Background Interleukin-6 (IL-6) is one of the known neuroactive-cytokines involved in neuronal plasticity and stress coping and is associated with depression. Depressive symptoms are common in patients with rheumatoid arthritis (RA), a disease characterized by high peripheral IL-6. Previous analysis of a Phase II study¹ showed that sirukumab, a human monoclonal antibody that selectively binds to the IL-6 cytokine with high affinity, can help reduce depressive symptoms in RA patients.

Objectives To further assess and validate the effects of sirukumab on relieving depressive symptoms in RA patients.

Methods We conducted a post-hoc analysis of 2 Phase III, randomized, double-blind, placebo-controlled trials evaluating efficacy and safety of sirukumab in the treatment of RA. SIRROUND-D enrolled patients with active RA despite disease-modifying anti-rheumatic drugs and having serum C-reactive protein (CRP)≥8mg/L at baseline. SIRROUND-T enrolled patients with active RA despite anti-TNF therapy and having serum CRP≥8mg/L or erythrocyte sedimentation rate≥28mm/h at baseline. Patients using antidepressants were excluded from the analysis. Patients were grouped by presence/absence of prevalent depressed mood and anhedonia (PDMA), based on the self-reported frequencies of these 2 core depressive symptoms in the SF-36, requiring one present at least “most of the time” and the other “some of the time” in the past 4 weeks. A depression score was derived based on the 2 core depressive symptoms of SF-36. Relief of depressive symptoms in patients with PDMA was evaluated by comparing changes in the depression score from baseline to week 8 between the placebo and combined sirukumab groups directly and with adjustment for RA activity as measured by the Disease Activity Score-28 with CRP. Changes in depression score were also analyzed in RA patients who did not have an ACR50 response to sirukumab. The combined effect of anti-IL-6 treatment was estimated using meta-analysis of 2 Phase III, 1 Phase II studies of sirukumab and 1 Phase II study of the anti-IL-6 cytokine antibody siltuximab.

Results At baseline, 19% and 22% of patients were classified as PDMA in the 2 studies, respectively. Sirukumab treatment, compared to placebo, significantly improved depressive symptoms by week 8 among PDMA patients (p=0.022 and 0.046 for the 2 studies, respectively) before adjusting for changes in RA activity. Within the sirukumab group, the reduction in depressive symptoms remained significant after adjusting for changes in RA activity (p<0.0001) and in ACR50 non-responders at week 8 (p<0.0001), while differences in improvements between the sirukumab and placebo group reduced to trends. Meta-analysis of 4 anti-IL-6 studies (1 siltuximab, 3 sirukumab) revealed that anti-IL-6 treatment helps alleviate depressive symptoms even after adjusting for changes in disease activity (Standardized Mean Difference =0.25, p=0.03).

Conclusions Our findings are consistent with previous results from a phase II RA study. Peripheral anti-IL-6 cytokine treatment is associated with improvement in depressive symptoms in RA patients, possibly supporting a role for IL-6 dysfunction in depression.

References

1. Ann Rheum Dis2015;74(Suppl2): 720.

References

Disclosure of Interest Y. Sun Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Develoment, LLC, B. Hsu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Develoment, LLC, D. Wang Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Develoment, LLC, M. Curran Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Develoment, LLC, W. Drevets: None declared, G. Chen: None declared, G. Wittenberg: None declared