Full-length ArticleThe effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman’s disease
Introduction
Neuroactive cytokines such as interleukin-6 (IL-6) regulate synaptic plasticity, neuronal development and survival, and neurogenesis (Erta et al., 2012, Gruol, 2015, Spooren et al., 2011). IL-6 can be produced both centrally by microglia, astrocytes, endothelial cells and certain neurons, and peripherally by T-cells and macrophages (Erta et al., 2012, Gruol, 2015, Hunter and Jones, 2015, Spooren et al., 2011). Peripheral IL-6 can enter the brain and exert central effects (Banks et al., 1994). IL-6 activates both cis- and trans-signaling, mediated respectively by the membrane bound IL-6 receptor (IL-6R) and the soluble IL-6 receptor (sIL-6R) (through which IL-6 signaling can impact cells that do not express the IL-6R (Hunter and Jones, 2015)).
Elevated levels of IL-6, both peripherally and centrally, have been reported in patients with major depressive disorder (MDD). Several clinical studies and meta-analyses have shown that IL-6 levels are significantly elevated in depressed patients in plasma or serum (Alesci et al., 2005, Dowlati et al., 2010, Fitzgerald et al., 2006, Frodl et al., 2012, Goldsmith et al., 2016, Maes et al., 1995, O’Brien et al., 2007, O’Donovan et al., 2013, Yoshimura et al., 2009, Yoshimura et al., 2010). Some studies have reported an association between peripheral IL-6 elevation and the symptom severity and chronicity of depression episodes, and between CSF IL-6 elevation and suicidal ideation (Lindqvist et al., 2011, Lindqvist et al., 2009, O’Donovan et al., 2013). Elevation of IL-6 mRNA levels is also found in leukocytes from depressed patients (Cattaneo et al., 2013). Peripheral IL-6 elevation has been linked to central changes through an association with reductions in hippocampal volume in depressed patients (Frodl et al., 2012). In addition, elevations of IL-6 mRNA in the brain regions from suicide patients are also reported in human postmortem studies (Pandey et al., 2012). In healthy volunteers, endotoxin caused increases in IL-6, TNFα and IL-10 in plasma and only IL-6 in CSF, which was associated with mood impairment (Engler et al., 2017). Together, the data suggest two sources of brain IL-6 elevation in depression, peripheral IL-6 entering the brain and brain de novo production of IL-6. Elevated levels of sIL-6R also have been reported in depressed patients (Maes et al., 1995) and IL-6 trans-signaling has been associated with depression and CNS dysfunction (Maes et al., 2014).
Interferon alpha (IFN-α) treatment in patients treated for Hepatitis C frequently induces symptoms of depression and fatigue with a concomitant increase in IL-6 plasma (Bonaccorso et al., 2001) and CSF (Raison et al., 2009) levels. A promoter polymorphism in the IL-6 gene (−174G/C, rs1800795) results in lower IL-6 transcription, and hepatitis C patients with this low efficiency IL-6 promoter show reduced risk of developing depressive symptoms when treated with IFN-α (Bull et al., 2009, Udina et al., 2013). High efficiency promoter of IL-6 gene is reported linked to increased appearances of depression episode during the course of INF-α/ribavirin treatment of chronic hepatitis C (Frydecka et al., 2016). In a Chinese-Han cohort, the frequencies of another IL-6 promotor allele (−597A/G, rs1800797) are significantly different between MDD and healthy subjects (Zhang et al., 2016). These data provide additional support for a role of IL-6 in depression.
Social and psychological stress is a key contributor to and putative trigger of clinical depression (Chen et al., 2010, Manji et al., 2001). Stress elevates cytokines including IL-6 and their downstream effectors in the blood and brain of animals (Beurel et al., 2013, Girotti et al., 2013, Gomez-Lazaro et al., 2011, Jiang et al., 2013, Kinsey et al., 2008, Mutlu et al., 2012, Sukoff Rizzo et al., 2012, Voorhees et al., 2013, Wohleb et al., 2011, Wu et al., 2011, Wu et al., 2013, You et al., 2011). The social defeat stress paradigm recapitulates some of the stress-associated vulnerability, neurobiological correlates, behavioral deficits, and treatment responsiveness of depression (Berton et al., 2006, Golden et al., 2011, Krishnan et al., 2007). In this paradigm, 60–70% of mice (susceptible) develop social interaction deficits and anhedonia-like abnormalities (Golden et al., 2011). Susceptible mice display higher production of IL-6 in their leukocytes prior to social defeat stress than resilient animals (Hodes et al., 2014). Transplanting hematopoietic progenitor cells from the bone marrow of stress-susceptible mice increases IL-6 production and results in greater social avoidance after stress, while IL-6 knockout mice, and mice treated with anti-IL-6 antibodies administered i.p. do not develop social interaction deficits (Hodes et al., 2014). These data support a role for peripheral IL-6 in depression and suggest peripheral IL-6 blockade as a therapeutic approach to treat depression.
Some autoimmune-related inflammatory disorders such as rheumatoid arthritis (RA) and psoriasis have been associated with elevated rates of depressive symptoms and MDD compared to relevant control conditions(Fleming et al., 2015, Matcham et al., 2013). Previous studies and meta-analyses have examined depressive symptoms improvement with treatments using biological therapies targeting tumor necrosis factor alpha (TNFα) (etanercept, adalimumab, infliximab), IL-12/23 (ustekinumab), IL-4 receptor alpha (dupilumab), and IL-6 receptor (tocilizumab) in patients with immune dysfunction (Kappelmann et al., 2016, Kohler et al., 2014, Raison et al., 2013, Tyring et al., 2006). An open label study of 29 patients with rheumatoid arthritis (RA) reported that after six months of treatment with tocilizumab (anti-IL-6 receptor antibody), the treatment reduced the depression scores of the Hospital Anxiety and Depression Scale (HADS), but the reduction did not reach statistical significance (Traki et al., 2014) The depression scores from the HADS are also reported from a large cohort of open-label four month treatments with tocilizumab in RA patients; however, the depression ratings before and after the treatment were not statistically compared(Gossec et al., 2015). Consequently, it remains unclear whether directly blocking IL-6 receptor is effective in reducing the severity of depression symptoms.
In contrast to tocilizumab, which targets IL-6 receptors, sirukumab and siltuximab are antibodies which directly interact with IL-6 and block its function. Based on studies in experimental animals, by neutralizing IL-6 in the periphery, IL-6 antibodies are thought to reduce the amount of peripherally synthesized IL-6 that enters the brain (Hodes et al., 2014). IL-6 antibodies have not been tested for efficacy in MDD or in major depressive episodes that arise co-morbidly with other medical diseases such as RA.
We obtained data sets from two double-blind, randomized, placebo-controlled clinical trials investigating the efficacy of two IL-6 monoclonal antibodies, sirukumab and siltuximab, in patients with methotrexate (MTX)-resistant RA and in patients with HHV8-negative multicentric Castleman’s disease (MCD), respectively. Excessive production of IL-6 is known in these two diseases, and additional evidence also suggests excessive IL-6 production contributes to pathology and symptoms of these two diseases. As well, the efficacies of two IL-6 antibodies, sirukumab and siltuximab, on these two diseases have been examined in clinical trials (Smolen et al., 2014, van Rhee et al., 2014). These existing trial data provide an opportunity to explore the impact of anti-IL-6 treatment on depressive symptoms. Within these studies we evaluated the treatment effect on depressive symptoms, and its association with improvement in primary disease symptoms. In post hoc analyses we explored the biomarker predictors of improvement in depressive symptoms and biomarker correlates of depressive symptoms in RA.
Section snippets
Sirukumab and siltuximab trials
Data are from two phase II randomized, double-blind, placebo-controlled clinical trials: NCT00718718 in 187 MTX-resistant RA patients with screening CRP ≥ 10mg/L (Smolen et al., 2014), and NCT01024036 in 79 HHV8-negative MCD patients with no prior exposure to IL-6 or IL-6R targeted therapies (van Rhee et al., 2014). The placebo was sterile liquid containing l-histidine and l-histidine monohydrochloride, sucrose, and polysorbate 80 for the sirukumab trial, or histidine, sucrose, and polysorbate 80
Participant sample characteristics
The key demographic and baseline characteristics of the patient cohorts with and without PDMA appear in Table 1. The only significant demographic differences identified between the subgroups were a slightly younger age among RA patients with PDMA and a difference in racial distribution. PDMA was evident at baseline in 46 (26%) of the 176 RA patients, and in 10 (15%) of the 65 MCD patients (Fig. 1). A significantly higher RA severity was detected in patients with PDMA (Table 1, Fig.1A). No
Discussion
Among patients enrolled in the studies presented here, with RA and MCD, 26% and 15%, respectively, meet criteria for prevalent depressed mood and anhedonia (PDMA) (Fig. 1). Within patients experiencing PDMA, peripheral IL-6 neutralization is associated with better improvements in depressed-mood and anhedonia in RA and MCD patients (Fig. 2). The data also revealed a potential link between the pretreatment level of sIL-6R and improvement of depressed mood and anhedonia in response to treatment
Conclusion
Using two cohorts of two different diseases, two distinct antibodies on same target, and two separate double-blind, placebo-control clinical phase 2 trials, post hoc analyzes revealed for the first time that the antibodies against IL-6, sirukumab and siltuximab, improved depressive symptoms in RA and MCD patients. More clinical and preclinical studies are needed to elucidate fully whether the depression symptom improvements are due to through direct blockage of elevated IL-6 function, secondary
Financial disclosures
CC: full time employee of Fred Hutchison Cancer Research Center in Seattle, and received research grants and consulted for Janssen R & D, LLC.; DW, YS, GS, BH, MC, JV, JMK, JS, WCD, GMW and GC: current full time employee of the Janssen Research & Development, LLC and stockholder of the Johnson & Johnson.
Acknowledgments
The author contributions are: DW and YS: post hoc study design, statistical analysis, drafting the manuscript; JS, GS, IC, JK, and WD: clinical and scientific input on study design and data interpretation, and providing critical review of manuscript. BH and MC: Sirukumab trial and clinical and scientific input; CC and JV: Siltuximab trial and clinical and scientific input; MC and WD: Conception and initiation of the post hoc study; GW and GC: Initial concept development, scientific input,
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