This was a large-scale cohort study using the KURAMA cohort . We investigated the association of RA disease activity with anxiety and depression symptoms after adjusting for physical disability, pain, and medication in RA patients. We used multiple models to investigate these associations and obtained several notable findings. First, the multivariable logistic regression analysis identified no association between DAS28-based-non-remission and anxiety and depression symptoms. Second, the severity of PtGA, a component of the DAS28 composite measure, was strongly associated with anxiety and depression symptoms, whereas other individual elements of DAS28-CRP (TJC, SJC, and CRP) were not. Third, HAQ-DI-based non-remission was independently and significantly associated with anxiety and depression symptoms. Fourth, patients taking steroids were more likely to have depression symptoms than those not taking steroids.
Findings of previous studies investigating the association between disease activity and anxiety and depression symptoms are inconsistent. Disease activity [23, 24], physical disability [13,14,15], and pain severity [16,17,18] are among the factors associated with anxiety and depression in RA patients. However, these studies have two key limitations: (1) DAS28 and pain scores were simultaneously analyzed, but HAQ-DI scores and drug use were not included as covariates  and (2) pain, HAQ-DI scores, and drug use were not included as covariates [9, 24]. Therefore, the association between DAS28 score and anxiety and depression symptoms was mainly evaluated independently, and the effects of other factors may not have been fully evaluated. In this study, we found that when disease activity, disability, pain, and medication were adjusted for, DAS28-based non-remission was not independently associated with anxiety and depression. The average DAS28-CRP score in this study was 1.91 ± 0.82, which was lower than scores found in previous studies (DAS28-CRP scores 6.26–6.77). Additionally, almost 80% of patients achieved remission of disease activity (42.4–56.3% in previous studies), and disease severity was low and controlled. Therefore, after adjustment, the effects of other factors associated with anxiety and depression symptoms may be more robust than disease activity.
We also found that PtGA (a component of the DAS28-CRP composite measure) was notably associated with anxiety and depression symptom, which is similar to findings from a previous study . Moreover, the multivariable analysis results suggested that inflammation (CRP, TJC, and SJC) was not associated with anxiety and depression. Previous studies have reported that systemic inflammation is a potential cause of depression [19,20,21] and that inflammatory markers correlate with depression , suggesting an association between inflammation and depression symptoms. In this study, we did not correlate the two variables because of low CRP. However, PtGA uses the VAS for overall patient self-assessment and is the main tool for measuring patient-reported outcomes . The present results suggest that patient self-assessment, and not inflammation, is associated with anxiety and depression symptoms in RA patients.
PtGA reflects various factors; physical disability [39, 40], pain [18, 39], and catastrophizing pain  are among the factors that exacerbate PtGA scores. Santos et al.  excluded a priori testing for a direct association between DAS28-CRP3 variables and depression symptoms and instead tested the effects of disease activity and disease impact on patients. They found no direct association between DAS28-CRP3V and depression. They also confirmed an indirect relationship between disease activity and depression symptoms mediated by disease impact, such as pain, physical well-being, functional disability, and coping. Thus, functional disability, pain, recognition, and self-evaluation of disease were reflected in PtGA scores and related to anxiety and depression symptoms. This suggests that individual responses to stress caused by chronic disease, coping mechanisms, and subjective experiences of well-being are at least as important as inflammatory factors in the association between RA and psychological problems [28, 42].
In addition, there is a gap between doctor and patient PtGA assessments . Therefore, to understand patients’ anxiety and depression symptoms, it is necessary to pay attention to patients’ subjective experience regardless of disease activity. Additionally, to reduce anxiety and depression symptoms in RA patients, it is important to improve patient self-assessment and well-being. Cognitive behavioral therapy and mindfulness [44,45,46] reduce the tendency to catastrophize and subsequently reduce pain and distress; therefore, these approaches may be effective interventions for RA patients.
We found that HAQ-DI score, which identifies physical disability, was associated with anxiety and depression symptoms in a multivariable analysis. Previous studies have found that HAQ-DI score [13,14,15] is related to anxiety and depression. Regardless of acute disease activity score, functional disability measured by the HAQ-DI is associated with depression [22, 23, 47]. If disability persists, the possibility of concurrent symptoms of anxiety and depression increases, irrespective of disease activity remission. Physical disability reportedly leads to reduced ability to perform household chores and other activities and increased job loss/professional loss . Impairment in the ability to perform daily life activities causes anxiety and depression [14, 47].
The effects of bone or joint damage were not clear because joint damage was not evaluated in this study. However, the patients were older and had a longer disease duration, low disease activity, and low inflammation. We suggest that anxiety and depression were caused by loss of activity in daily life owing to prolonged limited function rather than acute symptoms of disease activity. It is important to confirm the effects of the disease on daily life. In the “treat to target” approach, the goal of treatment is to restore physical function so that RA patients can participate in social activities again, thereby maintaining long-term QOL . Improving QOL by supporting daily activities and possibly replacing or recovering lost activities to maintain and improve physical functions may relieve symptoms of anxiety and depression.
Finally, in Model 1, younger RA patients tended to experience anxiety symptoms. Younger RA patients may be more anxious about the future regarding factors such as disease-related concerns, medication, pregnancy, household chores, education, and job-related/professional work. In Model 2, patients taking steroids were more likely to have depression symptoms. Depression side effects may be caused by the pharmacological actions of steroids , so appropriate treatment strategies are needed that consider this risk of side effects.
One of the strengths of this study is that it used a large cohort to investigate the associations between disease activity and anxiety and depression symptoms while adjusting for factors that potentially affect these symptoms. Although a range of scales have been used to evaluate anxiety and depression in RA patients, the HADS was used in this study because scores are unaffected by the physical symptoms associated with the development of RA, such as fatigue and insomnia. Therefore, use of the HADS can help to avoid overestimating anxiety and depression symptoms. The HADS assesses the prevalence of anxiety and depression more accurately than other scales.
Despite our findings, this study had some limitations. First, instead of a formal psychiatric diagnosis, we used self-reported symptoms to determine anxiety and depression levels. Additionally, although we only considered the effects of currently used medication, we could not exclude the effects of prior treatment and drug amounts. Because this study was conducted at a single university hospital, selection bias may also have occurred; most patients had a lengthy disease duration and were in remission or had low disease activity. We also did not collect detailed demographic and socioeconomic data on participants, and therefore the analysis is unable to take such factors into account. Given these limitations, care must be taken in generalizing our findings.