Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis.
OBJECTIVE
To measure markers of atherogenesis and thrombogenesis in patients with rheumatoid arthritis (RA) and in matched controls, and to relate these variables to markers of inflammation and endothelial activation, and to the presence of atherosclerosis.


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-2sR alpha, 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-2sR alpha. 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-2sR alpha, PAI-1, tPA activity, vWF, D-dimer, homocysteine, aCL (IgA), and MDA-LDL ab (IgA) correlated with sICAM-1. ESR, haptoglobin, IL-2sR alpha, 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-2sR alpha and together with antibodies of, in particular, IgM type of another one.


CONCLUSIONS
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 IL2sR alpha. 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.
Wållberg-Jonsson
Solveig
S
Department of Rheumatology, University Hospital, Umeå, Sweden. Solveig.Wallberg.Jonsson@medicin.umu.se
Cvetkovic
Jasmina Trifunovic
JT
Sundqvist
Karl-Gösta
KG
Lefvert
Ann Kari
AK
Rantapää-Dahlqvist
Solbritt
S
D000210:Acute-Phase Reaction / Q000276:immunology; D000328:Adult; D000368:Aged; D017153:Antibodies, Anticardiolipin / Q000097:blood; D001161:Arteriosclerosis / Q000097:blood / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D015415:Biomarkers; D002097:C-Reactive Protein / Q000378:metabolism; D019040:E-Selectin / Q000097:blood; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007107:Immune System / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008077:Lipoproteins, LDL / Q000276:immunology; D008297:Male; D008315:Malondialdehyde / Q000276:immunology; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D015375:Receptors, Interleukin-2 / Q000097:blood; D013927:Thrombosis / Q000097:blood / Q000276:immunology*; D014841:von Willebrand Factor / Q000378:metabolism
D017153:Antibodies, Anticardiolipin; D015415:Biomarkers; D019040:E-Selectin; D005338:Fibrin Fibrinogen Degradation Products; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D017395:Plasminogen Activator Inhibitor 1; D015375:Receptors, Interleukin-2; C036309:fibrin fragment D; C099252:oxidized low density lipoprotein; D014841:von Willebrand Factor; D006710:Homocysteine; D018799:Intercellular Adhesion Molecule-1; D008315:Malondialdehyde; D002097:C-Reactive Protein