Online Medical Reference

Cardiovascular Risk and Prevention in Rheumatic Diseases

Elaine Husni

Atul Khasnis

Published: August 2010

We now recognize coronary artery disease (CAD) as a significant contributor to morbidity and mortality in various rheumatic diseases. This enlightenment has stemmed from clinical observations in patients as well as from basic research that is providing a better understanding of this connection. Improved understanding of the underlying mechanisms, better ability to assess the cardiovascular risk in these patients, and institution of timely intervention can result in improved outcomes. An ideal risk-assessment model is still needed, and an alliance between preventive cardiology and rheumatology can be immensely useful in comprehensive delivery of care to patients with rheumatic diseases.

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Connection Between Coronary Artery Disease and Rheumatic Disease

What is the connection between CAD and rheumatic diseases?

The inflammatory nature of atherosclerosis has been proved beyond doubt.1 Atherosclerotic affliction of the endothelium and rheumatoid affliction of the synovium can be envisioned as similar inflammatory processes that affect single-cell-thick layers and result from infiltration by cells of the immune system (macrophages, T-cells) as well as transformation and dysfunction of resident cells (endothelial and synovial fibroblasts, respectively). Abnormalities in cadherins, which are transmembrane adhesion proteins, have been proposed to play a role in synovial fibroblast proliferation in rheumatoid arthritis (RA)2 and smooth muscle proliferation in atherosclerosis.3 Identical clonal T-cell subset (CD4+ CD28-) expansion has been observed in the synovium of patients with RA and in the atherosclerotic plaques of patients with unstable angina.4 The initial inciting event in either process is unknown, but ultimately the earliest observed pathology is cellular dysfunction that creates an imbalance in a host of cellular processes that are finely regulated at various levels. Most systemic autoimmune diseases are characterized by inflammation, and this is hypothesized to be the driver fueling accelerated atherosclerosis observed in these diseases (Box 1).

Box 1 Mechanisms of Accelerated Atherosclerosis in Systemic Inflammatory Autoimmune Disease
Direct Effects
Endothelial dysfunction
  • Antibody mediated endothelial cell damage
  • Immune complex mediated endothelial cell damage
  • Cytokine mediated
Prothrombotic milieu
Dysfunctional high-density lipoprotein
Autoantibodies
Indirect Effects
Hypertension
Diabetes/insulin resistance
Renal dysfunction
Increased body mass index
Dyslipidemia
Hyperhomocystinemia

Endothelial dysfunction is the earliest event that signals the development of atherosclerosis. Circulating cytokines that cause endothelial dysfunction accompany systemic inflammation. The normal endothelium is a single-cell-thick semipermeable membrane that has myriad balanced functions (antithrombotic, vasodilator, anti-inflammatory, nonadhesive for platelets, semipermeable). Inflammatory processes disrupt many of these functions. In addition to causing direct effects on the endothelium, inflammation can promote atherosclerosis by indirect mechanisms such as unfavorable alteration of the lipid profile, arterial wall stiffening, and alteration of body-mass index. Tumor necrosis factor α (TNF-α) is a key cytokine in many inflammatory rheumatic diseases such as RA and psoriatic arthritis.

One of the earliest actions of TNF-α discovered was its ability to cause dyslipidemia (hypertriglyceridemia) in patients with Trypanosoma brucei infection.5 This dyslipidemic action of TNF-α is mediated by suppression of lipoprotein lipase in adipocytes6 and also by release of the most active form of the enzyme from the endothelial cell surface.7 TNF-α directly affects endothelium, rendering it a promoter of coagulation and inflammation by altered cell morphology and altered surface expression of molecules.8 Other cytokines commonly released during inflammatory diseases such as interferon-ɣ (INF-ɣ), interleukin-1 (IL-1), and IL-6 also have an adverse effect on the lipid profile, rendering it proatherogenic.

INF-ɣ is also known to inhibit lipoprotein lipase (similar to TNF-α), but it might have an antiatherogenic role as well.9 The resulting lipid profile is hypertriglyceridemia, low total cholesterol, low high-density cholesterol (HDL), and increased oxidized low-density cholesterol (ox-LDL). The dyslipidemia also correlates with the degree of inflammation in various diseases with improvement in atherogenic profile seen after treatment.10

Other mechanisms of accelerated atherosclerosis include hyperhomocysteinemia11 and dysfunctional HDL cholesterol observed in diseases such as systemic lupus erythematosus (SLE) and RA. C-reactive protein (CRP), which is a commonly elevated acute phase reactant in systemic inflammatory autoimmune diseases, might serve as a marker for underlying inflammation, but it also might play a pathogenic role in endothelial damage via complement activation.12 (see Box 1)

Studies of plaque histology in patients with RA have shown extensive involvement of cells of the immune system in plaque formation and potential destabilization resulting in plaque rupture that often underlies precipitation of clinical acute coronary syndromes.13 The presence of T and B lymphocytes in the atherosclerotic plaque might also be the missing link that implicates infection as a causative factor in this disease. In a study of atherosclerotic plaques from two patients who were dying of ischemic heart disease, prominent B lymphocytes were described in the adventitia and within the plaque, suggesting different immune alterations than those observed in traditional atherosclerosis.14

Circulating immune complexes abound in SLE, and these might have a role in myocardial infarction.15 Studies have shown that IFN-ɣ and immune complexes bound to C1q reduce expression of the enzyme cholesterol 27-hydroxylase in human aortic endothelial cells, peripheral blood mononuclear cells, and monocyte-derived macrophages. Immune complexes down-regulate the enzyme only after complement fixation via interaction with the 126-kD C1qRp protein on endothelial cells.16 The CD40 ligand (CD40L) on the T cell that binds CD40 on the macrophage as a costimulatory interaction has also received a lot of attention in atherosclerotic mechanisms in SLE; T cell activation via this mechanism is common to both.17,18 Interestingly, although CD40L plays a role in atherosclerotic plaques, soluble CD40L does not correlate with measures of subclinical atherosclerosis in SLE.19 The presence and titers of antibodies to oxidized LDL (oxLDL) have been shown to be specific for SLE.20 but their exact role in pathogenesis remains to be determined. Insulin resistance as measured by the Homeostasis Model Assessment (HOMA) has been found to be more elevated in patients with RA (correlating with IL-6 and TNF-α levels) than in SLE (correlating with body mass index).21

There is ongoing research to unravel other mechanistic connections between atherosclerosis and systemic autoimmune disease. The main difficulty lies in determining whether the discovered molecule or cell is truly pathogenic, an innocent bystander, or merely an epiphenomenon. To this end, applying principles similar to Koch’s postulates in whole or part may be necessary.

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Specific Disease States

Rheumatoid Arthritis

In a prospective cohort study of 114,342 women participating in the Nurses’ Health Study who were free of cardiovascular disease and RA at baseline in 1976, 527 incident cases of RA and 3622 myocardial infarctions and strokes were confirmed during 2.4 million person-years of follow-up. The adjusted relative risk in women with RA was 2.0 for myocardial infarction and 1.48 for stroke. Women with at least 10-year duration of RA had a threefold risk for myocardial infarction.22 In a British cohort study, the mere presence of rheumatoid factor (RF) has been associated with a threefold risk of ischemic heart disease in men, independent of traditional cardiovascular risk factors.23 This has also been shown in a Finnish study of more than 4000 patients who were followed for 15 years. The presence of moderate titer RF (>1 : 28) predicted worse survival even in patients who did not develop RA (false-positive RF).24 This raises the question about what RF positivity might actually represent in terms of being a marker for other systemic processes that ultimately accelerate senescence.

In a study of 606 seropositive RA patients over 15 years from North Sweden, the standardized mortality ratio in both sexes for cardiovascular disease was 1.46 and for ischemic heart disease was 1.54 compared to the reference population. Using multiple Cox regression analyses, male sex, higher age at disease onset, and former cardiovascular event increased the death rate. Male sex, high age at disease onset, and hypertension increased the risk of cardiovascular events. Interestingly, traditional risk factors such as diabetes mellitus or treatment with corticosteroids, DMARD, or hormone replacement therapy did not influence the risks of death or first cardiovascular event.25 The combination of positivity for RF and anti–cyclic citrullinated peptide (anti-CCP) antibodies with smoking carries the highest risk (eightfold) of cardiovascular mortality.26 An older age of onset of RA is also associated with more-severe CAD.27 Because inflammation is a major determinant of accelerated atherosclerosis in RA, it is not surprising that more severe and extra-articular disease is associated with onset of coronary artery disease and the first-ever clinical cardiovascular event.28 Patients with RA also have a more-severe quality of atherosclerosis that is characterized by inflammatory plaques that are more unstable and prone to rupture.29 The increased cardiovascular risk in RA stems from risk factors directly related to disease as well as worsening traditional cardiovascular risk factors.

An increased incidence of the metabolic syndrome has been observed in patients with RA. In a study of 154 patients with RA, the metabolic syndrome was present in 42% of patients with long- standing RA, 30% with early RA, and 22% of controls (P = 0.03). Patients with the metabolic syndrome had a twofold increase in coronary-artery calcification scores on electron beam computed tomography (EBCT) independent of age and sex.30 The role of TNF-α and its downstream signaling molecule nuclear factor κB (NF-κB) are well established in RA. Osteoprotegerin is a decoy receptor for the NF-κB ligand. Patients with RA have been found to have elevated osteoprotegerin levels that correlate with coronary-artery calcification independently of cardiovascular risk factors and disease activity.31 Osteoprotegerin is being studied as a biomarker for heart failure and long-term outcomes after acute coronary syndromes, but it has not been studied in RA.32

Significant subclinical atherosclerosis exists in patients with RA. If subclinical atherosclerosis is detected, risk factors, including inflammation, will have to be modified more aggressively. Subclinical atherosclerosis has been assessed using EBCT,33 and carotid artery plaque has been assessed by measuring intima-medial thickness (IMT) using B-mode ultrasound.34 Other measures for assessing vascular disease include measurement of pulse wave velocity and augmentation index (measures of arterial stiffness)35 and echocardiographic assessment of coronary flow reserve (for coronary microcirculation).36 Abnormalities in all these measures have been reported in patients with RA and correlate with duration of disease. These alterations reflect the multilevel cardiac and vascular dysfunction associated with RA. Silent myocardial ischemia is common in patients with RA.37 When patients develop clinical acute coronary syndromes, their presentation is more likely to be atypical.38 The Framingham score is useful and correlates with the duration of disease and presence of coronary calcification.39

Controlling disease activity is key to improving survival in these patients. Methotrexate, one of the most commonly used drugs for RA, has been shown to reduce cardiovascular mortality in these patients (hazard ratio 0.3 for cardiovascular death and 0.6 for noncardiovascular death).40 However, hyperhomocysteinemia has been reported in patients on methotrexate and sulfasalazine and in patients with a mutation in the methylene tetrahydrofolate reductase (MHTFR) gene.41 A study of the British Biologics Register comparing rates of myocardial infarction (MI) in 8670 RA patients treated with anti–TNF-α agents and 2170 patients with active RA treated with traditional disease-modifying antirheumatic drugs (DMARDs) found that RA patients treated with anti–TNF-α did not have a lower incidence of MI, but the risk of MI was significantly lower in those who responded to therapy by 6 months compared with nonresponders (3.5 vs. 9.4 per 1000 person-years).42 This reflects better control of inflammation in these patients.

Statins are now well known to have immunomodulating properties. In patients with RA treated with atorvastatin (40 mg), significant improvement in disease activity scores for RA were observed at 6 months, with a clinically meaningful response achieved in patients on atorvastatin compared to placebo (31% vs. 10%). C-reactive protein, erythrocyte sedimentation rate, and swollen joint count all improved in the atorvastatin group.43

One of the largest trials, the QUEST-RA study conducted in 15 countries and including more than 4000 patients, echoes the previous findings of male susceptibility to cardiovascular disease and myocardial infarction, the association of cardiovascular disease with extra-articular RA disease, and reduction in mortality with use of disease-modifying therapy.44

The search for understanding the pathophysiology of atherosclerosis in patients with RA aspires to provide a better explanation for the observed but unaccounted-for increased cardiovascular risk and possible therapeutic targets for intervention. One of the breakthroughs in this area has been the discovery of proinflammatory HDL.45 This is observed in 20% of patients with RA and is dysfunctional in that it does not protect LDL against oxidation, thereby removing this intrinsic protective mechanism against atherosclerosis. Another molecule of interest has been the receptor for advanced glycosylation end products (RAGE), which might influence the response to inflammation.46

Systemic Lupus Erythematosus

The bimodal distribution of mortality in lupus was recognized three decades ago; the first peak results from the disease, and the second peak is an effect of premature cardiovascular mortality. Patients with SLE have a 4- to 10-fold greater risk of atherosclerotic cardiovascular disease and a 50-fold increase in myocardial infarction compared with the general population.47 The mean age of first myocardial infarction among SLE patients is approximately 49 years.48 Among SLE patients younger than 35 years, acute myocardial infarction is the most common initial clinical presentation of CAD, followed by congestive heart failure, sudden death, and angina.49 Coronary artery affliction from SLE can result from myriad mechanisms, including but not limited to accelerated atherosclerosis, dyslipidemia, hyperhomocystinemia, hypercoagulability related to antiphospholipid antibodies, and vasculitis.

In 1975, Bulkley and Roberts noted coronary atherosclerosis in 8 of 36 young SLE patients at autopsy and first implicated corticosteroids in its etiology.50 Similar to RA, subclinical atherosclerosis has been well documented in patients with SLE using IMT,51 pulse wave velocity,52 and determination of coronary flow reserve53; accelerated atherosclerosis has been reported despite good disease control in long-standing SLE, underlining subclinical inflammation.54 Subclinical atherosclerosis on EBCT also correlates with cardiac risk scores such as the Framingham Risk calculator and the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) score.55 Similar to patients with RA, this well-appreciated increased cardiovascular risk is based on a combination of traditional cardiovascular risk factors, systemic inflammation, and yet-unknown drivers of the atherosclerotic process. Older age at diagnosis, longer disease duration, higher cumulative corticosteroid dose, hypertension, and hypercholesterolemia, have all been shown to predict cardiovascular mortality.56 The relationship with corticosteroid use may be direct from ensuing dyslipidemia or diabetes, but the need to use of corticosteroids could also reflect greater underlying inflammation. Other risk factors include male sex, elevated homocysteine, and renal insufficiency.57 Hydroxycholoroquine has a beneficial effect on the lipid profile in patients with SLE.58 Increased IMT in patients with SLE has been correlated with hypertension, systematic coronary risk evaluation index, CRP, vascular cell adhesion molecule-1 (VCAM-1), von Willebrand’s factor, matrix metalloproteinase 3 (MMP-3), and tissue inhibitor of metalloproteinase 1 (TIMP-1) and inversely correlated with MMP-9.59 This has an impact on arterial remodeling in patients with SLE. We now know from studies of coronary artery disease that arterial remodeling is as important a determinant of luminal narrowing as plaque progression. Negative or constrictive remodeling is detrimental to maintaining arterial patency.

Compared to patients with primary antiphospholipid syndrome (APS), carotid plaque was more prevalent and appeared earlier in patients with SLE. SLE patients with secondary APS had a higher prevalence of carotid plaque than patients with primary APS (37.5% vs. 8%, P = 0.03). The presence of plaque in SLE patients correlated with higher disease activity scores and older age.60 However a clear pathogenic role for antiphospholipid antibodies (APLAs) in atherosclerosis in patients with SLE has not been borne out by other studies.61 The presence of antiphospholipid antibodies is linked more directly to acute coronary events such as myocardial infarction rather than stable coronary artery disease. APLAs predispose to thrombosis over plaques, probably resulting in acute worsening of myocardial ischemia.62 Some newer risk factors that could contribute to development of atherosclerosis include CRP and antibodies to β2 glycoprotein I (anti-β2GPI), oxidized low-density lipoprotein (anti-oxLDL), and heat shock protein (anti-HSP) 60/65 antibodies.63 The long-term use of corticosteroids is also associated with accelerated atherosclerosis, probably through worsening dyslipidemia.64,65 Atorvastatin use over an 8-week period has produced improved endothelial function in patients with SLE.66 Proinflammatory (dysfunctional) HDL has been reported in 45% of patients with SLE, which is twice the number of patients with RA and 10 times the number of control patients.45 Antibodies to lipoprotein lipase have been reported in patients with SLE.

In a study using myocardial perfusion scintigraphy with single photon emission computed tomography (SPECT) using technetium-sestamibi scanning in 90 female SLE patients (20-55 years old, with disease duration >5 years and current or previous steroid treatment for >1 year), 30 of the 90 had myocardial perfusion defects. Angiography in 21 of these 30 patients showed plaques in 8 of the 21 patients (38%). Abnormal angiographic findings were associated with higher number of CAD risk factors, higher SLE disease activity scores, presence of hypertension, and postmenopausal status. In patients with more than four risk factors for CAD, coronary stenosis was present in 67%. Based on this study, myocardial scintigraphy appears to be a reasonable tool to screen SLE patients for CAD. Patients with abnormal scintigraphy results and more than four risk factors for CAD should undergo coronary angiography.67 Intravascular ultrasound of the coronary arteries in a patient with SLE showed diffuse plaque formation, intimal thickening, partial calcification, and partial eccentric lipid-rich plaque, which reflects the observed histopathology in these patients.68

Large-scale studies regarding outcomes of therapeutic coronary interventions are not available due to the rare nature of the underlying disease. Coronary artery bypass grafting has been successfully reported in two patients with SLE.69 Studies involving greater numbers of patients are needed in order to study the outcomes of coronary intervention in these patients. This is especially true in an era of advances in cardiovascular technology, where recognition of possible adverse outcomes (complications or reintervention) can allow early recognition and treatment.

Systemic Sclerosis

Systemic sclerosis (SSc) is a unique autoimmune disease that has a significant microvasculopathy component. Endothelial dysfunction is a key abnormality in this disease. However, it is an exceedingly rare disease. Cardiac involvement in SSc is characterized by patchy myocardial fibrosis (from repeated microvascular ischemia and inflammation), diastolic dysfunction, and pulmonary hypertension. Cardiac arrhythmias and conduction disturbances are a hallmark of cardiac involvement, especially worsened by autonomic dysfunction. Renal involvement often leads to hypertension, which exacerbates the diastolic dysfunction. Chest pain can occur from a mismatch of perfusion and oxygen supply to the right ventricular musculature in patients with pulmonary hypertension, but the coronary angiographic picture may be completely normal.

Subclinical atherosclerosis and associated elevated proinflammatory HDL have been reported in patients with SSc.70 Increased lipoprotein(a), oxLDL, inflammation, vasospasm, and endothelial dysfunction are well known in SSc. Generalized premature atherosclerosis has not been detected in SSc.71 Noninvasive strategies such as strain rate imaging, transthoracic coronary flow reserve, and brachial artery flow-mediated dilatation are noninvasive modalities for detecting left ventricular myocardial and vascular involvement caused by SSc.

In an angiographic study of 172 patients with SSc, the prevalence of CAD was found to be similar to that in the population without SSc. There was no association between SSc subsets, duration of the disease, duration of Raynaud’s phenomenon, skin sclerosis score, autoantibody profile, and CAD.72 However, SSc is characterized by microvascular dysfunction, an entity that cannot be evaluated by conventional coronary angiography.

Measures of diastolic dysfunction such as impaired ventricular relaxation times and abnormal ratios of early to late diastolic filling (E/A ratios) can be quantitated using modalities such as Doppler myocardial imaging.73 Early microvascular dysfunction, which is common in diffuse SSc, can be evaluated using coronary flow reserve measurements on echocardiography before and after pharmacologic stress and by sestamibi SPECT scanning.74,75

On angiography, patients with SSc are 34 times more likely to have normal coronary arteries.76 This underlines the microvascular dysfunction seen in this disease. In 14 asymptomatic female patients with SSc, the angiographic abnormalities observed were ectasia, slow flow, spasm, stenosis, tortuosity, and calcification of the coronary arteries.77 This suggests that angiographic abnormalities do not correlate with clinical symptoms. Increased arterial stiffness has also been reported in these patients.78 Statins, by virtue of their effects on endothelial dysfunction and inflammation, might have some benefit in patients with SSc.79

There remains much to be desired in exploring the mechanisms of microvascular ischemia, injury, and consequences thereof that define SSc. Owing to the rarity of this disease, large-scale studies are difficult to perform. It would be useful to remember that because there exists microvascular insufficiency, in some patients it may be unrealistic to expect that correction of macroscopic obstructive epicardial coronary disease will lead to abatement of symptoms. We still need better means to quantitate the microvascular disease, the real target in these patients. There is no large body of data available on surgical or percutaneous intervention for CAD in these patients.

Spondyloarthropathies

The spondyloarthropathy family is also a group of inflammatory disorders that is not exempt from its accompanying burden of the cardiovascular consequences of chronic inflammation. Endothelial dysfunction has been observed in patients with ankylosing spondylitis and psoriatic arthritis.80,812 Patients with psoriasis have been found to have a higher incidence of multiple cardiovascular risk factors, especially those characterizing the metabolic syndrome.82 Patients with psoriatic arthritis have higher subclinical atherosclerosis measured by carotid IMT even in the absence of clinically obvious cardiovascular risk factors.83 However, other studies have failed to show subclinical atherosclerosis in patients treated for psoriatic arthritis in the absence of traditional cardiovascular risk factors,84 again highlighting the importance of treatment in controlling inflammation in this disease.

In a cross-sectional study of prevalence and risk factors for RA, psoriatic arthritis and ankylosing spondylitis, the prevalence ratios of IHD, atherosclerosis, peripheral vascular disease, congestive heart failure, cerebrovascular disease, type 2 diabetes mellitus, hyperlipidemia, and hypertension were higher in patients than controls.85 A proatherogenic milieu is reported in patients with psoriatic arthritis.86 Although large studies on coronary artery involvement in reactive arthritis have not been done, there is one case report of coronary ostial narrowing as a complication of aortitis.87 Improvement in microvascular dysfunction after treatment of ankylosing spondylitis with etanercept has been documented.88 Aortic valve involvement occurs in ankylosing spondylitis and reactive arthritis, and the ensuing aortic regurgitation might have consequences on coronary blood flow as well.

Primary Vasculitides

The vasculitides are characterized by histopathologic evidence of inflammation of blood vessels. Because inflammation of blood vessels is the hallmark, endothelial dysfunction is inherent in these diseases. Atherosclerosis is now increasingly recognized in patients with primary vasculitides. The mechanisms include direct endothelial dysfunction including increased expression of adhesion molecules, circulating CRP and cytokines, antibodies to endothelial cells, thrombosis, and heightened traditional cardiovascular risk factors.89

Giant cell arteritis typically occurs in patients older than 50 years, a population that has accumulated traditional cardiovascular risk factors for atherosclerotic disease, so it is not surprising to find an increased incidence of cardiovascular disease. In a retrospective Canadian study of 1141 patients with GCA, the composite end point of subsequent diagnosis or surgical treatment for CAD, stroke, peripheral arterial disease, or aneurysm or dissection of the aorta was more common in patients with GCA than in patients with osteoarthritis (12.1 vs. 7.3/1000 person-years). The adjusted hazard ratio for cardiovascular disease was 1.6 in patients with GCA compared to patients with osteoarthritis and 2.1 in patients with GCA versus unaffected control patients.90

In a study of 50 patients with small-vessel vasculitis, subclinical atherosclerosis as measured by IMT in the carotid, aorta, and femoral arteries was greater than in the control group.91 This finding was independent of traditional cardiovascular risk factors and CRP levels, suggesting direct endothelial abnormalities separate from systemic inflammation.

Coronary artery involvement in Takayasu’s arteritis is often ostial from the arteritis rather than from atherosclerotic disease.

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Assessing the Risk

The first step to risk assessment is to acknowledge the risk. Most patients with systemic inflammatory autoimmune diseases are seen at regular intervals, and this provides an opportunity to assess them for premature cardiovascular disease. The Framingham risk score is still a useful score that has been validated in patients with RA to assess cardiovascular risk. Higher Framingham scores correlate with longer disease duration and coronary calcium scores.39

The evaluation of these patients is similar to other patients without these conditions but with a lower clinical threshold and increased awareness on the part of the physician. A composite assessment of history, physical examination, laboratory studies, and imaging can provide a good baseline estimate of the patient’s cardiovascular health. The history should include questions about angina or angina equivalents, symptoms of cerebrovascular insufficiency, and claudication in pertinent patients. A good physical examination can reveal signs of hyperlipidemia, diagnose hypertension, and clinically assess large-vessel status and valvular heart disease in these patients. Laboratory tests should include a lipid profile, creatinine, and markers of inflammation at regular intervals as needed and guided by therapy. Checking homocysteine levels may be necessary in specific cases.

Patients with symptoms or abnormalities on screening should be referred to specialist colleagues for further detailed evaluation and therapy as deemed indicated. A collaborative effort with preventive cardiology can go a long way in optimizing the cardiovascular health of these patients. This has been shown and recommended based on the experience of patients with SLE in the Pittsburgh cohort.92 This also offers the potential to build a combined rheumatology and cardiology database of these patients that can help evaluate, design, and infer meaningful data about clinical and basic science queries related to cardiovascular disease in this population.

Routine imaging for subclinical atherosclerosis is not standard of care or recommended at this time. However, the development of risk score tools such as SHAPE (Screening for Heart Attack Prevention and Education) are the first step toward measuring the burden of subclinical atherosclerosis.93 The need to assess peripheral arterial disease in these patients as a significant component of the vascular disease burden cannot be overemphasized.

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Treatment

Therapy in these patients is not much different in terms of managing traditional cardiovascular risk factors such as controlling blood pressure, reducing hyperlipidemia, quitting smoking, taking regular exercise and improving diet. Because inflammation is the common thread that runs through all systemic autoimmune diseases and atherosclerosis, it is key to control systemic inflammation. This is evident from trials that demonstrate improved cardiovascular outcomes from the use of various immunosuppressive medications in the treatment of systemic rheumatic diseases.

Hydroxychloroquine is a unique medication that has lipid- lowering and antithrombotic properties. This medication should be used regularly in patients with SLE. Cardiologists regularly use statins owing their multiple beneficial effects for patients with hyperlipidemia and CAD. Statins have now been shown to have anti-inflammatory actions, which might serve the dual purpose of cardioprotection and rheumatic disease modification. Low-dose aspirin should also be used for these patients in the absence of contraindications to its use. Because a larger cumulative dose of corticosteroids has been shown to contribute to accelerated atherosclerosis, trying to achieve disease control with other DMARDs while trying to minimize prednisone use should be one of the goals of therapy.

Folate supplementation in patients taking methotrexate might reduce the consequent hyperhomocystinemia and provide added cardiovascular protection.94 The use of newer medications, such as anticytokine therapies, might result in better cardiovascular outcomes than before. This remains to be studied, because some of the newer therapies have been available only in recent years.

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The Future

Where do we go from here? The future holds a lot of hope. With increasing awareness and literature regarding the cardiovascular risk in systemic autoimmune diseases, new mechanistic insights are being gained each day with the ultimate goal being their translation into therapeutic targets. The alliance between cardiology and rheumatology has to grow stronger, especially because there are multiple shared mechanisms in atherosclerosis and systemic rheumatic diseases. Newer medications will be available in both specialties in the future, and their effects on atherosclerosis progression remain to be seen.

The development of a composite cardiovascular score to assess this risk is imperative. The integration of clinical information, laboratory data, and imaging information will equip us to provide the most clinically meaningful therapies for our patients. There are ongoing studies to assess the utility of available imaging modalities such as multirow detector CT (MDCT) and cardiac MRI in measuring atherosclerotic burden of disease.

The role of systemic inflammation in promoting atherosclerosis as it is understood today is still an oversimplification of myriad processes at work. A number of mechanistic explanations will come from the research bench; strong clinical research will be necessary to transform these basic science insights into strategies for better risk modification and management. Diabetes mellitus is well accepted as a CAD equivalent due to the risk it portends for outcomes in ischemic heart disease. Rheumatoid arthritis has a risk comparable to that in diabetes for myocardial infarction (odds ratio, ˜ 3.0). Lipid-lowering guidelines recommend specific targets for lipid lowering in patients with diabetes; no such recommendations exist for systemic rheumatic diseases, most likely due to lack of well-done trials.

In the future, the availability of pharmacogenomic data could refine the approach to drug selection for individual patients, with the ability to confidently predict a therapeutic response. Until then, we must use our heightened awareness and clinical judgment to produce the best cardiovascular outcomes in our patients with systemic inflammatory autoimmune diseases.

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Summary

  • Risk of coronary artery disease is increased in patients with systemic rheumatic diseases.
  • Increased risk occurs as a consequence of traditional and nontraditional risk factors.
  • Collaborate with preventive cardiology.
  • Controlling inflammation (disease activity) at all costs is central to management.
  • Minimize prednisone use; use DMARDs for disease control.
  • Use hydroxychloroquine for its anti-inflammatory, lipid lowering, and antithrombotic properties.
  • Treat traditional cardiovascular risk factors as well.

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References

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