There is limited literature discussing depression in the context of autoimmune diseases as a group, specifically MS and RA. MS is a neurological disease affecting the central nervous system and associated sensory motor functions primarily, while RA is a disease of the rheumatoid spectrum, affecting joints and internal organs. However, both diseases are thought to be autoimmune in nature [1, 2]. Depressive symptoms and manifest depression accompanying MS and RA are frequent, yet not well understood. The purpose of this commentary is to compare depression in MS and RA, including underlying pathomechanisms. The prevalence of depression is higher in MS compared to the general population [3], reported to be between 25–50% [3]. Similar findings have been reported in RA with prevalence ranging between 9–68% [4] while the frequency of depression in the general population has been reported to be between 3–7% [5]. Whether this association represents a coincidence or if there are causal factors leading to the higher rate of depression in both, MS and RA is still controversial. However, current research suggests several explanations, out of which two are discussed most frequently: Either depression in these two autoimmune diseases occurs due to a common neurobiological correlate in the central nervous system (CNS) as part of the underlying disease or depression is simply a reactive component, as both MS and RA are typically incurable and progress over time, causing adverse psychological reactions. Moreover, a minority of researchers have suggested reverse causality, i.e., depression may promote the development of MS or RA.

MS is a chronic, progressive, autoimmune inflammatory disorder of the central nervous system [6]. Patients show a variability of symptoms ranging from sensory problems and motor disabilities to fatigue and cognitive deficits. Not uncommon during the progression of the disease are psychiatric disturbances, for example depression, emotional lability, and bipolar disorder [7]. The origins of MS remain unclear. Multifactorial causes, including genetic predisposition, environmental triggers and infectious agents are discussed [1]. The disease affects mainly young adults. At least 2.5 million adults worldwide are diagnosed with MS, with women affected roughly three times as often as men [1]. For the purpose of this commentary, MS will be discussed regardless of clinical phenotype. Immunomodulatory medication and symptomatic therapy are the two most common therapeutic methods [8]. Depressive symptoms, as well as fatigue are common in patients with MS [9]. The lifetime incidence rate of depression in MS patients is between 40–50%, influencing their quality of life and adherence to treatments as well as the progression of the disease [3, 10].

RA is an autoimmune and inflammatory disorder, characterized by joint pain, synovial destruction and swelling; also internal organs, for instance lung, blood vessels or the heart can be affected. In later stages joint damage may result in immobility, affecting quality of life severely. While RA is well established as an autoimmune disease, the underlying mechanisms that cause autoimmunity are unknown. Covariates in the genesis of RA include environmental, genetic, and infectious agents, but their interplay and exact contribution is not known. Behavioral changes are common in RA and include depression, sleep disorders, increased pain sensitivity and affective disturbances [11, 12]. The prevalence of RA is approximately 1% in Caucasians but can vary from 0.1 to 5 percent depending on ethnicity [13]. Annually, approximately 40 out of 100,000 people are affected, with a 2-to-3-time higher risk for women [14]. RA is an autoimmune disease, where autoantibodies against common antigens found in or near joints and some internal organs cause inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs), such as Aspirin, Fenoprofen and Celecoxib are not only pain relievers but also help in reducing inflammation since they reduce the production of prostaglandins which promote pain and fever. Disease-modifying antirheumatic drugs (DMARDs) are also frequently used in the treatment of RA [15]. These immunosuppressives will slow-down damage to joints and help in maintaining remission and reduce the likelihood of peaks (flare-ups).

Major Depressive Disorder (MDD) or depression is a mood disorder where patients are feeling sad and hopeless and lose their interest in activities they previously enjoyed¹ (¹World Health Organization. International statistical classification of diseases and related health problems. 2020; 11th edition).

According to WHO depression is a leading cause of disability and causes considerable morbidity and mortality² (²World Health Organization. World health statistics 2013. 2013; World Health Organization). Based on substantial evidence from both clinical and biomarker-studies there is a shift towards a dimensional view of depression which is based on the grading of its severity as well as by different associated clinical features. It has been suggested that sedentary lifestyle is one of the contributing risk-factors for developing an MDD. Supporting evidence comes from studies in physically disabled people, where also higher rates of depression compared to the normal population have been found. Both facts point in the direction of inflammation as the key pathological mechanism for depression [16].

Based on DSM-5 criteria, subjects have to experience five or more symptoms (e.g., significant weight changes, cognitive disturbance, psychomotor agitation or retardation, feeling of worthlessness, suicidal ideation, fatigue) during the last two weeks and one of the symptoms to diagnose a depression has to be either a depressed mood or a loss of interest or pleasure to diagnose a depression. All these symptoms have to be clinically significant, leading to a meaningful impairment in everyday activities. They cannot be explained by any other medical condition or substance abuse³ (³American Psychiatric Association (APA). Depressive Disorders in Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 2013; Fifth edition). MDD with melancholic features, previously called melancholic depression, is a particular severe form of MDD characterized by anxiety, reduced responsiveness, loss of appetite and sleep-disturbances with symptoms usually ameliorating in the evening.

Patients with MDD with melancholic features have higher cortisol level while patients with atypical depression are characterized by reactive mood, increased appetite, insomnia, leaden paralysis and interpersonal rejection sensitivity. These patients show an increase in abdominal circumference and BMI, and higher circulating levels of C-reactive protein, interleukin (IL)-6 and tumor necrosis factor (TNF)-$\alpha$. Moreover, their levels of plasma triglycerides and glucose are higher and their levels of high-density lipoprotein cholesterol is lower than in MDD patients with melancholic features [17].

Depression is very common in MS patients and is one of the most significant predictors of low quality of life. Furthermore, suicide rates are increased in depressed MS patients [3]. Depression influences the response to treatment and can accelerate the progression of the disease [10]. It is therefore important to understand the link between both diseases. Perhaps the obvious view is that patients suffering from MS due to increased motor disabilities, cognitive dysfunctions or other symptoms realize that this chronic, autoimmune disease threatens to severely impact their quality of life. This view would lead to identifying depression as “reactive” to impact the primary disease has on the patients. Another perspective tries to understand whether there are shared features in the pathophysiology of MS and depression without necessarily attributing a causal link between them. Is depression caused by MS or are there underlying shared pathological mechanisms in both diseases?

Since both depression and RA are common diseases in adults it is not surprising that in many patients both diseases co-occur. However, this correlation does neither preclude causality nor direction of causality. Nonetheless, a robust and clinically significant association between RA and depression has been suggested in several studies [47, 48].

An interesting study focusing on cognition was published by Whitehouse et al. [62]. While the main point of their research did not focus on depression, substantial number of patients in the study either had MDD or other symptoms of depression.

The authors studied whether there is an association between cognitive impairment and autoimmune diseases by assessing different cognitive domains in RA (n = 154) and MS (n = 255). Four dimensions of cognitive impairment were assessed in RA and MS as well as two autoimmune diseases. The domains for cognitive impairment studied were processing speed, working memory, verbal learning and delayed recall memory. Participants also completed a structured psychiatric interview and underwent anxiety and depression assessment. Results were adjusted according to age, sex and education. Both groups exhibited higher rates of cognitive impairment which were more profound in patients with MS, though the only statistically significant difference between MS and RA was found for processing speed (p $\le$ 0.001) [62]. Besides confirming the well-known association between cognitive impairment and MS, the authors extended our knowledge about the cognitive effects of autoimmune diseases by showing a similar pattern of cognitive deficits in RA.

To our knowledge, this is the first approach to compare Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) in regards of depression.

Depressed MS and RA patients share many similarities, i.e., sex, median age of onset and incidence and prevalence rates are comparable. While the causes for both autoimmune diseases remain unclear, it is assumed that the combination of genetic, immunological, and psychosocial factors contribute to the development of depression in both MS and RA. Table 1 (Ref. [4, 10, 12, 21, 35, 55, 56, 60, 62]) gives an overview of similarities and differences of depression in MS versus RA patients. Many publications have dealt with studying the association of mental disorders with chronic diseases, such as MS and RA. MS and depression commonly occur together, a conservative estimate suggests a prevalence for both diseases together to be 16% [63]. In RA, the co-occurrence is estimated to be 17% [4]. Of note, it has been suggested that these numbers severely underestimate the occurrence of depression due to lack of consistent screening tools and inconsistent application of “gold-standard” interview questionnaires, as evidenced by some individual studies suggesting prevalence rates up to 45% in RA [64]. This contrasts to incidence figures of depression reported in the general population in the US of 7.1%⁴ (⁴Adams K. et al. Results from the 2017 National Survey on Drug Use and Health: Detailed tables. 2017. Retrieved from https://www.samhsa.gov/data/sites/default/files/cbhsq-reports/NSDUHFFR2017/NSDUHFFR2017.pdf (Accessed: 10 April 2021).). The WHO estimates that in 2019, approximately 264 million people of all ages suffered from depression, which corresponds to 3.4% of the global population [5]. It is therefore evident that depression is at least 2–3 times more common in patients with MS and RA than in the general population. For both MS and RA, the exact etiology and pathophysiology is poorly understood, yet it is well documented for both diseases that immune inflammatory processes play a major role. This is further illustrated by the fact that treatment for both diseases, while different due to the target structures affected (CNS in MS, peripheral joints and organs in RA) is largely focused on curbing or eliminating inflammation and autoimmune reactions by means of immunosuppressants, immunomodulatory and anti-inflammatory drugs.

There is still a debate whether in both conditions depression is a corollary due to disease-associated symptoms, such as pain, physical limitations, fatigue and many other consequences, or whether depression co-exists and shares a common pathophysiology with MS and RA. In several studies and also in a metanalysis of the available evidence it is however suggested that a purely downstream association, i.e., MS and RA are causing depression due to difficulties in coping with the hardship of these diseases, is unlikely. For MS it has been suggested that a mere 15.7% of depressive episodes or depression could be explained by a psychosocial reaction to the underlying disease [10]. To complicate the issue further, specifically for RA it has been found that depression may play an etiopathogenetic role in developing RA [65].

Since incidence rates of depression in RA patients have not been reported it is therefore difficult to understand whether RA induces depression, or the latter facilitates development of RA. The immune-inflammatory nature of both MS and RA early on came into focus and it has been studied extensively how inflammatory signals (such as IL-1$\beta$, IL-6, TNF-$\alpha$, etc.) are more prevalent in depressed patients with MS or RA [66]. Meanwhile there are multiple lines of evidence emerging from both animal as well as human studies suggesting that inflammatory processes might contribute to the pathogenesis of depression, either via direct actions on the CNS or indirect pathways connecting the brain with the peripheral organs. Studies have documented that individuals with major depression, as a group, have increased inflammatory activity. Elevated peripheral blood chemokine levels and increased stress-induced nuclear factor -$\kappa$B levels have been reported in several studies. Moreover, there is growing evidence pointing to the contribution of inflammatory cytokines in the development of mood disorders in both medically ill and medically healthy individuals. Cytokines may exert their behavioral effects by activating cerebral inflammatory signaling pathways, thus leading to monoamine, glutamate, and neuropeptide imbalance, and attenuating neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), thereby adversely influencing neurogenesis and neuroplasticity. More precisely, peripheral cytokines are able to trespass the CNS-barrier thereby upregulating the production of local inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nitric oxide (NO), cytokines, and chemokines by endothelial cells, perivascular macrophages, and microglia. They are also associated with an increased oxidative stress and generation of reactive oxygen (ROS) and reactive nitrogen species (RNS). As a consequence, increased ROS and RNS contribute to oxidation of tetrahydrobiopterin (BH4), a co-factor required for monoamine-synthesis.

Another pathway influencing the monoamine metabolism is their role in signal transduction pathways such as p38 mitogen- activated protein kinases (MAPKs). There is both in vivo and in vitro evidence showing that a stimulation of the p38 MAPK pathways increases serotonin transporter expression and activity. Moreover, inflammatory cytokines may decrease expression or function of the vesicular monoamine transporter 2 (VMAT2) and/or increase expression or function of serotonin and dopamine transporters (5-HTT/DAT). The glutamatergic system is also affected by inflammatory cytokines. This is done by activation of the enzyme, indoleamine-2,3-dioxygenase (IDO), that is required to catabolize tryptophan, the primary amino-acid precursor of 5-HT, into kynurenine [67].

In addition to the direct influence of some proinflammatory molecules discussed so far, the HPA axis and GR alterations seem to play a major role in depressed individuals with MS [37, 38, 49, 60].

Conversely, it has been shown that patients with depression respond less well to the treatment of their MS and RA in terms of functional progression and treatment responses [67], suggesting that successful treatment of depression may positively influence the overall treatment success of the underlying diseases. This again, speaks in favor of a bidirectional relationship between inflammatory processes and neuropsychiatric mood disturbances. Keeping in mind that cytokines can induce both neurotrophic and neurotoxic effects it becomes evident that the effects depend on their concentration and condition, which might vary according to the disease progression. This complicates a causal interpretation since there is a huge variability in the methods how depression in MS and RA is diagnosed, including which symptom scores are used and how long patients are followed. Most studies that looked at the association between MS or RA and depression are cross-sectional while longitudinal and/or prospective studies are still scarce. Yet such studies would be helpful in determining causality and also in understanding the effect of interventions over a longer period. This, and the different assessment methods when structural (MRI) or functional (fMRI) brain studies that have been implied to understand morphologic and functional changes add to the complexity of understanding the association between depression and MS or RA. This is further complicated by the fact that in MS the target organ is the brain, with frequent changes in the white and gray matter and in several specific regions, such as the hippocampus, while this is not the case in RA. Nevertheless, for both diseases, no conclusive link between structural findings in brain imaging or in functional studies (fMRI) has yet been identified that would allow for a clear association between depression and RA or MS.

Depression is viewed as a complex disease involving psychosocial, symptomatic effects and immuno-neuroendocrine factors. All of these factors play a role in both MS and RA, but likely they represent the downstream inflammatory response of the body rather than a specific manifestation of a yet to be determined underlying disease explaining the association between MS and depression or RA and depression. It is, however, still remarkable that two diseases that are phenotypically very different share almost identical rates of depression that are at least 2–3 higher than in the general population, and that imaging studies as well as neurobiology findings reveal similar pathophysiological pathways associated with the immune-inflammatory axis in both diseases. Finally, both MS and RA are highly complex diseases in their pathophysiology and are still insufficiently understood when it comes to underlying genetic or environmental factors that cause them, and the same is true for depression. Hence, we can assume that an elevated rate of depression in both, RA and MS is a consequence of a cascade of events in which several factors are interwoven and whose downstream-effects might be best explained assuming a biopsychosocial stance: the same genetic susceptibility that makes a person more prone to develop an autoimmune disease might promote a shift towards a proinflammatory immunotranscriptome which influences body as well as brain structures and function by their bidirectional pathways involving immune and endocrine systems. This might then, together with a negative lifestyle and poorly understood environmental factors, lead to behavioral alterations (i.e., mood disturbances) which are further pandered and maintained by adverse psychosocial circumstances and an unpropitious personality makeup (Fig. 1).

Fig. 1.

Overview of the complex and multifactorial association between depression in Multiple Sclerosis and Rheumatoid Arthritis. It is evident that similar patterns exist between these two autoimmune diseases. Causality and direction of causality is poorly understood.

Though MS and RA are based on different pathologies, targeting different structures, both diseases are thought to be autoimmune in nature and hence are associated with an elevated inflammatory activity which, together with a hyperactive HPA-axis may lead to a monoaminergic imbalance causing sickness-behavior and mood disturbances. While there is compelling evidence speaking in favor of a mutual interdependence between depression and inflammation it is still difficult to define a clear cause-effect-relationship from the available studies, for several reasons: first, most of the studies that approached this issue have applied a multitude of definitions of RA and/or MS, both in terms of severity and in terms of subtypes under study. Second, the definitions of depression adopted in these studies have not been applied consistently and, in most studies referring either to RA or MS, depression has not been further sampled according to pertinent subentities (e.g., other types of depression vs MDD with melancholic features). Moreover, many studies only included clinical samples which favors a selection bias that might explain the high prevalence rates of both depressed MS and RA patients [19]. Third, while most studies compared people with MS with or without depression, only few studies with small sample size compared people with MS and depression with people that only had depression without having MS. Finally, to further elucidate the question of causality, it is indispensable to adopt long-term approaches. To improve research in this field, it would be helpful if future studies apply a rigorous definition of MS/RA and depression. It is indispensable to compare MS and RA (and possibly other autoimmune conditions) in the same study, as to avoid reporting bias and also validate more consistently the similar and/or different underlying mechanisms or findings. Since available risk estimates for mood disorders in autoimmune diseases are substantially elevated compared to the general population without such illness it is mandatory to routinely screen MS and RA patients for signs of depression [68]. Many studies suggest that depression is severely underreported, and, consequently, also not treated. Furthermore, even in those where a diagnosis of depression is established, too often it is not treated appropriately, following the idea it is purely “reactive” and symptoms may attenuate by treatment of the underlying disease [32]. A case-control-approach to better understand the overlapping and contrasting risk factors of depression amongst patients with MS and depression in RA should be considered in future studies.

The upregulation of the immune system causes proinflammatory cytokines to bind through the vagus nerve to receptors in the brain that are responsible for emotion regulation occurs both in MS and RA. This shared immunologic pathway in both conditions can be assumed to be predestined for the development of affective disorders.

In summary, it could be demonstrated that several similarities exist between depression in RA and depression in MS, perhaps more than appear obvious when viewing these phenotypically very different diseases. The underlying pathogenesis is poorly understood, but biochemical findings, imaging, and psychosocial studies point to the idea that depression is not purely a psychological consequence in reaction to a life-threatening disease but also might represent a downstream consequence of similar underlying neurohumoral and neuroimmunological mechanisms that are pertinent to both, MS and RA. Whether this may lead to clinical utility, e.g., extending the use of anti-inflammatory drugs proven to be effective in one diseases at this point purely speculative and remains to be further elucidated.

BDI-II, Beck Depression Inventory II; BDNF, brain-derived neurotrophic factor; BMI, Body Mass Index; CNS, central nervous system; COX-2, cyclooxygenase-2; CRP, c-reactive protein; CSF, cerebrospinal fluid; DMARDs, disease-modifying antirheumatic drugs; DSM-V, Diagnostic and Statistical Manual of Mental Disorders (5th edition); (f)MRI, functional magnetic resonance imaging; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal; 5-HTT/DAT, serotonin and dopamine transporter; IL, interleukin; MDD, Major Depressive Disorder; MRI, Magnetic Resonance Imaging; MS, Multiple Sclerosis; NO, nitric oxide; NSAIDs, non-steroidal anti-inflammatory drugs; PGE2, prostaglandin E2; RA, Rheumatoid Arthritis; RRMS, relapsing-remitting multiple sclerosis; sIL-2R, soluble form of interleukin 2-receptor; STAI-Y, State/Trait Anxiety Inventory; TNF, tumor-necrosis factor; VMAT2, vesicular monoamine transporter 2; WHO, World Health Organization.

AW and PC conceived and designed the review; AW performed the literature analysis and overview; AW and PC wrote the paper.

Not applicable.

We thank our anonymous reviewers for their fruitful comments on our article.

This research received no external funding.

The authors declare no conflict of interest.