Principal findings
We used Czech national register-based data to investigate the associations between RA or axSpA and a wide range of mental disorders, considering them to be a potential clinical model of inflammatory mechanisms in mental disorders. We demonstrated that both inflammatory illnesses were associated with mood disorders, anxiety disorders and behavioural syndromes. Our evidence triangulation showed that the associations with mood disorders, and depression in particular, showed a strong decreasing age-at-inflammatory-illness gradient in both inflammatory illnesses. Compared with counterparts who had other chronic illnesses, people with RA or axSpA demonstrated associations with mood disorders, including depression. Also, compared with analyses including also prevalent cases of depression, the association between axSpA and incident cases of depression attenuated, whereas the association between RA and incident depression was consistent with a null effect, this being suggestive of RA not strictly temporally preceding depression. Furthermore, we detected consistent inverse associations between RA and schizophrenia and between RA and Alzheimer’s disease.
Comparison with existing evidence and potential mechanisms
For tractability, we provide indepth discussion for only a subset of detected associations that we consider to be of highest relevance and importance.
RA and depression
The association we detected between RA and depression is consistent with findings from register-based studies from Sweden,22 Taiwan23 and the UK.24 The stronger associations in younger individuals with RA, also aligning with a study from the UK,24 the lack of evidence of RA strictly temporally preceding depression and the stronger association between RA and depression compared with those between other chronic illnesses and depression might support the notion of a shared aetiology. In RA, the interleukin 6 pathway is involved in inflammatory processes25 and elevated C reactive protein levels reflect disease activity,26 and meta-analytical evidence shows associations between these markers and depression.1 27 28 Importantly, RA and depression share several immune alterations,29 and the involvement of these inflammatory markers in both RA and depression might be the consequence of such alterations. This would then further align with the possibility of shared causal elements.29
However, two Mendelian randomisation studies failed to detect any evidence of causality between RA and depression,30 31 while another Mendelian randomisation study showed that inflammatory cytokines may not be the mediating mechanism between RA and depression.32 The lack of causality demonstrated in these studies should be nonetheless interpreted cautiously, considering that Mendelian randomisation is highly sensitive to genetic instrument strength. While genome-wide association studies of depression had considerably large samples, those for inflammatory illnesses and inflammatory cytokines involved much smaller sample sizes and might have therefore lacked the power to detect an effect.30–32 However, these Mendelian randomisation findings do point to an alternative primary explanation for the presence of depression in people with RA.
RA onset earlier in life might translate into more severe, active and potentially treatment-resistant forms of the disease. This in turn may cause more disability and reduced quality of life and then contribute to developing depression, even in the absence of a common biological cause. This alternative explanation, however, is not supported by our findings, which show that excluding prevalent cases of depression nullifies the RA–depression association.
RA and schizophrenia
We demonstrated a consistent inverse association between RA and schizophrenia. This inverse association between RA and schizophrenia has been shown previously in register-based studies from Sweden,33 Denmark34 and Taiwan.35 Explanations for these inverse associations might include the potentially prophylactic effect of antipsychotic medications on RA onset later in life36 or the potential involvement of RA treatments in reducing the risk of schizophrenia. For instance, methotrexate had a prominent position in the Czech as well as in international clinical guidelines for RA over the course of this study, while this medication is generally not indicated for treatment of axSpA. A small, early-phase trial of methotrexate indicated antidisease activity potential in schizophrenia.37 Thus, its differential use in the treatment of RA and axSpA might be one of the reasons the two patient groups demonstrated differential risks for psychoses, including schizophrenia.
An alternative explanation that involves under-reporting or underdiagnosis cannot be discounted, given that people with schizophrenia are well known for having reluctance or difficulties in accessing or engaging with healthcare systems. This is broadly supported by the findings of a Swedish register-based study that showed decreased risk of RA in people with schizophrenia but with risks consistent with a null effect in their children, siblings or parents.33 However, the same study also demonstrated a decreased risk of seronegative RA in siblings and children of people with schizophrenia; this would thus suggest that part of these associations can also be due to shared common biological causes.33
RA and Alzheimer’s disease
We detected a consistent inverse association between RA and Alzheimer’s disease. A similar inverse association was demonstrated by register-based studies from Taiwan38 and the UK.39 A Mendelian randomisation study demonstrated a decreased risk between genetically predicted RA and Alzheimer’s disease; however, the results were not robust across all analyses.40 The same study demonstrated an elevated risk for Alzheimer’s disease using register-based data from the UK.40
The lack of consistency in evidence largely precludes us from proposing potential mechanisms responsible for these associations; however, a multinational, multidatabase, case–control study demonstrated a lower risk of—broadly defined—dementia in people who previously used methotrexate,41 a medication that has been used widely to treat RA over the studied period.
Methodological considerations
The strengths of this study include the use of national, routinely collected, standardised health and mortality data. This supported the analysis of usefully precise matched cohorts of people with and without inflammatory illnesses and their psychiatric outcomes. Furthermore, the follow-up period for most individuals was such that we could capture the outcomes over a substantially long period.
This study has some limitations. First, we are aware that a proportion of the studied inflammatory illnesses and mental disorders will be diagnosed and treated in community settings (ie, primary and outpatient care). It is possible—given that this study is based on inpatient services data—that we might be biased towards the more severe end of the inflammatory and psychiatric condition spectrum. However, it is important to remark that the inpatient services data we have been using cover any presenting complaints at the time of the admission and are not limited to admissions due to inflammatory and psychiatric conditions, implying that the bias might be generally towards people with increased inpatient care needs (ie, informative presence bias42) and not specifically towards our conditions of interest. Consequently, the bias would not impact the internal validity of the study, but rather the potential generalisability to other healthcare settings. Second, we did not have information on several important sociodemographic, behavioural and clinical characteristics; thus, we cannot rule out that part of the observed associations is due to residual confounding. In particular, we had no information on the results of biochemical examinations, disease activity and disease severity, all of which are likely to be strongly associated with the outcomes. Relatedly, in analyses involving comparisons with people who had other chronic illnesses, we could not match on the precise levels of disease severity. Third, the matched counterparts without autoimmune arthritides were retrieved from the inpatient care register, and they likely had elevated levels of inflammation themselves, considering that inflammation is a hallmark of many health conditions. Consequently, our results might have underestimated the true effect of having an inflammatory illness on psychiatric outcomes. Fourth, we had neither data on genetics nor data on psychosocial functioning to directly study their potential involvement in the associations between inflammatory illnesses and mental disorders. Fifth, to date, there has been no formal evaluation of all diagnoses used in this study, and we cannot rule out the possibility of under-registration and/or misclassification of diagnoses. Sixth, in our age-stratified models, we used information recorded on the index record; however, this can differ from both the first-ever diagnosis age and the symptom onset age for a given individual. Lastly, the number of outcomes in certain analyses, particularly age-stratified ones, was low, resulting in large uncertainty about the effects.
Clinical implications
This study was not designed to ascertain the specific biological mechanisms underpinning the associations between inflammation and mental disorders. However, our findings might have implications for clinical practice. The findings suggest that people with either RA or axSpA are more likely to experience certain groups of mental disorders, particularly mood disorders, even relative to counterparts who have other chronic illnesses with similar burden. Despite the presence of substantial psychiatric morbidity in these people, high-profile international guidelines on the management of RA and axSpA contain no43 or only perfunctory44 45 mention of the importance of assessing and treating mental disorders in people with these inflammatory illnesses.
Thus, concerted efforts to better recognise and actively address neuropsychiatric conditions in people with either RA or axSpA are imperative. This could entail having a multidisciplinary approach to inflammatory illnesses or incorporating psychiatry professionals/assessments as part of the clinical pathway, among others. Providing such holistic care for inflammatory and psychiatric conditions has the potential to improve outcomes in both health domains.
