ISSN: 2455-2976
Journal of Cardiovascular Medicine and Cardiology
Mini Review       Open Access      Peer-Reviewed

The risk of cardiovascular disease in patients with rheumatoid arthritis: A discussion of the link, response to treatment, and the path forward

Jennifer Ben Shimol*

Department of Rheumatology, E. Wolfson Medical Center, Holon, Israel
*Corresponding author: Jennifer Ben Shimol, MD, Department of Rheumatology, E. Wolfson Medical Center, Holon, Israel, Email: JenniferB@wmc.gov.il
Received: 08 June, 2021 | Accepted: 17 June, 2021 | Published: 21 June, 2021

Cite this as

Ben Shimol J (2021) The risk of cardiovascular disease in patients with rheumatoid arthritis: A discussion of the link, response to treatment, and the path forward. J Cardiovasc Med Cardiol 8(2): 055-058. DOI: 10.17352/2455-2976.000170

Introduction

Increased risk of Cardiovascular Disease (CVD) in patients with Rheumatoid Arthritis (RA) has been well established for decades and bolstered by countless studies since the 1950’s [1,2]. Numerous papers have explored the pathogenesis and have demonstrated that the systemic inflammation caused in RA increases arterial stiffness, which may result from loss of elasticity and stenosis [3,4]. The inflammation also impairs cholesterol efflux and leads to destabilization of coronary plaque, increasing the risk of rupture and infarction [5,6]. Studies have further demonstrated that active RA causes an imbalance in the dilatation and vasoconstriction of the endothelium, and enhanced residence of reactive oxygen species and proinflammatory factors within the endothelial walls, leading to barrier permeability and leakage of inflammatory mediators into the Cardiovascular (CV) tissue [7,8].

Epidemiology of cardiovascular disease in rheumatoid arthritis

The elevated risk of developing CVD is associated with significant morbidity and mortality as well as high healthcare related costs [9]. Prior research has shown a mortality that is 1.5 times higher in patients with RA compared with the general population and that CVD is the leading source of mortality, accounting for 30–40% of deaths [10]. Despite more aggressive strategies of early RA treatment, increased premature mortality persists [11].

Impact of rheumatoid arthritis disease management on cardiovascular risk

Multiple studies have shown that effectively combatting RA decreases the risk of clinical CVD [12]. Dampening of articular inflammation has been shown to improve arterial stiffness [13]. Moreover, disease control results in lowered levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), homeostasis model assessment-estimated insulin resistance, total cholesterol, and high-density lipoprotein cholesterol (TC/HDL-C), all validated biomarkers of CVD [14,15].

The Cardiovascular Inflammation Reduction Trial showed that treatment with methotrexate (MTX), the gold standard choice for initial therapy in RA, in particular, reduces the risk of congestive heart failure (CHF) related hospitalizations [16]. MTX also reduces all-cause CVD. Furthermore, studies have illustrated its role in reducing levels of high sensitivity C-reactive protein, interleukin (IL) 6, and tumor necrosis factor α (TNF-α) [17]. MTX also helps to restore vascular endothelial vasodilation, most likely as a result of its potent anti-inflammatory effects [18].

Role of cytokine inhibitors in lowering cardiovascular risk

The cardioprotective effect provided by use of MTX is enhanced by the use of anti-TNF-α agents in treating patients with RA. Use of TNF-α blocking agents is associated with a decreased risk of composite CV outcomes which is most notable in patients who are 65 years or older [19]. Similarly, a meta-analysis found that anti-TNF-α therapy results in a reduction in the risk of all CV events, including Myocardial Infarction (MI) and stroke [20]. Moreover, utilization of anti-TNF-α agents results in improvement in parameters of arterial stiffness and improves endothelial function and flow-mediated vasodilation [21,22].

Tocilizumab, an antibody targeting the IL-6 receptor with well established efficacy in the management of RA, has also been shown to harbor cardiac benefits and has been illustrated to reduce NT-proBNP levels [23,24]. Moreover, treatment with tocilizumab results in an increase in endothelial glycocalx thickness, enhancing arterial elastic properties and improving the efficiency of myocardial work [25]. This effect is explained by tocilizumab’s role in reducing inflammation and oxidative stress [26].

Abatacept, a novel RA medication which binds to antigen presenting cells preventing delivery of the co-stimulatory signal to T cells, also possesses cardioprotective effects. It is associated with a reduced risk of composite CV events. Moreover, the risk of MI and coronary revascularization is lower in patients treated with abatacept compared with TNF-α inhibitors [27]. This may be related to its downstream anti-inflammatory effect, beyond cytokine-mediated pathways, as demonstrated by a prevention in the progression of atherosclerosis in mouse models [28].

Use of Janus Kinase Inhibitors (JAKi) in the medical treatment of RA results in an unfavorable lipid profile, which may be caused as a result of reducing lipid accumulation in the synovium, promoting an increase in circulating cholesterol [29]. Despite these shifts in lipid levels, studies have shown that they are not associated with an increased risk of CVD [30]. In fact, JAKi agents improve arterial stiffness in patients with RA and attenuate the development of atherosclerosis in rabbits [31,32]. Tofacitinib in particular reduces levels of NT-proBNP and improves endothelial function [33,34]. Furthermore, upadacitinib, a newer JAKi, has been shown to assist with efflux of cholesterol, in parallel with a rise in high density lipoprotein and a drop in C-reactive protein [35].

The influence of patient-physician communication

Detection of CV events is frequently delayed or even missed as clinical CVD can present both atypically and at younger ages in patients with RA [36]. Strikingly, between 70 and 90 percent of RA patients have not been made aware of the increased incidence of CVD, especially among those at highest risk [37]. Prior papers have illustrated that insufficient information regarding the link between CVD and RA is being conveyed to the relevant patients, explaining in large part the poor awareness [38].

At the same time, enrollment in programs which provide clear information about the increased risk of CVD have result in feelings of relief, motivation, and control in patients with RA [39]. Patients with greater awareness tend to modify lifestyle risk factors and advocate for risk-reducing medical treatments [40]. Furthermore, increased knowledge is linked with increased adherence with medical therapy [41]. Moreover, reduced rates of MI and CHF have been detected in patients who have been provided with an educational intervention [42].

Conclusion

Early treat-to-target therapies, as recommended by the American College of Rheumatology and European League Against Rheumatism, are fundamental to providing optimal care to patients with RA in order to control disease activity, providing symptom relief and preventing progression of disease [43,44]. Furthermore, such strategies, with the currently available arsenal of conventional and biologic disease modifying agents, is essential for modulating the increased risk of CVD in this disease population [45]. Moreover, the development and increased use of diagnostic tools and clinical disease scales allow for continued re-assessment and effect disease course management [46].

At the same time, pharmacotherapy must be combined with a patient-centered approach in which physicians educate patients on the nature of their disease and its link to CVD. In this way, patients may take a more active approach in controlling their illness and mitigating the associated risks. In an era where novel educational instruments are increasingly being integrated into clinical practice, especially in response to the COVID-19 pandemic, further studies are warranted to assess for which tools are most effective in providing clear information to patients and result in demonstrable markers of quality improvement.  

  1. Cobb S, Anderson F, Bauer W (1953) Length of life and cause of death in rheumatoid arthritis. N Engl J Med  249: 553–556. Link: https://bit.ly/3wK2GGe
  2. Chen J, Norling LV, Cooper D (2021) Cardiac Dysfunction in Rheumatoid Arthritis: The Role of Inflammation. Cells 10: 881. Link: https://bit.ly/3gQPmJd .
  3. Castañeda S, Nurmohamed MT, González-Gay MA (2016) Cardiovascular disease in inflammatory rheumatic diseases. Best Pract Res Clin Rheumatol  30: 851-869. Link: https://bit.ly/3qlu5vS
  4. Sharifzadeh B, Kalbasi R, Jahangiri M, Toghraie D, Karimipour A (2020) Computer modeling of pulsatile blood flow in elastic artery using a software program for application in biomedical engineering. Computer Methods and Programs in Biomedicine 192: 105442. Link: https://bit.ly/3wNU5Cy
  5. Charles-Schoeman C, Lee YY, Grijalva V, Amjadi S, FitzGerald J, et al. (2012) Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis. Annals of the Rheumatic Diseases 71: 1157–1162. Link: https://bit.ly/3zL33T0
  6. Wållberg-Jonsson S, Caidahl K, Klintland N, Nyberg G, Rantapää-Dahlqvist S (2008) Increased arterial stiffness and indication of endothelial dysfunction in long-standing rheumatoid arthritis. Scandinavian Journal of Rheumatology 37: 1–5. Link: https://bit.ly/3xHsBP3
  7. He M, Liang X, He L, Wen W, Zhao S, et al. (2013) Endothelial dysfunction in rheumatoid arthritis: the role of monocyte chemotactic protein-1-induced protein. Arteriosclerosis Thrombosis and Vascular Biology 33: 1384–1391. Link: https://bit.ly/3vKwfG8
  8. Sun HJ, Wu ZY, Nie XW, Bian JS (2020) Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Frontiers  Pharmacology 10: 1568. Link: https://bit.ly/3vJ7L04
  9. WHO (2000) Cardiovascular diseases. Link: https://bit.ly/3zHEoyr  
  10. van den Hoek J, Boshuizen HC, Roorda LD, Tijhuis GJ, Nurmohamed MT, et al. (2017) Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study. Rheumatology international 37: 487–493. Link: https://bit.ly/3vH63MD
  11. Widdifield J, Bernatsky S, Paterson JM, Tomlinson G, Tu K, et al. (2015) Trends in Excess Mortality Among Patients With Rheumatoid Arthritis in Ontario, Canada. Arthritis care & research 67: 1047–1053. Link: https://bit.ly/2SGwAwr
  12. Chodara AM, Wattiaux A, Bartel CM (2017) Managing Cardiovascular Disease Risk in Rheumatoid Arthritis: Clinical Updates and Three Strategic Approaches. Current Rheumatology Reports 19: 16. Link: https://bit.ly/3vSWvP3
  13. Bissell LA, Erhayiem B, Fent G, Hensor E, Burska A, et al. (2018) Carotid artery volumetric measures associate with clinical ten-year cardiovascular (CV) risk scores and individual traditional CV risk factors in rheumatoid arthritis; a carotid-MRI feasibility study. Arthritis Research & Therapy 20: 266. Link: https://bit.ly/3wFLDoG
  14. Bradham WS, Ormseth MJ, Oeser A, Solus JF, Gebretsadik T, et al. (2014) Insulin resistance is associated with increased concentrations of NT-proBNP in rheumatoid arthritis: IL-6 as a potential mediator. Inflammation 37: 801–808. Link: https://bit.ly/3gGuTbq
  15. Urman A, Taklalsingh N, Sorrento C, McFarlane IM (2018) Inflammation beyond the Joints: Rheumatoid Arthritis and Cardiovascular Disease. Scifed J Cardiol 2: 1000019. Link: https://bit.ly/2TOuryX
  16. Bernatsky S, Hudson M, Suissa S (2005) Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology (Oxford, England) 44: 677–680. Link: https://bit.ly/2UgP9HH
  17. Marks JL, Edwards CJ (2012) Protective effect of methotrexate in patients with rheumatoid arthritis and cardiovascular comorbidity. Therapeutic Advances in Musculoskeletal Disease 4: 149–157. Link: https://bit.ly/3gRRZdM
  18. Deyab G, Hokstad I, Whist JE, Smastuen MC, Agewall S, et al. (2017) Methotrexate and anti-tumor necrosis factor treatment improves endothelial function in patients with inflammatory arthritis. Arthritis Research & Therapy 19: 232. Link: https://bit.ly/3zKnizV
  19. Solomon DH, Reed GW, Kremer JM, Curtis JR, Farkouh ME, et al. (2015) Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis & Rheumatology (Hoboken, N.J.) 67: 1449-1455. Link: https://bit.ly/3ja6NYn
  20. Barnabe C, Martin BJ, Ghali WA (2011) Systematic review and meta-analysis: anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care  Res 63: 522–529. Link: https://bit.ly/3xtoFRM
  21. Galarraga B, Khan F, Kumar P, Pullar T, Belch JJ (2009) Etanercept improves inflammation-associated arterial stiffness in rheumatoid arthritis. Rheumatology (Oxford, England) 48: 1418–1423. Link: https://bit.ly/3zENZWN
  22. Kotani K, Miyamoto M, Ando H (2017) The Effect of Treatments for Rheumatoid Arthritis on Endothelial Dysfunction Evaluated by Flow-Mediated Vasodilation in Patients with Rheumatoid Arthritis. Current Vascular Pharmacology 15: 10–18. Link: https://bit.ly/3gIlwIn
  23. Hoffman E, Rahat MA, Feld J, Elias M, Rosner I, et al. (2019) Effects of Tocilizumab, an Anti-Interleukin-6 Receptor Antibody, on Serum Lipid and Adipokine Levels in Patients with Rheumatoid Arthritis. Int J Mol Sci 20: 4633. Link: https://bit.ly/3vHDRcD
  24. Yokoe I, Kobayashi H, Kobayashi Y, Giles JT, Yoneyama K, et al. (2018) Impact of tocilizumab on N-terminal pro-brain natriuretic peptide levels in patients with active rheumatoid arthritis without cardiac symptoms. Scand J Rheumatol 47: 364-370. Link: https://bit.ly/3zHjIXq
  25. Ikonomidis I, Pavlidis G, Katsimbri P, Lambadiari V, Parissis J, et al. (2020) Tocilizumab improves oxidative stress and endothelial glycocalyx: A mechanism that may explain the effects of biological treatment on COVID-19. Food and Chemical Toxicology 145: 111694. Link: https://bit.ly/3iVSaYh
  26. Ikonomidis I, Pavlidis G, Katsimbri P, Andreadou I, Triantafyllidi H, et al. (2019) Differential effects of inhibition of interleukin 1 and 6 on myocardial, coronary and vascular function. Clin Res Cardiol  108: 1093–1101. Link: https://bit.ly/3gSx0I9
  27. Kang EH, Jin Y, Brill G, Lewey J, Patorno E, et al. (2018) Comparative Cardiovascular Risk of Abatacept and Tumor Necrosis Factor Inhibitors in Patients With Rheumatoid Arthritis With and Without Diabetes Mellitus: A Multidatabase Cohort Study. Journal of the American Heart Association 7: e007393. Link: https://bit.ly/3gMN7qn
  28. Matsumoto T, Sasaki N, Yamashita T, Emoto T, Kasahara K, et al. (2016) Overexpression of Cytotoxic T-Lymphocyte-Associated Antigen-4 Prevents Atherosclerosis in Mice. Arteriosclerosis, thrombosis, and vascular biology 36: 1141–1151. Link: https://bit.ly/3cXFQ6a
  29. Pérez-Baos S, Barrasa JI, Gratal P, Larrañaga-Vera A, Prieto-Potin I, et al. (2017) Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis. British Journal Pharmacology 174: 3018–3031. Link: https://bit.ly/3cYJpsJ
  30. Wolk R, Armstrong EJ, Hansen PR, Thiers B, Lan S, et al. (2017) Effect of tofacitinib on lipid levels and lipid-related parameters in patients with moderate to severe psoriasis. J Clin Lipidol  11: 1243-1256. Link: https://bit.ly/35EQlXX
  31. Kume K, Amano K, Yamada S, Kanazawa T, Ohta H, et al. (2017) Tofacitinib improves atherosclerosis despite up-regulating serum cholesterol in patients with active rheumatoid arthritis: a cohort study. Rheumatology International 37: 2079–2085. Link: https://bit.ly/3xCR488
  32. Yang X, Jia J, Yu Z, Duanmu Z, He H, et al. (2020) Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit. BMC cardiovascular disorders 20: 133. Link: https://bit.ly/3xtpkme
  33. Novikova D, Kirillova I, Markelova E, Udachkina H, Gerasimova H, et al. (2019) The first report of significantly improvement of NT-proBNP level in rheumatoid arthritis patients treated with tofacitinib during 12-month follow-up, European Heart Journal 40: ehz745.0836. Link: https://bit.ly/3xAiD1z                
  34. Syngle A, Garg N, Chauhan K (2021) POS0205 Amelioration of endothelial dysfunction with JAK inhibition in rheumatoid arthritis: JAK CV-Risk reduction study. Annals of the Rheumatic Diseases 80: 318-319. Link: https://bit.ly/35GZGP8
  35. Charles-Schoeman C, et al. (2019) Treatment with upadactinib is associated with improvements in reverse cholesterol transport in patients with rheumatoid arthritis: Correlation with changes in inflammation and HDL levels. Annals of the Rheumatic Diseases. 78: 356.2-357. Link: https://bit.ly/3cWPKVL
  36. Giles JT (2015) Cardiovascular disease in rheumatoid arthritis: Current perspectives on assessing and mitigating risk in clinical practice. Best practice & research. Clinical Rheumatology 29: 597–613. Link: https://bit.ly/3xE9FRg
  37. Ghosh-Swaby OR, Kuriya B (2019) Awareness and perceived risk of cardiovascular disease among individuals living with rheumatoid arthritis is low: results of a systematic literature review. Arthritis Research & Therapy 21: 33. Link: https://bit.ly/3wJC0pd  
  38. Barber CE, Esdaile JM, Martin LO, Faris P, Barnabe C, et al. (2016) Gaps in Addressing Cardiovascular Risk in Rheumatoid Arthritis: Assessing Performance Using Cardiovascular Quality Indicators. Journal of Rheumatology 43: 1965–1973. Link: https://bit.ly/3qeEBVv
  39. Frølund JC, Primdahl J (2015) Patients' Experiences of Nurse-Led Screening for Cardiovascular Risk in Rheumatoid Arthritis. Musculoskeletal care 13: 236–247.
  40. Boo S, Oh H, Froelicher ES, Suh CH (2017) Knowledge and perception of cardiovascular disease risk among patients with rheumatoid arthritis. PloS One 12: e0176291. Link: https://bit.ly/3zJm1ZW
  41. Alm-Roijer C, Stagmo M, Udén G, Erhardt L (2004) Better knowledge improves adherence to lifestyle changes and medication in patients with coronary heart disease. European journal of cardiovascular nursing : journal of the Working Group on Cardiovascular Nursing of the European Society of Cardiology 3: 321-330. Link: https://bit.ly/3wJ2mYo
  42. Kaczorowski J, Chambers LW, Dolovich L, Paterson JM, Karwalajtys T, et al. (2011) Improving cardiovascular health at population level: 39 community cluster randomised trial of Cardiovascular Health Awareness Program (CHAP). BMJ (Clinical research ed.), 342.
  43. Singh JA, Saag KG, Bridges SL,  Akl EA, Bannuru RR, et al. (2016) 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care & Research 68: 1-25. Link: https://bit.ly/3cXcvsl  
  44. Smolen JS, Landewé R, Bijlsma J, Burmester GR, Dougados M, et al. (2020) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79: 685–699. Link: https://bit.ly/3vErdLn
  45. Arts EE, Fransen J, Den Broeder AA, van Riel P, Popa CD (2017) Low disease activity (DAS28≤3.2) reduces the risk of first cardiovascular event in rheumatoid arthritis: a time-dependent Cox regression analysis in a large cohort study. Ann Rheum Dis  76: 1693–1699. Link: https://bit.ly/3zJrLDd
  46. Roodenrijs N, Kedves M, Hamar A, Nagy G, van Laar JM, et al. (2021) Diagnostic issues in difficult-to-treat rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis. RMD Open 7: e001511. Link: https://bit.ly/3gQnsNA
© 2021 Ben Shimol J. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.