title: Advanced glycation endproducts are increased in rheumatoid arthritis patients with controlled disease.
abstract: BACKGROUND
  Advanced glycation end products (AGEs) are produced and can accumulate during chronic inflammation, as might be present in patients with rheumatoid arthritis (RA). AGEs are involved in the development of cardiovascular disease. The aim of this study is to evaluate whether AGEs are increased in patients with long-standing RA and whether AGE accumulation is related to disease activity, disease severity and measures of (premature) atherosclerosis, such as endothelial activation, endothelial dysfunction and intima media thickness (IMT).
  
  
  METHODS
  In a cross-sectional study, 49 consecutive RA patients with longstanding disease (median disease duration of 12.3 years (range 9.3 to 15.1)), receiving standard of care, were included and compared with 49 age- and sex-matched healthy controls (HC). AGEs were determined by skin autofluorescence. Disease activity was evaluated by the Disease Activity Score of 28 joints (DAS-28) score and joint damage by modified Sharp-v.d. Heijde score. Endothelial activation (soluble vascular cellular adhesion molecule-1) sVCAM-1, von Willebrand factor (vWF), thrombomodulin), endothelial dysfunction (determined by small artery elasticity (SAE)) and IMT were measured and related to AGE accumulation.
  
  
  RESULTS
  AGEs were increased in RA patients (median 2.4 arbitrary units (a.u.), range 1.6 to 4.2) compared to HC (2.2, 1.3 to 3.8). RA patients had a DAS-28 score of 2.9 (0.8 to 6.9) and a modified Sharp-v.d. Heijde score of 19 (0 to 103). sVCAM-1 and vWF levels were higher in RA patients. SAE was significantly decreased in RA (3.9 ml/mmHg (1.4 to 12.2) vs. 6.1 in HC (1.7 to 12.9). IMT did not differ between the two groups. Combining both groups' AGEs correlated with vWF, sVCAM-1 and IMT, and was inversely related to SAE. In RA, AGEs had an inverse relation with SAE, but did not relate to disease activity or radiological damage. In multivariate analysis for both groups, smoking, glucose levels, vWF, SAE and male gender were significantly related to the formation of AGEs.
  
  
  CONCLUSIONS
  AGEs were increased in RA patients with long-standing disease and without signs of premature atherosclerosis. AGEs were related to endothelial activation and endothelial dysfunction. This supports the hypothesis that in RA AGEs may be an early marker of cardiovascular disease.
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Centre, University of Groningen, Groningen, The Netherlands. lodewijk.de.groot@reuma.umcg.nl
authors.forename: Lodewijk
authors.initials: L
authors.lastname: de Groot
authors.forename: Helmy
authors.initials: H
authors.lastname: Hinkema
authors.forename: Johanna
authors.initials: J
authors.lastname: Westra
authors.forename: Andries J
authors.initials: AJ
authors.lastname: Smit
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.forename: Marc
authors.initials: M
authors.lastname: Bijl
authors.forename: Marcel D
authors.initials: MD
authors.lastname: Posthumus
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007596:Joints / Q000378:metabolism / Q000473:pathology; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012307:Risk Factors; D012720:Severity of Illness Index; D012737:Sex Factors; D011795:Surveys and Questionnaires; D018180:Thrombomodulin / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017127:Glycation End Products, Advanced; D018180:Thrombomodulin; D019010:Vascular Cell Adhesion Molecule-1; D014841:von Willebrand Factor; D002097:C-Reactive Protein