Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* Adults ≥ 18 years \< 75 years.
* Physician diagnosis of RA
* ACR definition of chronic widespread pain
* Able and willing to maintain usual/ medication for the 6-week study duration
* CRP \> 6mg/L or ESR \> 20mm/hr

  •≥1 swollen joint
* Right-handed (to reduce neuroimaging heterogeneity)

Exclusion Criteria:

* Inability to provide written informed consent.
* Severe physical impairment (e.g. blindness, deafness, paraplegia).
* Pregnant, planning pregnancy or breast feeding.
* Severe claustrophobia precluding MRI.
* Contraindications to MRI(e.g. metal implants/ pacemaker).
* Contraindication to TMS (e.g. history of seizures).