Joint–brain communication in rheumatoid arthritis: glial mechanisms, pain phenotypes, and translational evidence

Rheumatoid arthritis (RA) is a systemic autoimmune disease in which persistent pain, fatigue, cognitive impairment, depression, and anxiety may involve altered central nervous system (CNS) processing. This narrative review synthesizes preclinical and clinical evidence concerning proposed glial cell-mediated joint–brain communication in RA. Joint-derived neural inputs and systemic inflammatory signals may communicate with the CNS through humoral, cellular, neural, neuroendocrine, and neurovascular pathways. Preclinical studies implicate microglia and astrocytes in neuroinflammatory responses, spinal central sensitization, impaired hippocampal plasticity, and neurovascular alterations. Human studies associate systemic inflammation with altered brain connectivity and CNS-related symptoms. Disease-modifying antirheumatic treatment, particularly tumor necrosis factor inhibition, has been associated with improvements in selected CNS-related outcomes. Adjunctive symptom management includes phenotype-guided analgesic approaches, rehabilitation, and psychological and sleep-focused interventions. Translational research explores glial modulators, pathway-specific interventions, vagal neuromodulation, neuroimaging, cerebrospinal fluid markers, and multidimensional patient stratification. The proposed joint–brain framework highlights the value of assessing inflammation alongside pain phenotype, cognition, mood, fatigue, sleep, and function. Future human studies should evaluate whether mechanistic and biomarker findings can improve individualized treatment selection and clinical outcomes.