Inflammation: Is It the Link Between Rheumatoid Arthritis and Depression?

Both depression and rheumatoid arthritis (RA) contribute substantially to global disability, and the diseases often cooccur. The prevalence of depression in patients with RA is approximately 19%, according to conservative estimates.¹ Some research has demonstrated a bidirectional link between RA and depression, with each disorder predicting an increased subsequent risk for the other, whereas other findings support the influence of arthritis on psychiatric disorders but not vice versa.^1.2

Depression and RA outcomes

In addition to the importance of addressing depressive symptoms, treating depression also appears to improve RA outcomes. Study results suggest that patients with vs without comorbid depression have greater disability, a lower likelihood of achieving remission and treatment response in RA, and reduced adherence to disease-modifying antirheumatic drug therapy.¹

In a 2018 study published in Rheumatology, patients with baseline depression showed a 30% reduction in the odds of achieving a positive response to biologic therapy, and their treatment response (as measured by Disease Activity Score 28) diminished over time.³

Depression in RA is also associated with increased mortality related to suicide and other causes.

The inflammation connection

Recent findings have led to a shift away from the concept that mental health disorders are a byproduct of pain and disability associated with physical diseases, and “evidence for a more complex, integrated pathophysiology is growing,” as stated in a review published online in October 2018 in Lancet Psychiatry.¹ Advances in the understanding of RA pathogenesis present the opportunity to elucidate mechanisms linking comorbidities such as depression with systemic inflammation.

Mechanisms underlying the relationship between depression and RA have not been clarified, but a growing body of research points to the potential role of inflammatory processes. Immune “perturbation could possibly drive both conditions and, therefore, the shared mediating factor in this association might be altered immune functionality,” the authors wrote.¹

It is well established that RA is mediated by inflammatory immune processes, and research increasingly suggests a significant role of inflammation in depression.¹ Many of the proinflammatory cytokines involved in RA have also been implicated in the pathogenesis of depression, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. In addition, elevated plasma concentrations of C-reactive protein have been observed in patients with treatment-resistant depression, which may indicate that those with higher levels of inflammation may be less likely to respond to standard treatment approaches.

“Of relevance to the neurobiology of depression, immune-mediated inflammation has effects on neurotransmission, neurogenesis, neuroendocrine activity (hypothalamic-pituitary-adrenal axis), and neuroplasticity,” according to the review.¹ For example, TNFα-associated increases in serotonin transporter expression have been noted, which presumably reduce the availability of serotonin in the brainstem, and inflammation has been found to reduce brain-derived neurotrophic factor and neurogenesis. In addition, inflammatory cytokines lead to hypothalamic-pituitary-adrenal axis dysfunction and glucocorticoid alterations, which are closely linked with depression.⁴

The authors note the difficulty of separating pain and fatigue — common symptoms in RA — from depression.¹ “Pain and fatigue can possibly cause and exacerbate depression through both shared mechanistic pathways and consequences on quality of life,” and they may also influence mood and mental health because of increased disability, they explained. However, the available data “highlight that, although difficult to completely disentangle from pain and fatigue, depression is a distinct phenomenon that can be directly affected through immune pathways.”

Results of neuroimaging studies further support the influence of systemic inflammation on depression, including a correlation between increased C-reactive protein levels and decreased functional connectivity within reward-related corticostriatal circuitry.⁵

Treatment implications

Molecular-targeted immune therapeutics have been shown to reduce disease activity in RA but also to lessen comorbidities including depression.¹ More than 20 clinical trials have examined the effects of cytokine-lowering therapeutics, including TNF inhibitors and IL-6 inhibitors, on depressive symptoms as a secondary outcome. These agents have demonstrated a significant antidepressant effect (standardized mean difference 0.40) compared with placebo.⁶ In a 2018 study of patients with psoriasis, those receiving biologic therapies had lower rates of depressive symptoms than patients receiving other therapies.⁷

Even if the antidepressant benefits of biologics in RA are confirmed, it is likely that most patients will still require standard pharmacologic and psychological therapies for depression. “Multidisciplinary approaches that include mental health professionals are likely to be an important part of disease management, regardless of immunological intervention,” the review authors concluded.¹ “Overall, we hope that the exploration of shared mechanisms in rheumatoid arthritis and depression will allow for findings that reach beyond these two disorders and direct biological psychiatric research towards the beginnings of a new approach to thinking about how mental and physical disorders interact.”

References

1. Nerurkar L, Siebert S, McInnes IB, Cavanagh J. Rheumatoid arthritis and depression: an inflammatory perspective [published online October 23, 2018]. Lancet Psychiatry. doi:10.1016/S2215-0366(18)30255-4
2. Lu MC, Guo HR, Lin MC, Livneh H, Lai NS, Tsai TY. Bidirectional associations between rheumatoid arthritis and depression: a nationwide longitudinal study.Sci Rep. 2016;6:20647.
3. Matcham F, Davies R, Hotopf M, et al. The relationship between depression and biologic treatment response in rheumatoid arthritis: an analysis of the British Society for Rheumatology Biologics Register.Rheumatology. 2018;57(5):835-843.
4. Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its behavioral and metabolic correlates: from HPA axis to glucocorticoid receptor dysfunction.Ann N Y Acad Sci. 2012;1261:55-63.
5. Felger JC, Li Z, Haroon E, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21(10):1358-1365.
6. Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions.Mol Psychiatry. 2016;23(2):335-343.
7. Strober B, Gooderham M, de Jong EMGJ, et al. Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR).J Am Acad Dermatol. 2018;78(1):70-80.