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Cardiovascular Risk in Rheumatoid Arthritis. An Update for General
Practitioners
Cocco Giuseppe1*, Amiet Philipp2 and Jerie Paul1
1
Cardiology Office, Marktgasse, Rheinfelden, Switzerland
2
Medical Office, Schiffackerweg, Rheinfelden, Switzerland

Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory articular pathology which affects almost 1% of the general
population and which is ranked among the top 15% of diseases causing major disability worldwide. RA shares
some pathologic features, genetic predisposition and risk factors with atherosclerosis. Inflammation plays a central
pathophysiologic role in both diseases.
As compared with the general population, in RA the prevalence of cardiovascular events is increased to an extent
comparable to that of type 2 diabetes mellitus. RA-Patients have a higher incidence of myocardial ischemia and
infarction, cardiac failure, valvular heart disease, pericarditis, myocarditis and, to a lesser extent, venous complications.
The occurrence of sudden cardiac death is two-fold increased and that of major adverse cardiovascular events is
augmented to almost 50%. Cardiovascular deaths increase seven years following symptoms onset.
Control of the joint pathology remains the principal therapeutic aim in RA, but the impact of cardiovascular
complications should not be forgotten. Patients with RA who are at high cardiovascular risk should be given the best
available therapies to reduce the cardiovascular complications.
There are things we know that we know. There are known unknowns. That is to say, there are things that we know
that we don’t know. But there are also unknown unknowns. There are things we don’t know we don’t know. Donald
Rumsfeld

Keywords: Rheumatoid arthritis; Cardiovascular risks; Pathology; quote their previous publications. One might maliciously say that
Heart disease; Venous complications these authors repeated data in different journals using their references
in order to increase their scientific impact factor. We selected papers
Abbreviations: BAs: Biological Agents; COXIBs: Cyclooxygenase-2 with large numbers of cases and ended with a total of 340 references.
inhibitors; CV: Cardiovascular; DMARDs: Disease Modifying From the abstracts we selected 166 full-text papers. Ninety-three papers
Antirheumatic Drugs; JAK Inhibitors: Janus Kinase-inhibitor’s; sufficed to get the ‘state of the art’ of cardiovascular complications (CV)
MACE: Major Adverse Cardiovascular Events; NSAIDs: Non-steroidal in RA. It is unavoidable that we may have either selected or omitted
Antinflamatory Drugs; RA: Rheumatoid Arthritis; TNFα: Tumor same papers by chance.
Necrosis Factor Alpha
Cardiovascular complications in RA
Introduction
As compared with the general population, in RA the prevalence
Rheumatoid arthritis (RA) is a chronic inflammatory joint of CV events is increased to an extent comparable to that of type 2
pathology which affects almost 1% of the general population [1] and diabetes mellitus [1-4]. RA-patients have an increased incidence of
which is ranked among the top 15% of diseases causing major disability myocardial ischemia and infarction, cardiac failure, valvular heart
worldwide [2]. RA shares several pathophysiologic features, genetic disease, pericarditis, myocarditis and, to a lesser extent, venous
predisposition and risk factors with atherosclerosis. Inflammation is complications [5-21]. The occurrence of major adverse cardiovascular
the central pathologic factor in both diseases [3]. The paper reviews events (MACE) augments to almost 50% and that of sudden cardiac
cardiovascular events and their therapy in RA. death increases two-fold. CV deaths appear with increasing frequency
7-10 years following symptoms onset.
Methodology
A review must rely on solid data, be objective and deliver the ‘state Risk factors and CV features in RA
of the art’ of the argument. The quest is a seemingly endless process. As compared with the general population, the prevalence
Writing is a solitary endeavor but data depend on the work of many of traditional CV risks factors, such as diabetes, hypertension,
individuals and institutions. We started a goal-oriented search in
English and German with the engines BioMedSearch.com, Cardio
source, Center Watch, ClinicalTrials.gov, Cochrane, Google Scholar, *Corresponding author: Cocco Giuseppe, Cardiology Office, Marktgasse 10 A,
Med Watch, Research Gate and PubMed. We settled a time-window CH-4310 Rheinfelden, Switzerland, Tel: 061 83145 55; E-mail: praxis@cocco.ch
2000-2016 with key words: RA, arthritis, cardiovascular risk in RA, and Received: June 02, 2016; Accepted: June 09, 2016; Published: June16, 2016
treatment of RA. Our search delivered more than 1 million of references. Citation: Giuseppe C, Philipp A, Paul J (2016) Cardiovascular Risk in Rheumatoid
The filter was restricted to guidelines and meta-analyses. This search Arthritis. An Update for General Practitioners. Cardiovas pathol 1: 109. doi:10.4172/
delivered more than 80,000 references. Using a plagiarism’s software cdpo.1000109
we found that few centers published more than 60% of the collected Copyright: © 2016 Giuseppe C, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
references, usually changing authors’ order, deleting or adding some unrestricted use, distribution, and reproduction in any medium, provided the
authors. Many papers present strikingly similar data. Many authors original author and source are credited.

Cardiovas pathol
ISSN: cdpo, an open access journal Volume 1 • Issue 2 • 1000109

4172/cdpo. anti-cyclic citrullinated peptide antibodies positivity and rheumatoid • Adhesion molecules. spondylitis. emission with concomitant computer tomographic registration. Indeed.5 was introduced to adapt SCORE for RA-patients [1. The beneficial effects of factor. Paul J (2016) Cardiovascular Risk in Rheumatoid Arthritis. Rarely. There is also strong evidence that immune against the possible CV protection. Two Other risk factors of the following criteria must be fulfilled: i) disease duration of RA over • Oxidative stress. Philipp A.43]. Of note. However. such as duration and disease Increased synthesis of inflammatory mediators severity of RA. especially in RA [1. As suggested in recent guidelines [44-46] cannot be the only explanation for the increased incidence of MACE it is recommended to reduce blood pressure to ≤140/80 mm Hg and in RA and accelerated atherosclerosis is the dominating pathologic LDL-cholesterol to <3 mmol/l (<116 mg/ml). The major risk factors are additive in predictive CV mortality is controversial. used in patients with other inflammatory diseases. and these strategies should also be • Extra-articular involvement (e. high-doses of most NSAIDs of multivessel disease and less severe coronary arteriosclerosis [37].23-32]. as disease (CAD) [1. factor 1. RA-patients have a (COXIBs) in RA has diminished. in some studies [56-58] the use of NSAIDs in RA was managements of RA-patients and is representative of typical European not associated with more frequent MACE and increased mortality from populations [41].7. Therefore.7. be noted that some of the deleterious CV effects of NSAIDs and COXIBs could be potentially counteracted by their anti-inflammatory The CV risk SCORE was developed to improve the medical effects. Altogether. vasculitis and lung involvement). power. • Abnormal vascular repair • Hyperhomocysteinemia.30-32]. confirming the most deleterious impacts of NSAIDs on the CV system is mediated by importance of the microvascular pathology in this disease. recommendations to reduce MACE in RA. systemic inflammation is the statins in RA might go beyond their cholesterol-lowering effect.25-36]. Indeed. that naproxen might have a lesser deleterious impact on the CV thrombosis and a higher rate of sudden death [38-40]. In untreated RA-patients benefit of antiplatelet agents in RA-patients with high CV risks is lower pathologic endothelial dysfunction and several vascular abnormalities than usually presumed [48] and yet the bleeding risk is increased [49]. The use is simple and SCORE can be opened using all causes. As estimated from angiography. dysregulation and female sex are contributing pathophysiologic factors in RA and that chronic inflammatory markers are independently Antirheumatic agents and CV risk in RA associated with CV morbidity and mortality [1. while naproxen should On the other hand. Readers interested in the antirheumatic properties of GLUCOR in Furthermore. with traditional CV risk factors.9. the role and effects of NSAIDs and COXIBs on the link in reference 41. Even in the most conservative estimate there screening with SCORE ought to be performed annually and be used is evidence that GLUCOR given in addition to standard therapy can to treat RA-patients.and sex-matched controls. systemic lupus erythematodes and psoriasis [1. This 6 months. Cardiovas pathol 1: 109. 10 years. intermediate (10-20%) and high (>20%). probably because of its artery medial and adventitial inflammation were significantly more antiplatelets effects. are associated with an increased risk of MACE. traditional CV risk factors calculated with SCORE [1]. doi:10. it is of note that available epidemiologic substantially reduce the rate of erosion progression in RA [59. and iii) presence of certain extra-articular manifestations. adiposity. leading to plaque vulnerability with rupture. RA nodules.1000109 Page 2 of 6 dyslipidemia. in a trial [47] it was found that in RA-patients. using fluorodeoxyglucose positron beneficial in RA. tobacco consumption and reduced physical and statins are preferred first-line therapies [44-46] and should be fitness is similar in RA-patients as in patients with coronary artery used in RA-patients with an intermediate or high 10-year risk. a finding not shared by indicated in RA-patients with established CV disease [1].Citation: Giuseppe C.9. A study [25].. Cardiovascular drugs in RA • Genetic polymorphism.55]. Antiplatelet agents for thromboembolic prophylaxis are only observation suggests subclinical vasculitis. The Non-steroidal antirheumatic drugs (NSAIDs) and cyclooxygenase-2 multiple interplaying mechanisms sustaining inflammation in RA are inhibitors (COXIBs): The therapeutic role of non-steroidal summarized in Table 1. An Update for General Practitioners. • Raised erythrocyte sedimentation rate. Assessing the CV risk in RA however. to reduce MACE • Seropositivity. Autoimmune induced arteritides aggravate lesional Therefore. in RA an system than other NSAIDs and COXIBs [53]. such as ankylosing • Iatrogenic factors. Angiotensin converting inhibitors or angiotensin receptor blockers Table 1: Factors responsible for CV in RA.g.5-20. studies on CV risks in RA did not classify patients according to SCORE. factor favor the occurrence of MACE [1.60].12. Cardiovas pathol ISSN: cdpo.22]. However. in RA-patients unstable plaques and coronary not be associated with excessive CV events. However. Experts recommend that a systematic CV risk-factor in the therapy of RA. 40 mg of atorvastatin added to antirheumatic drugs lowered CRP after demonstrated aortic inflammation in patients with active RA. Thus a multiplication • Chemokines and cytokines. the higher risk of gastrointestinal events of antiplatelets inflammation thus making plaques more vulnerable to rupture and agents in RA-patients with concomitant NSAIDs has to be weighed thrombosis [10. there are doubts about the suggestion frequent and prominent. which significantly increase MACE [1. • Immune dysregulation with perturbation in T-cells subsets. It has also been found that the use of all NSAIDs increases the occurrence of atrial fibrillation [54.15.42].28. but these drugs are still commonly higher prevalence of unrecognized CAD but have a reduced prevalence used. the patients with stable CAD without RA. an open access journal Volume 1 • Issue 2 • 1000109 . According to meta-analyses [50-52]. It should.8.42]. in RA experts recommend the same strategies established in patients • Joint synovitis and/or erosions. It is suggested that the acute coronary syndrome may occur without CAD [21]. • Female sex. SCORE underestimates the CV risk in RA because it does not consider non-traditional risk factors. The CV risk is stratified as low (<10%). antirheumatic drugs (NSAIDs) and cyclooxygenase-2 inhibitors Compared to age.20.3. because major pathologic factor accounting for the high incidence of MACE these drugs seem to possess anti-inflammatory properties.36]. • Autoantibodies against endothelial cells components or anti-apoA1 lipoprotein.6.14. ii) rheuma-factor or anti-cyclic citrullinated peptide positivity. their hypertensive effect [52]. We lack solid data supporting the validity of available • Elevated protein C levels. have been detected. Indeed. The risk for CAD is usually predictive for a 10-year Glucocorticosteroids: Glucorticosteroids (GLUCOR) are often used risk of MACE.

DMARDs and BAs DMARDs and BAs may lower the CV risk either by directly influencing the atherosclerotic process or indirectly through suppression of inflammation or by affecting some CV risk factors [1. by increasing body current recommendations TNFα-antagonists should be considered weight. Altogether. controversial data suggest that leflunomide might reduce MACE in RA-patients [74.90].36. count. Long-term studies are not available. baricitinib.Citation: Giuseppe C. However. Paul J (2016) Cardiovascular Risk in Rheumatoid Arthritis. In one study in RA-patients with RA. Altogether. Glucocorticosteroids may promote CV disease because by inducing insulin resistance. use of these agents was associated with a reduced risk for cardiac deaths. risk in RA. Janus kinases (JAK) are gold.36. Philipp A. On the other hand. Glucocorticoids it seems that an insufficient use of corticosteroids in RA may increase the CV risk and that the combined use of corticosteroids with DMARDs in RA-patients with persistent disease activity should minimize the CV. Low-dose methotrexate may mitigate the CV risk in RA.1000109 Page 3 of 6 Agents Effect on CV risk Some studies show that the use of these agents is associated with an increased risk of MACE and atrial fibrillation. GLUCOR have a complex antagonists revolutionized the management of RA and catalyzed the relationship with atherosclerosis [28. At present we lack data of the impact of JAK-inhibitors on the CV system.76-78]. and by worsening/inducing hypertension and dyslipidemia a first-line therapy in RA [42. sulphasalazine. Nonetheless. and physical function also improved [93. Some studies reported a significant reduction in MACE in RA-patients treated with TNFα antagonists. Other studies NSAIDs and COXIBs indicated that the use of these agents was not associated with an increase MACE and mortality from all causes. at present the effect of these agents on MACE is controversial.36. In placebo.42]. d-penicillamine.67]. RA should read specific articles [59. The effect of preferentially inhibits JAK1 and JAK3 and is available for the treatment of MTX on CV risk in RA is uncertain. Also. However.36. The new TNFα- pre-existing CAD was associated with a reduced risk for cardiac deaths antagonist remicade can prevent RA from progressing but about 20 % [61-63].70]. Altogether. azathioprine and cyclosporine: there is no evidence that these agents reduce MACE in RA. The impact of antirheumatic agents on the CV risk in RA remains unsettled. However.59-61]. The antirheumatic effects of [20. According to promote CV disease by inducing insulin resistance.60]. tofacitinib. rituximab and tocilizumab) Disease modifying antirheumatic drugs: Disease modifying BAs on MACE and CV mortality remain to be determined [85. inhibits JAK1 and JAK2. Controversial data suggest that leflunomide might reduce CV risk in RA. The JAK-inhibitor. an open access journal Volume 1 • Issue 2 • 1000109 . available TNFα antagonists seem to may increase the CV risk [64]. another type of BAs can be taken orally. Some RA-patients Possible side effects may include anemia. azathioprine and cyclosporine reduce MACE in RA [65]. as for NSAIDs and COXIBs the effect of glucocorticosteroids and CV mortality is controversial. in RA-patients with pre-existing CAD. Parenteral gold has the potential for negative effects on renal function and should the occurrence of MACE in RA. and reduce CV morbidity. In RA CV mortality and MACE remain high. oral and parenteral gold. Altogether. the effect of GLUCOR on CV reduce aortic stiffness and improve endothelial dysfunction [79-81] mortality is controversial. azathioprine. the role and effects of these agents on CV mortality is controversial. rare effects on white blood cell develop hypertension when treated with this agent [73]. The effects of available and newer (abatacept.42.35. The antirheumatic effects of Not surprisingly. at present we have conflicting data on the effect of BAs on MACE in RA-patients and we lack sufficiently powered long-term studies Biologic agents: The introduction of tumor necrosis factor-α (TNFα) (Table 2). Nonetheless. especially in responders [14. GLUCOR may development of other biologic agents (BAs) [20. MTX may improve the binding to a common gamma chain used by these receptors and can be lipid profile of RA-patients [66. increasing body weight. the combined use of GLUCOR with other antirheumatic of patients do not respond to other TNFα-antagonists remicade [76. JAK-inhibitors block these pathways by should increase the occurrence of MACE in RA. leflunomide and methotrexate (MTX). doi:10. Table 2: Effects of antirheumatic drugs on the CV risk in RA.77].86]. it of several important cytokines. use of GLUCOR in RA-patients with TNFα-antagonists are presented in a recent update [76]. effects of lipid lowering pharmacotherapy in RA-patients. if taken orally and that they are no longer active after getting digested [91]. subsequent studies suggest 500 patients with active RA refractory to one or more TNFα-antagonists that the anti-inflammatory effect of MTX in RA reduces MACE and (and to other BAs in some cases). some studies did not detect a positive effect of TNFα DMARDs in RA are presented in an editorial by Wollheim [65]. the therapeutic impact administered orally.72]. available TNFα-antagonists may induce/worsen congestive CV risk [36]. cyclosporine. Another oral JAK-inhibitor.94]. not all agents d-penicillamine.46. there is no evidence that antimalarials. Cardiovas pathol ISSN: cdpo. In a recently published randomized trial of over in patients treated with MTX.59-61]. there summary. the effects of BAs on the arterial system vary. d-penicillamine. improve stiffness [87] and the positive effect may also be transient [88]. sulphasalazine. However. However. Ongoing trials are evaluating the effect to achieve an ACR20 response at 12 weeks with baricitinib compared with of MTX and inhibition of interleukin-1β on MACE in RA [71. Antimalarials. An Update for General Practitioners.61]. Other studies reported no significant effects on MACE. One of these drug blocks syk kinase (spleen tyrosine of its minor lipid lowering effect on reducing MACE in RA remains kinase) and some research has suggested that this drug may work in people speculative and so far we have no data from intervention trials on the who do not respond to TNF blockers [92]. it seems that an insufficient use of GLUCOR in RA heart failure [61]. In summary. However.81-84]. most data suggest that low-dose MTX may mitigate the CV are still many questions that need to be answered about JAK inhibitors. and some elevation of blood fats [91]. antirheumatic drugs (DMARDs) include antimalarials. oral and parenteral gold. However.42]. Few data are available on leflunomide. DMARDs can lower the CV risk either by directly influencing New BAs for RA: Two of the main roadblocks in the quest to develop the atherosclerotic process or indirectly through suppression of oral BAs have been that these protein molecules are too large to be absorbed inflammation or by affecting some CV risk factors [1. Lastly. and worsening/ inducing hypertension and dyslipidemia. Cardiovas pathol 1: 109.4172/cdpo. sulphasalazine. is established CAD [68] the occurrence of sudden death was increased under investigation for RA. drugs in RA-patients with persistent disease activity should reduce the Of note. cytoplasmic protein tyrosine kinases that are critical for signal transduction Parenteral gold may negatively affect renal function and therefore. antagonists on MACE in RA-patients [89.75]. patients were significantly more likely associated mortality [69. Also.

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