targeting cardiovascular risk in rheumatoid arthritis: a dual role for statins

nature reviews | rheumatology volume 6 | marCH 2010 | 157

Department of Clinical Immunology and Rheumatology (r. J. Bisoendial, P. P. tak), Department of Vascular Medicine (e. S. g. Stroes, J. J. P. Kastelein), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Correspondence to: R. J. Bisoendial r.j.bisoendial@ amc.uva.nl

targeting cardiovascular risk in rheumatoid arthritis: a dual role for statinsRadjesh J. Bisoendial, Erik S. G. Stroes, John J. P. Kastelein and Paul Peter Tak

abstract | Rheumatoid arthritis (RA) is a prototypical immune-mediated inflammatory disease that is characterized by increased cardiovascular morbidity and mortality, independent of the traditional risk factors for cardiovascular disease. The chronic inflammatory state—a hallmark of RA—is considered to be a driving force for accelerated atherogenesis. Consequently, aggressive control of RA disease activity is thought to be instrumental for cardiovascular risk reduction. Currently, statin-mediated reduction of LDL-cholesterol levels is considered to be the cornerstone of cardiovascular disease prevention. In addition to their lipid-lowering capabilities, statins exert immunomodulatory effects, which could be of dual benefit in the treatment of RA. Guidelines on the reduction of cardiovascular risk in patients with RA are lacking, however, largely owing to the absence of data from randomized controlled trials. This Review focuses on the pathophysiology of cardiovascular events in RA, as well as the need to adjust cardiovascular risk engines to better-accommodate the impact of chronic inflammatory disease over and above the established risk factors to predict cardiovascular risk in patients with RA.

Bisoendial, R. J. et al. Nat. Rev. Rheumatol. 6, 157–164 (2010); published online 9 February 2010; doi:10.1038/nrrheum.2009.277

Introductionsince the early 1990s, rheumatoid arthritis (ra) has emerged has a recognized risk factor for increased cardio vascular morbidity and mortality, irrespective of the presence of traditional cardiovascular risk factors such as smoking and obesity.1,2 notably, studies that have found an increased risk of cardiovascular mortality in ra have included far higher numbers of patients than studies that failed to reveal such an association (tables 1 and 2). in 2004, a well-conducted study of almost 3,900 patients with ra followed from 1980 to 1997 identified reductions in the number of atherosclerosis-related deaths.3 the determinants of a beneficial effect on the cardio vascular risk profile of these patients included diminished use of nsaiDs, greater functional status and physical activity, and potent suppression of inflammation.4,5

the efficacy of 3-hydroxy-3-methyl glutaryl co enzyme a (HmG-Coa) reductase inhibitors, also known as statins, in the prevention of cardiovascular events among various high-risk populations has been firmly established.6–11 Beyond their lipid-lowering capacity, statins exert potent anti-inflammatory effects on a number of immune-mediated inflammatory disorders. this review focuses on the potential impact of statins on the cardiovascular risk profile of patients with ra.

Cardiovascular disease in RAearly atherosclerotic disease is characterized by a loss of vascular protection against ‘atherosclerotic insults’, also referred to as endothelial dysfunction, followed

by progressive structural derangements. the severity of endothelial dysfunction has been shown to correlate strongly with the future risk of cardiovascular events.12 active ra has consistently been associated with endo-thelial dysfunction, which can be reversed by treatment of the original cause of inflammation. in 10 patients with newly diagnosed ra, Bergholm et al.13 demonstrated reduced acetylcholine-mediated vasodilation, as mea-sured by venous plethysmography, which indicated a decrease in vascular nitric oxide bioavailability. in these patients, 6 months of routine anti-inflammatory therapy mitigated clinical and biochemical markers of inflam-mation, resulting in improved endothelial vasomotor function. similar observations have been made in other small-scale studies, where the amelioration of endo thelial dysfunction following treatment with tumor necrosis factor (tnF) inhibitors or the anti-CD20 monoclonal antibody rituximab parallel ed reductions in systemic inflammation and 28-count Disease activity scores (Das28).14–16 taken together, the data implicate impaired endothelial vasomotor function as an integral part of the pathogenesis of ra.

morphological changes in the wall of the carotid artery, visualized by ultrasonography as increased intima-media thickening (imt), are thought to precede the develop ment of overt atherosclerotic lesions by at least 1–2 decades. Carotid artery imt is increased in patients with ra com-pared with controls,17 and tends to be greater in patients who smoke than in non smokers.18 additional studies have revealed an increased prevalence and severity of coro-nary artery calcification in patients with established ra compared with those with a shorter disease duration.19,20

Competing interestsThe authors declare no competing interests.

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Furthermore, roman and colleagues21 showed a three-fold higher prevalence of athero sclerotic plaques in the carotid arteries of patients with ra (n = 98) compared with matched controls. in these patients, the presence of athero sclerotic plaque was associated with increased age, hypertension and anti-tnF therapy. these findings, however, might have been confounded by the inclusion of a subgroup of patients with severe ra.

once cardiovascular disease becomes manifest, patients with ra exhibit a higher prevalence of multi-vessel disease and a greater need for revascularization than age-matched and sex-matched controls.22 Con-sistent with this notion, angiographic scores indicate that patients with ra are at increased risk of multi-vessel disease compared with matched controls.23 From the data, therefore, it seems safe to assume that ra can be considered a high-risk condition for cardiovascular events, and that patients in whom cardio vascular disease has developed have a worse prognos is than those without cardiovascular manifestations.

Mechanisms of accelerated atherogenesisaccelerated atherogenesis in ra can involve numerous inflammatory and noninflammatory factors. owing to space limitations, however, only brief insights into the most common mechanisms involved in atherogenesis in patients with ra are provided.

Innate immunitymonocytes have been strongly implicated in the patho-genesis of atherosclerosis, starting with their adhesion to the endothelium and migration into the intima in the early stages of atherogenesis, followed by their differ en-tiation into macrophages. macrophages are crucial to the development of ra and other immune-mediated inflam-matory disorders.24–26 these cells are pheno typically polarized by specific signals and secrete a variety of proinflammatory cytokines and proteinases that can accelerate atherosclerosis progression.

among its numerous proatherosclerotic activities tnF, a key inflammatory cytokine, induces potent atherogenic effects on the arterial wall, including cell apoptosis and upregulation of adhesion molecules and endothelial cells, which adopt a more procoagulant and vasoconstrictor phenotype.27–29 matrix metalloproteinases are proteo-lytic enzymes that can degrade collagen and render the growing plaque’s cap thin and susceptible to rupture.30 neutrophils can infiltrate the atherosclerotic plaque and

Key points

Rheumatoid arthritis (RA) is an independent risk factor for cardiovascular ■events, with an impact over and above established risk factors for cardiovascular disease

Proper management of cardiovascular risk primarily requires aggressive control ■of RA disease activity

statins are the cornerstone of cardiovascular risk management, offering both ■lipid-lowering efficacy and anti-inflammatory effects

Routine initiation of statins in patients with RA is not recommended until the ■results of large randomized, controlled trials become available

express destabilizing factors such as myeloperoxidase, gelatinase-associated lipocalin, proteolytic enzymes, and tissue factor, and have been increasingly linked to accelerated atherogenesis.31,32 with regard to inflam-ma tory proteins, the acute phase reactant C-reactive protein (CrP) has emerged as a direct contributor to the develop ment of atherosclerosis. CrP infusions in humans render the endothelium dysfunctional, with ensuing pro coagulant responses, particularly under hyper cholesterolemic condi tions.33 the atherogenic role of the terminal comple ment pathway was confirmed in 2009 by wu et al.,34 who showed that the absence of CD59, a key regula tor of the assembly of the membrane attack complex of human complement, accelerated disease in an experimental model of atherosclerosis. in addition, a neutral izing antimouse C5 antibody attenu-ated athero sclerosis in this model.34 a number of studies have indicated that the severity of inflammatory activity is a predictor of cardio vascular events and mortality.35,36

adaptive immunityPeripheral blood CD4+ t cells that lack CD28 surface expression might contribute to increased cardio vascular risk in ra.37 Patients in whom expansion of this t-cell subset with a proinflammatory phenotype and tissue-damaging potential is detected show impaired flow- mediated dilation (FmD) and increased imt compared with those lacking this t-cell subset.38,39 tnF blockade in these patients induces CD28 expression on the surface of CD4+ t cells.37 other t cell activities that have been linked to atherogenesis include production of interleukin (il)-17 and interferon γ by coronary-artery-infiltrating t cells, which generates a pro inflammatory response in vascular smooth muscle cells.40 Furthermore, CXCr6, a chemokine receptor expressed on a subset of CD4+ t helper 1 cells and natural killer t cells, has been impli-cated in lymphocyte homing and in the local immune response within the arterial wall.41 in addition, dendritic cells at the media–adventitia junction are thought to have important roles in pathogen recognition and t-cell stimu-latory functions. Dendritic cells modulate wall- infiltrating t cells to display vessel-specific activation profiles, includ-ing that of atherosclerosis, with differen tial production of CD40 ligand, lymphotoxin α, and interferon γ in medium and large human arteries.42

Noninflammatory factorsthe presence of rheumatoid factor in ra has been associ-ated with increased mortality attributable to cardio vascular conditions, as well as other causes.43,44 Further more, ra has been associated with an atherogenic lipid profile—that is, elevated levels of apolipoprotein-B-containing lipo-proteins and low HDl levels. this lipid profile correlates closely with clinical scores and inflammatory activity, and is reversible with effective treatment.45–47 improvements in the lipid profile are accompanied by atheroprotective alterations in HDl composition upon tnF blockade. another noninflammatory mechanism of atherogenesis involves endothelial progenitor cells (ePCs), which have been associated with cardiovascular risk and therefore

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constitute a biomarker for vascular malfunction.48 in ra, the number of peripheral ePCs was shown to corre-late inversely with disease activity.49 statin therapy, at least in an experimental adjuvant-induced model of ra, seems to have favorable effects on the presence of ePCs.50 Few ra treatment modalities are thought to exacerbate

individual cardiovascular risk factors. these treatment include long-term glucocorticoid use and leflunomide and cy clooxygenase-2 inhibitors;51–53 however, the data are inconsistent.

the mechanisms by which chronic inflammation can contribute to the pathogenesis of atherosclerosis in ra

Table 1 | Cohort studies that found increased cardiovascular mortality in patients with RA

First author, year

Study participants length of follow-up (years)

main findings

Reilly, 199070 100 patients with RA 25 excess mortality of 40%; death from cerebrovascular disease more common than expected

Jacobsson, 199371

2,979 Pima Indians from Arizona

24 Higher age-adjusted and sex-adjusted mortality rates in patient with RA than controls (mortality rate ratio 1.28, 95% CI 1.01–1.62)Risk of death highest in older male participants and in those with proteinuria

Pincus, 199472

75 patients with RA 15 sMR for cardiovascular death 1.62 (95% CI 1.12–2.21).5-year survival in patients with the poorest disease status similar to that of patients with three-vessel CAD or stage 4 Hodgkin lymphoma

wolfe, 19941 3,501 patients with RA Up to 35 sMR for cardiovascular death 2.26, with excess of deaths attributable to CVDIndependent predictors of mortality included increased age, male sex, reduced function, increased RF levels, raised esR, high joint count, and prednisone use

Myllykangas-Luosujarvi, 199573

All women in Finland who died in 1989 and were presumed to have RA

NA CVD caused of half of all deaths and 34% excess of deathsMedian age at death in women with RA was 2.5 years lower than that in the whole population, with deaths due to CVD

wallberg-Jonsson, 199774

606 patients with RA

15 sMRs for CVD and ischemic heart disease compared with reference population 1.46 and 1.54, respectivelyMale sex, higher age at disease onset, and a former cardiovascular event increased the risk of death

symmons, 199875

448 patients with RA Up to 27 sMR for cardiovascular death compared with general population 2.7 (95% CI 2.4–3.1)Most excess deaths attributed to CVD

Kvalvik, 200076

149 patients with RA 15 sMR for cardiovascular death 149 (95% CI 115–188)excess deaths attributed to malignant disease in males and CVD in females

Del Rincón, 200177

263 RA patients; and 4,635 controls

8 Age-stratified and sex-stratified incidence rate ratio, after controlling for traditional cardiovascular risk factors, 3.17 (95% CI 1.33–6.36)

Bjornadal, 200278

46,917 patients with RA 20 All-cause mortality was twice that expected, whereas CAD was the major cause of mortality (sMR 1.79, 95% CI 1.75–1.83)Females aged 20–39 years at first discharge had >5-fold risk of coronary death (sMR 5.48, 95% CI 3.45–5.71)Decline in all-cause mortality after 1975

Mikuls, 200279

31,336 healthy women (Iowa women’s Health study)

NA Increased mortality risk in women with RA than in those without RA (RR 1.52; 95% CI 1.05–2.20).Mortality higher among seropositive participants, but a trend towards increased proportions of RA-related deaths from circulatory disease (RR 1.46; 95% CI 0.76–2.81)

Gabriel, 200380

609 patients with newly diagnosed RA

40 sMR for cardiovascular death 1.27 (95% CI 1.13–1.41).excess mortality more pronounced among women than menPresence of at least one extra-articular manifestation strongest predictor of mortality

solomon, 20032

114,324 healthy women (Nurses’ Health study)

18 Adjusted RR of MI and stroke 2.0 (95% CI 1.23–3.29) and 1.48 (95% CI 0.70–3.12), respectivelyDuration of RA >10 years increased adjusted risk of MI to 3.1 (95% CI 1.64–5.87)

Krishnan, 20043

3,862 patients with RA

17 sMR for cardiovascular death 1.59 (95% CI 1.36–1.86), particularly in older age groups and in menAdjusted risk of acute MI declined in successive incidence years

Abbreviations: CAD, coronary artery disease; CVD, cardiovascular disease; MI, myocardial infarction; NA, not applicable; RA, rheumatoid arthritis; RF, rheumatoid factor; RR, relative risk; sMR, standardized mortality ratio.

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are multifactorial. increased disease activity promotes an inflammatory endothelial and leukocyte phenotype combin ed with a proatherogenic lipid profile, which together stimulates plaque growth and destabilization, ultimately culminating in an acute clinical event.

The effects of statins in RAstatins block the conversion of HmG-Coa to mevalo nate by inhibiting the rate-limiting enzyme of the mevalonate path way, HmG-Coa reductase. the end products of the mevalonate pathway, including sterols (such as chol-e sterol) and ubiquinone (also known as coenzyme Q), are required for a number of essential cellular functions that involve membrane integrity, steroid production, electron transport and/or cell respiration, and (glyco)protein synthesis. in this regard, statins display potent biological effects beyond their lipid-lowering activities. whether or not these activities are relevant in clinical terms remains the subject of intense debate.

Data from in vitro and experimental studiesstatins can attenuate proinflammatory cytokine pro-duction, tnF-induced cell proliferation, and nuclear factor κB (nFκB) activation in fibroblast-like synovio-cytes from patients with ra (Figure 1).54,55 the mecha-nisms of these anti-inflammatory effects relate to the direct inhibition of both ras homolog gene family, member a (rhoa), which serves as a key regulator of nFκB activation, and the secretion of pro inflammatory cytokines.56 in addition, statins have been shown to promote apoptosis in cultured ra synoviocytes.57 these data are of importance as in adequate apoptosis of

Table 2 | studies that found decreased cardiovascular mortality in patients with RA

First author, year

Study participants Study type; length of follow-up (years)

main findings

Linos, 198081 Residents from Rochester, MN, UsA

Population-based; 24 Mortality similar among patients with RA and the general population

Allebeck, 198182 293 RA patients, 453 controls Cohort study; 11 Mortality in RA group elevated and correlated with the severity of the disease

Vandenbroucke, 198483

209 patients with RA Prospective study; 25 Median life expectancy in RA shortened by 7 years in males and by 3 years in females compared with general population

Lindqvist, 199984 183 patients with RA Cohort study; up to 12 No increased mortality during the first 8–13 years of RA

sokka, 199985 135 patients with RA Cohort study; 8–14 Overall sMR for cardiovascular death 1.28 (95% CI 0.83–1.89); 1.69 (95% CI 0.92–2.82) for women and 0.98 (95% CI 0.49–1.74) for menAge at baseline was the sole significant predictor for death

Kroot, 200086 622 patients with RA Cohort study; 10 No excess mortality among patients with RA

Riise, 200187 187 patients with RA, 930 controls

Prospective study; 17 Total mortality in patients was twice that of controls, without increased mortality from cancer or cardiovascular disease

Peltomaa, 200288

150 DMARD-naive patients with early RA

Cohort study; 7–14 No increase in mortality in patients with RAHigh disease activity at onset and presence of extra-articular features were associated with mortality

Abbreviations: RA, rheumatoid arthritis; sMR, standardized mortality ratio.

Osteoclast

LDL

Endothelial cell

Lamina intima

Growth factorsMMPs

Lamina media

Proinflammatorycytokines

Foam cell

Statin

Macrophage

Smooth muscle cell

NOAdhesion moleculesThrombosis

Hyperplasticsynovial lining

Joint capsuleBone

Cartilage

Joint space

Synovialmembrane

PannusNeutrophil

TNF

CH3

CH3

O

O

O OH

H3C

H3C

H3C

O

Figure 1 | Anti-inflammatory actions of statins in rheumatoid arthritis. Beyond their lipid-lowering effects, statins can attenuate the production of proinflammatory cytokines, cell proliferation and nuclear factor κB activation, particularly in fibroblast-like synoviocytes. In addition, statins can block neutrophil influx in the joint space, stimulate anti-inflammatory mechanisms and promote adequate apoptosis of fibroblast-like synoviocytes. Finally, statins might have a role in cartilage-protection in rheumatoid arthritis. Abbreviations: MMP, matrix metalloproteinase; NO, nitric oxide; TNF, tumor necrosis factor.

▶

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fibroblast-like synoviocytes could increase the accumula-tion of activated immune cells in the intimal lining of the inflamed synovium. Finally, statins might have a role in protecting the cartilage.58

the relevance of these in vitro findings has, to a certain extent, been substantiated by data from animal studies. in an adjuvant-induced model of arthritis, treatment with oral atorvastatin markedly ameliorated histo patho-logical findings and hypernociception in the inflamed joints.59 these effects were paralelled by successful block-ade of neutrophil influx, a decline in pro inflammatory cyto kines and chemokines, and an increase in the anti- inflammatory cytokine, il-10. By contrast, another in vivo study did not find any effect of statins in a murine model of collagen-induced arthritis.60

Data from human studiesin an open-label trial of 15 patients with ra and an unsatis factory response to methotrexate mono therapy, the addition of simvastatin 40 mg to low-dose methro-trexate resulted in an american College of rheumatology criteria for 50% improvement (aCr50) response in 9 out of 10 individuals; no effect was seen in the five patients who were treated with chloroquine and methotrexate.61 Furthermore, CrP levels decreased by more than twofold following just 4 weeks of statin therapy. another study showed that 12 weeks of low-dose simvastatin (10 mg/day) combined with stable anti rheumatic therapy suppressed biomarkers of inflammation in 24 patients with ra.62 erythrocyte sedimentation rates and rheumatoid factor levels were also reduced, and these declines were associ-ated with clinical improvement. strikingly, statin treat-ment resulted in aCr20 and aCr50 responses in 62% and 38% of patients, respectively.62

in the largest, double-blind, placebo-controlled trial of statin therapy in ra to date (trial of atorvastatin in rheumatoid arthritis [tara]), 116 patients with moderate- term to long-term active disease were rando-m ized to receive 40 mg atorvastatin or placebo added to existing DmarD treatment for 6 months.63 the addition of statin therapy was accompanied by improvements in disease activity, including Das28 scores and european league against rheumatism response criteria, as well as by a decline in systemic inflammatory activity. although the clinical relevance of the targeted therapeutic pathways needs further clarification, these findings reflect the dual nature of statins: beyond lipid-lowering, these agents could modify cardiovascular risk by way of their immuno-modulatory function on inflammatory factors. markedly, in tara, statin treatment was not associated with more adverse events than placebo.63 these findings were con-firmed by a large, cross-sectional study from Japan, which included 4,152 patients with ra derived from a cohort of 7,512 patients.64 in this study, consider able improve-ments in disease activity (defined by patient’s assessment for pain, physician’s assessment, and swollen joint counts) were observed in a small proportion of patients taking statins (6.7%), with a concurrent reduction in serum CrP levels. although corticosteroid use was greater among patients on statins than those who were not on statins,

the beneficial effects of statin therapy remained after the results were controlled for confounders, in cluding co rticosteroid use.

evidence from both experimental and clinical studies is mounting, therefore, in support of the immuno-modulatory effects of statins, which could alter the clini-cal course of ra. the effects of statins include silencing of immune active cells, suppression of the systemic cytokine reaction and/or complement activation, and alteration of t-cell-mediated immune responses. as well as attenuating inflammatory activity in inflamed joints, statin use could also decrease secondary complications of synovial inflammation such as cartilage degradation and bone destruction.

Statins change cardiovascular riskFew clinical trials have addressed the effects of statins on the risk of cardiovascular events in ra. in 20 patients with active ra, treatment with 20 mg simva statin or 10 mg ezetimibe (an inhibitor of intestinal chole sterol absorption) resulted in equal improvements in inflam-ma tory markers and Das28-measured disease ac tivity, despite a clear demonstration of more- pronounced reductions in lDl-cholesterol (lDl-C) in the statin group.65 in both groups, endothelial function improved significantly follow ing cholesterol reduction. although this small study does not accommodate the long-term

Box 1 | Indications for statin therapy in patients with RA

recommended indications for statin use

Long history of active RA ■

Higher age at disease onset ■

LDL-C ≥190 mg/dl ■

Family history for dyslipidemia ■

established indications for statin therapy according to the uS National Cholesterol education Program adult treatment Panel III guidelines89

High-risk (10-year risk of cardiovascular events >20%): start statin therapy at LDL-C level ≥100 mg/dl

History of CHD, including MI, unstable or stable angina, coronary artery ■procedures, or evidence of clinically significant MI*

CHD equivalents, including clinical forms of noncoronary atherosclerotic ■disease, such as peripheral artery disease, abdominal aortic aneurysms and carotid artery disease, diabetes, or at least 2 cardiovascular risk factors‡

Moderately high risk (10-year risk of cardiovascular events ~10–20%): consider statin therapy at LDL-C level ≥130 mg/dl

At least 2 cardiovascular risk factors ■ ‡

Moderate risk (10-year risk of cardiovascular events <10%): consider statin therapy at LDL-C level ≥160 mg/dl

At least 2 cardiovascular risk factors ■ ‡

Low-risk: consider statin therapy ≥190 mg/dl

0–1 cardiovascular risk factors ■ ‡

*Clinically significant MI: Q-waves indicating past MI and biochemical signs of MI without electrocardiographically determined abnormalities. ‡Risk factors include: cigarette smoking, hypertension, low HDL-cholesterol (<40 mg/dl), family of premature CHD and age. Abbreviations: CHD, coronary heart disease; LDL-C, LDL-cholesterol; MI, myocardial infarction; RA, rheumatoid arthritis.

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consequences of lDl-C reduction with statins, the data suggest that cholesterol-lowering per se might be suffi-cient to explain the observed short-term benefits. these findings were confirmed in another small study, in which 20 patients with ra were randomized to receive simva-statin 40 mg per day for 4 weeks followed by 4 weeks of placebo, or vice versa.66 methotrexate treatment in 13 out of 20 patients remained unchanged throughout the study course. statin treatment resulted in reductions in lDl-C and oxidized lDl levels, as well as in the ratio of oxidized lDl to lDl-C, which was parallel ed by a significant improvement of endothelial function, as measured by FmD. notably, patients with higher inflammatory activ-ity showed considerably greater improvements in FmD than patients with low markers of inflammation.66

serum HDl level has emerged as a key player in the attenuation of inflammation and preservation of vas-cular function.67,68 However, these protective properties could in part be lost in chronic inflammatory disorders. a study conducted in 2007 showed that 12 weeks of high-dose atorvastatin combined with antirheumatic therapy restored the anti-inflammatory capacity of HDl in 20 patients with active ra, although clinical disease activity was unaltered.69 these findings are in sharp contrast with those of the tara trial,63 and could imply that statin-mediated beneficial effects on ra activity manifest only after 12 weeks.

the paucity of trials investigating the effects of statins on ra, and the small number of patients included in these studies, indicates that little attention has been paid to adequate cardiovascular prevention in these patients. the ongoing Heart Protection study 2 includes more than 8,000 patients from the uK with ra, among others with established cardiovascular diseases treated with simvastatin and subsequently randomized to receive niacin or placebo. it is hoped that the results of this study will provide more insights into the impact of simvastatin on cardiovascular morbidity and mortality in high-risk populations. while we await the outcomes of this pivotal

trial, the available data clearly support a benefit of early statin initiation in patients with ra (Box 1).

Conclusionsover the past two decades it has become increasingly clear that ra is an independent risk factor for cardio-vascular events, with an impact over and above that of the traditional risk factors for cardiovascular disease. as ra is a protracted disease, a focus on adequate cardio-vascular prevention in these patients is long overdue. Chronic inflammation is a hallmark of active ra, and provides a direct pathophysiological link between the disease and accelerated atherogenesis. Proper manage-ment of cardiovascular risk, therefore, requires immediate aggressive control of ra disease activity. statins are the cornerstone of cardiovascular risk management, offer-ing both lipid-lowering efficacy and anti- inflammatory effects. the use of statin therapy in patients with ra can both bene ficially alter ra disease activity and reduce the rate of cardiovascular events. although limited data suggest that nonstatin-mediated reduction of lDl-C is also advantageous to the cardiovascular risk profile, the majority of evidence favors statin therapy. as cardio-vascular risk does not often exceed 20% in a 10-year time span, routine initiation of statins in all patients with ra is not recommended until the results of large randomized, controlled trials become available.

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Review criteria

A search of PubMed, OVID and Cochrane databases was conducted using the terms “statins”, “HMG-coA reductase inhibitor”, “cardiovascular disease”, “atherosclerosis”, “mortality” and “morbidity” in conjunction with “rheumatoid arthritis”. The references lists of identified papers were also reviewed for studies relevant to this Review. The scientific statements and Practice Guidelines sections of the American Heart Association website and the website of the American College of Rheumatology were accessed for clinical guidelines.

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targeting cardiovascular risk in rheumatoid arthritis: a dual role for statins

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