Ciregia Federica, Nys Gwenaël, Cobraiville Gaël, Badot Valérie, Di Romana Silvana, Sidiras Paschalis, Sokolova Tatiana, Durez Patrick, Fillet Marianne, Malaise Michel G, de Seny Dominique
Laboratory of Rheumatology, University of Liège, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.
Laboratory for the Analysis of Medicines, Centre Interdisciplinaire De Recherche Sur Le Médicament (CIRM), Department of Pharmacy, University of Liège, Liège, Belgium.
Front Immunol. 2021 Aug 20;12:638814. doi: 10.3389/fimmu.2021.638814. eCollection 2021.
Nowadays, in the study of rheumatoid arthritis (RA), more and more interest is directed towards an earlier effective therapeutic intervention and the determination of companion markers for predicting response to therapy with the goal to prevent progressive joint damage, deformities, and functional disability. With the present work, we aimed at quantifying in a cohort of early RA (ERA) patients naïve to DMARD therapy, proteins whose increase was previously found associated with RA: serum amyloid A (A-SAA) and alarmins. Five A-SAA variants (SAA1α, SAA1β, SAA1γ, SAA2α, and SAA2β) but also S100A8 and S100A9 proteins were simultaneously quantified in plasma applying a method based on single targeted bottom-up proteomics LC-MS/MS. First, we compared their expression between ERA (n = 100) and healthy subjects (n = 100), then we focused on their trend by monitoring ERA patients naïve to DMARD treatment, 1 year after starting therapy. Only SAA1α and SAA2α levels were increased in ERA patients, and SAA2α appears to mostly mediate the pathological role of A-SAA. Levels of these variants, together with SAA1β, only decreased under biologic DMARD treatment but not under methotrexate monotherapy. This study highlights the importance to better understand the modulation of expression of these variants in ERA in order to subsequently better characterize their biological function. On the other hand, alarmin expression increased in ERA compared to controls but remained elevated after 12 months of methotrexate or biologic treatment. The work overcomes the concept of considering these proteins as biomarkers for diagnosis, demonstrating that SAA1α, SAA1β, and SAA2α variants but also S100A8 and S100A9 do not respond to all early treatment in ERA and should be rather considered as companion markers useful to improve the follow-up of treatment response and remission state. Moreover, it suggests that earlier use of biologics in addition to methotrexate may be worth considering.
如今，在类风湿性关节炎（RA）的研究中，越来越多的兴趣点集中在更早进行有效的治疗干预以及确定预测治疗反应的伴随标志物，目标是预防关节的渐进性损伤、畸形和功能残疾。通过本研究，我们旨在对一组初治的早期类风湿性关节炎（ERA）患者中，先前发现其增加与类风湿性关节炎相关的蛋白质：血清淀粉样蛋白A（A-SAA）和警报素进行定量分析。应用基于单靶向自下而上蛋白质组学的液相色谱-串联质谱法（LC-MS/MS），同时对血浆中的五种A-SAA变体（SAA1α、SAA1β、SAA1γ、SAA2α和SAA2β）以及S100A8和S100A9蛋白进行定量分析。首先，我们比较了ERA患者（n = 100）和健康受试者（n = 100）之间它们的表达情况，然后通过监测初治的ERA患者在开始治疗1年后的情况，关注它们的变化趋势。在ERA患者中，只有SAA1α和SAA2α水平升高，并且SAA2α似乎在很大程度上介导了A-SAA的病理作用。这些变体以及SAA1β的水平，仅在生物性改善病情抗风湿药（DMARD）治疗下降低，而在甲氨蝶呤单药治疗下并未降低。这项研究强调了更好地了解ERA中这些变体表达调节的重要性，以便随后更好地表征它们的生物学功能。另一方面，与对照组相比，ERA患者中警报素的表达增加，但在甲氨蝶呤或生物制剂治疗12个月后仍保持升高。这项研究突破了将这些蛋白质视为诊断生物标志物的概念，表明SAA1α、SAA1β和SAA2α变体以及S100A8和S100A9对ERA中的所有早期治疗均无反应，而应被视为有助于改善治疗反应和缓解状态随访的伴随标志物。此外，这表明除甲氨蝶呤外更早使用生物制剂可能值得考虑。
