Research shows that depression increases the risk of disability in patients with rheumatoid arthritis

In a review published in Nature Reviews Rheumatologyresearchers discussed the interactions between central and peripheral immunobiological mechanisms associated with rheumatoid arthritis (RA) and major depressive disorder (MDD).

They further described the role of inflammatory proteins, the effect of peripheral inflammation on different parts of the brain, and the relationship between changes in the brain and inflammation-induced depression.

Study: Immune mechanisms of depression in rheumatoid arthritis. Image credits: pikselstock/Shutterstock.com

Background

RA is a chronic autoimmune inflammatory disease that negatively affects synovial joints and several other organs. Depression is a common, clinically heterogeneous condition that affects all other patients with RA. There is increasing evidence that RA and depression have overlapping features and can be modulated by each other.

Data suggest that depression is a risk factor for RA, and that patients diagnosed with RA at a young age are more susceptible to depression. Furthermore, RA patients with depression are observed to exhibit functional progression as well as decreased response to treatment, leading to poor outcomes. However, the precise biological mechanisms underlying this association are not clearly understood.

Therefore, this review focuses on understanding the link between these two conditions and the underlying mechanisms, while exploring the interplay between the nervous system and the immune system in RA patients.

Shared cytokines in RA and depression

Proinflammatory cytokines amplified in RA are also known to be causally linked to depression. Several cytokines have been implicated in RA and depression, including interleukin (IL)-16, IL-18, IL-1, IL-6, and tumor necrosis factor (TNF).

Peripheral immune signals to the brain

The peripheral immune system signals the brain through two known pathways: neural and humoral. In the neural pathway, molecules that mediate inflammation can bind and activate receptors on sensory neurons, including those in the dorsal root ganglia (DRG) and the vagus nerve.

The activated sensory neurons then send the signal back to the cerebral cortex of the brain via the spinal cord. The signal is then passed on to higher brain centers, which modulate the immune system locally and systemically.

Through the humoral pathway, immune cells release molecules capable of crossing the blood-brain barrier (BBB) ​​and affecting brain cells or activating the endothelial cells of BBB.

As observed in experimental studies in mice, this pathway leads to the release of chemokines involved in neuronal plasticity, resulting in depression-like behavior and cognitive impairment.

Immune responses in the brain

In the brain, existing neural cells and recruited immune cells release various inflammatory proteins that support neuroimmune communication. When cytokines and chemokines are released by neurons, microglia, astrocytes, peripheral immune cells and endothelial cells, they influence neurological and immunological processes.

For example, during inflammation, the recruitment of peripheral monocytes to the brain is associated with dendritic remodeling and cognitive impairment, potentially leading to depression. Chronic peripheral inflammation in RA induces local microglial activation in the brain, leading to altered microglial expression.

Although microglia are often associated with inflammatory changes in the brain, recent studies indicate a more complex role for microglia in neurological health.

Contrary to previous belief, microglia found in the brain, according to studies in mice, originate not only from peripheral blood, but also from meninges and bone marrow in the skull. However, there is a lack of studies examining this aspect in humans.

Astrocytes also play a role in brain inflammation. Activation of astrocytes by cytokines from microglia has been shown to result in the release of neurotoxic factors that influence neuronal health and behavior.

Mechanisms linking depression and inflammation

Immune-related inflammation has been implicated in the pathophysiology of depression. In RA, several pathways are activated, which can lead to inflammation-related behavior.

These pathways include inflammasome activation, the kynurenine pathway, neuroplasticity, and the pathways of the glutamatergic and serotonergic systems.

Regional variation in the brain

Although regional changes in the brain and the underlying mechanisms continue to be studied, mainly using animal models, neuroimaging studies in humans have significantly improved our understanding of inflammation-related changes in the brain.

Advances in magnetic resonance imaging (MRI) have provided insights into the role of inflammation in depression beyond traditional structural assessments and histology-based studies. Emerging evidence suggests that the brain regions affected by inflammation and depression are the striatum, hippocampus, amygdala, and insula.

Conclusion

This review article provides a comprehensive overview of the association between immune mechanisms and depression in patients with rheumatoid arthritis. It highlights the need for further research in this area.

Furthermore, data from clinical trials suggest that immune modulation may be a promising approach for treating comorbid depression in patients with rheumatoid arthritis, potentially reducing the global burden of this debilitating condition.