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  • Review Article
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Immune mechanisms of depression in rheumatoid arthritis

Nature Reviews Rheumatology volume 19, pages 790–804 (2023)Cite this article

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Abstract

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.

Key points

  • 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.

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Fig. 1: Immunobiology of rheumatoid arthritis.
Fig. 2: Effects of anti-inflammatory and immunomodulatory drugs on depression.
Fig. 3: Peripheral immune signals to the brain: neural and humoral routes.
Fig. 4: Viscerosensory hub transmission following cytokine-mediated afferent signalling.
Fig. 5: The glutamatergic and serotonergic systems.
Fig. 6: The kynurenine pathway and key metabolites in inflammatory conditions.

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Authors and Affiliations

  1. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK

    James Brock, Neil Basu, Iain B. McInnes & Jonathan Cavanagh

  2. Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA

    Johannes C. M. Schlachetzki

  3. Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

    Georg Schett

  4. Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

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All authors researched data for the article. J.C., J.B., N.B. and J.C.M.S. wrote the article and reviewed and/or edited the manuscript before submission. J.C. and J.B. contributed substantially to discussion of the content.

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Brock, J., Basu, N., Schlachetzki, J.C.M. et al. Immune mechanisms of depression in rheumatoid arthritis. Nat Rev Rheumatol 19, 790–804 (2023). https://doi.org/10.1038/s41584-023-01037-w

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