Beyond Joints: Neuropsychiatric Benefits of TNF-α and IL-6 Inhibitors in Rheumatoid Arthritis – a Narrative Review

Rheumatoid arthritis (RA) is a systemic autoimmune disease that, beyond joint destruc-tion, contributes to neuropsychiatric symptoms such as depression, anxiety, and cogni-tive impairment. These symptoms are often underrecognized despite their major impact on quality of life. Accumulating evidence suggests that pro-inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), play a key role in this neuroimmune interface. This narrative review examined 16 clinical studies evaluating the effects of biologic therapies targeting TNF-α and IL-6 on mental health outcomes in RA. The total study population comprised 9,939 patients, including 2,467 treated with TNF-α inhibitors and 7,472 with IL-6 or IL-6 receptor inhibitors. TNF-α inhibitors were associated with improved depressive symptoms and emotional well-being. IL-6 inhibitors demonstrated similar psychiatric benefits, particularly in patients with elevated IL-6 levels. The findings highlight that biological therapies in RA may influence not only physical symptoms but also mental health, likely through modulation of neuroimmune pathways including blood–brain barrier permeability, microglial acti-vation, and HPA axis regulation. Future research is needed to clarify these Effects in populations stratified by psychiatric comorbidity and inflammatory biomarkers. Clini-cal implications: Incorporating psychiatric symptom screening and considering neuroin-flammatory profiles may help guide the selection of biologic therapy in RA, particularly in patients with comorbid depression or fatigue.