Volume 2, Issue 2 pp. 69-75

REVIEW

Open Access

Depression in patients with ankylosing spondylitis

Tianjiao Ma,

Tianjiao Ma

Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

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Yingying Geng,

Yingying Geng

Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

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Ping Li,

Corresponding Author

Ping Li

[email protected]

Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

Correspondence Ping Li, Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Str, Changchun 130033, Jilin, China.

Email: [email protected]

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Tianjiao Ma,

Tianjiao Ma

Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

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Yingying Geng,

Yingying Geng

Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

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Ping Li,

Corresponding Author

Ping Li

[email protected]

Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

Correspondence Ping Li, Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Str, Changchun 130033, Jilin, China.

Email: [email protected]

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First published: 24 April 2022

https://doi.org/10.1002/rai2.12020

Citations: 4

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Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory spondyloarthropathy that can cause severe physical and functional damage. The risk of depression is higher in AS patients than in the general population. Depression in AS patients affects disease prognosis and is receiving greater attention. By mining the literature on depression in AS patients in China and other countries, we analyzed research gaps and flaws in this area. In this review, we describe current knowledge regarding depression status, pathogenesis, disease relevance, and treatment of depression in AS patients. The findings may help to prevent depression, improve treatment, and enhance chronic disease management in AS patients.

Key points

The risk of depression is higher in ankylosing spondylitis (AS) patients than in the general population.
Depressive symptoms in AS patients may be caused by the psychological stress, physical damage associated, and immune inflammation.
Treatment with cytokine inhibitors (including tumor necrosis factor-α, interleukin-17, and Janus kinase inhibitors) can improve clinical depression symptoms.

Ankylosing spondylitis (AS) is a chronic progressive inflammatory spondyloarthritis. Research on AS often focuses on spinal and joint injuries and neglects many other systemic effects and comorbidities. Recent evidence indicates that the effects of AS are not limited to spine and joint problems but include inflammatory bowel disease; acute anterior uveitis; psoriasis¹; cardiovascular disease²; osteoporosis³; comorbidities of the lungs, kidneys, and nervous system⁴; and depression and anxiety.⁵ Compared with other AS comorbidities, depression has not been well studied. Depression negatively affects the prognosis and quality of life of AS patients. This article reviews research progress on the effects of depression associated with AS.

1 THE OCCURRENCE OF DEPRESSION

Research on psychiatric comorbidities in AS patients has increased over the last decade. One population-based cohort study demonstrated that over a 13-year observation period, 10% of patients in the AS cohort received a physician diagnosis of depression according to the International Classification of Diseases 10th Revision diagnostic criteria, whereas only 6% of the reference population was similarly diagnosed, suggesting a substantially higher risk of depression in AS patients.⁵ Hopkins et al.⁶ systematically reviewed 17 cross-sectional studies on the prevalence of depression in AS patients and reported prevalence estimates ranging from 4.9% to 55.5%. In a systematic review of depression and anxiety in AS patients, Park et al.⁷ identified 783 studies and reviewed 39 articles. Four studies evaluated the incidence of AS depression. Three studies reported the overall estimated risk of depression in 5947 AS patients. A meta-analysis of these three studies produced a combined depression incidence rate of 1.51 (95% confidence interval: 1.28–1.79). The reported estimated prevalence of depression in AS patients varies widely. The use of different assessment methods across studies may be one of the main reasons for the large differences in the reported prevalence of depression in AS patients. Such differences may also reflect variations in sample characteristics (e.g., race/ethnicity). Frequently used depression assessment tools include the Hospital Anxiety and Depression Scale,⁸ Self-Rating Depression Scale,⁹ Hamilton Depression Scale (HAMD),¹⁰ Beck Depression Inventory (BDI-II),¹¹ Self-Rating Symptom Checklist (SCL-90),¹² and the Patient Health Questionnaire-9.¹³

2 PATHOGENESIS

Recent research suggests several possible reasons for the higher risk of depression in patients with AS. First, depressive symptoms in AS patients may be caused by the psychological stress and physical damage associated with AS. For example, the symptoms and outcomes of AS, such as pain, fatigue, work disorder, and financial burden, probably contribute to the occurrence of depression in AS patients.^14-18 Second, depression may be a direct consequence of AS disease activity and inflammation. There is evidence that inflammation plays a role in the pathophysiology of depression; patients with major depressive disorder (MDD) show overexpression of proinflammatory cytokines, acute phase reactants, and chemokines in plasma.¹⁹ Inflammation is also an important factor that links depression and chronic diseases.²⁰ Depressed patients have elevated levels of proinflammatory factors, such as interleukin-6 (IL-6), IL-17, and tumor necrosis factor-α (TNF-α).^21-23 These proinflammatory factors may play an important role in the pathogenesis and progression of AS.

Immune inflammation is one of the hallmarks of the pathogenesis of depression. The interaction between brain inflammation and the nervous system promotes the development of depression.²⁴ Many studies have described how proinflammatory cytokines, including TNF-α, enter the brain via humoral pathways, neural pathways, and cellular pathways.²² These pathways involve leakage through the blood–brain barrier, active transport mechanisms, and binding with peripheral afferent nerve fibers such as the vagus nerve.^{25, 26} After passing through the blood–brain barrier, cytokines induce depression by increasing the brain immune cell response, activating the neuroendocrine axis, inhibiting monoamine neurotransmitters, and changing the structure and function of brain regions related to emotion regulation.²⁷

This cytokine influx and the subsequent downstream effects may affect several neurotransmitter systems in the brain, including the 5-hydroxytryptamine (5-HT) pathway, the dopamine and glutamate pathways, and the kynurenine pathway, which produces the neurotoxic metabolite quinolinic acid.²² Specifically, proinflammatory cytokines such as IL-1 and TNF-α are potent inducers of indoleamine-2,3-dioxygenase,²⁸ an enzyme that metabolizes tryptophan to produce kynurenine and quinolinic acid, and limits amino acid synthesis. Tryptophan is a precursor of the kynurenine pathway and of 5-HT.²⁹ In vitro studies have shown that IL-1 and TNF-α increase serotonin transporter activity. This effect is mediated by the activation of p38 mitogen activator protein kinase,³⁰ resulting in reduced synaptic availability of 5-HT and subsequent depression-like behaviors in experimental animal models.³¹

Research shows that the TNF-α inhibitor infliximab can reduce both AS symptoms and depressive symptoms in patients with AS.³² The nonsteroidal anti-inflammatory drug celecoxib also reduces depressive symptoms and does not increase the risk of adverse side effects.³³ These studies suggest that the occurrence and development of AS depression may be strongly associated with inflammation. Thus, anti-inflammatory treatments may improve both AS symptoms and depression in AS patients.

Depression and AS may share several genetic and environmental factors associated with inflammatory responses. Human leukocyte antigen B27 (HLA-B27) is the main gene that determines AS susceptibility, although IL-23 receptor, internal environmental factor plasma reticulum aminopeptidase 1, and IL-1 region gene are also associated with an increased risk of AS.³⁴ HLA-B27 may affect autoimmunity by regulating cytokine production and triggering central nervous system inflammation. This can cause depression symptoms and affects susceptibility to depression, disease manifestation, and prognosis. AS is a complex disease that involves many factors, including genetic and environmental factors. One study found substantially higher levels of Bacteroides, Proteus, and Actinobacteria in MDD patients compared with a control group.³⁵ Wen et al.³⁶ found that AS patients also have an abundance of actinomycetes. Therefore, depression in AS patients may result from intestinal inflammation caused by the intestinal flora that activates the immune system and damage the hypothalamic–pituitary–adrenal axis.

3 CORRELATIONS BETWEEN AS DISEASE SYMPTOMS AND DEPRESSION

AS patients with psychological disorders consume more medical resources, have lower treatment compliance, and lower quality of life. Many studies have been conducted on the influencing factors of depression in AS patients with the aim of improving the mental health of this population. However, their findings are conflicting. The occurrence of depression in AS patients is affected by many factors, including age, gender, occupation, education level, family economic status, and smoking history.^37-45 However, because of the correlation between depression and AS disease symptoms, many studies have examined the association between depression in AS patients and measures such as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, Bath Ankylosing Spondylitis Function Index (BASFI) scores, Bath Ankylosing Spondylitis Metrology Index (BASMI) scores, pain, fatigue, sleep disturbance, and quality of life.

3.1 ASDAI, BASFI, and BASMI scores

There is conflicting evidence regarding the correlations between BASDAI, BASFI, and BASMI scores and depression in AS patients. Martindale et al.⁴⁶ found high correlations between depression and BASDAI, BASFI, and BASMI scores but a lower correlation between depression and BASMI scores. Xu et al.⁴⁷ found a positive correlation between depression and BASDAI scores (p < .05) but no correlation between depression and BASFI and BASMI scores. However, some studies have found no correlation between BASDAI scores and depression, and no association between changes in BASDAI scores after treatment and changes in depression scores.^{48, 49}

Findings suggest that AS patients with higher depression scores may self-report more functional limitations (i.e., reporting bias).⁴³ The BASDAI and BASFI are self-assessment instruments and thus scores are likely to be affected by the patient's subjective emotional experience. In contrast, the BASMI is scored by health professionals; therefore, BASMI scores are not affected by the patient's subjective emotional experience. When evaluating the functional limitations of AS patients in observational or interventional studies, relevant psychological variables should also be considered and evaluated. Patients with high BASDAI, BASFI, and BASMI scores should be screened for depressive symptoms as early as possible, and AS treatment for such patients should address any comorbid depression.

3.2 Pain

Pain is a common symptom of AS. There is a strong correlation between pain and depression in AS patients, and AS patients who experience more pain are more likely to have depression. Durmus et al.¹⁸ found a positive correlation between pain and depression in AS patients. Pain causes reduced activity and poor sleep quality in patients with AS. Pain is a chronic noxious stimulus that causes negative emotions such as depression in AS patients.

Increasing evidence supports the biopsychosocial model of pain, which posits that the process of affective cognition is the main cause of individual differences in the perception and response to pain. Some researchers have suggested that depression in patients with inflammatory arthritis increases pain sensitivity and affects the pain response.⁵⁰ There is evidence of a two-way causal relationship between pain and depressive symptoms, which suggests they have a common pathophysiological basis.^{51, 52}

3.3 Fatigue

Fatigue is the third most common complaint of AS patients, after pain and stiffness.¹⁶ The relationship between fatigue and mental health status has not been examined in detail. The results of several studies demonstrate a positive correlation between fatigue and depression and anxiety symptoms in AS patients.^15-18 However, some researchers have suggested that fatigue has no sensitivity or specificity in the detection of depression.^53-55 Therefore, a large-sample, prospective study is needed to clarify the relationship between fatigue and mental health in AS patients.

3.4 Sleep disorders

Sleep disorders in patients with AS are often accompanied by depression and anxiety.⁵⁶ A study on the prevalence and related factors of sleep disorders in AS outpatients in China found that 67.6% of AS patients have sleep disorders.⁵⁷ Hakkou et al.⁵⁸ showed that depression is an independent risk factor for sleep disorders. A systematic analysis by Leverment et al.⁵⁹ demonstrated that poor sleep quality is associated with disease activity, physical function, fatigue, pain, quality of life, anxiety, and depression in patients with AS. A large-scale study on AS sleep disorders by Wadeley et al.⁶⁰ similarly showed that AS patients with good sleep quality have a much lower rate of depression than those with poor sleep quality. Patients with poor sleep quality also showed more disease activity and a higher incidence of depression than patients with good sleep quality.

3.5 Quality of life

One study found that AS patients with higher depression scores had poorer quality of life, and the psychological status of AS patients was closely related to the quality of life.⁶¹ The lower quality of life experienced by patients with AS is likely to cause mental health problems such as anxiety and depression. Hakkou et al.⁶² found that 36-item Short-Form Health Survey (SF-36) scores were significantly higher in a depressed group than in a nondepressed group (p < .05). Xu et al.⁴⁷ found that scores on all dimensions of the SF-36 were positively correlated with depression (p < .05), and a multiple linear stepwise regression analysis showed that energy is an important influencing factor of depression.

4 TREATMENT

The treatment of AS patients with comorbid depression aims to improve depressive symptoms; reduce disease activity; improve quality of life; prevent recurrence; reduce psychological, rehabilitation, and drug treatment medical expenses; and reduce mortality.

4.1 Psychotherapy

AS psychological education can improve patient compliance with exercise and other adjuvant treatments.^{63, 64} Targeted and individualized psychological interventions and psychological care can reduce negative emotions and psychological states in AS patients, enhance treatment confidence, improve physical and mental functionality, and reduce long-term medical care consumption.

4.2 Rehabilitation

There is evidence that aerobic exercises and multidimensional exercises can substantially improve depression in AS patients.^{65, 66} In two studies, a family exercise intervention significantly reduced BASDAI, depression, and pain scores in AS patients.^{67, 68} A simultaneous intervention comprising exercise training and the use of TNF-α inhibitors for patients with AS increased the range of motion of the spine and joints; reduced disease activity; and improved mood, fatigue, and quality of life.^{69, 70} A prospective follow-up study showed that a simultaneous intervention comprising a Global Posture Reeducation Campaign and TNF-α inhibitor treatment significantly improved disease activity, physical function, fatigue, sleep quality, and depressive symptoms in patients with active AS.⁷¹

4.3 Antidepressants

The antidepressants of choice for patients with AS and depression are selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, fluvoxamine, citalopram, and sertraline.^{72, 73} A case-control study of the effect of duloxetine on depression and anxiety in AS patients showed that patients treated with duloxetine experienced significantly greater remission of AS symptoms and depression compared with a control group.⁷⁴ Another prospective observational cohort study showed that SSRIs can improve cognitive function in depressed patients independent of their effect on affective symptoms,⁷⁵ a finding that may help to improve the treatment of patients with AS. Understanding and compliance with treatment can increase the therapeutic effect of AS interventions.

4.4 TNF-α inhibition

MDD patients show elevated serum TNF-α concentrations; therefore, reducing serum TNF-α concentration may reverse depressive symptoms in these patients.⁷⁶ Many studies have shown that TNF-α inhibitors substantially improve depressive symptoms in patients with AS.^{32, 48, 49} For example, treatment with anti-TNF-α inhibitors significantly reduced scores on the HAMD⁴⁹ and BDI³² in AS patients. The use of antidepressants and benzodiazepine-related hypnotic drugs in AS patients is lower after TNF-α inhibitor treatment. TNF-α inhibitors can also improve sleep continuity in patients with refractory depression and high inflammation.⁷⁷ Raison et al.⁷⁸ found that TNF-α inhibitors improved depression symptoms in refractory depression patients, but the effect was observed only in patients with high baseline inflammation (e.g., C-reactive protein [CRP] > 5 mg/L). Raison et al.⁷⁸ also found an association between baseline concentrations of the inflammation biomarker hypersensitive CRP and subsequent treatment response to infliximab. The superiority of infliximab over a placebo for depression-related outcomes increased as baseline values of hypersensitive CRP increased.

Mehta et al.⁷⁹ examined the predictors and targets of infliximab response. They found that baseline transcriptional characteristics reflecting changes in glucose and lipid metabolism predicted the antidepressant response of infliximab. Monoclonal antibody responses involve the regulation of metabolism-related genes and the inhibition of genes related to innate immune activation. Although there are different opinions about the association between CRP, erythrocyte sedimentation rate, and depression scores,⁴⁸ infliximab may regulate the cytokines involved in the pathogenesis of AS depression and inhibit proinflammatory cytokines or other inflammatory factors to block the role of TNF-α in the pathophysiological process of depression.⁴⁸

Soluble TNF-α receptors can be used as reliable markers of inflammatory activity in patients with MDD.⁸⁰ The results of a clinical trial evaluating the efficacy of cytokine inhibitors for depression and depressive symptoms indicate that in individuals with immune dysfunction (e.g., elevated levels of proinflammatory cytokines), cytokine blockers may improve clinical MDD symptoms to a level unattainable with current traditional antidepressants. However, research has mainly focused on the effect of infliximab on AS depression. There is a lack of research on other TNF-α inhibitors; thus, further work on this topic is needed.

4.5 Cytokine inhibition

Immune inflammation is a hallmark of depression pathogenesis. Treatment with cytokine inhibitors (including TNF-α, IL-17, and Janus kinase inhibitors) can improve clinical depression symptoms. Some progress has been made on the use of cytokine inhibitors for rheumatoid arthritis and related diseases, but such treatments are still at the clinical research stage (Table 1).

Table 1. Treatment of rheumatoid immune diseases and related diseases with cytokine inhibitors

Cytokine inhibitor	Target	The results
Etanercept	TNF-α	Results of a double-blind randomized controlled trial show improvement in depressive symptoms in patients with psoriasis⁸¹
Adalimumab	TNF-α	Results of double-blind randomized controlled trials showed that it could improve depressive symptoms in patients with Crohn's disease⁸² and psoriasis⁸³
Remicade	TNF-α	Single-blind trial results showed improvement in depressive symptoms in Crohn's disease patients⁸⁴
Tocilizumab	IL-6R	Non-blind trial results showed that it could improve depressive symptoms in patients with rheumatoid arthritis⁸⁵
Ustekinumab	IL-12, 23	Results of a double-blind randomized controlled trial showed improvement in depressive symptoms in patients with psoriasis⁸⁶
Dupilumab	IL-4R-α	Results of a double-blind randomized controlled trial showed improvement in depressive symptoms in patients with atopic dermatitis⁸⁷

Abbreviations: IL, interleukin; TNF-α, tumor necrosis factor-α.

4.6 Other treatments

Studies have suggested that the nonsteroidal anti-inflammatory drug celecoxib is a potential adjuvant therapy for MDD⁸⁸; celecoxib reduces depression without increasing the risk of adverse side effects.³³ Whole-body cryotherapy has also been used in medical psychiatry to treat depression. A randomized controlled trial showed that whole-body cryoadjuvant drug therapy is effective for depression.⁸⁹ This treatment can reduce mental health problems, particularly mood disorders such as depression, and may help to improve quality of life.

A consensus on the prognosis and treatment of comorbid depression in AS patients has yet to be reached. Therefore, more large-scale, prospective studies are needed. The pathogenesis of depression is complex and involves multiple physiological systems. Research on single systems cannot capture the phenomenon of depression or completely explain its pathogenesis. The associations between immune-inflammatory responses, depression, and mechanisms of action need to be demonstrated at multiple levels and from multiple perspectives. New mechanisms linking depression, AS, pain, and inflammation require exploration. Such investigations may facilitate the discovery of new AS treatment drugs. Interventions for AS patients should actively treat AS disease symptoms and enhance the immune system to improve symptoms. In addition, the patient's mood and mental state should be treated to prevent anxiety and depression. Multidisciplinary and complementary perspectives are needed to appropriately, effectively, and comprehensively treat mood disorders and mental health problems in AS patients.

AUTHOR CONTRIBUTIONS

Yingying Geng and Tianjiao Ma: Collected data, conceived and wrote the manuscript. Ping Li: Revised the manuscript critically for important intellectual content and supervised the research group and has given the final approval of the version to be published.

ACKNOWLEDGMENT

None.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.

ETHICS STATEMENT

Ethical approval is not applicable for this article.

Open Research

DATA AVAILABILITY STATEMENT

Data Availability Statement Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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Volume2, Issue2

June 2022

Pages 69-75

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Depression in patients with ankylosing spondylitis

Abstract

Key points

1 THE OCCURRENCE OF DEPRESSION

2 PATHOGENESIS

3 CORRELATIONS BETWEEN AS DISEASE SYMPTOMS AND DEPRESSION

3.1 ASDAI, BASFI, and BASMI scores

3.2 Pain

3.3 Fatigue

3.4 Sleep disorders

3.5 Quality of life

4 TREATMENT

4.1 Psychotherapy

4.2 Rehabilitation

4.3 Antidepressants

4.4 TNF-α inhibition

4.5 Cytokine inhibition

4.6 Other treatments

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENT

CONFLICTS OF INTEREST

ETHICS STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

REFERENCES

Citing Literature

References

Information

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Depression in patients with ankylosing spondylitis

Abstract

Key points

1 THE OCCURRENCE OF DEPRESSION

2 PATHOGENESIS

3 CORRELATIONS BETWEEN AS DISEASE SYMPTOMS AND DEPRESSION

3.1 ASDAI, BASFI, and BASMI scores

3.2 Pain

3.3 Fatigue

3.4 Sleep disorders

3.5 Quality of life

4 TREATMENT

4.1 Psychotherapy

4.2 Rehabilitation

4.3 Antidepressants

4.4 TNF-α inhibition

4.5 Cytokine inhibition

4.6 Other treatments

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENT

CONFLICTS OF INTEREST

ETHICS STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

REFERENCES

Citing Literature

References

Related

Information