Exploiting Leading Edge 7T MRI Brain Imaging to Decipher Olumiant's Mode of Analgesic Action in Rheumatoid Arthritis
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Olumiant
Intervention type(s): Drug
Intervention description(s): Olumiant (4mg) will be administered in line with standard of care guidance.
Other intervention name(s): Baricitinib
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients with active RA attending clinics in NHS Greater Glasgow and Clyde who are
        scheduled to begin Olumiant as part of their standard NHS clinical care will be asked to
        contribute to this study by their point of care team.
      
Biospecimen description: 
      Blood samples will be obtained to allow analysis of inflmamatory markers considered importnat
      in Rheumatoid Arthritis.