Rheumatoid arthritis patients with higher levels of paraoxonase have lower incidence of MACE and cancer

Paraoxidase-1 (PON1) is a major enzyme associated with high-density lipoprotein cholesterol (HDL-c). This enzyme is atheroprotective and has implications in innate immunity, bacterial quorum sensing, and cancer development. According to a study published in the Journal of Rheumatology, researchers have demonstrated that patients receiving tofacitinib for rheumatoid arthritis (RA) with higher paraoxonase activity over time demonstrate a lower risk of major adverse cardiovascular events and malignancy (MACE).

To investigate the connection between PON1 and the risks of MACE and malignancy in RA patients receiving tofacitinib, Charles-Schoeman and his colleagues conducted a post-hoc analysis of 11 clinical studies. This analysis included 1,969 patients who received tofacitinib and had a measurement of PON1 activity available. The results showed that higher paraoxonase activity over time was significantly associated with a reduced risk of MACE and malignancies, with the exception of non-melanoma skin cancer, in tofacitinib-treated patients with moderate to severe RA.

In 2019, Charles-Schoeman et al. conducted similar studies and reported that after 24 weeks of tofacitinib treatment, an increase in HDL cholesterol was associated with a lower risk of future MACE. However, there were no significant increases observed in LDL cholesterol or total cholesterol.

In a post hoc analysis, Fleischmann et al. discovered that patients with moderate to severe RA, treated with tofacitinib, and exhibiting higher paraoxonase activity, had a significantly reduced risk of MACE and malignancies (excluding NMSC). However, a higher risk of MACE and venous thromboembolism (VTE) was observed in high-risk populations with RA.

Higher paraoxonase activity over time has been found to be linked to areduced risk of future MACE and malignancies, excluding NMSC, in patients with RA who received tofacitinib. However, no significant association was found between PON1 activity and NMSC risk. Given the importance of biomarkers in medical research, a comprehensive investigation into PON1’s potential in this context is imperative.


  1. Charles-Schoeman C, Hyde C, Guan S, Parikh N, Wang J, Shahbazian A, et al. Relationship Between Paraoxonase-1 Genotype and Activity, and Major Adverse Cardiovascular Events and Malignancies in Patients With Rheumatoid Arthritis Receiving Tofacitinib. The Journal of Rheumatology [Internet]. 2023 Jul 15 [cited 2023 Oct 17].
  2. Charles-Schoeman C, DeMasi R, Valdez H, Soma K, Hwang LJ, Boy MG, et al. Risk Factors for Major Adverse Cardiovascular Events in Phase III and Long-Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2019 Sep;71(9):1450–9.
  3. Fleischmann R, Curtis JR, Charles-Schoeman C, Mysler E, Yamaoka K, Richez C, et al. Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme. Annals of Rheumatic Diseases. 2023 Sep 1;82(9):1130–41.