{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:19:01Z","timestamp":1784823541637,"version":"3.55.0"},"reference-count":55,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"unspecified","delay-in-days":58,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"German Federal Ministry of Education and Research","award":["01KG1603"],"award-info":[{"award-number":["01KG1603"]}]},{"DOI":"10.13039\/501100003035","name":"Aase og Ejnar Danielsens Fond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003035","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center for Cellular Signal Patterns","award":["DNRF135"],"award-info":[{"award-number":["DNRF135"]}]},{"DOI":"10.13039\/501100001732","name":"Danish National Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001732","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008368","name":"Danish Rheumatism Association","doi-asserted-by":"crossref","award":["A6093"],"award-info":[{"award-number":["A6093"]}],"id":[{"id":"10.13039\/100008368","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008368","name":"Danish Rheumatism Association","doi-asserted-by":"crossref","award":["A6462"],"award-info":[{"award-number":["A6462"]}],"id":[{"id":"10.13039\/100008368","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Graduate School of HEALTH, Aarhus University, Denmark"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2025,11,7]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate complement system activation and complement protein levels in relation to radiographic progression in axial spondyloarthritis (axSpA) within a longitudinal randomised controlled trial (RCT) of radiographic axSpA patients initiating tumour necrosis factor inhibitor (TNFi) therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Serum samples from 96 patients with active radiographic axSpA in the multicentre RCT CONSUL were analysed by immunoassays for complement activation, that is, C3dg and complement proteins (MBL, CL-L1, M-, H- and L-ficolin; MASP-1,\u20132 and \u22123; and MAp44) before and after 108 weeks of TNF inhibitor therapy with golimumab.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Baseline serum levels of total complement activation, that is, C3dg and lectin pathway activating protease MASP-1 were elevated in patients with new bone formation (new syndesmophytes and\/or growth of existing syndesmophytes) after 2 years of follow-up, whereas baseline MASP-3 levels were decreased. Assessed by univariate logistic regression, baseline levels of MASP-1, MASP-3 and C3dg were associated with the development of new bone formation and remained significant in a corresponding multivariate logistic regression analysis. At follow-up, serum levels of C3dg and complement lectin pathway initiator L-ficolin were elevated in patients with new bone formation, and C3dg remained significant in a corresponding multivariate logistic regression analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Complement activation marker C3dg, MASP-1 and MASP-3 levels before TNFi therapy predicted new bone formation after 2 years of follow-up among axSpA patients with a high risk of radiographic progression. Furthermore, levels of L-ficolin and C3dg at follow-up were elevated in axSpA patients with new bone formation. Our findings support an association between activation of the complement system and radiographic spinal progression in patients with axSpA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rmdopen-2025-006087","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T12:50:27Z","timestamp":1764334227000},"page":"e006087","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Complement system activation is associated with spinal radiographic progression in axial spondyloarthritis after 2 years of follow-up: findings from the CONSUL RCT"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6359-2192","authenticated-orcid":false,"given":"Clara","family":"Mistegaard","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark"},{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"},{"name":"Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9501-1268","authenticated-orcid":false,"given":"Anne","family":"Troldborg","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark"},{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"},{"name":"Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4600-9484","authenticated-orcid":false,"given":"Murat","family":"Torgutalp","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Infectiology, and Rheumatology (including Nutrition Medicine), Charite Universitatsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Gitte","family":"Loft","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark"},{"name":"Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Thiel","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4104-5080","authenticated-orcid":false,"given":"Burkhard","family":"Muche","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Infectiology, and Rheumatology (including Nutrition Medicine), Charite Universitatsmedizin Berlin, Berlin, Germany"},{"name":"Department of Rheumatology CCM, Charite Universitatsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5612-043X","authenticated-orcid":false,"given":"Valeria","family":"Rios Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Infectiology, and Rheumatology (including Nutrition Medicine), Charite Universitatsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4840-5069","authenticated-orcid":false,"given":"Mikhail","family":"Protopopov","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Infectiology, and Rheumatology (including Nutrition Medicine), Charite Universitatsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Listing","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Infectiology, and Rheumatology (including Nutrition Medicine), Charite Universitatsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0285-9890","authenticated-orcid":false,"given":"Joachim","family":"Sieper","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Infectiology, and Rheumatology (including Nutrition Medicine), Charite Universitatsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Poddubnyy","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Infectiology, and Rheumatology (including Nutrition Medicine), Charite Universitatsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4306-033X","authenticated-orcid":false,"given":"Fabian","family":"Proft","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Infectiology, and Rheumatology (including Nutrition Medicine), Charite Universitatsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"2025112804501142000_11.4.e006087.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31591-4"},{"key":"2025112804501142000_11.4.e006087.2","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-223296"},{"key":"2025112804501142000_11.4.e006087.3","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1093\/rheumatology\/keab543","article-title":"Impact of filgotinib on sacroiliac joint magnetic resonance imaging structural lesions at 12\u2009weeks in patients with active ankylosing spondylitis (TORTUGA trial)","volume":"61","author":"Maksymowych","year":"2022","journal-title":"Rheumatology (Oxford)"},{"key":"2025112804501142000_11.4.e006087.4","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-211605"},{"key":"2025112804501142000_11.4.e006087.5","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2023-003884","article-title":"Long-term clinical outcomes of certolizumab pegol treatment in non-radiographic axial spondyloarthritis stratified by baseline MRI and CRP status","volume":"10","author":"Rudwaleit","year":"2024","journal-title":"RMD Open"},{"key":"2025112804501142000_11.4.e006087.6","doi-asserted-by":"publisher","DOI":"10.1002\/art.38070"},{"key":"2025112804501142000_11.4.e006087.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.rdc.2012.08.003"},{"key":"2025112804501142000_11.4.e006087.8","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2015.00262","article-title":"Complement System Part I - Molecular Mechanisms of Activation and Regulation","volume":"6","author":"Merle","year":"2015","journal-title":"Front Immunol"},{"key":"2025112804501142000_11.4.e006087.9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700518"},{"key":"2025112804501142000_11.4.e006087.10","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1923"},{"key":"2025112804501142000_11.4.e006087.11","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2015.00257","article-title":"Complement System Part II: Role in Immunity","volume":"6","author":"Merle","year":"2015","journal-title":"Front Immunol"},{"key":"2025112804501142000_11.4.e006087.12","doi-asserted-by":"crossref","DOI":"10.4110\/in.2021.21.e45","article-title":"A Potential New Mouse Model of Axial Spondyloarthritis Involving the Complement System","volume":"21","author":"Holers","year":"2021","journal-title":"Immune Netw"},{"key":"2025112804501142000_11.4.e006087.13","doi-asserted-by":"crossref","first-page":"34643","DOI":"10.1038\/srep34643","article-title":"Inhibition of Complement Retards Ankylosing Spondylitis Progression","volume":"6","author":"Yang","year":"2016","journal-title":"Sci Rep"},{"key":"2025112804501142000_11.4.e006087.14","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/cei.13374","article-title":"Plasma levels of H- and L-ficolin are increased in axial spondyloarthritis: improvement of disease identification","volume":"199","author":"Troldborg","year":"2020","journal-title":"Clin Exp Immunol"},{"key":"2025112804501142000_11.4.e006087.15","doi-asserted-by":"crossref","unstructured":"Mistegaard CE , Troldborg A , Hansen A , et al . Complement proteins L-ficolin and M-ficolin are increased in axial spondyloarthritis patients and decrease after TNF-inhibitor treatment. J Rheumatol 2023.","DOI":"10.3899\/jrheum.2023-0164"},{"key":"2025112804501142000_11.4.e006087.16","doi-asserted-by":"crossref","DOI":"10.1186\/s13075-023-03044-4","article-title":"Quantitative proteomic screening uncovers candidate diagnostic and monitoring serum biomarkers of ankylosing spondylitis","volume":"25","author":"Hwang","year":"2023","journal-title":"Arthritis Res Ther"},{"key":"2025112804501142000_11.4.e006087.17","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2024-004127","article-title":"Exploring complement biomarkers in suspected axial spondyloarthritis","volume":"10","author":"Misteg\u00e5rd","year":"2024","journal-title":"RMD Open"},{"key":"2025112804501142000_11.4.e006087.18","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0220079","article-title":"Tumor necrosis factor inhibitors are associated with reduced complement activation in spondylarthropathies: An observational study","volume":"14","author":"Hokstad","year":"2019","journal-title":"PLoS One"},{"key":"2025112804501142000_11.4.e006087.19","doi-asserted-by":"crossref","DOI":"10.1093\/rap\/rkaf007","article-title":"Complement proteins in axial spondyloarthritis: associations with disease activity and TNFi treatment response in a multicentre RCT","volume":"9","author":"Mistegaard","year":"2025","journal-title":"Rheumatol Adv Pract"},{"key":"2025112804501142000_11.4.e006087.20","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2016-014591","article-title":"Study protocol: COmparison of the effect of treatment with Nonsteroidal anti-inflammatory drugs added to anti-tumour necrosis factor a therapy versus anti-tumour necrosis factor a therapy alone on progression of StrUctural damage in the spine over two years in patients with ankyLosing spondylitis (CONSUL) - an open-label randomized controlled multicenter trial","volume":"7","author":"Proft","year":"2017","journal-title":"BMJ Open"},{"key":"2025112804501142000_11.4.e006087.21","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-224699"},{"key":"2025112804501142000_11.4.e006087.22","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.133488"},{"key":"2025112804501142000_11.4.e006087.23","doi-asserted-by":"publisher","DOI":"10.1078\/0171-2985-00145"},{"key":"2025112804501142000_11.4.e006087.24","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.2.1052-1060.2005"},{"key":"2025112804501142000_11.4.e006087.25","doi-asserted-by":"publisher","DOI":"10.1159\/000218324"},{"key":"2025112804501142000_11.4.e006087.26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.492603"},{"key":"2025112804501142000_11.4.e006087.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2010.07.006"},{"key":"2025112804501142000_11.4.e006087.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2003.08.012"},{"key":"2025112804501142000_11.4.e006087.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2011.08.006"},{"key":"2025112804501142000_11.4.e006087.30","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12909"},{"key":"2025112804501142000_11.4.e006087.31","doi-asserted-by":"crossref","first-page":"112866","DOI":"10.1016\/j.jim.2020.112866","article-title":"Complement activation in human autoimmune diseases and mouse models; employing a sandwich immunoassay specific for C3dg","volume":"486","author":"Troldborg","year":"2020","journal-title":"J Immunol Methods"},{"key":"2025112804501142000_11.4.e006087.32","doi-asserted-by":"publisher","DOI":"10.1002\/art.33465"},{"key":"2025112804501142000_11.4.e006087.33","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209209"},{"key":"2025112804501142000_11.4.e006087.34","doi-asserted-by":"publisher","DOI":"10.1002\/art.21054"},{"key":"2025112804501142000_11.4.e006087.35","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-207897"},{"key":"2025112804501142000_11.4.e006087.36","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2022-222324"},{"key":"2025112804501142000_11.4.e006087.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2018.01.001"},{"key":"2025112804501142000_11.4.e006087.38","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-01-263590"},{"key":"2025112804501142000_11.4.e006087.39","doi-asserted-by":"publisher","DOI":"10.1210\/en.133.1.397"},{"key":"2025112804501142000_11.4.e006087.40","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.23186"},{"key":"2025112804501142000_11.4.e006087.41","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1016\/j.ymthe.2023.04.022","article-title":"Inhibition of C5AR1 impairs osteoclast mobilization and prevents bone loss","volume":"31","author":"Pimenta-Lopes","year":"2023","journal-title":"Mol Ther"},{"key":"2025112804501142000_11.4.e006087.42","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0179512","article-title":"Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing","volume":"12","author":"Bergdolt","year":"2017","journal-title":"PLoS One"},{"key":"2025112804501142000_11.4.e006087.43","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ajpath.2018.09.011","article-title":"Reduced Terminal Complement Complex Formation in Mice Manifests in Low Bone Mass and Impaired Fracture Healing","volume":"189","author":"M\u00f6dinger","year":"2019","journal-title":"Am J Pathol"},{"key":"2025112804501142000_11.4.e006087.44","doi-asserted-by":"crossref","first-page":"50","DOI":"10.17925\/RMD.2022.1.2.50","article-title":"The Complement System in Spondyloarthritis: What Do We Know?","volume":"1","author":"Mistegaard","year":"2022","journal-title":"Rheumatology (Sunnyvale)"},{"key":"2025112804501142000_11.4.e006087.45","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1007\/s11914-011-0058-z","article-title":"Osteoporosis: a paradox in ankylosing spondylitis","volume":"9","author":"Carter","year":"2011","journal-title":"Curr Osteoporos Rep"},{"key":"2025112804501142000_11.4.e006087.46","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.ijsu.2013.02.022","article-title":"Bone healing and mannose-binding lectin","volume":"11","author":"Van der Ende","year":"2013","journal-title":"Int J Surg"},{"key":"2025112804501142000_11.4.e006087.47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1406849111"},{"key":"2025112804501142000_11.4.e006087.48","doi-asserted-by":"publisher","DOI":"10.1038\/srep31877"},{"key":"2025112804501142000_11.4.e006087.49","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407161200"},{"key":"2025112804501142000_11.4.e006087.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2008.03.014"},{"key":"2025112804501142000_11.4.e006087.51","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3841"},{"key":"2025112804501142000_11.4.e006087.52","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601500"},{"key":"2025112804501142000_11.4.e006087.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2006.04.002"},{"key":"2025112804501142000_11.4.e006087.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2016.01.008"},{"key":"2025112804501142000_11.4.e006087.55","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00607-13"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2025-006087","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T12:50:39Z","timestamp":1764334239000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2025-006087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,11,28]]},"published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1136\/rmdopen-2025-006087"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2025-006087","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]}}}