1239: JAK inhibition appears to alter clinical and neurobiological markers of nociplastic pain in rheumatoid arthritis: a 7T MRI Brain study

Background/Purpose: Pain remains a prevalent and highly impactful issue for people with rheumatoid arthritis (RA). Among modern day targeted therapies, the janus kinase (JAK) inhibitors are especially effective in reducing RA pain, however the mechanisms of their analgesic action are not fully known, and do not appear to be entirely explained by classical nociceptive pain mediators.

In this study of RA, we hypothesised that filgotinib, a selective JAK-1 inhibitor, additionally modifies nociplastic pain mechanisms, as typified in fibromyalgia (FM). Specifically, we predicted that peripherally driven dimensions of nociplastic pain would be altered as demonstrated by modification of functional brain connectivity between the posterior insula and inferior parietal lobe (IPL), an established neurobiological marker of ‘bottom up’ nociplastic pain which is most powerfully measured by 7 Tesla (7T) functional MR brain imaging (fMRI).

Methods: A single centre, observational test re-test study of people with moderate to severe RA who have been newly prescribed filogotinib as per standard care. Immediately prior to drug initiation, recruits underwent a clinical evaluation which included the ACR FM 2011 survey criteria (a validated subjective score of nociplastic pain, range 0-31). They then undertook an ultra-high resolution (7T) MRI brain scan, incorporating a 10-minute simultaneous-multi-slice (SMS) echo-planar imaging (EPI) sequence to capture resting state fMRI. During the resting state, subjects were instructed not to undertake any task and to stay awake with their eyes open on a fixation cross. To enable structural co-localisation, a whole-brain T1-weighted structural image was collected using a twice magnetization-prepared rapid gradient echo (MP2RAGE) sequence. Subjects then were invited to return to repeat these measures 12 (±1) weeks later. FMRI data was pre-processed and analysed using statistical parametric mapping (SPM) version 12 and the CONN functional connectivity toolbox, both running on MATLAB 2017a. Seed-based connectivity analyses were applied to determine the connectivity maps informed by our a priori determined regions of interest (IPL-Posterior insula). Simple descriptive statistics were employed to derive baseline characterisation and evaluation of longitudinal differences.

Results: Of the n=20 recruited, n=16 (75% female; mean age 56.9 [SD 9.6] years, baseline DAS28 4.6 [SD 1.4]) completed study follow-up. Clinically, this group reported a large and statistically significant change (p= 0.001) in their mean ACR FM scores from 14.4 [SD 5.6] to 7.9 [SD 5.4] at follow up. A statistically significant change in functional connectivity between the left IPL and left posterior insula was also observed (p=0.021).

Conclusion: Filgotinib significantly reduced patient reported nociplastic pain, possibly through the attenuation of aberrant posterior insula-IPL brain functional connectivity – a marker of peripherally driven nociplastic pain in RA.