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Activation of the Immune System and Inflammatory Activity in Relation to Markers of Atherothrombotic Disease and Atherosclerosis in Rheumatoid Arthritis
SOLVEIG WÅLLBERG-JONSSON, JASMINA TRIFUNOVIC CVETKOVIC, KARL-GÖSTA SUNDQVIST, ANN KARI LEFVERT, and SOLBRITT RANTAPÄÄ-DAHLQVIST
ABSTRACT. Methods. Thirty-nine patients with RA with disease onset between 1974 and 1978, who were younger than 65 years at the present study in 1997, were investigated together with 39 age and sex matched controls. IgG, IgA, and IgM antibodies against oxidized low density lipoprotein (oxLDL ab), malondialdehyde LDL (MDA-LDL ab) and cardiolipin (aCL) were measured by ELISA, circulating immune complexes (CIC) were isolated by precipitation, and homocysteine was measured with HPLC. Hemostatic factors of endothelial origin, i.e., plasminogen activator inhibitor-1 (PAI-1 mass), von Willebrand Factor (vWF), and D-dimer were analyzed by ELISA, and tissue plasminogen activator (tPA) activity was analyzed by a chromogen method. The products analyzed in the RA group correlated with soluble adhesion molecules (sICAM-1, sE-selectin), acute phase reactants, interleukin 6 (IL-6), and IL-2sRa, all measured by ELISA, and with accumulated disease activity. The factors were also related to the presence of plaque measured by duplex scanning. Factor analysis was performed to subgroup data in order to find latent variables. Results. Patients with RA had significantly higher levels of oxLDL ab (IgM), MDA-LDL ab (IgA, IgM classes), aCL (IgG, IgA, IgM classes), CIC, homocysteine, PAI-1 mass, and D-dimer than controls. Patients also had significantly higher levels of sICAM-1, sE-selectin, IL-6, and IL-2sRa. PAI-1 mass, D-dimer, vWF, CIC, and aCL (IgM, IgA) correlated with erythrocyte sedimentation rate (ESR), and, with the exception of vWF, to accumulated disease activity. CIC correlated significantly with IgM antibodies against oxLDL and aCL. ESR, IL-2sRa, PAI-1, tPA activity, vWF, D-dimer, homocysteine, aCL (IgA), and MDA-LDL ab (IgA) correlated with sICAM-1. ESR, haptoglobin, IL-2sRa, PAI-1 mass, D-dimer, aCL (IgM), and MDA-LDL ab (IgM) correlated with sE-selectin. sICAM-1 was significantly higher in patients with plaque. In factor analysis, presence of atherosclerotic plaque had loadings of one latent variable together with adhesion molecules and IL-2sRa and together with antibodies of, in particular, IgM type of another one. Conclusion. Several different etiopathogenic mechanisms for increased cardiovascular mortality in RA are implicated. Continuous endothelial activation is suggested by increased levels of adhesion molecules sICAM-1 and sE-selectin, which correlate with hemostatic factors of endothelial origin and with T cell activation as measured by IL2sRa. That factor analysis showed loadings of one variable on antilipid antibodies and plaque and another on T cell activation and plaque indicates that the immune system is involved in the development of atherosclerosis in RA. (J Rheumatol 2002;29:875-82) Key Indexing Terms:
RHEUMATOID ARTHRITIS
From the Departments of Rheumatology and Clinical Immunology, University Hospital, Umeå; and Department of Cell and Molecular Medicine, Karolinska Hospital, Stockholm, Sweden. Supported by the Medical Faculty of University of Umeå, Borgerskapet i Umeå forskningsstiftelse för Ekonomi, geriatrik och reumatologi, The Swedish Rheumatism Association, The Swedish Medical Research Council, The Swedish Heart-Lung Foundation, The Foundation of Börje Dahlin, The Swedish Society of Medicine, and The Foundation of Professor Nanna Swartz. S. Wållberg-Jonsson, MD, PhD, Consultant, Department of Rheumatology, Umeå Hospital; J. Trifunovic Cvetkovic, MSc, Department of Cell and Molecular Medicine, Karolinska Hospital; K-G. Sundqvist, MD, PhD, Department of Clinical Immunology, Umeå Hospital; A-K. Lefvert, MD, PhD, Consultant; Department of Cell and Molecular Medicine, Karolinska Hospital; S. Rantapää-Dahlqvist, MD, PhD, Consultant. Address reprint requests to Dr. S. Wållberg-Jonsson, Department of Rheumatology, University Hospital, S-901 85 Umeå, Sweden. E-mail: Solveig.Wallberg.Jonsson@medicin.umu.se Submitted June 26, 2001; revision accepted November 30, 2001. |