Rewiring the Brain-Immune Axis for Chronic Pain Using Transcranial Magnetic Stimulation in Psoriatic Arthritis

Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease (IMID) characterised by musculoskeletal pain, enthesitis, and synovitis. While advances in immunomodulatory therapies have improved control of inflammation, approximately one-third of people with PsA continue to report persistent pain despite achieving low disease activity by clinical criteria. This dissociation between detectable inflammation and ongoing pain suggests a role for central nervous system (CNS) mechanisms in the persistence of symptoms. Emerging evidence from neuroimaging studies has highlighted the inferior parietal lobule (IPL) as a brain region implicated in both pain perception and immune signalling. Prior work in inflammatory arthritis shows that IPL grey-matter volume and functional connectivity correlate with peripheral inflammation and pain.

These findings suggest that the IPL may act as a neuroimmune hub, integrating nociceptive input and modulating pain perception and immune function via top-down signalling pathways. Recent translational research across cancer, cardiovascular, and IMIDs has established that brain activity can shape peripheral immune responses, and thereby influence disease progression.

In PsA, chronic pain may therefore reflect not only residual joint pathology but also maladaptive brain immune interactions that perpetuate inflammation and amplify pain processing. This under-explored pathophysiological loop constitutes a critical unmet therapeutic target in PsA and other IMIDs.

Psoriatic 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 30% of patients continue to report disabling levels of pain, thus comprising an urgent unmet clinical need.

Our group has been among the first to evidence a contributory role of the CNS as an explanation for this debilitating symptom. Neuroimaging studies in inflammatory arthritis have highlighted the inferior parietal lobule (IPL) as a potential neuroimmune hub: altered IPL grey-matter volume and functional connectivity have been linked to both systemic inflammation and pain, suggesting this region may integrate nociceptive and immune signals. These findings are consistent with broader evidence implicating IPL hyperconnectivity in pro-nociceptive brain networks observed in chronic pain conditions such as fibromyalgia.

The investigators therefore propose that in PsA, the IPL acts as a key interface between the CNS and the immune system, contributing to persistent pain via maladaptive neuroimmune signalling. A recent feasibility study (Pro-BEPP) conducted by the investigative team provided preliminary support for this mechanism, demonstrating that a single session of L-IPL-targeted TMS reduced pain and modulated immune activity, specifically decreasing STAT3 phosphorylation in circulating monocytes. These findings support a novel model of top-down immune regulation, wherein modulation of brain activity reprograms systemic inflammatory responses.

Given the neuroplasticity of pain networks and the immunological relevance of monocytes and CD8⁺ T cells in PsA pathogenesis, the investigators hypothesise that rTMS targeting the L-IPL (an approach already approved in the NHS for treatment-resistant depression), can induce sustained immune adaptation and provide clinically meaningful pain relief. By combining neuromodulation with immune profiling, this study aims to generate mechanistic feasibility data to establish rTMS as a biologically grounded, non-pharmacological intervention for persistent pain in PsA.

The investigators hypothesise that the L-IPL functions as a neuroimmune interface in PsA, contributing to persistent pain via maladaptive signalling between the brain and the immune system. Specifically, the investigators propose that ongoing IPL hyperactivity and altered connectivity with pain-related networks contribute to heightened pain perception, even when peripheral inflammation appears well-controlled. This brain-immune dysregulation may further sustain or amplify systemic inflammation through top-down modulation of immune cells such as monocytes and CD8⁺ T cells, which are known to play key roles in PsA pathogenesis.

If this model is correct, then rTMS targeted to the left IPL will rebalance brain network activity and induce downstream changes in immune cell signalling, particularly reducing pro-inflammatory markers (e.g. STAT3 phosphorylation). The investigators expect this to translate into measurable improvements in pain and related symptoms, such as fatigue, representing a novel neuromodulatory approach for addressing persistent pain in PsA.

• Changes in genetic expression of circulating immune cells, monocytes and CD8+ T-cells, using transcriptomic assays (RNA-seq). [Срок оценки: Week 1 to Week 4]
• Changes in trained immunity set-points in monocytes and CD8+ T-cells, by investigating their epigenetic profile changes using Cleavage Under Targets and Tagmentation (CUT&TAG assay). [Срок оценки: Week 1 to Week 4]
• Changes in pain severity as measured by the Pain Number Rating Scale. [Срок оценки: Week 1 to Week 4]
• Changes in pain severity as measured by Widespread Pain as part of the American College of Rheumatology Fibromyalgia scale. [Срок оценки: Week 1 to Week 4]
• Changes in putative pain confounders as measured by PROMIS-Fatigue. [Срок оценки: Week 1 to Week 4]
• Changes in putative pain confounders as measured by PROMIS-Depression. [Срок оценки: Week 1 to Week 4]
• Changes in putative pain confounders as measured by PROMIS-Sleep Related Impairment. [Срок оценки: Week 1 to Week 4]
• Changes in putative pain confounders as measured by PROMIS-Physical functioning short form. [Срок оценки: Week 1 to Week 4]
• Changes in putative pain confounders as measured by PROMIS-Pain Interference. [Срок оценки: Week 1 to Week 4]
• Changes in PsA disease activity as measured by Disease Activity in Psoriatic Arthritis (DAPSA). [Срок оценки: Week 0 to Week 4]
• Changes in PsA disease activity as measured by Minimal Disease Activity (MDA). [Срок оценки: Week 0 to Week 4]
• Changes in PsA disease activity as measured by Body Surface Area (BSA). [Срок оценки: Week 0 to Week 4]