Antibodies to synthetic citrullinated peptide epitope correlate with disease activity and flares in rheumatoid arthritis

Rheumatoid arthritis (RA), caused by the abnormal recognition of human joint cells by autoimmune antibodies, remains the world’s most prevalent autoimmune disease, with over five million people affected and as much as 4% of the population at risk of RA. To prevent rapid disease development, hormonal and anti-inflammatory therapies require fast and reliable RA diagnosis. However, difficulty in detecting early specific biomarkers for RA means that it is unclear when treatment needs to begin. Here, we combined synthesis of citrullinated peptide epitopes with molecular diagnostics to verify a new specific biomarker for early RA diagnosis and flare prediction. A fibrinogen-derived 21-amino-acid-long citrullinated peptide showed high reactivity toward autoantibodies in RA samples. Additionally, the level of antibodies to this epitope was elevated prior to flares. In contrast, other citrullinated protein variants had lower reactivity and poorer sensitivity to disease activity. In conclusion, fibrinogen-derived epitope E2 subjected to citrullination facilitated a reliable RA diagnosis with a strong correlation to disease activity. This is of a high value for the diagnosis and management of RA patients who respond poorly to treatment.

类风湿关节炎（Rheumatoid arthritis, RA）是因自身抗体异常识别人体关节细胞所引发的自身免疫性疾病，亦是全球范围内最常见的自身免疫性疾病，目前全球超500万人群受其困扰，约4%的人口存在患病风险。为阻止病情快速进展，激素与抗炎治疗需依托快速且可靠的RA诊断手段，但当前难以检测RA的早期特异性生物标志物，导致临床无法明确治疗启动时机。本研究将瓜氨酸化肽表位的合成技术与分子诊断方法相结合，旨在验证可用于RA早期诊断与疾病发作预判的新型特异性生物标志物。实验结果显示，一种源自纤维蛋白原的21个氨基酸长度的瓜氨酸化肽，在RA患者样本中可与自身抗体展现出高反应性；此外，该表位对应的抗体水平在疾病发作前即出现升高。与之相比，其他瓜氨酸化蛋白变体的反应性更低，且对疾病活动度的检测敏感性更差。综上，经瓜氨酸化修饰的纤维蛋白原衍生表位E2可实现可靠的RA诊断，且与疾病活动度存在显著相关性，该发现对治疗应答不佳的RA患者的诊断与管理具有重要应用价值。