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Abstract
Inflammatory joint disorders (IJD), including rheumatoid arthritis (RA), ankylosing spondylitis (ASp) and psoriatic arthritis (PsA), are prevalent conditions worldwide with a considerable burden on healthcare systems. IJD are associated with increased cardiovascular (CV) disease-related morbidity and mortality. In this review, we present an overview of the literature. Standardised mortality ratios are increased in IJD compared with the general population, that is, RA 1.3–2.3, ASp 1.6–1.9 and PsA 0.8–1.6. This premature mortality is mainly caused by atherosclerotic events. In RA, this CV risk is comparable to that in type 2 diabetes. Traditional CV risk factors are more often present and partially a consequence of changes in physical function related to the underlying IJD. Also, chronic systemic inflammation itself is an independent CV risk factor. Optimal control of disease activity with conventional synthetic, targeted synthetic and biological disease-modifying antirheumatic drugs decreases this excess risk. High-grade inflammation as well as anti-inflammatory treatment alter traditional CV risk factors, such as lipids. In view of the above-mentioned CV burden in patients with IJD, CV risk management is necessary. Presently, this CV risk management is still lacking in usual care. Patients, general practitioners, cardiologists, internists and rheumatologists need to be aware of the substantially increased CV risk in IJD and should make a combined effort to timely initiate CV risk management in accordance with prevailing guidelines together with optimal control of rheumatic disease activity. CV screening and treatment strategies need to be implemented in usual care.
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Introduction
Inflammatory joint disorders (IJD) are characterised by chronic inflammation of the joints and related tissues. IJD comprise a broad range of related disorders of which rheumatoid arthritis (RA) and spondyloarthropathies are the most common.
RA is the archetype of a systemic immune-mediated disease and it is defined as a chronic symmetric inflammation primarily involving the synovial joints (table 1).1 RA affects approximately 1% of the general population worldwide and the prevalence increases with age.2 Alongside joint involvement, the systemic inflammation distinctive for RA can affect other organs including the bowels, skin, lungs, kidneys, nervous system and also the heart and blood vessels.2 RA leads to severe pain, major disability and premature death.1 ,2 The majority of these deaths are attributed to atherosclerotic cardiovascular (CV) disease in particular.3 Spondyloarthropathies are a group of various rheumatic diseases of which ankylosing spondylitis (ASp) and psoriatic arthritis (PsA) are the most frequently occurring disorders (table 1). Shared clinical features of spondyloarthropathies are axial joint inflammation, enthesitis, dactylitis and oligoarthritis.4 In addition, there is a genetic association with HLA-B27.4 Extra-articular organ systems such as the eyes (anterior uveitis), bowels (inflammatory bowel disease or Crohn’s disease), skin (psoriasis) and the CV system are often affected.5 Like RA, mortality is increased in ASp and PsA5 and it is linked to CV comorbidities. Approximately, 0.4–1.9% of the general population suffers from spondyloarthropathies, of which 0.1–0.6% accounts for ASp4 and 0.04–1% for PsA.6
Characteristics of the major rheumatic diseases
As IJD are prevalent conditions worldwide with a considerable burden to healthcare systems, knowledge and awareness of the increased CV risk is required to timely initiate CV risk management in these patients. In this review, we present an overview of the literature on this subject.
CV morbidity and mortality in IJD
Mortality rates are significantly increased in patients with RA compared with the general population, with reported standardised mortality ratios between 1.3 and 2.3.3 A large excess of these deaths is attributable to CV disease, predominantly ischaemic heart disease and cerebrovascular disease. A recent meta-analysis of 14 observational cohort studies comprising over 40 000 patients with RA shows an overall increased relative risk of a first ever CV event in patients with RA of 1.48 (95% CI 1.36 to 1.62), mainly caused by an increased risk of myocardial infarction, cerebrovascular accidents and congestive heart failure.7 These CV events were predominantly of atherosclerotic origin, but vasculitis, primary thrombogenesis and myocarditis may have played a pathogenetic role in their development. Although some studies suggest that the disease course of RA has become milder in recent years as a result of advances in medicinal treatment, CV disease-related mortality has remained equally elevated over the past five decades. This might be due to under-recognition and undertreatment of CV risk factors, a lack of optimal disease control by medication or favourable effects of anti-inflammatory therapy on CV risk may only be noticeable on a population average after decades of treatment. Similar to RA, mortality is also increased in ASp, with standardised mortality ratios up to 1.9. An increased incidence of atherosclerotic events is responsible for the majority of deaths in this disease.8 In PsA, standardised mortality ratios are reported up to 1.6. These patients are at an increased risk of myocardial infarction, but data on cerebrovascular disease are conflicting. A recent study reports an increased risk of major atherosclerotic events (HR 1.24 95% CI 1.03 to 1.49) in patients with untreated PsA, even after adjustment for traditional CV risk factors.9
Conventional CV risk factors in IJD
Smoking
Smoking is an acknowledged cause of CV morbidity and mortality. The CV risk associated with smoking is dose and duration dependent, but there is no lower limit for detrimental effects. The exact mechanism by which smoking increases CV risk is unknown, but it is suggested that smoking has effects on endothelial function, platelet function, fibrinolysis, lipids and vasomotor function through reactive oxygen species triggering inflammatory processes in arterial tissues. Any type of smoking is an environmental risk factor for the development of RA and it is also associated with increased disease severity.10 A higher prevalence of smoking is reported in patients with RA compared with controls.11 Smoking does not appear to be associated with the development of ASp but it does influence clinical, functional and radiological disease outcomes. Data regarding the prevalence of smoking in both ASp and PsA are not univocal with several studies reporting increased prevalences whereas others do not.
Physical activity
In the general population exercise reduces CV risk, possibly through dampening of inflammation measured by C reactive protein levels. Therefore, exercise might also have beneficial effects on CV risk in IJD. On average, patients with RA are less physically active, which has been associated with a higher risk of CV events. Recent studies show a beneficial effect of exercise therapy on vascular function, cardiorespiratory fitness and CV risk in RA.12 Active disease and disease-related deterioration of functional status renders patients with ASp and PsA less physically active than controls, which has been associated with a worse prognosis and premature death.5 For ASp, physical training is the cornerstone of treatment, positively affecting disease activity and probably simultaneously decreasing CV risk.
Dyslipidaemia
While high serum total cholesterol (TC), low-density lipoprotein cholesterol (LDLc) and triglycerides (TG) are associated with increased CV risk in the general population, patients with RA with active disease have instead low serum levels of TC and LDLc, while the CV risk is elevated.13 Possibly, the simultaneous decrease in high-density lipoprotein cholesterol (HDLc) during disease flares and the negative effects of inflammation on the antiatherogenic properties of HDLc and LDLc cause this increased CV risk. The lipid profile in ASp and PsA is similarly affected by disease activity.5 In addition to inflammatory changes in lipids, certain lipid particles themselves are capable of influencing inflammatory pathways. HDLc is able to intervene in the interaction between T cell lymphocytes and macrophages, making it an inflammation modifier. Decreasing inflammatory activity through medical treatment generally improves, that is, normalises, the lipid profile in IJD as HDLc levels also improve with treatment. Thus, the increase in TC and LDLc after anti-inflammatory treatment does not translate into an increased CV risk but is a reflection of a good response to therapy. In addition, suppressing inflammation may enhance HDLc efflux function even in the absence of quantitative changes in lipids. However, the clinical relevance of short-term changes in lipid particles on CV outcomes remains to be determined.
Dyslipidaemia in the general population can be effectively treated with statins reducing CV risk. Statins appear equally effective in patients with IJD.14 Furthermore, statins have anti-inflammatory properties and may thus induce an additional CV risk reduction when combined with anti-inflammatory therapy. In addition, it should be noted that lipid levels during high disease activity are lower in IJD and this leads to a possible underestimation of CV risk. Therefore, lipid levels should be assessed during periods of low disease activity or disease remission. If this is not possible, the TC/HDLc ratio should be used as this is the most stable lipid marker under inflammatory conditions.15 This ratio correlates better with C reactive protein levels and subsequent CV event risk in comparison to TC or HDLc alone and is therefore a more appropriate predictor of CV risk in IJD rather than the individual lipid levels.15
Blood pressure
A recent meta-analysis found no clear difference in blood pressure between patients with RA and non-RA controls, whereas most other studies found an increased prevalence of hypertension.11 ,16 This disparity might be explained by under-recognition of hypertension in RA. The prevalence of hypertension and its contribution to CV risk in ASp is also unclear, as several studies report increased prevalences of hypertension in ASp, whereas others do not.5 In PsA, several studies report increased prevalences of hypertension. Overall, there seems to be a tendency towards an increased prevalence of hypertension in RA, ASp and PsA. Currently, there is no evidence for a preferred antihypertensive agent in IJD disregarding an older report that ACE inhibitors and ATII antagonists should be preferred in view of their anti-inflammatory properties. A far more important issue to address is that adequate treatment of hypertension in IJD is often lacking.
Body weight and body composition
Whether the body mass index differs between patients with RA and the general population is unclear, but a low body mass index is associated with increased CV risk.16 Patients with RA do seem to have more body fat for a given body mass index than controls. Rheumatoid cachexia, a condition in which the lean body mass or muscle mass is lost while fat mass is preserved or increased, is not uncommon in RA.17 Interestingly, several small-scale studies in patients with RA with active disease or a disease flare reported lower body mass index and fat-free mass as compared with healthy controls, disappearing after treatment. Moreover, in most patients the body mass index often remains stable over the course of RA while the fat-free mass is lost and fat mass is increased. Therefore, assessing only body mass index may underestimate CV risk in patients with RA. ASp is associated with an increased body mass index that correlates with disease activity. Patients with PsA are reported to be more often overweight, which correlates with physical health. Reducing body weight to a normal range through exercise improves body composition in IJD and could therefore simultaneously improve both CV risk and disease outcomes in these patients.
Insulin resistance and diabetes
Studies report conflicting results regarding the prevalence of diabetes mellitus type 2 in patients with RA. Both insulin resistance and diabetes mellitus type 2 are associated with CV disease in RA similar to the general population. Insulin resistance seems increased in patients with RA compared with controls. Insulin resistance in RA is associated with increased levels of C reactive protein, erythrocyte sedimentation rate, interleukin-6 and tumour necrosis factor-α. Whether RA and diabetes mellitus type 2 are associated in a pathophysiological way is less clear. Insulin resistance is not increased in ASp, but it is increased in PsA, which might be due to a relatively higher body mass index in these patients. Similarly, diabetes mellitus type 2 prevalence is higher in PsA versus controls, but this was not observed in ASp.
Systemic inflammation inherent to IJD
Although traditional risk factors for CV disease are generally more often present in patients with IJD, the excess morbidity and mortality cannot be explained by these risk factors alone. A study from 2010 demonstrated that RA is independently associated with CV disease development after adjustment for known traditional CV risk factors.18 The CV risk in RA appears equal to that of diabetes mellitus type 2.18 ,19 A plausible explanation is that the chronic inflammatory burden of RA enhances endothelial dysfunction and consequently induces or accelerates atherosclerosis, as a higher inflammatory burden and an increased number of disease flares were associated with CV events in patients with RA.20 Moreover, atherosclerosis itself is regarded as an inflammatory process with inflammatory cells involved in all its stages.21 ,22
The carotid intima media thickness is generally seen as a reliable surrogate marker for (preclinical) CV disease and is increased in patients with RA as compared with matched non-RA controls. Inflammation causes maladaptive outward remodelling of the carotid artery, which is associated with plaque instability and rupture.23 This adverse remodelling might further increase CV risk in RA.23 It is currently unknown to what extent inflammation affects CV risk in ASp or PsA, but it is conceivable that the CV effects of inflammation in these patients are similar to that in RA. This is also implicated by numerous reports that carotid intima media thickness is also increased in ASp and PsA, and the lipid profile is affected similar to RA.
Effects of anti-inflammatory therapy on CV risk
The antirheumatic treatment of RA is initiated with disease-modifying antirheumatic drugs (DMARDs), agents capable of interfering with the systemic inflammatory disease process, reducing or reversing disease symptoms and simultaneously improving quality of life. There are several classes of DMARDs including conventional synthetic DMARDs (csDMARDs), targeted synthetic DMARDs (tsDMARDs) and biological DMARDs, such as tumour necrosis factor-α inhibitors (TNFi, table 2).
Treatment options for rheumatic diseases and their cardiovascular effects
RA therapy starts with csDMARDs, often with methotrexate alone or combined with sulfasalazine or hydroxychloroquine, or (bridging) glucocorticosteroids. When remission or low disease activity according to the American College of Rheumatology–EUropean League Against Rheumatism (EULAR) definition is not reached within 6 months, a different csDMARD combination can be tried or one of the TNFi is added. Both csDMARDs and TNFi significantly reduce CV risk in patients with RA (table 3). Several studies have shown beneficial effects of csDMARDs and TNFi on carotid intima media thickness,24 lipid profile, insulin resistance and metabolic syndrome in RA. Generally, treatment with csDMARDs and TNFi increases all lipid components, but predominantly HDLc resulting in a beneficial TC/HDLc ratio.25 However, tocilizumab and tofacitinib may increase lipids, presumably due to interleukin-6 inhibition. Sustained elevations of lipids after treatment with these agents can effectively be reduced with statin therapy. Glucocorticosteroids rapidly and effectively lower inflammation in RA, but they have been associated with a dose-dependent increased risk of CV disease. Although the cumulative corticosteroid dose is significantly associated with CV disease, reducing high-grade inflammation in patients with active disease may counter this adverse effect.
Effects of anti-inflammatory therapy on CV events
In ASp, treatment starts with non-steroidal anti-inflammatory drugs (NSAIDs) in combination with regular physical exercise.26 NSAIDs effectively reduce disease activity in the majority of patients with ASp, but they might have a twofold effect on CV risk in ASp. The lowering of inflammatory burden, subsequent increase in physical activity and deceleration of bone remodelling might lead to a decreased CV risk. In contrast, side effects of NSAIDs like hypertension and renal damage might increase CV risk, especially in young patients with ASp.27 The average CV effects of NSAIDs in ASp remain unclear, and it is therefore unknown whether NSAIDs should be used intermittently or continuously. csDMARDs are generally not effective in ASp but may be used for patients with ASp with concurrent peripheral arthritis. If NSAIDs treatment fails, TNFi are initiated.26 TNFi treatment in ASp is highly effective and possibly improves overall CV risk as improvements in lipid profile, vascular function and carotid intima media thickness are described after treatment. Patients with PsA are treated similar to patients with RA, initially with csDMARDs and with TNFi in patients with persistent active disease. The effects of these treatments on CV risk in PsA are currently unknown. However, similar to RA, TNFi improve the lipid profile and carotid intima media thickness in PsA.
CV risk estimation in IJD
Currently, there are no IJD-specific CV risk prediction models with a validated performance. Risk prediction models for the general population underestimate the CV risk in IJD.28 ,29 The EULAR recommendations for CV risk management advise the use of the SCORE algorithm with a multiplication factor of 1.5 for patients with RA.30 In apparently healthy persons, a 10-year risk of a first ever atherosclerotic event can be estimated with this algorithm, which includes gender, age, smoking status, blood pressure and TC or TC/HDLc ratio. In patients with established CV disease CV risk management should be initiated on all risk factors as there is already an inherent high risk of future events. As mentioned earlier, the TC/HDLc ratio is a more appropriate predictor in IJD than individual lipids. Whether novel and IJD-specific factors such as carotid intima media thickness or specific biomarkers will improve risk prediction in IJD remains to be elucidated.
Discussion
Patients with IJD have an increased CV risk. Contributing factors are the increased presence of traditional CV risk factors and the CV effects of chronic inflammation inherent to IJD (figure 1).
Interplay between cardiovascular (CV) risk, inflammation and traditional CV risk factors.
It is widely acknowledged that the process of inflammation accelerates atherosclerosis in patients with IJD. Furthermore, inflammation regardless of its aetiology weakens the plaques cap, making the plaque unstable and more prone to rupture. It is currently unknown whether anti-inflammatory treatment can halt or even reverse this accelerated atherosclerotic process, but small studies do point towards this direction. As all antirheumatic treatments aim for inflammation reduction, they favourably affect CV risk. However, their use might also cause CV complications by causing an increased blood pressure, increases in lipids, kidney failure and even congestive heart failure. Therefore, while effective anti-inflammatory treatment might be beneficial in the average patient with IJD, CV and antirheumatic treatment should always be individually evaluated, especially in case of CV disease history.
As there is overwhelming evidence for an increased CV risk in RA, these patients are considered to be a high-risk category (see online supplementary file for the full literature list). Therefore, in 2009, a specific CV risk management guideline from the EULAR taskforce recommended to use a 1.5 multiplication factor when estimating CV risk in patients with RA. For ASp and PsA, the evidence was less pronounced and thus the multiplication factor was not recommended.
Conclusions
Patients with IJD are at increased risk of CV disease-related morbidity and mortality, particularly caused by an increased incidence of atherosclerotic CV disease. For RA, this risk equals that of diabetes mellitus type 2. CV risk factors in IJD are the systemic inflammatory burden, the higher prevalence of traditional risk factors such as hypertension and dyslipidaemia, limitations in physical activity and medication use (figure 2). Patients, general practitioners, cardiologists, internists and rheumatologists should therefore all be aware of this significantly increased CV disease risk and need to initiate effective CV risk management according to existing guidelines, such as the EULAR evidence-based recommendations for CV risk management in patients with RA and other forms of inflammatory arthritis and the European Society of Cardiology guideline for CV disease prevention in clinical practice. Specific CV disease screening and treatment strategies for patients with IJD need to be implemented as part of usual care. The rheumatologist should be responsible for ensuring that CV risk management is done, while the involvement of other healthcare professionals and the implementation of CV disease prevention programmes may be defined locally. At present, effective CV risk management is lacking in clinical practice.
Inflammatory joint disorders and cardiovascular (CV) disease.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Data supplement 1 - Online references
Footnotes
Contributors All authors have contributed substantially to the preparation and design of this manuscript. RA and SCH wrote the initial manuscript. VPVH and MTN have contributed to the design of this paper and were responsible for critically revising the contents of the manuscript. RA and SCH have done the literature searches. The final manuscript has been read and approved by all authors.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.