Multimodal analysis reveals characteristic central nervous system alterations in difficult-to-treat rheumatoid arthritis

Inflammation and/or pain persists in 30% of rheumatoid arthritis patients despite adequate treatment considered as difficult-to-treat (D2T), but susceptibility factors and mechanisms are unclear. Therefore, we explored the bidirectional communication in the joint-brain axis with multidisciplinary approach integrating brain functional magnetic resonance imaging, psychological analyses, peripheral blood mononuclear cell transcriptomics, and plasma metabolomics. The activity and connectivity of several brain regions, including the somatosensory cortex and the posterior cingulate cortex, the main hub of the default mode network, were altered in D2T RA. These results support cognitive, coping, and emotional dysregulations. Mediators, pathways and signaling mechanisms (Neuregulin 1, Type 1 interferon signaling, amino acid-, lipid metabolism) associated with neuroinflammation and synaptic plasticity identified by multi-omic blood analysis could serve as prognostic biomarkers for patient stratification, disease monitoring and novel drug targets. Multidisciplinary, personalized intervention targeting altered central nervous system activities could lead to optimal disease control and reduce D2T RA.

尽管接受了规范治疗，仍有30%的类风湿关节炎（rheumatoid arthritis, RA）患者持续存在炎症和/或疼痛，这类患者被归类为难治性类风湿关节炎（difficult-to-treat RA, D2T RA），但其易感因素与发病机制尚不明确。
为此，本研究采用多学科研究策略，整合脑功能磁共振成像（functional magnetic resonance imaging, fMRI）、心理学分析、外周血单个核细胞转录组学（peripheral blood mononuclear cell transcriptomics）与血浆代谢组学（plasma metabolomics），对关节-脑轴的双向通信机制展开系统性探究。
研究结果显示，难治性类风湿关节炎患者的多个脑区活动与功能连接出现异常，涉及体感皮层（somatosensory cortex）以及作为默认模式网络（default mode network）核心枢纽的后扣带回皮层（posterior cingulate cortex）。
上述发现进一步佐证了难治性类风湿关节炎患者存在认知、应对方式与情绪调节功能异常。
通过多组学血液分析鉴定出的与神经炎症及突触可塑性（synaptic plasticity）相关的介质、通路及信号机制（包括神经调节蛋白1（Neuregulin 1）、I型干扰素信号通路（Type 1 interferon signaling）、氨基酸代谢与脂质代谢），可作为患者分层、疾病监测的预后生物标志物，同时亦可作为新型药物研发靶点。
针对中枢神经系统（central nervous system）活动异常实施多学科个性化干预，有望实现疾病的最优管控，进而改善难治性类风湿关节炎的疾病控制效果。