Background/Purpose: Rheumatoid arthritis (RA), a chronic inflammatory disease, is associated with insulin resistance.  Experimental evidence indicates that the relationship between insulin resistance and inflammation is bi-directional: inflammation promotes insulin resistance, and insulin resistance promotes inflammation. Therefore, we examined the hypothesis that improving insulin sensitivity with pioglitazone, a thiazolidinedione PPAR-γ agonist, would decrease inflammation in patients with RA.

Methods: In a single center, randomized, double blind, placebo-controlled cross-over trial of 20 weeks duration, patients with RA (n=34) and moderate disease activity receiving stable disease modifying anti-rheumatic drug therapy were randomized to receive either pioglitazone 45mg daily (n=17) or matching  placebo (n=17) for 8 weeks in addition to current therapy. This was followed by a 4 week wash-out period and then patients received the alternative regimen for the next 8 weeks.  Primary outcome measures were change in DAS28 score; individual components of the DAS28 score including tender and swollen joint count, patient reported disease activity based on visual analog scale (VAS), and acute phase reactants; and change in insulin resistance determined by the homeostatic model assessment for insulin resistance (HOMA). Disease activity variables, inflammatory markers, and fasting insulin and glucose were measured. Analysis was by intention to treat and linear mixed effect models were used to determine the effect of pioglitazone on outcome measures.

Results: Patients had a median [IQR] age of 52.5 years [44.2-59.5 years], 82% were female and baseline median DAS28 CRP was 4.24 [3.62-5.6]. Compared to placebo, the addition of pioglitazone was associated with a 0.368 unit (95% CI, 0.0002-0.735) reduction in DAS28 CRP, (P=0.036), a 48.7% (28.5-63.1%) decrease in CRP (P<0.001), and a 23.7% (1.1-41.1%) decrease in insulin resistance as measured by HOMA (P=0.04). There was no significant reduction in swollen (P=0.83) or tender joint count (P=0.43), and a non-significant trend toward decreased patient reported disease activity VAS by 9.8mm (-0.1-19.7mm) (P=0.05). There was no significant change in ESR (p=0.27) or DAS28 ESR (P=0.92). Lower extremity edema was more common during pioglitazone (16%) treatment than placebo (0%); otherwise, adverse events occurred with similar frequency.

Conclusion: The addition of pioglitazone to current RA treatment improves insulin resistance and modestly reduces RA disease activity measured by DAS28 CRP and CRP levels.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/peroxisome-proliferator-activated-receptor-gamma-agonist-treatment-for-rheumatoid-arthritis-a-proof-of-concept-randomized-controlled-trial/