies (ACPA) which target deiminated proteins. The exposition of autoantigens during NETosis may lead to the formation of ACPA [61]. Second, neutrophils in the peripheral blood and in the synovial fluid of RA patients display an enhanced capacity to form NETs compared to controls, and it may correlate to serum levels of CRP, ACPA, IL-17, and erythrocyte sedimentation rate [62]. IL-17-A and TNF-alpha can induce NETosis in RA neutrophils [62]. Consecutively, NETs can activate RA fibroblast-like synoviocytes to secrete

proinflammatory cytokines like IL-6 and IL-8, chemokines, and adhesion molecules [62]. Neutrophil extracellular traps in atherosclerosis NETs are detected in atherosclerotic lesions and arterial thrombi, and the inhibition of PAD4 (crucial for the formation of NETs) by chloramidin treatment prevents the development of NETs and retards atherothrombosis in a mouse model of atherosclerosis suggesting a role of NETs in atherosclerosis [63]. Indeed, NETs can activate endothelial cells, leucocytes, and platelets inducing endothelial dysfunction and the production of matrix metalloproteinases, TNF-alpha, and IL-12, leading to plaque destabilization and rupture [63]. Thus, NETs are implicated in the pathogenesis of RA and atherosclerosis and may contribute to the heightened CV risk in RA.

Lipids, lipoproteins, and RA Perturbations of the lipid profile have long been known to contribute to CV disease. Low levels of HDL and high levels of LDL cholesterol are associated with an increased CV risk in the general population [66]. The metabolism of lipids and

Semin Immunopathol

lipoproteins is complex, and several pathways can be affected by inflammation and RA (Fig. 1) [47, 67]. High-density lipoproteins HDL is a particle composed principally of a shell of apolipoprotein A-I (ApoA-I) and molecules of phosphatidylcholine, with a core of both esterified and unesterified cholesterols [68]. The composition may be very heterogeneous regarding the contents of the principal constituents (ApoA-I, phosphatidylcholine, cholesterol, and sphingomyelin) with great variations of the size of the particles [69]. HDL particles may also contain more than 50 other different proteins and lipids involved in lipid transport, metabolism, oxidation, innate immune response, and cell regulation [70]. The principal mechanism by which HDL may exert its cardioprotective effect is by removing cholesterol from peripheral cells, particularly foam cells, which has been termed the Breverse cholesterol transport^ [71]. The precursor of HDL, pre-β1-HDL, is constituted of poorly lipidated or lipid-free ApoA-I secreted by hepatocytes and intestinal epithelium or derived from chylomicrons, very low-density proteins, or mature HDL particles [70]. ApoA-I in pre-β1-HDL binds to ATP-binding cassette transporter A1 (ABCA1) on macrophage cells and facilitates cholesterol efflux into the particle, forming the pre-β-HDL or very small HDL [71]. Cholesterol in the particle is then esterified by the enzyme lecithine-cholesterol acyltransferase (LCAT), preventing the passive reflux in the peripheral cells and forming the mature HDL [70]. By direct delivery from the HDL particles or by an indirect route through the transfer to LDL particles, cholesterol is brought to the liver and then excreted by the biliary tract into the intestine [70]. Scavenger receptor class B member 1 (SR-BI) mediates the selective uptake of cholesteryl esters from HDL into the liver [67, 70]. HDL might also act directly on the endothelial cells by stimulating NO release, increasing the expression of endothelial nitric oxide synthase (eNOS), and repressing the expression of adhesion molecules, reducing the adhesion of leucocytes [70]. HDL can also lessen tissue factor expression in endothelial cells exposed to cytokines and diminish platelet activation exerting anti-thrombotic effect, boost endothelial repair after vascular damage, and reduce endothelial cell apoptosis [70]. Triglycerides, VLDL, and LDL After ingestion, dietary lipids enter enterocytes of the small intestine from which they are secreted into the portal system as chylomicrons, a type of lipoprotein formed by the combination of triglycerides, phospholipids, cholesterol, and apolipoprotein B 48 [72]. After hydrolyzation of the triglyceride core by lipoprotein lipase and cofactor apolipoprotein C-2 into free fatty acids and glycerol, the chylomicron

remnants are taken up by hepatocytes expressing the LDLlike receptor protein. The liver then releases into the blood very-low-density lipoproteins that are rich in triglycerides and contain cholesterol, phospholipids, cholesteryl esters, and a single molecule of apoliprotein B-100 (ApoB-100). The triglycerides are hydrolyzed by a surface lipoprotein lipase on endothelial cells, releasing free fatty acids, which are taken up by adipocytes and muscle cells [72–74]. With this successive hydrolysis, the very-low- density lipoproteins (VLDLs) transform to intermediate- density lipoproteins (IDLs) then LDL [73]. Cellular uptake of LDL depends on the cholesterol content of macrophages [75]. When LDL is oxidized by free radicals produced by macrophages, endothelial cells, and smooth muscle cells, the particle is no longer recognized by the LDL receptor on macrophages, but rather by scavenger receptors [76]. The binding of the oxidized LDL to scavenger receptors leads to cellular uptake independent from the cell cholesterol concentration and transforms the macrophages into foam cells, constituting the fatty streak [75]. Oxidized LDL further promotes atherosclerosis by inducing the expression of adhesion molecules, chemoattractants, and growth factors from endothelial cells and smooth muscle cells and the secretion of proinflammatory cytokines by macrophages [77].

Transfer of lipids between particles Interconversion of lipoproteins occurs between the different particles. Cholesteryl ester transfer protein (CETP) exchanges triglycerides of VLDL or LDL for cholesteryl esters of HDL. Phospholipid transfer protein (PLTP) catalyzes reactions leading to the transfer of phospholipids from ApoB-containing lipoproteins to HDL [70, 71].

Other lipid-associated proteins Lipoprotein(a) (Lp(a)) is composed of an LDL particle, and apolipoprotein(a) [47, 67, 78]. Lp(a) has a thrombogenic effect, inhibiting tissue plasminogen activator, enhancing the expression of plasminogen activator inhibitor 1, and competing with plasminogen’s binding on plasminogen receptor, fibrinogen, and fibrin [78]. Several genetic and Mendelian randomization studies have shown an association with CV disease, and elevated plasma concentration of Lp(a) may cause early atherosclerosis [47, 67, 78, 79]. Phospholipase A2 (sPLA2) hydrolyzes phospholipids to lysophospholipids and fatty acids [80]. Increased plasma levels and increased sPLA2 activity is associated with an increased risk of CVevents [79, 80]. Serum amyloid A (SAA) is an acute-phase reactant associated primarily to HDL and a biomarker of an increased CV risk [79, 81].

Semin Immunopathol

Paraoxonase-I Paraoxonase I (PON-1) is an enzyme located in a subfraction of HDL [82]. Several lines of evidence suggest a cardioprotective effect of this enzyme. Overexpression of PON-1 in a mouse model inhibits atherosclerosis [83]. Genetic polymorphisms associated with reduced enzymatic activity are linked to an increase in CV events in humans [84]. PON-1 might exert its cardioprotective effect through multiple pathways. PON-1 in HDL protects low-density lipoprotein from oxidation by hydrolyzation of specific oxidized lipids [85]. PON-1 may limit the biosynthesis of cholesterol within macrophages and promote the efflux of cholesterol into HDL particles [86]. Modifications in lipoproteins during inflammation During the acute-phase response, cytokines like IL-6, TNF, and IL-1 lead to a systemic reaction with production of acute-phase proteins, particularly CRP [67]. In cancer patients, injections of TNF, IL-2, and IFN-γ led to an increase in TG and VLDL with a decrease in HDL levels [87–90], and the injection of IL-6 is associated with a reduction of serum levels of total cholesterol [48]. A similar lipid profile follows the administration of IL-6 in mice [67]. The increase of VLDL and TG may be secondary to an increase in VLDL production and/or a decrease in VLDL clearance. Many cytokines, including TNF, IL-1, IL-6, and IFN-α, can induce the hepatic synthesis of fatty acids, triglycerides, and ApoB, leading to an increased production of VLDL [67]. It is less clear if the VLDL clearance is diminished, although proinflammatory cytokines can decrease the expression of ApoE, which is required for the elimination of lipoproteins rich in triglycerides, and lipoprotein lipase [67]. During inflammation and infection, multiple proteins involved in the reverse cholesterol pathway are altered, decreasing the cholesterol efflux as HDL [67]. A decrease in LCAT activity can also impair the esterification of pre-β-HDL in mature HDL, and a diminution in CETP and PLTP activities reduces the exchange of phospholipids between in HDL and ApoB-containing lipoproteins, reducing HDL particles [67]. The acute-phase response can convert HDL into a proinflammatory form, stimulating the oxidization of LDL and the production of chemotactic factors by monocytes [81]. Proinflammatory HDL contains more SAA and less ApoA-I [67]. The level of proinflammatory HDL is increased in patients with CV events compared to controls [91]. sPLA2 is markedly increased during infection and inflammation, while an increase in Lp(a) has not been clearly demonstrated in these settings [67].

inflammatory process, an increase in TG and VLDL and a decrease in HDL are seen during active disease [47]. Changes in lipid profiles may even appear before RA symptoms [47]. Several modifications of HDL are also present in RA patients. PON-1 activity is decreased in RA compared to the general population [93], and RA patients with PON-1 genotypes associated with a decreased enzymatic activity are at increased risk of atherosclerosis [94]. As a result of elevated disease activity and higher systemic inflammation, RA patients also present altered levels of HDL with proinflammatory properties [95]. Elevated levels of Lp(a) have been demonstrated in RA patients [47, 79]. Reduction of inflammation in RA as demonstrated by a decrease in CRP is associated with increased LDL and improvement in the HDL cholesterol efflux capacity [96]. Effects of RA drugs on lipoproteins Disease-modifying anti-rheumatic drugs (DMARDs) do not have the same effects on cholesterol levels in RA patients, suggesting that they may act on different pathways to influence the metabolism of lipoproteins (Table 1). Under sulphasalazine, methotrexate, and prednisolone, there is an increase in total cholesterol (TC) and HDL, particularly in responders [97]. Higher levels of LDL were inconsistently shown with methotrexate in monotherapy or in combination and with other conventional synthetic DMARDs [47, 98]. Treatment with hydroxychloroquine is associated with lower TC, LDL, and triglycerides (TG) and higher HDL [47, 99]. There is an increase of HDL, TC, LDL, ApoB, and paraoxonase-1 and a decrease in Lp(a) with TNF inhibitors [47, 79]. In spondyloarthritis patients, etanercept lowers HDL-SAA [47]. Elevated HDL, LDL, TG, and TC have been reported with tocilizumab (TCZ), a monoclonal anti-IL-6R antibody [47, 79]. TCZ increases HDL and LDL and decreases HDL-SAA, secretory type II A phospholipase A2 (sPLA2-IIA), and Lp(a) more than adalimumab, a TNF inhibitor [79]. The JAK inhibitor tofacitinib increases HDL and LDL more than adalimumab [47]. The JAK inhibitor baricitinib increases HDL, LDL, ApoA-I, ApoB, and ApoCIII and reduces HDL-SAA and Lp(a) [49]. In a single study of five RA patients, rituximab increased HDL and decreased TC [49].

Autoimmunity and genetic predisposition Anti-citrullinated peptide antibodies and rheumatoid factors

Lipoproteins in RA In RA, cytokines of the acute-phase response such as IL-6, IL-1, and TNF are produced [92]. Similar to other

Prospective cohorts of clinically verified RA found that the presence of anti-citrullinated peptide antibodies (ACPA) and rheumatoid factors (RFs) was an independent predictor of CV

Semin Immunopathol Table 1 Effects of DMARDs on lipoproteins

Methotrexate

↑ HDL, ↑ LDL?, ↑ TC

Hydroxychloroquine TNF inhibitors

↓ TC, ↓ LDL, ↓ TG, and ↑ HDL ↑ HDL, ↑ TC, ↑ Apo-B, ↑ paraoxonase-1, ↓ Lp(a), ↓ HDL-SAA

TCZ

↑ HDL, ↑ LDL, ↑ TG, ↑ TC, ↓ HDL-SAA, ↓ sPLA2-IIA, and ↓ Lp(a)

Tofacitinib Baricitinib

↑ HDL, ↑ LDL ↑ HDL, ↑ LDL, ↑ ApoA-I, ApoB, ApoCIII, ↓ Lp(a), ↓ HDL-SAA

Rituximab

↑ HDL?, ↓ TC?

DMARDs disease-modifying antirheumatic drugs, HDL high-density lipoprotein, LDL low-density lipoprotein, TC total cholesterol, apo-B apolipoprotein B, Lp(a) lipoprotein(a), HDL-SAA HDL serum amyloid A, sPLA2-IIA secretory type II A phospholipase A2, ApoA-I apolipoprotein A-I, ApoB apolipoprotein B, ApoCIII apolipoprotein CIII

mortality [30, 31]. However, more recently, in a large cohort study of the Women’s Health Initiative of self-reported RA, there was no association between seropositivity and CV risk [100]. Nevertheless, none of these studies took into consideration the disease activity, seropositive RA being knowingly associated with a more severe disease course [101].

Anti-apolipoprotein A1 antibodies Anti-apolipoprotein A-1 antibody (anti-ApoA-1) IgG has been identified in a significant portion of patients after myocardial infarction and is an independent predictor of major CV events in the general population [102]. ApoA-1 is a negative acute-phase protein and the primary protein component of HDL cholesterol [68]. Anti-ApoA-1 IgG may destabilize the plaque by decreasing the plaque collagen and increasing the neutrophil and matrix metalloproteinase-9 content [103]. Elevated serum levels of anti-ApoA-1 IgG were found in systemic lupus erythematosus, another autoimmune disease associated with an increase CV risk [104]. In RA patients, antiApoA-1 IgG is an independent predictor of major CV events and is associated with higher circulating levels of IL-8, oxidized LDL, matrix metalloproteinase-9, and promatrix metalloproteinase-9 activity, which are all associated with an increased CV risk [105].

HLA-DRB1 Genetic and environmental factors contribute to the onset of RA [106]. The principal genes implicated in RA susceptibility are located in the HLA region. In particular, several of the major histocompatibility complex class II HLA-DRB1 alleles are associated with the development of RA. Notably, HLADRB1*04 correlates with extraarticular features and a more severe disease [106]. This allele may favor persisting inflammation and is associated with an increased risk of CV events and CV mortality in RA patients [106].

Clinical picture of CV events in RA The typical features of acute coronary syndrome (ACS) include acute chest, epigastric, neck, jaw, or arm pain with ECG changes and positive biomarkers [107]. The clinical picture is different in RA, with patients describing less frequently typical symptoms and suffering more frequently from collapse, sudden death, and silent ischemic attack than the general population [108, 109]. The outcome after a single ACS is poorer in RA patients, and it is not explained by the severity of the CV event alone [110].

Prediction of CV risk in RA Scores In the general population, models have been developed to estimate the CV risk to effectively detect medium-risk to high-risk patients and treat them accordingly (e.g., Framingham, SCORE) [111]. These algorithms are not adapted to RA patients and fail to identify a large part of high-risk patients [112–114]. Furthermore, traditional scores may not correctly estimate the risk in women, which constitute the majority of RA patients [115]. The European League Against Rheumatism (EULAR) 2010 recommendations suggested to multiply these scores by 1.5 in the presence of two of three risk factors, i.e., a disease present since at least 10 years, seropositivity, and extraarticular manifestations [116]. Unfortunately, this approach only reclassifies a minority of the patients correctly [117]. On the contrary, the QRESEARCH Cardiovascular Risk Algorithm (QRisk) II, a score that includes the presence of RA as a risk factor in the estimation, tends to overestimate the risk [114]. The 2015/ 2016 EULAR recommendations no longer require the presence of RA-specific criteria to apply the multiplication factor, but it is not currently known if the evaluation of CV risk in RA is substantially better with this approach [118].

Semin Immunopathol

Carotid intima-media thickness evaluation In the general population, the presence of carotid plaques and the thickness of the carotid intima-media measured noninvasively by ultrasound correlate with the incidence of CV events and are used to improve the classification of CV risk [119]. In RA patients, disease activity and disease duration are associated with the size and vulnerability of carotid plaques. Most importantly, the combination of traditional CV risk factors and inflammation as assessed by the erythrocyte sedimentation rate was shown to synergize with an increased progression of intima-media thickness [120–122]. As in the general population, carotid atherosclerosis can also predict a higher incidence of CV events and might help to better stratify CV risk, particularly in RA patients classified as moderate risk with the modified traditional scores [123, 124]. Albeit, the measurement of carotid intima-media thickness by ultrasound needs expertise and skills that are not always available. For this reason, carotid ultrasound is actually more a study tool than a clinical one, but it should be used when accessible, being the more precise way currently available to correctly assess the CV risk in RA patients [118].

interactions between inflammation and lipoproteins in the development of atherosclerosis and CV events. Several biological markers of inflammation and lipid metabolism associated with susceptibility to CV disease have been shown in RA patients. An optimal control of the disease activity and the management of traditional CV risks factors are consequently a pillar of CV prevention. Further studies are needed to better understand the pathogenesis of atherosclerosis in RA patients and the role of lipoproteins, how DMARDs act on lipid metabolism and atherosclerosis, and the clinical implication of these findings. Compliance with ethical standards Conflict of interest CG has received research grants from Roche, Pfizer, and AB2 Bio and fees as speaker or consultant from Roche, Pfizer, MSD, BMS, AbbVie, Novartis, Celgene, Sanofi, Regeneron, and AB2 Bio. KL has nothing to disclose.

References 1.

Management The EULAR recommendations for CV disease risk management insist that clinicians should be aware of the higher risk for CV events in patients with RA compared with the general population and that the rheumatologist should ensure that CV risk management is performed. Considering the important role of inflammation in CV risk, the control of disease activity is the mainstay of treatment [118]. DMARDs such as methotrexate or TNF inhibitors independently decrease the risk of CV morbidity and mortality in RA [125, 126], and patients with a good response to treatment have a short-term risk of acute coronary syndrome similar to the general population [28]. Remission or lower disease activity can also improve the physical activity with subsequent reduction of CV risk in RA patients [118]. As with the general population, advice regarding lifestyle and treatment of traditional CV risk factors should be a part of the treatment [118]. Unfortunately, like other patients with chronic diseases, RA patients still benefit less than optimally from the identification and management of CV risk factors, despite their elevated CV risk [127, 128].

Conclusion CV disease is an important contributor of morbidity and mortality in RA, affecting RA patients independently of traditional risk factors. Substantial evidence implicates numerous

Cobb S, Anderson F, Bauer W (1953) Length of life and cause of death in rheumatoid arthritis. N Engl J Med 249:553–556. doi:10. 1056/NEJM195310012491402 2. Wolfe F, Mitchell DM, Sibley JT et al (1994) The mortality of rheumatoid arthritis. Arthritis Rheum 37:481–494. doi:10.1002/ art.1780370408 3. Gabriel SE, Crowson CS, Kremers HM et al (2003) Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum 48:54–58. doi:10.1002/art.10705 4. Doran MF, Crowson CS, Pond GR et al (2002) Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 46:2287–2293. doi:10.1002/art.10524 5. Mellemkjaer L, Linet MS, Gridley G et al (1996) Rheumatoid arthritis and cancer risk. Eur J Cancer 32A:1753–1757. doi:10. 1016/0959-8049(96)00210-9 6. Bongartz T, Nannini C, Medina-Velasquez YF et al (2010) Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum 62:1583– 1591. doi:10.1002/art.27405 7. Solomon DH, Karlson EW, Rimm EB et al (2003) Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 107:1303–1307. doi:10.1161/01.CIR. 0000054612.26458.B2 8. Aviña-Zubieta JA, Choi HK, Sadatsafavi M et al (2008) Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 59: 1690–1697. doi:10.1002/art.24092 9. Kremers HM, Crowson CS, Therneau TM et al (2008) High tenyear risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: a population-based cohort study. Arthritis Rheum 58:2268–2274. doi:10.1002/art.23650 10. Holmqvist ME, Wedrén S, Jacobsson LTH et al (2009) No increased occurrence of ischemic heart disease prior to the onset of rheumatoid arthritis: results from two Swedish population-based rheumatoid arthritis cohorts. Arthritis Rheum 60:2861–2869. doi: 10.1002/art.24855

Semin Immunopathol 11. 12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

Wilson PW (1994) Established risk factors and coronary artery disease: the Framingham study. Am J Hypertens 7:7S–12S Panoulas VF, Douglas KMJ, Milionis HJ et al (2007) Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology (Oxford) 46:1477–1482. doi: 10.1093/rheumatology/kem169 Boyer J-F, Gourraud P-A, Cantagrel A et al (2011) Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis. Joint Bone Spine 78:179–183. doi:10.1016/j.jbspin.2010.07.016 Solomon DH, Curhan GC, Rimm EB et al (2004) Cardiovascular risk factors in women with and without rheumatoid arthritis. Arthritis Rheum 50:3444–3449. doi:10.1002/art.20636 Gonzalez A, Maradit Kremers H, Crowson CS et al (2008) Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients? Ann Rheum Dis 67:64–69. doi:10.1136/ard. 2006.059980 Metsios GS, Stavropoulos-Kalinoglou A, Panoulas VF et al (2009) Association of physical inactivity with increased cardiovascular risk in patients with rheumatoid arthritis. Eur J Cardiovasc Prev Rehabil 16:188–194. doi:10.1097/HJR. 0b013e3283271ceb Panoulas VF, Metsios GS, Pace AV et al (2008) Hypertension in rheumatoid arthritis. Rheumatology (Oxford) 47:1286–1298. doi: 10.1093/rheumatology/ken159 Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85– 97. doi:10.1038/nri2921 Gonzalez-Gay MA, Gonzalez-Juanatey C, Vazquez-Rodriguez TR et al (2010) Insulin resistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy. Ann N Y Acad Sci 1193:153– 159. doi:10.1111/j.1749-6632.2009.05287.x Giles JT, Danielides S, Szklo M et al (2015) Insulin resistance in rheumatoid arthritis: disease-related indicators and associations with the presence and progression of subclinical atherosclerosis. Arthritis Rheumatol (Hoboken, NJ) 67:626–636. doi:10.1002/art. 38986 Stavropoulos-Kalinoglou A, Metsios GS, Panoulas VF et al (2012) Anti-tumour necrosis factor alpha therapy improves insulin sensitivity in normal-weight but not in obese patients with rheumatoid arthritis. Arthritis Res Ther 14:R160. doi:10.1186/ar3900 Klareskog L, Stolt P, Lundberg K et al (2006) A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54:38–46. doi:10.1002/art. 21575 Papadopoulos NG, Alamanos Y, Voulgari PV et al (2005) Does cigarette smoking influence disease expression, activity and severity in early rheumatoid arthritis patients? Clin Exp Rheumatol 23(6):861–866 Saag KG, Cerhan JR, Kolluri S et al (1997) Cigarette smoking and rheumatoid arthritis severity. Ann Rheum Dis 56:463–469. doi:10. 1136/ard.56.8.463 Hyrich KL, Watson KD, Silman AJ et al (2006) Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 45:1558–1565. doi: 10.1093/rheumatology/kel149 Saevarsdottir S, Wedrén S, Seddighzadeh M et al (2011) Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the epidemiological investigation of rheumatoid arthritis and the Swedish Rheumatology Reg. Arthritis Rheum 63:26–36. doi:10.1002/art.27758 Kaushik P, Solomon DH, Greenberg JD et al (2015) Subcutaneous nodules are associated with cardiovascular events in patients with

28.

29.

30.

31.

32.

33.

34.

35.

36. 37.

38.

39.

40. 41.

42.

43.

44.

45.

rheumatoid arthritis: results from a large US registry. Clin Rheumatol 34:1697–1704. doi:10.1007/s10067-015-3032-9 Ljung L, Rantapää-Dahlqvist S, Jacobsson LTH, et al (2016) Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis. Ann Rheum Dis annrheumdis2015-208995. doi: 10.1136/annrheumdis-2015-208995 Solomon DH, Reed GW, Kremer JM et al (2015) Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol (Hoboken, NJ) 67:1449–1455. doi:10.1002/ art.39098 Goodson NJ, Wiles NJ, Lunt M et al (2002) Mortality in early inflammatory polyarthritis: cardiovascular mortality is increased in seropositive patients. Arthritis Rheum 46:2010–2019. doi:10. 1002/art.10419 López-Longo FJ, Oliver-Miñarro D, de la Torre I et al (2009) Association between anti-cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis. Arthritis Rheum 61:419–424. doi:10.1002/art.24390 Homocysteine Studies Collaboration (2002) Homocysteine and risk of ischemic heart disease and stroke. JAMA 288:2015. doi: 10.1001/jama.288.16.2015 Klerk M, Verhoef P, Clarke R et al (2002) MTHFR 677C–>T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288:2023–2031 Lonn E, Yusuf S, Arnold MJ et al (2006) Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354:1567–1577. doi:10.1056/NEJMoa060900 van Ede AE, Laan RFJM, Blom HJ et al (2002) Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford) 41:658–665. doi:10.1093/ rheumatology/41.6.658 Calle EE, Thun MJ, Petrelli JM et al (1999) Body-mass index and mortality in a prospective cohort. N Engl J Med 341:1097–1105 Després JP (2012) Body fat distribution and risk of cardiovascular disease: an update. Circulation 126:1301–1313. doi:10.1161/ CIRCULATIONAHA.111.067264 Kremers HM, Nicola PJ, Crowson CS et al (2004) Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis. Arthritis Rheum 50:3450–3457. doi:10.1002/art.20612 Giles JT, Allison M, Blumenthal RS et al (2010) Abdominal adiposity in rheumatoid arthritis: association with cardiometabolic risk factors and disease characteristics. Arthritis Rheum 62: 3173–3182. doi:10.1002/art.27629 Walsmith J, Roubenoff R (2002) Cachexia in rheumatoid arthritis. Int J Cardiol 85:89–99. doi:10.1016/S0167-5273(02)00237-1 Rajbhandary R, Khezri A, Panush RS (2011) Rheumatoid cachexia: what is it and why is it important? J Rheumatol 38:406–408. doi:10.3899/jrheum.101036 Souverein PC, Berard A, Van Staa TP et al (2004) Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart 90:859– 865. doi:10.1136/hrt.2003.020180 Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J et al (2013) Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: metaanalyses of individual participant data from randomised trials. Lancet 382:769–779. doi:10.1016/S0140-6736(13)60900-9 Verhoeven F, Prati C, Maguin-Gaté K et al (2016) Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis. Arthritis Res Ther 18:258. doi:10.1186/s13075016-1157-0 del Rincón I, Battafarano DF, Restrepo JF et al (2014) Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol (Hoboken, NJ) 66:264–272. doi:10.1002/art.38210

Semin Immunopathol 46.

Choy E, Sattar N (2009) Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis 68:460–469. doi:10.1136/ard.2008.101964 47. Robertson J, Peters MJ, McInnes IB, Sattar N (2013) Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat Rev Rheumatol 9:513–523. doi:10.1038/nrrheum. 2013.91 48. van Gameren MM, Willemse PH, Mulder NH et al (1994) Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. Blood 84:1434–1441 49. Kremer J, Genovese MC, Keystone E et al (2016) Effects of baricitinib on lipid, apolipoprotein, and lipoprotein particle profiles in a phase 2b study in patients with active rheumatoid arthritis. Arthritis Rheumatol (Hoboken, NJ) 11:300–308. doi:10.1002/ art.40036 50. del Rincón ID, Williams K, Stern MP et al (2001) High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 44: 2737–2745. doi:10.1002/1529-0131(200112)44:12<2737::AIDART460>3.0.CO;2-# 51. Skeoch S, Bruce IN (2015) Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol 11:1–11. doi: 10.1038/nrrheum.2015.40 52. Ridker PM, Buring JE, Shih J et al (1998) Prospective study of Creactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 98:731–733 53. Zacho J, Tybjaerg-Hansen A, Jensen JS et al (2008) Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 359:1897–1908. doi:10.1056/NEJMoa0707402 54. Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143. doi:10.1161/hc0902. 104353 55. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695. doi:10.1056/ NEJMra043430 56. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126. doi:10.1016/S1053-0770(99)90233-1 57. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868– 874. doi:10.1038/nature01323 58. Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115: 1285–1295. doi:10.1161/CIRCULATIONAHA.106.652859 59. Libby P (2013) Mechanisms of acute coronary syndromes and their implications for therapy pathogenesis of acute coronary syndromes. N Engl J Med 36821368:2004–2013. doi:10.1056/ NEJMra1216063 60. Davignon J, Ganz P (2004) Role of endothelial dysfunction in atherosclerosis. Circulation 109:III27–III32. doi:10.1161/01.CIR. 0000131515.03336.f8 61. Wright HL, Moots RJ, Edwards SW (2014) The multifactorial role of neutrophils in rheumatoid arthritis. Nat Publ Gr 10:593–601. doi:10.1038/nrrheum.2014.80 62. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A et al (2013) NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 5:178ra40. doi:10.1126/scitranslmed. 3005580 63. Döring Y, Soehnlein O, Weber C (2017) Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ Res 120:736– 743. doi:10.1161/CIRCRESAHA.116.309692 64. Hannawi S, Haluska B, Marwick TH, Thomas R (2007) Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Res Ther 9: R116. doi:10.1186/ar2323

65.

Rho YH, Chung CP, Oeser A et al (2009) Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis. Arthritis Rheum 61:1580–1585. doi:10.1002/art.25009 66. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and T of HBC in A (Adult TPI (2002) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–3421. doi:10.1115/1.802915.ch1 67. Khovidhunkit W, Kim M-S, Memon RA et al (2004) Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 45:1169– 1196. doi:10.1194/jlr.R300019-JLR200 68. Huang R, Silva RAGD, Jerome WG et al (2011) Apolipoprotein A-I structural organization in high-density lipoproteins isolated from human plasma. Nat Struct Mol Biol 18:416–422. doi:10. 1038/nsmb.2028 69. Rosenson RS, Brewer HB, Chapman MJ et al (2011) HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin Chem 57:392–410. doi:10.1373/clinchem.2010.155333 70. Lüscher TF, Landmesser U, Von Eckardstein A, Fogelman AM (2014) High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target. Circ Res 114:171– 182. doi:10.1161/CIRCRESAHA.114.300935 71. Rosenson RS, Brewer HB, Davidson WS et al (2012) Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 125:1905–1919. doi:10.1161/ CIRCULATIONAHA.111.066589 72. Kwiterovich PO (2000) The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: a current review. Am J Cardiol 86:5–10. doi:10.1016/S0002-9149(00) 01461-2 73. Esterbauer H, Gebicki J, Puhl H, Jürgens G (1992) The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med 13:341–390. doi:10.1016/08915849(92)90181-F 74. Segrest JP, Jones MK, De Loof H, Dashti N (2001) Structure of apolipoprotein B-100 in low density lipoproteins. J Lipid Res 42: 1346–1367 75. Berliner JA, Navab M, Fogelman AM et al (1995) Atherosclerosis: basic mechanisms. Circulation 91 76. Steinberg D (2009) The LDL modification hypothesis of atherogenesis: an update. J Lipid Res 50 Suppl:S376–S381. doi:10. 1194/jlr.R800087-JLR200 77. Bentzon JF, Otsuka F, Virmani R, Falk E (2014) Mechanisms of plaque formation and rupture. Circ Res 114:1852–1866. doi:10. 1161/CIRCRESAHA.114.302721 78. Kronenberg F, Kronenberg MF, Kiechl S et al (1999) Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation 100:1154– 1160. doi:10.1161/01.CIR.100.11.1154 79. Gabay C, McInnes IB, Kavanaugh A et al (2015) Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis. doi:10.1136/annrheumdis2015-207872 80. Mallat Z, Benessiano J, Simon T et al (2007) Circulating secretory phospholipase A2 activity and risk of incident coronary events in healthy men and women: the EPIC-NORFOLK study. Arterioscler Thromb Vasc Biol 27:1177–1183. doi:10.1161/ ATVBAHA.107.139352 81. Van Lenten BJ, Hama SY, Beer FC et al (1995) Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. J Clin Invest 96:2758–2767

Semin Immunopathol 82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

Durrington P, Mackness B, Mackness M (2001) Paraoxonase and atherosclerosis. Arter Thromb Vasc Biol 21:473–480. doi:10. 1161/01.ATV.21.4.473 Mackness B, Quarck R, Verreth W et al (2006) Human paraoxonase-1 overexpression inhibits atherosclerosis in a mouse model of metabolic syndrome. Arterioscler Thromb Vasc Biol 26: 1545–1550. doi:10.1161/01.ATV.0000222924.62641.aa Bhattacharyya T, Nicholls SJ, Topol EJ et al (2008) Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 299:1265–1276. doi:10.1001/jama.299.11.1265 Mackness MI, Arrol S, Durrington PN (1991) Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett 286:152–154 Aviram M, Rosenblat M (2004) Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. Free Radic Biol Med 37:1304–1316. doi:10. 1016/j.freeradbiomed.2004.06.030 Malmendier CL, Lontie JF, Sculier JP, Dubois DY (1988) Modifications of plasma lipids, lipoproteins and apolipoproteins in advanced cancer patients treated with recombinant interleukin2 and autologous lymphokine-activated killer cells. Atherosclerosis 73:173–180. doi:10.1016/0021-9150(88)90039-1 Kurzrock R, Rohde MF, Quesada JR et al (1986) Recombinant gamma interferon induces hypertriglyceridemia and inhibits postheparin lipase activity in cancer patients. J Exp Med 164:1093– 1101 Sherman ML, Spriggs DR, Arthur KA et al (1988) Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism. JClinOncol 6:344–350 Starnes HF, Warren RS, Jeevanandam M et al (1988) Tumor necrosis factor and the acute metabolic response to tissue injury in man. J Clin Invest 82:1321–1325. doi:10.1172/JCI113733 Ansell BJ, Navab M, Hama S et al (2003) Inflammatory/ antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 108:2751–2756. doi:10.1161/01.CIR. 0000103624.14436.4B McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219. doi:10.1056/ NEJMra1004965 Tanimoto N, Kumon Y, Suehiro T et al (2003) Serum paraoxonase activity decreases in rheumatoid arthritis. Life Sci 72:2877–2885. doi:10.1016/S0024-3205(03)00195-4 Charles-Schoeman C, Lee YY, Shahbazian A et al (2013) Association of paraoxonase 1 gene polymorphism and enzyme activity with carotid plaque in rheumatoid arthritis. Arthritis Rheum 65:2765–2772. doi:10.1002/art.38118 Charles-Schoeman C, Watanabe J, Lee YY et al (2009) Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis. Arthritis Rheum 60:2870–2879. doi:10.1002/art.24802 Liao KP, Playford MP, Frits M et al (2015) The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. JAmHeart Assoc 4:1–8. doi:10.1161/JAHA.114.001588 Boers M, Nurmohamed MT, Doelman CJA et al (2003) Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis 62:842–845. doi:10.1136/ard.62.9.842 Charles-Schoeman C, Gonzalez-Gay MA, Kaplan I et al (2016) Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist. Semin Arthritis Rheum 46:71–80. doi:10.1016/j.semarthrit.2016.03.004

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

Restrepo JF, del Rincon I, Molina E et al (2017) Use of hydroxychloroquine is associated with improved lipid profile in rheumatoid arthritis patients. J Clin Rheumatol. doi:10.1097/ RHU.0000000000000502 Mackey RH, Kuller LH, Deane KD et al (2015) Rheumatoid arthritis, anti-cyclic citrullinated peptide positivity, and cardiovascular disease risk in the Women’s Health Initiative. Arthritis Rheumatol 67:2311–2322. doi:10.1002/art.39198 Ajeganova S, Huizinga TWJ (2015) Seronegative and seropositive RA: alike but different? Nat Rev Rheumatol 11:8–9. doi:10. 1038/nrrheum.2014.194 Vuilleumier N, Rossier MF, Pagano S et al (2010) Antiapolipoprotein A-1 IgG as an independent cardiovascular prognostic marker affecting basal heart rate in myocardial infarction. Eur Heart J 31:815–823. doi:10.1093/eurheartj/ehq055 Montecucco F, Vuilleumier N, Pagano S et al (2011) Antiapolipoprotein A-1 auto-antibodies are active mediators of atherosclerotic plaque vulnerability. Eur Heart J 32:412–421. doi:10. 1093/eurheartj/ehq521 O’Neill SG, Giles I, Lambrianides A et al (2010) Antibodies to apolipoprotein A-I, high-density lipoprotein, and C-reactive protein are associated with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 62:845–854. doi:10.1002/ art.27286 Vuilleumier N, Bas S, Pagano S et al (2010) Anti-apolipoprotein A-1 IgG predicts major cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum 62:2640–2650. doi:10. 1002/art.27546 Gonzalez-Gay MA, Gonzalez-Juanatey C, Lopez-Diaz MJ et al (2007) HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis. Arthritis Rheum 57:125–132. doi: 10.1002/art.22482 Luepker RV, Apple FS, Christenson RH et al (2003) Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on epidemiology and prevention. Circulation 108:2543–2549. doi:10.1161/ 01.CIR.0000100560.46946.EA Douglas KMJ, Pace AV, Treharne GJ et al (2006) Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome. Ann Rheum Dis 65:348–353. doi:10.1136/ard.2005. 037978 Maradit-Kremers H, Crowson CS, Nicola PJ et al (2005) Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 52:402–411. doi:10.1002/art.20853 Mantel Ä, Holmqvist M, Jernberg T et al (2015) Rheumatoid arthritis is associated with a more severe presentation of acute coronary syndrome and worse short-term outcome. Eur Heart J 36:3413–3422. doi:10.1093/eurheartj/ehv461 Zhao D, Liu J, Xie W, Qi Y (2015) Cardiovascular risk assessment: a global perspective. Nat Rev Cardiol 12:301–311. doi:10. 1038/nrcardio.2015.28 Crowson CS, Matteson EL, Roger VL et al (2012) Usefulness of risk scores to estimate the risk of cardiovascular disease in patients with rheumatoid arthritis. Am J Cardiol 110:420–424. doi:10. 1016/j.amjcard.2012.03.044 Kawai VK, Chung CP, Solus JF et al (2015) Brief report: 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 Rheumatol 67:381–385. doi:10.1002/art.38944 Arts EE, Popa C, Den Broeder AA et al (2015) Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis. Ann Rheum Dis 74:668– 674. doi:10.1136/annrheumdis-2013-204024

Semin Immunopathol 115.

Mosca L, Benjamin EJ, Berra K et al (2011) Effectiveness-based guidelines for the prevention of cardiovascular disease in women2011 update: a guideline from the American Heart Association. Circulation 123:1243–1262. doi:10.1161/CIR.0b013e31820faaf8 116. Peters MJL, Symmons DPM, McCarey D et al (2010) EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 69:325–331. doi:10.1136/ ard.2009.113696 117. Gómez-Vaquero C, Corrales A, Zacarías A et al (2013) SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis. Arthritis Res Ther 15:R91. doi:10.1186/ar4271 118. Agca R, Heslinga SC, Rollefstad S, et al (2016) EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. 1–12. doi: 10.1136/annrheumdis2016-209775 119. Inaba Y, Chen JA, Bergmann SR et al (2011) Carotid intima-media thickness and cardiovascular events. N Engl J Med 365:1640– 1641. 1640-2. doi:10.1056/NEJMc1109714#SA1 120. del Rincón I, Polak JF, O’Leary DH et al (2015) Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann Rheum Dis 74:1118– 1123. doi:10.1136/annrheumdis-2013-205058 121. Semb AG, Rollefstad S, Provan SA et al (2013) Carotid plaque characteristics and disease activity in rheumatoid arthritis. J Rheumatol 40:359–368. doi:10.3899/jrheum.120621 122. González-Juanatey C, Llorca J, González-Gay MA (2011) Correlation between endothelial function and carotid

atherosclerosis in rheumatoid arthritis patients with longstanding disease. Arthritis Res Ther 13:R101. doi:10.1186/ar3382 123. Evans MR, Escalante A, Battafarano DF et al (2011) Carotid atherosclerosis predicts incident acute coronary syndromes in rheumatoid arthritis. Arthritis Rheum 63:1211–1220. doi:10.1002/art. 30265 124. Corrales A, Parra JA, González-Juanatey C et al (2013) Cardiovascular risk stratification in rheumatic diseases: carotid ultrasound is more sensitive than coronary artery calcification score to detect subclinical atherosclerosis in patients with rheumatoid arthritis. Ann Rheum Dis 72:1764–1770. doi:10.1136/ annrheumdis-2013-203688 125. Micha R, Imamura F, Wyler von Ballmoos M et al (2011) Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 108:1362–1370. doi:10. 1016/j.amjcard.2011.06.054 126. Low ASL, Symmons DPM, Lunt M et al (2017) Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis. Ann Rheum Dis. doi:10.1136/ annrheumdis-2016-209784 127. Desai SS, Myles JD, Kaplan MJ (2012) Suboptimal cardiovascular risk factor identification and management in patients with rheumatoid arthritis: a cohort analysis. Arthritis Res Ther 14:R270. doi:10.1186/ar4118 128. van den Oever IAM, Heslinga M, Griep EN, et al (2017) Cardiovascular risk management in rheumatoid arthritis patients still suboptimal: the Implementation of Cardiovascular Risk Management in Rheumatoid Arthritis project. Rheumatology 1– 7. doi:10.1093/rheumatology/kew497