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

The revolution in treatments for rheumatoid arthritis (RA) has transformed patient outcomes, but many patients continue to experience life disabling pain. Even those who achieve full disease remission with state-of-the-art treatments report substantially higher levels of pain when compared to the general population. Researchers believe this disconnect is due to the existence of pain sources that are in addition to those present in the joints. In particular, the central nervous system (CNS) may have an important role in determining RA pain.

According to a recent study, RA patients who received treatment with Olumiant (a Janus Kinase (JAK) inhibitor that works by interfering with the inflammatory processes that lead to the symptoms of RA) reported better and quicker pain improvements compared to those receiving other types of therapy. However, this could not be explained by levels of peripheral inflammation alone and remains to be fully understood. Investigators think this improvement may be related to the role of the JAK pathway in the brain and that inhibition of this pathway with Olumiant could normalise brain connectivity in respect to pain processing.

Advanced brain scanning methods have already helped to identify specific regions of the brain that are thought to be important in pain processing and peripheral inflammation; a) enhanced functional connectivity between the Default Mode Network (DMN) and insula and b) enhanced functional connectivity between the Dorsal Attention Network (DAN) and the left inferior parietal lobule (LIPL). This study aims to elucidate the mechanisms of analgesic action of Olumiant by examining changes in functional connectivity and glutamate levels within the CNS and exploring the relationship between MRI markers, pain, clinical phenotype and peripheral immune markers.

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.

Eligibility 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