Establishing the Salience of Type 1 Interferon Pathway Blockade in the Central Mechanisms of SLE Related Fatigue

Overview

Systemic Lupus Erythematosus (SLE) is a multi-system autoimmune disorder, characterised by activation of the interferon system. Of the multiple domains of this disease, patients identify fatigue as the most pervasive and disabling aspect. As many as 90% report significant levels of fatigue, a prevalence far in excess of that observed in the general population and most other chronic disorders. Moreover, its impact permeates all aspects of living as reflected by fatigue's strong relationship with impaired quality of life3 and work disability. Despite these substantial consequences, relatively little is known about this symptom and so the current dearth of accepted therapies is unsurprising. A better understanding of the underlying mechanisms of fatigue will be vital if efficacious interventions are to be developed in the future. The investigators will recruit 25 SLE patients to achieve 20 full data sets. They will attend for a baseline 7T brain scan to primarily measure basal ganglia glutamate and then receive 5 months of a pharmacological blocker that antagonises type 1 interferon receptors before completing the study with a final 7T brain scan to undertake repeat measure of basal ganglia glutamate.

Our epidemiological investigations of fatigue in autoimmune disease have identified strong associations with central nervous system factors such as mental health and cognitive dysfunctions, and the investigators have subsequently pioneered the application of advanced MRI brain methods in order to derive neurobiological mechanistic insights into fatigue. As a result, the investigators have implicated basal ganglia volume to be a key marker of fatigue severity. The basal ganglia has been considered pivotal in neuroimaging studies of fatigue across the chronic disease spectrum11 and fatigue is a defining clinical characteristic of basal ganglia disorders such as Parkinson's disease. Intriguingly, a 3 Tesla (3T) MRI spectroscopy study of Hepatitis C patients evidenced possible increases in basal ganglia glutamate concentrations following treatment with interferon α which in turn correlated with worsening reported levels of fatigue. Glutamate is the brain's foremost excitatory neurotransmitter. Pre-clinical experiments suggest that inflammatory cytokines can enhance extracellular glutamate levels through various mechanisms including decreasing activity of glutamate metabolising enzymes and reversing cellular efflux. The consequences of heightened glutamate include altered neuronal integrity and microglial activation. Correspondingly, it is notable that peripheral administration of interferon α in a mouse model induced both molecular and phenotypic activation in microglia. Basal ganglia glutamate could be an important mediator of fatigue in diseases, such as SLE, which are underpinned by type 1 interferon pathway activation. However, until recently, it has not been possible to robustly investigate this possibility further in humans. Standard 3T MRI scanners fail to provide sufficient spectral resolution to distinguish glutamate from glutamine (a distinct metabolite) and so previous studies offer only preliminary evidence. The University of Glasgow now benefits from one of the few UK ultra-high field 7T MRI scanners to be embedded in a clinical research facility. The use of 7T rather than 3T MRS (Magnetic Resonance Spectroscopy) permits a highly resolved quantifiable glutamate signal within small subcortical regions due to higher Larmor frequency and improved chemical shift dispersion. The investigators have successfully applied single voxel MRS sequences at 7T to quantify glutamate in autoimmune disease, which enables the required precision to robustly measure glutatmate. A downstream impact of any glutamate imbalance may be dysfunctional brain activity. Functional MRI (fMRI) leverages the differential magnetic strength of oxygenated and deoxygenated haemoglobin to generate a Blood Oxygen Level Dependent (BOLD) signal, a surrogate measure of brain activity. In autoimmune disease, the investigators have also related fatigue to enhanced fMRI connectivity to a number of brain regions, in particular the Dorsal Attention Network. Fatigue was also significantly associated with increased Default Mode Network to insula functional connectivity. This is the most reproducible biomarker of fibromyalgia, a chronic pain disorders that is defined by co-existing fatigue and is conspicuously prevalent in SLE where it is indeed a major predictor of fatigue. These innovations in MRI imaging now allow us to opportunely use anifrolumab to pharmacologically block type 1 interferon receptors in order to test our hypothesis that blockade of the type 1 interferon pathway will lead to reductions in brain basal ganglia glutamate. This in turn will facilitate understanding of the mechanism of fatigue being caused in people with SLE.