Irani, Anushka

Abstract Pain treatments have modest effects. Health outcomes might be improved if treatments are matched to mechanisms underlying the persistence and biopsychosocial impact of an individual's pain. The International Association for the Study of Pain (IASP) defines 3 mechanistic pain descriptors presumed to involve different mechanisms—nociceptive, neuropathic, and nociplastic. Although treatments to address each descriptor have been proposed, there is no consensus on how to assign descriptors to clinical presentations. A recent consensus identified candidate clinical features to discriminate between descriptors in clinical practice and research. These need refinement to progress towards a tool. This study aimed to determine the rank and relative weight of identified clinical features to aid discrimination between mechanistic pain descriptors. Candidate clinical features (n = 196) were refined by the IASP Terminology Task Force to converge similar and remove redundant features. The Task Force (n = 24) and an expert panel (n = 39) ranked features using 1000minds conjoint analysis software and assigned weights based on discrete pairwise choices. Participants nominated from pairs of scenarios, which most likely indicated that pain aligned predominantly to a descriptor. Highest ranked features for neuropathic and nociplastic pain were aligned with IASP Clinical Criteria. Criteria for nociceptive pain have not been established. A ranked list of features shared by 2 mechanisms (indicating mixed mechanisms) was also identified. This study identified expert consensus on the highest ranked clinical features with potential to discriminate between pain descriptors, reflective of different underlying mechanisms. This study extends current frameworks by identifying and refining key discriminators for future operationalisation and validation.

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.

Functional neurological disorder (FND) is a prevalent neurologic condition, yet existing treatment approaches yield inconsistent outcomes. We propose a unifying framework that conceptualizes FND as a disorder triggered and perpetuated by individuals lacking targeted tools to reconcile the cumulative impact of intolerance of uncertainty (IU) and multidimensional allostatic overload. Expanding upon predictive coding and IU theories from neuroscience and psychology research, we argue that during times of uncertainty, individuals with FND exhibit a higher rate of prediction error but lack the energy, resources, and adaptive capacity to respond. This sustained hyperactivation of the brain and body trigger and perpetuate FND. We propose that FND treatment requires a strategic and progressively tiered behavioral approach. First, the individual with FND must be taught behavioral skills to gain immediate symptom control and shift automatic, hyperactive processes into conscious awareness. Only then, can practices from Acceptance and Commitment Therapy, Dialectical Behavioral Therapy, and Mindfulness Therapy be leveraged. These practices help explicitly identify sources of uncertainty and teach how to effectively respond to hyperactive processes with skills that optimize function, commitment to values, and well-being. This framework offers testable hypotheses and a pathway to more effective, individualized care for FND.

Abstract Objectives We aimed to evaluate the effects of GLP-1 receptor agonists (GLP-1RA) on symptom burden and opioid use in patients with fibromyalgia using real-world data. Methods We conducted a retrospective cohort study using the TriNetX Research Network. Patients with fibromyalgia (≥2 diagnostic encounters) were divided into two groups: those with and without ≥2 prescriptions for GLP-1RA. Propensity score matching at a 1:1 ratio for age, sex and key comorbidities, including diabetes mellitus, obesity, osteoarthritis, inflammatory arthritis, ischemic heart disease, sleep disorders, migraine and medication use, was performed. Outcomes were assessed over a five-year follow-up period. This included opioid use, diagnostic codes for pain, fatigue and disability, body mass index and haemoglobin A1C. Statistical analysis included odds ratios, risk differences and t tests. Results After propensity score matching, there were 48 025 patients in each cohort. Baseline characteristics were well matched, though BMI and Haemoglobin A1c were higher in the GLP-1RA cohort than in non-GLP-1RA users. GLP-1RA use was associated with significantly reduced odds of opioid prescription (OR 0.65), pain diagnostic codes (OR 0.79) and fatigue diagnostic codes (OR 0.68) (all P < 0.001). There was no significant difference in disability-related diagnostic codes. BMI and HbA1C remained higher in patients on GLP-1RA. Conclusion GLP-1RA use was associated with reduced opioid prescription and a reduction in the use of ICD-10 codes related to fibromyalgia, potentially reflecting lower symptom burden. Further studies using validated outcome measures are needed to confirm these findings.

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

Objective To examine real‐world patterns in pain management among adults with systemic lupus erythematosus (SLE), we focused on the sequencing of pain modalities, polypharmacy, and demographic variation. Methods We conducted a retrospective analysis of electronic health records from adults with SLE treated at a single academic medical center between 2005 and 2024. We included patients who received at least one pain‐related therapy, including glucocorticoids, opioids, nonsteroidal anti‐inflammatory drugs (NSAIDs), antidepressants, anticonvulsants, muscle relaxants, and nonpharmacologic interventions. We used sequence analysis and Sankey diagrams to map treatment trajectories and compared patterns across two periods: 2005 to 2014 and 2015 to 2024. Polypharmacy was defined as receiving five or more pain‐related prescriptions within 12 months. We examined trends by age, sex, and race or ethnicity. Results Among 769 patients, initiation of glucocorticoids and opioids declined over time (58%–51% and 28%–22%, respectively), whereas NSAID use increased (19%–29%). The median number of pain prescriptions decreased, and polypharmacy prevalence dropped from 53% to 45%. In recent years, younger adults and men received more prescriptions, with 69% of men receiving five or more compared with 43% of women. Racial disparities narrowed overall in recent years but persisted in sensitivity analyses excluding glucocorticoids. Conclusion Pain management in SLE is shifting away from high‐risk therapies; however, prescribing intensity remains high and varies by demographic group. Visualizations serve as a complementary lens to traditional prescription counts, allowing representation of polypharmacy not only by volume but also by the diversity and sequencing of therapeutic classes over time.

Objective Patients with chronic illness share their experiences in online communities and generate rich data on pain management. This study applied natural language processing methods, including large language models (LLMs), to Reddit discussions from lupus communities to characterize multidimensional pain experiences framed in the biopsychosocial model. Methods We extracted Reddit posts from the r/Lupus and r/LupusSupport subreddits posted from June 9, 2010, through December 31, 2023. Pain‐related posts were identified using a clinically informed pain lexicon. Topic modeling was used to identify thematic patterns, which were then compared with structured summaries generated by LLM instructions that were fine‐tuned using the biopsychosocial model of pain. Two reviewers conducted content analysis of the LLM‐generated summaries, evaluating thematic accuracy and coverage. Results Data from Reddit included 31,785 posts from 10,857 authors. We identified common pain complaints, management strategies, and sociocultural, affective, and nociplastic dimensions of pain. Instruction fine‐tuned LLMs produced structured summaries with an average thematic accuracy score of 3.1 of 4 (kappa = .09) and content coverage score of 2.9 of 4 (kappa = .38). Sociocultural features presented in 123 posts (33.8%), including peer support and validation (n = 106) and provider interactions or access issues (n = 35). Nociplastic pain presented in 205 posts (56.3%). Conclusion Natural language processing methods can be used to extract rich, multidimensional insights into pain experiences from online communities focused on lupus. These approaches highlight the psychological, social, and cultural facets of pain that may be underrepresented in clinical settings, supporting more patient‐centered approaches to care in rheumatology.

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.