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Established and emerging therapies offer effective disease control for many patients, though they often have underwhelming efficacy for pain relief. The uncoupling of pain intensity from disease activity and inflammation presents an ongoing challenge in both our understanding of the pathophysiology and our ability to treat joint pain. The generation of high-parameter, unbiased -omic data sets generated from patient-derived tissues is changing how we think about rheumatoid arthritis pain. In this review, we discuss the peripheral drivers of pain in rheumatoid arthritis-affected joints and their innervating primary afferents. We evaluate how human molecular immunology and neuroscience approaches are helping us unravel the heterogeneity of pain in rheumatoid arthritis and propose future directions to clarify how pain is maintained in the absence of inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Recent findings<\/jats:title>\n                    <jats:p>Synovial fibroblasts have emerged as key pronociceptive drivers within the rheumatic joint. Further to the classical proinflammatory mediators known to drive pain, such as cytokines and prostaglandins, bone morphogenetic proteins, ephrin signaling, and netrins appear to be upregulated in both rheumatoid arthritis-affected synovium and the innervating sensory neurons. Resulting adaptations to innervating primary afferents such as synaptogenesis and neurite outgrowth may occur in a sensory neuron subtype-specific manner causing pain that is disproportionate to inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>Nociceptor sprouting in the joint may explain why pain tends to persist despite adequate disease control. Future mechanistic work exploring the conditions under which these nociceptors sprout into the joint will provide new therapeutic avenues for ensuring that pain resolves alongside the inflammation associated with rheumatoid arthritis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11926-025-01198-5","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T17:59:43Z","timestamp":1752688783000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ectopic Nociceptor Sprouting as a Key Peripheral Driver of Pain in Rheumatoid Arthritis"],"prefix":"10.1007","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5305-4350","authenticated-orcid":false,"given":"Jayden A.","family":"O\u2019Brien","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph B.","family":"Lesnak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore J.","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"issue":"3","key":"1198_CR1","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.yfrne.2014.04.004","volume":"35","author":"ST Ngo","year":"2014","unstructured":"Ngo ST, Steyn FJ, McCombe PA. 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Clin Rheumatol. 2024;43(11):3525\u201336.","journal-title":"Clin Rheumatol"}],"container-title":["Current Rheumatology Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11926-025-01198-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11926-025-01198-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11926-025-01198-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T19:05:01Z","timestamp":1770750301000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11926-025-01198-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":91,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["1198"],"URL":"https:\/\/doi.org\/10.1007\/s11926-025-01198-5","relation":{},"ISSN":["1523-3774","1534-6307"],"issn-type":[{"value":"1523-3774","type":"print"},{"value":"1534-6307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,16]]},"assertion":[{"value":"9 July 2025","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2025","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Disclosures: T.J.P. is a co-founder and holds equity in 4E Therapeutics, NuvoNuro, PARMedics, and Nerveli. T.J.P. has received research grants from AbbVie, Eli Lilly, Gr\u00fcnenthal, Evommune, Hoba Therapeutics, and The National Institutes of Health. The other authors declare no competing interests. Funding Statement: This research was supported by the National Institute Of Neurological Disorders And Stroke of the National Institutes of Health through the PRECISION Human Pain Network (RRID:SCR_025458), part of the NIH HEAL Initiative (\n                      \n                      ) under award number U19NS130608 to T.J.P. and by R01AR078192 to T.J.P. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All reported studies\/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional\/national research committee standards, and international\/national\/institutional guidelines).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights"}}],"article-number":"30"}}