Managing cardiovascular risk in patients with inflammatory arthritis: practical considerations

Rheumatoid arthritis

One-half of all deaths in RA are due to CV diseases [Aviña-Zubieta et al. 2008]. The CV mortality is increased by 50% and the risk of CV disease by 48% in the RA population compared with the general population [Aviña-Zubieta et al. 2012]. Increased mortality concerns both heart disease (68%) and cerebrovascular events (41%), affecting equally females and males [Aviña-Zubieta et al. 2008, 2012]. The highest CV mortality is observed in patients with long disease duration [Naz et al. 2008], rheumatoid factor or anti-CCP autoantibodies [Humphreys et al. 2014], and extra-articular manifestations [Gabriel et al. 2003]. RA itself is an independent CV risk factor that carries as much weight as diabetes mellitus [Peters et al. 2009]. In the Danish nationwide study, the overall incidence rate ratio of myocardial infarction (MI) in RA was estimated at 1.7 [95% confidence interval (CI) 1.5–1.9], which is similar to that observed in diabetes mellitus [Lindhardsen et al. 2011]. Particularly, the risk was shown to be markedly raised in women <50 years old (six-fold increase), thereby corresponding to the MI risk in subjects without RA, yet 10 years older. Several studies have demonstrated a premature MI risk, observed as soon as RA is diagnosed [Holmqvist et al. 2010] and, according to the Mayo Clinic, even before patients meet the full diagnostic criteria for RA [Maradit-Kremers et al. 2005]. One study reported a two-fold increased risk of congestive heart failure, particularly in patients with rheumatoid factor [Nicola et al. 2005].

Psoriatic arthritis and ankylosing spondylitis

Similarly to RA, SpA was associated with increased CV mortality [Mathieu et al. 2011; Exarchou et al. 2015]. Coronary heart disease risk was shown to be particularly increased in PsA, by at least 50% [Eder et al. 2015; Gladman et al. 2009; Han et al. 2006; Horreau et al. 2013]. In a single UK population-based cohort, the risk of major CV events, after adjusting for standard CV risk factors, was higher in patients with PsA and psoriasis compared with the general population [Ogdie et al. 2015].

Although CV mortality was reported to be increased in AS [Exarchou et al. 2015], conflicting data were published with respect to CV morbidity. In our first meta-analysis published in 2011 [Mathieu et al. 2011] a higher, yet insignificant, risk of MI was revealed, in line with results reported in a more recent retrospective British cohort study [Brophy et al. 2012]. Since 2011, two large cohort studies conducted in Canada and Sweden [Szabo et al. 2011; Zöller et al. 2012] and a population-based longitudinal follow-up study [Huang et al. 2013] have reported increased rates of both cerebrovascular events and ischemic heart disease. We updated our meta-analysis conducted from August 2009 to January 2014 focusing on MI and stroke [Mathieu et al. 2015], with the conclusion that there was an increased risk for both MI and stroke in AS patients compared with controls [odds ratio (OR) = 1.60 (95% CI 1.32–1.93) and OR = 1.50 (95% CI 1.39–1.62) respectively].

Standard CV risk factors

Standard CV risk factors, such as smoking, hypertension, diabetes, hypercholesterolemia, and obesity, independently impact CV morbidity [Baghdadi et al. 2015]. Although the association between smoking and CV risk in RA is less significant than in the general population [Symmons and Gabriel, 2011], a higher prevalence of smoking is well-established in RA, SA, and PsA compared with controls [Boyer et al. 2011; Divecha et al. 2005; Favato, 2008; Peters et al. 2004]. Hypertension is common in RA but it is not clear whether its incidence differs from that of the general population [Boyer et al. 2011; Liao and Solomon, 2013; Protogerou et al. 2013]. This condition may affect nearly half of all RA patients, is often under-diagnosed, and poorly controlled [Bartels et al. 2014; Protogerou et al. 2013]. Diabetes prevalence is increased in RA compared with controls (OR 1.74; 95% CI 1.22–2.50) [Boyer et al. 2011]. Although an association between insulin resistance and RA was reported in several studies [Dessein and Joffe, 2006; Giles et al. 2015], the homeostatic model assessment (HOMA) used to quantify insulin resistance was not correlated with subclinical atherosclerosis measurements among RA patients [Giles et al. 2015]. In a recent meta-analysis, RA patients were shown to exhibit a higher risk of metabolic syndrome with an overall OR of 1.24 (95% CI 1.03–1.50) [Zhang et al. 2013]. Among RA patients and in contrast with the general population, low body mass index (BMI) was associated with a significantly increased risk of CV death, and overweight/obesity with a reduction in CV risk, likely related to cachexia-associated metabolic disorders [Baker et al. 2015; Kremers et al. 2004; Wolfe and Michaud, 2012].

Similarly to RA, AS and PsA were associated with an increased prevalence of standard CV risk factors [Johnsson et al. 2012; Mathieu et al. 2011; Papagoras et al. 2014]. Metabolic syndrome was particularly increased in PsA [Malesci et al. 2007; Mok et al. 2011; Papadakis et al. 2009], as was hyperuricemia, which is considered a CV risk factor [González-Gay et al. 2009; Skak-Nielsen et al. 2013]. In a recent cohort involving 88 AS patients, no differences were found regarding hypertension, BMI, physical activity, diet, or smoking in this patient population compared with 351 age- and sex-matched controls. The authors thus concluded that excessive CV risk was not linked to CV risk factors, but rather to chronic low-grade inflammation or nonsteroidal anti-inflammatory drugs (NSAIDs) [Sundström et al. 2014].

Accelerated atherosclerosis

Several studies demonstrated subclinical atherosclerosis in inflammatory arthritis with altered vascular function and morphologic changes as assessed by endothelial dysfunction, in addition to increased arterial stiffness and carotid intima-media thickness [Bodnar et al. 2011; González-Juanatey et al. 2007; Kimhi et al. 2007; Mathieu et al. 2008; Sandoo et al. 2011]. These vascular changes were shown to correlate with the coronary circulation and able to predict CV events. However, the link between inflammation and disease activity was not demonstrated, and there were conflicting results published regarding the effects of conventional and biological disease-modifying antirheumatic drugs (DMARDs) on both vascular function and morphology [Mathieu et al. 2008, 2012, 2013a, 2013b; Sandoo et al. 2011]. CV treatments may exert a greater beneficial effect on endothelial function compared with anti-inflammatory medications [Sandoo et al. 2011].

Inflammation

While standard CV risk factors partly explain CV risk, they do not fully explain the CV risk excess observed in rheumatic diseases [van Halm et al. 2009; Peters et al. 2009; Symmons and Gabriel, 2011]. The excessive CV risk persists after adjusting for standard CV risk factors. Inflammation that promotes atherogenesis and exacerbates established CV risk factors may account for this part of increased risk [Choy et al. 2014; Zhang et al. 2014]. High C-reactive protein (CRP) levels in RA patients without diabetes mellitus or metabolic syndrome were shown to increase two-fold the risk of coronary artery disease [Zhang et al. 2014]. In SpA, the cardiometabolic profile may be driven by systemic inflammation, as revealed by several studies [Divecha et al. 2005; Tam et al. 2008]. However, the exact contribution of inflammation to the CV risk excess has not yet been elucidated [Grad and Danenberg, 2013]. It is still unclear if high CRP levels associated with CV risk factors [obesity, hypertension, triglycerides, and low high-density lipoprotein (HDL) cholesterol levels] are a marker of atherosclerosis or whether they directly contribute to atherothrombosis [Grad and Danenberg, 2013]. Pro-inflammatory cytokines [tumor necrosis factor-alpha (TNFα), interleukin-1 (IL1) and interleukin-6 (IL6)] are independently implicated in the atherogenic process by promoting dyslipidemia, insulin resistance, and endothelial dysfunction [Choy et al. 2014]. IL6 and TNFα can lead to an approximately two-fold increased MI risk [Ridker et al. 2000a, 2000b]. In addition, genetic studies pointed towards an IL6 involvement in atherogenesis [IL6 Receptor Mendelian Randomization Analysis Consortium, 2012]. In PsA, TNFα and IL1 were shown to exert pro-inflammatory activity on endothelium, thereby contributing to oxidative stress and leukocyte recruitment into atherosclerotic plaques [Russolillo et al. 2013]. Inflammation may alter the nitric oxide (NO) response that controls vasodilatation and interactions with leukocytes and platelets, and likely result in endothelial dysfunction, which in turn is associated with atherosclerosis and plaque modification. Plaque rupture or destabilization is the result of interactions between plaque components and pro-inflammatory mediators, such as adhesion molecules, cytokines, and chemokines, regulated in part by NO [Lerman and Zeiher, 2005]. In addition, inflammation induces changes in the lipoprotein composition, thereby altering protective functions of HDL cholesterol (HDLc), such as antioxidative properties and cholesterol efflux capacities. This promotes pro-inflammatory oxidized low-density lipoprotein (LDL) cholesterol (LDLc) that in turn activates endothelial cells to produce inflammatory cytokines like TNFα, and IL1, while recruiting monocytes into the arterial wall.

Lipid paradox

Besides the inflammatory cascade that exacerbates endothelial dysfunction and accelerates atherosclerosis, quantitative and qualitative abnormalities in lipid profiles are observed in inflammatory rheumatic diseases [González-Gay and González-Juanatey, 2014; Myasoedova et al. 2010]. The standard atherogenic lipid profile characterized by increased LDLc and decreased HLDc levels was not observed in inflammatory arthritis. Paradoxically, an inverse relationship between CV risk and lipid levels, also termed ‘lipid paradox’, was reported during chronic inflammatory states leading to reduced levels of total cholesterol, LDLc, and HDLc, though the CV risk was enhanced. In the Apolipoprotein MOrtality RISk (AMORIS) study, total cholesterol levels were decreased compared with controls, whereas CV events were increased by 60% in RA patients [Semb et al. 2010]. Moreover, a nonlinear relationship with a u-shaped curve between total cholesterol and CV disease risk was observed in RA patients, with a 3.3-fold increased risk associated with lower total cholesterol levels, yet no increased risk above 155 mg/dl levels [Myasoedova et al. 2011].

In addition to quantitative abnormalities, lipoprotein dysfunctions, particularly those pertaining to HDLc, could partly explain the CV risk excess [Annema and von Eckardstein, 2013]. Thus, a decrease in atheroprotective function or proatherogenic properties was reported in both RA and PsA [Annema and von Eckardstein, 2013]. HDL cholesterol efflux capacity was shown to be altered in RA patients with high disease activity. Among active RA patients, a reduction in CRP was associated with a significant increase in LDLc levels, along with an improved HDLc efflux capacity [Liao et al. 2015]. This improvement in atheroprotective function of HDLc may counterbalance the increased LDLc levels associated with CV risk.

From a practical consideration, lipid profiles should be assessed and interpreted when the disease is under control. This procedure should be repeated when DMARDs are initiated due to the impact of biologic agents on lipid profiles [Souto et al. 2015] .

Avoid deleterious treatments

NSAIDs were shown to increase mortality in the general population, the risk being highest for cyclooxygenase-2 inhibitors and diclofenac, whereas naproxen was associated with less vascular risk [Coxib and Traditional NSAID Trialists (CNT) Collaboration, 2013; Soubrier et al. 2013]. In RA, the risk of vascular events was also increased with NSAIDs, but the increase in vascular risk was statistically significant only for cyclooxygenase-2 inhibitors [Roubille et al. 2015]. In AS, the use of NSAIDs might reduce the risk of CV disease [Tsai et al. 2015]. Paracetamol may increase CV mortality in the general population, but this must be confirmed after adjusting for concomitant NSAID use and channeling bias [Roberts et al. 2015].

Corticosteroids could contribute to atherogenesis, for they were reported to be linked to increased insulin resistance, metabolic syndrome, and hypertension. On the other hand, by reducing systemic inflammation, they could decrease CV risk. A recent meta-analysis demonstrated a significant increase in CV events with glucocorticosteroids (OR 1.47; 95% CI 1.34–1.60), whether for MI (OR 1.41; 95% CI 1.22–1.63), stroke (OR 1.57; 95% CI 1.05–2.35), or congestive heart failure (OR 1.42; 95% CI 1.10–1.82) [Roubille et al. 2015]. Glucocorticosteroids were shown to be associated with an increased MI risk in RA, in a dose- and duration-dependent manner [Aviña-Zubieta et al. 2013].

As a result, the lowest glucocorticosteroid dose for the shortest possible time must be prescribed.

Control the disease activity

As previously discussed, the link between systemic inflammation and atherogenesis renders tight disease activity control absolutely essential in inflammatory arthritis. Patients with active RA present significantly higher CV risk markers (hypertension, CV biomarkers, and subclinical atherosclerosis) than patients in remission [Provan et al. 2011]. In a longitudinal United States cohort, reduction in disease activity paralleled the reduction in CV events independently of antirheumatic treatments [Solomon et al. 2015b]. In a meta-analysis, methotrexate and TNF-inhibitors were shown to decrease CV events by a third [Roubille et al. 2015]. The impact of anti-rheumatic treatments on lipid profile and CV risk has been well studied. TNF inhibitors were shown to increase total cholesterol and HDLc levels, whereas the atherogenic index remained stable [Daïen et al. 2012; Payet et al. 2012]. In addition, TNF inhibitors may be able to restore anti-inflammatory properties of HDLc [Robertson et al. 2013]. Conflicting results were published with respect to rituximab [Mathieu et al. 2012; Robertson et al. 2013]. Tocilizumab increased the atherogenic index but improved HDL atheroprotective functions [McInnes et al. 2015; Robertson et al. 2013]. In a recent meta-analysis, changes in the lipid profile of RA patients were only observed with tocilizumab and tofacitinib, but not with TNF antagonists [Souto et al. 2015].

The impact of biologicals on CV diseases and mortality has not been well established in SpA. Several studies assessing the effect of TNF blockade on subclinical atherosclerosis have been published reporting conflicting results [Angel et al. 2010; Brezinski et al. 2014; Mathieu et al. 2008, 2013b; Tam et al. 2008]. It was put forth that TNF blockade may slow down atherosclerosis [van Sijl et al. 2015].

Cardiovascular disease risk stratification

In order to predict 10-year CV mortality risk, different equations were developed with algorithm combinations taking into account standard CV risk factors like age, gender, smoking status, hypertension, genetic, and LDLc levels. For the general population, dyslipidemia management guidelines for preventing CV diseases are based on the Systematic Coronary Risk Evaluation (SCORE) equation in Europe (ESC guidelines) and the Framingham (ATP-III guidelines) and new Pooled Cohort equations (ACC/AHA) in the United States [Catapano et al. 2011; Grundy et al. 2004; Stone et al. 2014]. Since 2010, the European League Against Rheumatism (EULAR) has been recommending to assess CV risk yearly in RA patients using risk equations, the SCORE equation, or a nationally validated equation. The SCORE equation allows identifying patients with very high CV risk (SCORE >10%, documented CV disease), high CV risk (SCORE >5% and <10%), moderate CV risk (SCORE >1% and <5%), or low CV risk (SCORE <1%). Based on the SCORE equation, LDLc targets have been defined [Catapano et al. 2011]. Therefore, for patients with very high CV risk, the treatment target for LDLc was estimated at 1.8 mmol/l (70 mg/dl), for those with high risk at <2.5 mmol/l (100 mg/dl), and for those with moderate risk at <3 mmol/l (115 mg/dl) [Catapano et al. 2011]. The risk calculated this way is requested to be multiplied by 1.5 when RA fulfills two of the following three conditions: disease duration >10 years, positive rheumatoid factor or presence of anti-CCP, and extra-articular manifestations [Peters et al. 2010]. Updated EULAR recommendations on CV risk management are scheduled to be published soon, including imaging markers for risk prediction, as well as CV risk score multiplication by a factor of 1.5 regardless of RA determinants [Nurmohamed, 2015] (Box 1).

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Box 1.

The 10 recommendations of EULAR for the management of CV risk in RA, PsA, AS [Peters et al. 2010]. In italic bold, 2015/2016 update recommendations [Nurmohamed, 2015].

RA, AS and PsA should be regarded as a condition associated with higher risk for CV disease.

The disease activity should be controlled optimally.

CV risk assessment is yearly recommended using national guidelines. CV risk assessment is recommended for all patients with RA, AS or PsA at least once every 5 years. Risk assessments should be repeated following major changes in anti-rheumatic therapy.

Risk score models should be adapted to RA by using a 1.5 multiplication factor whenRA meets two of the following three criteria: disease duration of more than 10 years, RF or anti-CCP positivity, Presence of certain extra-articular manifestations

CV risk score models should be adapted for patients with RA by a 1.5 multiplication factor.

Total/HDL cholesterol ratio should be used in the SCORE model. Lipids should ideally be measured when disease activity is stable or in remission.

National guidelines should be considered for intervention. If no national guideline is available, the SCORE CV risk model should be used.

Statins, ACE inhibitors and/or AT-II blockers are preferred treatment options

Use NSAIDs with caution and corticosteroids with the lowest dose and duration possible.

Recommend smoking cessation and lifestyle changes

Screening for asymptomatic atherosclerotic plaques by use of carotid ultrasound may be considered as part of the CVD risk evaluation in patients with RA.

Despite the development of new risk prediction equations and guidelines, the interplay between standard risk factors, systemic inflammation, and lipid properties renders the evaluation of CV risk in inflammatory arthritis very complex. Risk assessment systems were shown not to perform well in patients with inflammatory arthritis, with the CV risk underestimated regardless the equation used [Arts et al. 2015; Corrales et al. 2014; Kawai et al. 2015]. Adapted SCORE algorithms taking into account additional RA-specific CV factors were not shown to improve CV risk prediction [Arts et al. 2015]. Whereas a new expanded risk model for CV risk prediction in RA performed well in a United States cohort; this model must still be validated before being used in other RA cohorts [Solomon et al. 2015a]. To improve CV risk prediction, carotid ultrasonography (US) including intima-media thickness assessment may prove useful, particularly for moderate-risk patients [Corrales et al. 2014]. Among the 327 RA patients analyzed (96 with low risk, 201 with moderate risk, 30 with high or very high risk) [Corrales et al. 2014], only 5 were reclassified as having high/very high CV risk when applying a multiplication factor as recommended by EULAR [Peters et al. 2010]. In contrast, increased intima-media thickness or carotid plaques were observed in 63% of RA patients with moderate risk enabling their reclassification as high risk [Corrales et al. 2014]. Similarly, 56% of PsA patients classified as intermediary with the Framingham Risk Score were reclassified into the high risk category when using carotid US [Eder et al. 2014]. For the new American College of Cardiology (ACC) and American Heart Association (AHA) American guidelines published in 2013, the new Pooled Cohort equation was employed to estimate 10-year atherosclerotic CV risk [Stone et al. 2014]. Compared with the ATP-III and ESC guidelines, the ACC/AHA guidelines place more importance on the calculated 10-year predicted risk than on absolute LDLc values. These guidelines have demonstrated greater sensitivity, especially in the elderly population (>65 years of age), yet less specificity. ACC/AHA guidelines recommend statin therapy for all patients with documented CV disease, with increased LDLc ⩾ 190 mg/dl, or CV risk > 7.5%. While expanding the proportion of RA patients recommended for statin therapy [Tournadre et al. 2015] and owing to the relevance of CV mortality and underestimation of CV risk, the new ACC/AHA treatment recommendations may be more suitable in the specific event of RA. However, further studies are warranted to better validate the risk prediction in specific RA populations. These studies should, in addition, clarify the impact of the new expanded guidelines on future CV events [Kawai et al. 2015; Tournadre et al. 2015].

Lifestyle and pharmacological interventions

Lifestyle modifications must be considered for all patients while including dietary recommendations, weight control, physical activity, and smoking cessation.

A number of large-scale clinical trials have demonstrated the efficacy of statin therapy in reducing CV morbidity and mortality both in primary and secondary prevention in the general population [Cholesterol Treatment Trialists Collaboration et al. 2010]. Though there have been no large-scale controlled studies assessing the effect of statins as primary CV risk prevention in RA, statin therapy initiation was shown to be associated with a lower mortality risk in RA patients [Schoenfeld et al. 2016]. In a Scottish cohort of 430 RA patients involving 181 statin-exposed and 249 statin-unexposed patients, with a mean follow-up period of 3.90 and 3.14 years respectively, statins reduced total cholesterol levels by 1% and were associated with primary prevention with reduced CV events [HR 0.45 (0.20–0.98)] and concomitant decrease in all-cause mortality [OR 0.43 (0.20–0.92)] [Sheng et al. 2012]. Intensive lipid lowering therapy with rosuvastatin decreased the atherosclerotic process assessed by carotid plaque height and LDLc levels [Rollefstad et al. 2015]. As secondary prevention, the statin-induced decrease in cholesterol levels and MI relapse were similar between RA patients and controls, while discontinuing statins was accompanied by a high risk of stroke [De Vera et al. 2011; Semb et al. 2012]. Despite the high CV mortality in RA, lipid-lowering agents appear to be underused in these patients, given that statin therapy is recommended in around 20% of RA patients according to the guidelines [Soubrier et al. 2006; Tournadre et al. 2015]. In addition to having their CV risk underestimated, RA patients seem to be under-treated in both primary and secondary prevention [Akkara Veetil et al. 2013; Lindhardsen et al. 2011; Toms et al. 2010].

Hypertension is one of the most significant preventable CV risk factor, and lowering blood pressure (BP) by 10 mmHg for systolic BP or by 5 mmHg for diastolic BP was shown to decrease MI risk by 22% and stroke risk by 41% [Law et al. 2009]. There are no specific guidelines for hypertension management in RA. Yet initial antihypertensive treatment should include angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (AT-II), as these agents have shown anti-inflammatory properties and were associated with improved endothelial function in RA patients [Peters et al. 2010].