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

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.

Inclusion criteria

• Adults ≥ 18 years < 65 years
• Fulfilment of the 2019 ACR (American College of Rheumatology)/EULAR (European Alliance of Associations for Rheumatology) classification criteria for SLE
• Persistent (>3 months) and clinically significant fatigue (≥6 on numerical rating 0-10 scale measuring average level of fatigue during the past 7 days)
• Attainment of Lupus low disease activity state (LLDAS)

Exclusion criteria

• Inability to provide informed written consent
• Moderate or severe active SLE
• Severe active CNS (Central Nervous System) Lupus and Lupus Nephritis
• Contra-indications to anifrolumab
• History of malignancy
• History of recurrent infections or known risk factors for infection
• Active or chronic infection
• Concomitant biological therapies
• Hypersensitivity to anifrolumab or excipients
• Current treatment with a biologic medicine or monoclonal antibody (including B cell depleting therapies in the previous 52 weeks)
• Previous exposure to anifrolumab
• Contra-indications to MRI
• Pregnant or breast-feeding
• Females of child-bearing potential who do not agree to use an effective method of birth control until 12 weeks after the final study visit (See appendix 1).)
• Severe physical impairment (e.g. blindness, paraplegia)
• Medical or psychiatric conditions that in the judgement of the study personnel would preclude participation in the study