Disease response in rheumatoid arthritis across four biologic therapies associates with improvement in paraoxonase-1 activity and oxylipins.

OBJECTIVE

Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, that has been implicated as a biomarker of cardiovascular risk in patients with rheumatoid arthritis (RA). We aimed to investigate how different biologic therapies affect levels of PON1 and oxylipins.

METHODS

1213 adult patients with RA in the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions cohort study with moderate-to-high disease activity (Clinical Disease Activity Index (CDAI) >10) who initiated a new biologic (tocilizumab (TCZ), n=296; abatacept, n=374; tumour necrosis factor inhibitors, n=427; rituximab, n=116) were followed prospectively with serum specimens analysed for PON1 activity by arylesterase (ARYL), lactonase (LAC) and PON assays at baseline and after 6 months of biologic therapy. A targeted panel of oxylipins was evaluated by liquid chromatography-mass spectrometry/mass spectrometry in a subset of patients with the lowest and highest 6-month Disease Activity Score 28 (DAS28)-C reactive protein (CRP) responses in each treatment group.

RESULTS

PON1 activity generally increased in the entire cohort after 6 months of new biologic therapy, showing the greatest, most consistent increases in the TCZ group. Increases in all three PON1 domains associated with significant decreases in disease activity in DAS28-CRP/CDAI (p<0.05), and increases in LAC/ARYL were significantly associated with the American College of Rheumatology 20/50/70 responses (OR (95% CI) of 1.12 (1.04, 1.22) and 1.13 (1.04, 1.23), p<0.01, respectively), after controlling for other RA disease characteristics. Some oxylipins, including 12-hydroxyeicosatetraenoic acid correlated with RA disease activity measures.

CONCLUSION

Improvement in disease activity across four classes of biologics is associated with enhanced PON1 activity, which has significant implications for cardiovascular safety.