Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways

Study Overview
=================
Brief 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.

Official Title
-----------------
Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways

Conditions
-----------------
Rheumatoid Arthritis

Participation Criteria
=================
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------
What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in functional connectivity and neuronal signal cohesion | Changes in functional connectivity and neuronal signal cohesion as measured by 7T MRI. Changes are baseline to post-treatment/sham. | 2 hours | 
| Changes in glutamate signal | Changes in glutamate signal in the L-IPL as measured by 7T MRS . Changes are baseline to post-treatment/sham. | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in pain severity | Changes in global pain as measures by the Pain-NRS scale from baseline to 2-hours post-treatment/sham and from baseline to 2-week follow up. | 2 weeks | 
| Changes from the Michigan Body Map Regional Pain. | Changes in regional pain severity as measured by the Michigan Body Map Regional Pain from baseline to 2-week follow-up. | 2 weeks | 
| Changes in RA disease activity as measured by SDAI. | Changes in Rheumatoid Arthritis disease activity as measured by the Simplified Disease Activity Index (SDAI) from baseline to 2-hours post-treatment/sham and from baseline to 2-week follow up. | 2 weeks | 
| Changes in RA disease activity as measured by CDAI. | Changes in Rheumatoid Arthritis disease activity as measured by the Clinical Disease Activity Index (CDAI) from baseline to 2-hours post-treatment/sham and from baseline to 2-week follow up. | 2 weeks | 
| Changes in putative pain confounders as measured by PROMIS-Fatigue | Changes in putative pain confounders as measured by PROMIS-Fatigue from baseline to 2-week follow-up. PROMIS stands for 'Patient-Reported Outcomes Measurement Information System'. Measures are scored via T-score metric where 50 is the mean of a relevant reference population and 10 is the standard deviation. On the T-score metric: A score of 40 is one standard deviation lower than the mean of the reference population. A score of 60 is one standard deviation higher than the mean of the reference population. The lower score indicates less of the concept being measured; the higher score indicates more of the concept being measured. | 2 weeks | 
| Changes in putative pain confounders as measured by PROMIS-Depression | Changes in putative pain confounders as measured by PROMIS-Depression, from baseline to 2-week follow-up. PROMIS stands for 'Patient-Reported Outcomes Measurement Information System'. Measures are scored via T-score metric where 50 is the mean of a relevant reference population and 10 is the standard deviation. On the T-score metric: A score of 40 is one standard deviation lower than the mean of the reference population. A score of 60 is one standard deviation higher than the mean of the reference population. The lower score indicates less of the concept being measured; the higher score indicates more of the concept being measured. | 2 weeks | 
| Changes in putative pain confounders as measured by PROMIS-Anxiety | Changes in putative pain confounders as measured by PROMIS-Anxiety from baseline to 2-week follow-up. PROMIS stands for 'Patient-Reported Outcomes Measurement Information System'. Measures are scored via T-score metric where 50 is the mean of a relevant reference population and 10 is the standard deviation. On the T-score metric: A score of 40 is one standard deviation lower than the mean of the reference population. A score of 60 is one standard deviation higher than the mean of the reference population. The lower score indicates less of the concept being measured; the higher score indicates more of the concept being measured. | 2 weeks | 
| Changes in putative pain confounders as measured by PROMIS-Sleep Related Impairment | Changes in putative pain confounders as measured by PROMIS-Sleep Related Impairment, from baseline to 2-week follow-up. PROMIS stands for 'Patient-Reported Outcomes Measurement Information System'. Measures are scored via T-score metric where 50 is the mean of a relevant reference population and 10 is the standard deviation. On the T-score metric: A score of 40 is one standard deviation lower than the mean of the reference population. A score of 60 is one standard deviation higher than the mean of the reference population. The lower score indicates less of the concept being measured; the higher score indicates more of the concept being measured. | 2 weeks | 
| Changes in putative pain confounders as measured by PROMIS-Physical functioning short form | Changes in putative pain confounders as measured by PROMIS-Physical functioning short form from baseline to 2-week follow-up. PROMIS stands for 'Patient-Reported Outcomes Measurement Information System'. Measures are scored via T-score metric where 50 is the mean of a relevant reference population and 10 is the standard deviation. On the T-score metric: A score of 40 is one standard deviation lower than the mean of the reference population. A score of 60 is one standard deviation higher than the mean of the reference population. The lower score indicates less of the concept being measured; the higher score indicates more of the concept being measured. | 2 weeks | 
| Changes in putative pain confounders as measured by PROMIS-Pain Interference | Changes in putative pain confounders as measured by PROMIS-Pain Interference from baseline to 2-week follow-up. PROMIS stands for 'Patient-Reported Outcomes Measurement Information System'. Measures are scored via T-score metric where 50 is the mean of a relevant reference population and 10 is the standard deviation. On the T-score metric: A score of 40 is one standard deviation lower than the mean of the reference population. A score of 60 is one standard deviation higher than the mean of the reference population. The lower score indicates less of the concept being measured; the higher score indicates more of the concept being measured. | 2 weeks | 
| Changes in putative pain confounders as measured by ACR Fibromyalgia Scale | Changes in putative pain confounders as measured by ACR Fibromyalgia Scale from baseline to 2-week follow-up. | 2 weeks | 
| Changes in blood protein levels of inflammatory cytokines/chemokines. | Changes in blood protein levels of inflammatory cytokines/chemokines from baseline to 2-week follow-up. | 2 weeks |