Rheumatoid ArthritisPro-BEPPNCT05693532
Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways
An observational study of Rheumatoid Arthritis, run by NHS Greater Glasgow and Clyde at 1 site in United Kingdom.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 74 years
- Conditions the study is for
- Rheumatoid Arthritis
- How many people
- 13 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 12 Nov 2021to 4 Sep 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 74 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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).
Who may be able to join
- 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)
Who cannot join
- 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).
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Queen Elizabeth University Hospital
Glasgow, Scotland, G51 4TF
About this study
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.
Read the 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.
- Conditions
- Rheumatoid Arthritis
- Medical subject headings
- Arthritis, Rheumatoid
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 2 hours
Secondary outcomes (12)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
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.
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.
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.
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.
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.
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.
Measured: 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.
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2023
- Study start12 Nov 2021
- Primary completion4 Sep 2023
- Study completion4 Sep 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- NHS Greater Glasgow and Clyde
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Neil Basu, MD, PhD, Principal investigator, University of Glasgow
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05693532
- Sponsor's protocol ID
- GN19RH007
- Acronym
- Pro-BEPP
- Status last verified
- Oct 2023
- First submitted
- 21 Dec 2022
- Last updated
- 1 Nov 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways
- ClinicalTrials.gov ID
- NCT05693532
- Acronym / sponsor ID
- Pro-BEPP / GN19RH007
- Conditions
- Rheumatoid Arthritis
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- NHS Greater Glasgow and ClydeUniversity, hospital or other
- Study start
- 12 Nov 2021 (actual)
- Primary completion
- 4 Sep 2023 (actual)
- Study completion
- 4 Sep 2023 (actual)
- First posted
- 23 Jan 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 to 74 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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).
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (6 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Changes in functional connectivity and neuronal signal cohesion
Time frame: 2 hours
Changes in functional connectivity and neuronal signal cohesion as measured by 7T MRI. Changes are baseline to post-treatment/sham.
Changes in glutamate signal
Time frame: 2 hours
Changes in glutamate signal in the L-IPL as measured by 7T MRS . Changes are baseline to post-treatment/sham.
12 secondary outcomes
Changes in pain severity
Time frame: 2 weeks
Changes from the Michigan Body Map Regional Pain.
Time frame: 2 weeks
Changes in RA disease activity as measured by SDAI.
Time frame: 2 weeks
Changes in RA disease activity as measured by CDAI.
Time frame: 2 weeks
Changes in putative pain confounders as measured by PROMIS-Fatigue
Time frame: 2 weeks
Changes in putative pain confounders as measured by PROMIS-Depression
Time frame: 2 weeks
Changes in putative pain confounders as measured by PROMIS-Anxiety
Time frame: 2 weeks
Changes in putative pain confounders as measured by PROMIS-Sleep Related Impairment
Time frame: 2 weeks
Changes in putative pain confounders as measured by PROMIS-Physical functioning short form
Time frame: 2 weeks
Changes in putative pain confounders as measured by PROMIS-Pain Interference
Time frame: 2 weeks
Changes in putative pain confounders as measured by ACR Fibromyalgia Scale
Time frame: 2 weeks
Changes in blood protein levels of inflammatory cytokines/chemokines.
Time frame: 2 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Nov 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Neil Basu, MD, PhD principal investigator
University of Glasgow
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Rheumatoid Arthritis, run by NHS Greater Glasgow and Clyde at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes in functional connectivity and neuronal signal cohesion (time frame: 2 hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2023.