Endothelial progenitor cells as cardiovascular surrogate markers in seropositive rheumatoid arthritis

Nidhi Garg, Ashit Syngle, Inderjeet Verma, Pawan Krishan
DOI: 10.15305/ijrci/v3i1/98



Bone marrow-derived endothelial progenitor cells (EPCs) confer protection against atherosclerotic vascular damage, thereby reducing the cardiovascular (CV) risk. Hence, the depletion of EPCs in rheumatoid arthritis (RA) is associated with enhanced CV risk. Patients with seropositive RA have increased risk of CV morbidity and mortality. The aim of this study was to investigate the endothelial progenitor cell population in seropositive and seronegative RA patients and its potential relationships with disease variables and proinflammatory cytokines.


Forty adult RA patients were classified into seropositive (n = 20) and seronegative (n = 20) groups based on the presence of rheumatoid factor (RF). EPCs (CD34+/CD133+) quantified by flow cytometry and proinflammatory cytokines (TNF- α, IL-6 and IL-1) were measured using standard ELISA kits, and disease activity by DAS28, CRP, and ESR.


EPCs were significantly reduced in total RA and seropositive patients compared to seronegative subjects (P <0.05).  Levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1) were significantly (P = 0.01) higher in seropositive patients as compared to seronegative but in total RA patients level of IL-6 and IL-1 were significantly (P <0.05) higher as compared to seronegative patients. Significant negative correlation was observed between percentage of EPCs and IL-1, TNF-α, and disease activity in seropositive patients, between RF and TNF-α in seropositive patients, and between EPCs and DAS 28 in total RA patients.


EPC depletion is inversely correlated with disease activity, RF, and proinflammatory cytokines in seropositive patients, suggesting the pivotal role of inflammation in depletion of EPCs. EPC may serve as a probable therapeutic target for preventing cardiovascular disease in seropositive RA.


Garg N, Syngle A, Verma I, Krishan P. IJRCI. 2015;3(1):OA1 (27 January 2015) DOI: 10.15305/ijrci/v3i1/98


Endothelial Progenitor Cells; Pro-inflammatory cytokines; Rheumatoid Arthritis; Seropositivity


1. Grisar JD, Aletaha CW, Steiner CW et al. Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy. Ann Rheum Dis 2007; 66: 1284–1288.

2. Paleolog E. It’s all in the blood: circulating endothelial progenitor cells link synovial vascularity with cardiovascular mortality in rheumatoid arthritis? Arthritis Res Ther 2005; 7: 270–272.

3. Avouac J, Georges U, Kahan A, Boileau C, Allanore Y. Endothelial progenitor cells and rheumatic disorders. Joint Bone Spine 2008; 75: 131–137.

4. Hill JM, Zalos G, Halcox JPJ et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593–600.

5. Werner N, Nickenig G. Influence of Cardiovascular Risk Factors on Endothelial Progenitor Cells. Limitations for Therapy? Arterio Throm Vas Biol 2006; 26: 257-266.

6. Koch AE. Angiogenesis as a target in Rheumatoid arthritis. Ann Rheum Dis 2003; 62: ii60-ii67.

7. Herbrig K, Haensel S, Oelschlaegel U, Pistrosch F, Foerster S, Passauer J. Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells. Ann Rheum Dis 2006; 65: 157-163.

8. Allanore Y, Batteux F, Avouac J, Assous N, Weill B, Kahan A. Levels of circulating endothelial progenitor cells in systemic sclerosis. Clin Exp Rheumatol 2007; 25: 60-66.

9. Moonen JR, de Leeuw K, van Seijen XJ et al. Reduced number and impaired function of circulating progenitor cells in patients with systemic lupus erythematosus. Arthritis Res Ther 2007; 9: R84.

10. de Groot K, Goldberg C, Bahlmann FH et al. Vascular endothelial damage and repair in antineutrophil cytoplasmic antibody–associated vasculitis. Arthritis Rheum 2007; 56: 3847-3853.

11. Grisar J, Aletaha D, Steiner CW et al. Depletion of endothelial progenitor cells in the peripheral blood of patients with rheumatoid arthritis. Circulation 2005; 111: 204-211.

12. Gabriel SE. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med 2008; 121: S9–14.

13. Goodson NJ, Wiles NJ, Lunt M, Barrett EM, Silman AJ, Symmons DP. Mortality in early inflammatory polyarthritis: cardiovascular mortality is increased in seropositive patients. Arthritis Rheum 2002; 46: 2010–2019.

14. Aletaha D, Neogi T, Silman AJ et al. Rheumatoid Arthritis Classification Criteria. Arthritis Rheum 2010; 62: 2569-2581.

15. Verma I, Syngle A, Krishan P. Endothelial progenitor cell biology in ankylosing spondylitis. Int J Rheum Dis 2014 doi: 10.1111/1756-185X.12487.

16. Choi JH, Kim KL, Huh W et al. Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 2004; 24: 1246–1252.

17. Firestein GS, Zvaifler NJ. Rheumatoid arthritis: a disease of disordered immunity. In Inflammation: Basic Principles and Clinical Correlates, 2nd ed. Raven Press, Ltd., New York. 959–975, 1992.

18. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996; 14: 397–440.

19. Dixon JS, Bird HA, Wright V. A comparison of serum biochemistry in ankylosing spondylitis, seronegative and seropositive rheumatoid arthritis. Ann Rheum Dis 1981; 40: 404-408.

20. Clermont PJG, Creager MA, Lorsordo DW, Lam GKW, Wassef M, Dzau VJ. Atherosclerosis 2005: Recent Discoveries and Novel Hypotheses. Circulation 2005 ;112 : 3348-3353.

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

22. Westerweel PE, Verhaar MC. Endothelial progenitor cell dysfunction in rheumatic disease. Nat Rev Rheumatol 2009; 5: 332–340.

23. Xu MG, Men LN, Zhao CY et al. The number and function of circulating endothelial progenitor cells in patients with Kawasaki disease. Eur J Pediatr 2010; 169: 289-296.

24. Radenkovic M, Stojanovic M, Potpara T et al. Therapeutic approach in the improvement of endothelial dysfunction: The current state of the art. Biomed Res Int 2013 doi: 10.1155/2013/252158.

25. Edwards CJ, Syddall H, Goswami R et al. The autoantibody rheumatoid factor may be an independent risk factor for ischaemic heart disease in men. Heart 2007; 93: 1263–1267.

26. Wallberg-Jonsson S, Johansson H, Ohman ML, Rantapaa-Dahlqvist S. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset. J Rheumatol 1999; 26: 2562–2571.

27. Bergholm R, Leirisalo-Repo M, Vehkavaara S, Makimattila S, Taskinen MR, Yki-Jarvinen H. Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis. Arterioscler Thromb Vasc Biol 2002; 22: 1637–1641.

28. Egan CG, Caporali FE, Garcia-Gonzalez E, Galeazzi M, Sorrentino V. Endothelial progenitor cells and colony-forming units in rheumatoid arthritis: association with clinical characteristics. Rheumatology 2008; 47: 1484–1488.