Endothelial dysfunction and atherosclerosis in rheumatoid arthritis: a multiparametric analysis using imaging techniques and laboratory markers of inflammation and autoimmunity.
OBJECTIVE
Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. We assessed endothelial dysfunction 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 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-gamma (IFN-gamma) 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-gamma 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-alpha(TNF-alpha) and IL-6 levels.


CONCLUSIONS
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-alpha, 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.
Kerekes
György
G
Cardiovascular Unit, Division of Rheumatology, and Laboratory of Immunology, Third Department of Medicine, Hungary.
Szekanecz
Zoltán
Z
Dér
Henriett
H
Sándor
Zsuzsa
Z
Lakos
Gabriella
G
Muszbek
László
L
Csipö
István
I
Sipka
Sándor
S
Seres
Ildikó
I
Paragh
György
G
Kappelmayer
János
J
Szomják
Edit
E
Veres
Katalin
K
Szegedi
Gyula
G
Shoenfeld
Yehuda
Y
Soltész
Pál
P
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000503:physiopathology*; D050197:Atherosclerosis / Q000150:complications* / Q000175:diagnosis* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D017536:Carotid Artery, Common / Q000473:pathology; D016022:Case-Control Studies; D004727:Endothelium / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017539:Tunica Intima / Q000473:pathology; D014664:Vasodilation / Q000187:drug effects / Q000276:immunology* / Q000502:physiology
D015415:Biomarkers