Peroxisome proliferator-activated receptor γ agonist effect on rheumatoid arthritis: a randomized controlled trial

Michelle J Ormseth, Annette M Oeser, Andrew Cunningham, Aihua Bian, Ayumi Shintani, Joseph Solus, S Tanner, C Michael Stein, Michelle J Ormseth, Annette M Oeser, Andrew Cunningham, Aihua Bian, Ayumi Shintani, Joseph Solus, S Tanner, C Michael Stein

Abstract

Introduction: Rheumatoid arthritis (RA), a chronic inflammatory disease, is associated with insulin resistance. Experimental evidence indicates that the relationship between insulin resistance and inflammation is bidirectional: Inflammation promotes insulin resistance, and insulin resistance promotes inflammation. Therefore, we examined the hypothesis that pioglitazone, a thiazolidinedione peroxisome proliferator-activated receptor γ agonist, would decrease inflammation and disease activity and improve insulin resistance in patients with RA.

Methods: In a single-center, randomized, double-blind, placebo-controlled crossover study patients with RA (N = 34) receiving stable therapy were randomized to also receive either pioglitazone 45 mg daily (n = 17) or matching placebo (n = 17) for eight weeks. This was followed by a four-week washout period and alternative treatment for eight weeks. Outcomes included change in Disease Activity Score in 28 joints (DAS28) score, individual components of the DAS28 score and homeostatic model assessment for insulin resistance (HOMA). Intention-to-treat analysis and linear mixed-effects models were used.

Results: Patients had a mean (± SD) age of 51 (± 14.2) years, 82.4% were female and baseline DAS28 high-sensitivity C-reactive protein (DAS28-CRP) was 4.58 (± 1.1) units. Addition of pioglitazone was associated with a 9.3% reduction (95% confidence interval (CI) = 0.17% to 17.6%) in DAS28-CRP (P = 0.046), but no significant change in DAS28 erythrocyte sedimentation rate (DAS28-ESR) (P = 0.92). There was a 10.7 mm (95% CI = 0.4 to 20.9 mm) improvement in patient-reported global health (P = 0.042), a 48.6% decrease (95% CI = 27.6% to 63.5%) in CRP (P < 0.001) and a 26.4% decrease (95% CI = 3.7% to 43.8%) in insulin resistance as measured by HOMA (P = 0.025), but no significant reduction in swollen or tender joint count or in ESR (all P > 0.05). Lower-extremity edema was more common during pioglitazone treatment (16%) than placebo (0%).

Conclusion: Addition of pioglitazone to RA therapy improves insulin resistance and modestly reduces RA disease activity measured by DAS28-CRP and two of its components, including patient-reported global health and CRP, but not DAS28-ESR or ESR.

Trial registration: NCT00763139.

Figures

Figure 1
Figure 1
Randomized, placebo-controlled, crossover trial design. Patients were screened for eligibility. Those meeting entry criteria were randomized to one of two treatment sequences: pioglitazone then placebo or placebo then pioglitazone. Patients were assessed every four weeks. Treatment phases were separated by a four-week washout period.
Figure 2
Figure 2
Randomization and follow-up of study participants. A total of 34 patients with rheumatoid arthritis (RA) were enrolled in the study. There was at least one follow-up visit for all patients. A total of 31 patients were exposed to pioglitazone, and 32 were exposed to placebo. LFT, liver function test.
Figure 3
Figure 3
Rheumatoid arthritis disease activity measured by Disease Activity Score in 28 joints score is decreased by pioglitazone. The graph on the left shows the change in Disease Activity Score in 28 joints high-sensitivity C-reactive protein (DAS28 CRP) scores among patients randomized to receive pioglitazone first, then placebo. The graph on the right shows change in DAS28-CRP scores among patients randomized to receive placebo first, then pioglitazone. Red designates patients taking pioglitazone, and black represents those taking placebo. Open circles represent mean change, and bars represent 95% confidence intervals.

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