Objective Excessive cholesterol accumulation in macrophages is the pivotal step underlying atherosclerotic plaque formation. We here explore factors in the serum of patients with rheumatoid arthritis (RA) and mechanisms through which they interact and influence cholesterol loading capacity (CLC) on macrophages. Methods In a cross-sectional observational cohort of 104 patients with RA, CLC was measured as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. LDL oxidation was measured as oxidized phospholipids on apoB100-containing particles (oxPL-apoB100). Antibodies against oxidized LDL (anti-oxLDL), proprotein convertase subtilisin/Kexin type-9 (PCSK9) and high-sensitivity CRP were also quantified. All analyses adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, obesity, total LDL, statin use, age at diagnosis, and anti-oxLDL IgM. Results OxPL-apoB100, anti-oxLDL IgG and PCSK9 positively associated with CLC (all p< 0.020). OxPL-apoB100 directly influenced CLC only in dual rheumatoid factor and anti-citrullinated protein antibody positive patients (unstandardized b [95% bootstrap confidence interval]=2.08 [0.38–3.79]). An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG increased along with level of CRP (index of moderated mediation = 0.55 [0.05–1.17]). CRP also moderated yet another indirect effect of oxPL-apoB100 on CLC through upregulation of PCSK9, but only among dual seropositive patients (conditional indirect effect = 0.64 [0.13–1.30]). Conclusion Oxidized LDL can directly influence CLC in dual seropositive RA patients. Two additional and independent pathways—via anti-oxLDL IgG and PCSK9—may mediate the effects of oxPL-apoB100 on CLC depending on CRP and seropositivity status. If externally validated, these findings may have clinical implications for cardiovascular risk prevention.

中文翻译：

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类风湿性关节炎患者血清胆固醇对巨噬细胞的负荷能力受血清阳性和 C 反应蛋白的调节

目的 巨噬细胞中过多的胆固醇积累是动脉粥样硬化斑块形成的关键步骤。我们在此探索类风湿性关节炎 (RA) 患者血清中的因素，以及它们相互作用和影响巨噬细胞胆固醇负荷能力 (CLC) 的机制。方法 在 104 名 RA 患者的横断面观察队列中，CLC 被测量为与患者血清孵育后人 THP-1 衍生的巨噬细胞中的细胞内胆固醇含量。LDL 氧化被测量为含 apoB100 的颗粒 (oxPL-apoB100) 上的氧化磷脂。还对氧化低密度脂蛋白抗体（抗 oxLDL）、前蛋白转化酶枯草杆菌蛋白酶/Kexin 9 型 (PCSK9) 和高敏 CRP 抗体进行了定量。所有分析均针对动脉粥样硬化性心血管疾病 (ASCVD) 风险评分、肥胖、总 LDL、他汀类药物的使用、诊断时的年龄和抗 oxLDL IgM。结果 OxPL-apoB100、抗 oxLDL IgG 和 PCSK9 与 CLC 呈正相关（所有 p < 0.020）。OxPL-apoB100 仅在双类风湿因子和抗瓜氨酸蛋白抗体阳性患者中直接影响 CLC（非标准化 b [95% bootstrap 置信区间]=2.08 [0.38–3.79]）。oxPL-apoB100 通过抗 oxLDL IgG 对 CLC 的间接影响随着 CRP 水平的增加而增加（调节指数 = 0.55 [0.05–1.17]）。CRP 还通过上调 PCSK9 来缓和 oxPL-apoB100 对 CLC 的另一种间接影响，但仅限于双血清阳性患者（条件间接影响 = 0.64 [0.13–1.30]）。结论 氧化型LDL可直接影响双血清阳性RA患者的CLC。两个额外的独立途径——通过抗 oxLDL IgG 和 PCSK9——可能根据 CRP 和血清阳性状态介导 oxPL-apoB100 对 CLC 的影响。如果经过外部验证，这些发现可能对心血管风险预防具有临床意义。