Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burden [1]. According to WHO it is one of the diseases with greater impact on the society and is an important contributor of global disability. It affects approximately 1 percent of the population[2]. The incidence of RA increases between age of 25 and 55 years of age after which it decreases. Chronic medical conditions like RA are associated with an increased risk of depression and suicide[3]. Depression affects patients with RA beyond the burden of mental illness itself & patients with RA and comorbid depression have worse health outcomes [4]. Also, patients with RA and associated depression have increased health service utilization and are less likely to be adherent with their medications[5]. In addition to these negative health consequences, depression may contribute to unemployment, loss of work productivity and increased healthcare costs in persons with arthritis [6]. Major depressive disorder is common in patients with RA, with a prevalence of 13-42% [7, 8, 9], at least double to four-times than that in the general population. The wide range in the prevalence of depression in clinical studies of RA is likely due to the different methods used for measuring depressive symptoms. The importance of defining and measuring depression in patients with RA pertains not only to treating a comorbid condition, but also to mitigate the indirect negative effects of depression on RA outcomes, both in terms of functional progression and treatment responses. Matcham, et.al[10], used data from the British Society of Rheumatology (BSR) biologics register and reported that depression at baseline contributed to an approximately 30% reduced odds of positive response to biologic therapy. Additionally, the DAS 28 response to biologic agents was reduced in these patients over time. Studies have also shown that of all mental health disorders, depression is most strongly associated with RA [11]. As with other complex biologic systems, relationship between depression and RA is multifactorial, as in some cases it is likely that depression is mediated by the socioeconomic results of RA and in other cases, it may be due to the systemic inflammation and the resulting pro- inflammatory cytokine milieu. There are also a few patients and disease factors related to depression. Female gender and younger age have well- known associations with depression [12]. Even race/ ethnicity has a role to play and is independently associated with RA. Asians with RA report less depression compared with Hispanics and Anglo society [13]. While precise pathological mechanisms causing depression or other neuropsychiatric manifestations are currently being investigated, most existing insights about the pathogenesis are derived from animal models. Adult hippocampal neurogenesis, the generation of new neurons in the dentate gyrus throughout lifetime, is a physiological process contributing to learning, memory, pattern separation and emotions. It is impaired in models of neurodegenerative diseases and depression but is also affected by local and systemic inflammation [14]. Of relevance to the neurobiology of depression, immune-mediated inflammation has effects on neurotransmission, neuro-genesis, neuroendocrine activity, hypothalamic- pituitary- adrenal axis (HPA axis), and neuroplasticity. Meta-analyses have showed that concentrations of cytokines, including IL-6, IL-1β, and TNFα, are raised in the peripheral blood of patients with depression compared with healthy controls [15]. Similarly, other meta-analyses have implicated chemokines (chemotactic cytokines central to the orchestration of the immune response) in depression [16]. Furthermore, higher plasma concentrations of C-reactive protein are associated with treatment-resistant depression, suggesting that those individuals with inflammatory burden are most likely to be non-responsive to conventional therapy [17]. The direct functional effect of inflammation on the HPA axis is also well documented; inflammatory cytokines, such as IL-1β, appear to be important mediators of this response [18, 19]. Hence, our study aims to assess the prevalence of depression in patients with RA and its correlation with disease activity and functional status. The knowledge about the prevalence will help physicians and rheumatologists combat this debilitating disease in a more integrated manner.

Study Design This was a descriptive cross-sectional study which included patients of RA attending the Department of Rheumatology at a tertiary care hospital over a period of 06 months (Jan 2021- July 2021). The study was conducted after obtaining ethical clearance from the Institutional Ethics Committee (IEC). All consecutive in-patients and out-patients who gave written informed consent and met the inclusion criteria were taken into consideration for the study. Study population Adult patients >= 18 years of age fulfilling the ACR- EULAR (2010) classification criteria for RA with a disease duration (since symptom onset) of atleast one year, were included. All study participants belonged to South-east Asian region (India). Pregnant patients, patients with overlap syndromes and those with underlying known psychiatric illness or concurrent malignancy were excluded from the study. Data collection and assessments The various demographic characteristics of the study participants were recorded, including documentation of co-morbid conditions and smoking status. RA clinical variables (disease activity & duration, TJC (tender joint count), SJC (swollen joint count), patient global assessment on VAS (PtGA), functional status, and ongoing pharmacological therapy) were also assessed in the same visit. For assessment of functional status, the Indian version of HAQ-DI was used. For disease activity evaluation, DAS 28 CRP was used. Patients with widespread pains were diagnosed to have concomitant fibromyalgia, if they satisfied the 2016 ACR criteria for diagnosis of fibromyalgia. All patients underwent a basic panel of tests which included- Complete blood count (CBC), kidney and liver function tests, Rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) along with tests for acute phase reactants including ESR and CRP. These tests were carried out in the laboratory of the institute. Serum CRP and RF was measured by nephelometry using an automated analyser system- Beckman Coulter Automated Nephelometer. The unit of measurement for CRP & RF was milligram/litre (mg/L) and units/ml (U/ml) respectively. ACPA was measured by commercially available second generation ELISA kits with units of measurement being arbitrary concentration units/ml (Au/ml). Seropositivity was defined as RF titres >20U/ml, Anti CCP titres >=15 Au/ml or both. Depression was evaluated with the help of Beck Depression inventory (BDI) Scale. It is a 21-item self-reported questionnaire. Responses to the 21 items are made on a 4-point scale, ranging from 0 to 3 (total scores can range from 0- 63) with higher scores indicating more severe symptoms. Generally, scores are interpreted as follows: 0-10: minimal or no depression, 11-16: mild depression, 17-20: borderline clinical depression, 21-30: moderate depression, 31-40: severe depression, and over 40: extreme depression. Sample size calculation The sample size was calculated using the formula- N= Z2P(1-P)/e2 Where N is the sample size, Z is 1.96, which corresponds to the desired level of confidence (95%), P is expected prevalence of depression in RA obtained from previous studies, approximating 27.5%, and e is the margin of error (which is 5% or 0.05). The required minimum sample size, using a confidence interval of 95% was found to be 152. Our study was undertaken with a sample size of 161 patients. Outcome measures Primary outcome measures were to assess prevalence of depression in Indian patients with RA and its correlation with disease activity and functional status. Secondary outcome measures included correlation between depression and fibromyalgia, between depression and bDMARD exposure; any association between smoking and depression and between depression and co-morbid conditions including diabetes mellitus, hypertension, etc. Statistical Analysis Statistical testing was conducted with the statistical package for the social science system (SPSS) software latest version. Continuous variables were presented as mean±SD or median if the data was unevenly distributed. Shapiro-Wilk test was used to assess whether or not, variables were normally distributed. Categorical variables were expressed as percentages. Nominal categorical data between the groups were compared using Chi-square test or Fisher’s exact test, as appropriate. Non-normal distributed continuous variables were compared using Mann Whitney U test or Kruskal Wallis test. Logistic regression models were used for comparison of binary outcomes. Tests for strength of association were performed using Spearman or Kendall Tau correlation tests. For all statistical tests, a p value less than 0.05 was taken to indicate a significant difference. A correlation coefficient of +1 indicated that the two variables were perfectly related in a positive linear manner, a correlation coefficient of -1 indicated that the two variables were perfectly related in a negative linear manner, while a correlation coefficient of zero indicated that there was no linear relationship between the two variables. In addition, point biserial correlation coefficient was used when one variable was dichotomous, like presence or absence of fibromyalgia/ deformities/ exposure to bDMARDs/ comorbid conditions. Results have been published as per STROBE guidelines.

Demographics & RA phenotype A total of 161 patients of were enrolled in the study. The mean (SD) age of the study population was 50.74 years (12.19). 21.1% were males and 78.9% of the participants were females. The mean (SD) disease duration was 10.43 (8.27) years, with mean age of disease onset being 40.3 years. 86.3% (n= 139) of the participants had positive Rheumatoid Factor. 90.1% (n=145) of the participants had Anti-CCP positivity and 80.7% of the participants had both RF and Anti CCP positivity. 4.34% (n= 07) patients were seronegative. 94% (n= 152) of the participants were non-smokers. 4.3% (n= 07) of the participants were reformed smokers and 1.2% (n= 02) of the participants were current smokers. A total of 45 (28.1%) patients had exposure to bDMARD therapy, out of which 14 had ongoing bDMARD therapy for disease control. Individuals with any co-morbid condition were 127 (78.9%). The most common comorbid condition was obesity. Patients were classified as being obese based on the WHO criteria for obesity for asian population. Obesity was followed by followed by diabetes mellitus (DM) and hypertension. Disease assessment The mean (SD)- DAS-28 was 3.62 (1.27), corresponding to moderate disease activity. Figure 1 shows the distribution of patients according to disease activity. The mean (SD) of HAQ DI was 0.83 (0.54) and it ranged from 0 - 2.2. Concurrent fibromyalgia was present in 9.9% of the patients. Fig 1: Histogram demonstrating distribution of DAS 28 Moderate depression and higher is usually considered as significant depression as per BDI scale. Hence, significant (clinical) depression was present in 49 (30.4%) patients. The mean (SD) of BDI score was 16.05 (8.66) and it ranged from 1 - 37. 23.6% (n= 38) and 16.8% (n= 27) had mild mood disturbances and borderline depression respectively. There was a signficant correlation between disease activity and BDI score (χ2 = 33.649, p = <0.001) and HAQDI and BDI score(χ2 = 36.123, p = <0.001), as depicted in table 1 below. Table 1: significant correlation between disease activity and BDI score& functional status and BDI score BDI Inference Kruskal Wallis Test Normal Mild Mood Disturbance Borderline Depression Moderate Depression Severe Depression χ2 p value DAS 28 (CRP) Mean (SD) 2.95 (1.07) 3.39 (1.20) 3.80 (1.25) 4.21 (1.07) 4.88 (1.26) 33.649 <0.001 HAQ DI Mean (SD) 0.59 (0.53) 0.66 (0.48) 0.87 (0.46) 1.12 (0.43) 1.41 (0.48) 36.123 <0.001 The median BDI score was highest in patients with deformities. It was also noted that, overall, there was no significant statistical difference in the prevalence of depression in patients with or without any metabolic co-morbid conditions. Subgroup analysis done, showed significantly higher prevalance of depression among those with secondary fibromyalgia. Also, depression was noted to be higher in patients who were currently on bDMARD therapy. No association was observed between depression and smoking status.

As a major public health concern, unipolar depression has been demonstrated to have estimated lifetime prevalence as high as 12% [20]. The relationship between depression and RA has been the subject of much research. Inflammatory pathways may hold the key to a link between depression and RA. Rifkin et al.[21] postulated that diagnosing major depression in physically ill patients may be difficult because- a) symptoms of depression overlap with symptoms of the physical disorder; b) the physical disorder itself may cause depression; and c) some degree of sadness, disappointment, and fear is normal and appropriate to the situation. In RA, the overlap of somatic symptoms includes fatigue and sleep disturbances. Insufficient treatment of depression in RA and other physical illnesses may be related to a misconception that depression is understandable and does not represent a treatable disorder [22]. Chronic inflammation has been linked to neuropsychiatric manifestations in RA. Adult hippocampal neurogenesis can been found to be profoundly affected in mice models of neurodegenerative diseases and depression and was also affected by local and systemic inflammation [13]. Inflammation has also been shown to decrease both brain-derived neurotrophic factor (BDNF) expression and neurogenesis [23]. Specifically, in a rat model of adjuvant-induced arthritis, significant reductions in concentrations of both cortical and hippocampal BDNF were noted, supporting the idea that inflammatory change in arthritis can drive changes associated with depression [24]. Chronic treatment with etanercept increased hippocampal BDNF concentrations in a rat model of dementia and diabetes, supporting the idea that immune-mediated pathways can affect aspects of depressive pathophysiology [25]. The effects inflammation has on neurotransmission are highlighted by upregulation of the enzyme indoleamine 2, 3-dioxygenase (IDO)—an enzyme involved in tryptophan metabolism—leading to increases in kynurenine and potentially reducing serotonin availability within the CNS, due to decreased tryptophan availability[26]. Kynurenine is catalysed by kynurenine3-monooxygenase to 3-hydroxykynurnenine. Quinolinic acid is one of the downstream products of this pathway and is glutamatergic and neurotoxic [27]. The IDO pathway in mature dendritic cells is a key component in the induction of immune tolerance via regulatory T-cell mechanisms; therefore, any targeting of this pathway should be done with caution [28]. Meta-analyses have shown that concentrations of cytokines, including IL-6, IL-1β, and TNFα, are raised in the peripheral blood of patients with depression compared with healthy controls[29]. Similarly, other meta-analyses have implicated chemokines (chemotactic cytokines central to the orchestration of theimmune response) in depression [30]. Disease activity, poor functional status, and pain severity are factors associated with depression in RA patients. Research has been conducted in the area of depression in RA to optimise management of RA as a whole. However, findings of previous studies investigating the same have not been very consistent. A cross sectional study was conducted in patients with RA by Genessis Maldonado et al[31], to determine prevalence of depression using the Patient Health Questionnaire (PHQ-9), and its relationship with disease activity using DAS-28. The HAQ-DI was used to determine functional disability. Depression was observed in 42.9% of the patients. An association was found between depression, DAS-28 and HAQ-DI. It was also found that 70% of the patients with high activity disease and 38% of the patients with signficant functional disability had moderate-severe depression. The number of painful and swollen joints was greater in patients with severe depression than in patients with mild depression. Patients with greater depression referred to more intense pain according to the visual analog pain scale. In another observational study conducted by Mukherjee et al, on adult RA patients, depression among RA patients was evaluated based on self-reported depression (SRD). SRD prevalence was found to be 21% with prevalence being higher in treatment naïve patients. Limitations of this study was, that, SRD is not a usual measure in research studies [32]. In our study, we analysed 161 patients of RA for the presence of depression using BDI scale and evaluated their disease activity using DAS 28 CRP and functional status using Indian version of HAQ -DI in the same sitting. To our knowledge, this is one of the largest single centre study from India that evaluated the prevalence of depression in RA patients and assessed the correlation with disease activity and functional status. The median disease duration in our study was 08 years, with almost 30% of patients having disease duration less than 05 years. This is a slightly higher proportion of patients with early disease as compared to older studies. This finding may be explained by the fact that more patients are now being diagnosed at an early stage of the disease. More than 95% patients in our study population were seropositive (RF or Anti CCP or both). Only 4.34% patients were seronegative. In different cohorts of reported studies worldwide, 20-30% of patients have been found to be seronegative, otherwise [8]. The lower point prevalence of seronegativity in our study can be attributed to the methodology of our study where the enrolled patients who already had a diagnosis of seonegative RA initially, were re-evaluated for their serological status. Many patients, who were previously described as being seronegative, turned out to be seropositive during the re-evaluation. In our study, we had used the BDI scale, since a validated Hindi version is also available for the same. Hence, this becomes relevant in our cohort of patients, where majority of individuals are acquainted with the Hindi language. The prevalence of depression in our study was 30.4%. A systematic review and meta-analysis was conducted by Matcham F et al.[10] assessing 72 studies on prevalence of depression in RA. It also included a few studies, that had used BDI as the scale for measuring depression, and major depressive disorder was found to range from 22-46% in those studies, which is consistent with findings of our study. In our study, there was a moderate positive correlation between depression and disease activity, and between depression and functional status, which is similar to the findings found in the studies by Imran YM et al.[32] and Matcham F et al. The correlation in our study was however, stronger. In addition, there was a moderate positive correlation between Patient VAS and BDI Score. This explains that depression is also a matter of subjective perception of a disease in totality. Patients with RA experience elevated risk of cardiovascular diseases (CVDs) with 50-70% higher risk of heart disease than the general population. The co-morbid conditions are also independent risk factors for developing depression. In our study, there was no significant statistical difference in the prevalence of depression in patients with or without any comorbidity. Smoking has traditionally been associated with an increased risk of depression. In a population based study by Weinberger AH et al., it was found that prevalence of depression was higher in people with history of smoking as compared to those who had never smoked and the difference was statistically significant [33]. In a study specifically done on RA patients, depression, was not significantly associated with current smoking [34]. This finding was also seen in our study, where smoking (current or reformed smoking) was not associated with depression. Another interesting finding that was noted, was a higher prevalence of depression in patients on bDMARD therapy. This can be attributed to the fact that many patients in our study, also had participated in the study at the time of initiation of bDMARD therapy, meaning they were having high disease activity at that particular time period and consequently, higher depression levels. Strengths of the study • This study, to the best of our knowledge, is one of the very few Indian studies assessing for depression and its correlation with functional status and disease activity. Previously, one large study by Mukherjee D et al. had assessed the prevalence depression in RA. A few small scale studies are also reported in the literature, but with much less sample size. • This study is a comprehensive study that has evaluated the relationship between depression with multiple entities including disease activity, functional status and fibromyalgia, and also evaluated the effect of comorbidities, smoking, bDMARD therapy on the prevalence of depression. • The sample size used in this study is fairly large compared to similar previous studies published in literature that have correlated depression with functional status and disease activity in RA. • Limitations of the study This study included patients from a single centre. Further validation of our study results requires a larger number of patients from multiple centres across India. A significant number of RA patients that attended our rheumatology clinic, were illiterate, hence many of them could not be enrolled for the study, which might have underestimated/ overestimated our results.

The prevalence of depression and its correlation with disease activity and functional status was studied in 161 patients of RA at a tertiary care hospital. The results were consistent with the published literature. Depression was assessed using self-reported questionnaire- BDI. Depression in RA can have significant overall health impact. It has a wide range of prevalence in different studies. In our study, clinically significant, moderate and severe depression was found in 30.4% patients. A significant positive correlation was also seen between depression with disease activity & functional status. Fibromyalgia was also found to be significantly more in patients with depression as compared to non- depressed RA patients. Other parameters like CVDs, history of smoking and obesity didn’t appear to have any impact on the prevalence of depression amongst our cohort of RA patients.

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