Determination of the Diagnostic Values of Asymmetric Dimethylarginine as an Indicator for Evaluation of the Endothelial Dysfunction in Patients with Rheumatoid Arthritis
Introduction. To compare the diagnostic values of laboratory variables, to present evaluations of the diagnostic test for asymmetric dimethyl arginine (ADMA), rheumatoid factor (RF), C-reactive protein (CRP), and DAS28 index, and to define the effect of untreated rheumatoid arthritis on endothelial function. In order to determine whether ADMA changes depending on the disease evolution, ADMA was used as an indicator for endothelial dysfunction. Methods. Using an ELISA technology of DLD-Diagnostika-GMBH for the detection of ADMA, the samples of serum and urine have been examined in 70 participants (35 RA who were not treated, 35 healthy controls). RF was defined with the test for agglutination (Latex RF test) in the same participants. Results. Out of 35 examined patients with RA, RF appeared in 17 patients (sensitivity of the test, 51.42%). In 20 of the 35 examined patients with RA, we found the presence of ADMA (sensitivity of the test, 57.14%). Anti-CCP antibody was present in 24 examined patients with RA (sensitivity of the test, 68.57%). Conclusion. ADMA has equal or very similar sensitivity and specificity to RF in untreated RA (sensitivity of 57.14% versus 48.57%, specificity of 88.57% versus 91.42%) in the detection of asymptomatic endothelial dysfunction in untreated RA. 1. Introduction Rheumatoid arthritis (RA) is a disease which encompasses up to 1% of the whole population and is associated with an increased risk for onset and development of cardiovascular diseases (CVD). Data show that those patients have 30–60% increased risk for CVD in comparison with patients with osteoarthritis [1]. Patients with RA with disease duration of more than 10 years have increased risk of myocardial infarction [2] and more expressed process of atherogenesis because of the chronic systemic inflammation. Circulatory markers of the systemic inflammation significantly increase the risk of cardiovascular morbidity and mortality in this group of patients, far more than traditional risk factors such as smoking, diabetes, and hypertension [3–9]. There are numerous analogues between RA and atheroclerosis, including macrophages, T-cell activation, unbalance between T helper 1 and T helper 2 lymphocytse, increased level of circulatory reactants of the acute phase and adhesion molecules, increased production of endothelins, oxidative radicals and increased neoangiogenesis in early but as well in long-lasting RA. Endothelial dysfunction occurs in the absence of manifest CVD and is not connected with traditional atherosclerotic risk factors [10–12]. 1.1. Biomarkers for
References
[1]
D. J. Watson, T. Rhodes, and H. A. Guess, “All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database,” The Journal of Rheumatology, vol. 30, no. 6, pp. 1196–1202, 2003.
[2]
D. H. Solomon, E. W. Karlson, E. B. Rimm et al., “Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis,” Circulation, vol. 107, no. 9, pp. 1303–1307, 2003.
[3]
I. Del Rincón, D. H. O'Leary, G. L. Freeman, and A. Escalante, “Acceleration of atherosclerosis during the course of rheumatoid arthritis,” Atherosclerosis, vol. 195, no. 2, pp. 354–360, 2007.
[4]
R. Ross, “Atherosclerosis—an inflammatory disease,” The New England Journal of Medicine, vol. 340, no. 2, pp. 115–126, 1999.
[5]
H. Maradit-Kremers, P. J. Nicola, C. S. Crowson, K. V. Ballman, and S. E. Gabriel, “Cardiovascular death in rheumatoid arthritis: a population-based study,” Arthritis & Rheumatism, vol. 52, no. 3, pp. 722–732, 2005.
[6]
I. Del Rincon, K. Williams, M. P. Stern, G. L. Freeman, and A. Escalante, “High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors,” Arthritis & Rheumatism, vol. 44, pp. 2737–2745, 2001.
[7]
I. Del Rincón, G. L. Freeman, R. W. Haas, D. H. O'Leary, and A. Escalante, “Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis,” Arthritis & Rheumatism, vol. 52, no. 11, pp. 3413–3423, 2005.
[8]
S. Van Doornum, G. McColl, and I. P. Wicks, “Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis?” Arthritis & Rheumatism, vol. 46, no. 4, pp. 862–873, 2002.
[9]
M. A. Gonzalez-Gay, C. Gonzalez-Juanatey, A. Pi?eiro, C. Garcia-Porrua, A. Testa, and J. Llorca, “High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis,” The Journal of Rheumatology, vol. 32, no. 7, pp. 1219–1223, 2005.
[10]
S. H?nsel, G. L?ssig, F. Pistrosch, and J. Passauer, “Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low disease activity,” Atherosclerosis, vol. 170, no. 1, pp. 177–180, 2003.
[11]
G. Vaudo, S. Marchesi, R. Gerli et al., “Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity,” Annals of the Rheumatic Diseases, vol. 63, no. 1, pp. 31–35, 2004.
[12]
P. H. Dessein, B. I. Joffe, and S. Singh, “Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis,” Arthritis Research & Therapy, vol. 7, no. 3, pp. R634–R643, 2005.
[13]
S. M. Bode-B?ger, F. Scalera, J. T. Kielstein et al., “Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease,” Journal of the American Society of Nephrology, vol. 17, no. 4, pp. 1128–1134, 2006.
[14]
J. T. Kielstein, S. R. Salpeter, S. M. Bode-Boeger, J. P. Cooke, and D. Fliser, “Symmetric dimethylarginine (SDMA) as endogenous marker of renal function—a meta-analysis,” Nephrology Dialysis Transplantation, vol. 21, no. 9, pp. 2446–2451, 2006.
[15]
P. Wanby, T. Teerlink, L. Brudin et al., “Asymmetric dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population,” Atherosclerosis, vol. 185, no. 2, pp. 271–277, 2006.
[16]
J. Murray-Rust, J. Leiper, M. McAlister, et al., “Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase,” Nature Structural Biology, vol. 8, pp. 679–683, 2001.
[17]
C. T. L. Tran, J. M. Leiper, and P. Vallance, “The DDAH/ADMA/NOS pathway,” Atherosclerosis Supplements, vol. 4, no. 4, pp. 33–40, 2003.
[18]
P. Vallance and J. Leiper, “Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 6, pp. 1023–1030, 2004.
[19]
A. Ito, P. S. Tsao, S. Adimoolam, M. Kimoto, T. Ogawa, and J. P. Cooke, “Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase,” Circulation, vol. 99, no. 24, pp. 3092–3095, 1999.
[20]
J. Leiper, J. Murray-Rust, N. McDonald, and P. Vallance, “S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13527–13532, 2002.
[21]
P. H. J. Remans, M. van Oosterhout, T. J. M. Smeets et al., “Intracellular free radical production in synovial T lymphocytes from patients with rheumatoid arthritis,” Arthritis & Rheumatism, vol. 52, no. 7, pp. 2003–2009, 2005.
[22]
H. Kaur and B. Halliwell, “Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients,” FEBS Letters, vol. 350, no. 1, pp. 9–12, 1994.
[23]
D. Hürlimann, A. Forster, G. Noll et al., “Anti-tumor necrosis factor-α treatment improves endothelial function in patients with rheumatoid arthritis,” Circulation, vol. 106, no. 17, pp. 2184–2187, 2002.
[24]
R. H. B?ger, K. Sydow, J. Borlak et al., “LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases,” Circulation Research, vol. 87, no. 2, pp. 99–105, 2000.
[25]
J. Middleton, L. Americh, R. Gayon et al., “Endothelial cell phenotypes in the rheumatoid synovium: activated, angiogenic, apoptotic and leaky,” Arthritis Research and Therapy, vol. 6, no. 2, pp. 60–72, 2004.
[26]
R. H. B?ger, S. M. Bode-B?ger, P. S. Tsao, P. S. Lin, J. R. Chan, and J. P. Cooke, “An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes,” Journal of the American College of Cardiology, vol. 36, no. 7, pp. 2287–2295, 2000.
[27]
L. J. Millatt, G. S. J. Whitley, D. Li et al., “Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension,” Circulation, vol. 108, no. 12, pp. 1493–1498, 2003.
[28]
E. B. Marliss, S. Chevalier, R. Gougeon et al., “Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover,” Diabetologia, vol. 49, no. 2, pp. 351–359, 2006.
[29]
T. Hedner, A. Himmelmann, and L. Hansson, “Homocysteine and ADMA—emerging risk factors for cardiovascular disease?” Blood Pressure, vol. 11, no. 4, pp. 197–200, 2002.
[30]
V. P. Valkonen, J. Laakso, H. P?iv?, et al., “Asymmetrical dimethylarginine (ADMA) and risk of acute coronary events. Does statin treatment influence plasma ADMA levels?” Atherosclerosis Supplements, vol. 4, pp. 19–22, 2003.
[31]
K. Sydow, B. Hornig, N. Arakawa et al., “Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA,” Vascular Medicine, vol. 9, no. 2, pp. 93–101, 2004.
[32]
M. Gorenflo, C. Zheng, E. Werle, W. Fiehn, and H. E. Ulmer, “Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension,” Journal of Cardiovascular Pharmacology, vol. 37, no. 4, pp. 489–492, 2001.
[33]
W. Z. Zhang, K. Venardos, J. Chin-Dusting, and D. M. Kaye, “Adverse effects of cigarette smoke on no bioavailability: role of arginine metabolism and oxidative stress,” Hypertension, vol. 48, no. 2, pp. 278–285, 2006.
[34]
K. Y. Lin, A. Ito, T. Asagami et al., “Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase,” Circulation, vol. 106, no. 8, pp. 987–992, 2002.
[35]
F. Mittermayer, K. Krzyzanowska, and M. Wolzt, “Asymmetric dimethylarginine (ADMA): a cardiovascular risk factor,” Wiener Klinische Wochenschrift, vol. 120, no. 15-16, pp. 462–466, 2008.
[36]
F. C. Arnett, S. M. Edworthy, D. A. Bloch et al., “The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis,” Arthritis & Rheumatism, vol. 31, no. 3, pp. 315–324, 1988.
[37]
A. M. Van Gestel, M. L. L. Prevoo, M. A. van 'T Hof, M. H. van Rijswijk, L. B. A. van de Putte, and P. L. C. M. van Riel, “Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis,” Arthritis & Rheumatism, vol. 39, no. 1, pp. 34–40, 1996.
[38]
M. L. L. Prevoo, M. A. van 'T Hof, H. H. Kuper, M. A. van Leeuwen, L. B. A. van de Putte, and P. L. C. M. van Riel, “Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis,” Arthritis & Rheumatism, vol. 38, no. 1, pp. 44–48, 1995.
[39]
A. Balsa, L. Carmona, I. González-álvaro, M. A. Belmonte, X. Tina, and R. Sanmartí, “Value of DAS-28 and DAS 28-3 as compared to ACR-defined remission in rheumatoid arthritis,” The Journal of Rheumatology, vol. 31, pp. 40–46, 2004.
[40]
M. L. L. Prevoo, A. M. van Gestel, M. A. van 'T Hof, M. H. van Rijswijk, L. B. A. van de Putte, and P. L. C. M. van Riel, “Remission in a prospective study of patients with rheumatoid arthritis. American rheumatism association preliminary remission criteria in relation to the disease activity score,” British Journal of Rheumatology, vol. 35, no. 11, pp. 1101–1105, 1996.
[41]
G. Vaudo, S. Marchesi, R. Gerli et al., “Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity,” Annals of the Rheumatic Diseases, vol. 63, no. 1, pp. 31–35, 2004.
[42]
A. Surdacki, J. Martens-Lobenhoffer, A. Wloch et al., “Plasma asymmetric dimethylarginine is related to anticitrullinated protein antibodies in rheumatoid arthritis of short duration,” Metabolism, vol. 58, no. 3, pp. 316–318, 2009.
[43]
M. Turiel, L. Tomasoni, S. Sitia et al., “Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis,” Cardiovascular Therapeutics, vol. 28, no. 5, pp. e53–e64, 2010.
[44]
F. Khan, B. Galarraga, and J. J. F. Belch, “The role of endothelial function and its assessment in rheumatoid arthritis,” Nature Reviews Rheumatology, vol. 6, no. 5, pp. 253–261, 2010.
[45]
M. E. Widlansky, N. Gokce, J. F. Keaney Jr., and J. A. Vita, “The clinical implications of endothelial dysfunction,” Journal of the American College of Cardiology, vol. 42, no. 7, pp. 1149–1160, 2003.
[46]
M. Wong, L. Toh, A. Wilson et al., “Reduced arterial elasticity in rheumatoid arthritis and the relationship to vascular disease risk factors and inflammation,” Arthritis & Rheumatism, vol. 48, no. 1, pp. 81–89, 2003.
[47]
C. Gonzalez-Juanatey, A. Testa, A. Garcia-Castelo et al., “HLA-DRB1 status affects endothelial function in treated patients with rheumatoid arthritis,” American Journal of Medicine, vol. 114, no. 8, pp. 647–652, 2003.
[48]
R. Bergholm, M. Leirisalo-Repo, S. Vehkavaara, S. M?kimattila, M. R. Taskinen, and H. Yki-J?rvinen, “Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 22, no. 10, pp. 1637–1641, 2002.
[49]
G. Vaudo, S. Marchesi, R. Gerli et al., “Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity,” Annals of the Rheumatic Diseases, vol. 63, no. 1, pp. 31–35, 2004.
[50]
K. M. M?ki-Pet?j?, F. C. Hall, A. D. Booth et al., “Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-α therapy,” Circulation, vol. 114, no. 11, pp. 1185–1192, 2006.
[51]
D. Datta, W. R. Ferrell, R. D. Sturrock, S. T. Jadhav, and N. Sattar, “Inflammatory suppression rapidly attenuates microvascular dysfunction in rheumatoid arthritis,” Atherosclerosis, vol. 192, no. 2, pp. 391–395, 2007.
[52]
C. Gonzalez-Juanatey, A. Testa, A. Garcia-Castelo, C. Garcia-Porrua, J. Llorca, and M. A. Gonzalez-Gay, “Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor α antibody,” Arthritis Care and Research, vol. 51, no. 3, pp. 447–450, 2004.
[53]
D. Hürlimann, A. Forster, G. Noll et al., “Anti-tumor necrosis factor-α treatment improves endothelial function in patients with rheumatoid arthritis,” Circulation, vol. 106, no. 17, pp. 2184–2187, 2002.