J Korean Med Sci.  2015 Nov;30(11):1589-1596. 10.3346/jkms.2015.30.11.1589.

Effects of Methotrexate on Carotid Intima-media Thickness in Patients with Rheumatoid Arthritis

• Kim HJ
• Kim MJ
• Lee CK
• Hong YH

• KMID: 2351108
• DOI: http://doi.org/10.3346/jkms.2015.30.11.1589

Abstract

The purpose of this study was to evaluate the effects of rheumatoid arthritis (RA) and antirheumatic drugs on atherosclerosis by comparing carotid intima-media thickness (CIMT) as an indicator for cardiovascular diseases (CVD). This study included 44 female RA patients who met the 2010 ACR/EULAR criteria and age-matched 22 healthy females. CIMT was measured on both carotid arteries using a B-mode ultrasound scan. The mean value of both sides was taken as the CIMT of the subject. The CIMT was evaluated according to the use of drugs, disease activity and CVD risk factors in RA patients as a case-control study. Higher CIMT was observed in RA patients as compared with healthy subjects (0.705 +/- 0.198 mm, 0.611 +/- 0.093 mm, respectively, P < 0.05). With adjustment for the CVD risk factors, disease activity and the use of anti-rheumatic drugs, methotrexate (MTX) only showed a favorable effect on CIMT in RA. A significantly lower CIMT was observed in RA with MTX as compared with RA without MTX (0.644 +/- 0.136 mm, 0.767 +/- 0.233 mm, respectively, P < 0.05). The effects were correlated with MTX dosage (beta = -0.029, P < 0.01). The use of MTX should be considered in high priority not only to control arthritis but also to reduce the RA-related CVD risk to mortality.

Keyword

Arthritis, Rheumatoid; Carotid Intima Media Thickness (CIMT); Methotrexate; Atherosclerosis

MeSH Terms

Adult
Aged
Aged, 80 and over
Antirheumatic Agents/therapeutic use
Arthritis, Rheumatoid/diagnosis/*drug therapy/*epidemiology
Carotid Artery Diseases/*drug therapy/*epidemiology/ultrasonography
*Carotid Intima-Media Thickness
Causality
Comorbidity
Female
Humans
Incidence
Male
Methotrexate/*therapeutic use
Middle Aged
Reproducibility of Results
Republic of Korea/epidemiology
Risk Factors
Sensitivity and Specificity
Antirheumatic Agents
Methotrexate

Reference

1. Watson DJ, Rhodes T, Guess HA. All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol. 2003; 30:1196–1202.

2. Bacon PA, Stevens RJ, Carruthers DM, Young SP, Kitas GD. Accelerated atherogenesis in autoimmune rheumatic diseases. Autoimmun Rev. 2002; 1:338–347.

3. Corrales A, Dessein PH, Tsang L, Pina T, Blanco R, Gonzalez-Juanatey C, Llorca J, Gonzalez-Gay MA. Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study. Arthritis Res Ther. 2015; 17:55.

4. Naz SM, Symmons DP. Mortality in established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007; 21:871–883.

5. Gasparyan AY, Stavropoulos-Kalinoglou A, Mikhailidis DP, Toms TE, Douglas KM, Kitas GD. The rationale for comparative studies of accelerated atherosclerosis in rheumatic diseases. Curr Vasc Pharmacol. 2010; 8:437–449.

6. Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation. 2003; 108:2957–2963.

7. Libby P. Inflammation in atherosclerosis. Nature. 2002; 420:868–874.

8. Kannel WB, McGee D, Gordon T. A general cardiovascular risk profile: the Framingham Study. Am J Cardiol. 1976; 38:46–51.

9. Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol. 2003; 23:554–566.

10. O'Leary DH, Bots ML. Imaging of atherosclerosis: carotid intima-media thickness. Eur Heart J. 2010; 31:1682–1689.

11. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Cardiovascular Health Study Collaborative Research Group. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med. 1999; 340:14–22.

12. Edwards CJ, Arden NK, Fisher D, Saperia JC, Reading I, Van Staa TP, Cooper C. The changing use of disease-modifying anti-rheumatic drugs in individuals with rheumatoid arthritis from the United Kingdom General Practice Research Database. Rheumatology (Oxford). 2005; 44:1394–1398.

13. Solomon DH, Goodson NJ, Katz JN, Weinblatt ME, Avorn J, Setoguchi S, Canning C, Schneeweiss S. Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis. 2006; 65:1608–1612.

14. Suissa S, Bernatsky S, Hudson M. Antirheumatic drug use and the risk of acute myocardial infarction. Arthritis Rheum. 2006; 55:531–536.

15. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010; 62:2569–2581.

16. Ristić GG, Lepić T, Glisić B, Stanisavljević D, Vojvodić D, Petronijević M, Stefanović D. Rheumatoid arthritis is an independent risk factor for increased carotid intima-media thickness: impact of anti-inflammatory treatment. Rheumatology (Oxford). 2010; 49:1076–1081.

17. Targońska-Stepniak B, Drelich-Zbroja A, Majdan M. The relationship between carotid intima-media thickness and the activity of rheumatoid arthritis. J Clin Rheumatol. 2011; 17:249–255.

18. Goodson N, Marks J, Lunt M, Symmons D. Cardiovascular admissions and mortality in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and 1990s. Ann Rheum Dis. 2005; 64:1595–1601.

19. Ambrosino P, Lupoli R, Di Minno A, Tasso M, Peluso R, Di Minno MN. Subclinical atherosclerosis in patients with rheumatoid arthritis. A meta-analysis of literature studies. Thromb Haemost. 2015; 113:916–930.

20. Goodson NJ, Symmons DP, Scott DG, Bunn D, Lunt M, Silman AJ. Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort. Arthritis Rheum. 2005; 52:2293–2299.

21. Maxwell SR, Moots RJ, Kendall MJ. Corticosteroids: do they damage the cardiovascular system? Postgrad Med J. 1994; 70:863–870.

22. Solomon DH, Avorn J, Katz JN, Weinblatt ME, Setoguchi S, Levin R, Schneeweiss S. Immunosuppressive medications and hospitalization for cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum. 2006; 54:3790–3798.

23. Davis JM 3rd, Maradit Kremers H, Crowson CS, Nicola PJ, Ballman KV, Therneau TM, Roger VL, Gabriel SE. Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2007; 56:820–830.

24. Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med. 2004; 141:764–770.

25. Goodson NJ, Brookhart AM, Symmons DP, Silman AJ, Solomon DH. Non-steroidal anti-inflammatory drug use does not appear to be associated with increased cardiovascular mortality in patients with inflammatory polyarthritis: results from a primary care based inception cohort of patients. Ann Rheum Dis. 2009; 68:367–372.

26. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, et al. VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343:1520–1528.

27. Lindhardsen J, Gislason GH, Jacobsen S, Ahlehoff O, Olsen AM, Madsen OR, Torp-Pedersen C, Hansen PR. Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis. 2013.

28. Westlake SL, Colebatch AN, Baird J, Kiely P, Quinn M, Choy E, Ostor AJ, Edwards CJ. The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology (Oxford). 2010; 49:295–307.

29. Muller DW, Topol EJ, Abrams GD, Gallagher KP, Ellis SG. Intramural methotrexate therapy for the prevention of neointimal thickening after balloon angioplasty. J Am Coll Cardiol. 1992; 20:460–466.

30. Thornton CC, Al-Rashed F, Calay D, Birdsey GM, Bauer A, Mylroie H, Morley BJ, Randi AM, Haskard DO, Boyle JJ, et al. Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation. Ann Rheum Dis. 2015.

31. Reiss AB, Carsons SE, Anwar K, Rao S, Edelman SD, Zhang H, Fernandez P, Cronstein BN, Chan ES. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum. 2008; 58:3675–3683.

32. Georgiadis AN, Papavasiliou EC, Lourida ES, Alamanos Y, Kostara C, Tselepis AD, Drosos AA. Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis: effect of early treatment--a prospective, controlled study. Arthritis Res Ther. 2006; 8:R82.

33. Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002; 359:1173–1177.