收稿日期: 2023-09-25
网络出版日期: 2024-03-18
基金资助
国家自然科学基金面上项目(81974251);国家自然科学基金青年项目(82201976);上海交通大学“交大之星”计划医工交叉研究基金重点项目-精准医学研究(YG2023ZD09)
Clinical research on progress of antinuclear antibody in rheumatoid arthritis
Received date: 2023-09-25
Online published: 2024-03-18
类风湿关节炎(rheumatoid arthritis, RA)是一种常见的以侵蚀性关节炎为主要特征的慢性、全身性自身免疫性疾病。全球RA患病率为0.25%~1.00%,其最终可能导致关节畸形和功能丧失。抗核抗体(antinuclear antibody, ANA)指以真核细胞各种成分为靶抗原的自身抗体的总称,在RA患者中的检出率为30%~60%,但在RA诊疗中的应用价值目前尚不明确。RA患者中ANA以低滴度为主,荧光核型以核颗粒型与均质型常见,ANA各种针对靶抗原抗体的检出率通常低于ANA。ANA阳性RA患者类风湿因子、抗环瓜氨酸肽抗体血清水平更高,影像学所见关节侵蚀更显著,因此ANA有望成为预测严重关节损伤的指标。ANA阳性RA患者更易出现关节外表现[如皮下结节(82%比46%)、眼部损害(38%比6%)和感染(38%比12%)],且更常伴随血管炎、继发干燥综合征,故需关注ANA高滴度患者。在RA合并症方面,相对于ANA阴性组,ANA阳性组中重度贫血(16.04%比6.9%、6.6%比0.07%)、干燥综合征(19.5%比4.1%)、血管炎(29%比7%)高。此外,ANA阳性是老年RA合并颈动脉内膜增厚(HR=4.089)的危险因素,也是女性RA不良妊娠结局(OR=3.268, P=0.045)的独立危险因素。在治疗方面,基线ANA阳性的RA患者对肿瘤坏死因子抑制剂(tumor necrosis factor-α inhibitor, TNFi)治疗反应较差,且基线ANA阳性尤其是高滴度患者更易产生抗药物抗体。药物诱导ANA滴度升高与TNFi继发无应答相关,监测ANA变化有望预测TNFi长期疗效。药物性狼疮是TNFi最常见的不良反应,已证实TNFi诱导抗双链DNA抗体与疗效不佳相关,但仍欠缺大样本研究证实ANA滴度升高或抗双链DNA抗体的产生与药物性狼疮的诱导存在相关性。本文综述RA群体ANA特征、ANA阳性RA临床表现、ANA与TNFi预后关联等方面的研究进展,为ANA作为RA新的生物标志物研究提供参考。
郦源, 张乐, 殷翰林, 郑冰, 吕良敬 . 抗核抗体在类风湿关节炎中的临床研究进展[J]. 诊断学理论与实践, 2023 , 22(06) : 579 -586 . DOI: 10.16150/j.1671-2870.2023.06.011
Rheumatoid arthritis (RA) is a common chronic, systemic autoimmune disease characterized by erosive arthritis, with a global prevalence of 0.25% to 1.00%, which may ultimately lead to joint deformity and loss of function. Antinuclear antibody (ANA) refers to auto-antibodies that target various components of eukaryotic cells. Although ANA may be frequently detected in RA patients, with a positive rate of 30% to 60%, the significance of ANA in the diagnosis and treatment of RA remains unclear. Nuclear patterns in RA population are dominated by speckled and homogeneous patterns, mainly at low titres. The detection rate of extractable nuclear antibodies is usually lower than that of ANA. The serum levels of rheumatoid factor and anti-cyclic citrullinated peptide antibody in ANA-positive RA patients are much higher than ANA-negative ones, and joint erosion of ANA-positive RA patients had more severe joint erosion on imaging as well. Therefore, ANA is a potential predictor of severe joint injury. ANA-positive RA patients are more likely to have extra-articular manifestations [such as subcutaneous nodules(82% vs 46%), ocular lesions(38% vs 6%), and infections(38% vs 12%)].In terms of RA comorbidities, compared to the ANA negative group, the ANA positive group had higher levels of moderate and severe anemia (16.04% vs 6.9%; 6.6% vs 0.07%), Sjogren's syndrome (19.5% vs 4.1%), and vasculitis (29% vs 7%). In addition, ANA positivity is an independent risk factor for elderly RA patients with carotid intimal thickening (HR=4.089) and adverse pregnancy outcomes in female RA (OR=3.268, P=0.045), respectively. Attention should be paid to high-titre ANA-positive RA patients for preventive measures. In terms of treatment, RA patients who are ANA-positive when given tumour necrosis factor-α inhibitor (TNFi) treatment got much poorer therapeutic response than ANA-negative ones, especially those with high titres were more prone to generating anti-drug antibodies. Increase of ANA titer induced by TNFi is associated with no response to TNFi treatment, thus monitoring the change of ANA may predict the long-term efficacy of TNFi. The most common adverse event of TNFi is drug-induced lupus. Although it has been confirmed that the induction of anti-double-stranded DNA antibodies is associated with poor efficacy of TNFi, large-scale studies are still needed to confirm the correlation between the increase of ANA titer or ocurence of dsDNA antibody and the induction of drug-induced lupus. In conclusion, this paper reviews the research progress on ANA characteristics in RA population, clinical manifestations of ANA-positive RA, and the association between ANA and TNFi prognosis. The potential of ANA as a new biomarker of RA needs to be further studied.
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