Elsevier

The Lancet Psychiatry

Volume 6, Issue 2, February 2019, Pages 164-173
The Lancet Psychiatry

Review
Rheumatoid arthritis and depression: an inflammatory perspective

https://doi.org/10.1016/S2215-0366(18)30255-4Get rights and content

Summary

The coexistence of immune-mediated inflammatory diseases with depression has long been recognised. Data that illustrate the intimate associations between peripheral and brain immune responses raise the possibility of shared pathophysiological mechanisms. These associations include the negative effects of proinflammatory cytokines on monoaminergic neurotransmission, neurotrophic factors, and measures of synaptic plasticity. The evidence supporting this association is accumulating and includes findings from clinical trials of immunomodulatory therapy, indicating that these interventions can provide benefits to mental health independent of improvements in physical disease scores. In this Review, we assess this evidence in relation to rheumatoid arthritis and depression, with a focus on innate immune and molecular responses to inflammation, and discuss the challenges of assessing causation in this population, acknowledging the difficulty of assessing the confounding and contributory effects of pain and fatigue. We also discuss how future clinical and preclinical research might improve diagnosis of depression in people with rheumatoid arthritis and shed light on mechanisms that could be substrates for therapeutic interventions.

Introduction

The Global Burden of Disease 2016 study indicates that depressive disorders (major depressive disorder and dysthymia) now account for the third largest share of the world's burden of disease in terms of years lost to disability.1 Rheumatoid arthritis is also a major contributor to global disability.1 Together depression and rheumatoid arthritis exact a severe toll upon population health. However, these conditions coexist more often than would be predicted by chance, which has also been noted for several other somatic conditions associated with systemic inflammatory responses, including cardiovascular disease,2 diabetes,3 and obesity.4 Although this association of depression with chronic inflammatory states might be a general phenomenon, rheumatoid arthritis offers a remarkable opportunity to examine mechanistic pathways that might link such comorbid clinical presentations during systemic inflammatory states, owing to the advances that have been made in understanding the immune pathogenesis of rheumatoid arthritis.

We are witnessing a change in the way we think about the interface between physical health and mental health. Rheumatoid arthritis is a chronic systemic inflammatory disease, the pathophysiology of which is now understood sufficiently to support the introduction of molecular-targeted immune therapeutics, which have transformed disease management and outcomes for patients. Benefits associated with targeted immune therapeutics have accrued not only upon primary articular disease but also in the reduction of attendant comorbidities, including depression. The traditional explanatory causation model, whereby pain and disability induced by physical illness lead to understandable mental health problems, is now in doubt. Instead, evidence for a more complex, integrated pathophysiology is growing.

In this Review, we describe the epidemiology of the association between rheumatoid arthritis and depression, focusing on the complex interactions illustrated by the effect of depression on rheumatoid arthritis and its responses to treatments. We also describe our understanding of potential pathways that might drive depressive symptomatology, highlighting putative neuroimmune mechanisms. After examining the effects of molecular-targeted immune therapeutics on psychiatric symptoms, we will speculate about the inflammatory pathways that are most likely to link psychological comorbidity to immune-mediated inflammatory disease.

Section snippets

Depression in rheumatoid arthritis

Mental health disorders have long been recognised as important comorbidities of rheumatoid arthritis, even though accurate measurement and diagnosis is variable between studies. For example, in one study,5 the presence of arthritis in younger populations (<45 years) was a risk factor for the development of mental health disorder after 3 years of follow up, but the converse was not true—mental health disorders did not predict arthritis.5 However, a study by Lu and colleagues6 did identify a

Why is depression in patients with rheumatoid arthritis important?

The importance of defining and measuring depression in patients with rheumatoid arthritis pertains not only to treating a comorbid debilitating mental health disorder, but also to mitigating the indirect negative effects depression has on rheumatoid arthritis outcomes, both in terms of functional progression and treatment responses.12

Depression can reduce the likelihood of achieving remission in rheumatoid arthritis,13 which is an important therapeutic goal of the treat-to-target strategy

How might inflammation in rheumatoid arthritis affect mental health?

The biological mechanisms underlying the association between rheumatoid arthritis and depression are yet to be fully understood. However, much progress has been made in identifying immune alterations present in both conditions and their effects on brain structure and function, linking these changes to neuropsychiatric symptoms (figure 1).

Rheumatoid arthritis is a well established immune-mediated inflammatory disease characterised by upregulation of major proinflammatory cytokines, such as

Is depression in people with rheumatoid arthritis just due to pain and fatigue?

Alongside these shared alterations in inflammatory pathways, cross-over between pain, fatigue, and depression is likely to have a role in the higher rates of depression observed in people with rheumatoid arthritis. Pain and fatigue are common in rheumatoid arthritis and frequently reported by patients as key areas of unmet need.64, 65 They are usually only partially amenable to immune-targeted interventions. Fatigue and pain, particularly in the context of chronicity, are associated with

Translational data from neuroimaging

Although many of the data previously described have been produced from preclinical models, neuroimaging studies in humans have shown some brain changes that correlate with systemic inflammation and mood (figure 4). Studies examining the effects of systemic or peripheral inflammation on the brain have revealed changes in areas that are central to affective control and regulation—eg, subgenual anterior cingulate cortex. Inflammation-induced insula activation has been shown to predict subjective

Clinical trials of anti-rheumatic biological drugs and depression

To the best of our knowledge, there have been no clinical trials of biological agents in rheumatoid arthritis with depression as the primary outcome. Over 20 clinical trials of cytokine-lowering therapeutics have measured depressive symptoms as a secondary outcome in a range of immune-mediated inflammatory diseases.87 These have included TNF inhibitors (usually in combination with conventional disease-modifying anti-rheumatic drugs) and IL6 inhibitors (tocilizumab) in patients with rheumatoid

Challenges of studying mechanisms of depression in rheumatoid arthritis

The accurate estimation of the prevalence of depression has been hindered by the large variety of methods and definitions used (panel). For example, depression has been defined in 40 different ways in 72 studies.9 A major challenge of studying inflammation and depression in rheumatoid arthritis is that the association is complex between depression, inflammation, and measured disease activity in rheumatoid arthritis. As mentioned, the presence of depression can worsen responses to

Conclusions

Rheumatoid arthritis and depression are common comorbid pathologies that both affect quality of life. Depression in patients with this comorbidity appears unlikely to be just a natural sequel to the distress and disability rheumatoid arthritis causes, but might be contributed to by immunological changes. Many of the immune alterations associated with rheumatoid arthritis are now also implicated in depressive pathology and this association might explain in part the enhanced burden of depression

Search strategy and selection criteria

We searched PubMed for articles published in English from Jan 1, 2000 to Dec 31, 2017, with the terms “rheumatoid” and “rheumatoid + arthritis”, “depression”, “major depressive disorder”, and “inflammation” and “immune-mediated”. We selected mainly articles published in the past 5 years, but we did not exclude frequently cited and highly regarded older articles. We also searched the reference lists of articles identified using this search strategy and chose papers that we judged to be relevant.

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