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.