{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:00:54Z","timestamp":1789729254747,"version":"4.0.1"},"reference-count":46,"publisher":"BMJ","issue":"1","funder":[{"DOI":"10.13039\/501100006315","name":"Reumafonds","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006315","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2017,11,24]]},"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>It is believed that therapy for rheumatoid arthritis (RA) is the most effective and beneficial within a short time frame around RA diagnosis. This insight has caused a shift from research in patients with established RA to patients at risk of developing RA and recently diagnosed patients. It is important for improvement of RA therapy to understand when and what changes occur in patients developing RA. This is true for both seropositive and seronegative patients. Activation of the immune system as presented by autoantibodies, increased cytokine and chemokine production, and alterations within several immune cells occur during RA development. In this review we describe RA pathogenesis with a focus on knowledge obtained from patients with arthralgia, pre-RA and recently diagnosed RA. Connections are proposed between altered immune cells, cytokines and chemokines, and events like synovial hyperplasia, pain and bone damage.<\/jats:p>","DOI":"10.1136\/rmdopen-2016-000256","type":"journal-article","created":{"date-parts":[[2018,1,13]],"date-time":"2018-01-13T20:10:13Z","timestamp":1515874213000},"page":"e000256","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":41,"title":["From patients with arthralgia, pre-RA and recently diagnosed RA: what is the current status of understanding RA pathogenesis?"],"prefix":"10.1136","volume":"4","author":[{"given":"Marlieke","family":"Molendijk","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna MW","family":"Hazes","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Lubberts","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2018,1,12]]},"reference":[{"key":"2025090313062139000_4.1.e000256.1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200990"},{"key":"2025090313062139000_4.1.e000256.2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.138461"},{"key":"2025090313062139000_4.1.e000256.3","doi-asserted-by":"publisher","DOI":"10.1002\/art.27638"},{"key":"2025090313062139000_4.1.e000256.4","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0035296","article-title":"Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis","volume":"7","author":"Sokolove","year":"2012","journal-title":"PLoS One"},{"key":"2025090313062139000_4.1.e000256.5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/art.27186","article-title":"Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis","volume":"62","author":"Kokkonen","year":"2010","journal-title":"Arthritis Rheum"},{"key":"2025090313062139000_4.1.e000256.6","doi-asserted-by":"crossref","first-page":"26021","DOI":"10.1038\/srep26021","article-title":"Analysis of serum immune markers in seropositive and seronegative rheumatoid arthritis and in high-risk seropositive arthralgia patients","volume":"6","author":"Chalan","year":"2016","journal-title":"Sci Rep"},{"key":"2025090313062139000_4.1.e000256.7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.it.2016.10.001","article-title":"Nociceptor sensory neuron-immune interactions in pain and inflammation","volume":"38","author":"Pinho-Ribeiro","year":"2017","journal-title":"Trends Immunol"},{"key":"2025090313062139000_4.1.e000256.8","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.150644"},{"key":"2025090313062139000_4.1.e000256.9","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0079370","article-title":"Circulating CD4+CD161+ T lymphocytes are increased in seropositive arthralgia patients but decreased in patients with newly diagnosed rheumatoid arthritis","volume":"8","author":"Chalan","year":"2013","journal-title":"PLoS One"},{"key":"2025090313062139000_4.1.e000256.10","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0162101","article-title":"Regulatory CD4+ T-Cell Subsets and anti-citrullinated protein antibody repertoire: potential biomarkers for arthritis development in seropositive arthralgia patients?","volume":"11","author":"Janssen","year":"2016","journal-title":"PLoS One"},{"key":"2025090313062139000_4.1.e000256.11","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/s13075-016-1102-2","article-title":"Changes in peripheral blood lymphocyte subsets during arthritis development in arthralgia patients","volume":"18","author":"L\u00fcbbers","year":"2016","journal-title":"Arthritis Res Ther"},{"key":"2025090313062139000_4.1.e000256.12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20102101"},{"key":"2025090313062139000_4.1.e000256.13","doi-asserted-by":"publisher","DOI":"10.1002\/art.20018"},{"key":"2025090313062139000_4.1.e000256.14","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/ni.3579","article-title":"Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease","volume":"18","author":"Pfeifle","year":"2017","journal-title":"Nat Immunol"},{"key":"2025090313062139000_4.1.e000256.15","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-203565"},{"key":"2025090313062139000_4.1.e000256.16","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202958"},{"key":"2025090313062139000_4.1.e000256.17","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2005.043869"},{"key":"2025090313062139000_4.1.e000256.18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60975"},{"key":"2025090313062139000_4.1.e000256.19","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208093"},{"key":"2025090313062139000_4.1.e000256.20","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208094"},{"key":"2025090313062139000_4.1.e000256.21","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.125849"},{"key":"2025090313062139000_4.1.e000256.22","doi-asserted-by":"publisher","DOI":"10.1002\/art.23760"},{"key":"2025090313062139000_4.1.e000256.23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.10.3146"},{"key":"2025090313062139000_4.1.e000256.24","doi-asserted-by":"publisher","DOI":"10.1136\/ard.54.11.916"},{"key":"2025090313062139000_4.1.e000256.25","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005580"},{"key":"2025090313062139000_4.1.e000256.26","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.53"},{"key":"2025090313062139000_4.1.e000256.27","doi-asserted-by":"publisher","DOI":"10.1002\/art.27622"},{"key":"2025090313062139000_4.1.e000256.28","doi-asserted-by":"publisher","DOI":"10.1002\/art.25043"},{"key":"2025090313062139000_4.1.e000256.29","doi-asserted-by":"publisher","DOI":"10.1002\/art.30093"},{"key":"2025090313062139000_4.1.e000256.30","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202373"},{"key":"2025090313062139000_4.1.e000256.31","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1002\/eji.201646393","article-title":"Lymph node biopsy analysis reveals an altered immunoregulatory balance already during the at-risk phase of autoantibody positive rheumatoid arthritis","volume":"46","author":"Ramwadhdoebe","year":"2016","journal-title":"Eur J Immunol"},{"key":"2025090313062139000_4.1.e000256.32","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1186\/s13075-015-0800-5","article-title":"CCR6(+) Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis","volume":"17","author":"Paulissen","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"2025090313062139000_4.1.e000256.33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.10.5103"},{"key":"2025090313062139000_4.1.e000256.34","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.085985"},{"key":"2025090313062139000_4.1.e000256.35","doi-asserted-by":"crossref","first-page":"R219","DOI":"10.1186\/ar4058","article-title":"Does digital X-ray radiogrammetry have a role in identifying patients at increased risk for joint destruction in early rheumatoid arthritis?","volume":"14","author":"Forslind","year":"2012","journal-title":"Arthritis Res Ther"},{"key":"2025090313062139000_4.1.e000256.36","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/acr.22199","article-title":"Decline in hand bone mineral density indicates increased risk of erosive change in early rheumatoid arthritis","volume":"66","author":"Black","year":"2014","journal-title":"Arthritis Care Res"},{"key":"2025090313062139000_4.1.e000256.37","doi-asserted-by":"publisher","DOI":"10.1186\/ar3025"},{"key":"2025090313062139000_4.1.e000256.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2006.02.005"},{"key":"2025090313062139000_4.1.e000256.39","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/art.38273","article-title":"Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis","volume":"66","author":"de Hair","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"2025090313062139000_4.1.e000256.40","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/38.11.1074"},{"issue":"5 Suppl 31","key":"2025090313062139000_4.1.e000256.41","first-page":"S28","article-title":"The histopathology of early synovitis","volume":"21","author":"Hitchon","year":"2003","journal-title":"Clin Exp Rheumatol"},{"key":"2025090313062139000_4.1.e000256.42","doi-asserted-by":"publisher","DOI":"10.1016\/0049-0172(94)90080-9"},{"key":"2025090313062139000_4.1.e000256.43","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13075-017-1248-6","article-title":"Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts","volume":"19","author":"Crowley","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"2025090313062139000_4.1.e000256.44","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201893"},{"key":"2025090313062139000_4.1.e000256.45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.4.2775"},{"key":"2025090313062139000_4.1.e000256.46","first-page":"1","article-title":"Elevated ratio of Th17 Cell-Derived Th1 Cells (CD161(+)Th1 Cells) to CD161(+)Th17 cells in peripheral blood of early-onset rheumatoid arthritis patients","volume":"2016","author":"Kotake","year":"2016","journal-title":"Biomed Res Int"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2016-000256","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T20:06:29Z","timestamp":1756929989000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2016-000256"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,1,12]]},"published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1136\/rmdopen-2016-000256"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2016-000256","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1]]}}}