{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:07:07Z","timestamp":1790683627879,"version":"4.1.0"},"reference-count":134,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Rheumatoid arthritis (RA) is a systemic autoimmune disease in which persistent pain, fatigue, cognitive impairment, depression, and anxiety may involve altered central nervous system (CNS) processing. This narrative review synthesizes preclinical and clinical evidence concerning proposed glial cell-mediated joint\u2013brain communication in RA. Joint-derived neural inputs and systemic inflammatory signals may communicate with the CNS through humoral, cellular, neural, neuroendocrine, and neurovascular pathways. Preclinical studies implicate microglia and astrocytes in neuroinflammatory responses, spinal central sensitization, impaired hippocampal plasticity, and neurovascular alterations. Human studies associate systemic inflammation with altered brain connectivity and CNS-related symptoms. Disease-modifying antirheumatic treatment, particularly tumor necrosis factor inhibition, has been associated with improvements in selected CNS-related outcomes. Adjunctive symptom management includes phenotype-guided analgesic approaches, rehabilitation, and psychological and sleep-focused interventions. Translational research explores glial modulators, pathway-specific interventions, vagal neuromodulation, neuroimaging, cerebrospinal fluid markers, and multidimensional patient stratification. The proposed joint\u2013brain framework highlights the value of assessing inflammation alongside pain phenotype, cognition, mood, fatigue, sleep, and function. Future human studies should evaluate whether mechanistic and biomarker findings can improve individualized treatment selection and clinical outcomes.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1889608","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:37:32Z","timestamp":1790681852000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Joint\u2013brain communication in rheumatoid arthritis: glial mechanisms, pain phenotypes, and translational evidence"],"prefix":"10.3389","volume":"17","author":[{"given":"Dong","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s13075-020-02180-5","article-title":"Cognitive dysfunction in autoimmune rheumatic diseases","volume":"22","author":"Ol\u00e1h","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"B3","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/acr.25532","article-title":"Longitudinal relationship between pain and depression in people with inflammatory arthritis: A narrative review","volume":"78","author":"Cox","year":"2026","journal-title":"Arthritis Care Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/acr.25245","article-title":"Prevalence, severity, and measures of anxiety in rheumatoid arthritis: A systematic review","volume":"76","author":"Meade","year":"2024","journal-title":"Arthritis Care Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.3390\/jcm15041601","article-title":"The association between neuropathic pain, pain intensity, and inflammatory activity in rheumatoid arthritis","volume":"15","author":"Akar","year":"2026","journal-title":"J Clin Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0217412","article-title":"New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis - Implications from the prospective multicenter VADERA II study","volume":"14","author":"Englbrecht","year":"2019","journal-title":"PloS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s11926-019-0870-5","article-title":"Inflammation and the central nervous system in inflammatory rheumatic disease","volume":"21","author":"Kaplan","year":"2019","journal-title":"Curr Rheumatol Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31472-1","article-title":"Pathogenetic insights from the treatment of rheumatoid arthritis","volume":"389","author":"McInnes","year":"2017","journal-title":"Lancet (London England)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-018-0473-5","article-title":"Mechanisms for joint pain in rheumatoid arthritis (RA): from cytokines to central sensitization","volume":"16","author":"Zhang","year":"2018","journal-title":"Curr osteoporosis Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/acr.25104","article-title":"Identifying and managing nociplastic pain in individuals with rheumatic diseases: A narrative review","volume":"75","author":"Murphy","year":"2023","journal-title":"Arthritis Care Res"},{"key":"B11","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1186\/s13075-021-02657-x","article-title":"Sustained microglial activation in the area postrema of collagen-induced arthritis mice","volume":"23","author":"Matsushita","year":"2021","journal-title":"Arthritis Res Ther"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.1038\/s41467-018-04648-0","article-title":"A multi-modal MRI study of the central response to inflammation in rheumatoid arthritis","volume":"9","author":"Schrepf","year":"2018","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-04114-7","article-title":"Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial","volume":"32","author":"Tesser","year":"2026","journal-title":"Nat Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2020.06.023","article-title":"Brain TNF drives post-inflammation depression-like behavior and persistent pain in experimental arthritis","volume":"89","author":"Lopes","year":"2020","journal-title":"Brain behavior Immun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15742","article-title":"Spinal pain processing in arthritis: Neuron and glia (inter)actions","volume":"168","author":"Schaible","year":"2024","journal-title":"J Neurochem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-225414","article-title":"Predictors for severe persisting pain in rheumatoid arthritis are associated with pain origin and appraisal of pain","volume":"83","author":"Baerwald","year":"2024","journal-title":"Ann rheumatic Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.1651","article-title":"The burden of pain in rheumatoid arthritis: Impact of disease activity and psychological factors","volume":"24","author":"Vergne-Salle","year":"2020","journal-title":"Eur J Pain (London England)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2019.01.001","article-title":"Discrete trajectories of resolving and persistent pain in people with rheumatoid arthritis despite undergoing treatment for inflammation: Results from three UK cohorts","volume":"20","author":"McWilliams","year":"2019","journal-title":"J Pain"},{"key":"B19","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1186\/s12888-022-04417-w","article-title":"Prevalence of cognitive impairment in patients with rheumatoid arthritis: a cross sectional study","volume":"22","author":"McDowell","year":"2022","journal-title":"BMC Psychiatry"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2022.152131","article-title":"Cognitive impairment in the immune-mediated inflammatory diseases compared with age-matched controls: Systematic review and meta-regression","volume":"58","author":"Gwinnutt","year":"2023","journal-title":"Semin Arthritis rheumatism"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1080\/13803395.2016.1167173","article-title":"Cognitive deficits early in the course of rheumatoid arthritis","volume":"38","author":"Simos","year":"2016","journal-title":"J Clin Exp Neuropsychol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000201489","article-title":"Inflammatory diseases, inflammatory biomarkers, and Alzheimer disease: An observational analysis and Mendelian randomization","volume":"100","author":"Huang","year":"2023","journal-title":"Neurology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000046518","article-title":"Impact of rheumatoid arthritis on Alzheimer\u2019s disease: A two-sample bidirectional Mendelian randomization study","volume":"104","author":"Zhong","year":"2025","journal-title":"Medicine"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2174\/0115672050289966240110041616","article-title":"Association of autoimmune disorders and disease-modifying antirheumatic drugs: (DMARDs) with the risk of Alzheimer\u2019s and\/or dementia: A population study using Medicare beneficiary data","volume":"20","author":"Ding","year":"2023","journal-title":"Curr Alzheimer Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2018.05.012","article-title":"The association of disease activity, pro-inflammatory cytokines, and neurotrophic factors with depression in patients with rheumatoid arthritis","volume":"73","author":"Cheon","year":"2018","journal-title":"Brain behavior Immun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab947","article-title":"Fatigue in early rheumatoid arthritis: data from the Early Rheumatoid Arthritis Network","volume":"61","author":"Ifesemen","year":"2022","journal-title":"Rheumatol (Oxford England)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1002\/art.41499","article-title":"Improvements in fatigue lag behind disease remission in early rheumatoid arthritis: Results from the Canadian Early Arthritis Cohort","volume":"73","author":"Holdren","year":"2021","journal-title":"Arthritis Rheumatol (Hoboken NJ)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1810553115","article-title":"Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis","volume":"115","author":"Andersson","year":"2018","journal-title":"PNAS"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2024.1468910","article-title":"Comparison of volumetric brain analysis in subjects with rheumatoid arthritis and ulcerative colitis","volume":"11","author":"Cox","year":"2024","journal-title":"Front Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"32010","DOI":"10.1038\/s41598-024-83559-1","article-title":"Volume and distribution of white matter hyperintensities in rheumatoid arthritis and ulcerative colitis patients","volume":"14","author":"Cox","year":"2024","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/s41398-025-03652-5","article-title":"Immunometabolic and brain structural alterations mediate increased risk of brain diseases in rheumatoid arthritis patients","volume":"15","author":"He","year":"2025","journal-title":"Transl Psychiatry"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(24)00190-5","article-title":"Cognitive impairment in individuals with rheumatic diseases: the role of systemic inflammation, immunomodulatory medications, and comorbidities","volume":"6","author":"Myasoedova","year":"2024","journal-title":"Lancet Rheumatol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/art.40451","article-title":"Neurobiologic features of fibromyalgia are also present among rheumatoid arthritis patients","volume":"70","author":"Basu","year":"2018","journal-title":"Arthritis Rheumatol (Hoboken NJ)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/art.41069","article-title":"Association of inflammation with pronociceptive brain connections in rheumatoid arthritis patients with concomitant fibromyalgia","volume":"72","author":"Kaplan","year":"2020","journal-title":"Arthritis Rheumatol (Hoboken NJ)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez132","article-title":"Functional and structural magnetic resonance imaging correlates of fatigue in patients with rheumatoid arthritis","volume":"58","author":"Basu","year":"2019","journal-title":"Rheumatol (Oxford England)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e99","DOI":"10.1016\/S2665-9913(23)00007-3","article-title":"Brain mapping inflammatory-arthritis-related fatigue in the pursuit of novel therapeutics","volume":"5","author":"Stefanov","year":"2023","journal-title":"Lancet Rheumatol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/acr.25694","article-title":"Beyond inflammation: Why understanding the brain matters in inflammatory arthritis","volume":"78","author":"Kelleher","year":"2026","journal-title":"Arthritis Care Res"},{"key":"B38","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1186\/s13075-015-0783-2","article-title":"Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success","volume":"17","author":"Sergeeva","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhad120","article-title":"Dynamics of corticocortical brain functional connectivity relevant to therapeutic response to biologics in inflammatory arthritis","volume":"33","author":"Sakiyama","year":"2023","journal-title":"Cereb Cortex (New York NY : 1991)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S571311","article-title":"Central sensitization and nociplastic pain: Shared mechanisms in fibromyalgia, osteoarthritis, and inflammatory arthritis","volume":"19","author":"Hladkykh","year":"2026","journal-title":"J Pain Res"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-225327","article-title":"From fibrositis to fibromyalgia to nociplastic pain: how rheumatology helped get us here and where do we go from here","volume":"83","author":"Clauw","year":"2024","journal-title":"Ann rheumatic Dis"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2022.105399","article-title":"Assessing central sensitization with quantitative sensory testing in inflammatory rheumatic diseases: A systematic review","volume":"89","author":"Trouvin","year":"2022","journal-title":"Joint Bone Spine"},{"key":"B43","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1186\/s13075-024-03407-5","article-title":"Contribution of inflammation markers and quantitative sensory testing (QST) indices of central sensitisation to rheumatoid arthritis pain","volume":"26","author":"Georgopoulos","year":"2024","journal-title":"Arthritis Res Ther"},{"key":"B44","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1002\/acr.23266","article-title":"Association between pain sensitization and disease activity in patients with rheumatoid arthritis: A cross-sectional study","volume":"70","author":"Lee","year":"2018","journal-title":"Arthritis Care Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000003599","article-title":"CRMP2 phosphorylation regulates polarization and spinal infiltration of CD4 + T lymphocytes, inhibits spinal glial activation, and arthritic pain","volume":"166","author":"Jiang","year":"2025","journal-title":"Pain"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0201021","article-title":"The spinal NR2BR\/ERK2 pathway as a target for the central sensitization of collagen-induced arthritis pain","volume":"13","author":"Xu","year":"2018","journal-title":"PloS One"},{"key":"B47","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1002\/acr.25668","article-title":"Association between discordance of disease activity indices and quantitative sensory testing measures of nociplastic pain in patients with rheumatoid arthritis","volume":"78","author":"Lin","year":"2026","journal-title":"Arthritis Care Res"},{"key":"B48","doi-asserted-by":"publisher","first-page":"101423","DOI":"10.1016\/j.berh.2019.06.005","article-title":"The prevalence and impact of comorbid fibromyalgia in inflammatory arthritis","volume":"33","author":"Zhao","year":"2019","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-021-06026-6","article-title":"Clinical and psychological assessment of patients with rheumatoid arthritis and fibromyalgia: a real-world study","volume":"41","author":"Gao","year":"2022","journal-title":"Clin Rheumatol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/art.41440","article-title":"Association of dysregulated central pain processing and response to disease-modifying antirheumatic drug therapy in rheumatoid arthritis","volume":"72","author":"Heisler","year":"2020","journal-title":"Arthritis Rheumatol (Hoboken NJ)"},{"key":"B51","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1038\/s41584-023-01037-w","article-title":"Immune mechanisms of depression in rheumatoid arthritis","volume":"19","author":"Brock","year":"2023","journal-title":"Nat Rev Rheumatol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.122.001380","article-title":"Transport of the proinflammatory chemokines C-C motif chemokine ligand 2 (MCP-1) and C-C motif chemokine ligand 5 (RANTES) across the intact mouse blood-brain barrier is inhibited by heparin and eprodisate and increased with systemic inflammation","volume":"384","author":"Quaranta","year":"2023","journal-title":"J Pharmacol Exp Ther"},{"key":"B53","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S1474-4422(23)00377-0","article-title":"Blood-brain barrier dysfunction in multiple sclerosis: causes, consequences, and potential effects of therapies","volume":"23","author":"Zierfuss","year":"2024","journal-title":"Lancet Neurol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118748109","article-title":"Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice","volume":"109","author":"Lampa","year":"2012","journal-title":"PNAS"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2017.04.003","article-title":"Modulation of experimental arthritis by vagal sensory and central brain stimulation","volume":"64","author":"Bassi","year":"2017","journal-title":"Brain Behavior Immun"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605635113","article-title":"Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis","volume":"113","author":"Koopman","year":"2016","journal-title":"PNAS"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23255","article-title":"Downregulation of spinal astrocytic connexin43 leads to upregulation of interleukin-6 and cyclooxygenase-2 and mechanical hypersensitivity in mice","volume":"66","author":"Morioka","year":"2018","journal-title":"Glia"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.626884","article-title":"Role of primary afferents in arthritis induced spinal microglial reactivity","volume":"12","author":"Kwok","year":"2021","journal-title":"Front Immunol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.bbi.2018.03.012","article-title":"VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis","volume":"74","author":"Beazley-Long","year":"2018","journal-title":"Brain Behavior Immun"},{"key":"B60","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1186\/s13075-025-03695-5","article-title":"Sustained hippocampal neuroinflammation and subsequent glutamatergic dysfunction in juvenile idiopathic arthritis: evidence from proton magnetic resonance spectroscopy ((1)H-MRS)","volume":"27","author":"Han","year":"2025","journal-title":"Arthritis Res Ther"},{"key":"B61","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s12974-021-02086-2","article-title":"Changes of blood-brain-barrier function and transfer of amyloid beta in rats with collagen-induced arthritis","volume":"18","author":"Lai","year":"2021","journal-title":"J Neuroinflamm"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aas9846","article-title":"Microglial pannexin-1 channel activation is a spinal determinant of joint pain","volume":"4","author":"Mousseau","year":"2018","journal-title":"Sci Adv"},{"key":"B63","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1186\/s12974-016-0556-0","article-title":"Neuron-immune mechanisms contribute to pain in early stages of arthritis","volume":"13","author":"Nieto","year":"2016","journal-title":"J Neuroinflamm"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14496","article-title":"Involvement of microglial P2X7 receptor in pain modulation","volume":"30","author":"Zhang","year":"2024","journal-title":"CNS Neurosci Ther"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1177\/17448069231179118","article-title":"Spinal cathepsin S promotes visceral hypersensitivity via FKN\/CX3CR1\/p38 MAPK signaling pathways","volume":"19","author":"Sun","year":"2023","journal-title":"Mol Pain"},{"key":"B66","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/s41598-017-18357-z","article-title":"Bidirectional modulation between infiltrating CD3(+) T-lymphocytes and astrocytes in the spinal cord drives the development of allodynia in monoarthritic rats","volume":"8","author":"Zhou","year":"2018","journal-title":"Sci Rep"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1253-12.2012","article-title":"Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1\u03b2 via p38 mitogen-activated protein kinase","volume":"32","author":"Tong","year":"2012","journal-title":"J Neuroscience: Off J Soc For Neurosci"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2017.11.006","article-title":"Brain-derived neurotrophic factor in adjuvant-induced arthritis in rats. Relationship with inflammation and endothelial dysfunction","volume":"82","author":"Pedard","year":"2018","journal-title":"Prog Neuro-Psychopharmacol Biol Psychiatry"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.01125","article-title":"The cerebral brain-derived neurotrophic factor pathway, either neuronal or endothelial, is impaired in rats with adjuvant-induced arthritis. Connection with endothelial dysfunction","volume":"8","author":"Pedard","year":"2017","journal-title":"Front Physiol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202101558R","article-title":"proBDNF\/p75NTR promotes rheumatoid arthritis and inflammatory response by activating proinflammatory cytokines","volume":"36","author":"Yang","year":"2022","journal-title":"FASEB Journal: Off Publ Fed Am Societies For Exp Biol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00504.2008","article-title":"Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells","volume":"296","author":"Hao","year":"2009","journal-title":"Am J Physiol Cell Physiol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150237","article-title":"NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes","volume":"214","author":"Freeman","year":"2017","journal-title":"J Exp Med"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0055-7","article-title":"Inflammasome signalling in brain function and neurodegenerative disease","volume":"19","author":"Heneka","year":"2018","journal-title":"Nat Rev Neurosci"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.TR119000468","article-title":"Lipid rafts in glial cells: role in neuroinflammation and pain processing","volume":"61","author":"Miller","year":"2020","journal-title":"J Lipid Res"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.11.017","article-title":"25-hydroxycholesterol suppress IFN-\u03b3-induced inflammation in microglia by disrupting lipid raft formation and caveolin-mediated signaling endosomes","volume":"179","author":"Lee","year":"2022","journal-title":"Free Radical Biol Med"},{"key":"B76","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/cns.13569","article-title":"Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms","volume":"27","author":"Huang","year":"2021","journal-title":"CNS Neurosci Ther"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23940","article-title":"Altered astrocytic function in experimental neuroinflammation and multiple sclerosis","volume":"69","author":"das Neves","year":"2021","journal-title":"Glia"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.123361","article-title":"Pain in rheumatoid arthritis: emerging role of high mobility group box 1 protein-HMGB1","volume":"362","author":"Krishna","year":"2025","journal-title":"Life Sci"},{"key":"B79","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1111\/jnc.15438","article-title":"Spinal interleukin-1\u03b2 induces mechanical spinal hyperexcitability in rats: interactions and redundancies with TNF and IL-6","volume":"158","author":"K\u00f6nig","year":"2021","journal-title":"J Neurochem"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2022.175256","article-title":"Ibuprofen treatment ameliorates memory deficits in rats with collagen-induced arthritis by normalizing aberrant MAPK\/NF-\u03baB and glutamatergic pathways","volume":"933","author":"Zhang","year":"2022","journal-title":"Eur J Pharmacol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2026.116693","article-title":"Abnormal FKN-CX3CR1-NR signal triggers hippocampal synaptic dysfunction in rheumatoid arthritis-related depression","volume":"181","author":"Yao","year":"2026","journal-title":"Int Immunopharmacol"},{"key":"B82","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1111\/joim.12626","article-title":"Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis","volume":"282","author":"Koopman","year":"2017","journal-title":"J Internal Med"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1080\/03009742.2020.1764617","article-title":"Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study","volume":"50","author":"Drewes","year":"2021","journal-title":"Scandinavian J Rheumatol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13635","article-title":"Adrenocortical dysfunction in rheumatoid arthritis: \u03b1 narrative review and future directions","volume":"52","author":"Filippa","year":"2022","journal-title":"Eur J Clin Invest"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212762","article-title":"Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis","volume":"77","author":"Koenen","year":"2018","journal-title":"Ann Rheumatic Dis"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.12659\/msm.906184","article-title":"Norepinephrine inhibits Th17 cells via \u03b22-adrenergic receptor (\u03b22-AR) signaling in a mouse model of rheumatoid arthritis","volume":"24","author":"Liu","year":"2018","journal-title":"Med Sci Monitor: Int Med J Exp Clin Res"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.119701","article-title":"Catecholamine-producing cells in the synovial tissue during arthritis: modulation of sympathetic neurotransmitters as new therapeutic target","volume":"69","author":"Capellino","year":"2010","journal-title":"Ann Rheumatic Dis"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2025.578773","article-title":"Over-excitation of tyrosine hydroxylase neurons in the paraventricular nucleus of the hypothalamus drives a neuroimmune positive feedback loop in rheumatoid arthritis","volume":"409","author":"Li","year":"2025","journal-title":"J Neuroimmunology"},{"key":"B89","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1002\/art.38271","article-title":"Involvement of peripheral and spinal tumor necrosis factor \u03b1 in spinal cord hyperexcitability during knee joint inflammation in rats","volume":"66","author":"K\u00f6nig","year":"2014","journal-title":"Arthritis Rheumatol (Hoboken NJ)"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-022-02754-1","article-title":"Inhibition of spinal interleukin-33 attenuates peripheral inflammation and hyperalgesia in experimental arthritis","volume":"59","author":"Huang","year":"2022","journal-title":"Mol Neurobiol"},{"key":"B91","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1002\/art.38328","article-title":"Activation of spinal NF-\u03baB\/p65 contributes to peripheral inflammation and hyperalgesia in rat adjuvant-induced arthritis","volume":"66","author":"Luo","year":"2014","journal-title":"Arthritis Rheumatol (Hoboken NJ)"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/2076328","article-title":"Pain mechanism in rheumatoid arthritis: from cytokines to central sensitization","volume":"2020","author":"Cao","year":"2020","journal-title":"Mediators Inflammation"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000929","article-title":"Fibromyalgia and centralized pain in the rheumatoid arthritis patient","volume":"35","author":"Minhas","year":"2023","journal-title":"Curr Opin Rheumatol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1909094","article-title":"Reframing immune-mediated inflammatory diseases through signature cytokine hubs","volume":"385","author":"Schett","year":"2021","journal-title":"N Engl J Med"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-203143","article-title":"Does stress affect the joints? Daily stressors, stress vulnerability, immune and HPA axis activity, and short-term disease and symptom fluctuations in rheumatoid arthritis","volume":"73","author":"Evers","year":"2014","journal-title":"Ann Rheumatic Dis"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-025-07754-9","article-title":"Rheumatoid arthritis in crisis: investigating the impact of stress on RA flares during the COVID-19 pandemic","volume":"45","author":"Morris","year":"2026","journal-title":"Clin Rheumatol"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1002\/acr.25543","article-title":"Perceived stress and prediction of worse patient-reported outcomes in a rheumatoid arthritis cohort","volume":"77","author":"Patterson","year":"2025","journal-title":"Arthritis Care Res"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.111046","article-title":"Chronic stress predisposes to the aggravation of inflammation in autoimmune diseases with focus on rheumatoid arthritis and psoriasis","volume":"125","author":"Chaudhary","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keu221","article-title":"Immune responses to stress in rheumatoid arthritis and psoriasis","volume":"53","author":"de Brouwer","year":"2014","journal-title":"Rheumatol (Oxford England)"},{"key":"B100","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1159\/000542489","article-title":"A tale of two treatments: a randomised controlled trial of mindfulness or cognitive behaviour therapy delivered online for people with rheumatoid arthritis","volume":"94","author":"Sharpe","year":"2025","journal-title":"Psychother Psychosomatics"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000845","article-title":"A tailored-guided internet-based cognitive-behavioral intervention for patients with rheumatoid arthritis as an adjunct to standard rheumatological care: results of a randomized controlled trial","volume":"158","author":"Ferwerda","year":"2017","journal-title":"Pain"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpr.2022.102124","article-title":"The effect of mindfulness-based interventions on immunity-related biomarkers: a comprehensive meta-analysis of randomised controlled trials","volume":"92","author":"Dunn","year":"2022","journal-title":"Clin Psychol Rev"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2023.05.006","article-title":"Comparative efficacy of psychological interventions on immune biomarkers: a systematic review and network meta-analysis (NMA)","volume":"111","author":"Ballesio","year":"2023","journal-title":"Brain Behavior Immun"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2020.02259","article-title":"Effect of an 8-week yoga-based lifestyle intervention on psycho-neuro-immune axis, disease activity, and perceived quality of life in rheumatoid arthritis patients: a randomized controlled trial","volume":"11","author":"Gautam","year":"2020","journal-title":"Front Psychol"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2025.1561140","article-title":"Impact of TNF inhibitors on inflammation-associated cognitive dysfunction in patients with rheumatoid arthritis: a prospective analysis","volume":"12","author":"Mena-V\u00e1zquez","year":"2025","journal-title":"Front Med"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-231329","article-title":"The RESIST study: Examining cognitive change in rheumatoid arthritis patients with mild cognitive impairment being treated with a TNF-inhibitor compared to a conventional synthetic disease-modifying anti-rheumatic drug","volume":"99","author":"Marr","year":"2024","journal-title":"J Alzheimer\u2019s Disease : JAD"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(25)00032-3","article-title":"Disease-associated brain activation predicts clinical response to TNF inhibition in rheumatoid arthritis (PreCePra): a randomised, multicentre, double-blind, placebo-controlled phase 3 study","volume":"7","author":"Hess","year":"2025","journal-title":"Lancet Rheumatol"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1159\/000544123","article-title":"The association between tumor necrosis factor-alpha inhibitor use and dementia risk in patients with rheumatoid arthritis: a systematic review and meta-analysis","volume":"71","author":"Chung","year":"2025","journal-title":"Gerontology"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.55563\/clinexprheumatol\/6oto0h","article-title":"Effect of TNF-\u03b1 blockers on reducing the risk of dementia in rheumatoid arthritis: a nationwide cohort study","volume":"43","author":"Chen","year":"2025","journal-title":"Clin Exp Rheumatol"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12465","article-title":"Potential long-term effect of tumor necrosis factor inhibitors on dementia risk: a propensity score matched retrospective cohort study in US veterans","volume":"18","author":"Zheng","year":"2022","journal-title":"Alzheimer\u2019s Dementia: J Alzheimer\u2019s Assoc"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2022.152083","article-title":"Incidence of dementia in patients with rheumatoid arthritis and association with disease modifying anti-rheumatic drugs - analysis of a national claims database","volume":"57","author":"Sattui","year":"2022","journal-title":"Semin Arthritis Rheumatism"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1111\/fcp.70072","article-title":"JAK inhibitors and memory impairment: Disproportionality analyses in the WHO global pharmacovigilance database, VigiBase","volume":"40","author":"Dubo\u00eblle","year":"2026","journal-title":"Fundam Clin Pharmacol"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200022050-00007","article-title":"Benefits and risks of minocycline in rheumatoid arthritis","volume":"22","author":"Langevitz","year":"2000","journal-title":"Drug Saf"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-122-2-199501150-00001","article-title":"Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group","volume":"122","author":"Tilley","year":"1995","journal-title":"Ann Internal Med"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.06.009","article-title":"Ibudilast produces anti-allodynic effects at the persistent phase of peripheral or central neuropathic pain in rats: Different inhibitory mechanism on spinal microglia from minocycline and propentofylline","volume":"833","author":"Fujita","year":"2018","journal-title":"Eur J Pharmacol"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1002\/art.40787","article-title":"Ibudilast inhibits chemokine expression in rheumatoid arthritis synovial fibroblasts and exhibits immunomodulatory activity in experimental arthritis","volume":"71","author":"Clanchy","year":"2019","journal-title":"Arthritis Rheumatol (Hoboken NJ)"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000003447","article-title":"Glial-modulating agents for the treatment of pain: a systematic review","volume":"166","author":"Gilron","year":"2025","journal-title":"Pain"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2022-072415","article-title":"Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews","volume":"380","author":"Ferreira","year":"2023","journal-title":"BMJ (Clinical Res Ed)"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD014682.pub2","article-title":"Antidepressants for pain management in adults with chronic pain: a network meta-analysis","volume":"5","author":"Birkinshaw","year":"2023","journal-title":"Cochrane Database Systematic Rev"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1807061","article-title":"Nonnarcotic methods of pain management","volume":"380","author":"Finnerup","year":"2019","journal-title":"N Engl J Med"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1177\/10600280211062271","article-title":"Evidence needed for efficacy of antidepressant medications among patients with rheumatoid arthritis","volume":"56","author":"Silva Almod\u00f3var","year":"2022","journal-title":"Ann Pharmacother"},{"key":"B122","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s12916-025-03870-0","article-title":"Pharmacological pain management in patients with rheumatoid arthritis: a narrative literature review","volume":"23","author":"Cox","year":"2025","journal-title":"BMC Med"},{"key":"B123","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1001\/jamainternmed.2019.0086","article-title":"A clinical overview of off-label use of gabapentinoid drugs","volume":"179","author":"Goodman","year":"2019","journal-title":"JAMA Intern Med"},{"key":"B124","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neuroscience.2024.07.047","article-title":"Gabapentin alleviates peripheral nerve sensitization induced by inflammatory arthritis via ionotropic glutamate receptor NR2B subunit","volume":"556","author":"Meng","year":"2024","journal-title":"Neuroscience"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.170797","article-title":"Rheumatoid arthritis magnetic resonance imaging score predicts therapy response: results of the German ArthroMark cohort","volume":"45","author":"Sewerin","year":"2018","journal-title":"J Rheumatol"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa496","article-title":"Predictors of joint damage progression and stringent remission in patients with established rheumatoid arthritis in clinical remission","volume":"60","author":"M\u00f8ller-Bisgaard","year":"2021","journal-title":"Rheumatol (Oxford England)"},{"key":"B127","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s13075-019-1846-6","article-title":"Mass spectrometry-based analysis of cerebrospinal fluid from arthritis patients-immune-related candidate proteins affected by TNF blocking treatment","volume":"21","author":"Estelius","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.6567","article-title":"Comparative risk of Alzheimer disease and related dementia among Medicare beneficiaries with rheumatoid arthritis treated with targeted disease-modifying antirheumatic agents","volume":"5","author":"Desai","year":"2022","journal-title":"JAMA Netw Open"},{"key":"B129","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/s41467-022-28473-8","article-title":"Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain","volume":"13","author":"Tansley","year":"2022","journal-title":"Nat Commun"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1812290","article-title":"Transcriptomics and AI-driven approaches to the diagnosis and treatment of rheumatoid arthritis","volume":"17","author":"Ciechomska","year":"2026","journal-title":"Front Immunol"},{"key":"B131","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1053\/j.semnuclmed.2022.08.010","article-title":"Update on imaging of inflammatory arthritis and related disorders","volume":"53","author":"Jamar","year":"2023","journal-title":"Semin Nucl Med"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.2174\/0929867324666170523144402","article-title":"Role of positron emission tomography for central nervous system involvement in systemic autoimmune diseases: status and perspectives","volume":"25","author":"Mauro","year":"2018","journal-title":"Curr Med Chem"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-017-3974-1","article-title":"Proteomic analysis of plasma from rheumatoid arthritis patients with mild cognitive impairment","volume":"37","author":"Yang","year":"2018","journal-title":"Clin Rheumatol"},{"key":"B134","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-020-05372-1","article-title":"Cognitive impairment in elderly patients with rheumatic disease and the effect of disease-modifying anti-rheumatic drugs","volume":"40","author":"Sood","year":"2021","journal-title":"Clin Rheumatol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1889608\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:37:34Z","timestamp":1790681854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1889608\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":134,"alternative-id":["10.3389\/fimmu.2026.1889608"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1889608","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"article-number":"1889608"}}