Immunometabolic and brain structural alterations mediate increased risk of brain diseases in rheumatoid arthritis patients

Rheumatoid arthritis (RA) is associated with an increased risk of brain diseases, yet the underlying biological mechanisms remain poorly understood. Using data from the UK Biobank, including blood-based biomarkers, brain imaging, and diagnostic records, we investigated the roles of immunometabolic and brain structure alterations in the link between RA and brain diseases. The effects of antirheumatic treatments were evaluated using Cox proportional hazards models. To ensure a clear temporal sequence, only individuals with RA diagnosed before baseline were included. The cohort comprised 2534 prevalent RA cases (mean age: 59.80 ± 6.99 years; 70.84% women), with a mean disease duration of 5.54 years (SD = 3.57). RA was significantly associated with depression (HR = 1.659 95% CI: 1.444-1.905), sleep disturbances (HR = 1.673 1.379-2.029), and dementia (HR = 1.466 1.225-1.755). Mediation analyses revealed that immunometabolic alterations (indirect effect = 0.0099, P < 0.001) and reduced white matter integrity (FA; indirect effect = 0.012, P = 0.002) mediated these associations. Notably, treatment with slow-acting antirheumatic drugs (SAARDs) was linked to a reduced risk of anxiety (P = 0.006). These findings indicate that immunometabolic alterations in RA may lead to a decrease in white matter integrity, thereby increasing susceptibility to brain diseases. They highlight the importance of managing systemic immunometabolic alterations to preserve brain health in RA patients.