Kelleher, Eoin

Abstract Introduction: Evidence increasingly shows small nerve fibre pathology in subsets of people with fibromyalgia through skin biopsy, corneal confocal microscopy, and microneurography. However, blood-based biomarkers of ongoing neuronal damage, particularly neurofilament light chain (NfL), an axonal structural protein, are not well established. Objectives: The aim of this study was to evaluate serum NfL concentrations in fibromyalgia compared with other chronic pain conditions and assess their relationship with neuropathic-like pain. Methods: We measured serum NfL using Simoa SR-X NF Light v2 digital-immunoassay in 60 participants with fibromyalgia, 61 with endometriosis (another traditionally considered non-neuropathic pain condition), 24 with small fibre neuropathy (a recognised neuropathic pain condition), and 30 healthy controls. Serum NfL concentrations were compared between the groups controlling for age and body mass index. Neuropathic-like pain was assessed using the painDETECT questionnaire for fibromyalgia and endometriosis and NeuPSIG grading criteria for small fibre neuropathy. Results: Compared with healthy controls (mean concentration = 6.77 pg/mL, Z-score = −1.15), serum NfL concentrations were significantly elevated in fibromyalgia (mean concentration = 8.52 pg/mL P = 0.048; Z-score = −0.30, and P = 0.006) and small fibre neuropathy (mean concentration = 8.98 pg/mL, P = 0.004; Z-score = 0.23, P = 0.0001), with endometriosis representing an intermediate phenotype (mean concentration = 5.57 pg/mL, P = 0.44; Z-score = −0.41, P = 0.024). Using PainDETECT, 44% of fibromyalgia and 26% of endometriosis participants met likely neuropathic pain criteria; using NeupSIG grading, 96% of small fibre neuropathy participants met probable/definite criteria. Conclusion: Our study provides serological evidence of nerve pathology in fibromyalgia at comparable levels with small fibre neuropathy, although this did not correlate with neuropathic-like pain presence or severity. These findings highlight the need for subgroup-specific treatment strategies.

Abstract Despite effective control of inflammation in rheumatoid arthritis (RA), persistent and severe pain remains a challenge. Dysregulated pain processing in the central nervous system may underlie this disconnect. The PainDETECT questionnaire, originally developed to identify neuropathic pain, may capture features of central sensitization. We hypothesized that neuropathic-like pain at diagnosis predicts worse pain prognosis in early RA, independent of baseline pain severity and inflammation. We also explored brain activation patterns using neuroimaging. In this prospective cohort study, adults with newly diagnosed RA completed the PainDETECT questionnaire at baseline. Bodily pain was measured using the SF-36 Bodily Pain Subscale at baseline, 3, 6, and 12 months. C-reactive protein (CRP) was monitored. Linear mixed-effects models examined associations between PainDETECT, as a continuous measure, and bodily pain and CRP over time, adjusting for baseline outcome values. A neuroimaging substudy (n = 27) used task-based functional MRI to assess brain responses to evoked pressure pain. Among 158 participants (mean age 58.4 years; 35% male), 24.7% had likely neuropathic-like pain (PainDETECT ≥19) at baseline. Higher baseline PainDETECT scores were associated with worse bodily pain throughout follow-up in fully adjusted models (β = −0.43; 95% CI: −0.84 to −0.02; P = 0.043), independent of socio-demographics and comorbidities. No association was found between PainDETECT and CRP. On neuroimaging, higher PainDETECT scores correlated with increased activation in the left insula, dorsal anterior cingulate cortex, and left amygdala during evoked wrist pain. Neuropathic-like pain at diagnosis predicts a worse pain prognosis in early RA, independently of inflammation. Early identification may support more targeted and effective pain management.

Persistent pain remains a major challenge in inflammatory arthritis, even when joint inflammation is well controlled. Pain and associated symptoms such as fatigue cannot be explained by peripheral inflammation alone but reflect altered central pain processing. These changes may arise through “top‐down” mechanisms, reflecting pre‐existing dysfunction in pain perception, or “bottom‐up” pathways, driven by peripheral inflammation acting on the brain. Neuroimaging has transformed understanding of these processes by providing in vivo markers of how brain function and structure are related to pain. Functional magnetic resonance imaging (MRI) demonstrates that both task‐evoked and resting‐state activity are altered in inflammatory arthritis. Connectivity changes involving the thalamus, insula, medial prefrontal cortex, and default mode and salience networks correlate with pain, fatigue, and affective symptoms. Notably, tumor necrosis factor α (TNF‐α) inhibitors rapidly normalize pain‐related activation, preceding improvements in joint swelling, strongly supporting a bottom‐up role for peripheral inflammation. Recent randomized controlled trial data show that baseline central nervous system pain activation predicts analgesic response to TNF‐α blockade, positioning neuroimaging as a potential tool for treatment stratification. Complementary modalities provide further insights. Proton electron tomography studies suggest altered pain responses, and novel tracers may clarify contributions of neuroinflammation. Magnetic resonance spectroscopy reveals neurochemical correlates such as increased choline and myo‐inositol linked to fatigue, although group‐level evidence for overt neuroinflammation remains limited. Structural MRI highlights gray matter changes in regions mediating sensory, cognitive, and affective processing. Together, this supports a dual top‐down and bottom‐up model of persistent pain in inflammatory arthritis, with important implications for mechanism‐based therapies targeting both immune and brain pathways. image

Abstract Chronic widespread pain (CWP) remains challenging due to its heterogeneous causes and complex mechanisms. A total of 2920 plasma proteins are analyzed from 29,254 UK Biobank participants. A total of 256 proteins are identified as cross‐sectionally correlated with CWP. A simple (top 10 proteins) and comprehensive (all significant proteins) proteomic‐based score (ProtS) is created for CWP diagnosis, both outperforming and improving the existing clinical score (area under the curve, AUC: 0.801, 0.723, and 0.791 alone, and 0.856 and 0.880 in combination). In addition, the protein score predicted 13‐years risk of pain‐related traits over the body, including pain onset, progression, and intensity; Moreover, it has stronger associations with nociplastic pain and fibromyalgia compared to nociceptive and neuropathic pain, implying a unique protein signature of different pain mechanisms. Finally, among 434 candidate proteins prioritized in the observational analysis, 18 are corroborated with causal relevance by Mendelian randomization, and importantly, four (CA14, DPEP1, LGALS3, and TNF) showed potential as novel drug targets repurposed for treating CWP.

Abstract Nociplastic pain is defined by altered nociceptive processing in the absence of clear peripheral damage or somatosensory lesions. The Fibromyalgia Index (FMI), derived from the 2016 diagnostic criteria, is increasingly used as a marker of nociplastic pain severity in clinical studies, yet its neurobiological validity remains untested at scale. Using multimodal neuroimaging data from over 40 000 participants in UK Biobank, we examined whether FMI scores were associated with altered functional and structural connectivity within the descending pain modulatory system (DPMS), a brain network involved in endogenous pain control and implicated in nociplastic pain conditions. Functional connectivity was assessed using resting-state functional MRI (rfMRI), and structural connectivity using diffusion-weighted MRI (dMRI) tractography. Connectivity was quantified between seven DPMS regions: periaqueductal grey (PAG), rostral ventromedial medulla (RVM), hypothalamus, amygdala, rostral and subgenual anterior cingulate cortex (rACC, sgACC), and dorsolateral prefrontal cortex (dlPFC). Multi-group structural equation models tested associations between FMI scores and connectivity, stratified by chronic pain status. Mediation models evaluated which aspects of nociplastic pain accounted for the observed associations: widespread pain and SPACE symptoms (sleep disturbance, pain, affect, cognitive problems, and low energy). To assess specificity, we repeated analyses using the Douleur Neuropathique 4 (DN4), a measure of neuropathic pain, and average pain intensity as comparison outcomes. In 22 139 individuals with chronic pain (58% female; mean age 64.8, standard deviation 7.59), FMI scores were associated with altered structural connectivity between the PAG and amygdala [β = 0.023, 95% confidence interval (CI): 0.0087 to 0.039; Pcorr = 0.0125] and between the PAG and hypothalamus (β = −0.029, 95% CI: −0.043 to −0.015; Pcorr = 0.0013). Functional connectivity in the same circuits showed smaller effects. These associations were not observed in individuals without chronic pain. Mediation analyses revealed that PAG-amygdala and PAG-hypothalamus connectivity were partially explained by fatigue, sleep duration, and widespread pain. DPMS connectivity was not significantly associated with neuropathic pain or average pain intensity. These findings suggest that FMI scores reflect biologically meaningful changes in brain connectivity, particularly in subcortical DPMS circuits implicated in affective and homeostatic dimensions of pain. Structural connectivity was more strongly associated with FMI than functional measures, possibly reflecting cumulative effects of chronic pain on white matter architecture. The absence of similar associations for other pain outcomes supports the specificity of FMI as a marker of nociplastic pain severity. These results provide a neurobiological basis for the FMI and support its use in population research and biomarker development for nociplastic pain.

Abstract Objectives Sleep disturbance is a key symptom of fibromyalgia and a risk factor for chronic widespread pain. This systematic review and meta-analysis aims to assess the effectiveness of pharmacological treatments and cognitive behavioural therapy (CBT) in improving sleep quality in fibromyalgia patients. Methods A systematic search of PubMed, MEDLINE, Embase, Cochrane CENTRAL and CINAHL was conducted for randomized controlled trials (RCTs) published up to April 2023. Studies assessing pharmacological or CBT interventions with sleep-related outcomes were included. Data were extracted, and meta-analyses were performed where applicable. Study quality and bias were evaluated using the Cochrane Risk of Bias tool. Results Forty-seven RCTs, including 11 094 participants, were reviewed. CBT for insomnia (CBT-I) showed a significant improvement in sleep quality (SMD −0.63, 95% CI −0.98 to −0.27), while CBT for pain (CBT-P) had no significant impact. Pharmacological agents such as pregabalin and sodium oxybate moderately improved sleep, but there was uncertainty around this evidence. Amitriptyline, milnacipran and duloxetine showed no significant benefit for sleep. Study heterogeneity was moderate, and no publication bias was detected. Conclusion CBT-I is a promising treatment for enhancing sleep quality in fibromyalgia. Pharmacological treatments like pregabalin may be beneficial but should be used cautiously due to potential risks. Future research should prioritize trials focusing on sleep as a primary outcome and explore the comparative effectiveness of pharmacological treatments and CBT-I in fibromyalgia. Understanding the mechanisms linking sleep and fibromyalgia will also help guide future therapies.

Abstract Background/Aims Features of centralised pain, encompassing widespread pain and non-pain features such as multisensory hypersensitivity, fatigue, and sleep disturbance are common in RA. We hypothesise that centralised pain in early RA affects response to standard first-line treatment. Methods Prospective cohort study of adults with a clinical diagnosis of RA recruited from the early inflammatory arthritis clinic, Oxford University Hospitals, who completed an online assessment within two weeks of starting a DMARD. Centralised pain was assessed using three measures: the 2016 Fibromyalgia Survey Criteria (0-31), Central Sensitisation Inventory (CSI, 0-100), and PainDetect (0-38). The primary outcome, bodily pain, was assessed using the Short Form-36 Bodily Pain Scale (BPS), where lower scores indicate worse pain severity. During follow-up, participants completed three sets of follow-up questionnaires at 3-, 6- and 12-months. Linear mixed effects models were used to account for repeated measurements and patient variability. Three models were fitted, for an association between baseline values of each centralised pain measure with BPS over time. An interaction between centralised pain scores with time was fitted to assess for effect of the exposure on change over time. Age, sex, and symptom duration at baseline were included as confounding variables. Ethical approval was granted by South Central Oxford B Research Ethics Committee. Results Of 149 participants, 117 (79%) completed follow-up: median (IQR) age 59.8 (24.6) years; 36% male; 30% with symptoms >1 year at baseline. There were no significant baseline differences among those lost to follow-up, apart from a longer symptom duration (53% vs 30% symptom duration >1 year; P = 0.033). At baseline, median (IQR) Fibromyalgia Survey Criteria, CSI, and PainDetect scores were 12 (6), 36 (17), and 14 (9) respectively. The median (IQR) BPS at baseline was 32.5 (22.5). Measures of centralised pain were moderately-to-strongly correlated with each other, and with BPS. Individuals with symptoms for >1 year had higher scores on the PainDetect (P = 0.0015), but not the CSI (P = 0.0545) or Fibromyalgia Survey Criteria (P = 0.672). After adjusting for age, sex, and symptom duration, there was a significant association between centralised pain at baseline and BPS over follow-up, e.g.; for every unit increase in the fibromyalgia survey criteria at baseline, the BPS decreased by 2.40 (95%CI -3.29, -1.49; P < 0.001) points over follow-up. Similar relationships were seen with the CSI and PainDetect scores. Conclusion Centralised pain measures in early RA patients can be indicative of the severity of bodily pain experienced during the subsequent 12 months after starting a DMARD treatment. Recognising and assessing centralised pain in early RA patients may enable us to tailor more effective and individualised treatment regimens. Further studies, especially those utilising neuroimaging and QST, are essential to elucidate the neural mechanisms underlying the impact of centralised pain on treatment outcomes in RA. Disclosure E. Kelleher: None. A.J. Wall: None. M.T. Sanchez-Santos: None. V. Wanigasekera: None. A. Irani (nee Soni): None.