This study showed that depressive symptoms are common in patients with AS that have high disease activity. Infliximab improved depressive symptoms in patients with AS after 24 weeks of treatment. This effect could largely be explained by the effect of infliximab on self-reported symptoms of AS.
Over half of the patients with AS and active disease had a CES-D score > 16 at baseline, indicative for possible depression. This high proportion seems to be on the upper end of the prevalence range as reported in the literature, but is likely the result of the inclusion criteria for ASSERT, which required patients to have active disease [1]. For comparison, in control populations in the Netherlands, a possible depression as measured by increased CES-D score has been reported in 5–22% [21,22,23].
The reduction in depressive symptoms in the infliximab group occurred already within the first weeks and was maintained during the remainder of follow-up. Importantly, treatment with infliximab was not only associated with a decrease in depressive symptoms, but also with decreased odds of CES-D scores above the threshold for (probable) depression. The substantial reduction (an estimated 98% reduction in odds of having an increased CES-D after 24 weeks of weeks of infliximab compared to placebo), although certainly an overestimation of the effect of infliximab on true clinical depression, seems clinically relevant. This implicates that, at least in a population of patients with active AS, infliximab not only decreases the severity of depressive symptoms and odds of probable depression, but potentially even lowers the odds of true clinical depression. Of note, even after up to 54 weeks of treatment, 20–25% of both groups still had CES-D scores suggestive of possible depression.
Comparing our results with other studies that investigated the effect of TNFi on depressive symptoms in AS is difficult, because other study designs and/or instruments were used to assess depressive symptoms (in none the CES-D was used) [6,7,8,9,10]. Two RCTs assessed the effect of etanercept on depressive symptoms as a secondary outcome or in post hoc analysis. The first study, comparing sulfasalazine to etanercept among 566 patients with AS, reported significant improvements in depressive symptoms after 16 weeks in both treatment arms, with larger improvements in the etanercept group [9]. In the second study, where 215 patients with nr-axSpA were treated with etanercept or placebo for 12 weeks followed by etanercept for all subjects for another 12 weeks, depressive symptoms did not differ between groups after 12 weeks or 24 weeks, but had improved from baseline after 24 weeks in both groups [10]. In addition, three observational studies on the effect of infliximab on depressive symptoms in AS were published, with a total of 52 patients and all of limited duration (6–12 weeks) [6,7,8]. In line with our findings, in these observational studies, similar proportions of patients with depression scores above the threshold for the respective depression instrument used at baseline and over time were observed [7, 8]. Also, improvements in depressive symptoms occurred already within the first weeks after initiation of infliximab. Of note, none of these studies explored whether these improvements can be fully explained by improvements in symptoms or inflammation.
It remains challenging whether our results can help to understand if AS has a direct (inflammatory) or indirect (through pain and limitations) effect on depressive symptoms. The association between treatment with infliximab and improvement of depressive symptoms largely disappeared after adjustment for AS-specific symptoms, i.e. self-reported disease activity and physical function, suggesting the change in depressive symptoms in these patients is (at least partially) secondary to changes in their AS-related symptoms. Of note, the relationship between self-reported depressive symptoms and self-reported AS-related symptoms could (partially) be bidirectional. In rheumatoid arthritis, for example, the patient visual analog scale component of the Disease Activity Score (DAS28) has been strongly associated with depression [24]. Likewise, in the current study, responses on BASDAI or BASFI could be influenced by the patient’s emotional state. Additionally, it is known some covariance exists between all self-reported measures, which likely adds to some overestimation of the observed associations. Notwithstanding, when considering an alternative explanation for the improvements in depressive symptoms, i.e. a reduction in inflammation, CRP did not seem to independently/directly contribute to the effect of infliximab treatment on depressive symptoms: adjustment for CRP did have a minor impact on the association between infliximab and depressive symptoms when compared to the effect of BASDAI or BASFI, suggesting little mediation of the effect of infliximab via CRP-mediated inflammation. This further suggests the mechanism behind depressive symptoms in these patients is mainly based on the impact of AS-related symptoms. It should be noted, however, that due to the small sample size, these secondary analyses were only exploratory and no elaborate path analyses could be conducted. Nonetheless, the association between CRP and depressive symptoms, compared with BASDAI or BASFI, was not only statistically non-significant but also very small numerically, suggesting a direct effect of CRP-mediated inflammation would be little (if any) in a larger sample. Overall, it remains challenging to unravel the intricate relationships between the inflammatory pathophysiological process behind AS, AS-related symptoms, and depression. While CRP is commonly used as inflammatory biomarker in axSpA, we cannot rule out CRP is not appropriate as a biomarker to identify a potential link between inflammation and depression in this disease. While the current results do not allow us to draw firm conclusions regarding these associations between markers of inflammation and depression, our data suggests other inflammatory biomarkers are likely more interesting to further explore than CRP.
In addition, two other interesting observations can be made. First, while all patients had high BASDAI and BASFI scores at baseline, only half of these patients had CES-D scores above the threshold for possible depression, indicating the relation between experienced pain or functional limitations and depression is not an absolute one. Second, baseline CES-D remained strongly associated with the course of CES-D over time, even when accounting for BASDAI or BASFI. This suggests that, while the effect of infliximab on depressive symptoms seems to be mostly mediated by improvement in pain and functional limitations, depressive symptoms as measured with the CES-D are additional and distinct phenomena rather than only a reflection of these pain and limitations. It would be interesting to further explore which patients with active disease have an increased susceptibility to depression, for example as a result of genetic predisposition or personality and coping traits [25]. On this line, it has recently been shown that illness perceptions have an important role in the relationship between back pain and mental health outcomes [26]. Further, in axSpA, patients with comorbid depression are much more likely to suffer from other mental health and substance abuse disorders, also suggesting an underlying vulnerability [27].
The main limitation of this study is the small number of patients restricting the power to detect significant changes and limiting the number of covariables that could be included in the models. However, strong and clinically relevant absolute changes and improvements in depressive symptoms were observed. Further, we should realize that the CES-D is a screening questionnaire which cannot be used to diagnose depression, for which the gold standard still is psychiatric interviewing and examination. On this line it should be noted the questions in the CES-D refer to the past week, which might further reflect reactive depressive symptoms (instead of clinical depression/chronic depression), overestimating the proportion with actual depression. The associations as observed in the analyses of the current study are possibly an overestimation (numerically), and the effect of infliximab on true (physician-diagnosed) clinical depression might be smaller in daily practice. Finally, we did not have data available on the individual BASDAI items, precluding analysis of the contribution of each item.
The findings in the present study have several implications. Rheumatologists should be aware of the high prevalence of depressive symptoms in patients with AS and active disease, while considering that these symptoms are not strictly a result of pain and loss of functioning. In addition, our results suggest that treatment with a TNFi is beneficial for depressive symptoms in the majority of this population. Still, a proportion of patients seem to maintain clinically significant depressive symptoms despite TNFi treatment, which might require specialized treatment.