Ted R. Mikuls, MD, MSPH

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review the management of traditional and nontraditional CVD cardiovascular disease risk factors in rheumatoid arthritis (RA).
• Methods: Literature review of the management of CVD risk in RA.
• Results: Because of the increased risk of CVD events and CVD mortality among RA patients, aggressive management of CVD risk is essential. Providers should follow national guidelines for the management of traditional CVD risk factors, including dyslipidemia, hypertension, and diabetes mellitus. Similar efforts are needed in counseling on lifestyle modifications, including smoking cessation, regular exercise, and maintaining a healthy body weight. Because higher RA disease activity is also linked with CVD risk, aggressive treatment of RA to a target of low disease activity or remission is critical. Furthermore, the selection of potentially “cardioprotective” agents such as methotrexate and tumor necrosis factor inhibitors, while limiting use of nonsteroidal anti-inflammatory drugs and glucocorticoids, are strategies that could be employed by rheumatologists to help mitigate CVD risk in their patients with RA.
• Conclusion: Routine assessment of CVD risk, management of traditional CVD risk factors, counseling on healthy lifestyle habits, and aggressive treatment of RA are essential to minimize CVD risk in this population.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment; cardiovascular risk management.

Editor’s note: This article is part 2 of a 2-part article. “Assessment of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the January/February 2019 issue.

Rheumatoid arthritis (RA) is a systemic autoimmune condition that contributes to an increased risk for cardiovascular disease (CVD) among affected patients. In persons with RA, the risk of incident CVD and CVD mortality are increased by approximately 50% compared with the general population.^1,2 To minimize CVD risk in this population, providers must routinely assess for CVD risk factors³ and aggressively manage both traditional and nontraditional CVD risk factors.

Managing Traditional Risk Factors

As in the general population, identification and management of traditional CVD risk factors are crucial to minimize CVD risk in the RA population. A prospective study of 201 RA patients demonstrated that traditional CVD risk factors were in fact more predictive of endothelial dysfunction and carotid atherosclerosis than were disease-related inflammatory markers in RA.⁴ Management of traditional risk factors is detailed in the following sections, and recommendations for managing all traditional CVD risk factors are summarized in the Table.

Dyslipidemia

The role of dyslipidemia in atherogenesis is well established, and as a result, lipid levels are nearly universally included in CVD risk stratification tools. However, the interpretation of lipid levels in the context of RA is challenging because of the effects of systemic inflammation on their absolute values. Compared to the general population, patients with RA have lower total cholesterol (TC) and low-density lipoprotein (LDL) levels independent of lipid-lowering therapy.^5,6 Despite this, RA patients are at increased risk for CVD. There is even some evidence to suggest a “lipid paradox” in RA, whereby lower TC (< 4 mmol/L) and LDL levels suggest an increased risk of CVD.^7,8 In contrast to LDL, higher levels of high-density lipoprotein (HDL) are typically associated with reduced CVD risk, as in the general population.^8,9 Interestingly, in a cohort of 16,085 RA patients and 48,499 age- and sex-matched controls, there was no significant difference in the relationship between LDL and CVD risk, suggesting that quantitative lipid levels alone may not entirely explain the CVD mortality gap in RA.⁹ As such, there is substantial interest in lipoprotein function within the context of CVD risk in RA. Recent investigations have identified impaired HDL function, with reduced cholesterol efflux capacity and antioxidant properties, as well as increased scavenger receptor expression and foam cell formation, in patients with RA.^10,11 More research is needed to elucidate how these alterations affect CVD morbidity and mortality and how their measurement could be integrated into improved CVD risk assessment.

Meta-analyses of randomized controlled trials have estimated that lipid-lowering therapy with HMG-CoA reductase inhibitors (statins) reduces the risk of CVD by 25% to 30%; as such, statin therapy has become the standard of care for reduction of CVD risk in the general population.¹² Benefits for primary prevention of CVD in RA have also been observed; statin therapy was associated with a reduced risk of CVD events (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-0.98) and all-cause mortality (HR, 0.43; 95% CI, 0.20-0.92) in a population-based cohort study.¹³ Statins appear to have similar lipid-lowering effects and result in similar CVD risk reduction when used for primary or secondary prevention in RA patients compared to non-RA controls.^14-16 Additionally, anti-inflammatory properties of statins may act in synergy with disease-modifying antirheumatic drugs (DMARDs) to improve RA disease activity. In a small study of RA patients, statin therapy improved subjective and objective markers of RA disease activity in conjunction with methotrexate.¹⁷

While statins provide robust reduction in CVD risk, some individuals cannot tolerate statin therapy or do not achieve goal LDL levels with statin therapy. Select non-statin LDL-cholesterol-lowering agents have shown promise for reducing CVD events in the general population.¹⁸ Ezetimibe, which inhibits cholesterol absorption in the small intestine, very modestly reduced CVD events when added to atorvastatin (relative risk [RR], 0.94; 95% CI, 0.89-0.99) in a double-blind randomized controlled trial.¹⁹ Novel monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibit the internalization of surface LDL receptors, promoting LDL clearance. Two PCSK-9 inhibitors, alirocumab and evolocumab, were approved by the US Food and Drug Administration (FDA) after randomized controlled trials demonstrated their efficacy in lowering LDL by approximately 60% and reducing CVD events by approximately 15% in patients on maximum-tolerated statin therapy.^20-22 To date, non-statin LDL-cholesterol-lowering agents have been subject to limited study in RA.²³

Identification and management of dyslipidemia offers an opportunity for substantial CVD risk reduction at the RA population level. Unfortunately, current rates of lipid screening are inadequate in this high-risk group. In a study of 3298 Medicare patients with RA, less than half of RA patients with an indication underwent appropriate lipid screening.²⁴ Additionally, statins are often underutilized for both primary and secondary prevention in RA patients. Only 27% of RA patients meeting National Cholesterol Education Program Adult Treatment Panel III criteria were initiated on statin therapy in a population-based cohort study.²⁵ Among patients discharged after a first myocardial infarction (MI), the odds of receiving lipid-lowering therapy were 31% lower for RA patients (odds ratio [OR], 0.69; 95% CI, 0.58-0.82).²⁶ Similar to the general population, adherence to statins in RA patients appears to be poor.^27-30 This raises particular concern considering that a population-based cohort study of RA patients demonstrated a 67% increased risk of MI associated with statin discontinuation, regardless of prior MI status.²⁷ Providers—rheumatologists, primary care providers, and cardiologists alike—need to remain vigilant in efforts to assess CVD risk to identify patients who will benefit from lipid-lowering therapy and to emphasize the importance to patients of statin adherence. Novel models of health-care delivery, health technologies, and patient engagement in care may prove useful for improving lipid screening and management in RA.

Tobacco Use

Cigarette smoking is a shared risk factor for both CVD and RA. Large cohort studies have identified a dose-dependent increased risk of incident RA, particularly seropositive RA, among smokers.^31-34 Tobacco smoking has also been associated with increased levels of inflammation and RA disease activity.³⁵ The consequences of tobacco use in the general population are staggering. Among individuals over the age of 30 years, tobacco use is responsible for 12% of all deaths and 10% of all CVD deaths.³⁶ Similar findings are observed in RA; a recent meta-analysis estimated there is a 50% increased risk of CVD events in RA related to smoking tobacco.³⁷ In the general population, smoking cessation markedly lowers CVD risk, and over time CVD risk may approach that of nonsmokers.^38,39 Thus, regular counseling and interventions to facilitate smoking cessation are critical to reducing CVD risk in RA patients. RA-specific smoking cessation programs have been proposed, but have yet to outperform standard smoking cessation programs.⁴⁰

Diabetes Mellitus

It is estimated that almost 10% of the US population has diabetes mellitus (DM), which in isolation portends substantial CVD risk.⁴¹ There is an increased prevalence of DM in RA, perhaps owing to factors such as physical inactivity and chronic glucocorticoid use, though a higher level of RA disease activity itself has been associated with increased insulin resistance.^42-45 In a cohort of 100 RA patients who were neither obese nor diabetic, RA patients had significantly higher fasting blood glucose and insulin levels than age- and sex-matched controls. These findings were even more pronounced in RA patients with higher levels of disease activity.⁴⁴ Similar to the general population, DM is associated with poor CVD outcomes in RA.³⁷ Therefore, both appropriate management of diabetes and control of RA disease activity are vitally important to minimize CVD risk related to DM.

Though not a universal finding, there may be an increased prevalence of hypertension in RA patients.^31,46 Nonsteroidal anti-inflammatory drug (NSAID) and glucocorticoid use may play a role in the development of hypertension, while DMARDs appear to exert a less substantial effect on blood pressure.^47,48 At least one study found that DMARD initiation (particularly for methotrexate and hydroxychloroquine) was associated with significant, albeit small, declines in both systolic and diastolic blood pressure over the first 6 months of treatment.⁴⁹

Despite its potentially higher prevalence in this population, hypertension is both underdiagnosed and undertreated in RA patients.^24,50-52 This is an important deficiency to target because, as in the general population, hypertension is associated with an increased risk of MI (RR, 1.84; 95% CI, 1.38-2.46) and composite CVD outcomes (RR, 2.24; 95% CI, 1.42-3.06) in RA.³⁷ Thresholds for initiation and escalation of antihypertensive therapy are not specific to the RA population; thus, diagnosis and management of hypertension should be informed by the American College of Cardiology/American Heart Association guidelines, treating those with in-office blood pressures exceeding 140/90 mm Hg (> 130/80 mm Hg if aged > 65 years or with concomitant CVD, DM, chronic kidney disease, or 10-year atherosclerotic cardiovascular disease risk > 10%), typically with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, or thiazide diuretics as comorbidities may dictate or allow.⁵³ Also, the use of NSAIDs and glucocorticoids should be minimized, particularly in those with concomitant hypertension.

Physical Activity

Likely due to factors such as articular pain and stiffness, as well as physical limitations, RA patients are more sedentary than the general population.^54,55 In a study of objectively assessed sedentary behavior in RA patients, greater average sedentary time per day and greater number of sedentary bouts (> 20 min) were associated with increased 10-year risk of CVD as assessed by the QRISK2.⁵⁶ Conversely, the beneficial effects of exercise are well documented. Light to moderate physical activity has been associated with improved cardiovascular outcomes, greater physical function, higher levels of HDL, as well as reduced systemic inflammation and disease activity, and improved endothelial function in RA patients.^57-61 While there has been concern that physical activity may result in accelerated joint damage, even high-intensity exercise was shown to be safe without causing significant progression of joint damage.⁵⁸

Obesity, Weight Loss, and Diet

While obesity is clearly associated with CVD risk in the general population, this relationship is much more complex in RA, as underweight RA patients are also at higher risk for CVD and CVD-related mortality.^62-64 One potential explanation for this finding is that pathological weight loss resulting in an underweight body mass index (BMI) is an independent predictor of CVD. In a study of US Veterans with RA, higher rates of weight loss (> 3 kg/m²/year) were associated with increased CVD mortality (HR, 2.27; 95% CI, 1.61-3.19) independent of BMI.⁶⁵ Systemic inflammation in RA can lead to “rheumatoid cachexia,” characterized by decreased muscle mass, increased adiposity, and increased CVD risk despite a normal or potentially decreased BMI.⁶⁶ Practitioners should be mindful of not only current body weight, but also patients’ weight trajectories when counseling on lifestyle practices such as healthy diet and regular exercise in RA patients. For obese individuals with RA, healthy weight loss should be encouraged. Interestingly, bariatric surgery in RA patients may improve RA disease activity in addition to its known effects on body weight and DM.⁶⁷

Counseling on healthy diet with a focus on limiting foods high in saturated- and trans-fatty acids and high glycemic index foods, and increasing consumption of fruits, vegetables, and mono-unsaturated fatty acids is a well-accepted and common practice to help minimize CVD risk in the general population.⁶⁸ No studies to date have investigated the effect of specific diets on CVD risk in RA patients, and thus we recommend adherence to general population recommendations.

Disease Activity

In addition to traditional risk factors, several studies have identified associations between the level of RA disease activity and risk of CVD. In a cohort of US Veterans with RA, CVD-related mortality increased in a dose-dependent manner with higher disease activity categories. In stark contrast, the CVD mortality rates of those in remission paralleled the rates from the general population (standardized mortality ratio [SMR], 0.68; 95% CI, 0.37-1.27).⁶⁹ In a separate cohort of 1157 RA patients without prior CVD, achieving low disease activity was associated with a lower risk of incident CVD events (HR, 0.65; 95% CI, 0.43-0.99).⁷⁰ Additionally, high disease activity has been associated with surrogate markers of CVD and other CVD risk factors including NT-proBNP and systolic blood pressure.^71,72 While no randomized controlled trial data is available to inform this recommendation, observational data suggest RA should be aggressively treated (ideally to achieve and maintain remission or low disease activity) to minimize CVD risk. While keeping this treatment goal in mind, the differential effects of specific RA therapies on CVD must also be considered.

Glucocorticoids and NSAIDs

With the expanding repertoire of DMARDs available and more aggressive treatment approaches, the role of glucocorticoids and NSAIDs in RA treatment is decreasing over time. While their efficacy for improving pain and stiffness is well established, concern regarding their contribution to CVD risk in RA patients is warranted.

Glucocorticoids are known to have detrimental effects on traditional CVD risk factors such as hypertension, insulin resistance, and dyslipidemia in the general population, as well as in RA patients.^73,74 In a meta-analysis of predominantly observational studies of RA patients, glucocorticoid use was associated with an increased risk of CVD events (RR, 1.47; 95% CI, 1.34-1.60), including MI, congestive heart failure (CHF), and cerebrovascular accident (CVA).⁷⁵ Evidence is conflicting in regards to a clear dose threshold that leads to increased CVD risk with glucocorticoids, though higher doses are associated with greater risk.^76-81 As RA patients requiring glucocorticoids typically have higher disease activity, confounding by indication remains a complicating factor in assessing the relative contributions of glucocorticoid use and RA disease activity to elevated CVD risk in many analyses.

The increased CVD risk with NSAID use is not specific to RA and has been well established in the general population.^82-84 In the previously mentioned meta-analysis, an increased overall risk of CVD events was observed with NSAID use in RA (RR, 1.18; 95% CI, 1.01-1.38). It should be noted that cyclo-oxygenase 2 (COX-2) inhibitors, in particular rofecoxib (now removed from the market), appeared to drive the majority of this risk (RR, 1.36; 95% CI, 1.10-1.67 in COX-2 inhibitors and RR 1.08, 95% CI, 0.94-1.24 in nonselective NSAIDs), suggesting a potential differential risk among NSAIDs.⁷⁵ While naproxen has been thought to carry the lowest risk of CVD based on initial studies, this has not been universally observed, including in a recent randomized controlled trial of more than 24,000 RA and osteoarthritis patients.^82,85,86

Providers should use the lowest possible dose and duration of glucocorticoids and NSAIDs to achieve symptom relief, with continual efforts to taper or discontinue. Candidates for glucocorticoid and NSAID therapy should be selected carefully, and use of these therapies should be avoided in those with prior CVD or at high risk for CVD based on traditional CVD risk factors. Most importantly, providers should focus on utilizing DMARDs for the management of RA, which more effectively treat RA as well as reduce CVD risk.

Methotrexate (MTX), a mainstay in the treatment of RA, is a conventional DMARD observed to improve overall survival and mitigate CVD risk in multiple RA cohorts.^75,87,88 In a recent meta-analysis comprised of 236,525 RA patients and 5410 CVD events, MTX use was associated with a 28% reduction in overall CVD events across 8 studies (RR, 0.72; 95% CI, 0.57-0.91), substantiating similar findings in a prior meta-analysis.^75,88 MTX use was specifically associated with a decreased risk of MI (RR, 0.81; 95% CI, 0.68-0.96). Case-control and cohort studies have cited a 20% to 50% reduced risk of CHF with MTX use.^89,90 The potential cardioprotective effect of MTX appears to be both multifactorial and complex, likely mediated through both direct and indirect mechanisms. MTX directly promotes anti-atherogenic lipoprotein function, improves endothelial function, and scavenges free radicals.^91,92 Indirectly, MTX likely reduces CVD risk by effectively reducing RA disease activity. Based on these and other data, MTX remains the cornerstone of DMARD therapy in RA patients when targeting CVD risk reduction.

Hydroxychloroquine

Emerging evidence suggests that hydroxychloroquine (HCQ), an antimalarial most often utilized in combination with alternative DMARDs in RA, prevents DM and has beneficial effects on lipid profiles. A recent meta-analysis compiled 3 homogenous observational studies that investigated the effect of HCQ on incident DM. RA patients ever exposed to HCQ had a 40% lower incidence of DM (HR, 0.59; 95% CI, 0.49-0.70).⁹³ Increased duration of HCQ use was shown to further reduce risk of incident DM.⁹⁴ The aforementioned meta-analysis also pooled 5 studies investigating the effect of HCQ on lipid profiles, with favorable mean differences in TC (–9.82 mg/dL), LDL (–10.61 mg/dL), HDL (4.13 mg/dL), and triglycerides (–19.15 mg/dL) in HCQ users compared to non-users.⁹³ Given these favorable changes to traditional CVD risk factors, it is not surprising that in a retrospective study of 1266 RA patients without prior CVD, HCQ was associated with significantly lower risk of incident CVD. While external validation of these findings is needed, HCQ is an attractive conventional DMARD to be used in RA for CVD risk reduction. Moreover, its combination with MTX and sulfasalazine also shows promise for CVD risk reduction.^95,96

TNF Inhibitors

Tumor necrosis factor (TNF) inhibitors are often the initial biologic DMARD therapy used in RA patients not responding to conventional DMARDs. In the previously described meta-analysis, TNF inhibitors were associated with similar reductions in CVD events as MTX (RR, 0.70; 95% CI, 0.54-0.90).⁷⁵ Of note, there was a trend toward reduced risk of CHF (RR, 0.75; 95% CI, 0.49-1.15) in this same meta-analysis, an area of concern with TNF inhibitor use due to a prior randomized controlled trial demonstrating worsening clinical status in patients with existing moderate-to-severe CHF treated with high-dose infliximab.⁹⁷ Current RA treatment guidelines recommend avoiding TNF inhibitor use in individuals with CHF.⁹⁸

Aside from the risk of CHF exacerbation, TNF inhibitors appear to be cardioprotective. Similar to MTX, the mechanism by which TNF inhibition reduces cardiovascular risk is complex and likely due to both direct and indirect mechanisms. Substantial research has been conducted on the effect of TNF inhibition on lipids, with a recent meta-analysis demonstrating increases in HDL and TC, with stable LDL and atherogenic index over treatment follow-up.⁹⁹ A subsequent meta-analysis not limited to RA patients yielded similar results.¹⁰⁰ In addition to quantitative lipid changes, alteration of lipoprotein function, improvement in myocardial function, reduced aortic stiffness, improved blood pressure, and reduced RA disease activity may also be responsible for cardioprotective benefits of these agents.^101,102

Non-TNF Biologic and Traditional Synthetic DMARDs

Tocilizumab, an IL-6 inhibitor, can potently increase LDL levels, but it does not appear to increase the risk of CVD events and may actually promote more favorable anti-atherogenic lipoprotein function.^103-106 Although these quantitative lipid changes received significant attention in the wake of early reports detailing this effect, similar lipid changes appear to accompany other DMARDs including TNF inhibitors and tofacitinib.¹⁰⁷ There have been few studies evaluating the risk of CVD with other non-TNF inhibitor biologic DMARDs and traditional synthetic DMARDs, warranting future study.

Conclusion

To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessments of CVD risk,³ and aggressively manage both traditional and nontraditional CVD risk factors. The differential roles in this effort may not be clear; thus, we have proposed a co-management strategy detailed in the Figure. Clear communication between providers is of the utmost importance to ensure effective management of CVD risk.

Given limited evidence for RA-specific CVD risk assessments and traditional risk factor treatment targets, management should follow pertinent national guidelines. The importance of lifestyle counseling should not be overlooked, with a focus on smoking cessation, healthy diet and body weight, and regular aerobic exercise. Finally, rheumatologists should aggressively manage RA using a treat-to-target approach, minimize the use of glucocorticoids and NSAIDs, and preferentially select DMARDs that have been associated with lower CVD risk. Through this comprehensive approach, recent trends of improved CVD outcomes in RA will hopefully become more widespread.¹⁰⁸

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; [email protected].

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review the management of traditional and nontraditional CVD cardiovascular disease risk factors in rheumatoid arthritis (RA).
• Methods: Literature review of the management of CVD risk in RA.
• Results: Because of the increased risk of CVD events and CVD mortality among RA patients, aggressive management of CVD risk is essential. Providers should follow national guidelines for the management of traditional CVD risk factors, including dyslipidemia, hypertension, and diabetes mellitus. Similar efforts are needed in counseling on lifestyle modifications, including smoking cessation, regular exercise, and maintaining a healthy body weight. Because higher RA disease activity is also linked with CVD risk, aggressive treatment of RA to a target of low disease activity or remission is critical. Furthermore, the selection of potentially “cardioprotective” agents such as methotrexate and tumor necrosis factor inhibitors, while limiting use of nonsteroidal anti-inflammatory drugs and glucocorticoids, are strategies that could be employed by rheumatologists to help mitigate CVD risk in their patients with RA.
• Conclusion: Routine assessment of CVD risk, management of traditional CVD risk factors, counseling on healthy lifestyle habits, and aggressive treatment of RA are essential to minimize CVD risk in this population.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment; cardiovascular risk management.

Editor’s note: This article is part 2 of a 2-part article. “Assessment of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the January/February 2019 issue.

Rheumatoid arthritis (RA) is a systemic autoimmune condition that contributes to an increased risk for cardiovascular disease (CVD) among affected patients. In persons with RA, the risk of incident CVD and CVD mortality are increased by approximately 50% compared with the general population.^1,2 To minimize CVD risk in this population, providers must routinely assess for CVD risk factors³ and aggressively manage both traditional and nontraditional CVD risk factors.

Managing Traditional Risk Factors

As in the general population, identification and management of traditional CVD risk factors are crucial to minimize CVD risk in the RA population. A prospective study of 201 RA patients demonstrated that traditional CVD risk factors were in fact more predictive of endothelial dysfunction and carotid atherosclerosis than were disease-related inflammatory markers in RA.⁴ Management of traditional risk factors is detailed in the following sections, and recommendations for managing all traditional CVD risk factors are summarized in the Table.

Dyslipidemia

The role of dyslipidemia in atherogenesis is well established, and as a result, lipid levels are nearly universally included in CVD risk stratification tools. However, the interpretation of lipid levels in the context of RA is challenging because of the effects of systemic inflammation on their absolute values. Compared to the general population, patients with RA have lower total cholesterol (TC) and low-density lipoprotein (LDL) levels independent of lipid-lowering therapy.^5,6 Despite this, RA patients are at increased risk for CVD. There is even some evidence to suggest a “lipid paradox” in RA, whereby lower TC (< 4 mmol/L) and LDL levels suggest an increased risk of CVD.^7,8 In contrast to LDL, higher levels of high-density lipoprotein (HDL) are typically associated with reduced CVD risk, as in the general population.^8,9 Interestingly, in a cohort of 16,085 RA patients and 48,499 age- and sex-matched controls, there was no significant difference in the relationship between LDL and CVD risk, suggesting that quantitative lipid levels alone may not entirely explain the CVD mortality gap in RA.⁹ As such, there is substantial interest in lipoprotein function within the context of CVD risk in RA. Recent investigations have identified impaired HDL function, with reduced cholesterol efflux capacity and antioxidant properties, as well as increased scavenger receptor expression and foam cell formation, in patients with RA.^10,11 More research is needed to elucidate how these alterations affect CVD morbidity and mortality and how their measurement could be integrated into improved CVD risk assessment.

Meta-analyses of randomized controlled trials have estimated that lipid-lowering therapy with HMG-CoA reductase inhibitors (statins) reduces the risk of CVD by 25% to 30%; as such, statin therapy has become the standard of care for reduction of CVD risk in the general population.¹² Benefits for primary prevention of CVD in RA have also been observed; statin therapy was associated with a reduced risk of CVD events (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-0.98) and all-cause mortality (HR, 0.43; 95% CI, 0.20-0.92) in a population-based cohort study.¹³ Statins appear to have similar lipid-lowering effects and result in similar CVD risk reduction when used for primary or secondary prevention in RA patients compared to non-RA controls.^14-16 Additionally, anti-inflammatory properties of statins may act in synergy with disease-modifying antirheumatic drugs (DMARDs) to improve RA disease activity. In a small study of RA patients, statin therapy improved subjective and objective markers of RA disease activity in conjunction with methotrexate.¹⁷

While statins provide robust reduction in CVD risk, some individuals cannot tolerate statin therapy or do not achieve goal LDL levels with statin therapy. Select non-statin LDL-cholesterol-lowering agents have shown promise for reducing CVD events in the general population.¹⁸ Ezetimibe, which inhibits cholesterol absorption in the small intestine, very modestly reduced CVD events when added to atorvastatin (relative risk [RR], 0.94; 95% CI, 0.89-0.99) in a double-blind randomized controlled trial.¹⁹ Novel monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibit the internalization of surface LDL receptors, promoting LDL clearance. Two PCSK-9 inhibitors, alirocumab and evolocumab, were approved by the US Food and Drug Administration (FDA) after randomized controlled trials demonstrated their efficacy in lowering LDL by approximately 60% and reducing CVD events by approximately 15% in patients on maximum-tolerated statin therapy.^20-22 To date, non-statin LDL-cholesterol-lowering agents have been subject to limited study in RA.²³

Identification and management of dyslipidemia offers an opportunity for substantial CVD risk reduction at the RA population level. Unfortunately, current rates of lipid screening are inadequate in this high-risk group. In a study of 3298 Medicare patients with RA, less than half of RA patients with an indication underwent appropriate lipid screening.²⁴ Additionally, statins are often underutilized for both primary and secondary prevention in RA patients. Only 27% of RA patients meeting National Cholesterol Education Program Adult Treatment Panel III criteria were initiated on statin therapy in a population-based cohort study.²⁵ Among patients discharged after a first myocardial infarction (MI), the odds of receiving lipid-lowering therapy were 31% lower for RA patients (odds ratio [OR], 0.69; 95% CI, 0.58-0.82).²⁶ Similar to the general population, adherence to statins in RA patients appears to be poor.^27-30 This raises particular concern considering that a population-based cohort study of RA patients demonstrated a 67% increased risk of MI associated with statin discontinuation, regardless of prior MI status.²⁷ Providers—rheumatologists, primary care providers, and cardiologists alike—need to remain vigilant in efforts to assess CVD risk to identify patients who will benefit from lipid-lowering therapy and to emphasize the importance to patients of statin adherence. Novel models of health-care delivery, health technologies, and patient engagement in care may prove useful for improving lipid screening and management in RA.

Tobacco Use

Cigarette smoking is a shared risk factor for both CVD and RA. Large cohort studies have identified a dose-dependent increased risk of incident RA, particularly seropositive RA, among smokers.^31-34 Tobacco smoking has also been associated with increased levels of inflammation and RA disease activity.³⁵ The consequences of tobacco use in the general population are staggering. Among individuals over the age of 30 years, tobacco use is responsible for 12% of all deaths and 10% of all CVD deaths.³⁶ Similar findings are observed in RA; a recent meta-analysis estimated there is a 50% increased risk of CVD events in RA related to smoking tobacco.³⁷ In the general population, smoking cessation markedly lowers CVD risk, and over time CVD risk may approach that of nonsmokers.^38,39 Thus, regular counseling and interventions to facilitate smoking cessation are critical to reducing CVD risk in RA patients. RA-specific smoking cessation programs have been proposed, but have yet to outperform standard smoking cessation programs.⁴⁰

Diabetes Mellitus

It is estimated that almost 10% of the US population has diabetes mellitus (DM), which in isolation portends substantial CVD risk.⁴¹ There is an increased prevalence of DM in RA, perhaps owing to factors such as physical inactivity and chronic glucocorticoid use, though a higher level of RA disease activity itself has been associated with increased insulin resistance.^42-45 In a cohort of 100 RA patients who were neither obese nor diabetic, RA patients had significantly higher fasting blood glucose and insulin levels than age- and sex-matched controls. These findings were even more pronounced in RA patients with higher levels of disease activity.⁴⁴ Similar to the general population, DM is associated with poor CVD outcomes in RA.³⁷ Therefore, both appropriate management of diabetes and control of RA disease activity are vitally important to minimize CVD risk related to DM.

Though not a universal finding, there may be an increased prevalence of hypertension in RA patients.^31,46 Nonsteroidal anti-inflammatory drug (NSAID) and glucocorticoid use may play a role in the development of hypertension, while DMARDs appear to exert a less substantial effect on blood pressure.^47,48 At least one study found that DMARD initiation (particularly for methotrexate and hydroxychloroquine) was associated with significant, albeit small, declines in both systolic and diastolic blood pressure over the first 6 months of treatment.⁴⁹

Despite its potentially higher prevalence in this population, hypertension is both underdiagnosed and undertreated in RA patients.^24,50-52 This is an important deficiency to target because, as in the general population, hypertension is associated with an increased risk of MI (RR, 1.84; 95% CI, 1.38-2.46) and composite CVD outcomes (RR, 2.24; 95% CI, 1.42-3.06) in RA.³⁷ Thresholds for initiation and escalation of antihypertensive therapy are not specific to the RA population; thus, diagnosis and management of hypertension should be informed by the American College of Cardiology/American Heart Association guidelines, treating those with in-office blood pressures exceeding 140/90 mm Hg (> 130/80 mm Hg if aged > 65 years or with concomitant CVD, DM, chronic kidney disease, or 10-year atherosclerotic cardiovascular disease risk > 10%), typically with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, or thiazide diuretics as comorbidities may dictate or allow.⁵³ Also, the use of NSAIDs and glucocorticoids should be minimized, particularly in those with concomitant hypertension.

Physical Activity

Likely due to factors such as articular pain and stiffness, as well as physical limitations, RA patients are more sedentary than the general population.^54,55 In a study of objectively assessed sedentary behavior in RA patients, greater average sedentary time per day and greater number of sedentary bouts (> 20 min) were associated with increased 10-year risk of CVD as assessed by the QRISK2.⁵⁶ Conversely, the beneficial effects of exercise are well documented. Light to moderate physical activity has been associated with improved cardiovascular outcomes, greater physical function, higher levels of HDL, as well as reduced systemic inflammation and disease activity, and improved endothelial function in RA patients.^57-61 While there has been concern that physical activity may result in accelerated joint damage, even high-intensity exercise was shown to be safe without causing significant progression of joint damage.⁵⁸

Obesity, Weight Loss, and Diet

While obesity is clearly associated with CVD risk in the general population, this relationship is much more complex in RA, as underweight RA patients are also at higher risk for CVD and CVD-related mortality.^62-64 One potential explanation for this finding is that pathological weight loss resulting in an underweight body mass index (BMI) is an independent predictor of CVD. In a study of US Veterans with RA, higher rates of weight loss (> 3 kg/m²/year) were associated with increased CVD mortality (HR, 2.27; 95% CI, 1.61-3.19) independent of BMI.⁶⁵ Systemic inflammation in RA can lead to “rheumatoid cachexia,” characterized by decreased muscle mass, increased adiposity, and increased CVD risk despite a normal or potentially decreased BMI.⁶⁶ Practitioners should be mindful of not only current body weight, but also patients’ weight trajectories when counseling on lifestyle practices such as healthy diet and regular exercise in RA patients. For obese individuals with RA, healthy weight loss should be encouraged. Interestingly, bariatric surgery in RA patients may improve RA disease activity in addition to its known effects on body weight and DM.⁶⁷

Counseling on healthy diet with a focus on limiting foods high in saturated- and trans-fatty acids and high glycemic index foods, and increasing consumption of fruits, vegetables, and mono-unsaturated fatty acids is a well-accepted and common practice to help minimize CVD risk in the general population.⁶⁸ No studies to date have investigated the effect of specific diets on CVD risk in RA patients, and thus we recommend adherence to general population recommendations.

Disease Activity

In addition to traditional risk factors, several studies have identified associations between the level of RA disease activity and risk of CVD. In a cohort of US Veterans with RA, CVD-related mortality increased in a dose-dependent manner with higher disease activity categories. In stark contrast, the CVD mortality rates of those in remission paralleled the rates from the general population (standardized mortality ratio [SMR], 0.68; 95% CI, 0.37-1.27).⁶⁹ In a separate cohort of 1157 RA patients without prior CVD, achieving low disease activity was associated with a lower risk of incident CVD events (HR, 0.65; 95% CI, 0.43-0.99).⁷⁰ Additionally, high disease activity has been associated with surrogate markers of CVD and other CVD risk factors including NT-proBNP and systolic blood pressure.^71,72 While no randomized controlled trial data is available to inform this recommendation, observational data suggest RA should be aggressively treated (ideally to achieve and maintain remission or low disease activity) to minimize CVD risk. While keeping this treatment goal in mind, the differential effects of specific RA therapies on CVD must also be considered.

Glucocorticoids and NSAIDs

With the expanding repertoire of DMARDs available and more aggressive treatment approaches, the role of glucocorticoids and NSAIDs in RA treatment is decreasing over time. While their efficacy for improving pain and stiffness is well established, concern regarding their contribution to CVD risk in RA patients is warranted.

Glucocorticoids are known to have detrimental effects on traditional CVD risk factors such as hypertension, insulin resistance, and dyslipidemia in the general population, as well as in RA patients.^73,74 In a meta-analysis of predominantly observational studies of RA patients, glucocorticoid use was associated with an increased risk of CVD events (RR, 1.47; 95% CI, 1.34-1.60), including MI, congestive heart failure (CHF), and cerebrovascular accident (CVA).⁷⁵ Evidence is conflicting in regards to a clear dose threshold that leads to increased CVD risk with glucocorticoids, though higher doses are associated with greater risk.^76-81 As RA patients requiring glucocorticoids typically have higher disease activity, confounding by indication remains a complicating factor in assessing the relative contributions of glucocorticoid use and RA disease activity to elevated CVD risk in many analyses.

The increased CVD risk with NSAID use is not specific to RA and has been well established in the general population.^82-84 In the previously mentioned meta-analysis, an increased overall risk of CVD events was observed with NSAID use in RA (RR, 1.18; 95% CI, 1.01-1.38). It should be noted that cyclo-oxygenase 2 (COX-2) inhibitors, in particular rofecoxib (now removed from the market), appeared to drive the majority of this risk (RR, 1.36; 95% CI, 1.10-1.67 in COX-2 inhibitors and RR 1.08, 95% CI, 0.94-1.24 in nonselective NSAIDs), suggesting a potential differential risk among NSAIDs.⁷⁵ While naproxen has been thought to carry the lowest risk of CVD based on initial studies, this has not been universally observed, including in a recent randomized controlled trial of more than 24,000 RA and osteoarthritis patients.^82,85,86

Providers should use the lowest possible dose and duration of glucocorticoids and NSAIDs to achieve symptom relief, with continual efforts to taper or discontinue. Candidates for glucocorticoid and NSAID therapy should be selected carefully, and use of these therapies should be avoided in those with prior CVD or at high risk for CVD based on traditional CVD risk factors. Most importantly, providers should focus on utilizing DMARDs for the management of RA, which more effectively treat RA as well as reduce CVD risk.

Methotrexate (MTX), a mainstay in the treatment of RA, is a conventional DMARD observed to improve overall survival and mitigate CVD risk in multiple RA cohorts.^75,87,88 In a recent meta-analysis comprised of 236,525 RA patients and 5410 CVD events, MTX use was associated with a 28% reduction in overall CVD events across 8 studies (RR, 0.72; 95% CI, 0.57-0.91), substantiating similar findings in a prior meta-analysis.^75,88 MTX use was specifically associated with a decreased risk of MI (RR, 0.81; 95% CI, 0.68-0.96). Case-control and cohort studies have cited a 20% to 50% reduced risk of CHF with MTX use.^89,90 The potential cardioprotective effect of MTX appears to be both multifactorial and complex, likely mediated through both direct and indirect mechanisms. MTX directly promotes anti-atherogenic lipoprotein function, improves endothelial function, and scavenges free radicals.^91,92 Indirectly, MTX likely reduces CVD risk by effectively reducing RA disease activity. Based on these and other data, MTX remains the cornerstone of DMARD therapy in RA patients when targeting CVD risk reduction.

Hydroxychloroquine

Emerging evidence suggests that hydroxychloroquine (HCQ), an antimalarial most often utilized in combination with alternative DMARDs in RA, prevents DM and has beneficial effects on lipid profiles. A recent meta-analysis compiled 3 homogenous observational studies that investigated the effect of HCQ on incident DM. RA patients ever exposed to HCQ had a 40% lower incidence of DM (HR, 0.59; 95% CI, 0.49-0.70).⁹³ Increased duration of HCQ use was shown to further reduce risk of incident DM.⁹⁴ The aforementioned meta-analysis also pooled 5 studies investigating the effect of HCQ on lipid profiles, with favorable mean differences in TC (–9.82 mg/dL), LDL (–10.61 mg/dL), HDL (4.13 mg/dL), and triglycerides (–19.15 mg/dL) in HCQ users compared to non-users.⁹³ Given these favorable changes to traditional CVD risk factors, it is not surprising that in a retrospective study of 1266 RA patients without prior CVD, HCQ was associated with significantly lower risk of incident CVD. While external validation of these findings is needed, HCQ is an attractive conventional DMARD to be used in RA for CVD risk reduction. Moreover, its combination with MTX and sulfasalazine also shows promise for CVD risk reduction.^95,96

TNF Inhibitors

Tumor necrosis factor (TNF) inhibitors are often the initial biologic DMARD therapy used in RA patients not responding to conventional DMARDs. In the previously described meta-analysis, TNF inhibitors were associated with similar reductions in CVD events as MTX (RR, 0.70; 95% CI, 0.54-0.90).⁷⁵ Of note, there was a trend toward reduced risk of CHF (RR, 0.75; 95% CI, 0.49-1.15) in this same meta-analysis, an area of concern with TNF inhibitor use due to a prior randomized controlled trial demonstrating worsening clinical status in patients with existing moderate-to-severe CHF treated with high-dose infliximab.⁹⁷ Current RA treatment guidelines recommend avoiding TNF inhibitor use in individuals with CHF.⁹⁸

Aside from the risk of CHF exacerbation, TNF inhibitors appear to be cardioprotective. Similar to MTX, the mechanism by which TNF inhibition reduces cardiovascular risk is complex and likely due to both direct and indirect mechanisms. Substantial research has been conducted on the effect of TNF inhibition on lipids, with a recent meta-analysis demonstrating increases in HDL and TC, with stable LDL and atherogenic index over treatment follow-up.⁹⁹ A subsequent meta-analysis not limited to RA patients yielded similar results.¹⁰⁰ In addition to quantitative lipid changes, alteration of lipoprotein function, improvement in myocardial function, reduced aortic stiffness, improved blood pressure, and reduced RA disease activity may also be responsible for cardioprotective benefits of these agents.^101,102

Non-TNF Biologic and Traditional Synthetic DMARDs

Tocilizumab, an IL-6 inhibitor, can potently increase LDL levels, but it does not appear to increase the risk of CVD events and may actually promote more favorable anti-atherogenic lipoprotein function.^103-106 Although these quantitative lipid changes received significant attention in the wake of early reports detailing this effect, similar lipid changes appear to accompany other DMARDs including TNF inhibitors and tofacitinib.¹⁰⁷ There have been few studies evaluating the risk of CVD with other non-TNF inhibitor biologic DMARDs and traditional synthetic DMARDs, warranting future study.

Conclusion

To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessments of CVD risk,³ and aggressively manage both traditional and nontraditional CVD risk factors. The differential roles in this effort may not be clear; thus, we have proposed a co-management strategy detailed in the Figure. Clear communication between providers is of the utmost importance to ensure effective management of CVD risk.

Given limited evidence for RA-specific CVD risk assessments and traditional risk factor treatment targets, management should follow pertinent national guidelines. The importance of lifestyle counseling should not be overlooked, with a focus on smoking cessation, healthy diet and body weight, and regular aerobic exercise. Finally, rheumatologists should aggressively manage RA using a treat-to-target approach, minimize the use of glucocorticoids and NSAIDs, and preferentially select DMARDs that have been associated with lower CVD risk. Through this comprehensive approach, recent trends of improved CVD outcomes in RA will hopefully become more widespread.¹⁰⁸

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; [email protected].

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review the management of traditional and nontraditional CVD cardiovascular disease risk factors in rheumatoid arthritis (RA).
• Methods: Literature review of the management of CVD risk in RA.
• Results: Because of the increased risk of CVD events and CVD mortality among RA patients, aggressive management of CVD risk is essential. Providers should follow national guidelines for the management of traditional CVD risk factors, including dyslipidemia, hypertension, and diabetes mellitus. Similar efforts are needed in counseling on lifestyle modifications, including smoking cessation, regular exercise, and maintaining a healthy body weight. Because higher RA disease activity is also linked with CVD risk, aggressive treatment of RA to a target of low disease activity or remission is critical. Furthermore, the selection of potentially “cardioprotective” agents such as methotrexate and tumor necrosis factor inhibitors, while limiting use of nonsteroidal anti-inflammatory drugs and glucocorticoids, are strategies that could be employed by rheumatologists to help mitigate CVD risk in their patients with RA.
• Conclusion: Routine assessment of CVD risk, management of traditional CVD risk factors, counseling on healthy lifestyle habits, and aggressive treatment of RA are essential to minimize CVD risk in this population.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment; cardiovascular risk management.

Editor’s note: This article is part 2 of a 2-part article. “Assessment of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the January/February 2019 issue.

Rheumatoid arthritis (RA) is a systemic autoimmune condition that contributes to an increased risk for cardiovascular disease (CVD) among affected patients. In persons with RA, the risk of incident CVD and CVD mortality are increased by approximately 50% compared with the general population.^1,2 To minimize CVD risk in this population, providers must routinely assess for CVD risk factors³ and aggressively manage both traditional and nontraditional CVD risk factors.

Managing Traditional Risk Factors

As in the general population, identification and management of traditional CVD risk factors are crucial to minimize CVD risk in the RA population. A prospective study of 201 RA patients demonstrated that traditional CVD risk factors were in fact more predictive of endothelial dysfunction and carotid atherosclerosis than were disease-related inflammatory markers in RA.⁴ Management of traditional risk factors is detailed in the following sections, and recommendations for managing all traditional CVD risk factors are summarized in the Table.

Dyslipidemia

The role of dyslipidemia in atherogenesis is well established, and as a result, lipid levels are nearly universally included in CVD risk stratification tools. However, the interpretation of lipid levels in the context of RA is challenging because of the effects of systemic inflammation on their absolute values. Compared to the general population, patients with RA have lower total cholesterol (TC) and low-density lipoprotein (LDL) levels independent of lipid-lowering therapy.^5,6 Despite this, RA patients are at increased risk for CVD. There is even some evidence to suggest a “lipid paradox” in RA, whereby lower TC (< 4 mmol/L) and LDL levels suggest an increased risk of CVD.^7,8 In contrast to LDL, higher levels of high-density lipoprotein (HDL) are typically associated with reduced CVD risk, as in the general population.^8,9 Interestingly, in a cohort of 16,085 RA patients and 48,499 age- and sex-matched controls, there was no significant difference in the relationship between LDL and CVD risk, suggesting that quantitative lipid levels alone may not entirely explain the CVD mortality gap in RA.⁹ As such, there is substantial interest in lipoprotein function within the context of CVD risk in RA. Recent investigations have identified impaired HDL function, with reduced cholesterol efflux capacity and antioxidant properties, as well as increased scavenger receptor expression and foam cell formation, in patients with RA.^10,11 More research is needed to elucidate how these alterations affect CVD morbidity and mortality and how their measurement could be integrated into improved CVD risk assessment.

Meta-analyses of randomized controlled trials have estimated that lipid-lowering therapy with HMG-CoA reductase inhibitors (statins) reduces the risk of CVD by 25% to 30%; as such, statin therapy has become the standard of care for reduction of CVD risk in the general population.¹² Benefits for primary prevention of CVD in RA have also been observed; statin therapy was associated with a reduced risk of CVD events (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-0.98) and all-cause mortality (HR, 0.43; 95% CI, 0.20-0.92) in a population-based cohort study.¹³ Statins appear to have similar lipid-lowering effects and result in similar CVD risk reduction when used for primary or secondary prevention in RA patients compared to non-RA controls.^14-16 Additionally, anti-inflammatory properties of statins may act in synergy with disease-modifying antirheumatic drugs (DMARDs) to improve RA disease activity. In a small study of RA patients, statin therapy improved subjective and objective markers of RA disease activity in conjunction with methotrexate.¹⁷

While statins provide robust reduction in CVD risk, some individuals cannot tolerate statin therapy or do not achieve goal LDL levels with statin therapy. Select non-statin LDL-cholesterol-lowering agents have shown promise for reducing CVD events in the general population.¹⁸ Ezetimibe, which inhibits cholesterol absorption in the small intestine, very modestly reduced CVD events when added to atorvastatin (relative risk [RR], 0.94; 95% CI, 0.89-0.99) in a double-blind randomized controlled trial.¹⁹ Novel monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibit the internalization of surface LDL receptors, promoting LDL clearance. Two PCSK-9 inhibitors, alirocumab and evolocumab, were approved by the US Food and Drug Administration (FDA) after randomized controlled trials demonstrated their efficacy in lowering LDL by approximately 60% and reducing CVD events by approximately 15% in patients on maximum-tolerated statin therapy.^20-22 To date, non-statin LDL-cholesterol-lowering agents have been subject to limited study in RA.²³

Identification and management of dyslipidemia offers an opportunity for substantial CVD risk reduction at the RA population level. Unfortunately, current rates of lipid screening are inadequate in this high-risk group. In a study of 3298 Medicare patients with RA, less than half of RA patients with an indication underwent appropriate lipid screening.²⁴ Additionally, statins are often underutilized for both primary and secondary prevention in RA patients. Only 27% of RA patients meeting National Cholesterol Education Program Adult Treatment Panel III criteria were initiated on statin therapy in a population-based cohort study.²⁵ Among patients discharged after a first myocardial infarction (MI), the odds of receiving lipid-lowering therapy were 31% lower for RA patients (odds ratio [OR], 0.69; 95% CI, 0.58-0.82).²⁶ Similar to the general population, adherence to statins in RA patients appears to be poor.^27-30 This raises particular concern considering that a population-based cohort study of RA patients demonstrated a 67% increased risk of MI associated with statin discontinuation, regardless of prior MI status.²⁷ Providers—rheumatologists, primary care providers, and cardiologists alike—need to remain vigilant in efforts to assess CVD risk to identify patients who will benefit from lipid-lowering therapy and to emphasize the importance to patients of statin adherence. Novel models of health-care delivery, health technologies, and patient engagement in care may prove useful for improving lipid screening and management in RA.

Tobacco Use

Cigarette smoking is a shared risk factor for both CVD and RA. Large cohort studies have identified a dose-dependent increased risk of incident RA, particularly seropositive RA, among smokers.^31-34 Tobacco smoking has also been associated with increased levels of inflammation and RA disease activity.³⁵ The consequences of tobacco use in the general population are staggering. Among individuals over the age of 30 years, tobacco use is responsible for 12% of all deaths and 10% of all CVD deaths.³⁶ Similar findings are observed in RA; a recent meta-analysis estimated there is a 50% increased risk of CVD events in RA related to smoking tobacco.³⁷ In the general population, smoking cessation markedly lowers CVD risk, and over time CVD risk may approach that of nonsmokers.^38,39 Thus, regular counseling and interventions to facilitate smoking cessation are critical to reducing CVD risk in RA patients. RA-specific smoking cessation programs have been proposed, but have yet to outperform standard smoking cessation programs.⁴⁰

Diabetes Mellitus

It is estimated that almost 10% of the US population has diabetes mellitus (DM), which in isolation portends substantial CVD risk.⁴¹ There is an increased prevalence of DM in RA, perhaps owing to factors such as physical inactivity and chronic glucocorticoid use, though a higher level of RA disease activity itself has been associated with increased insulin resistance.^42-45 In a cohort of 100 RA patients who were neither obese nor diabetic, RA patients had significantly higher fasting blood glucose and insulin levels than age- and sex-matched controls. These findings were even more pronounced in RA patients with higher levels of disease activity.⁴⁴ Similar to the general population, DM is associated with poor CVD outcomes in RA.³⁷ Therefore, both appropriate management of diabetes and control of RA disease activity are vitally important to minimize CVD risk related to DM.

Though not a universal finding, there may be an increased prevalence of hypertension in RA patients.^31,46 Nonsteroidal anti-inflammatory drug (NSAID) and glucocorticoid use may play a role in the development of hypertension, while DMARDs appear to exert a less substantial effect on blood pressure.^47,48 At least one study found that DMARD initiation (particularly for methotrexate and hydroxychloroquine) was associated with significant, albeit small, declines in both systolic and diastolic blood pressure over the first 6 months of treatment.⁴⁹

Despite its potentially higher prevalence in this population, hypertension is both underdiagnosed and undertreated in RA patients.^24,50-52 This is an important deficiency to target because, as in the general population, hypertension is associated with an increased risk of MI (RR, 1.84; 95% CI, 1.38-2.46) and composite CVD outcomes (RR, 2.24; 95% CI, 1.42-3.06) in RA.³⁷ Thresholds for initiation and escalation of antihypertensive therapy are not specific to the RA population; thus, diagnosis and management of hypertension should be informed by the American College of Cardiology/American Heart Association guidelines, treating those with in-office blood pressures exceeding 140/90 mm Hg (> 130/80 mm Hg if aged > 65 years or with concomitant CVD, DM, chronic kidney disease, or 10-year atherosclerotic cardiovascular disease risk > 10%), typically with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, or thiazide diuretics as comorbidities may dictate or allow.⁵³ Also, the use of NSAIDs and glucocorticoids should be minimized, particularly in those with concomitant hypertension.

Physical Activity

Likely due to factors such as articular pain and stiffness, as well as physical limitations, RA patients are more sedentary than the general population.^54,55 In a study of objectively assessed sedentary behavior in RA patients, greater average sedentary time per day and greater number of sedentary bouts (> 20 min) were associated with increased 10-year risk of CVD as assessed by the QRISK2.⁵⁶ Conversely, the beneficial effects of exercise are well documented. Light to moderate physical activity has been associated with improved cardiovascular outcomes, greater physical function, higher levels of HDL, as well as reduced systemic inflammation and disease activity, and improved endothelial function in RA patients.^57-61 While there has been concern that physical activity may result in accelerated joint damage, even high-intensity exercise was shown to be safe without causing significant progression of joint damage.⁵⁸

Obesity, Weight Loss, and Diet

While obesity is clearly associated with CVD risk in the general population, this relationship is much more complex in RA, as underweight RA patients are also at higher risk for CVD and CVD-related mortality.^62-64 One potential explanation for this finding is that pathological weight loss resulting in an underweight body mass index (BMI) is an independent predictor of CVD. In a study of US Veterans with RA, higher rates of weight loss (> 3 kg/m²/year) were associated with increased CVD mortality (HR, 2.27; 95% CI, 1.61-3.19) independent of BMI.⁶⁵ Systemic inflammation in RA can lead to “rheumatoid cachexia,” characterized by decreased muscle mass, increased adiposity, and increased CVD risk despite a normal or potentially decreased BMI.⁶⁶ Practitioners should be mindful of not only current body weight, but also patients’ weight trajectories when counseling on lifestyle practices such as healthy diet and regular exercise in RA patients. For obese individuals with RA, healthy weight loss should be encouraged. Interestingly, bariatric surgery in RA patients may improve RA disease activity in addition to its known effects on body weight and DM.⁶⁷

Counseling on healthy diet with a focus on limiting foods high in saturated- and trans-fatty acids and high glycemic index foods, and increasing consumption of fruits, vegetables, and mono-unsaturated fatty acids is a well-accepted and common practice to help minimize CVD risk in the general population.⁶⁸ No studies to date have investigated the effect of specific diets on CVD risk in RA patients, and thus we recommend adherence to general population recommendations.

Disease Activity

In addition to traditional risk factors, several studies have identified associations between the level of RA disease activity and risk of CVD. In a cohort of US Veterans with RA, CVD-related mortality increased in a dose-dependent manner with higher disease activity categories. In stark contrast, the CVD mortality rates of those in remission paralleled the rates from the general population (standardized mortality ratio [SMR], 0.68; 95% CI, 0.37-1.27).⁶⁹ In a separate cohort of 1157 RA patients without prior CVD, achieving low disease activity was associated with a lower risk of incident CVD events (HR, 0.65; 95% CI, 0.43-0.99).⁷⁰ Additionally, high disease activity has been associated with surrogate markers of CVD and other CVD risk factors including NT-proBNP and systolic blood pressure.^71,72 While no randomized controlled trial data is available to inform this recommendation, observational data suggest RA should be aggressively treated (ideally to achieve and maintain remission or low disease activity) to minimize CVD risk. While keeping this treatment goal in mind, the differential effects of specific RA therapies on CVD must also be considered.

Glucocorticoids and NSAIDs

With the expanding repertoire of DMARDs available and more aggressive treatment approaches, the role of glucocorticoids and NSAIDs in RA treatment is decreasing over time. While their efficacy for improving pain and stiffness is well established, concern regarding their contribution to CVD risk in RA patients is warranted.

Glucocorticoids are known to have detrimental effects on traditional CVD risk factors such as hypertension, insulin resistance, and dyslipidemia in the general population, as well as in RA patients.^73,74 In a meta-analysis of predominantly observational studies of RA patients, glucocorticoid use was associated with an increased risk of CVD events (RR, 1.47; 95% CI, 1.34-1.60), including MI, congestive heart failure (CHF), and cerebrovascular accident (CVA).⁷⁵ Evidence is conflicting in regards to a clear dose threshold that leads to increased CVD risk with glucocorticoids, though higher doses are associated with greater risk.^76-81 As RA patients requiring glucocorticoids typically have higher disease activity, confounding by indication remains a complicating factor in assessing the relative contributions of glucocorticoid use and RA disease activity to elevated CVD risk in many analyses.

The increased CVD risk with NSAID use is not specific to RA and has been well established in the general population.^82-84 In the previously mentioned meta-analysis, an increased overall risk of CVD events was observed with NSAID use in RA (RR, 1.18; 95% CI, 1.01-1.38). It should be noted that cyclo-oxygenase 2 (COX-2) inhibitors, in particular rofecoxib (now removed from the market), appeared to drive the majority of this risk (RR, 1.36; 95% CI, 1.10-1.67 in COX-2 inhibitors and RR 1.08, 95% CI, 0.94-1.24 in nonselective NSAIDs), suggesting a potential differential risk among NSAIDs.⁷⁵ While naproxen has been thought to carry the lowest risk of CVD based on initial studies, this has not been universally observed, including in a recent randomized controlled trial of more than 24,000 RA and osteoarthritis patients.^82,85,86

Providers should use the lowest possible dose and duration of glucocorticoids and NSAIDs to achieve symptom relief, with continual efforts to taper or discontinue. Candidates for glucocorticoid and NSAID therapy should be selected carefully, and use of these therapies should be avoided in those with prior CVD or at high risk for CVD based on traditional CVD risk factors. Most importantly, providers should focus on utilizing DMARDs for the management of RA, which more effectively treat RA as well as reduce CVD risk.

Methotrexate (MTX), a mainstay in the treatment of RA, is a conventional DMARD observed to improve overall survival and mitigate CVD risk in multiple RA cohorts.^75,87,88 In a recent meta-analysis comprised of 236,525 RA patients and 5410 CVD events, MTX use was associated with a 28% reduction in overall CVD events across 8 studies (RR, 0.72; 95% CI, 0.57-0.91), substantiating similar findings in a prior meta-analysis.^75,88 MTX use was specifically associated with a decreased risk of MI (RR, 0.81; 95% CI, 0.68-0.96). Case-control and cohort studies have cited a 20% to 50% reduced risk of CHF with MTX use.^89,90 The potential cardioprotective effect of MTX appears to be both multifactorial and complex, likely mediated through both direct and indirect mechanisms. MTX directly promotes anti-atherogenic lipoprotein function, improves endothelial function, and scavenges free radicals.^91,92 Indirectly, MTX likely reduces CVD risk by effectively reducing RA disease activity. Based on these and other data, MTX remains the cornerstone of DMARD therapy in RA patients when targeting CVD risk reduction.

Hydroxychloroquine

Emerging evidence suggests that hydroxychloroquine (HCQ), an antimalarial most often utilized in combination with alternative DMARDs in RA, prevents DM and has beneficial effects on lipid profiles. A recent meta-analysis compiled 3 homogenous observational studies that investigated the effect of HCQ on incident DM. RA patients ever exposed to HCQ had a 40% lower incidence of DM (HR, 0.59; 95% CI, 0.49-0.70).⁹³ Increased duration of HCQ use was shown to further reduce risk of incident DM.⁹⁴ The aforementioned meta-analysis also pooled 5 studies investigating the effect of HCQ on lipid profiles, with favorable mean differences in TC (–9.82 mg/dL), LDL (–10.61 mg/dL), HDL (4.13 mg/dL), and triglycerides (–19.15 mg/dL) in HCQ users compared to non-users.⁹³ Given these favorable changes to traditional CVD risk factors, it is not surprising that in a retrospective study of 1266 RA patients without prior CVD, HCQ was associated with significantly lower risk of incident CVD. While external validation of these findings is needed, HCQ is an attractive conventional DMARD to be used in RA for CVD risk reduction. Moreover, its combination with MTX and sulfasalazine also shows promise for CVD risk reduction.^95,96

TNF Inhibitors

Tumor necrosis factor (TNF) inhibitors are often the initial biologic DMARD therapy used in RA patients not responding to conventional DMARDs. In the previously described meta-analysis, TNF inhibitors were associated with similar reductions in CVD events as MTX (RR, 0.70; 95% CI, 0.54-0.90).⁷⁵ Of note, there was a trend toward reduced risk of CHF (RR, 0.75; 95% CI, 0.49-1.15) in this same meta-analysis, an area of concern with TNF inhibitor use due to a prior randomized controlled trial demonstrating worsening clinical status in patients with existing moderate-to-severe CHF treated with high-dose infliximab.⁹⁷ Current RA treatment guidelines recommend avoiding TNF inhibitor use in individuals with CHF.⁹⁸

Aside from the risk of CHF exacerbation, TNF inhibitors appear to be cardioprotective. Similar to MTX, the mechanism by which TNF inhibition reduces cardiovascular risk is complex and likely due to both direct and indirect mechanisms. Substantial research has been conducted on the effect of TNF inhibition on lipids, with a recent meta-analysis demonstrating increases in HDL and TC, with stable LDL and atherogenic index over treatment follow-up.⁹⁹ A subsequent meta-analysis not limited to RA patients yielded similar results.¹⁰⁰ In addition to quantitative lipid changes, alteration of lipoprotein function, improvement in myocardial function, reduced aortic stiffness, improved blood pressure, and reduced RA disease activity may also be responsible for cardioprotective benefits of these agents.^101,102

Non-TNF Biologic and Traditional Synthetic DMARDs

Tocilizumab, an IL-6 inhibitor, can potently increase LDL levels, but it does not appear to increase the risk of CVD events and may actually promote more favorable anti-atherogenic lipoprotein function.^103-106 Although these quantitative lipid changes received significant attention in the wake of early reports detailing this effect, similar lipid changes appear to accompany other DMARDs including TNF inhibitors and tofacitinib.¹⁰⁷ There have been few studies evaluating the risk of CVD with other non-TNF inhibitor biologic DMARDs and traditional synthetic DMARDs, warranting future study.

Conclusion

To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessments of CVD risk,³ and aggressively manage both traditional and nontraditional CVD risk factors. The differential roles in this effort may not be clear; thus, we have proposed a co-management strategy detailed in the Figure. Clear communication between providers is of the utmost importance to ensure effective management of CVD risk.

Given limited evidence for RA-specific CVD risk assessments and traditional risk factor treatment targets, management should follow pertinent national guidelines. The importance of lifestyle counseling should not be overlooked, with a focus on smoking cessation, healthy diet and body weight, and regular aerobic exercise. Finally, rheumatologists should aggressively manage RA using a treat-to-target approach, minimize the use of glucocorticoids and NSAIDs, and preferentially select DMARDs that have been associated with lower CVD risk. Through this comprehensive approach, recent trends of improved CVD outcomes in RA will hopefully become more widespread.¹⁰⁸

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; [email protected].

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review cardiovascular disease (CVD) risk assessment in patients with rheumatoid arthritis (RA).
• Methods: Literature review of the assessment of CVD risk in RA.
• Results: CVD is the leading cause of death among RA patients. Because of the increased risk of CVD events and CVD mortality in patients with RA, regular assessment of CVD risk and aggressive management of CVD risk in these patients is crucial. CVD risk estimation typically centers on the use of well-established CVD risk calculators. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing, while novel RA-derived CVD risk scores that incorporate RA-related factors have had limited external validity testing. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk.
• Conclusion: Primary care and rheumatology providers must be aware of the increased risk of CVD in RA, a risk that approaches that of diabetic patients. Routine assessment of CVD risk is an essential first step in minimizing CVD risk in this population. Until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment.

Editor’s note: This article is part 1 of a 2-part article. “Management of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the March/April 2019 issue.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory arthritis affecting up to 1% of the US population that can lead to joint damage, functional disability, and reduced quality of life.¹ In addition to articular involvement, systemic inflammation accompanying RA may lead to extra-articular manifestations and increase the risk of premature death.² Cardiovascular disease (CVD), accounting for nearly half of all deaths among RA patients, is now recognized as a critical extra-articular manifestation of RA.^2,3 As such, assessment and management of CVD risk is essential to the comprehensive care of the RA patient. This article reviews the approach to assessing CVD risk in patients with RA; the management of both traditional and RA-specific risk factors is discussed in a separate article.

Scope of the Problem

In a large meta-analysis of observational studies that included more than 111,000 patients with RA, CVD-related mortality rates were 1.5 times higher among RA patients than among general population controls.⁴ The risk of overall CVD, including nonfatal events, is similar; a separate meta-analysis of observational studies that included more than 41,000 patients with RA calculated a pooled relative risk for incident CVD of 1.48.⁵ Individual analyses identified heightened risk of acute coronary syndrome (ACS), cerebrovascular accident, and congestive heart failure (CHF).⁵ Perhaps more illustrative of the magnitude of the problem, the risk of CVD in RA approaches that observed among individuals with diabetes mellitus.^6,7

Coronary artery disease (CAD) accounts for a significant portion of the CVD risk in RA, but its presentation may be atypical in RA patients. RA patients are at higher risk of suffering unrecognized myocardial infarction (MI) and sudden cardiac death.⁸ The reasons for silent ischemia in RA are not fully known, but have been hypothesized to include imbalances of inflammatory cytokines, alterations in pain sensitization, or the female predominance of RA (with women more often presenting with atypical symptoms of myocardial ischemia).⁹ Alarmingly, a retrospective chart review study reported that RA patients admitted for an acute MI were less likely to receive appropriate reperfusion therapy as well as secondary prevention with beta-blockers and lipid-lowering agents.¹⁰ Even with appropriate therapy, long-term outcomes such as mortality and recurrent ischemic events are more likely to occur in RA patients after acute MI.^11-13

Independent of ischemic heart disease, RA patients are at increased risk of CHF.^14-16 RA patients are at particular risk for CHF with preserved ejection fraction,¹⁷ which may be a result of systemic inflammation causing left ventricular stiffening.^18,19 Similar to CAD, patients with RA are less likely to present with typical CHF symptoms, are less likely to receive guideline-concordant care, and have higher mortality rates following presentation with CHF.¹⁷

Although accounting for a lower proportion of the excess CVD morbidity and mortality in RA, the risk of noncardiac vascular disease is also increased in RA patients. Large meta-analyses have identified positive associations between RA with both ischemic (odds ratio [OR], 1.64 [95% confidence interval {CI}, 1.32-2.05]) and hemorrhagic (OR, 1.68 [95% CI, 1.11-2.53]) stroke.²⁰ Similarly, RA patients appear to have an approximately twofold higher risk of venous thromboembolic events.²¹ Less frequently studied than other forms of CVD, peripheral arterial disease may be increased in RA patients independent of other CVD and CVD risk factors.^22,23

Assessing CVD Risk in RA

CVD Risk Scores

In order to identify patients who may benefit from primary prevention interventions, such as lipid-lowering therapy, CVD risk estimation typically centers on the use of well-established CVD risk calculators (Table). CVD risk scores such as the Framingham Risk Score (FRS), Systematic Coronary Risk Evaluation (SCORE), and American College of Cardiology/ American Heart Association (ACC/AHA) Pooled Cohort Equation incorporate traditional CVD risk factors, including age, sex, smoking status, blood pressure, lipid levels, and presence of diabetes mellitus.^24,25 However, CVD risk in RA patients appears to be inadequately explained by traditional CVD risk factors,²⁶ with disease activity and inflammation being associated with higher CVD risk. Recognizing that inflammation may contribute to CVD risk even among non-RA patients, the Reynolds Risk Score includes high-sensitivity C-reactive protein (hsCRP) in its calculation.²⁷ In contrast to more robust performance in the general population, these well-established CVD risk scores have had variable predictive potential of incident CVD in RA patients.^28-30

Several models, or adaptations to existing models, have been proposed to improve CVD risk assessment in RA populations (Table). In 2009, the European League Against Rheumatism (EULAR) task force suggested using a correction factor of 1.5 with traditional CVD risk models in RA patients with 2 of the following criteria: disease duration exceeding 10 years, rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibody positivity, or extra-articular manifestations of RA.³¹ An update to these recommendations in 2015 continued to propose the use of a 1.5 correction factor, but suggested applying this to all RA patients.³² QRISK2, a modification to QRISK1 which was developed to predict CVD in the UK general population, includes the diagnosis of RA as a risk factor, and in early validation efforts more accurately discriminated patients in the general population at increased risk of CVD compared to the FRS.³³ Additional disease-specific risk factors such as systemic lupus, steroid use, severe mental illness, and steroid and atypical antipsychotic use were incorporated in the QRISK3 algorithm, with model performance similar to the QRISK2.³⁴ The Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) was specifically developed to assess CVD risk in RA patients by including RA disease activity, level of physical disability, RA disease duration, and prednisone use.³⁵ Despite efforts to develop “RA-specific” risk scores, these have not consistently outperformed traditional CVD risk calculators.^36-38 In one study involving more than 1700 RA patients, the ERS-RA performed similarly to the FRS and Reynolds Risk Score, with a net reclassification index of just 2.3% versus the FRS.³⁶

Imaging Modalities

Imaging modalities may assist in characterizing the increased risk of CVD in RA and the subclinical CVD manifestations that occur. For example, RA patients were shown to have more prevalent and unstable coronary plaque, higher carotid intima media thickness, and impaired myocardial function with computed tomography (CT) angiography and carotid ultrasound.^39,40 However, studies harnessing noninvasive imaging to augment CVD risk assessment in RA patients are limited.

Carotid ultrasound has been the most extensively studied imaging modality for CVD risk assessment in RA. In a cohort of 599 RA patients with no history of ACS, rates of ACS were nearly 4 times higher in RA patients with bilateral carotid plaque on carotid ultrasound, and the association with ACS was independent of other traditional and RA-related risk factors.⁴¹ Presence of bilateral carotid plaques was similarly associated with an increased risk of overall CVD events (hazard ratio [HR], 3.34 [95% CI, 1.21-9.22]), ACS alone (HR, 6.31 [95% CI, 1.27-31.40]), and a lower mean CVD event-free survival (13.9 versus 15.2 years, P = 0.01) in a separate inception cohort of 105 RA patients with no prior history of CVD.⁴² The most useful application of carotid ultrasound may be in conjunction with clinical CVD risk models. Use of carotid ultrasound improved CVD risk stratification among RA patients who were considered at moderate risk by the EULAR-modified SCORE calculator.⁴³ Beyond carotid ultrasound, measurement of arterial stiffness through ultrasound could also aid in CVD risk stratification. Aortic pulse wave velocity and augmentation index, measures of arterial stiffness, are predictive of CVD in the general population as well as RA patients and improve with reduction in RA disease activity.^44,45 Peripheral arterial stiffness (brachial-ankle elasticity index) is impaired in RA patients and predictive of CVD morbidity and mortality in the general population.^46,47

CT coronary angiography and coronary artery calcium (CAC) scores are reliable measures of coronary artery atherosclerosis and have been validated for CVD risk assessment in the general population.^48-52 While the association between RA and CT-related findings of atherosclerosis is well established, assessment of CT-mediated evaluation as a prognostic tool for CVD in RA is limited. In one cohort study, CAC predicted higher rates of CVD events in Chinese patients with RA and systemic lupus erythematosus in a pooled analysis, although results were limited by low event rates and the absence of RA-only subanalyses.⁵³

While the aforementioned imaging modalities have focused on enhancing the identification of atherosclerosis, echocardiography or cardiac magnetic resonance imaging (MRI) may be useful for detecting subclinical structural and/or functional abnormalities that predispose to CHF. Structural abnormalities including increased left ventricular mass and hypertrophy are more prevalent in RA patients and predict incident CHF in the general population.^54-56 MRI measures of myocardial inflammation, including T1 mapping and extracellular volume, are associated with higher mortality rates and also appear to be elevated in RA patients.^57,58 Whether identification of these imaging findings influences the cost-effective clinical management of RA patients needs further study.

Biomarkers

Serum biomarkers, such as the anti-CCP antibody, have become crucial to the evaluation of patients suspected to have RA. With the growing understanding of the role pro-inflammatory mediators play in CVD pathogenesis and the relative ease with which they can be measured, serum biomarkers have potential to inform CVD risk assessment. In the general population, hsCRP concentrations are predictive of CVD and are included in the Reynolds Risk Score.²⁷ In RA, CRP concentrations are typically much higher than those observed among individuals in the general population solely at increased CVD risk, yet elevated levels remain predictive of CVD death independent of RA disease activity and traditional CVD risk factors.⁵⁹ Several additional cytokines, chemokines, and adhesion molecules have been associated with surrogate markers of CVD in RA patients, although further study is needed to elucidate thresholds that signify increased CVD risk in a population characterized by the presence of systemic inflammation.⁶⁰

Cardiac biomarkers used frequently in the general population may be useful to assess CVD risk in RA patients. N-terminal-pro brain natriuretic peptide (NT-pro BNP) is a biomarker typically used to evaluate CHF severity, but it may also predict long-term mortality in patients with coronary heart disease.^61,62 Circulating NT-pro BNP concentrations are elevated in RA independent of prevalent CHF and may serve as a useful tool to identify subclinical cardiac disease in RA patients.⁶³ High-sensitivity cardiac troponin I (HS-cTnI) assays are capable of detecting levels of cardiac troponin below the threshold typically used to diagnose ACS. HS-cTnI levels are increased in RA patients independent of additional CVD risk factors, and elevated levels (> 1.5 pg/mL) were associated with more severe CT angiography findings of coronary plaque as well as increased risk of CVD events.^64,65

A fully validated algorithm for CVD risk assessment in RA is lacking. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing. In contrast, novel RA-derived CVD risk scores incorporate RA-related factors, but have had limited external validity testing. Additionally, RA-derived risk scores are less likely to be utilized and adopted by primary care providers and cardiologists involved in RA patients’ care. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk. Therefore, until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Conclusion

RA patients are at increased risk of CVD and CVD-related mortality relative to the general population. The disproportionate CVD burden seen in RA appears to be multifactorial, owing to the complex effects of systemic inflammation, endothelial dysfunction, and pro-atherogenic lipoprotein modifications. Additionally, many traditional CVD risk factors are more prevalent and suboptimally managed in RA patients. To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessment of CVD risk, and aggressively manage both traditional and nontraditional CVD risk factors. The management of CVD risk factors is discussed in detail in the second part of this article.

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; [email protected].

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review cardiovascular disease (CVD) risk assessment in patients with rheumatoid arthritis (RA).
• Methods: Literature review of the assessment of CVD risk in RA.
• Results: CVD is the leading cause of death among RA patients. Because of the increased risk of CVD events and CVD mortality in patients with RA, regular assessment of CVD risk and aggressive management of CVD risk in these patients is crucial. CVD risk estimation typically centers on the use of well-established CVD risk calculators. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing, while novel RA-derived CVD risk scores that incorporate RA-related factors have had limited external validity testing. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk.
• Conclusion: Primary care and rheumatology providers must be aware of the increased risk of CVD in RA, a risk that approaches that of diabetic patients. Routine assessment of CVD risk is an essential first step in minimizing CVD risk in this population. Until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment.

Editor’s note: This article is part 1 of a 2-part article. “Management of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the March/April 2019 issue.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory arthritis affecting up to 1% of the US population that can lead to joint damage, functional disability, and reduced quality of life.¹ In addition to articular involvement, systemic inflammation accompanying RA may lead to extra-articular manifestations and increase the risk of premature death.² Cardiovascular disease (CVD), accounting for nearly half of all deaths among RA patients, is now recognized as a critical extra-articular manifestation of RA.^2,3 As such, assessment and management of CVD risk is essential to the comprehensive care of the RA patient. This article reviews the approach to assessing CVD risk in patients with RA; the management of both traditional and RA-specific risk factors is discussed in a separate article.

Scope of the Problem

In a large meta-analysis of observational studies that included more than 111,000 patients with RA, CVD-related mortality rates were 1.5 times higher among RA patients than among general population controls.⁴ The risk of overall CVD, including nonfatal events, is similar; a separate meta-analysis of observational studies that included more than 41,000 patients with RA calculated a pooled relative risk for incident CVD of 1.48.⁵ Individual analyses identified heightened risk of acute coronary syndrome (ACS), cerebrovascular accident, and congestive heart failure (CHF).⁵ Perhaps more illustrative of the magnitude of the problem, the risk of CVD in RA approaches that observed among individuals with diabetes mellitus.^6,7

Coronary artery disease (CAD) accounts for a significant portion of the CVD risk in RA, but its presentation may be atypical in RA patients. RA patients are at higher risk of suffering unrecognized myocardial infarction (MI) and sudden cardiac death.⁸ The reasons for silent ischemia in RA are not fully known, but have been hypothesized to include imbalances of inflammatory cytokines, alterations in pain sensitization, or the female predominance of RA (with women more often presenting with atypical symptoms of myocardial ischemia).⁹ Alarmingly, a retrospective chart review study reported that RA patients admitted for an acute MI were less likely to receive appropriate reperfusion therapy as well as secondary prevention with beta-blockers and lipid-lowering agents.¹⁰ Even with appropriate therapy, long-term outcomes such as mortality and recurrent ischemic events are more likely to occur in RA patients after acute MI.^11-13

Independent of ischemic heart disease, RA patients are at increased risk of CHF.^14-16 RA patients are at particular risk for CHF with preserved ejection fraction,¹⁷ which may be a result of systemic inflammation causing left ventricular stiffening.^18,19 Similar to CAD, patients with RA are less likely to present with typical CHF symptoms, are less likely to receive guideline-concordant care, and have higher mortality rates following presentation with CHF.¹⁷

Although accounting for a lower proportion of the excess CVD morbidity and mortality in RA, the risk of noncardiac vascular disease is also increased in RA patients. Large meta-analyses have identified positive associations between RA with both ischemic (odds ratio [OR], 1.64 [95% confidence interval {CI}, 1.32-2.05]) and hemorrhagic (OR, 1.68 [95% CI, 1.11-2.53]) stroke.²⁰ Similarly, RA patients appear to have an approximately twofold higher risk of venous thromboembolic events.²¹ Less frequently studied than other forms of CVD, peripheral arterial disease may be increased in RA patients independent of other CVD and CVD risk factors.^22,23

Assessing CVD Risk in RA

CVD Risk Scores

In order to identify patients who may benefit from primary prevention interventions, such as lipid-lowering therapy, CVD risk estimation typically centers on the use of well-established CVD risk calculators (Table). CVD risk scores such as the Framingham Risk Score (FRS), Systematic Coronary Risk Evaluation (SCORE), and American College of Cardiology/ American Heart Association (ACC/AHA) Pooled Cohort Equation incorporate traditional CVD risk factors, including age, sex, smoking status, blood pressure, lipid levels, and presence of diabetes mellitus.^24,25 However, CVD risk in RA patients appears to be inadequately explained by traditional CVD risk factors,²⁶ with disease activity and inflammation being associated with higher CVD risk. Recognizing that inflammation may contribute to CVD risk even among non-RA patients, the Reynolds Risk Score includes high-sensitivity C-reactive protein (hsCRP) in its calculation.²⁷ In contrast to more robust performance in the general population, these well-established CVD risk scores have had variable predictive potential of incident CVD in RA patients.^28-30

Several models, or adaptations to existing models, have been proposed to improve CVD risk assessment in RA populations (Table). In 2009, the European League Against Rheumatism (EULAR) task force suggested using a correction factor of 1.5 with traditional CVD risk models in RA patients with 2 of the following criteria: disease duration exceeding 10 years, rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibody positivity, or extra-articular manifestations of RA.³¹ An update to these recommendations in 2015 continued to propose the use of a 1.5 correction factor, but suggested applying this to all RA patients.³² QRISK2, a modification to QRISK1 which was developed to predict CVD in the UK general population, includes the diagnosis of RA as a risk factor, and in early validation efforts more accurately discriminated patients in the general population at increased risk of CVD compared to the FRS.³³ Additional disease-specific risk factors such as systemic lupus, steroid use, severe mental illness, and steroid and atypical antipsychotic use were incorporated in the QRISK3 algorithm, with model performance similar to the QRISK2.³⁴ The Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) was specifically developed to assess CVD risk in RA patients by including RA disease activity, level of physical disability, RA disease duration, and prednisone use.³⁵ Despite efforts to develop “RA-specific” risk scores, these have not consistently outperformed traditional CVD risk calculators.^36-38 In one study involving more than 1700 RA patients, the ERS-RA performed similarly to the FRS and Reynolds Risk Score, with a net reclassification index of just 2.3% versus the FRS.³⁶

Imaging Modalities

Imaging modalities may assist in characterizing the increased risk of CVD in RA and the subclinical CVD manifestations that occur. For example, RA patients were shown to have more prevalent and unstable coronary plaque, higher carotid intima media thickness, and impaired myocardial function with computed tomography (CT) angiography and carotid ultrasound.^39,40 However, studies harnessing noninvasive imaging to augment CVD risk assessment in RA patients are limited.

Carotid ultrasound has been the most extensively studied imaging modality for CVD risk assessment in RA. In a cohort of 599 RA patients with no history of ACS, rates of ACS were nearly 4 times higher in RA patients with bilateral carotid plaque on carotid ultrasound, and the association with ACS was independent of other traditional and RA-related risk factors.⁴¹ Presence of bilateral carotid plaques was similarly associated with an increased risk of overall CVD events (hazard ratio [HR], 3.34 [95% CI, 1.21-9.22]), ACS alone (HR, 6.31 [95% CI, 1.27-31.40]), and a lower mean CVD event-free survival (13.9 versus 15.2 years, P = 0.01) in a separate inception cohort of 105 RA patients with no prior history of CVD.⁴² The most useful application of carotid ultrasound may be in conjunction with clinical CVD risk models. Use of carotid ultrasound improved CVD risk stratification among RA patients who were considered at moderate risk by the EULAR-modified SCORE calculator.⁴³ Beyond carotid ultrasound, measurement of arterial stiffness through ultrasound could also aid in CVD risk stratification. Aortic pulse wave velocity and augmentation index, measures of arterial stiffness, are predictive of CVD in the general population as well as RA patients and improve with reduction in RA disease activity.^44,45 Peripheral arterial stiffness (brachial-ankle elasticity index) is impaired in RA patients and predictive of CVD morbidity and mortality in the general population.^46,47

CT coronary angiography and coronary artery calcium (CAC) scores are reliable measures of coronary artery atherosclerosis and have been validated for CVD risk assessment in the general population.^48-52 While the association between RA and CT-related findings of atherosclerosis is well established, assessment of CT-mediated evaluation as a prognostic tool for CVD in RA is limited. In one cohort study, CAC predicted higher rates of CVD events in Chinese patients with RA and systemic lupus erythematosus in a pooled analysis, although results were limited by low event rates and the absence of RA-only subanalyses.⁵³

While the aforementioned imaging modalities have focused on enhancing the identification of atherosclerosis, echocardiography or cardiac magnetic resonance imaging (MRI) may be useful for detecting subclinical structural and/or functional abnormalities that predispose to CHF. Structural abnormalities including increased left ventricular mass and hypertrophy are more prevalent in RA patients and predict incident CHF in the general population.^54-56 MRI measures of myocardial inflammation, including T1 mapping and extracellular volume, are associated with higher mortality rates and also appear to be elevated in RA patients.^57,58 Whether identification of these imaging findings influences the cost-effective clinical management of RA patients needs further study.

Biomarkers

Serum biomarkers, such as the anti-CCP antibody, have become crucial to the evaluation of patients suspected to have RA. With the growing understanding of the role pro-inflammatory mediators play in CVD pathogenesis and the relative ease with which they can be measured, serum biomarkers have potential to inform CVD risk assessment. In the general population, hsCRP concentrations are predictive of CVD and are included in the Reynolds Risk Score.²⁷ In RA, CRP concentrations are typically much higher than those observed among individuals in the general population solely at increased CVD risk, yet elevated levels remain predictive of CVD death independent of RA disease activity and traditional CVD risk factors.⁵⁹ Several additional cytokines, chemokines, and adhesion molecules have been associated with surrogate markers of CVD in RA patients, although further study is needed to elucidate thresholds that signify increased CVD risk in a population characterized by the presence of systemic inflammation.⁶⁰

Cardiac biomarkers used frequently in the general population may be useful to assess CVD risk in RA patients. N-terminal-pro brain natriuretic peptide (NT-pro BNP) is a biomarker typically used to evaluate CHF severity, but it may also predict long-term mortality in patients with coronary heart disease.^61,62 Circulating NT-pro BNP concentrations are elevated in RA independent of prevalent CHF and may serve as a useful tool to identify subclinical cardiac disease in RA patients.⁶³ High-sensitivity cardiac troponin I (HS-cTnI) assays are capable of detecting levels of cardiac troponin below the threshold typically used to diagnose ACS. HS-cTnI levels are increased in RA patients independent of additional CVD risk factors, and elevated levels (> 1.5 pg/mL) were associated with more severe CT angiography findings of coronary plaque as well as increased risk of CVD events.^64,65

A fully validated algorithm for CVD risk assessment in RA is lacking. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing. In contrast, novel RA-derived CVD risk scores incorporate RA-related factors, but have had limited external validity testing. Additionally, RA-derived risk scores are less likely to be utilized and adopted by primary care providers and cardiologists involved in RA patients’ care. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk. Therefore, until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Conclusion

RA patients are at increased risk of CVD and CVD-related mortality relative to the general population. The disproportionate CVD burden seen in RA appears to be multifactorial, owing to the complex effects of systemic inflammation, endothelial dysfunction, and pro-atherogenic lipoprotein modifications. Additionally, many traditional CVD risk factors are more prevalent and suboptimally managed in RA patients. To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessment of CVD risk, and aggressively manage both traditional and nontraditional CVD risk factors. The management of CVD risk factors is discussed in detail in the second part of this article.

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; [email protected].

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review cardiovascular disease (CVD) risk assessment in patients with rheumatoid arthritis (RA).
• Methods: Literature review of the assessment of CVD risk in RA.
• Results: CVD is the leading cause of death among RA patients. Because of the increased risk of CVD events and CVD mortality in patients with RA, regular assessment of CVD risk and aggressive management of CVD risk in these patients is crucial. CVD risk estimation typically centers on the use of well-established CVD risk calculators. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing, while novel RA-derived CVD risk scores that incorporate RA-related factors have had limited external validity testing. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk.
• Conclusion: Primary care and rheumatology providers must be aware of the increased risk of CVD in RA, a risk that approaches that of diabetic patients. Routine assessment of CVD risk is an essential first step in minimizing CVD risk in this population. Until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment.

Editor’s note: This article is part 1 of a 2-part article. “Management of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the March/April 2019 issue.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory arthritis affecting up to 1% of the US population that can lead to joint damage, functional disability, and reduced quality of life.¹ In addition to articular involvement, systemic inflammation accompanying RA may lead to extra-articular manifestations and increase the risk of premature death.² Cardiovascular disease (CVD), accounting for nearly half of all deaths among RA patients, is now recognized as a critical extra-articular manifestation of RA.^2,3 As such, assessment and management of CVD risk is essential to the comprehensive care of the RA patient. This article reviews the approach to assessing CVD risk in patients with RA; the management of both traditional and RA-specific risk factors is discussed in a separate article.

Scope of the Problem

In a large meta-analysis of observational studies that included more than 111,000 patients with RA, CVD-related mortality rates were 1.5 times higher among RA patients than among general population controls.⁴ The risk of overall CVD, including nonfatal events, is similar; a separate meta-analysis of observational studies that included more than 41,000 patients with RA calculated a pooled relative risk for incident CVD of 1.48.⁵ Individual analyses identified heightened risk of acute coronary syndrome (ACS), cerebrovascular accident, and congestive heart failure (CHF).⁵ Perhaps more illustrative of the magnitude of the problem, the risk of CVD in RA approaches that observed among individuals with diabetes mellitus.^6,7

Coronary artery disease (CAD) accounts for a significant portion of the CVD risk in RA, but its presentation may be atypical in RA patients. RA patients are at higher risk of suffering unrecognized myocardial infarction (MI) and sudden cardiac death.⁸ The reasons for silent ischemia in RA are not fully known, but have been hypothesized to include imbalances of inflammatory cytokines, alterations in pain sensitization, or the female predominance of RA (with women more often presenting with atypical symptoms of myocardial ischemia).⁹ Alarmingly, a retrospective chart review study reported that RA patients admitted for an acute MI were less likely to receive appropriate reperfusion therapy as well as secondary prevention with beta-blockers and lipid-lowering agents.¹⁰ Even with appropriate therapy, long-term outcomes such as mortality and recurrent ischemic events are more likely to occur in RA patients after acute MI.^11-13

Independent of ischemic heart disease, RA patients are at increased risk of CHF.^14-16 RA patients are at particular risk for CHF with preserved ejection fraction,¹⁷ which may be a result of systemic inflammation causing left ventricular stiffening.^18,19 Similar to CAD, patients with RA are less likely to present with typical CHF symptoms, are less likely to receive guideline-concordant care, and have higher mortality rates following presentation with CHF.¹⁷

Although accounting for a lower proportion of the excess CVD morbidity and mortality in RA, the risk of noncardiac vascular disease is also increased in RA patients. Large meta-analyses have identified positive associations between RA with both ischemic (odds ratio [OR], 1.64 [95% confidence interval {CI}, 1.32-2.05]) and hemorrhagic (OR, 1.68 [95% CI, 1.11-2.53]) stroke.²⁰ Similarly, RA patients appear to have an approximately twofold higher risk of venous thromboembolic events.²¹ Less frequently studied than other forms of CVD, peripheral arterial disease may be increased in RA patients independent of other CVD and CVD risk factors.^22,23

Assessing CVD Risk in RA

CVD Risk Scores

In order to identify patients who may benefit from primary prevention interventions, such as lipid-lowering therapy, CVD risk estimation typically centers on the use of well-established CVD risk calculators (Table). CVD risk scores such as the Framingham Risk Score (FRS), Systematic Coronary Risk Evaluation (SCORE), and American College of Cardiology/ American Heart Association (ACC/AHA) Pooled Cohort Equation incorporate traditional CVD risk factors, including age, sex, smoking status, blood pressure, lipid levels, and presence of diabetes mellitus.^24,25 However, CVD risk in RA patients appears to be inadequately explained by traditional CVD risk factors,²⁶ with disease activity and inflammation being associated with higher CVD risk. Recognizing that inflammation may contribute to CVD risk even among non-RA patients, the Reynolds Risk Score includes high-sensitivity C-reactive protein (hsCRP) in its calculation.²⁷ In contrast to more robust performance in the general population, these well-established CVD risk scores have had variable predictive potential of incident CVD in RA patients.^28-30

Several models, or adaptations to existing models, have been proposed to improve CVD risk assessment in RA populations (Table). In 2009, the European League Against Rheumatism (EULAR) task force suggested using a correction factor of 1.5 with traditional CVD risk models in RA patients with 2 of the following criteria: disease duration exceeding 10 years, rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibody positivity, or extra-articular manifestations of RA.³¹ An update to these recommendations in 2015 continued to propose the use of a 1.5 correction factor, but suggested applying this to all RA patients.³² QRISK2, a modification to QRISK1 which was developed to predict CVD in the UK general population, includes the diagnosis of RA as a risk factor, and in early validation efforts more accurately discriminated patients in the general population at increased risk of CVD compared to the FRS.³³ Additional disease-specific risk factors such as systemic lupus, steroid use, severe mental illness, and steroid and atypical antipsychotic use were incorporated in the QRISK3 algorithm, with model performance similar to the QRISK2.³⁴ The Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) was specifically developed to assess CVD risk in RA patients by including RA disease activity, level of physical disability, RA disease duration, and prednisone use.³⁵ Despite efforts to develop “RA-specific” risk scores, these have not consistently outperformed traditional CVD risk calculators.^36-38 In one study involving more than 1700 RA patients, the ERS-RA performed similarly to the FRS and Reynolds Risk Score, with a net reclassification index of just 2.3% versus the FRS.³⁶

Imaging Modalities

Imaging modalities may assist in characterizing the increased risk of CVD in RA and the subclinical CVD manifestations that occur. For example, RA patients were shown to have more prevalent and unstable coronary plaque, higher carotid intima media thickness, and impaired myocardial function with computed tomography (CT) angiography and carotid ultrasound.^39,40 However, studies harnessing noninvasive imaging to augment CVD risk assessment in RA patients are limited.

Carotid ultrasound has been the most extensively studied imaging modality for CVD risk assessment in RA. In a cohort of 599 RA patients with no history of ACS, rates of ACS were nearly 4 times higher in RA patients with bilateral carotid plaque on carotid ultrasound, and the association with ACS was independent of other traditional and RA-related risk factors.⁴¹ Presence of bilateral carotid plaques was similarly associated with an increased risk of overall CVD events (hazard ratio [HR], 3.34 [95% CI, 1.21-9.22]), ACS alone (HR, 6.31 [95% CI, 1.27-31.40]), and a lower mean CVD event-free survival (13.9 versus 15.2 years, P = 0.01) in a separate inception cohort of 105 RA patients with no prior history of CVD.⁴² The most useful application of carotid ultrasound may be in conjunction with clinical CVD risk models. Use of carotid ultrasound improved CVD risk stratification among RA patients who were considered at moderate risk by the EULAR-modified SCORE calculator.⁴³ Beyond carotid ultrasound, measurement of arterial stiffness through ultrasound could also aid in CVD risk stratification. Aortic pulse wave velocity and augmentation index, measures of arterial stiffness, are predictive of CVD in the general population as well as RA patients and improve with reduction in RA disease activity.^44,45 Peripheral arterial stiffness (brachial-ankle elasticity index) is impaired in RA patients and predictive of CVD morbidity and mortality in the general population.^46,47

CT coronary angiography and coronary artery calcium (CAC) scores are reliable measures of coronary artery atherosclerosis and have been validated for CVD risk assessment in the general population.^48-52 While the association between RA and CT-related findings of atherosclerosis is well established, assessment of CT-mediated evaluation as a prognostic tool for CVD in RA is limited. In one cohort study, CAC predicted higher rates of CVD events in Chinese patients with RA and systemic lupus erythematosus in a pooled analysis, although results were limited by low event rates and the absence of RA-only subanalyses.⁵³

While the aforementioned imaging modalities have focused on enhancing the identification of atherosclerosis, echocardiography or cardiac magnetic resonance imaging (MRI) may be useful for detecting subclinical structural and/or functional abnormalities that predispose to CHF. Structural abnormalities including increased left ventricular mass and hypertrophy are more prevalent in RA patients and predict incident CHF in the general population.^54-56 MRI measures of myocardial inflammation, including T1 mapping and extracellular volume, are associated with higher mortality rates and also appear to be elevated in RA patients.^57,58 Whether identification of these imaging findings influences the cost-effective clinical management of RA patients needs further study.

Biomarkers

Serum biomarkers, such as the anti-CCP antibody, have become crucial to the evaluation of patients suspected to have RA. With the growing understanding of the role pro-inflammatory mediators play in CVD pathogenesis and the relative ease with which they can be measured, serum biomarkers have potential to inform CVD risk assessment. In the general population, hsCRP concentrations are predictive of CVD and are included in the Reynolds Risk Score.²⁷ In RA, CRP concentrations are typically much higher than those observed among individuals in the general population solely at increased CVD risk, yet elevated levels remain predictive of CVD death independent of RA disease activity and traditional CVD risk factors.⁵⁹ Several additional cytokines, chemokines, and adhesion molecules have been associated with surrogate markers of CVD in RA patients, although further study is needed to elucidate thresholds that signify increased CVD risk in a population characterized by the presence of systemic inflammation.⁶⁰

Cardiac biomarkers used frequently in the general population may be useful to assess CVD risk in RA patients. N-terminal-pro brain natriuretic peptide (NT-pro BNP) is a biomarker typically used to evaluate CHF severity, but it may also predict long-term mortality in patients with coronary heart disease.^61,62 Circulating NT-pro BNP concentrations are elevated in RA independent of prevalent CHF and may serve as a useful tool to identify subclinical cardiac disease in RA patients.⁶³ High-sensitivity cardiac troponin I (HS-cTnI) assays are capable of detecting levels of cardiac troponin below the threshold typically used to diagnose ACS. HS-cTnI levels are increased in RA patients independent of additional CVD risk factors, and elevated levels (> 1.5 pg/mL) were associated with more severe CT angiography findings of coronary plaque as well as increased risk of CVD events.^64,65

A fully validated algorithm for CVD risk assessment in RA is lacking. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing. In contrast, novel RA-derived CVD risk scores incorporate RA-related factors, but have had limited external validity testing. Additionally, RA-derived risk scores are less likely to be utilized and adopted by primary care providers and cardiologists involved in RA patients’ care. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk. Therefore, until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Conclusion

RA patients are at increased risk of CVD and CVD-related mortality relative to the general population. The disproportionate CVD burden seen in RA appears to be multifactorial, owing to the complex effects of systemic inflammation, endothelial dysfunction, and pro-atherogenic lipoprotein modifications. Additionally, many traditional CVD risk factors are more prevalent and suboptimally managed in RA patients. To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessment of CVD risk, and aggressively manage both traditional and nontraditional CVD risk factors. The management of CVD risk factors is discussed in detail in the second part of this article.

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; [email protected].

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).