Cardiovascular risk and inflammatory rheumatic diseases

Systemic lupus erythematosus

Patients with SLE have an increased prevalence of certain classic CVD risk factors including:

• hypertension and diabetes compared with healthy controls¹

• dyslipidemia with higher triglycerides and lower high-density lipoprotein (HDL) than unaffected controls¹

• metabolic syndrome which may develop in part due to active disease, especially active nephritis, and also as a consequence of corticosteroid use.⁸

Lupus-related factors, including pre-existing damage in other organ systems, may also contribute to CVD risk.¹ Over time, chronic inflammatory disease will increase CVD risk and this is reflected by the association of increased C-reactive protein (CRP) and/or low C3 complement with both clinical and subclinical atherosclerosis seen in some SLE patients.¹

With regards to therapy, high-dose and long-term corticosteroid usage also increase CVD risk; this may, in part, result from exacerbation of classic risk factors including hypertension, diabetes mellitus and dyslipidaemia.¹ By contrast, the use of anti-malarials seems to mitigate cardiovascular risk factors, having both lipid- and glucose-lowering effects, and might be especially beneficial when the patient is taking steroids.¹

Rheumatoid arthritis

Meta-analysis demonstrates increased prevalence of smoking, diabetes and reduced HDL-cholesterol level in RA.⁹ Indeed cigarette smoking is an important risk factor for developing RA, in particular seropositive disease which has a poorer overall prognosis. Interestingly, some of the traditional risk factors do not act as expected when predicting future CVD morbidity and mortality in RA. Of particular note is the observation that lower total cholesterol is associated with increased risk of CVD in RA.¹⁰ This is probably due to the contribution of chronic inflammation to a ‘cachectic’ effect on RA patients, as well as chronic inflammation affecting lipid subsets to induce a more pro-atherogenic profile.

There is a reported positive association between inflammation and CVD mortality in RA patients.¹¹ Similarly in this group, elevated levels of CRP and erythrocyte sedimentation rate (ESR) are associated with increased all-cause and CVD mortality. Interestingly, seropositivity for rheumatoid factor (RF) and/or anti-cyclic citrullinated protein antibodies (ACPA) and the shared epitope are also associated with increased risk of CVD.¹² In relation to drug therapy, several reports, including a systematic review, have noted a reduction in CVD morbidity and mortality among methotrexate-treated patients.¹³ The use of biological agents such as tumour necrosis factor (TNF)-inhibitors is also associated with improved disease activity and reduced inflammatory burden. The effect of biological agents on individual events and on CVD mortality is still the subject of intense study, and larger studies are needed to completely resolve this question. However, a meta-analysis of studies published to date suggests that use of anti-TNF drugs might reduce the risk of future CVD when compared to standard disease-modifying anti-rheumatic drug (DMARD) therapy.¹⁴

Spondyloarthritis

Less is known about risk factors for CVD in patients with psoriatic arthritis (PsA). There is an increased prevalence of obesity, hypertension and diabetes mellitus in patients with PsA when compared to healthy controls.¹⁵ The inflammatory process may also increase the risk of CVD in PsA; one report found that levels of CRP and ESR were associated with increased carotid intima medial thickness and endothelial dysfunction.¹⁶

As is the case for PsA, no conclusive studies have been published on CVD risk factors in AS. In addition to classic risk factors, inflammation and genetic predisposition may contribute to increased CVD risk.

There is also some evidence of increased hypertension, dyslipidemia and physical inactivity in patients with JIA compared to healthy individuals.¹⁷

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

The European League Against Rheumatism (EULAR) has developed recommendations focused on CVD risk management in patients with RA and other inflammatory arthropathies (PsA and AS).¹⁸ These recommendations recognise the association between chronic inflammation and atherosclerosis in patients with inflammatory arthritis. Thus, pro-active control of inflammatory disease activity is recommended to reduce CVD risk. Annual assessment of classic CVD risk factors is recommended for all patients, and it is recommended that 10-year CVD risk is calculated in individual countries according to a nationally used prediction model, such as the Systematic Coronary Risk Evaluation (SCORE). Such models should be adjusted to take in to account the excess CVD risk in RA by multiplying the calculated risk by 1.5 if two of the following three criteria apply:

• disease duration >10 years

• positive rheumatoid factor

• positive anti-cyclic citrullinated peptide (anti-CCP) antibodies.

It should also be noted that in the UK, the QRISK2 model for predicting CVD risk already includes the diagnosis of RA and this model can therefore be used as the primary risk calculator without need for additional adjustment.¹⁹ Statins and angiotensin converting enzyme inhibitors are favoured drugs for lipid lowering and -control of blood pressure, respectively, because of their proposed pleotropic effects. Cyclo-oxygenase 2 inhibitors and non-steroidal anti-inflammatory drugs should be prescribed cautiously and sparingly, especially in patients who have CVD or CVD risk factors. In addition, therapy adjustment, especially minimizing the use of steroids and the introduction of anti-malarials where appropriate, can also help in risk management. Lifestyle changes, especially smoking cessation and weight management, are vital. Large-scale studies are, however, needed to identify the most effective approaches for primary and secondary prevention of CVD in RA.

Similarly, in PsA and AS, the use of the available risk management tools with an appropriate adjustment according to EULAR guidance is advisable until clearer risk models are available. With regards to JIA, no current evidence on risk management is available.

Systemic lupus erythematosus

A proposed approach to CVD risk management²⁰ recommends annual assessment of individual risk factors and that screening should involve measuring fasting lipid profiles and blood glucose. As the relative risk of CVD in SLE is much higher than in other conditions, an adjustment or multiplier might be prone to significant error. Therefore, in contrast to the approach in RA, a target-based approach to CVD risk factors has been suggested in SLE (Box 1). This approach recognises that SLE is a very high-risk condition and can be viewed as a ‘coronary heart disease equivalent’. As such, stringent targets for each risk factor should be set as ‘ideal’.