cardio en reuma

8/18/2019 Cardio en Reuma

1/12NATURE REVIEWS | RHEUMATOLOGY ADVANCE ONLINE PUBLICATION | 1

AmsterdamRheumatology andImmunology Center,VU University MedicalCenter, PO Box 7057,1007 MB Amsterdam,Netherlands (M.T.N.).AmsterdamRheumatology andImmunology Center,

Reade, PO Box 58271,1040 HG Amsterdam,Netherlands (M.H.).Department ofRheumatology andResearch &DevelopmentDirectorate, DudleyGroup NHS FoundationTrust, Russells HallHospital, ClinicalResearch Unit,Dudley DY1 2HQ, UK(G.D.K.).

Correspondence to:[email protected]

Cardiovascular comorbidity in rheumatic

diseasesMichael T. Nurmohamed, Maaike Heslinga and George D. Kitas

Abstract | Patients with rheumatoid arthritis (RA) and other inflammatory joint diseases (IJDs) have an

increased risk of premature death compared with the general population, mainly because of the risk of

cardiovascular disease, which is similar in patients with RA and in those with diabetes mellitus. Pathogenic

mechanisms and clinical expression of cardiovascular comorbidities vary greatly between different rheumatic

diseases, but atherosclerosis seems to be associated with all IJDs. Traditional risk factors such as age,

gender, dyslipidaemia, hypertension, smoking, obesity and diabetes mellitus, together with inflammation,

are the main contributors to the increased cardiovascular risk in patients with IJDs. Although cardiovascular

risk assessment should be part of routine care in such patients, no disease-specific models are currently

available for this purpose. The main pillars of cardiovascular risk reduction are pharmacological andnonpharmacological management of cardiovascular risk factors, as well as tight control of disease activity.

Nurmohamed, M. T. et al. Nat. Rev. Rheumatol. advance online publication 18 August 2015; doi:10.1038/nrrheum.2015.112

Introduction

Compared with the general population, patients withrheumatic diseases are at increased risk of developingseveral comorbid conditions, of which cardio vascularcomorbidities are the most common and have the greatesteffect on mortality.1 The epidemiology and pathogenesisof cardiovascular comorbidities in inflammatory jointdiseases (IJDs) are particularly well-studied for rheum-atoid arthritis (RA), but have also been investigated for

rheumatic diseases such as ankylosing spondylitis (AS)and systemic lupus erythematosus (SLE). Growingawareness of this increased cardio vascular risk has ledto several efforts to unravel the underlying mechanisms,especially in RA. The elevated risk is only partly explainedby increased prevalence of traditional cardio vascularrisk factors such as age, gender, dyslipidaemia, hyper-tension, smoking, obesity and diabetes mellitus; sys-temic inflammation, genetic factors and treatment effectsmight also have important roles (Figure 1). Pathogenicmechanisms and clinical expression of cardio vascularcomorbidities vary greatly between different rheumaticdiseases, but atherosclerosis seems to be a shared factor

in all IJDs. However, not all cardio vascular comorbidityand mortality can be attributed to atherosclerosis: non-ischaemic heart failure (HF), micro vascular dysfunc-tion, cardiac autonomic neuropathy and arrhythmiasare emerging as major contributors to the cardiovascular

burden, and medications to treat the rheumatic diseasecan influence cardiovascular risk positively or nega-tively. Some cardiac manifestations show a degree ofdisease specificity—conduction disturbances and aorticinsufficiency, for example, are associated with AS.2

In this Review we focus on cardiovascular comorbid-ities resulting largely from atherosclerosis, with RA asthe predominant model. Additional (nonatherosclerotic)

mechanisms occurring in other autoimmune diseases,particularly SLE, are also considered. A logical conse-quence of the increased awareness of cardiovascularcomorbidity in rheumatic disease is a shift from its recog-nition towards prevention and treatment. Developmentof cardiovascular risk assessment models in patients withIJD is being attempted, and more evidence is emerging ofthe effects of rheumatological and cardiovascular treat-ments on cardiovascular risk and outcomes. However,despite these advances, much remains to be learned inthis field.

IJD and cardiovascular disease burden

RAPatients with RA have an increased risk of prematuredeath compared with the general population.3 The maincause for this increase in mortality is cardio vasculardisease. Several observational cohort studies have exam-ined the magnitude of the increased risk by studying theoccurrence of cardiovascular events in patients with rheu-matic diseases (generally RA). In a meta-analysis1 thatpooled study results from different parts of the world, anoverall 48% (pooled RR 1.48, 95% CI 1.36–1.62) increasedrisk for incident cardiovascular disease was observedin patients with RA, compared with the general popu-lation. The results of a prospective study of a Dutch RA

Competing interests

M.T.N. has received honoraria for lectures or advisory boardsfrom Abbvie, BMS, Janssen, Merck, Pfizer and Roche, andunrestricted educational grants from Abbvie, BMS, Pfizer andRoche. G.D.K. has received honoraria for lectures or advisoryboards, as well as hospitality, from Abbvie, BMS, Lilly, Novartis,Pfizer, Roche and UCB, and unrestricted educational grantsfrom Pfizer. M.H. declares no competing interests.

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cohort suggested that the magnitude of the cardiovascularrisk increase in RA (around twofold) is similar to thatobserved in patients with diabetes mellitus.4 This findingwas corroborated by the results of a Danish nationwidestudy 5 and attributed to a similar rate of acceleration ofatherosclerosis in these two conditions.6

In patients with RA, relative to unaffected indivi-duals, the increased risk of myocardial infarction (MI)is greater (around 68%) than that of cerebrovascular

accident (around 41%).7–9 In one study,10 compared withunaffected controls, an 87% increased risk of congestiveHF in RA was observed, mostly in rheumatoid-factor-positive patients, but whether this level of risk wouldexist in contemporary RA cohorts is unclear. Evidencederived from observational studies suggests that effec-tive control of inflammation—either with biologic ornonbiologic DMARDs, particularly anti-TNF agentsand methotrexate—is associated with reduction ofcardio vascular disease risk. Although developments intherapeutic strategies in the past couple of decades arereflected by a decline in mortality rates,11 the mortalitygap between patients with RA and the general population

Key points

■ Patients with inflammatory joint diseases (IJDs) have an increased burdenof cardiovascular disease compared with the general population

■ Inflammation and traditional risk factors contribute to the cardiovascular

risk associated with IJDs

■ IJDs and atherosclerosis are thought to have a common, inflammatorypathogenesis

■ Cardiovascular risk management is unsatisfactory in patients with IJD

■ The main pillars of cardiovascular management in IJD are pharmacologicaland nonpharmacological approaches to reduce cardiovascular r isk factors,along with tight control of disease activity

■ Coordination of care between rheumatologists, internists, cardiologists and

primary-care physicians should be increased to optimize management of

cardiovascular risk in patients with IJD

has not improved, demonstrating that cardiovasculardisease is still of major importance in these patients.12 Reports of studies in this field focus on the incidence ofatherosclerotic and ischaemic events rather than non-ischaemic cardiovascular disease. However, patientswith RA and other IJDs are not just at increased riskfor ischaemic cardio vascular disease: a range of cardiacmanifestations can present during the course of rheu-matic disease (Table 1). Classic cardiac complicationsof RA owing to inflammation, such as pericarditis andendocarditis, or long-term development of amyloid-osis are rare and seldom cause clinical ly overt diseasenowadays.13 However, recent developments in cardiacimaging suggest that microvascular disease and myo-carditis are common,14 as is cardiac autonomic neuro-pathy,15,16 particularly during active phases of the disease.The effects of these pathologies on cardiac function andrisk of sudden cardiac death need to be further evaluated.

Spondylarthropathies

Available data on spondylarthropathies indicate that,

compared with unaffected individuals, patients withpsoriatic arthritis and AS have an increased cardiovascular risk,17,18 which approaches the magnitude seenin RA. A meta-analysis assessing the occurrence of MI orstroke in patients with AS showed significant increases inMI (OR 1.60, 95% CI 1.32–1.93) and in stroke (OR 1.50,95% CI 1.39–1.62) relative to control groups.19 For psor-iatic arthritis, compared with the general population, ameta-analysis showed an increased risk of MI (OR 1.57,95% CI 1.08–2.27) and inconclusive results for stroke;pooled results included all patients with psoriasis anddid not focus on patients with psoriatic arthritis.20 Aswith RA, not all cardiovascular morbidity and mortal-

ity in spondylarthropathies can be attributed to athero-sclerosis. In patients with AS, aortitis involving the aorticroot and the ascending aorta (leading to valvular insuf-ficiency) can occur, but it rarely does so nowadays.21 The fibrosis that occurs with aortitis can extend into thecardiac tissue and cause conduction abnormalities.

SLE

In SLE, cardiac comorbidities are also common. SLE isassociated with a bimodal mortality distribution, andcardiovascular disease is by far the most importantcontributor to the second (late) peak in mortality.22 Infact, amongst rheumatic diseases, SLE is associated with

the greatest increase in cardiovascular disease risk, andthe results of an epidemiological study showed thatwomen 44–50 years old with SLE have a 50-fold increasedrisk of MI compared with women of similar age in thegeneral population.23 The cause of the increased cardiovascular disease risk in SLE is multifactorial (more sothan in IJDs). Traditional risk factors and inflamma-tion are important, but other mechanisms of endothelialdamage, such as the prothrombotic environment whereinautoantibodies against phospholipids and endothelialcells contribute to a vulnerable plaque phenotype alsoadd to the cardio vascular disease burden.24 In addition,treatment can lead to substantial corticosteroid exposure.

+

Inflammation

Medication effectsDMARDs

GlucocorticosteroidsNSAIDs and COXIBs

Cardiovasculardisease

–

Traditional risk factors

Tobacco smoking

ExerciseBlood pressure

Lipid profileGender

AgeDiabetes

Figure 1 | Contributors to cardiovascular risk in IJDs. Patients with IJDs haveincreased risk of cardiovascular disease compared with the general population,mainly resulting from traditional risk factors and inflammation. Traditionalcardiovascular risk factors include age, gender, dyslipidaemia, hypertension,smoking, obesity, lack of exercise and diabetes mellitus. Medication can affectcardiovascular risk by targeting inflammation, but can also have undesiredeffects—glucocorticosteroids, for example, are associated with dyslipidaemia

and hypertension. Inflammation can modify some traditional risk factors, thebest-known example being the influence on lipid profile. Abbreviations: COXIB,cyclooxygenase-2 selective inhibitor; IJD, inflammatory joint disease.

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Some of the mechanisms that increase cardio vascular

risk are specific for SLE and differ from those in otherIJDs.25 An example is lipid metabolism—in SLE, auto-antibodies might alter the metabolism of lipoproteinsinvolved in atherogenesis and thereby contribute toatherosclerosis. For instance, low levels of HDL can becaused by the presence of high levels of antibodies toHDL and apolipoprotein A1 in patients with SLE andcoronary ischaemia.26 Furthermore, IFNα is involvedin the pathophysiology of SLE and causes the uptake oflipids by macrophages and their transformation into foamcells, linking it to plaque formation in patients with SLE.27 These findings suggest that the management of cardiovascular risk factors in SLE should have stricter targets for

dyslipidaemia—and possibly for hypertension—than thetargets used in the general population.28

Contributions of known risk factors

Traditional risk factors are important contributors to thecardiovascular risk in the general population as well asin patients with IJD. Despite this fact, when adjusting fortraditional risk factors, the absolute cardiovascular riskfor patients with RA is still increased when comparedwith the general population. As such, RA (and possi-bly other IJDs) is an independent risk factor for cardiovascular disease.29 Traditional cardiovascular risk factorscontribute to the excess cardiovascular disease seen in

IJD, albeit in a different way than in the general popu-lation. In patients with RA, for example, smoking, malegender and history of cardiovascular disease confer pro-portionately less to the risk of developing cardio vasculardisease than in the general population,29 but this disparityis because of the presence of additional risk factors ratherthan lesser importance of traditional risk factors in IJD.

Cholesterol

Cholesterol is an example of a risk factor with specificcharacteristics in patients with RA. Hypercholesterolaemiais an important risk factor for cardiovascular disease in thegeneral population. However, assessment of cholesterol

is complicated in patients with RA. Several studies have

evaluated lipid profiles in patients with IJDs, especiallyRA,30,31 and the overall consensus is that active inflamma-tion in RA leads to a decline in levels of total cholesterol,LDL cholesterol, and HDL cholesterol compared withindividuals without RA.32 The greatest suppression occursin levels of HDL cholesterol, leading to an unfavourablelipid profile. This ‘lipid paradox’, whereby a reductionin lipid levels is associated with higher cardio vascularrisk, has also been reported in other inflammatory dis-eases as well as in sepsis.33,34 However, the results are not allconsistent, and levels of HDL cholesterol have been bothpositively 35 and negatively 36 associated with cardiovasculardisease risk in studies of patients with RA.

The lipid paradox in RA could be explained by modi-fication of lipids by inflammation, which not only lowerslipid levels, but also alters lipid structure and function,changing the usual antiatherogenic effects of HDLcholesterol into proatherogenic effects.37 At the geneticlevel, polymorphisms traditionally associated with poorrheumatological outcome in RA are also associatedwith dyslipidaemia.38 A potential explanation for theabnormal lipid profile observed in RA is that the lowcholesterol levels detected in patients with active RAare driven by high cholesterol ester fractional catabolicrates.39 In support of this hypothesis, in patients with RA,treatment with a Janus-kinase inhibitor reduces chol-

esterol ester catabolism, thereby increasing levels of HDLcholesterol and LDL cholesterol relative to pretreatmentlevels.39 In the context of cardiovascular risk assessmentin patients with RA, measurement of the ratio of totalcholesterol to HDL cholesterol is recommended in clini-cal practice, and it might be reasonable to suggest thatlipid measurements during inactive stages of the diseaseare the most representative of the overall situation in agiven patient.37,33 Evidence suggests that lipid-lowering(statin) therapy is substantially underutilized in patientswith RA who fulfill even the general population thresh-olds for this treatment.40 This unmet need for manage-ment of dyslipidaemia is also seen in patients with other

Table 1 | Cardiac involvement in inflammatory joint diseases

Cardiovascular disease Inflammatory joint disease

Rheumatoid arthritis Ankylosing spondylitis Systemic lupus

erythematosus

Atheroscleroticcardiovascular disease

Increased risk ofmyocardial infarction,cerebrovascular accident

Increased risk ofmyocardial infarction,cerebrovascular accident

Risk is mainly increasedin young women

Pericarditis Increased prevalence, usuallyof no clinical significance

Rare Common, often asymptomatic

Myocarditis Rare, associated withactive disease

Rare High prevalence in autopsystudies, often subclinical

Heart failure Common, mostly diastolicheart failure

Unknown Increased risk, mainlyin young women

Valvular heart disease Rare, mostly notclinically significant

Aortic root disease and aorticregurgitation, rare nowadays

Rare, possible association withantiphospholipid antibodies

Conduction abnormalities Uncommon, mostlyatrioventricular block or RBBB

Common, associationwith HLA-B27

Uncommon, mostlysinus tachycardia

Cardiac manifestations that can occur during the course of rheumatic disease. Increase in risk is relative to the general population. Abbreviation: RBBB, rightbundle branch block.

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IJDs,41 and could have adverse consequences in termsof cardiovascular outcome.

Body weight and physical inactivity

Another factor that seems paradoxical in patients with RAis BMI. In the general population, high BMI increases thecardiovascular risk compared with normal-to-low BMI,which seems to be protective. In a study involving Africanwomen with established RA, BMI was positively associatedwith carotid artery intima–media thickness (cIMT) andwaist-to-hip ratio was positively associated with the pres-ence of carotid artery plaque, but only in Caucasian womenfrom a ‘developed population’.42 However, patients withRA and low BMI (



Thyroid disease

Autoimmunity is often a cause of hypothyroidism, andthe coexistence of these two diseases can affect cardiovascular risk.77 Among patients with RA, those withhypothyroidism have an increased cardiovascular riskcompared with those having normal thyroid function.

This effect of hypothyroidism has traditionally beenattributed to impaired vascular endothelial function,hypertension and adverse effects on lipid profiles. Inpatients with RA, the presence of thyroid peroxidase anti-bodies, which is strongly predictive of autoimmune hypo-thyroidism, is associated with greater cIMT progressionthan in the absence of such antibodies.78 This associationsuggests that assessment of thyroid function is impor-tant in the context of cardiovascular risk management inpatients with IJD.

Genetic factors

Genetic factors have a potential role in the link between

atherosclerosis and IJDs, in particular RA. Severalpolymorphisms at loci both inside and outside theMHC region of the genome are associated with sub-clinical atherosclerosis and cardiovascular events.79–81 In this regard, associations have been found betweenHLA-DRB1*04 shared epitope alleles and endothelialdysfunction80 or cardiovascular morbidity.79 In the pres-ence of the shared epitope, the TNF-308 (rs1800629)polymorphism predisposes patients with RA to cardiovascular disease.81 Polymorphisms at loci outside theMHC region seem to be associated with the risk ofcardiovascular events independently of the presenceof traditional cardiovascular risk factors.76,82,83 In patients

with RA, polymorphisms have also been linked to dyslipi-daemia,38,84,85 hypertension65–67 and biomarkers of endo-thelial function such as asymmetric dimethylarginine.86 Some of these associations might be modified by life-style factors, such as obesity or smoking. These studiesof genetic risk factors suggest new avenues of scientificenquiry in this field.

Inflammation and cardiovascular risk

In addition to traditional risk factors, inflammation isan important independent contributor to cardio vascularrisk. The link was first established in the general popula-tion, in which C-reactive protein (CRP) levels are asso-ciated with cardiovascular risk.87 In patients with IJD,markers of active inflammation, including levels of CRP,erythrocyte sedimentation rates, numbers of affected joints and disease activity scores, as well as disease sever-ity or cumulative inflammation (estimated by radio-graphic scores), have all been linked to cardio vascularrisk.79,88–92 IJDs and atherosclerosis are considered tohave an inflammatory pathogenesis, in which the mecha-

nisms of formation, progression, instability and ruptureof the atherosclerotic plaque resemble the mechanismsobserved in synovitis.93 Although high-grade systemicinflammation seems to be central to the cardio vascularrisk in patients with IJD (Figure 2), the interactionbetween inflammation, traditional risk factors, geneticfactors and medication effects has not yet been elucidated.

Effects on vascular function and morphology

The striking similarities between the inflammatory pro-cesses in blood vessels and in joints of individuals withIJDs, together with the links between markers of inflam-mation and cardiovascular disease in the general popu-

lation, have led to the hypothesis that inflammation isa major contributor to accelerated atherosclerosis.94

The pathways by which rheumatic inflammation leadsto accelerated atherosclerosis are not completely clear.The endothelium has a key role in vascular function asan endocrine organ, producing vasoactive factors thatcontrol vasomotor tone, homeostasis and interactionsbetween the vessel wall and circulating blood cells. Nitricoxide is one of the most important of these factors, andinflammation can disrupt the equilibrium between theproduction of nitric oxide and other vasoactive factors,leading to endothelial-cell dysfunction, which in turn isassociated with atherosclerosis.95

Noninvasive techniques for the assessment of periph-eral vascular function and morphology, which correlatewith coronary circulation, provide the means to assess vascular health without compromising patient safety.96 Endothelial function can be assessed by testing the abilityof endothelial cells to release nitric oxide in response to various stimuli, which is determined by quantificationof vessel dilation. Assessment of pulse-wave velocityand pulse-wave analysis provide information on arterialstiffness as an outcome of functional and morphologicalchanges in the vasculature. Structural changes result-ing from advanced atherosclerosis can be assessed bymeasurement of cIMT.

Nonischaemic

cardiovascular diseaseProthrombotic state

Accelerated

atherosclerosis

Plaque composition

Stable plaque Unstable, ruptured plaque

Inflammation

Figure 2 | Contribution of inflammation to cardiovascular disease. Rheumatic

inflammation is thought to be a major contributor to accelerated atherosclerosis.IJD is associated with frequency, severity and vulnerability of coronary plaques.Patients with IJD have higher risk of infarction after plaque rupture than individualswithout IJD, because of a hypercoagulable state induced by inflammation.Nonischaemic heart disease like myocarditis, heart failure and myocardialdysfunction also contributes to the burden of cardiovascular disease in IJD.Abbreviation: IJD, inflammatory joint disease.

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Vascular function and morphology are both affectedin patients with RA, but a clear association with inflam-mation has not been demonstrated.97 The results ofexaminations of the effects of antirheumatic treatmenton vascular function and morphology are inconsistent,possibly owing to variation in patients’ clinical responses.

Effects on plaque composition

In addition to accelerated atherosclerosis, the compo-sition of the atherosclerotic plaque has a role in theincidence of cardiovascular disease in patients with IJD.In patients with RA and no history of cardiovasculardisease, compared with matched controls without RA,coronary plaques are more frequent (71% versus 45%),more severe and more prone to rupture.98 Plaque vulner-ability is associated with rheumatic disease activity,demonstrating a link between inflammation and plaquecomposition.98,99 Plaques in patients with RA who haveactive disease are more vulnerable than in those with RAin clinical remission.99 Compared with matched controlswithout RA, patients with RA have worse outcomes after

acute coronary syndrome, with increased deaths andincreased and earlier recurrence of MI.100 The histo-logical features of coronary artery disease in patients withRA include vascular inflammation and unstable plaquecomposition with higher frequency than in controls,suggesting that the mechanisms responsible for cardiovascular morbidity and mortality are different in patientswith RA compared with the general population.101

Effects on prothrombotic phenomena

In addition to accelerated atherosclerosis and unstableplaques with increased chance of rupture, patients withIJD have higher risk of infarction after plaque rupture

than individuals without IJD, owing to a hypercoagulablestate induced by inflammation in IJD.102 The immune andcoagulation systems are closely linked:102 inflammatorycytokines induce expression of tissue factor, inhibit theprotein C system and act as inhibitors of fibrinolysis,promoting a hypercoagulable state. Platelets are impor-tant factors in normal homeostasis and also have a rolein inflammation with the release of a range of thromboticand inflammatory molecules; the adhesion and aggre-gation of platelets are key to the processes that occurat the onset of MI after plaque rupture.103,104 Althoughdata relating to venous thrombotic events in IJDs arescarce, it seems that the risks of pulmonary embolism

and deep-vein thrombosis are increased in patientswith RA when compared with the general population.105 Hypercoagulability is of particular interest in SLE becauseantiphospholipid autoantibodies are highly prevalent inthis disease (and to a lesser extent in RA), so patients withSLE have a high risk of (venous) thrombosis.106,107

Nonischaemic cardiovascular disease

In addition to atherosclerotic ischaemic heart disease,myocarditis and myocardial dysfunction also con-tribute to the burden of cardiovascular disease in IJD.Myocarditis is common in RA, with a reported post-mortem incidence of 11–50%,108 but other inflammatory

pathologies, such as cardiac tamponade or constrictivepericarditis, are very rare. Myocarditis has been linkedto HF,109 but is not always recognized as a cause of HFin patients with RA because myocarditis is not detectedby echocardiography—cardiovascular magnetic reson-ance (CMR) might be a better tool for this purpose butrequires prospective evaluation.110 HF is more commonin patients with RA than in the general population, with atwofold higher incidence.10 Affected patients present withdiastolic dysfunction but preserved left ventricle ejectionfraction, reflecting the influence of chronic inflamma-tion on the myocardium, which induces hypertrophy andfibrosis and causes impairment in contractility.110,111 Left ventricular diastolic dysfunction and pulmonary hyper-tension have been observed in patients with longstandingRA without history of cardiovascular events and withoutclassic cardiovascular risk factors.112 Not only do patientswith RA and HF present differently from those withoutHF, their prognoses are also worse, with significantlyhigher mortality.113

Predicting cardiovascular risk in IJDRisk-prediction models

The well-established cardiovascular risk in patientswith RA, and to a lesser extent with other IJDs, impliesthat cardiovascular risk assessment should be part ofroutine care in such patients. Clinicians should be ableto identify those patients at highest risk, to adapt theirmanagement accordingly. Unfortunately, cardiovascularrisk in patients with RA is still underestimated in clini-cal practice,114 and despite improvements in the under-standing of the risk and the recommendations given bythe European League Against Rheumatism (EULAR)Task Force, the management of cardiovascular risk

remains unsatisfactory.63,115In the past 12 years, several algorithms have been

developed to aid the prediction of risk for cardiovascular disease, such as the Framingham Risk Score,116 the Reynolds Risk Score,117,118 QRISK®2 (EMIS and theUniversity of Nottingham, UK)119 and SCORE.120 Theserisk models are largely based on longitudinal cohortstudies performed in the general population, raising thequestion of whether they can also be of use in patientswith IJD. QRISK®2 was developed in a population thatincluded patients with RA, and RA is an independentrisk factor in the algorithm. The Reynolds Risk scoreincorporates CRP levels, but not within the range seen

in high-grade inflammatory diseases. None of these riskmodels takes account of the influence of inflammationand antirheumatic medication on lipids and other classicrisk factors, nor considers systematic differences betweenIJD populations (which are predominantly female, withrestricted age ranges) and the general population. Someattempts have been made to address these problems.For instance, the EULAR Task Force has recommendedadapting risk models when calculating cardio vascularrisk in patients with RA by incorporating a multiplicationfactor of 1.5 when a patient meets two or more of thefollowing three criteria: disease duration longer than10 years, positivity for rheumatoid factor or ACPA and

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presence of extra-articular manifestations.121 The 2012ESC guidelines,122 as well as QRISK®2, incorporate RA asan independent cardiovascular risk factor in their models,although in the ESC recommendations the presence ofRA has no inf luence on clinical management, in con-trast to QRISK®2. However, neither of these approachesseems to improve accuracy in estimates of cardio vascularrisk in patients with IJD relative to models that do notinclude RA,123,124 and risk-stratification models for thisgroup of patients require improvement. The 2013 guide-lines of the joint task force of the American College ofCardiology (ACC) and American Heart Association(AHA) used the novel Pooled Cohort Equations to cal-culate the 10-year risk of atherosclerotic cardiovasculardisease.125 Compared with previous guidelines, in patientswith RA, this calculation considerably increased thenumber who would be recommended for cholesterol-lowering statin treatment, but did not improve predictionof cardiovascular risk.126,127

Patients with RA often suffer from asymptomaticatherosclerosis and silent ischaemic disease in the pres-

ence of an unstable plaque, which can lead to suddendeath.128 An early diagnosis of atherosclerosis, beforethe onset of clinically evident cardiovascular disease,can enable earlier and more aggressive primary preven-tion measures. Imaging studies and specific biomarkerscould potentially help with early diagnosis. Alternatively,IJD-specific risk-prediction models might not be neces-sary if an approach of ‘blanket primary prevention’ ofspecific lipid and blood-pressure targets was taken in allpatients with IJD, similar to the practice associated withdiabetes.122 Whereas such an approach would be simplerthan developing specific models, its safety, effectivenessand cost-effectiveness in these populations would need

to be formally assessed.

Imaging techniques

The underestimation of the cardiovascular risk in RAmight occur partly because of the high prevalence ofasymptomatic atherosclerosis in this group of patients.Carotid ultrasonography is a noninvasive technique usedto detect atherosclerotic plaques in the carotid artery. Thepresence of carotid atherosclerosis can be used as a surro-gate for coronary atherosclerosis. In addition, carotidultrasonography provides measurements of the cIMT.In RA, cIMT is increased compared with individualswithout RA,129 and this increase is associated with a higher

incidence of cardiovascular events.130 In the 2012 ESCguidelines,122 the presence of carotid plaques was recog-nized to be equal to having cardiovascular disease,whichimplies that the addition of ultrasonography to riskassessment would result in the classification of morepatients as being at high risk than current models withoutimaging. In a study of the use of carotid ultrasonographyin patients with RA, this technique led to the categoriza-tion of 39% of patients into the group with high risk ofcardio vascular disease, whereas only 7% were estimatedto be at high risk with the Framingham Risk Score. 92 Similarly, in patients with RA, compared with the modi-fied EULAR SCORE alone, addition of the findings of

carotid ultrasonography improves the sensitivity in thehigh cardio vascular-risk group.131 In patients with psori-atic arthritis, ultrasonographic assessment of indi vidualsstratified by Framingham Risk Score results in reclassifi-cation of a considerable number of patients into highercardio vascular risk categories.132 Although these resultssuggest that the addition of carotid ultrasonography couldimprove cardiovascular risk assessment in patients withIJD, it has not yet been demonstrated that this inclusionwould ultimately lead to decreased cardiovascular risk.Issues of feasibility, accessibility and cost relating to theuse of carotid ultrasonography also need to be addressedbefore it can be recommended.

Biomarkers

In addition to imaging techniques, the value of a numberof biomarkers in cardiovascular-risk prediction hasbeen investigated, at least in the general population.These biomarkers include genetic factors, markers ofinflammation, immunological markers and markersof endothelial function.6 For example, levels of the cyto-

kine receptor osteoprotegerin (also known as tumornecrosis factor receptor superfamily member 11B) areassociated with the presence of cardiovascular diseasein patients with RA,133 possibly through an associationwith endothelial activation and carotid atherosclerosis.134 Angiopoietin-2 is another marker of endothelial functionthat correlates with cardio vascular disease in patientswith RA.135 Researchers have also evaluated the utility ofB-type natriuretic peptide as a marker for cardiovascularrisk in the presence of rheumatic disease.136 Serum uricacid levels have associations with hypertension,137 renaldysfunction138 and cardiovascular disease139 in patientswith RA, in the general population and in other at-risk

populations, but it remains unclear whether they reflectspecific pathogenic pathways or are epiphenomena.140 Microalbuminuria141 and mean platelet volume142 areassociated with hypertension in patients with RA, butthe utility of these factors in the prediction of cardiovascular risk is not known. Asymmetric dimethylarginineand symmetric dimethylarginine are potential biomark-ers of cumulative inflammatory vascular damage andcardiovascular disease in RA.143–145

The use of biomarkers in risk-prediction models toimprove cardiovascular risk stratification was demon-strated in a large European population wherein addi-tional measurement of the combination of N-terminal

pro-brain natriuretic peptide, CRP and troponin I ledto an improved 10-year-risk estimation, compared witha conventional-risk-factor model alone.146 The valueof these biomarkers for risk prediction in the presenceof IJDs is not known. A difficulty in the assessment ofthis value is that the influence of IJD activity and treat-ment on biomarker levels has not yet been determined.Another issue is that, whereas in the general populationlarge sample sizes are available, IJD cohorts are muchsmaller, making it more difficult to validate biomarkersagainst specific end points (such as MI), meaning thatinternational collaborations are likely to be required inthis field.

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Cardiovascular risk management

Risk assessment provides opportunities for disease prevention. From the perspective of the rheumatologist, themanagement of cardiovascular comorbidity of patients

with IJD has three main principles: pharmacologicalmanagement and nonpharmacological management ofcardiovascular risk factors, and tight control of diseaseactivity (Figure 3). Unfortunately, the risk of cardiovascular disease in patients with RA is still not fully rec-ognized, and these patients receive preventive measuresless often than the general population.

Lifestyle interventions

Lifestyle interventions should be the first steps in cardiovascular risk management, and patients should be advisedto quit tobacco smoking and to engage in regular physi-cal activity. Evidence pertaining to lifestyle interventions

demonstrates that exercise has several cardio vascularbenefits in patients with RA.46 Structured exercisetherapy improves microvascular and macro vascularfunction and cardiorespiratory fitness, and decreasescardiovascular risk.46,47

Pharmacological interventions

In the general population, and also in patients with dia-betes, preventive measures such as lowering blood pres-sure and lipid levels are effective in reducing the burden ofcardiovascular disease.147 Whether these measures are alsobeneficial for patients with IJD has not yet been studiedsufficiently, although, notably, it seems that statins have a

moderate anti-inflammatory effect in RA.148 Large, ran-domized, controlled trials are necessary to compare theeffects of preventive measures, with cardio vascular diseaseoutcomes as end points. Such trials require large numbersof patients and several years of follow-up observation, andare very difficult to conduct in populations of patients withIJDs. Despite the limited availability of evidence relatingto the management of traditional risk factors in patientswith rheumatic diseases, wide-ranging support exists forthe practice of offering cardiovascular risk managementto all patients meeting the criteria set for risk reduction inthe general population. This strategy would require thatall patients with IJD are screened regularly, and when anincrease in risk is identified, patients should be managedaccordingly. However, a key question remains regardingwho is responsible for the preventive care of this group ofpatients. In most countries, primary-care physicians carryout cardiovascular risk management. Currently, aware-ness of the high risk in this group of patients is inadequateamong all health-care professionals, from primary-carephysicians to cardiologists and even rheumatologists.

Therefore, achieving adequate awareness is an importantobjective, which should lead to appropriate cardiovascularrisk screening and preventive measures.

Control of disease activity

Tight disease control is thought to improve all outcomesin IJDs, including cardiovascular outcomes, although ran-domized trials investigating cardio vascular outcomes inthis disease management approach are lacking. Chronicsystemic inflammation contributes substantially to thecardiovascular risk associated with IJDs, and adequatesuppression of disease activity is necessary to reduce thisrisk. This goal can be achieved by early diagnosis and

treatment of IJDs. However, from the cardiovascular pointof view, the best way to control inflammation is unknown.Several DMARDs are available for treatment of IJDs, andalthough they might all decrease cardiovascular risk byreducing inflammation, other possible cardioprotectiveor deleterious properties are also important to consider.The influence of antirheumatic therapies on lipid levelshas received particular attention because of the inter-action between lipids and inflammation, although theclinical relevance of this influence is uncertain. Notably,all the available evidence relating to the effects of anti-rheumatic therapy on cardiovascular disease is derivedfrom obser vational studies, and caution is required when

making conclusions on the basis of this evidence, becauseof potential sources of bias.

NSAIDs and cyclooxygenase-2 inhibitors

Although the development of synthetic and biologicDMARDs has led to substantial reductions in the chronicuse of NSAIDs and cyclooxygenase-2 selective inhibi-tors (COXIBs) in the treatment of IJDs, these agents stillhave important roles in disease management. However,the use of NSAIDs and COXIBs is associated with cardiovascular risk in the general population.149 Subgroup ana-lysis150 identified patients with RA as a cardio vascular-riskgroup, but only in association with the use of rofecoxib

Cardiovascular risk management

Control ofdisease activity

Early diagnosis

Antirheumatic therapy Nonbiologic DMARDs

Biologic DMARDs

NSAIDs

Glucocorticosteroids

Nonpharmacologicalmanagement of

risk factors

Smoking cessation

Physical activity

Healthy diet

Pharmacological

managementof risk factors

Statins

Antihypertensives

Figure 3 | Principles of cardiovascular risk management by rheumatologists.

From the perspective of the rheumatologist, the management of cardiovascularcomorbidity of patients with IJD has three main principles. Pharmacologicalmanagement of cardiovascular risk factors includes medication to control bloodpressure and lipid levels. Nonpharmacological management of cardiovascular riskfactors includes lifestyle interventions such as cessation of tobacco smoking andengagement in regular physical activity. Control of disease activity consists ofstrategies to control the chronic systemic inflammation in IJD, by means ofDMARDs, NSAIDs, cyclooxygenase-2 selective inhibitors and glucocorticosteroids.Abbreviation: IJD, inflammatory joint disease.

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and valdecoxib, both of which have now been withdrawnfrom the market. A systematic review and meta-analysis,151 published in 2015, also identified cardiovascular risk inpatients with IJDs, which was largely associated withthe use of rofecoxib, and not with NSAIDs or celecoxib.Notably, treatment with NSAIDs and COXIBs can havebeneficial effects in many patients with RA, perhaps byreduction of inflammation and improvement of physi-cal activity. The risks and benefits resulting from theseanti-inflammatory treatments in patients with IJDsrequire clarification.

Glucocorticosteroids

Glucocorticosteroids have a complex and contro versialrelationship with cardiovascular risk. They are veryeffective at treating inflammation, which is associatedwith cardiovascular risk. However, glucocorticosteroidtreatment can increase insulin resistance from baselinelevels, induce hypertension and cause metabolic syn-drome, thereby increasing cardiovascular risk. Long-term use of high-dose glucocorticosteroids (>7.5 mg of

prednisolone equivalent daily) is associated with mortal-ity in patients with RA, but the net cardiovascular effectof limiting glucocorticosteroid exposure needs to befurther elucidated.152

Nonbiologic DMARDs

Studies examining the effect of nonbiologic DMARDs oncardiovascular risk have mainly focused on methotrex-ate, which is the cornerstone of RA therapy. In patientswith RA, methotrexate treatment seems to reduce cardiovascular risk relative to patients without methotrexate, butthe mechanisms responsible for this protective propertyare not clear.151 In terms of the activity of methotrexate,

suppression of inflammation seems to be the most impor-tant pathway for lowering cardiovascular morbidity andmortality. Currently, this inflammatory hypothesis is beingtested by administration of low doses of methotrexate topatients with prior MI and persistently elevated CRP,to determine whether methotrexate can have a role in theprevention of secondary cardiovascular disease.153

Biologic DMARDs

Inhibitors of TNF are utilized in the treatment of IJDs.Anti-TNF therapy reduces inflammation and is associated

with cardiovascular risk reduction, compared with non-biologic DMARDs, in patients with RA.151,154 Anti-TNFtherapy in patients with RA also modifies lipid levels frombaseline, increasing total cholesterol, HDL cholesterol, tri-glycerides and possibly LDL cholesterol.155 These changesprobably reflect a normalization of lipid levels by sup-pression of inflammation. Moreover, the antiatherogenicproperties of HDL cholesterol seem to be restored by TNFblockade.85 Lipid changes are also frequently reported inclinical trials of tocilizumab, a humanized monoclonalantibody against the IL-6 receptor that inhibits the IL-6signalling pathway. A meta-analysis identified an effectin patients with RA of treatment with tocilizumab (andalso tofacitinib, but not anti-TNFs), with increased levelsof total cholesterol, HDL cholesterol and LDL cholesterolcompared with placebo.156 The greater effect of tocili-zumab on lipid levels relative to other biologic agents isnot a complete surprise, because IL-6 affects serum lipidlevels by fatty acid mobilization into peripheral tissues.157

Conclusion and future perspectives

The body of evidence relating to cardiovascular diseasein IJDs is growing, but the mechanisms underlying theincreased cardiovascular risk in patients affected by theseconditions compared with the general population are notyet clear. The results of further research could delineatespecific mechanisms in the pathogenesis of ischaemicheart disease and address other pathologies, such asmicrovascular dysfunction and autonomic neuropathy.This knowledge will help to identify novel therapeutictargets for the prevention and treatment of heart diseasein patients with IJDs. Existing models for the predictionof cardiovascular risk are not sufficiently accurate inthese patients, and the development of disease-specific

approaches is necessary—although very challenging.Prospective clinical trials are needed to assess the rolesof antirheumatic therapies, pharmacological controlof traditional risk factors and lifestyle-modificationstrategies in the potential reduction of cardiovascularrisk in IJDs. In the meantime, systematic screening forcardiovascular risk and coordination of care betweenrheumatologists, internists, cardiologists and primary-care physicians is imperative to achieve optimal manage-ment of cardiovascular risk and cardiovascular disease inpatients with IJDs.

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Author contributions

All authors contributed equally to discussion ofcontent, writing the ar ticle and reviewing and editingthe manuscript before submission.

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