Introduction

Cardiovascular disease (CVD) is the leading cause of death in all high income and many middle income countries worldwide, accounting for about one-third of deaths in the USA [1] and Canada [2]. Increasing evidence suggests that patients with chronic inflammatory diseases have an elevated risk of cardiovascular morbidity and mortality compared to the general population [3–7]. Although this risk is largely attributable to co-existing traditional risk factors for CVD, including diabetes mellitus, hypertension, hyperlipidemia, smoking, obesity, and sedentary lifestyle; the contributing role of inflammation in atherosclerosis suggests that systemic inflammation may independently contribute to the elevated risk. Expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) are common to the pathogenesis of both atherosclerosis and other chronic inflammatory diseases [8].

Treatments for chronic inflammatory diseases often aim to reduce underlying inflammation with systemic anti-inflammatory agents or anti-pro-inflammatory cytokines (e.g., anti-TNF and anti-IL-6 agents). Given the connection between inflammation and atherosclerosis, many have suggested that reducing systemic inflammation may also reduce cardiovascular risk. Coupled with management of cardiovascular comorbidities and traditional risk factors, this reduction may help mitigate cardiovascular risk in patients with chronic inflammatory diseases. However, the risks and benefits of treatment appear to be agent-specific, and thus warrant vigilance by healthcare providers, and a comprehensive care plan.

This review examines the magnitude of cardiovascular risk in common chronic inflammatory diseases, including: rheumatoid arthritis, psoriasis, and psoriatic arthritis. The effect of conventional treatments on cardiovascular risk and how practical management strategies can mitigate cardiovascular risk in these diseases is presented.

Methods

PubMed was searched for all English language publications from May 2005 to May 2010 (Fig. 1). The search strategy used MeSH and keyword headings. Search terms included “cardiovascular risk” and “therapy”, in combination with “inflammation”, “rheumatoid arthritis”, “psoriasis” or “psoriatic arthritis”. Abstracts were screened to identify relevant publications. Clinical trial and registry data regarding risk factors in patients with chronic inflammatory diseases were excluded if no control was reported. Overall, 313 articles were identified, 168 articles were selected based on their abstract, and, finally, 16 were found to be suitable for this review based on relevance. Literature was then hand-searched for background information regarding inflammation and atherosclerotic processes (n = 2) and available cardiovascular guidelines/risk scores (n = 7). Additional references were identified (n = 25) either through hand-searching reference lists from publications identified in the original search, or through PubMed/electronic updates of journal table of contents. The same inclusion/exclusion criteria were used to screen these publications. No statistical analysis or evidence grading was performed.

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Literature search flow diagram

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Prevalence of cardiovascular morbidity and the role of other risk factors in patients with chronic inflammatory diseases

Role of inflammation

Inflammatory diseases are characterized by increased local and systemic inflammation. Historically, atherosclerosis was thought to be a process characterized by accumulation of lipids within the artery wall, leading to vascular remodeling, plaque formation, and eventually thrombotic complications due to plaque rupture or erosion. However, it is now generally accepted that atherosclerosis is an inflammatory process [8]. Chronic inflammatory diseases and atherosclerosis therefore share similar inflammatory pathophysiology, which may accelerate the atherosclerotic process in patients with chronic inflammatory diseases. For example, serum markers of inflammation in rheumatoid arthritis have been shown to be markers for atherosclerotic complications and may also reduce plaque stability and potentiate atherosclerosis [8, 9]. Additionally, psoriasis is mediated by T-helper-1 (Th-1) and Th-17-dominant T-cell populations, which parallel chronic inflammatory pathways involved in endothelial erosion and plaque rupture [8].

Comorbidities and adverse events

Patients with chronic inflammatory diseases are prone to traditional risk factors that elevate cardiovascular risk, including but not limited to obesity, diabetes, hypertension, hyperlipidemia, and smoking (Table 1). This evidence is most abundant in rheumatoid arthritis [5, 10] and psoriasis [3, 4, 11–14], but also exists to a lesser extent in psoriatic arthritis [6]. Generally, patients with more severe inflammatory disease have higher cardiovascular risk, as seen in patients with moderate-to-severe psoriasis, who have an increased prevalence of cardiovascular comorbidities and elevated cardiovascular risk compared to patients with mild disease [3, 11, 12]. Additionally, patients with higher rheumatoid arthritis disease activity have shown an increased risk of developing heart failure [15].

Table 1 Prevalence of risk factors in select chronic inflammatory diseases
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The increase in traditional risk factors place patients at higher risk of mortality. Specifically, rheumatoid arthritis itself may be an independent risk factor for the overall increased incidence of these cardiovascular events [7]. Analysis of 2.37 million patients in the UK compared patients with rheumatoid arthritis to the general population and found an increased all-cause mortality ratio of 1.6 (95% CI 1.6–1.6) and a vascular mortality ratio of 1.5 (95% CI 1.4–1.6) [16]. An analysis of 13 studies comparing rheumatoid arthritis patients to the USA/Canadian general population by Wolfe et al. also found standardized mortality ratios ranging from 1.16 to as high as 3.00 [17].

Inflammatory conditions are also associated with an increased risk of specific nonfatal cardiovascular complications, including myocardial infarction and cerebrovascular accidents. Analysis of rheumatoid arthritis patients in the UK found an increased incidence of myocardial infarction and cerebrovascular accidents (stroke, subarachnoid hemorrhage and subdural hematoma), with an adjusted relative risk of 1.6 (95% CI 1.5–1.7) and 1.4 (95% CI 1.3–1.5), respectively [16]. The Nurses’ Health Study, a large prospective cohort of 114,342 women, found an adjusted relative risk of myocardial infarction of 2.0 (95% CI 1.23–3.29) in patients with rheumatoid arthritis, compared to patients without rheumatoid arthritis, although no increase in cerebrovascular accidents was seen. Women who had rheumatoid arthritis for at least 10 years had a further increased risk of myocardial infarction of 3.10 (95% CI 1.64–5.87) [5].

A prospective longitudinal study using the Consortium of Rheumatology Researchers of North America registry reported an incidence of cardiovascular events among rheumatoid arthritis patients of 3.98 (95% CI 3.08–4.88) per 1,000 patient-years. When stratified by number of cardiovascular risk factors, the incidence rate for cardiovascular events in patients with two or more cardiovascular risk factors and three or more markers of rheumatoid arthritis severity was 7.47 (95% CI 4.21–10.73) per 1,000 patient-years [18]. This suggests that the risk of adverse cardiovascular events may increase as the number of cardiovascular risk factors and markers of rheumatoid arthritis disease severity increases.

Psoriasis may also be an independent risk factor for all-cause mortality, with an odds ratio of 1.86 (95% CI 1.56–2.21) when adjusted for comorbidities compared with patients without psoriasis [4]. Patients with severe psoriasis have an increased risk of cardiovascular mortality [13] and overall cardiovascular events [12] that are independent of traditional cardiovascular risk factors [13]. These psoriatic patients show a high prevalence of cardiovascular risk factors and may consequently be predisposed to CVDs [19]. Specifically, patients with psoriasis have been shown to be associated with an increased risk of atherosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease [4], and myocardial infarction [11, 14].

The effect of anti-inflammatory medications on cardiovascular risk

Background

Common treatments for chronic inflammatory conditions [e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), and biologic agents] may also impact both cardiovascular morbidity and mortality (Tables 2 and 3). Since the goal of these treatments is to decrease inflammatory burden, successful treatment may theoretically reduce cardiovascular risk [20]. There is evidence supporting a decrease in cardiovascular risk in rheumatoid arthritis patients following the initiation of antirheumatic therapy, including DMARDs and anti-TNF therapy. However, other therapies, such as NSAIDs and cyclooxygenase-2 inhibitors (coxibs) may paradoxically increase cardiovascular risk [21]. An increasing body of literature on biologic therapy as a primary treatment for systemic inflammatory diseases which provides insight on cardiovascular outcomes. However, new biologics focusing on inflammatory mediators, such as IL-6 and IL-12/IL-23 have recently been introduced and more research is needed to identify specific effects on cardiovascular risk. Treatment-specific effects are discussed below.

Table 2 Summary of studies analyzing cardiovascular risk in patients treated with DMARDs
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Table 3 Summary of studies analyzing cardiovascular risk in patients treated with biologics
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Nonsteroidal anti-inflammatory drugs

Some NSAIDs and coxibs have been shown to increase cardiovascular risk, however the precise mechanisms involved are not fully understood [22–25]. Specifically, rofecoxib was found to increase cardiovascular risk [25], cerebrovascular accidents [24], and myocardial infarction [22, 23] and has been withdrawn from the market. However, the risks posed by other NSAIDs and coxibs are less clear and differ within each drug, dosage, and specific database examined. Therefore, weighing the individual risk and benefit of each patient is essential.

Corticosteroids

Corticosteroids increase cardiovascular risk due to negative effects on lipids, glucose tolerance, insulin production and sensitivity, blood pressure, and obesity [26]. The increased cardiovascular risk is highest in patients treated with long-term and high doses of corticosteroids, although the risk of using low doses is not negligible [27].

In rheumatoid arthritis, corticosteroid use has been associated with an increased incidence of myocardial infarction [28]. In the Medicines Monitoring Scotland National Health Service rheumatoid arthritis database, patients with inflammatory joint diseases taking more than 7.5 mg/day prednisone equivalent had a higher risk of cardiovascular events (RR 3.3, 95% CI 1.56–6.96) than those on lower doses (RR 1.5, 95% CI 0.98–2.30) [27]. Data from The General Practice Research Database also showed that rheumatoid arthritis patients treated with glucocorticoids had increased risk for myocardial infarction (OR 1.2, 95% CI 1.11–1.29) and heart failure (OR 2.6, 95% CI 2.46–2.87) but not ischemic cerebrovascular accidents [29]. Corticosteroid use may also increase the risk of diabetes and hypertension [26, 28], which indirectly contributes to the overall risk of myocardial infarction [28]. Accordingly, use of corticosteroids is recommended only if absolutely necessary and at the lowest dose for the shortest duration wherever possible [21].

Disease-modifying antirheumatic drugs

Generally, patients with severe disease are more likely to be treated with DMARD and biologic therapy. Some evidence suggests that methotrexate (MTX) decreases the incidence of cardiovascular events in patients with rheumatoid arthritis (HR 0.4; 95% CI 0.2–0.8) [30]. One study comparing both rheumatoid arthritis and psoriasis patients treated and not treated with MTX reported a reduction in risk of vascular disease (0.83 (95% CI 0.71–0.96); 0.73 (95% CI 0.55–0.98), respectively) [31]. Conversely, some evidence has shown that lower than normal doses of MTX may promote atherosclerosis in patients with pre-existing signs of atherosclerotic vascular disease. The observation is specific for low/moderate-dose MTX, because no link between any of the other DMARDs and the presence of CVD with regards to mortality was found [32]. One study found that azathioprine, cyclosporine, and leflunomide were associated with an 80% increased risk of cardiovascular events compared to MTX monotherapy [33]. Additionally, hypertension is a recognized side effect of both cyclosporine and leflunomide [33].

Biologics

The majority of literature regarding the effect of biologic therapy on cardiovascular comorbidities and events involves anti-TNF therapy. TNF-alpha is a mediator of endothelial dysfunction, vascular instability, and disease progression in atherosclerosis. It is thought that there may be an association between treatment with biologic therapy and a direct or indirect effect on cardiovascular risk [34]. Indeed, the risk of developing CVD was shown to be lower in patients with rheumatoid arthritis treated with anti-TNF therapy versus anti-TNF therapy-naive patients [20]. In a study by Wolfe et al., anti-TNF therapy was associated with a 1.2% lower frequency of heart failure after adjustment for Health Assessment Questionnaire disability index, pain, global severity, prednisone use, age, age-squared, and sex. Additionally, patients from this study who did not have pre-existing CVD had a low risk of heart failure (0.4%) that was not related to anti-TNF therapy [35]. BIOBADASER, a Spanish registry for active long-term follow-up of safety of biologic treatments for rheumatoid arthritis patients, also showed a reduction in both all-cause mortality and cardiovascular events (0.32 (95% CI 0.20–0.53) and 0.58 (95% CI 0.24–1.41), respectively) [36]. Results from multiple independent long-term registries [15, 35, 37] have provided additional evidence that treatment with anti-TNF therapy was effective for treating rheumatoid arthritis and mitigating the risk of adverse cardiovascular events. Studies have also found no association between anti-TNF therapy and an increase in all-cause mortality [38] or ischemic cerebrovascular accidents [24]. Some studies have also analyzed the effect of biologic therapy on surrogate markers of cardiovascular risk, such as CRP or apolipoprotein B. Reduction of these surrogate markers may imply downstream reduction in cardiovascular risk, although specific proof needs to be generated.

Several studies using anti-TNF therapy as a targeted treatment for congestive heart failure in patients without inflammatory disease did not show any benefit. Two large clinical trials evaluating etanercept in the treatment of congestive heart failure (RENAISSANCE and RECOVER) were terminated due to lack of efficacy. On the other hand, a single study of infliximab (ATTACH) showed a statistically significant increase in risk of all-cause mortality or hospitalization for heart failure in patients receiving the 10 mg/kg dose [39]. Therefore, primary prevention of cardiovascular complications with biologics appears to be very different from attempting to treat and reverse advanced CVDs such as heart failure.

Assessing and managing cardiovascular risk

There is no gold standard for managing and preventing CVDs in patients with chronic inflammatory diseases. However, various resources can be used to assist in managing these populations. A two-pronged approach aimed at controlling the inflammatory burden of disease and managing traditional cardiovascular risk factors is recommended [21].

Chronic inflammatory diseases may be considered to be a cardiovascular risk factor on par with hypertension and diabetes mellitus. One study found that preclinical atherosclerosis appears to be equally as frequent and severe in both rheumatoid arthritis and diabetes, despite having differential profiles in traditional risk factors and systemic inflammation [10]. Other studies have began to compare chronic inflammatory diseases to other cardiovascular risk factors, as is shown in a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science, which developed a stratification protocol with three tiers. Chronic inflammatory diseases were placed in tier 2, along with type 2 diabetes mellitus. Tier 2 indicates a moderate risk, of which there is pathophysiologic evidence for arterial dysfunction indicative of accelerated atherosclerosis before 30 years of age [40].

Patients may also be unaware of their cardiovascular risks and may even be undertreated for their cardiovascular comorbidities or events. Some evidence suggests a higher risk of death in rheumatoid arthritis patients after an acute myocardial infarction, which may be attributed to a delay in seeking medical attention and/or delay in diagnosis. For example, patients and/or physicians may attribute chest pain to the chronic inflammatory disease instead of a cardiovascular-related cause. Additionally, rheumatoid arthritis patients may have decreased pain perception and generalized hyposensitivity to myocardial ischemia, as has been observed in other patients with diabetes or renal failure [41]. Suboptimal quality of care for cardiovascular comorbidities among rheumatoid arthritis patients has also been shown. It is possible that the patient and/or physician are focused on one disease, contributing to a delay in diagnosis, and highlighting the need for increased awareness of concomitant cardiovascular comorbidities in patients with chronic inflammatory diseases [42].

A proposed strategy in mitigating cardiovascular risk in chronic inflammatory diseases is to gain control of disease with treatments including NSAIDs, corticosteroids, DMARDs and biologics. Some evidence suggests that biologics may indeed lower cardiovascular risk in patients with inflammatory diseases [20, 24, 35, 36, 38].

Increased prevalence of traditional cardiovascular risk factors and comorbidities also necessitates management of these risk factors. Several guidelines are available, including the 2009 American College of Cardiology Foundation/American Heart Association Guidelines [1] and 2009 Canadian Cardiovascular Society Guidelines [2], among others. Generally, patients should have an overall assessment of lifestyles and risk factors associated with CVD is recommended, which can include multivariable risk scores to help estimate absolute risk for coronary heart disease (Table 4). Several risk score models may also be useful to assess cardiovascular risk. The 1998 Framingham Risk Score has been validated in the broadest range of populations and has the longest duration of follow-up [43]. A newer version was published in 2008 that can predict 1-year global CVD risk and specific CVD end points (coronary heart disease, cerebrovascular accidents, heart failure, and peripheral arterial disease) [44]. The European risk assessment system Systematic Coronary Risk Evaluation (SCORE), which estimates fatal CVD risk [45] and the Reynolds Risk Score, which estimates womens’ risk for CVD, including cerebrovascular accidents and revascularization [46] may be suitable alternatives.

Table 4 Practical management strategies for risk factors in patients with chronic inflammatory diseases
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The 2009 European League Against Rheumatism evidence-based recommendations for cardiovascular risk management suggest using the SCORE model in patients with rheumatoid arthritis. The recommendations also note that all cardiovascular risk models may under-represent risk in patients with chronic inflammatory diseases and multiplying scores by a factor of 1.5 (when two of the following are met: disease duration >10 years, RF or anti-CCP positivity, presence of certain extra-articular manifestations) may accurately gauge risk in rheumatoid arthritis patients [21]. Ultimately, assessment should promote lifestyle changes through counseling, which can reduce or avoid the need for medical therapies and ensure patients follow a healthy diet and engage in regular physical exercise. Measuring weight, body mass index, and/or waist circumference can be used to monitor progress [1].

Blood pressure should be measured in all patients and an appropriate antihypertensive regimen should be prescribed for those with hypertension. The recommended target below which represents satisfactory blood pressure control is 140/90 mmHg. A lower threshold (130/80 mmHg) has been suggested for patients with diabetes and should also be considered for patients with rheumatoid arthritis, although there are no prospective studies to validate this. Patients actively smoking or using tobacco should be counseled and enrolled in smoking cessation programs [1]. A fasting lipid profile should be performed and lipid levels monitored and aggressively treated, as there is evidence to show that there are a high percentage of patients with rheumatoid arthritis for whom intervention may be required. Evidence suggests that cholesterol lowering therapy is under-prescribed in this patient group [47]. There is some evidence that certain biologic therapies (e.g., anti-IL-6 therapy) may affect lipid profiles and therefore may require additional attention and/or therapy.

Once the risk profile has been established and in the case that treatment with cholesterol lowering therapy has been initiated, regular monitoring (e.g., every 3–6 months depending on severity) is required to ensure that patients are at the appropriate target for treatment and remain adherent to the treatment and prevention regimen.

Conclusion

Available data supports the conclusion that patients with chronic inflammatory diseases have an increased prevalence of concomitant traditional risk factors for CVD leading to increased cardiovascular mortality and complications. The risk/benefit ratio of treatment options should be carefully weighed and individualized therapy and specific patient management strategies to address the chronic inflammatory disease itself and the cardiovascular risk factors and comorbidities will achieve the best overall outcomes for these patients.