Experimental medicine approach linking brain and peripheral immune mechanisms mediating sickness behaviours in people with rheumatoid arthritis

发生在免疫介导性炎症性疾病(IMID)(如类风湿性关节炎(RA))的人身上的疾病行为--包括情绪变化和疲劳--是一种主要的未得到满足的临床需求。这类行为对预后、治疗反应和结果有显著的额外负面影响。重要的是，它们始终是患者最关心的问题之一。这一领域的治疗进展需要对支撑症状的机制有更深刻的理解，我们建议在RA中使用一种被证明有益的精致具体的干预措施，靶向肿瘤坏死因子，以利用对推动疾病行为的外周免疫的机制的理解。我们将把临床指征治疗与高度创新的神经成像技术结合起来，以获得迄今为止仅在动物研究中可用的人类机制数据。该提案将建立在少数先前研究的基础上，这些研究使用神经成像来显示在类风湿性关节炎等IMIDs的背景下的异常脑通路，以及在肿瘤坏死因子抑制后这些神经成像参数的变化。广泛的临床前和动物研究表明，将外周炎症蛋白与疾病行为联系起来的一个假定机制是单核细胞进入大脑，以及随后由单核细胞衍生的肿瘤坏死因子影响的神经变化，最显著的是通过谷氨酸能作用。因此，使用超高场(7T)MRI和MRS以及创新的SPECT-CT来测量循环标记的单核细胞对中枢神经系统的渗透，我们将检验以下假设：i)抗肿瘤坏死因子治疗将影响脑网络连接和大脑中谷氨酸定量的变化。ii)RA患者将表现出与疾病行为相关的脑网络连接和谷氨酸定量的变化。iii)RA患者将表现出与疾病行为相关的单核细胞向大脑渗透的变化。这些成像终点(加上次级认知行为、临床和外周免疫终点)将在基线和4周后测量多达50名RA患者，随机1：1接受抗肿瘤坏死因子抗体治疗或安慰剂治疗。基线数据将使我们能够检验外周血单核细胞渗透和谷氨酸兴奋毒性作为疾病行为机制的两个关键假说。肿瘤坏死因子抑制剂的应用将解决我们的第三个假设。这项研究将提供对亚服务于疾病行为的机制的洞察，从而提供新的工具和靶点，以支持未来针对RA和其他IMID的此类行为的创新药物治疗的发展。

Sickness behaviours - including mood change and fatigue - that occur in people with immune-mediated inflammatory disorders (IMIDs) such as rheumatoid arthritis (RA) are a major unmet clinical need. Behaviours of this kind have a significant additional negative impact on prognosis, therapeutic response and outcomes. Importantly, they are consistently among the most commanding of patients' concerns. Therapeutic progress in this area requires a more profound understanding of the mechanisms underpinning the symptoms Here we propose to use an exquisitely specific intervention of proven benefit in RA, targeting TNF, to leverage a mechanistic understanding of the peripheral immune to brain communications that drive sickness behaviour. We will combine the administration of a clinically indicated therapy with highly innovative neuroimaging technologies to obtain mechanistic data in humans that has hitherto only been available in animal studies. The proposal will build on a small number of prior studies that have used neuroimaging to show abnormal brain pathways in the context of IMIDs such as RA and changes in these neuroimaging parameters following TNF inhibition. A putative mechanism linking peripheral inflammatory proteins to sickness behaviour, implicated by extensive pre-clinical and animal studies, is monocyte ingress to the brain and subsequent neural change effected by monocyte-derived TNF, most notably via glutamatergic action. Thus using ultra high-field (7T) MRI and MRS alongside innovative SPECT-CT to measure CNS infiltration by circulating labelled monocytes, we will test the following hypotheses: i) Anti-TNF therapy will effect changes in brain network connectivity and glutamate quantification in the brain.ii) RA patients will show changes in brain network connectivity and glutamate quantification correlated with sickness behaviours.iii) RA patients will show changes in monocyte infiltration to the brain that are correlated with sickness behaviours.These imaging endpoints (plus secondary cognitive-behavioural, clinical and peripheral immune endpoints) will be measured at baseline and 4 weeks later in up to 50 patients with RA, randomised 1:1 to treatment with anti-TNF antibody or placebo infusion. The baseline data will allow us to test the two key hypotheses of peripheral monocyte infiltration and glutamatergic excitoxicity as mechanisms contributing to sickness behaviour. TNF inhibitor administration will address our third hypothesis.Together this study will provide insight to the mechanisms that sub-serve sickness behaviours, and thereby new tools and targets to support future development of innovative drug treatments for such behaviours in RA and other IMIDs.