The peroxisome proliferator activated receptor-γ pioglitazone improves vascular function and decreases disease activity in patients with rheumatoid arthritis

Wendy Marder, Shokoufeh Khalatbari, James D Myles, Rita Hench, Susan Lustig, Srilakshmi Yalavarthi, Aishwarya Parameswaran, Robert D Brook, Mariana J Kaplan, Wendy Marder, Shokoufeh Khalatbari, James D Myles, Rita Hench, Susan Lustig, Srilakshmi Yalavarthi, Aishwarya Parameswaran, Robert D Brook, Mariana J Kaplan

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.

Methods and 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.

Clinical trial registration url: ClinicalTrials.gov Unique Identifier: NCT00554853.

Keywords: drugs; inflammation; rheumatoid arthritis; vasodilation.

Figures

Figure 1.
Figure 1.
Study population recruitment summary.
Figure 2.
Figure 2.
Change in various CV measures and inflammatory markers during study. Mean change is plotted over time between groups. The dash line represents the mean change for individuals who started the treatment with pioglitazone; the solid line represents the mean change of individuals who started the treatment with placebo. CRP indicates C‐reactive protein; CV, cardiovascular; DAS28, 28‐Joint Disease Activity Scale; HDL, high‐density lipoprotein; HOMA IR, homeostasis model of assessment‐insulin resistance; NMD, nitroglycerin mediated dilatation; Pl/Tx, placebo/treatment group; PWV, pulse wave velocity.

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