{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T03:34:21Z","timestamp":1789875261843,"version":"4.0.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T00:00:00Z","timestamp":1769212800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":24,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"The \"Pancretan Health Organization\u201d"},{"name":"\u201cHellenic Society of Rheumatology\u201d"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"DOI":"10.1186\/s13075-026-03732-x","type":"journal-article","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T10:05:10Z","timestamp":1769249110000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Difficult to manage axial spondyloarthritis patients have high burden of pain-related comorbidities and adverse long-term outcome"],"prefix":"10.1186","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3515-2488","authenticated-orcid":false,"given":"Antonios","family":"Bertsias","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6966-1304","authenticated-orcid":false,"given":"Irini","family":"Flouri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7584-203X","authenticated-orcid":false,"given":"Evgenia","family":"Emmanouilidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1044-2449","authenticated-orcid":false,"given":"Argyro","family":"Repa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3436-4016","authenticated-orcid":false,"given":"Nestor","family":"Avgoustidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7930-3545","authenticated-orcid":false,"given":"Eleni","family":"Kalogiannaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9422-3931","authenticated-orcid":false,"given":"Sofia","family":"Pitsigavdaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5299-1406","authenticated-orcid":false,"given":"Georgios","family":"Bertsias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9607-0326","authenticated-orcid":false,"given":"Prodromos","family":"Sidiropoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,24]]},"reference":[{"issue":"10473","key":"3732_CR1","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/S0140-6736(24)02263-3","volume":"405","author":"V Navarro-Compan","year":"2025","unstructured":"Navarro-Compan V, Sepriano A, Capelusnik D, Baraliakos X. Axial spondyloarthritis. Lancet. 2025;405(10473):159\u201372.","journal-title":"Lancet"},{"issue":"1","key":"3732_CR2","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1136\/ard-2022-223298","volume":"82","author":"C Webers","year":"2023","unstructured":"Webers C, Ortolan A, Sepriano A, Falzon L, Baraliakos X, Landewe RBM, et al. Efficacy and safety of biological dmards: a systematic literature review informing the 2022 update of the ASAS-EULAR recommendations for the management of axial spondyloarthritis. Ann Rheum Dis. 2023;82(1):130\u201341.","journal-title":"Ann Rheum Dis"},{"issue":"4","key":"3732_CR3","doi-asserted-by":"publisher","first-page":"e057850","DOI":"10.1136\/bmjopen-2021-057850","volume":"12","author":"D Benavent","year":"2022","unstructured":"Benavent D, Franco-Gomez K, Plasencia-Rodriguez C, Novella-Navarro M, Bogas P, Nieto R, et al. Achievement rate and predictive factors of the recommended therapeutical target in patients with axial spondyloarthritis who remain on biological therapy: a prospective cohort study in Spain. BMJ Open. 2022;12(4):e057850.","journal-title":"BMJ Open"},{"key":"3732_CR4","doi-asserted-by":"publisher","first-page":"152081","DOI":"10.1016\/j.semarthrit.2022.152081","volume":"56","author":"LM Ornbjerg","year":"2022","unstructured":"Ornbjerg LM, Linde L, Georgiadis S, Rasmussen SH, Lindstrom U, Askling J, et al. Predictors of ASDAS-CRP inactive disease in axial spondyloarthritis during treatment with TNF-inhibitors: data from the EuroSpA collaboration. Semin Arthritis Rheum. 2022;56:152081.","journal-title":"Semin Arthritis Rheum"},{"issue":"9","key":"3732_CR5","doi-asserted-by":"publisher","first-page":"3647","DOI":"10.1093\/rheumatology\/keab946","volume":"61","author":"D Di Giuseppe","year":"2022","unstructured":"Di Giuseppe D, Lindstrom U, Aaltonen K, Relas H, Provan S, Gudbjornsson B, et al. The occurrence of multiple treatment switches in axial spondyloarthritis. Results from five nordic rheumatology registries. Rheumatology (Oxford). 2022;61(9):3647\u201356.","journal-title":"Rheumatology (Oxford)"},{"issue":"4","key":"3732_CR6","doi-asserted-by":"publisher","first-page":"e274","DOI":"10.1016\/S2665-9913(24)00340-0","volume":"7","author":"G Nagy","year":"2025","unstructured":"Nagy G, Gunkl-Toth L, Dorgo AM, McInnes IB. The concept of difficult-to-treat disease in rheumatology: where next? Lancet Rheumatol. 2025;7(4):e274\u201389.","journal-title":"Lancet Rheumatol"},{"issue":"4","key":"3732_CR7","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.ard.2025.01.035","volume":"84","author":"D Poddubnyy","year":"2025","unstructured":"Poddubnyy D, Navarro-Compan V, Torgutalp M, Arends S, Aydin SZ, Battista S, et al. The assessment of spondyloarthritis international society (ASAS) Consensus-Based expert definition of Difficult-to-Manage, including Treatment-Refractory, axial spondyloarthritis. Ann Rheum Dis. 2025;84(4):538\u201346.","journal-title":"Ann Rheum Dis"},{"issue":"2","key":"3732_CR8","doi-asserted-by":"publisher","first-page":"105670","DOI":"10.1016\/j.jbspin.2023.105670","volume":"91","author":"C Philippoteaux","year":"2024","unstructured":"Philippoteaux C, Delepine T, Cailliau E, Philippe P, Taisne N, Pascart T, et al. Characteristics of difficult-to-treat axial spondyloarthritis: results of a real-world multicentric study. Joint Bone Spine. 2024;91(2):105670.","journal-title":"Joint Bone Spine"},{"key":"3732_CR9","doi-asserted-by":"crossref","unstructured":"Fakih O, Desmarets M, Martin B, Prati C, Monnet E, Verhoeven F, et al. Difficult-to-treat axial spondyloarthritis is associated with psoriasis, peripheral involvement and comorbidities: results of an observational nationwide study. RMD Open. 2023;9:e003461.","DOI":"10.1136\/rmdopen-2023-003461"},{"key":"3732_CR10","doi-asserted-by":"crossref","unstructured":"Garcia-Salinas R, Mejia-Maggi N, Ruta S, Reyes-Jara G, Arguello J, Magri SJ. Difficult-to-Manage axial spondyloarthritis according to ASAS criteria in Reuma-Check cohort: Frequency, predictive Factors, and treatment patterns. Clin Rheumatol. 2025;44(10):3959\u201365.","DOI":"10.1007\/s10067-025-07626-2"},{"issue":"5","key":"3732_CR11","doi-asserted-by":"publisher","first-page":"e70242","DOI":"10.1111\/1756-185X.70242","volume":"28","author":"KA Lee","year":"2025","unstructured":"Lee KA, Lee H, Kim HS. Prevalence and predictive factors of Difficult-To-Manage axial spondyloarthritis: results from the KOBIO registry. Int J Rheum Dis. 2025;28(5):e70242.","journal-title":"Int J Rheum Dis"},{"issue":"6","key":"3732_CR12","doi-asserted-by":"publisher","first-page":"3816","DOI":"10.1093\/rheumatology\/keaf120","volume":"64","author":"ML Smits","year":"2025","unstructured":"Smits ML, Webers C, Vonkeman HE, van Tubergen A. Exploring difficult-to-manage axial spondyloarthritis: results from a Dutch clinical practice registry. Rheumatology (Oxford). 2025;64(6):3816\u201325.","journal-title":"Rheumatology (Oxford)"},{"key":"3732_CR13","doi-asserted-by":"crossref","unstructured":"Bertsias A, Flouri ID, Repa A, Avgoustidis N, Kalogiannaki E, Pitsigavdaki S, et al. Patterns of comorbidities differentially affect long-term functional evolution and disease activity in patients with \u2018difficult to treat\u2019 rheumatoid arthritis. RMD Open. 2024;10:e003808.","DOI":"10.1136\/rmdopen-2023-003808"},{"issue":"6","key":"3732_CR14","doi-asserted-by":"publisher","first-page":"785","DOI":"10.3899\/jrheum.170477","volume":"45","author":"ID Flouri","year":"2018","unstructured":"Flouri ID, Markatseli TE, Boki KA, Papadopoulos I, Skopouli FN, Voulgari PV, et al. Comparative analysis and predictors of 10-year tumor necrosis factor inhibitors drug survival in patients with spondyloarthritis: First-year response predicts longterm drug persistence. J Rheumatol. 2018;45(6):785\u201394.","journal-title":"J Rheumatol"},{"issue":"1","key":"3732_CR15","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1186\/s13075-020-02313-w","volume":"22","author":"I Genitsaridi","year":"2020","unstructured":"Genitsaridi I, Flouri I, Plexousakis D, Marias K, Boki K, Skopouli F, et al. Rheumatoid arthritis patients on persistent moderate disease activity on biologics have adverse 5-year outcome compared to persistent low-remission status and represent a heterogeneous group. Arthritis Res Ther. 2020;22(1):226.","journal-title":"Arthritis Res Ther"},{"issue":"1","key":"3732_CR16","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s13075-022-02826-6","volume":"24","author":"A Bertsias","year":"2022","unstructured":"Bertsias A, Avgoustidis N, Papalopoulos I, Repa A, Kougkas N, Kalogiannaki E, et al. Rheumatoid arthritis patients initiating rituximab with low number of previous bDMARDs failures May effectively reduce rituximab dose and experience fewer serious adverse events than patients on full dose: a 5-year cohort study. Arthritis Res Ther. 2022;24(1):132.","journal-title":"Arthritis Res Ther"},{"issue":"6","key":"3732_CR17","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1136\/ard.2009.108233","volume":"68","author":"M Rudwaleit","year":"2009","unstructured":"Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J, et al. The development of assessment of spondyloarthritis international society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009;68(6):777\u201383.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"3732_CR18","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1136\/ard.2010.138594","volume":"70","author":"P Machado","year":"2011","unstructured":"Machado P, Landewe R, Lie E, Kvien TK, Braun J, Baker D, et al. Ankylosing spondylitis disease activity score (ASDAS): defining cut-off values for disease activity States and improvement scores. Ann Rheum Dis. 2011;70(1):47\u201353.","journal-title":"Ann Rheum Dis"},{"issue":"6","key":"3732_CR19","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1002\/acr.22456","volume":"67","author":"BR England","year":"2015","unstructured":"England BR, Sayles H, Mikuls TR, Johnson DS, Michaud K. Validation of the rheumatic disease comorbidity index. Arthritis Care Res (Hoboken). 2015;67(6):865\u201372.","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"5","key":"3732_CR20","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.berh.2007.06.002","volume":"21","author":"K Michaud","year":"2007","unstructured":"Michaud K, Wolfe F. Comorbidities in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007;21(5):885\u2013906.","journal-title":"Best Pract Res Clin Rheumatol"},{"issue":"2","key":"3732_CR21","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1002\/acr.24956","volume":"75","author":"BR England","year":"2023","unstructured":"England BR, Yang Y, Roul P, Haas C, Najjar L, Sayles H, et al. Identification of Multimorbidity patterns in rheumatoid arthritis through machine learning. Arthritis Care Res (Hoboken). 2023;75(2):220\u201330.","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"1","key":"3732_CR22","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/s13075-019-1908-9","volume":"21","author":"U Lindstrom","year":"2019","unstructured":"Lindstrom U, Olofsson T, Wedren S, Qirjazo I, Askling J. Biological treatment of ankylosing spondylitis: a nationwide study of treatment trajectories on a patient level in clinical practice. Arthritis Res Ther. 2019;21(1):128.","journal-title":"Arthritis Res Ther"},{"issue":"3","key":"3732_CR23","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1136\/annrheumdis-2020-218282","volume":"80","author":"BR England","year":"2021","unstructured":"England BR, Roul P, Yang Y, Sayles H, Yu F, Michaud K, et al. Burden and trajectory of Multimorbidity in rheumatoid arthritis: a matched cohort study from 2006 to 2015. Ann Rheum Dis. 2021;80(3):286\u201392.","journal-title":"Ann Rheum Dis"},{"issue":"11","key":"3732_CR24","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1002\/art.40185","volume":"69","author":"GJ Macfarlane","year":"2017","unstructured":"Macfarlane GJ, Barnish MS, Pathan E, Martin KR, Haywood KL, Siebert S, et al. Co-Occurrence and characteristics of patients with axial spondyloarthritis who Meet criteria for fibromyalgia: results from a UK National register. Arthritis Rheumatol. 2017;69(11):2144\u201350.","journal-title":"Arthritis Rheumatol"},{"issue":"11","key":"3732_CR25","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1093\/rheumatology\/key206","volume":"57","author":"GJ Macfarlane","year":"2018","unstructured":"Macfarlane GJ, MacDonald RIR, Pathan E, Siebert S, Gaffney K, Choy E, et al. Influence of co-morbid fibromyalgia on disease activity measures and response to tumour necrosis factor inhibitors in axial spondyloarthritis: results from a UK National register. Rheumatology (Oxford). 2018;57(11):1982\u201390.","journal-title":"Rheumatology (Oxford)"},{"issue":"11","key":"3732_CR26","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.3899\/jrheum.210137","volume":"48","author":"MN Magrey","year":"2021","unstructured":"Magrey MN, Mease PJ. Pain in axial spondyloarthritis: more to it than just inflammation. J Rheumatol. 2021;48(11):1632\u20134.","journal-title":"J Rheumatol"},{"issue":"11","key":"3732_CR27","doi-asserted-by":"publisher","first-page":"1672","DOI":"10.3899\/jrheum.200872","volume":"48","author":"E Mogard","year":"2021","unstructured":"Mogard E, Olofsson T, Bergman S, Bremander A, Kristensen LE, Olsen JK, et al. Chronic pain and assessment of pain sensitivity in patients with axial spondyloarthritis: results from the SPARTAKUS cohort. J Rheumatol. 2021;48(11):1672\u20139.","journal-title":"J Rheumatol"},{"issue":"2","key":"3732_CR28","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1136\/annrheumdis-2019-216143","volume":"79","author":"GJ Macfarlane","year":"2020","unstructured":"Macfarlane GJ, Rotariu O, Jones GT, Pathan E, Dean LE. Determining factors related to poor quality of life in patients with axial spondyloarthritis: results from the British society for rheumatology biologics register (BSRBR-AS). Ann Rheum Dis. 2020;79(2):202\u20138.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"3732_CR29","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s13075-023-03055-1","volume":"25","author":"WP Maksymowych","year":"2023","unstructured":"Maksymowych WP, Inman RD, Bessette L, Rahman P, Rampakakis E, Asin-Milan O, et al. Sustained low functional impairment in axial spondyloarthritis (axSpA): which are the primary outcomes that should be targeted to achieve this? Arthritis Res Ther. 2023;25(1):70.","journal-title":"Arthritis Res Ther"},{"issue":"3","key":"3732_CR30","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.semarthrit.2021.04.007","volume":"51","author":"D Capelusnik","year":"2021","unstructured":"Capelusnik D, Ramiro S, Schneeberger EE, Citera G. Peripheral arthritis and higher disease activity lead to more functional impairment in axial spondyloarthritis: longitudinal analysis from ESPAXIA. Semin Arthritis Rheum. 2021;51(3):553\u20138.","journal-title":"Semin Arthritis Rheum"},{"issue":"4","key":"3732_CR31","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1093\/rheumatology\/kex475","volume":"57","author":"D Poddubnyy","year":"2018","unstructured":"Poddubnyy D, Listing J, Haibel H, Knuppel S, Rudwaleit M, Sieper J. Functional relevance of radiographic spinal progression in axial spondyloarthritis: results from the GErman spondyloarthritis inception cohort. Rheumatology (Oxford). 2018;57(4):703\u201311.","journal-title":"Rheumatology (Oxford)"},{"issue":"6","key":"3732_CR32","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1136\/ard.2008.091793","volume":"68","author":"R Landewe","year":"2009","unstructured":"Landewe R, Dougados M, Mielants H, van der Tempel H, van der Heijde D. Physical function in ankylosing spondylitis is independently determined by both disease activity and radiographic damage of the spine. Ann Rheum Dis. 2009;68(6):863\u20137.","journal-title":"Ann Rheum Dis"},{"issue":"8","key":"3732_CR33","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1136\/annrheumdis-2014-205178","volume":"73","author":"S Ramiro","year":"2014","unstructured":"Ramiro S, van der Heijde D, van Tubergen A, Stolwijk C, Dougados M, van den Bosch F, et al. Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort. Ann Rheum Dis. 2014;73(8):1455\u201361.","journal-title":"Ann Rheum Dis"}],"container-title":["Arthritis Research & Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13075-026-03732-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-026-03732-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-026-03732-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T11:00:45Z","timestamp":1771326045000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13075-026-03732-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,24]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3732"],"URL":"https:\/\/doi.org\/10.1186\/s13075-026-03732-x","relation":{},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,24]]},"assertion":[{"value":"8 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was obtained from the Institutional Review-Board of the University Hospital of Heraklion, Crete (decision-number:1476\/20-03-2012). All participants provided written informed consents.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"45"}}