Characteristic central nervous system fingerprints and related molecular signatures in difficult-to-treat rheumatoid arthritis

Abstract Background Despite guideline-recommended treatment, approximately 30% of rheumatoid arthritis (RA) patients remain symptomatic and are classified as difficult-to-treat (D2T), representing an unmet clinical need. D2T RA is a heterogeneous state potentially involving differences across several biological and psychological levels, but the exact underlying mechanisms remain unclear. To capture this complexity, our multimodal cross-sectional study aimed to characterize the contributing factors of the D2T state with a multimodal approach. Methods 31 D2T RA (defined by EULAR, 2021), 18 non-D2T RA patients, and 32 healthy controls (HCs) were included. All participants underwent a clinical assessment, psychological analysis (in-depth interviews, the Rorschach test, and questionnaires), two resting-state functional MRI (fMRI) scans with standardized heat pain stimulation in between, and peripheral blood transcriptomic analysis. Results The activity and connectivity of brain regions, especially the somatosensory cortex and the posterior cingulate cortex, one of the main hubs of the default mode network (DMN), showed significant alterations in D2T RA. Furthermore, acute pain stimulation influenced connectivity patterns of D2T patients differently compared to non-D2T patients and HCs. These results are in line with the psychological profiles of D2T patients characterized by cognitive, coping, and emotional dysregulations as well as altered pain processing. Transcriptomic analysis identified mediators, pathways, and signaling mechanisms such as neuregulin 1 (NRG1) and type I interferon signaling associated with neuroinflammation and synaptic plasticity. Conclusion Our findings identify central nervous system (CNS) alterations as a meaningful contributor to the D2T RA phenotype, helping to explain persistent symptom burden beyond inflammation. These characteristic neuroimmune signatures support multidisciplinary, personalized interventions that target CNS processes alongside inflammation control to improve outcomes.