Axial spondyloarthritis (SpA) describes a spectrum of inflammatory rheumatologic diseases that share common clinical, genetic, and radiological features. This spectrum of diseases ranges from early stage undifferentiated SpA to late-stage ankylosing spondylitis (AS). The most common and presenting symptom is chronic inflammatory back pain (IBP), which is usually a nocturnal pain that wakes the patient early in the morning in severe pain and stiffness. Other painful symptoms such as peripheral arthritis and enthesitis and fatigue are common symptoms. All subtypes show strong association with the human leucocyte antigen-B27 (HLA-B27).
AS is defined by the 1984 modified New York (MNY) classification criteria , which are widely used by rheumatologists. It is based on clinical features of IBP, and radiological features of sacroiliitis. However, radiographs only detected the irreversible joint damage of chronic inflammation but performed poorly in visualizing early inflammatory changes. The result was a diagnostic delay of 5–11 years after the onset of IBP [2, 3]. The development of magnetic resonance imaging (MRI) in detecting early inflammatory changes redefined the classification of axial SpA. The 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria [4,5] of axial SpA are based on MRI features and HLA-B27 status. This allowed early diagnosis  and, hence, early treatment.
Disease activity (inflammation) and functional status are commonly measured by self-rating instruments, which may be affected by psychological status. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)  measures pain, fatigue, and stiffness. The Bath Ankylosing Spondylitis Functional Index (BASFI)  measures daily functioning.
2 Epidemiology of depression and anxiety in axial SpA
Of all the rheumatologic diseases, AS was previously believed to be the least affected by psychological factors. In 1972, Hart and Huskisson described patients with AS as having “their usual cheerful outlook and absence of depression…[despite] severe daily pain.” .
However, in the 1990s, Barlow et al undermined this assumption by reporting elevated depressive symptoms in one-third of the patients with AS  using the Center for Epidemiological Studies—Depression (CES-D) scale, a generalized self-rating scale developed for use in the general population.
In the mid-2000s, the Hospital Anxiety and Depression Scale (HADS)  was first used in the prevalence studies. The HADS was developed as a self-rating scale to detect anxiety and depression in non-psychiatric hospital patients, and it was the most widely used scale in patients with AS for this purpose. It consists of 14 items in the full scale, 7 items each in the depression and anxiety subscales, rated on a scale of 0–3. Various cut-off scores were used based on the studies in other patient populations and the original authors’ recommendations.
In the United Kingdom, Martindale et al found 12.4% prevalence of depression and 20.2% prevalence of anxiety in an 18-month prospective study conducted in 89 patients with AS, using HADS depression subscale ≥11 to define depression and anxiety subscale ≥11 to define anxiety, with cut-off scores based on validation in other patient populations . Subsequently, use of the Arabic version  and Turkish version  of the HADS reported widely variable rates of depression 40–55% and anxiety 20–60% using various cut-off scores. These highly variable rates reflected the lack of validation studies in AS and axial SpA, and possible cultural differences in the various versions of HADS.
Most studies of psychological status were done in AS because the 2009 ASAS classification criteria for axial SpA was a relatively new development. To date, only one study had used definitive diagnosis by a psychiatrist to determine the prevalence of depression and anxiety in axial SpA. Chan et al found 10.6% prevalence of current major depressive disorder and 15.6% prevalence of anxiety disorder in axial SpA, based on the Chinesebilingual version of the Structure Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders 4th edition (Axis I) (CB-SCID-I/P) . These rates were remarkably comparable to the earliest UK data using HADS. The current prevalence of depression in axial SpA was higher than the 12-month prevalence of major depressive disorder of 8.4% in a community sample in Hong Kong .
3 Impact of depression and anxiety on clinical outcomes
All the studies on psychological status in AS [12,13,14] and axial SpA  found that those with depression or anxiety had worse disease activity. Analysis of individual items of the BASDAI found that pain (spinal, peripheral, and tendon) and fatigue were significantly associated with depression . As BASDAI is a self-rating instrument, the severity of pain and fatigue may be significantly influenced by psychological status.
Pain, fatigue, and depression are intricately linked due to overlapping symptomatology and multidirectionality. Chronic pain is well known to be associated with depression in a bidirectional manner. In a large review, the prevalence of pain ranged from 15% to 100% in patients with depression and, conversely, the prevalence of depression ranged from 27% to 56% in patients with chronic pain . Population data in the United Kingdom  and the United States  reported odds ratios of comorbid mood disorders in subjects with chronic pain of 3.2 and 2.0, respectively, when compared to those without chronic pain. In a local study, chronic spinal pain, headache, or joint pain were associated with a relative risk of depression between 1.6 and 3.4 in Hong Kong Chinese .
Pain and fatigue may be somatic symptoms of depression, especially in the Chinese who tend to express depression somatically . Patients with emotional distress, which is usually reflected in anxiety and depression components in questionnaires, may lead to inappropriate description of symptoms , particularly in self-rated scales. In a group of patients with rheumatic disease, those with high depression and neuroticism scores rated current pain as worse than previous pain in the absence of actual change in pain ratings .
Anxiety may be an early or comorbid symptom of depression. There is evidence that anxiety interacts with depression to increase its strength of association with chronic pain. The World Health Mental Survey Initiative found that the strength of association with chronic pain conditions is greatest with comorbid depressive-anxiety disorder than either non-comorbid depressive or noncomorbid anxiety disorders alone . In further analysis, females had a higher prevalence of depression–anxiety comorbid with chronic pain than males . Compared with depression, anxiety had the strongest association with each of migraine, arthritis, and back pain in a large population-based US study . Furthermore, anxiety in chronic low back pain predicted major depression .
In patients with inflammatory rheumatic disease, severity of depression was found to be an independent predictor of work disability . In local patients with AS, unemployment rates were found to be 3–7 times higher than those in the general population in Hong Kong , incurring two-thirds of the total societal costs. Similarly, in local patients with axial SpA, unemployment rates were significantly increased in those aged above 40 years, when compared with the general population .
Depression is a potentially modifiable risk factor affecting treatment adherence. Nonadherence was found to be significantly correlated with depression in a systematic review of immune-mediated inflammatory diseases that included rheumatologic conditions , which was independent of demographic, clinical, or treatment factors. Of the rheumatologic conditions, patients with AS were found to have lower adherence to pharmacological treatment when compared with patients with rheumatoid arthritis . Depression potentially affects cognitive function, memory, and altered beliefs about treatment efficacy and safety.
Depression is strongly associated with cigarette smoking, which is a well-known poor prognostic factor in axial SpA. Smoking has established associations with increased inflammation and structural damage and poorer functional status and quality of life . Cigarette smoking is well known to be associated with depression in large cross-sectional and prospective data alike. Large epidemiological data found that a lifetime history of smoking was correlated with a lifetime history of major depressive disorder . A 5-year prospective study conducted in 1,000 young adults found that depression increased the risk of progression to daily smoking and that daily smoking increased the risk of developing depression . Furthermore, a 21-year prospective study also found that smokers with depression were more likely to progress to daily smoking and nicotine dependence . There is a complex bidirectional relationship between depression and smoking.
Smokers with depression were less likely to quit , suggesting that cigarette smoking may be a form of “self-treatment.” Successful quitting was associated with relapse of depressive symptoms  similar to symptoms of nicotine withdrawal. However, a recent meta-analysis found that smoking cessation improved depression and anxiety . These seemingly contradictory findings suggest that although smoking cessation initially increased the risk of depression, successful smoking cessation improved depression and anxiety in the long term. The data suggests that smoking cessation and treatment of depression is mutually beneficial.
4 Screening of depression and anxiety in SpA
The Chinese version of HADS was validated as a screening tool for depressive and anxiety disorders in axial SpA . The full-scale HADS yielded an optimal cut-off score of ≥13 in screening for all depressive disorders, with sensitivity of 80.6% and specificity of 72.3%. The HADS anxiety (HADSA) subscale yielded an optimal cut-off of ≥6 in screening for anxiety disorders, with a sensitivity of 88.0% and specificity of 74.4%.
The superior performance of the full-scale HADS over the HADS depression (HADS-D) subscale may be due to genuine anxiety symptoms in depression or psychometric characteristics of the Chinese version of HADS. A comprehensive review found that the mean correlation between the depression and anxiety subscales was r = 0.63 , mainly due to real coincidence of depression and anxiety in the same patient. A validation study of the Chinese version in inpatient consultation referrals  found a two-factor structure in which two items on the anxiety subscale loaded onto depression or onto both. The full-scale HADS captured these two items of the HADS-A which would have been missed had only the HADS-D subscale been used.
5 Implications for management
There is increasing evidence for the role of inflammation in the pathogenesis of depression. The cytokine theory of depression proposed by Ur et al highlighted the crucial role of proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor α (TNFα) released in inflammatory, autoimmune, and infectious processes . Further unifying theories postulated that chronic psychological stress maintains inflammation and depression  and that social threat and adversity upregulates inflammatory processes to produce a “proinflammatory phenotype” . The direct action of these cytokines on brain pathways caused a “sickness response” that resembled fatigue and depression , which enhanced survival during acute infection, but became maladaptive in chronic inflammation.
Proinflammatory cytokines acting on various central pathways may form the unifying basis of the major biological theories of depression . Their action on monoamine neurotransmitter depletion is the basis for the “monoamine hypothesis” of depression. Their activation of the hypothalamic–pituitary–adrenal (HPA) axis results in elevated cortisol levels. Chronic elevations of cortisol, as well as proinflammatory cytokines, have been found to directly affect neuronal processes such as inhibiting neurogenesis, promoting neurotoxicity, and causing hippocampal atrophy .
One such cytokine, IL-6, was found to be associated with depression in many longitudinal studies  in clinical and community samples . IL-6 in cerebral spinal fluid was associated with current depression in older women . Sirukumab is an IL-6 antagonist with potential antidepressive effects. A randomized placebocontrol trial found that sirukumab improved depressive symptoms in patients with rheumatoid arthritis ; however, no studies were done in axial SpA or AS.
In the periphery, proinflammatory cytokines stimulate the production of c-reactive protein (CRP), a common inflammatory marker, from the liver. Multiple large-scale epidemiological studies have reported an association between depression and inflammatory markers, with variable gender differences. In a large US national cohort of 6900, Ford et al found that a history of major depression was strongly associated with CRP, especially in men with recent depressive episodes and men with recurrent depression . A 1-year longitudinal study also found CRP to be associated with clinically significant depressive symptoms, with a stronger association in women . In a systematic review of longitudinal studies, increased inflammatory markers, CRP and IL-6, were found to increase the risk of subsequent development of depressive symptoms .
However, Douglas et al only found a weak correlation between depressive symptoms and CRP . In patients with rheumatic disease, the ratio of monocytes, a marker of production of pro-inflammatory markers, was found to be correlated with the intensity of depressive symptoms . In Chinese patients with axial SpA, CRP was only weakly associated with inflammation . Newer MRI technique might be a better method for assessing axial SpA activity .
Antidepressant medications such as specific serotonin-reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) may have direct anti-inflammatory effects. O’Brien et al.  found that treatment of depression with SSRIs was found to decrease serum CRP levels, independent of clinical response. The antidepressant desipramine was found to decrease TNF-α levels, thereby enhancing noradrenaline transmission .
TNF-α inhibitors may have beneficial effects on depression. A few prospective studies [57, 58] found that depression and anxiety symptoms were significantly decreased, independent of BASDAI scores, after 6-week treatment with infliximab. However, in another study , the effect on depression was in concordance with measures of disease activity. A systematic review and meta-analysis of 6 randomized control trials in chronic inflammatory rheumatic diseases found that anti-TNF therapy was associated with decreased depression, although the effect sizes were small . This may be a further area of research.
Lifestyle modification such as exercise has concomitant benefits on clinical and psychological variables. Home-based exercise programs decreased depression in treatment-naive patients [61, 62] as well as in those receiving anti-TNF treatment , when compared with controls, regardless of swimming, walking, or conventional exercise . A meta-analysis of 6 studies found that home-based exercise significantly reduced BASDAI, BASFI, depression, and pain scores . For anxiety, a hospital-based calisthenics exercise program was found to be better than a home-base program .
Specific treatments of depression and anxiety in axial SpA or AS have received limited research. One small case–control study  found that combination treatment with duloxetine and conventional therapy in AS resulted in significant improvements in both clinical and psychological parameters, when compared to conventional therapy alone. The National Institute of Health and Clinical Excellence  guidelines recommend antidepressant medications for the treatment of moderate to severe depression. Antidepressants are effective in anxiety disorders, whether isolated or comorbid with depression. Cognitive behavioral therapy (CBT) is beneficial in milder forms of depression and anxiety disorders, and in combination with medication in more severe forms. Multidisciplinary care involving mental health professionals would benefit the psychological as well as clinical status of patients with axial SpA.
Depression and anxiety in axial SpA are more common than once thought. It is important to screen for psychological distress because depression and anxiety were found to be associated with worse disease activity, poorer functional status, work disability, and poorer quality of life. Depression and anxiety are readily modifiable factors that impact on the medical outcomes.
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Rudwaleit M, Landewe R, van der Heijde D, Listing J, Brandt J, Braun J et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainly appraisal. Ann Rheum Dis. 2009;68(6):770-6.)| false 10.1136/ard.2009.108217
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Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009; 68(6):777-83.)| false 10.1136/ard.2009.108233
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