398 The Journal of Rheumatology 2008; 35:3 Personal non-commercial use only. The Journal of Rheumatology Copyright © 2008. All rights reserved. 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. Objective. Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. We assessed endothelial dysfunc- tion and atherosclerosis in RA in context with laboratory markers. 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 corre- lated 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-γ (IFN-γ) 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 significant- ly 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-γ 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 pro- duction. Paraoxonase-1 (PON-1) activity correlated with serum tumor necrosis factor-α (TNF-α) 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, circu- lating immune complexes, IgM, TNF-α, 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 athero- sclerosis, 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 ENDOTHELIAL DYSFUNCTION ATHEROSCLEROSIS FLOW-MEDIATED VASODILATATION NITRATE-MEDIATED VASODILATATION CAROTID INTIMA-MEDIA THICKNESS 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 www.jrheum.org Downloaded on January 22, 2022 from