Neuroscience Therapeutic Areas, Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, United States.
Immunology Therapeutic Areas, Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, United States.
Brain Behav Immun. 2017 Nov;66:156-164. doi: 10.1016/j.bbi.2017.06.014. Epub 2017 Jul 1.
Cytokines, including interleukin-6 (IL-6), modulate neuronal plasticity and stress coping. Depressive symptoms and major depressive disorder (MDD) have been associated with changes in cytokines and their signaling. The current study examined the effect of IL-6 monoclonal antibody administration on depressive symptoms in patients with rheumatoid arthritis (RA) or multicentric Castleman's disease (MCD). The data were obtained from two phase 2, double-blind, placebo-controlled trials designed to test the efficacy of sirukumab in RA (N=176) or of siltuximab in MCD (N=65), and were analyzed post hoc to investigate the effects of these IL-6 antibodies on depressive symptoms. The SF-36 questionnaire items on depressed-mood and anhedonia were combined as the measure for depressive symptoms. The study participants were grouped by the presence/absence of prevalent depressed mood and anhedonia (PDMA, meaning either depressed mood or anhedonia was present at least 'most of the time' and the other at least 'some of the time' for four weeks) at baseline; 26.1% of the RA sample and 15.4% of the MCD sample met criteria for PDMA at baseline. Compared with placebo, sirukumab and siltuximab produced significantly greater improvements on depressive symptoms. To account for an effect on mood due to changes in RA or MCD, the analysis was (1) adjusted for symptom severities using DAS28-CRP for RA and MCDOS for MCD alone or together with bodily pain and physical functioning, and (2) performed within RA and MCD non-responders. Improvement in depressive symptoms remained significant in the treated group for both drugs. The significance over placebo was also observed in the siltuximab study. The improvement in depressive symptoms by sirukumab correlated positively with the baseline soluble IL-6 receptor levels. The data together suggest that the IL-6 antibodies improve depressive symptoms in patients with RA and MCD. Further studies are needed to elucidate to what extents the IL-6 antibodies improve depressive symptoms through improving primary disease dependent and independent mechanisms, especially in RA patients, and the brain mechanisms underlying depressive symptom improvements.
细胞因子，包括白细胞介素-6（IL-6），调节神经元可塑性和应激应对。抑郁症状和重度抑郁症（MDD）与细胞因子及其信号转导的变化有关。本研究考察了白细胞介素-6 单克隆抗体给药对类风湿关节炎（RA）或多中心卡斯特曼病（MCD）患者抑郁症状的影响。这些数据来自两项 2 期、双盲、安慰剂对照试验，旨在测试 sirukumab 在 RA 中的疗效（N=176）或 siltuximab 在 MCD 中的疗效（N=65），并进行了事后分析，以研究这些白细胞介素-6 抗体对抑郁症状的影响。SF-36 问卷项目中的抑郁情绪和快感缺失被合并为抑郁症状的测量指标。研究参与者根据基线时是否存在/不存在常见的抑郁情绪和快感缺失（PDMA，即抑郁情绪或快感缺失至少在四周内“大多数时间”存在，而另一种至少在“某些时间”存在）进行分组；RA 样本的 26.1%和 MCD 样本的 15.4%在基线时符合 PDMA 标准。与安慰剂相比，sirukumab 和 siltuximab 显著改善了抑郁症状。为了说明由于 RA 或 MCD 变化对情绪的影响，分析（1）使用 DAS28-CRP 对 RA 进行调整，使用 MCDOS 对 MCD 进行调整，或者与身体疼痛和身体功能一起进行调整，或者（2）在 RA 和 MCD 无反应者中进行调整。在两种药物治疗组中，抑郁症状的改善仍然显著。在 siltuximab 研究中也观察到与安慰剂相比的显著意义。sirukumab 改善抑郁症状与基线可溶性白细胞介素-6 受体水平呈正相关。这些数据表明，白细胞介素-6 抗体改善了 RA 和 MCD 患者的抑郁症状。需要进一步研究阐明白细胞介素-6 抗体通过改善原发性疾病相关和不相关机制，特别是在 RA 患者中，以及改善抑郁症状的大脑机制，在多大程度上改善抑郁症状。
