Relationship Between Paraoxonase-1 Genotype and Activity, and Major Adverse Cardiovascular Events and Malignancies in Patients With Rheumatoid Arthritis Receiving Tofacitinib

医学 对氧磷酶 电源1 内科学 狼牙棒 芳基酯酶 类风湿性关节炎 苯乙酸 托法替尼 肿瘤科 不利影响 胃肠病学 基因型 心肌梗塞 生物 氧化应激 遗传学 基因 生物化学 传统PCI
作者
Christina Charles‐Schoeman,Craig Hyde,Shunjie Guan,Neil Parikh,Jennifer Wang,Ani Shahbazian,Lori Stockert,John S. Andrews
出处
期刊:The Journal of Rheumatology [The Journal of Rheumatology Publishing Company Limited]
卷期号:50 (12): 1573-1580 被引量:3
标识
DOI:10.3899/jrheum.2023-0112
摘要

This posthoc analysis investigated the relationship between paraoxonase-1 (PON1) genotype and activity, and risk of major adverse cardiovascular events (MACE) and malignancies in clinical studies of tofacitinib in patients with rheumatoid arthritis (RA).Data were pooled from 9 phase II/III studies and the associated long-term extension studies (all completed by October 2017). PON1 activities in plasma were measured using paraoxon (paraoxonase activity), dihydrocoumarin (lactonase activity), and phenylacetate (arylesterase activity) as substrates. PON1 Q192R genotype effect on baseline PON1 activity was assessed using linear regression for each study, with fixed-effects metaanalysis across studies. MACE and malignancy risk by time-varying enzyme activity was determined using Cox proportional hazards regression.The analysis included 1969 patients with RA. Compared with the QQ genotype, the RR genotype had a significant positive association with baseline paraoxonase activity and a significant negative association with baseline lactonase and arylesterase activity (all P < 0.001). Time-varying models demonstrated a significant association of increased paraoxonase activity over time with lower risk of MACE (P < 0.001) and malignancies (excluding nonmelanoma skin cancer [NMSC]; P ≤ 0.05), even after controlling for risk factors identified in univariate analysis and RA disease activity. A similar trend was observed for lactonase and arylesterase for MACE.Higher paraoxonase activity over time was associated with significantly reduced risk of future MACE and malignancies (excluding NMSC), but not NMSC, in patients with RA receiving tofacitinib. Further investigation of PON1 as a novel functional lipid biomarker of MACE/malignancy risk in patients with RA is warranted. (ClinicalTrials.gov: NCT01059864, NCT00550446, NCT00687193, NCT00960440, NCT00814307, NCT00856544, NCT00853385, NCT00847613, NCT01039688, NCT00413699, NCT00661661).
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