Tocilizumab Therapy and Incident Depression in Rheumatoid Arthritis: A Retrospective Cohort Study of the All of Us...

Depression is a common and disabling comorbidity in rheumatoid arthritis (RA). Experimental and genetic evidence implicates interleukin-6 (IL-6) signaling in the pathogenesis of depression, but the association between pharmacologic IL-6 receptor inhibition and incident depression in patients with RA remains uncertain.

We conducted a retrospective cohort study using the National Institutes of Health's All of Us Research Program. Adults with RA and no history of depression before cohort entry were included. Tocilizumab exposure was defined by documented drug administration. The primary outcome was incident depression after the index date. Multivariable logistic regression adjusted for age, sex, race, and ethnicity, inverse probability of treatment weighting (IPTW), and Cox proportional hazards regression were used to estimate the association between tocilizumab exposure and the risk of depression.

The study included 9,826 patients with RA, including 299 treated with tocilizumab and 9,527 untreated controls. Incident depression occurred in 66 of 299 patients (22.1%) treated with tocilizumab and 3,288 of 9,527 patients (34.5%) in the untreated group. Tocilizumab was associated with a lower risk of incident depression in unadjusted analysis (odds ratio (OR), 0.54; 95% confidence interval (CI), 0.42-0.72; P<0.001). The association remained significant after multivariable adjustment (OR, 0.56; 95% CI, 0.42-0.74; P<0.001) and IPTW analysis (OR, 0.58; 95% CI, 0.54-0.61; P<0.001). Cox regression likewise demonstrated a reduced hazard of depression among tocilizumab-treated patients (adjusted hazard ratio (HR), 0.70; 95% CI, 0.55-0.90; P=0.003 by the log-rank test).

Tocilizumab therapy was associated with a significantly lower risk of incident depression among patients with RA. These findings support a potential role for IL-6 receptor blockade in modifying depression risk and warrant prospective studies to determine whether IL-6 inhibition has direct antidepressant effects independent of its effects on inflammatory disease control.