title: The peroxisome proliferator activated receptor-γ pioglitazone improves vascular function and decreases disease activity in patients with rheumatoid arthritis.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is associated with heightened mortality due to atherosclerotic cardiovascular disease (CVD). Inflammatory pathways in RA negatively affect vascular physiology and promote metabolic disturbances that contribute to CVD. We hypothesized that the peroxisome proliferator activated receptor-γ (PPAR-γ) pioglitazone could promote potent vasculoprotective and anti-inflammatory effects in RA.
  
  
  RESULTS
  One hundred forty-three non-diabetic adult RA patients (76.2% female, age 55.2 ± 12.1 [mean ± SD]) on stable RA standard of care treatment were enrolled in a randomized, double-blind placebo controlled crossover trial of 45 mg daily pioglitazone versus placebo, with a 3-month duration/arm and a 2-month washout period. Pulse wave velocity of the aorta (PWV), brachial artery flow mediated dilatation (FMD), nitroglycerin mediated dilatation (NMD), microvascular endothelial function (reactive hyperemia index [RHI]), and circulating biomarkers of inflammation, insulin resistance, and atherosclerosis risk all were quantified. RA disease activity was assessed with the 28-Joint Count Disease Activity Score (DAS-28) C-reactive protein (CRP) and the Short Form (36) Health Survey quality of life questionnaire. When added to standard of care RA treatment, pioglitazone significantly decreased pulse wave velocity (ie, aortic stiffness) (P=0.01), while FMD and RHI remained unchanged when compared to treatment with placebo. Further, pioglitazone significantly reduced RA disease activity (P=0.02) and CRP levels (P=0.001), while improving lipid profiles. The drug was well tolerated.
  
  
  CONCLUSIONS
  Addition of pioglitazone to RA standard of care significantly improves aortic elasticity and decreases inflammation and disease activity with minimal safety issues. The clinical implications of these findings remain to be established.
  
  
  BACKGROUND
  ClinicalTrials.gov Unique Identifier: NCT00554853.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Wendy
authors.initials: W
authors.lastname: Marder
authors.forename: Shokoufeh
authors.initials: S
authors.lastname: Khalatbari
authors.forename: James D
authors.initials: JD
authors.lastname: Myles
authors.forename: Rita
authors.initials: R
authors.lastname: Hench
authors.forename: Susan
authors.initials: S
authors.lastname: Lustig
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Yalavarthi
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Parameswaran
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brook
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002097:C-Reactive Protein / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004548:Elasticity; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D008824:Michigan; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D063177:Pulse Wave Analysis; D011788:Quality of Life; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D059289:Vascular Stiffness / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D015415:Biomarkers; D008055:Lipids; D047495:PPAR gamma; D045162:Thiazolidinediones; D002097:C-Reactive Protein; D000077205:Pioglitazone
keywords: drugs; inflammation; rheumatoid arthritis; vasodilation