Factors of Progression and Occurrence of Atherosclerosis in Rheumatoid Arthritis

Aim      To determine in a prospective study factors of progressive atherosclerotic lesion of blood vessels in patients with rheumatoid arthritis (RA).

Material and methods  This prospective study included 124 patients with RA and suspected ischemic heart disease (IHD) and 30 patients with IHD (comparison group) aged 58 [52; 63] years. On enrollment to the study and at 3 years of follow-up, all patients underwent clinical and instrumental examination according to European and Russian guidelines for diagnosis and treatment of stable IHD (2013), including coronography as indicated. For all RA patients of the comparison group, risk factors (RF) were evaluated, including arterial hypertension, smoking, excessive body weight, family history of cardiovascular diseases (CVD), diabetes mellitus, and dyslipidemia. The following laboratory data were evaluated: blood count; biochemistry, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), rheumatoid factor (RhF), cyclic citrullinated peptide antibodies, and high-sensitivity C-reactive protein (hsCRP). Proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF- α), were measured in RA patients once, at 3 years of follow-up.

Results Incidence of FRs for CVD was similar in RA patients and in the comparison group. Median RA duration before inclusion into the study was 11 years, and median DAS28 index score was 3.8. Incidence of dyslipidemia due to increased TC, LDL-C, and HDL-C was higher for RA patients at baseline. The LDL-C goal (<1.8 mmol/l) was achieved only in 3 (10 %) patients of the comparison group and 10 (8 %) RA patients. RA patients had higher levels of the inflammation indexes, hsCRP (0.75 mg/dl vs. 0.16 mg/dl; p<0.05) and erythrocyte sedimentation rate (ESR) (15 mm/h vs. 11.5 mm/h; p<0.05). In the RA group at baseline, atherosclerotic plaques with carotid artery (CTA) stenosis of 20% or more were found in 94 (77 %) patients; in 3 of them, CA stenosis was >50%. Patients with RA frequently had unchanged or slightly changed coronary arteries (CA) (47% of patients), and less frequently they had hemodynamically significant multi-arterial coronary atherosclerotic lesions (7 % vs. 57 % of patients in comparison group). At 37.5 months, 21 (23 %) of 94 RA patients had progressive atherosclerosis in CA and/or CTA; 12 (13 %) RA patients had only progressive CA atherosclerosis; 7 (8 %) had only progressive CTA atherosclerosis; and 2 (2 %) had simultaneous progression of CA and CTA atherosclerosis. Two groups of RA patients were formed, with the progression of atherosclerosis (n=21) and without the progression of atherosclerosis (n=69). RFs for the development/progression of atherosclerosis in RA patients included smoking, family history of CVD, and duration of the disease. Levels of lipids did not differ. Levels of proinflammatory cytokines (IL-1β, IL-6, TNF-α) were higher in RA patients with progressive atherosclerosis. No effects of the anti-rheumatic therapy on the progression of atherosclerosis were observed.

Conclusion      Progression of atherosclerosis in RA remains in disease with low and moderate activity during the anti-rheumatic and hypolipidemic treatment. The development of atherosclerosis in RA is determined by lipid, inflammatory, and immune disorders.

1. Nasonov E.L., Nasonova V.A. Rheumatology: National Leadership. -M.: GEOTAR-Media;2008.–714 p. ISBN 978-5-9704-0672-4

2. Yazdanyar A, Wasko MC, Kraemer KL, Ward MM. Perioperative allcause mortality and cardiovascular events in patients with rheumatoid arthritis: Comparison with unaffected controls and persons with diabetes mellitus. Arthritis & Rheumatism. 2012;64(8):2429–37. DOI: 10.1002/art.34428

3. Ranganath VK, Maranian P, Elashoff DA, Woodworth T, Khanna D, Hahn T et al. Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis. Rheumatology. 2013;52(10):1809–17. DOI: 10.1093/rheumatology/ket224

4. Meune C, Touze E, Trinquart L, Allanore Y. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology. 2009;48(10):1309–13. DOI: 10.1093/rheumatology/kep252

5. Semb AG, Kvien TK, Aastveit AH, Jungner I, Pedersen TR, Walldius G et al. Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) Study. Annals of the Rheumatic Diseases. 2010;69(11):1996–2001. DOI: 10.1136/ard.2009.126128

6. Boyer J-F, Gourraud P-A, Cantagrel A, Davignon J-L, Constantin A. Traditional cardiovascular risk factors in rheumatoid arthritis: A meta-analysis. Joint Bone Spine. 2011;78(2):179–83. DOI: 10.1016/j.jbspin.2010.07.016

7. Choy E, Sattar N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Annals of the Rheumatic Diseases. 2009;68(4):460–9. DOI: 10.1136/ard.2008.101964

8. Corrigendum to: ‘2016 ESC/EAS Guidelines for the Management of Dyslipidaemias’. European Heart Journal. 2018;39(15):1254. DOI: 10.1093/eurheartj/ehx180

9. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European Heart Journal. 2020;41(1):111–88. DOI: 10.1093/eurheartj/ehz455

10. Karlson EW, Chibnik LB, Tworoger SS, Lee I-M, Buring JE, Shadick NA et al. Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies. Arthritis & Rheumatism. 2009;60(3):641–52. DOI: 10.1002/art.24350

11. Libby P. Vascular biology of atherosclerosis: overview and state of the art. The American Journal of Cardiology. 2003;91(3A):3A-6A. DOI: 10.1016/S0002-9149(02)03143-0

12. Popkova T.V., Novikova D.S., Pisarev V.V., Mach E.S., Nasonov E.L. Risk factors of cardiovascular diseases in rheumatoid arthritis. Rheumatology Science and Practice. 2009;3:4–11.

13. Kondratyeva L.V., Popkova T.V., Nasonov E.L. Metabolic syndrome in rheumatoid arthritis. Rheumatology Science and Practice. 2013;51(3):302–12.

14. Papadopoulos NG, Alamanos Y, Voulgari PV, Epagelis EK, Tsifetaki N, Drosos AA. Does cigarette smoking influence disease expression, activity and severity in early rheumatoid arthritis patients? Clinical and Experimental Rheumatology. 2005;23(6):861–6. PMID: 16396705

15. Targońska-Stępniak B, Piotrowski M, Zwolak R, Drelich-Zbroja A, Majdan M. Prospective assessment of cardiovascular risk parameters in patients with rheumatoid arthritis. Cardiovascular Ultrasound. 2018;16(1):18. DOI: 10.1186/s12947-018-0136-9

16. Arida A, Protogerou AD, Konstantonis G, Fragiadaki K, Kitas GD, Sfikakis PP. Atherosclerosis is not accelerated in rheumatoid arthritis of low activity or remission, regardless of antirheumatic treatment modalities. Rheumatology. 2017;56(6):934–9. DOI: 10.1093/rheumatology/kew506

17. Liu J-H, Ng M-Y, Cheung T, Chung H-Y, Chen Y, Zhen Z et al. Tenyear progression of coronary artery, carotid artery, and aortic calcification in patients with rheumatoid arthritis. Clinical Rheumatology. 2017;36(4):807–16. DOI: 10.1007/s10067-016-3536-y

18. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A et al. 2013 ESC guidelines on the management of stable coronary artery disease. Russian Journal of Cardiology. 2014;19(7):7–79. DOI: 10.15829/1560-4071-2014-7-7-79

19. Montecucco F, Mach F. Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology. 2008;48(1):11–22. DOI: 10.1093/rheumatology/ken395

20. Bruschke AVG, Reiber JHC, Lie KI, Wellens HJJ. Lipid-Lowering Therapy and Progression of Coronary Atherosclerosis. -Dordrecht: Springer Netherlands;1996. ISBN 978-94-009-0143-8

21. Cavagna L, Boffini N, Cagnotto G, Inverardi F, Grosso V, Caporali R. Atherosclerosis and Rheumatoid Arthritis: More Than a Simple Association. Mediators of Inflammation. 2012;2012:1–8. DOI: 10.1155/2012/147354

22. Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD et al. Preclinical Carotid Atherosclerosis in Patients with Rheumatoid Arthritis. Annals of Internal Medicine. 2006;144(4):249. DOI: 10.7326/0003-4819-144-4-200602210-00006

23. Pope JE, Nevskaya T, Barra L, Parraga G. Carotid Artery Atherosclerosis in Patients with Active Rheumatoid Arthritis: Predictors of Plaque Occurrence and Progression Over 24 Weeks. The Open Rheumatology Journal. 2016;10(1):49–59. DOI: 10.2174/1874312901610010049

24. Söderlin M, Petersson I, Geborek P. The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug. Scandinavian Journal of Rheumatology. 2012;41(1):1–9. DOI: 10.3109/03009742.2011.599073

25. Arts EEA, Fransen J, den Broeder AA, Popa CD, van Riel PLCM. The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients. Annals of the Rheumatic Diseases. 2015;74(6):998–1003. DOI: 10.1136/annrheumdis-2013-204531

26. Boyer J-F, Bongard V, Cantagrel A, Jamard B, Gottenberg J-E, Mariette X et al. Link between traditional cardiovascular risk factors and inflammation in patients with early arthritis: Results from a French Multicenter Cohort. Arthritis Care & Research. 2012;64(6):872–80. DOI: 10.1002/acr.21623

27. Innala L, Möller B, Ljung L, Magnusson S, Smedby T, Södergren A et al. Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study. Arthritis Research & Therapy. 2011;13(4):R131. DOI: 10.1186/ar3442

28. Crowson CS, Rollefstad S, Ikdahl E, Kitas GD, van Riel PLCM, Gabriel SE et al. Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 2018;77(1):48–54. DOI: 10.1136/annrheumdis-2017-211735

29. Libby P, Ridker PM, Hansson GK. Inflammation in Atherosclerosis. Journal of the American College of Cardiology. 2009;54(23):2129– 38. DOI: 10.1016/j.jacc.2009.09.009

30. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868–74. DOI: 10.1038/nature01323

31. Arida A, Protogerou A, Kitas G, Sfikakis P. Systemic Inflammatory Response and Atherosclerosis: The Paradigm of Chronic Inflammatory Rheumatic Diseases. International Journal of Molecular Sciences. 2018;19(7):1890. DOI: 10.3390/ijms19071890

32. Hannawi S, Haluska B, Marwick TH, Thomas R. Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Research & Therapy. 2007;9(6):R116. DOI: 10.1186/ar2323

33. Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. Journal of Clinical Investigation. 2008;118(11):3537–45. DOI: 10.1172/JCI36389

34. Ramji DP, Davies TS. Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets. Cytokine & Growth Factor Reviews. 2015;26(6):673–85. DOI: 10.1016/j.cytogfr.2015.04.003

35. van Sijl AM, Peters MJL, Knol DL, de Vet RHC, Sattar N, Dijkmans BAC et al. The Effect of TNF-alpha Blocking Therapy on Lipid Levels in Rheumatoid Arthritis: A Meta-Analysis. Seminars in Arthritis and Rheumatism. 2011;41(3):393–400. DOI: 10.1016/j.semarthrit.2011.04.003

36. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. New England Journal of Medicine. 2017;377(12):1119–31. DOI: 10.1056/NEJMoa1707914

37. Liao KP, Cai T, Gainer VS, Cagan A, Murphy SN, Liu C et al. Lipid and Lipoprotein Levels and Trend in Rheumatoid Arthritis Compared to the General Population: Comparing Lipids in RA to the General Population. Arthritis Care & Research. 2013;65(12):2046–50. DOI: 10.1002/acr.22091

38. Popkova T.V., Novikova D.S. According to the materials of the 2015/2016 new european league against rheumatism (EULAR) guidelines for reducing cardiovascular risk in patients with inflammatory arthritis: general characterization and discussion problems. Rheumatology Science and Practice. 2018;56(3):272–9. DOI: 10.14412/1995-4484-2018-272-279

39. Filippatos TD, Derdemezis CS, Voulgari PV, Tsimihodimos V, Elisaf MS, Tselepis AD et al. Effects of 12 months of treatment with disease-modifying anti-rheumatic drugs on low and high density lipoprotein subclass distribution in patients with early rheumatoid arthritis: a pilot study. Scandinavian Journal of Rheumatology. 2013;42(3):169–75. DOI: 10.3109/03009742.2012.745013

40. Myasoedova E, Crowson CS, Kremers HM, Roger VL, Fitz-Gibbon PD, Therneau TM et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Annals of the Rheumatic Diseases. 2011;70(3):482–7. DOI: 10.1136/ard.2010.135871

41. Semb AG, Kvien TK, DeMicco DA, Fayyad R, Wun C-C, LaRosa JC et al. Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease. Arthritis & Rheumatism. 2012;64(9):2836–46. DOI: 10.1002/art.34524

42. Gorbunova Yu.N., Novikova D.S., Popkova T.V., Markelova E.I., Korsakova Yu.O., Fomicheva O.A. et al. Cardiovascular risk in patients with early rheumatoid arthritis before disease-modifying antirheumatic therapy (preliminary data of the REMARCА study). Rheumatology Science and Practice. 2014;52(4):381–6. DOI: 10.14412/1995-4484-2014-381-386

43. Svantesson M, Rollefstad S, Kløw N-E, Hisdal J, Ikdahl E, Sexton J et al. Effects of long-term statin-treatment on coronary atherosclerosis in patients with inflammatory joint diseases. PLOS ONE. 2019;14(12):e0226479. DOI: 10.1371/journal.pone.0226479

44. Crowson CS, Rollefstad S, Ikdahl E, Kitas GD, van Riel PLCM, Gabriel SE, Matteson EL, Kvien TK, Douglas K, Sandoo A, Arts E, WållbergJonsson S, Innala L, Karpouzas G, Dessein PH, Tsang L, El-Gabalawy H, Hitchon C, Ramos VP, Yáñez IC, Sfikakis PP, Zampeli E, Gonzalez-Gay MA, Corrales A, Laar MV, Vonkeman HE, Meek I, Semb AG; A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis. Ann Rheum Dis. 2018 Jan;77(1):48-54. doi: 10.1136/annrheumdis-2017-211735. Epub 2017 Sep 6. PMID: 28877868; PMCID: PMC5726925.