An update on the relationships between rheumatoid arthritis and atherosclerosis

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Contents lists available atScienceDirect

Atherosclerosis

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / a t h e r o s c l e r o s i s

Review

An update on the relationships between rheumatoid arthritis and atherosclerosis

Zeynep Ozbalkan

a,∗

_{, Cumali Efe}

b

_{, Mustafa Cesur}

c

_{, Sibel Ertek}

d

_{, Narin Nasiroglu}

b

_{, Kaspar Berneis}

e,f

_,

Manfredi Rizzo

g

a_{Department of Rheumatology, Ankara Numune Hospital, Turkey} b_{Department of Internal Medicine, Ankara Numune Hospital, Turkey} c_{Department of Endocrinology, Ankara Güven Hospital, Turkey} d_{Department of Endocrinology, Ufuk University Hospital, Ankara, Turkey}

e_{Division of Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Switzerland} f_{Zurich Center for Integrative Human Physiology, University of Zurich, Switzerland}

g_{Department of Clinical Medicine and Emerging Diseases, University of Palermo, Italy}

a r t i c l e i n f o

Article history:

Received 26 January 2010

Received in revised form 22 March 2010 Accepted 22 March 2010

Available online 4 April 2010 Keywords: Atherosclerosis Rheumatoid arthritis Inﬂammation Cardiovascular risk

a b s t r a c t

Rheumatoid arthritis is a chronic inflammatory disease. Cardiovascular events are the most important cause of mortality and morbidity in patients with rheumatoid arthritis. Beyond the traditional cardiovas-cular risk factors, chronic systemic inflammation has been shown to be a crucial factor in atherosclerosis development and progression from endothelial dysfunction to plaque rupture and thrombosis. Many studies have shown that atherosclerosis is not a passive event like accumulation of lipids in the ves-sel walls; by contrast, it represents an active inflammation of the vesves-sels. Inflammatory cells such as macrophages, monocytes and T cells play important roles in the development of both rheumatoid arthri-tis and atherosclerosis. In this article we analyse the relationships between rheumatoid arthriarthri-tis and atherosclerosis.

Contents

1. Introduction . . . 378

2. Synovial and vascular inﬂammation . . . 378

3. Clinical and subclinical atherosclerosis in patients with RA . . . 378

3.1. Cardiovascular mortality . . . 378

3.2. Subclinical atherosclerosis . . . 379

4. Pro-atherogenic alterations in patients with RA . . . 379

4.1. Endothelial dysfunction . . . 379

4.2. Arterial stiffness . . . 379

4.3. Atherogenic T-cell upregulation . . . 379

4.4. Dyslipidemia and oxidative stress . . . 379

4.5. Insulin resistance . . . 380

5. Traditional and emerging cardiovascular risk factors in patients with RA . . . 380

5.1. New potential cardiovascular risk factors . . . 380

5.2. Traditional cardiovascular risk factors . . . 380

6. The effects of anti-rheumatic treatments on cardiovascular risk . . . 380

6.1. Non-steroidal anti-inﬂammatory drugs and cyclo-oxygenase II inhibitors . . . 380

6.2. Glucocorticoids . . . 380 6.3. Methotrexate . . . 381 6.4. TNF-blocking agents . . . 381 6.5. Statin treatment . . . 381 7. Conclusions . . . 381 References . . . 381

∗ Corresponding author at: Sehit Ismail Eres Sok, Sahinler Apt 4/9, 06570 Maltepe-Ankara, Turkey. Tel.: +90 312 5084677; fax: +90 505 5025596.

E-mail address:zaslar@hotmail.com(Z. Ozbalkan).

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1. Introduction

Rheumatoid arthritis (RA) is a chronic systemic inﬂammatory disease characterized by articular and extra-articular involve-ments. Among RA patients, cardiovascular disease (CVD) is the most important cause of mortality and morbidity[1]. Several studies have suggested that development of atherosclerosis, the underly-ing process for CVD, is increased in RA. The cause of accelerated atherosclerosis in RA is unclear and increased risks cannot be fully explained by traditional risk factors such as age, gender, smok-ing, hypertension or type-2 diabetes (DM)[2]. Clinical, laboratory and epidemiological studies have shown that enhanced systemic inﬂammation is one of the non-traditional factors of increasing cardiovascular risk in these patients[3].

Previously, atherosclerosis was thought to be a passive accumu-lation of lipids in the vessel wall but, at present, it is recognised as a dynamic inflammatory process begins with activation of vascular endothelium, immigration of leukocytes, lipid oxidation and culmi-nating with plaque destabilization and thrombosis[4]. In this view, RA is the prototype of a chronic systemic inflammatory disease and, interestingly, striking similarities have been noted between the inflammatory pathways in atherosclerosis and RA[5]. More-over, it is known that chronic systemic inflammation in both the general population and RA patients leads to increased CVD beyond the traditional risk factors.

The increased risk of CVD in patients with RA has recently become the focus of intense investigations. Future studies are needed to explain how systemic inﬂammation leads to acceler-ated atherosclerosis and this may help the development of new therapeutic targets able to reduce CVD risk in RA; this may also may lead ultimately to understand inﬂammatory mechanisms of atherosclerosis in general.

2. Synovial and vascular inﬂammation

Atherosclerotic plaque and the inﬂamed synovium shows marked similarities in the accumulation of inﬂammatory

macrophages, monocytes and T cells. RA and atherosclero-sis share a similar proﬁle of both systemic and local immune activation: Mast and T-cell activation, tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6) production, increased extra-cellular matrix metalloproteinases and expression of leukocyte adhesion molecules. Furthermore, both RA and atherosclerosis are associated with upregulation of the Th1 related immune response [4,5].

The most obvious site of inflammation in RA is synovium, but pro-inflammatory cytokines such as TNF-␣ and IL-6 are released into the systemic circulation and they have many effects on distant organs, including liver, adipose tissue, skeletal muscle, immune system and endothelium [6]. The result of increased systemic inflammation in the whole body leads to a pro-atherogenic profile namely, oxidative stress, atherogenic lipid abnormalities, insulin resistance, increased arterial stiffness, endothelial dysfunction and upregulation of atherogenic T cells (Fig. 1).

3. Clinical and subclinical atherosclerosis in patients with RA

3.1. Cardiovascular mortality

RA is an independent risk factor other than traditional cardio-vascular risk factors for CVD. In the Nurses Health Study, traditional cardiovascular risk factors were similar between RA patients and control group, but the adjusted relative risk for myocardial infarc-tion was 2.0, and up to 3.1 for women with RA for more than 10 years[7]. In a prospective Dutch study, non-diabetic RA patients from the CARRE study (n = 294) were compared with non-diabetic individuals (n = 258) and individuals with type-2 DM (n = 194) from the Hoorn study. The prevalence of CVD was 13% in RA patients, 12% in diabetic individuals and 5% in non-diabetic individuals, respec-tively. The gender and age adjusted odds ratios for CVD were 3.1 in RA patients, and 2.3 in individuals with DM in comparison to non-diabetics. These results suggested that the prevalence of CVD in RA may be higher than DM[8]. Another study has shown that

Fig. 1. Inﬂammatory pathways linked to the development of atherosclerosis in patients with rheumatoid arthritis. TNF: tumor necrosis factor; IL: interleukin; EPC: endothelial

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even after adjusting for traditional cardiovascular risk factors, the risk of cardiovascular events in RA was only slightly reduced from 3.96 to 3.17[2].

Moreover, in RA patients, in contrast to the general popula-tion, the risk of CVD is particularly increased in younger patients and females. Low body mass index (<20 kg/m2_{) is also associated} with a high cardiovascular mortality. Probably this is related to the increased inflammatory cytokines inducing a catabolic state[7,9]. Several clinical studies have shown that elevated levels of inflam-matory markers predict some cardiovascular events in the general population. In particular, excess of 10 mg/L in C-reactive protein (CRP) levels is associated with a significant increase in cardiovas-cular risk[10]. In RA cardiovascular mortality is associated with CRP and erythrocyte sedimentation rate (ESR) levels. However, it is not clear if the same levels of CRP in RA and non-RA patients confer the same risk for CVD[11]. Baseline CRP levels higher than 5 mg/L were associated with a hazard ratio for cardiovascular death of 3.9 in men, and 4.2 in women with RA[12].

Further, TNF-␣ and IL-6 are pro-inflammatory cytokines that have shown an independent predictive role for future cardiovas-cular events [13]. These cytokines have important roles in the pathogenesis of RA and they were found with elevated concentra-tions in patients with RA. Furthermore, duration and activity of the disease, multiple joint involvements, presence of rheumatoid fac-tor (RF) and rheumatoid nodules, extra-articular manifestations are also specific determinants of RA for CVD[14]. All of these findings suggest that untreated systemic inflammation may incur damage before it affects on the joints and that long-term exposure to sys-temic inflammation increases the risk of CVD.

3.2. Subclinical atherosclerosis

Carotid intima-media thickness (cIMT) is an important marker for early, subclinical atherosclerosis and a strong predictor of future cardiovascular events[15,16]. cIMT was measured in 631 consec-utive RA patients and the rate at which it increased per unit of age steepened in proportion of the RA duration, from 0.154 mm/10 years among patients with RA for 7 years or less, to 0.295 mm/10 years among patients with RA for 20 years or more[17]. The clini-cal relevance of subcliniclini-cal atherosclerosis was further assessed in a cohort of 47 RA patients; during the 5-year follow-up, 17 patients experienced cardiovascular events. When cIMT was divided in quartiles, none of the RA patients with cIMT <0.77 mm had car-diovascular events versus 6 of the 10 patients with cIMT >0.91 mm had cardiovascular events[18]. Finally, Georgiadis et al. examined cIMT in 40 patients with early RA with no medical history of CVD. At baseline, RA patients had significantly greater cIMT than con-trols, although the prevalence of plaques in the carotid artery was not different between cases and controls. After a 1-year treatment, cIMT significantly decreased in RA patients and independently than changes in serum lipids or inflammatory markers[19].

4. Pro-atherogenic alterations in patients with RA

4.1. Endothelial dysfunction

Endothelial dysfunction is a pivotal early step in atherosclero-sis and it is deﬁned as an abnormal response of the vascular wall to physiological stimulus[20]. Pro-inﬂammatory mediators, such as TNF-␣ and IL-6, are strongly associated with endothelial acti-vation and dysfunction. Persistent endothelial actiacti-vation leads to endothelial dysfunction, characterized by decreased production of nitric oxide (NO), increased expression of cytokines and adhesion molecules[21]. TNF-␣ impairs NO bioavailability, blocks activation of endothelial NO and inhibits cyclo-oxygenase-1 which are

impor-tant molecules for maintaining endothelial stability[22]. Increased adhesion molecules such as E-selectin, VCAM-1 and ICAM-1 con-tribute to endothelial dysfunction and their serum levels strongly correlate with other inﬂammatory markers[23].

Endothelial dysfunction is measured non-invasively by brachial artery flow-mediated vasodilatation (FMD). In a recent study of 52 patients with RA, FMD was impaired in RA subjects compared to controls (5.3% vs. 8.3%) and also negatively correlated with cIMT [24]. Another study including 32 well-controlled RA patients fur-ther reported impaired FMD in those with RA compared to controls (3.2% vs. 5.7%)[25]. Finally, Hannawi et al. evaluated 20 early RA patients and controls and reported that mean FMD was significantly lower in early RA patients than controls; yet, FMD significantly improved over a 1-year treatment period[26]. Although FMD has a great sensitivity for cardiovascular risk in RA, its utility has been very limited, probably due to inadequate characterization of the interaction between FMD and clinical or laboratory indicators of RA activity.

4.2. Arterial stiffness

Arterial stiffness is an important indicator of vascular disease as well as an independent predictor factor of CVD, particularly in hypertensive patients[27]. Several studies have shown that arte-rial stiffness is increased in RA patients, even in those with normal endothelial function. In one study, the increased arterial stiffness found in RA patients signiﬁcantly correlated with disease duration and inﬂammatory markers, such as CRP and IL-6, although the low blood pressure levels[28].

4.3. Atherogenic T-cell upregulation

Immunologic pathways are associated with chronic inflamma-tion. This is very important in RA as well as for the development of CVD. Increased endothelial MHC class II expression leads to activa-tion and migraactiva-tion of the CD4+_{helper T-cells which are involved} in activating monocytes and macrophages. An unusual subpop-ulation of CD4+ _{T-cells lacking co-stimulatory CD28 molecule} (CD4+_/CD28−_{) have been implicated in atherosclerotic plaque} dis-ruption and associated with inflammation related vascular damage in the general population and in patients with RA. Increased lev-els of CD4+_/CD28−_{T cells correlate with subclinical atherosclerotic} disease and endothelial dysfunction. These cells are also elevated in patients with acute coronary syndrome and usually reflect the severity of the disease[29,30].

4.4. Dyslipidemia and oxidative stress

It is known that systemic inﬂammation leads to structural changes in lipoproteins that may promote their atherogenic poten-tial, and these changes cannot be detected by routine analyses[31]. Camejo et al. reported that patients with long-term RA showed lower low-density lipoprotein (LDL) size due to increased levels of small dense LDL, which represent an emerging cardiovascular risk factor associated with a higher prevalence of CVD. Further, we have recently shown reduced LDL size with increased levels of small dense LDL in drug-naïve patients with early RA[32,33].

Inflammation may also change the constituents of high-density lipoproteins (HDL), reducing their ability to remove cholesterol from atherosclerotic plaque and impairing their anti-oxidant capacity [34]. Unfavourable lipid profiles, including higher total cholesterol/HDL-cholesterol ratio, or the so-called atherogenic lipoprotein phenotype, characterized by decreased HDL, raised triglycerides and increased levels of small dense LDL, are associated with RA. Such pro-atherogenic lipid profiles are linked to increased cardiovascular risk, beyond LDL-cholesterol levels [35,36].

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Lipoprotein (a), which plays an important role in promoting atherogenesis, has been found elevated in patients with RA, but this could also be secondary to chronic inﬂammation[37].

Overall, RA patients have increased oxidative stress and poor anti-oxidant capacity. More studies are necessary to further explain how inﬂammation leads to pro-atherogenic lipoprotein alterations in RA.

4.5. Insulin resistance

It has been shown that high-grade inflammation correlates with increased insulin resistance in RA patients[38]. Inflammatory markers, such as TNF-␣, impair the uptake of glucose in skeletal muscle and stimulate lipolysis in the adipose tissue, suggesting one of the mechanisms of insulin resistance in RA patients[39]. Subsequently increased lipolysis and fatty acids levels provoke an inflammatory response of macrophages that further stimulates TNF-␣ and IL-6, with a positive feedback cycle[40].

5. Traditional and emerging cardiovascular risk factors in patients with RA

5.1. New potential cardiovascular risk factors

Endothelial progenitor cells (EPCs) are mononuclear cells, expressing speciﬁc endothelial markers and helping the injured endothelium. In the general population several studies have shown that low levels of EPCs are associated with cardiovascular risk. Thus, it is not surprising that in RA patients levels of EPCs were found to be low and this may further enhance the cardiovascular risk of such subjects[41,42]. Prothrombotic factors were also studied in order to explain the cardiovascular risk in RA patients. McEntegart et al. reported increased serum levels of ﬁbrinogen, von Willebrand factor and tissue plasminogen activator antigen compared to con-trols and these markers have been shown to be able to predict cardiovascular risk in patients with RA[43].

Also hyperhomocysteinemia is a risk factor for CVD, and this has been reported in RA patients too, with serum homocysteine levels correlating with CRP, ESR and the severity of RA[44]. In addi-tion, several studies have shown increased homocysteine levels in patients treated with low-dose methotrexate; although this can be reduced by the use of folic acid in the general population, no differ-ences were observed between the folic acid users and non-users in the occurrence of cardiovascular events[45].

It is known that not all RA patients have the same cardiovascular outcome, and it has been speculated that genetic susceptibil-ity to atherosclerosis may play a role. The HLA-DRB1*0404 is a predisposition gene for RA and it has been associated with the severity of RA. However, RA patients with HLA-DRB1*0404 gene shared epitope-positive have more endothelial dysfunction and particularly increased cardiovascular mortality compared to the epitope-negative RA patients[13,46].

5.2. Traditional cardiovascular risk factors

Smoking is an important risk factor for the development of both RA and CVD. Moreover, smoking is associated with severe RA, for instance with more erosive disease or extra-articular involvement. Smokers are more likely to have positive RF and anti-CCP antibodies which are predictors of aggressive RA, but it is not clear if smok-ing confer the same relative risk for CVD compared to the general population[47,48].

Patients with RA have a greater risk of physical inactivity compared to the general population. The degree of inactivity is associated with a reduced life expectancy in the general popula-tion as well as in RA patients[49]. However, physical inactivity in

the general population is associated with an increased prevalence of risk factors for CVD such as obesity, hypertension and dyslipi-demia[50]; yet, there is still no data on the prevalence of these risk factors in RA patients in relation to the general population.

A systemic review of hypertension in RA suggests that the prevalence lies between 3.8 and 73%. Systemic inflamma-tion, physical inactivity, obesity and medications [non-steroidal anti-inflammatory drugs (NSAIDs), cyclo-oxygenase II inhibitors (COX˙IBS), corticosteroids, leflunomide and cyclosporine] may lead to high rate and poor control of hypertension in patients with RA [51]. Hypertension is one of the most important risk factors for CVD but its control is far from adequate both in general popu-lation and in RA. In a recent study, the rate of controlled HT in RA was significantly lower than in general population (13.2% vs. 21–23%)[52,53]. Uncontrolled hypertension has many cardiovas-cular effects such as premature CVD, heart failure, cerebro-vascardiovas-cular disease and arhythmias. This highlights the importance of the con-trol of blood pressure in RA patients; yet, it has not been fully elucidated the net effect of well-controlled blood pressure in RA patients.

Raised levels of systemic inﬂammation have been shown to pre-dispose to developing insulin resistance in RA patients. But still there is no clear data, whether the prevalence of DM is increased in RA patients[54]. Several studies have shown that the preva-lence and incidence of traditional cardiovascular risk factors are similar between RA patients and age- and gender-matched nor-mal population[55]. It remains unclear if or how traditional risk factors interact between non-traditional risk factors to increase CVD. However, some traditional risk factors, including male, gen-der, smoking and previous cardiovascular events, appear to have an association with CVD in patients with RA, but their contribution to the CVD rates seems weak[56]. Overall, patients with RA have at least a twofold increased cardiovascular risk in comparison to the general population, adjusting for all traditional risk factors. These ﬁndings further suggest that RA is an important and independent cardiovascular risk factor.

6. The effects of anti-rheumatic treatments on cardiovascular risk

6.1. Non-steroidal anti-inﬂammatory drugs and cyclo-oxygenase II inhibitors

Regarding NSAIDs, the data are still inconclusive and two meta-analyses of randomized studies were published. Kearney et al. found that high doses of ibuprofen and diclofenac were related with an increased cardiovascular risk, but naproxen was not[57]. In another study only diclofenac was associated with an increased car-diovascular risk but naproxen and piroxicam were not[58]. Thus, after careful cardiovascular risk evaluation, naproxen and piroxi-cam may be used in lower doses in RA patients. The current data suggests to avoid COXIBs use, because of the increased risk for cardiovascular events[59].

6.2. Glucocorticoids

Glucocorticoid therapy is associated with an increased risk for hypertension, glucose intolerance, lipid abnormalities and cardio-vascular events[60]. Davis et al. reported increased cardiovascular events in patients positive for the RF but not in those negative for it. In one study the steroid therapy surprisingly reduced cardiovas-cular events and related death in RA patients with a recent history of CVD[61]. In another study, treatment with low doses of steroids was not associated with a beneﬁcial effect on endothelial function in RA subjects[62]. However, the cardiovascular effect of different

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doses and durations of steroid treatment has not been fully elu-cidated. Large population-based studies are required to postulate it.

6.3. Methotrexate

The current evidence suggests that using of methotrexate (MTX) is associated with a reduced risk of CVD events in RA patients. A large US population-based study demonstrated that 70% reduction of deaths from CVD in patients recently treated with MTX com-pared with those never treated[45]. Another study reported a 35% decreased risk of CVD events in patients treated with MTX, in a year prior to the diagnosis of RA, for up to 3.9 years of follow-up compared with non-users[63]. Naranjo et al. demonstrated a 18% reduction in the risk of myocardial infarction in patients treated for 1 year with MTX[64].

Other case-control studies compared MTX use and congestive heart failure (CHF). Current users of MTX had 20% reduction in the risk of hospitalization due to CHF compared with non-current users [65]. The use of MTX in RA is associated with a decreased risk of CVD mortality and morbidity but association between MTX use and subclinical atherosclerosis, lipid proﬁles or insulin resistance was found.

6.4. TNF-blocking agents

TNF-blocking agents are very effective in the treatment of RA. From a pathophysiological point of view, it is expected that TNF-blockers lead to decrease cardiovascular mortality. Recently, in a community-based study, including RA registers in Sweden, treatment with TNF-blockers was associated with a lower risk of ﬁrst-ever CVD events[66]. Further, follow-up of this cohort has shown a reduced overall mortality in RA patients treated with TNF-blockers[67]. By contrast, TNF-blockers were associated with increased mortality rate in patients with CHF[68]. It is likely that this side effect is conﬁned to patients already suffering from estab-lished CHF.

The role of TNF-blockers in atherosclerosis is supported by the observations that TNF-blockers improve endothelial dysfunctions [69], arterial stiffness[70]and insulin sensitivity[71]. In addition, TNF-blockers reduce cIMT[72]and upregulate CD28 expression in CD4+ T cells[73]. These ﬁndings suggest that successful suppres-sion of inﬂammation by TNF-blockers can outweigh the potential risks of drug toxicity. Moreover, it is important to note that long-term studies in patients treated with TNF-blockers are necessary to postulate their effects on cardiovascular events and mortality. 6.5. Statin treatment

Statins are used in patients with RA because of their favourable effects on inﬂammation and endothelial dysfunction. Two stud-ies have shown that statins may improve endothelial dysfunction, reduce arterial stiffness, lipid oxidation and inﬂammatory markers

[74,75]. The trial of Atorvastatin in Rheumatoid Arthritis (TARA)

study revealed a significant reduction in CRP, ESR and useful effect on arthritis. As expected, the anti-inflammatory effect was paral-leled with the reduction in total- and LDL-cholesterol levels[76]. Based on the current data, we suggest that statins should be consid-ered in patients with severe RA and an unfavourable lipid profile; yet, since total- and LDL-cholesterol were found to be lower in RA patients due to active inflammation, target levels of such lipid parameters may be slightly modified for patients with RA.

Further, the high risk of CVD in patients with RA has been postulated to be analogous to DM. Based to this assumption, Van Doornum et al. suggested speciﬁc target values for patients with RA and traditional risk factors[77]. Yet, since the excess risk of CVD in

RA cannot be explained by an increased prevalence of traditional risk factors only, we need to be very careful in modifying the target values validated for the general population.

7. Conclusions

There is well-established evidence that CVD is a major cause of morbidity and mortality in RA patients. The proposed mecha-nisms leading to increase CVD and related mortality include a direct impact of chronic inﬂammation. Effective suppression of inﬂamma-tion by anti-rheumatic drugs may reduce the risk of CVD events. Based on the current data, RA should be considered as a new, inde-pendent, cardiovascular risk factor with a similar magnitude as that of DM.

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