Exploiting Leading Edge 7 Tesla MRI Brain Imaging to Decipher Filgotinib's Mode of Analgesic Action in Rheumatoid Arthritis
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Rheumatoid Arthritis
- Sponsor
- NHS Greater Glasgow and Clyde
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- To evaluate the effects of Filgotinib in RA on CNS pain sensitisation (as measured by MRI brain) for insular glutamate levels at 12 weeks.
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This is an experimental medicine, single-centre, observational test-retest study to evaluate Filgotinib's mechanism of analgesic action in RA patients.
The investigators hypothesize that Filgotinib's mechanism of analgesic action is determined by at least two factors. The first is related to those CNS sensitization pathways seen in fibromyalgia, specifically DMN-insula brain functional connectivity and insular glutamate.
The second is related to peripheral inflammation, specifically joint synovitis, blood cytokines/chemokines and DAN-LIPL functional brain connectivity. The CNS sensitization pain pathways related to fibromyalgia are more quickly modified compared to those related to peripheral inflammation and help explain Filgotinib's rapid onset of effect.
Detailed Description
The revolution in rheumatoid arthritis (RA) therapeutics has been transformative for many patient outcomes. Yet most patients continue to experience life disabling pain. Strikingly, even those who achieve full disease remission with state-of-the-art anti-tumour necrosis factor (TNF) treatments report substantially higher levels of pain when compared to the general population. Such disconnect presents one of the greatest contemporary challenges to the care of patients with RA. Considering the ongoing excess burden of pain in this patient population, trials of Janus kinase inhibitors (JAKinibs) present welcome data. JAKinibs deliver superior pain improvements in comparison to those receiving anti-TNF therapy. Of note, the majority of this effect has not been fully explained by markers of peripheral inflammation and remains to be understood. Moreover, JAKinibs appear to offer rapid analgesic benefit. Traditional DMARDS and modern biologics commonly take several weeks to bring relief whereas JAKinibs, such as filgotinib, begin to improve pain as early as 2 weeks, even before the observed attenuation of peripheral clinical inflammation. In light of these clinical observations, the 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 our group were the first to delineate distinct neurobiological pain signatures in the brains of RA patients by employing 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, the investigators identified and replicated two distinct pain signatures: 1. 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 (the prototypical CNS pain sensitization disorder, and 2. enhanced functional connectivity between the Dorsal Attention Network (DAN) and the left inferior parietal lobule (LIPL) which was related to levels of peripheral inflammation. Pre-clinical experiments have not only implicated the Janus kinase-signal transducer and activator of transcription (JAK-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. 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. Increases in glutamate and subsequent binding to NMDA receptors cause chaotic and incoherent neuronal functional activity. Human studies of fibromyalgia have consistently evidenced both elevated glutamate levels within the insula and dysfunctional neural connectivity. Moreover, fibromyalgia pharmacotherapy (pregablin), considered to reduce neural glutamate, rectifies both insular glutamate and 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with moderate to severe active RA who have been prescribed filgotinib in line with the Summary of Product Characterisation and are:
- •Adults ≥18 years \< 75 years.
- •Right-handed (to reduce neuroimaging heterogeneity).
Exclusion Criteria
- •Inability to provide written informed consent.
- •Severe physical impairment (e.g. blindness, deafness, paraplegia).
- •Pregnant or breast feeding.
- •Severe claustrophobia precluding MRI.
- •Contraindications to MRI.
- •Major confounding neurological disease including MS, Stroke, Traumatic Brain Injury.
- •Previous targeted synthetic (e.g. baricitinib, tofacitinib) DMARD exposure for RA.
Outcomes
Primary Outcomes
To evaluate the effects of Filgotinib in RA on CNS pain sensitisation (as measured by MRI brain) for insular glutamate levels at 12 weeks.
Time Frame: 12 weeks
A magnetic resonance spectroscopy scan will be undertaken in order to detect the glutamate concentration. A single voxel sequence will be employed with semi-LASER preparation. A 20x20 mm3 voxel will be placed in the R posterior insula and shimming oA magnetic resonance spectroscopy scan will be undertaken in order to detect the glutamate concentration. A single voxel sequence will be employed with semi-LASER preparation. A 20x20 mm3 voxel will be placed in the R posterior insula and shimming of the static magnetic field will be performed using advanced methods best suited to MRS acquisition at 7T, such as FASTMAP. Spectra will be analysed and quantified in JMRUI or LCModel. In addition, multi-voxel techniques will be employed to provide quantitative maps of chemical concentration across the brain.
To evaluate the effects of Filgotinib in RA on CNS pain sensitisation (as measured by MRI brain) for DMN-Insula fMRI brain connectivity at 12 weeks.
Time Frame: 12 weeks
Functional connectivity MRI (fMRI) investigations are conducted with subjects resting in the scanner. Ten minutes of whole-brain resting state fMRI data will be collected using a simultaneous-multi-slice (SMS) echoplanar-imaging (EPI) sequence of factor=3. A whole-brain T1-weighted structural image will also be collected using a twice magnetization-prepared rapid gradient echo (MP2RAGE) sequence. During the resting state, subjects will be instructed not to undertake any particular task and to stay awake with their eyes open on a fixation cross. Whole brain coverage will be performed. Upon collection of resting state fMRI data, pre-processing steps will include the removal of physiological artefacts, motion correction, realignment, registration, normalization and smoothing. Connectivity indices will be generated from matrices informed by our a priori determined regions of interest (DMN-Insula).
Secondary Outcomes
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Physical functioning short form in the medium.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by the Sickness Questionnaire in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on peripheral inflammation related pain as measured by blood cytokine/chemokines in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on CNS pain sensitisation (as measured by MRI brain) for insular glutamate levels at 4 weeks.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on peripheral inflammation related pain as measured by MRI brain for DAN-LIPL fMRI brain connectivity (neurobiological marker of peripheral inflammatory pain) in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on CNS pain sensitisation (as measured by MRI brain) for DMN-Insula fMRI brain connectivity at 4 weeks.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on peripheral inflammation related pain as measured by MRI brain for DAN-LIPL fMRI brain connectivity (neurobiological marker of peripheral inflammatory pain) in the medium term.(12 weeks)
- To evaluate the effects of Filgotinib in RA as measured by FACIT-F in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Sleep related impairment in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Sleep related impairment in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Physical functioning short form in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Depression in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA as measured by the McGill Pain Questionnaire in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA as measured by the McGill Pain Questionnaire in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by Global Impression of Change in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on peripheral inflammation related pain as measured by ultrasound joint, in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on peripheral inflammation related pain as measured by ultrasound joint, in the medium term.(12 weeks)
- To evaluate the effects of Filgotinib in RA on peripheral inflammation related pain as measured by blood cytokine/chemokines in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Pain interference in the medium.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Fatigue in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Fatigue in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by the Sickness Questionnaire in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA as measured by FACIT-F in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Anxiety in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Anxiety in the medium term.(0-12 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Pain interference in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by PROMIS-Depression in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA on as measured by Global Impression of Change in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA as measured by Cognitive Failures Questionnaire in the short term.(0-4 weeks)
- To evaluate the effects of Filgotinib in RA as measured by Cognitive Failures Questionnaire in the medium term.(0-12 weeks)