Mediators of the association between rheumatoid arthritis and depression

The etiology of rheumatoid arthritis (RA) comorbid with depression is poorly defined. This study aims to investigate the mediating factors in RA co-morbid depression. Through the multicenter, cross-sectional study method, the variables that may become mediating factors were collected. Depression was assessed with the Patient Health Questionnaire-9 (PHQ-9). The generalized linear model and Structural Equation Model (SEM) were used to explore the mediators. Mendelian randomization (MR) was employed to validate the results. A total of 746 subjects were enrolled, including 506 RA patients and 240 non-RA patients. Correlation analysis showed that Health assessment questionnaire disability index (HAQ-DI) (β = 0.04; 95%CI = 0.01, 0.07; P = 0.002), Fatigue Self-Assessment Scale (FSAS) (β = 0.21; 95%CI = 0.19, 0.23; P < 0.0001), and Pittsburgh sleep quality index (PSQI) (β = 0.26; 95%CI = 0.19, 0.33; P < 0.0001) were positively correlated with RA co-morbid depression. Among these, FSAS was a mediator in the causal pathway from RA to depression (Effect estimate = 0.39; 95% CI = 0.30, 0.53). MR analysis supports the mediating role of frailty. In addition, HAQ-DI indirectly mediated the effect of RA on depression through a sequential pathway involving ESR and FSAS, serving as another key factor in this causal pathway. Fatigue and disability are primary mediators contributing to the comorbidity of RA and depression. Therefore, targeting these mediating factors through clinical interventions may represent an effective strategy for preventing and treating depression in this population.