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Endothelial Dysfunction and Atherosclerosis in Rheumatoid Arthritis: A Multiparametric Analysis Using Imaging Techniques and Laboratory Markers of Inflammation and Autoimmunity
GYÖRGY KEREKES, ZOLTÁN SZEKANECZ, HENRIETT DÉR, ZSUZSA SÁNDOR, GABRIELLA LAKOS, LÁSZLÓ MUSZBEK, ISTVÁN CSIPÖ, SÁNDOR SIPKA, ILDIKÓ SERES, GYÖRGY PARAGH, JÁNOS KAPPELMAYER, EDIT SZOMJÁK, KATALIN VERES, GYULA SZEGEDI, YEHUDA SHOENFELD, and PÁL SOLTÉSZ
ABSTRACT. Methods. Fifty-two patients with RA and 40 matched healthy controls were studied. We assessed common carotid intima-media thickness (ccIMT) and flow- (FMD) and nitroglycerine-mediated vasodilation (NMD). We also assayed numerous immunological and metabolic laboratory markers. Results. FMD was significantly lower in RA (5.32% ± 4.66%) compared to controls (8.30% ± 3.96%) (p = 0.001). NMD was preserved in RA. ccIMT was significantly greater in patients with RA (0.63 ± 0.14 mm) versus controls (0.54 ± 0.15 mm) (p = 0.012). In patients with RA, ccIMT correlated with FMD% (R = –0.318, p = 0.022), age (R = 0.831, p < 0.001), and anti-dsDNA levels (R = 0.463, p = 0.006). FMD% correlated with serum interferon-g (IFN-g) levels (R = 0.516, p = 0.014). NMD% correlated inversely with the percentage of Th0 lymphocytes (R = –0.636, p = 0.006), serum immune complex (R = –0.692, p < 0.001), and IgM levels (R = –0.606, p = 0.003). Patients with RA were divided as "low" (< 0.65 mm) versus "high" (> 0.65 mm) ccIMT groups, and into "normal" (> 5%) versus "impaired" (< 5%) FMD% subsets. Low and high ccIMT groups differed significantly in age and serum interleukin 1 (IL-1) and anti-dsDNA levels. RA patients with normal versus impaired FMD% differed significantly in age, disease duration, and serum IFN-g levels. Lipoprotein(a) [Lp(a)] also correlated with rheumatoid factor (RF) and C-reactive protein (CRP); homocysteine (HCy) correlated with CRP and correlated inversely with folate and vitamin B12 production. Paraoxonase-1 (PON-1) activity correlated with serum tumor necrosis factor-a (TNF-a) and IL-6 levels. Conclusion. This was a well characterized RA population, where FMD and ccIMT were impaired, indicating early endothelial dysfunction and accelerated atherosclerosis, respectively. RA-related autoimmune-inflammatory mechanisms and metabolic factors including anti-CCP, RF, CRP, circulating immune complexes, IgM, TNF-a, IL-6, Th0/Th1 ratio, HCy, folate, vitamin B12, and PON-1 may all be involved in the development of vascular disease in RA. Although ccIMT and FMD, as well as some laboratory factors, have been assessed by other investigators in RA-associated atherosclerosis, our results regarding the possible involvement of anti-CCP, anti-dsDNA, Lp(a), some cytokines, and PON-1 activity are novel. Early determination of FMD% and ccIMT may be useful to assess RA patients with high cardiovascular risk. (First Release Jan 15 2008; J Rheumatol 2008;35:398-406) Key Indexing Terms:
RHEUMATOID ARTHRITIS
From the Cardiovascular Unit, Division of Rheumatology, and Laboratory of Immunology, Third Department of Medicine; Department of Pathology; Center for Clinical Research; Division of Metabolic Diseases, First Department of Medicine; and Department of Clinical Biochemistry and Molecular Pathology, University of Debrecen Medical and Health Science Center; Research Center for Autoimmune Diseases, Hungarian Academy of Sciences, Debrecen, Hungary; and the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel. Supported by research grants T048541 (ZS) and T046517 (PS) from the National Foundation for Scientific Research (OTKA), a Bolyai Research Grant (PS), and a research grant from the Hungarian Academy of Sciences (GS). Drs. Kerekes and Szekanecz contributed equally to this report. G. Kerekes, MD; H. Dér, MD; E. Szomják, MD; K. Veres, MD; P. Soltész, MD, PhD, Cardiovascular Unit; Z. Szekanecz, MD, PhD, Division of Rheumatology, Third Department of Medicine; Z. Sándor, MD, Division of Rheumatology, Third Department of Medicine and Department of Pathology; G. Lakos, MD, PhD; I. Csipö, MD, PhD; S. Sipka, MD, PhD, Laboratory of Immunology, Third Department of Medicine; L. Muszbek, MD, Center for Clinical Research; I. Seres, MD, PhD; G. Paragh, MD, PhD, Division of Metabolic Diseases, First Department of Medicine; J. Kappelmayer, MD, PhD, Department of Clinical Biochemistry and Molecular Pathology, University of Debrecen Medical and Health Science Center; G. Szegedi, MD, PhD, Research Center for Autoimmune Diseases, Hungarian Academy of Sciences; Y. Shoenfeld, MD, PhD, Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center. Address reprint requests to Dr. Z. Szekanecz, Third Department of Internal Medicine, Rheumatology Division, University of Debrecen, Medical and Health Science Center, Móricz Zs krt. 22., H-4004 Debrecen, Hungary. E-mail: szekanecz@iiibel.dote.hu Accepted for publication October 16, 2007. |
