UCLA

Background/Purpose: Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, which has been implicated as a biomarker of cardiovascular (CV) risk in patients with rheumatoid arthritis (RA).

Methods: 1213 adult RA patients in the CERTAIN registry with moderate or high disease activity (CDAI >10) who initiated a biologic agent that had not been previously used for their treatment (tocilizumab (TCZ), n=296; abatacept (ABA), n= 374; TNFα inhibitors (TNFi) n= 427; rituximab (RTX), n=116) had serum specimens analyzed for PON1 activity by arylesterase (ARYL), lactonase (LAC) and paraoxonase (PON) assays at baseline and after 6 months of new biologic therapy. A targeted panel of oxylipins was evaluated in a subset of patients with the lowest and highest 6-month DAS28 responses in each treatment group.

Results: PON1 activity increased in the entire cohort after 6 months of new biologic therapy, showing the greatest, most consistent increases in the TCZ group. Increases in the LAC and ARYL activities of PON1 after 6 months of therapy associated with treatment response to new biologic therapies measured by DAS28, CDAI, and ACR 20, 50, or 70 responses (OR (CI 95%) of 3.33 (1.52, 7.27), and 3.37 (1.45, 7.83), p<0.005 for ACR responses (LAC/ARYL) respectively), after controlling for other RA disease characteristics. DAS28-CRP high responders had significantly greater decreases in 12-HETE (p=0.0005) than low responders.

Conclusion: Improvement in disease activity across 4 classes of biologic therapies with different mechanisms of action associates with improvement in the activity of PON1, a protein associated with reduction in systemic oxidative stress and CV risk.