Immune mechanisms of depression in rheumatoid arthritis

Depression is a common and disabling comorbidity in rheumatoid arthritis that not only decreases the likelihood of remission and treatment adherence but also increases the risk of disability and mortality in patients with rheumatoid arthritis. Compelling data that link immune mechanisms to major depressive disorder indicate possible common mechanisms that drive the pathology of the two conditions. Preclinical evidence suggests that pro-inflammatory cytokines, which are prevalent in rheumatoid arthritis, have various effects on monoaminergic neurotransmission, neurotrophic factors and measures of synaptic plasticity. Neuroimaging studies provide insight into the consequences of inflammation on the brain (for example, on neural connectivity), and clinical trial data highlight the beneficial effects of immune modulation on comorbid depression. Major depressive disorder occurs more frequently in patients with rheumatoid arthritis than in the general population, and major depressive disorder also increases the risk of a future diagnosis of rheumatoid arthritis, further highlighting the link between rheumatoid arthritis and major depressive disorder. This Review focuses on interactions between peripheral and central immunobiological mechanisms in the context of both rheumatoid arthritis and major depressive disorder. Understanding these mechanisms will provide a basis for future therapeutic development, not least in depression. Depression is a common comorbidity in rheumatoid arthritis, and shared immune mechanisms link the two conditions. This Review explores potential peripheral and central interactions between the immune system and brain, the understanding of which could aid in the development of novel therapeutics. Rheumatoid arthritis (RA) and depression have overlapping features, including similar implicated immuno-mechanistic pathways.Crosstalk between the peripheral immune response and central nervous system provides compelling evidence of a role for immune-mediated inflammation in the pathophysiology of depression, including in RA.Pro-inflammatory molecules can signal to the brain through humoral routes (via the blood-brain barrier and circumventricular organs) and neural routes (via vagal nerve and dorsal root ganglia afferent signalling).Neuroimmune communication in the brain involves the production of inflammatory proteins by both recruited myeloid cells from the periphery and resident microglial cells and can result in activation of glial cells.The peripheral immune system could modulate neurological processes through various mechanisms, including through modulation of the glutamatergic and serotonergic systems, the kynurenine pathway, inflammasome activation and neuroplasticity.Determining the mechanisms that link immune-mediated disorders such as RA with depression should aid in the identification of molecular targets and development of targeted therapy.