Lowering RA Disease Activity With Biologics Enhances Protective Cardiovascular PON1 Activity

Amir A. Razmjou, MD, MS

Credit: UCLA

A new study assessing disease activity across 4 biologics for rheumatoid arthritis (RA) found associations with improved disease activity and enhanced PON1 activity, indicating a lowered risk of cardiovascular (CV) events.¹

“Lower PON1 activity is associated with increased risk of CV events in the general population, and it predicts risk of CV and malignancy events after controlling for traditional risk factors in patients with RA treated with the Janus kinase (JAK) inhibitor tofacitinib.2 PON1 activity is suppressed by active disease, and growing data also suggest that moderate-to-high RA disease activity is associated with increased CV risk in RA, while low disease activity or remission is associated with decreased CV risk,” lead investigator Amir A. Razmjou, MD, MS, clinical instructor of medicine, rheumatology, University of California Los Angeles Health, and colleagues wrote.¹

Razmjou and colleagues analyzed data from 1213 adult participants with moderate-to-high disease activity RA in the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions cohort study. Participants had initiated either tocilizumab (TCZ; n = 296), abatacept (n = 374), tumor necrosis factor inhibitors (n = 427), or rituximab (n = 116) and were followed prospectively with serum specimens analyzed for PON1 activity by arylesterase (ARYL), lactonase (LAC) and PON assays at baseline and after 6 months of biologic therapy. The investigators also conducted liquid chromatography-mass spectrometry/mass spectrometry on a targeted panel of oxylipins 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.

The investigators found that PON1 activity generally increased across the biologic arms after 6 months of therapy, with the TCZ group experiencing the greatest and most consistent increases. Increases in all 3 PON1 domains were associated with significant improvements in DAS28-CRP/CDAI scores (P <.05), and increases in LAC (odds ratio [OR], 1.12 [95% CI, 1.04-1.22) and ARYL (OR, 1.13 [95% CI, 1.04-1.23]; both P <.01) were significantly associated with the American College of Rheumatology 20/50/70 responses after multivariable adjustment for disease characteristics.¹

Comparing oxylipins in in patients with the lowest and highest 6-month (DAS28)-CRP responses, Razmjou and colleagues found that those with the highest scores had significantly greater decreases in 12-hydroxyeicosatetraenoic (12-HETE) than low responders (P = .0005). By biologic treatment, there were also significant decreases of oxylipins in high responders to TNFi (5-oxo-HETE), RTX (TXB2, 12-HETE) and TCZ (14S-HDHA (14S-HDoHE)) (all P <.05).¹

“Improvement in disease activity across four classes of biologic therapies with different mechanisms of action is associated with an increase in the activity of PON1, a protein linked to CV risk reduction. Increases in PON1 activity were most pronounced in the TCZ group, which also exhibited the greatest increases in TC, LDL cholesterol and HDL-C levels. Across treatment groups, improvement in PON1 activity was associated with greater odds of treatment response. These findings suggest a potential mechanism by which improvement in RA disease activity across multiple therapies reduces CV risk through enhanced PON1 activity,” Razmjou and colleagues concluded.¹

REFERENCES
1. Razmjou AA, Kremer JM, Pappas DA, et al. Disease response in rheumatoid arthritis across four biologic therapies associates with improvement in paraoxonase-1 activity and oxylipins. RMD Open 2024;10:e004829. doi: 10.1136/rmdopen-2024-004829

2. Charles-Schoeman C , Buch MH, DougadosM , et al . Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis 2023;82:119–29. doi:10.1136/ard-2022-222259