Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Observational

Summary: 
      Rheumatoid arthritis (RA) is a common disease which is characterised by severe joint
      inflammation and chronic pain. The discovery of new joint specific treatments has transformed
      patient outcomes and yet most patients, even those whose joints respond fully to these
      treatments, continue to experience significant levels of pain. The investigators therefore
      believe that RA pain is caused by alternative sources in addition to the joints. Our group
      are pioneering the investigation of a possible link between the brain and the pain which RA
      patients experience. By employing sophisticated brain scanning methods, the investigators
      have shown that high levels of pain and blood inflammation are associated with changes within
      a specific region of the brain known as the left inferior parietal lobule(L-IPL). This region
      exhibited abnormal connections with other brain regions already known to be associated with
      pain in another chronic pain disorder called fibromyalgia. Fibromyalgia is a musculoskeletal
      condition which is not classically related to high levels of blood inflammation, although,
      interestingly, it is not uncommon for it to co-exist in RA patients. In light of our
      preliminary brain scan studies, the investigators now think that fibromyalgia in the context
      of RA may be partially influenced by inflammation. In order to fully understand the precise
      processes that lead to this potential relationship, it is important to characterise the
      biological abnormalities that underlie our brain scan observations. Previous animal
      experiments have consistently observed abnormalities, such as high levels of the brain
      chemical glutamate and haphazard brain activity, in the context of inflammation. Conducting
      similar experiments in humans is not practical due to the inherent dangers of sampling live
      brain tissue. Instead, neuroscientists commonly use non-invasive methods to manipulate
      specific parts of the brain in order to better understand how they function. In conjunction,
      the latest scanners are now able to indirectly measure the effect of the brain modulation on
      relevant aspects of brain biology without the need to remove tissue. This information will
      help us to better understand the relationship between inflammation and pain in the RA brain.
    

Detailed description: 
      Rheumatoid Arthritis-related pain is only partially explained by joint specific inflammation.
      Despite excellent control of peripheral inflammation by contemporary immune modulatory
      regimes, as many as 50% of patients continue to report disabling levels of pain, thus
      comprising an urgent unmet clinical need. The investigators have been among the first to
      evidence a contributory role of the central nervous system (CNS) as an explanation for this
      apparent disconnect. Our cross-sectional neuroimaging studies have implicated the left
      inferior parietal lobule of the brain as a critical interface between inflammation and pain.
      Not only did this region associate with levels of patient reported pain and indicators of
      systemic inflammation, but it was found to be functionally hyperconnected to brain networks
      established to be pro-nociceptive in CNS based chronic pain disorders such as fibromyalgia.
      In parallel, preclinical experiments suggest that systemic inflammation leads to heightened
      glutamate neurotransmission, which in turn results in disorganised neuronal signal activity
      and ultimately altered functional connectivity between regions of the brain. In RA patients,
      the investigators hypothesise that systemic inflammation-related neural glutamate enhancement
      triggers chaotic neuronal signaling, followed by compensatory hyperconnectivity with
      pro-nociceptive functional brain networks. Thereby, the investigators believe that
      dysfunctional inflammatory processes in RA not only mediate nociception in vulnerable joints
      but also nociception in vulnerable regions of the brain.

      Given the clear practical constraints of sampling fresh human brain tissue, the investigators
      propose to test our hypothesis by combining state-of-the-art non-invasive brain modulatory
      techniques alongside leading-edge neurobiological surrogate imaging measures. Transcranial
      magnetic stimulation (TMS) is the neural modulatory probe of choice for neuroscientists
      seeking to infer causality of specific brain cortical regions. Ultra-high resolution 7T MRI
      enables measurement of functional connectivity and haphazard neuronal signal activity at
      significantly superior spatial resolution compared to standard 3T approaches and can uniquely
      assess regional glutamate. As a critical first step, this feasibility study aims to pilot a
      transcranial magnetic stimulation (TMS) protocol designed to target the L-IPL in RA. The
      investigators will evaluate its effect employing ultra-high resolution 7T functional and
      glutamate measures. This novel project will inform a larger study which will aim to provide
      more robust evidence for the proposed neural pain interface between systemic inflammation and
      pain. Such knowledge could potentially support the analgesic testing of existing compounds
      e.g. alternative/augmented immunosuppressants or neural glutamate modulatory agents; and
      reverse translated in order to more precisely dissect the culprit mechanisms which in turn
      may inform the development of novel pain therapeutics. Both represent core aims of Versus
      Arthritis and address critical priorities among the patient populations that the
      investigators serve.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        The study will involve participants aged over 18 years with active inflammatory RA who meet
        the inclusion criteria below and who have none of the specified exclusion criteria. All
        will give full informed consent. Rheumatoid arthritis patients attending secondary care
        clinics in NHS GG&C and in NHS Lanarkshire will be screened for eligibility. NHS
        Lanarkshire will act as a participant identification centre (PIC) and all study
        participants will undertake study procedures at the University of Glasgow and the Queen
        Elizabeth University Hospital (NHS GG&C).
      
Biospecimen description: 
      Venous blood samples will be taken for peripheral immunophenotyping including proteomic and
      transcriptomic analysis.