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

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.

We currently do not fully understand what underlies common, but complex, behaviours like sickness behaviour in humans. This study is focused on leveraging a mechanistic understanding of the role of one cytokine, TNF, in driving sickness behaviours. The project will use state-of-the-art neuroimaging to probe the relationship between TNF and glutamate and the related effects on brain network connectivity as well as explore the potential role of monocytes recruited from periphery to brain. To do this we will use existing, effective anti-TNF therapy (etanercept) in the context of routine clinical care for rheumatoid arthritis. We will examine glutamate biochemistry via 7T MRS and brain connectivity via 7T resting state and task-based fMRI. An exploratory component will examine the role of CD14+ monocytes recruited from peripheral blood to the brain using autologous CD14+ monocytes radiolabelled with Technetium-99m and the chelating agent HMPAO.

WHO MIGHT BENEFIT FROM THIS RESEARCH?
Advancing our understanding of the mechanisms that drive sickness behaviours will allow development of target specific treatments for what remain areas of significant unmet clinical need.
The clinicians caring for these patients will have greater information of the role of currently available clinical tools in the treatment of sickness behaviour and potential specificity of these therapies for particular symptoms.
Carers of those with sickness behaviour will be provided with a more rational approach to difficult-to-treat features of illness.
Researchers will benefit from an enhanced biological profile of sickness behaviour in humans.

WHAT BENEFITS MIGHT BE EXPERIENCED?
The elucidation of mechanistically specific biomarkers for sickness behaviour in human immune mediated inflammatory diseases.
Development of novel and tractable therapeutic targets and thus engagement with Industry.
Reverse translation with the development of predictive animal models.