INTRODUCTION

Rheumatoid arthritis (RA) is a chronic inflammatory arthritis with both musculoskeletal and systemic features. RA is associated with several physical (eg, cardiovascular) and psychological comorbidities and it is increasingly recognised that depression and anxiety are associated with high disease activity, worse disease outcomes and decreased quality of life.^1–6 Most studies investigating the association of RA with depression and anxiety are cross-sectional and performed in patients with established RA of several years’ duration^{2 4} and/or in patients having received treatment for RA.^{1 3} The frequency and relationship of psychological factors in early RA has been less studied and may differ from established RA. Here, we examine longitudinally the frequency of depression and anxiety in a large inception cohort of early RA patients and the relationship with demographic characteristics and disease-related measures.

RESULTS

Prevalence of anxiety and depression over time

Frequency of anxiety and depression at baseline in early RA were higher than in healthy individuals (anxiety: 19.0% vs 1.7%, p=0.0002; depression: 12.2% vs 1.7%, p=0.009) and displayed an improving trend, over time. In fact, prevalence of anxiety and depression at 6 months was 15% and 9.7% and at 12 months, 13.4% and 8.1%, respectively (figure 1A). Anxiety and depression HADS scores were also highest at baseline and were decreased at 6 months and 12 months. Median (interquartile range—IQR) scores at baseline, 6 months and 12 months for anxiety were: 6.0 (3.0–9.0), 5.0 (2.0–8.0), 4.0 (1.8–8.0), respectively, and for depression were: 5.0 (2.0–8.0), 3.0 (1.0–7.0) and 3.0 (1.0–6.0), respectively. All Wilcoxon matched paired tests (6 months and 12 months, compared to baseline) are statistically significant (p<0.0001) (figure 1B,C). Separate subgroup analysis of the 81 patients who were already treated with psychotropic drugs at baseline indicated that the improving trend for both anxiety and depression was also observed in this group. However, statistical significance was only reached for comparisons between baseline and 12 months (online supplemental figure 1). In general, the internal consistency of the anxiety and depression scales was good. Cronbach’s alpha at baseline, 6 months and 12 months for depression were: 0.834, 0.860 and 0.855, and for anxiety were: 0.865, 0.888 and 0.892, respectively.

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Figure 1

(A) Prevalence of anxiety and depression measured by hospital anxiety and depression scale (HADS) in early rheumatoid arthritis over time from baseline (cut-off ≥11 for both). Longitudinal HADS anxiety (B) and depression (C) scores. Bars and lines represent mean and SEM, respectively. All Wilcoxon matched paired test (6 months and 12 months, compared to baseline are statistically significant, p<0.0001).

DISCUSSION

Depression and anxiety are important comorbidities in RA and are associated with less favourable disease outcomes and reduced quality of life. The prevalence of depression in our cohort was 13%. The reported frequency of depression in published RA studies ranges between 13% and 56%.^{9 10} However, investigators examining psychological comorbidities in RA have used different tools to assess this, making it difficult to compare between studies. Our study used HADS, which is highly reliable in the detection of depression in RA.¹¹ A meta-analysis estimated that depression, measured by HADS, occurred in 14.8% of RA patients.¹⁰ Anxiety is even more frequent than depression in both our cohort (19%) and the published literature (25–46%).^{1 3}

It is generally recognised that depression and anxiety scores in RA decrease over time, which was also observed in our cohort over the first 12 months following diagnosis.^{12 13} The reasons for this are currently unclear but several parameters (eg, better control of RA, less inflammation) might contribute. As also observed in our study, depression score is associated with RA disease activity,¹³ although the direction of this relationship has not been defined¹⁴ and causality cannot be inferred from observational studies. Of note, correlations between disease activity and anxiety scores were weaker compared to that recorded for depression scores.

Several studies report that baseline depression and anxiety levels in RA are associated with decreased likelihood of achieving remission,^{1 3 4} although others have not found this.² On the other hand, studies in early RA report that higher joint counts at baseline are associated with increased depression at month 6.¹³ Another study suggested that the HAQ score was the most important predictor of psychological stress in early RA,¹² with a variety of other demographic and socio-economical features like occupation and family income to be associated with depression and anxiety in RA.¹² In our study, univariate analyses identified a number of factors associated with HADS anxiety or depression scores at all time-points including baseline depression and anxiety scores, unemployment, being single, younger age, HAQ score and increased disease activity measures.

Multiple linear regression analysis indicated that current HAQ scores and baseline depression and anxiety scores were the strongest predictors of depression and anxiety scores. The association between HAQ and depression is consistent with findings from another study using data from SERA cohort, which reported that functional disability at 1-year after RA diagnosis was predicted by depression and anxiety among other factors.¹⁵ Similarly, another study examining predictors of depression in a multi-ethnic RA cohort showed that higher HAQ scores were associated with depression.⁹ Furthermore, in the multivariable analysis in our study, CRP and PGA-VAS were the only measures of disease activity assessed by DAS28 associated with depression.

Notably, CRP was associated with depression but not anxiety at all time-points in univariate analysis and at 6 months and 12 months in the multivariable analysis, suggesting a close relationship between inflammation and depression. This is consistent with a previous cross-sectional study, which reported that CRP was significantly correlated with depression levels in RA.¹⁶ Another study of RA patients with DAS28≥3.2 and disease duration between 3 months and 2 years reported higher CRP levels at baseline in patients who had depression compared to those who did not.¹

There appears to be a complex interplay between depression and RA, with shared inflammatory pathways postulated.¹⁷ It has been suggested that the aberrant immune responses in RA could cause alterations in the central nervous system via neuronal and humoral pathways.¹⁷ Notably, Schrepf et al ¹⁸ have demonstrated how chronic inflammation in RA has an impact on the brain. Higher peripheral inflammation was consistently correlated with neural connectivity patterns, particularly inferior parietal lobule and medial prefrontal cortex over a 6-month period. The RA-depression immunobiological axis is evidenced by various data. For example, in RA blockade of systemic TNF has beneficial effects on centrally mediated behaviours including mood.¹⁹ Further, anti-TNF therapy in RA acutely alters fMRI brain activation.^{20 21} This aligns with significant overall improvement in well-being, which patients can report often in advance of any objective improvement in their peripheral joint inflammation for example, swollen joints. Said that, as mentioned earlier, in the multiple regression analysis of our study, depression was associated with CRP and PGA-VAS but not with tender or swollen joints count. Our data, especially those showing the relationship between CRP and depression over time support this peripheral blood-neural network link in RA. It also provides a supportive perspective on the increasingly compelling data implicating the immune-inflammatory response in some aspects of the pathophysiology of mental disorders¹⁷ notably major depressive disorder.^22–24

Herein, we show, as previously reported,¹³ that anxiety is highly prevalent in early RA. In our study, patient global VAS correlated with anxiety levels, which could partially explain the association between anxiety and worse disease activity outcomes in RA.²⁵ However, in contrast to what we observed for depression in our cohort (as outlined above), anxiety was not associated with CRP, neither in univariate nor in multivariable analysis. The reasons for this are not clear and merit further investigation. It should also be noted that ‘anxiety’ encompasses a heterogenous spectrum of symptoms, ranging from contextual physiological anxiety through to anxiety disorders,²⁶ with some but not others associated with some degree of inflammation.²⁷ A more focused analysis might reveal whether there is an ‘anxiety phenotype’ in RA that is possibly linked with inflammation.

The inverse correlation between BMI and anxiety (but not depression) levels at 6 and 12 months in our study is not surprising, considering that large population studies have shown a U-shape relationship between anxiety and BMI.²⁸ Data from the Rochester Epidemiology Project indicate that anxiety is increased in underweight and obese, but not overweight, people. This association was more pronounced in females.^28.Finally, in our early RA cohort, baseline anxiety levels were found to be significantly associated with subsequent anxiety scores, highlighting that anxiety should also be considered in the treatment plan of patients with RA, from the early stages of disease.

Many studies examining psychological comorbidities in RA typically focus on depressive symptomatology and disregard anxiety or describe the psychological burden without distinguishing between depression and anxiety. However, as shown here, there are differences between depression and anxiety, at least in terms of the associating factors in RA, further reinforcing the notion that they should be assessed separately.

We acknowledge that our study has certain limitations. First, consistent with the design of this inception cohort, no data are available for depression, anxiety or disease activity at time-points between baseline and the 6 months and 12 months visits. Given the stable trend of our results, we speculate that it is unlikely that an important finding would have been missed. Similarly, limited data were available for patients followed-up for a longer time period. These, however, are continuously recorded and will be analysed in future studies. Furthermore, the number of healthy individuals is small compared that of RA patients and there may be some differences in the performance of the HADS questionnaire between healthy and RA individuals. Therefore, the differences between these two groups should be interpreted with caution. Finally, although some of the findings have been shown by other studies as well, our early RA inception cohort is one of the largest, examining longitudinally mental health disorders, with a validated tool in these patients.

In conclusion, our study indicates that clinicians should be alert to neuro-psychiatric comorbidity in RA from the earliest stages of the disease when the prevalence and levels of depression and anxiety appear to be highest. While depression and anxiety have been shown to have a negative impact on outcomes in RA, it remains to be determined whether more intense screening and treatment for psychiatric comorbidities, especially in some subgroups of patients (eg, those with high CRP, high HAQ scores) can improve outcomes. Our results also highlight again the link between inflammation and depressive symptomatology. The intertwining of these conditions points to potential common pathophysiology thus opening the possibility of greater mechanistic understanding and thus greater therapeutic opportunity.