Exploiting Leading Edge 7T MRI Brain Imaging to Decipher Olumiant's Mode of Analgesic Action in Rheumatoid Arthritis

Investigators believe that RA is a mixed pain state i.e. pain pathways exist in addition to established peripheral inflammatory nociceptive mechanisms. In particular, the central nervous system (CNS) may have an important role in determining RA pain. Recently this group were the first to delineate distinct neurobiological pain signatures in the brains of RA patients by employing 3T functional connectivity magnetic resonance imaging (fcMRI) - a recent adaptation of functional MRI data that examines the synchrony of neural activity which modulates the efficiency and extent of neuronal transmission between brain regions. Specifically, researchers identified and replicated two distinct pain signatures: a) enhanced functional connectivity between the Default Mode Network (DMN) and insula which was unrelated to levels of peripheral inflammation but, intriguingly, is an established neurobiological marker of fibromyalgia (an archetypal CNS determined chronic pain disorder) and b) enhanced functional connectivity between the Dorsal Attention Network (DAN) and the left inferior parietal lobule (LIPL)6 which was related to levels of peripheral inflammation.

Pre-clinical experiments have not only implicated the JAK- signal transducer and activator of transcription (STAT) pathway with peripheral immune system functioning but also the brain. In the CNS, this pathway promotes gene expression associated with inflammation which in turn generates pro-nociceptive cytokines such as TNFα. However, there is now also emerging evidence to support the pathway's direct role in synaptic transmission and neurotransmitter receptor modulation. Specifically, the JAK-STAT pathway appears important in N-methyl-d-aspartate (NMDA) related synaptic plasticity - a ubiquitous glutamate receptor of the human brain. Their induction is selectively blocked by JAK inhibitors and JAK2 knockdown abolishes NMDA functioning. Increases in glutamate and subsequent binding to NMDA receptors cause chaotic and incoherent neuronal functional activity. In human studies of fibromyalgia, we have consistently evidenced both elevated glutamate levels within the insula and dysfunctional neural connectivity. Moreover, this group have shown that fibromyalgia pharmacotherapy (pregablin), considered to reduce neural glutamate, rectifies both insular glutamate and pro-nociceptive brain functional connectivity (DMN-insula). JAK inhibition (JAKi) may facilitate the reduction of glutamate-NMDA binding and ultimately pain alleviation by normalising the functional activity of these same neural connections.

There are clear practical constraints of sampling fresh human brain tissue in order to interrogate these possible mechanisms. Instead, neurobiological surrogate imaging measures may be employed. Glasgow benefits from the only clinical based ultra-high resolution 7T MRI scanner in the UK. Unlike lesser resolutions, 7T can distinguish the resonance of glutamate from other metabolites and so more precisely quantify the chemical of interest. Further, the superior spatial resolution of 7T enhances capacity to indirectly measure neuronal functional connectivity.

Investigators hypothesise that Olumiant's mechanism of analgesic action is determined by at least two factors. The first is related to those pathways seen in fibromyalgia, mediated via DMN-insula connectivity and insular glutamate. The second is related to peripheral inflammation, mediated via DAN-LIPL.

The study objectives include: 1) To evaluate the effects of Olumiant on DMN-Insula connectivity and insular glutamate levels in RA (neurobiological markers of fibromyalgia). 2) To evaluate the effects of Olumiant on DAN-LIPL connectivity in RA (neurobiological marker of peripheral inflammation). 3) To explore the relationship between pain, clinical phenotype, peripheral immune markers and their change with MRI markers indicative of CNS pathway function. The study will involve participants aged over 18 years with RA who are scheduled to start outpatient Olumiant as part of standard clinical practice, and who meet the inclusion criteria and none of the exclusion criteria.

Inclusion criteria

• Adults ≥ 18 years < 75 years.
• Clinical diagnosis of RA
• Selected to start Olumiant by their usual rheumatology clinical team in line with local guidance (previous failure of at least 2 DMARDs and moderate to severe disease active disease)
• Right-handed (to reduce neuroimaging heterogeneity)

Exclusion criteria

• Inability to provide written informed consent.
• Severe physical impairment (e.g. blindness, deafness, paraplegia).
• Pregnant or breast feeding.
• Contraindications to MRI (e.g. severe claustrophobia).
• Major confounding neurological disease including Multiple Sclerosis, Stroke, Traumatic Brain Injury, Parkinson's Disease, Alzheimer's Disease
• Previous targeted synthetic (e.g. Oluminant, tofacitinib) DMARD exposure.
• Co-morbid medical conditions that may significantly impair physical functional status
• Medical or psychiatric conditions that in the judgment of study personnel would preclude participation in this study (e.g., malignancy, psychosis, suicidal ideation)
• BMI > 40 or unable to lie comfortably in MRI