{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T13:37:08Z","timestamp":1791466628255,"version":"4.3.4"},"reference-count":46,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T00:00:00Z","timestamp":1651795200000},"content-version":"unspecified","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2022,4,6]]},"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Axial spondyloarthritis (axSpA) comprises both radiographic and non-radiographic disease. However, the paucity of specific objective measures for the disease and current classification criteria showing suboptimal specificity contribute to disease heterogeneity observed in clinical practice and research. We used a historical cohort of patients with axSpA to assess sources of heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The study involved 363 axSpA probands recruited from membership of the Swiss Ankylosing Spondylitis Patient Society. Participants underwent examination by a rheumatologist, completed questionnaires and provided blood samples for HLA typing. Patients underwent radiography of sacroiliac joints and were categorised according to the New York (NY) criteria (ankylosing spondylitis (AS) or non-radiographic axSpA (nr-axSpA)) and HLA-B27 status. Genetic characterisation by single nucleotide polymorphism microarray was performed and AS polygenic risk scores (PRS) were calculated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Considerable heterogeneity was observed. The male to female ratio for AS (NY+) was 3:1, but 1:1 for nr-axSpA. For HLA-27(+) AS, the ratio was 2.5:1, but nearly 1:1 for HLA-B27(\u2212) disease. Women with nr-axSpA had strikingly lower mean PRS and lower HLA-B27 prevalence than men with nr-axSpA or NY(+) male and female patients with AS. PRS was able to distinguish male but not female patients with nr-axSpA from related healthy first-degree relatives. Radiographic sacroiliitis was strongly associated with HLA-B27, especially in men.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Women clinically diagnosed with axSpA but without radiographic sacroiliitis as a group have a disease that is distinct from AS by the modified New York criteria overall and from nr-axSpA in men. Given the high degree of heterogeneity, stratified or adjusted analysis of effectiveness studies is indicated, taking genetics, sex and radiographic damage (sacroiliitis) into account.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rmdopen-2022-002302","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T12:32:50Z","timestamp":1651840370000},"page":"e002302","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Heterogeneity of axial spondyloarthritis: genetics, sex and structural damage matter"],"prefix":"10.1136","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2924-9120","authenticated-orcid":false,"given":"Zhixiu","family":"Li","sequence":"first","affiliation":[{"name":"Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland, Australia"},{"name":"Centre for Genomics and Personalised Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0087-0351","authenticated-orcid":false,"given":"Sjef M","family":"van der Linden","sequence":"additional","affiliation":[{"name":"University of Bern, Bern, Switzerland"},{"name":"Department of Internal Medicine, University of Maastricht, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4704-8311","authenticated-orcid":false,"given":"Muhammad Asim","family":"Khan","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz","family":"Baumberger","sequence":"additional","affiliation":[{"name":"SVMB, Flims, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermine van","family":"Zandwijk","sequence":"additional","affiliation":[{"name":"Rheumatology Research, Mortroux, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9857-0578","authenticated-orcid":false,"given":"Mohammad Kazim","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Mathematical Sciences, Kent State University, Kent, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8859-9964","authenticated-orcid":false,"given":"Peter M","family":"Villiger","sequence":"additional","affiliation":[{"name":"Medical Center Monbijou, Meikirch, Switzerland"},{"name":"Rheumatology and Clinical Immunology, Medical Center Monbijou, Meikirch, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0538-8211","authenticated-orcid":false,"given":"Matthew A","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, King's College London, London, UK"},{"name":"Genomics England, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,5,6]]},"reference":[{"key":"2025090313373366000_8.1.e002302.1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.20.3.215"},{"key":"2025090313373366000_8.1.e002302.2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21577"},{"key":"2025090313373366000_8.1.e002302.3","doi-asserted-by":"publisher","DOI":"10.1080\/03009740600904243"},{"key":"2025090313373366000_8.1.e002302.4","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0627-0"},{"key":"2025090313373366000_8.1.e002302.5","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.141598"},{"key":"2025090313373366000_8.1.e002302.6","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-005-1106-9"},{"key":"2025090313373366000_8.1.e002302.7","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1002\/acr.22831","article-title":"Global prevalence of spondyloarthritis: a systematic review and meta-regression analysis","volume":"68","author":"Stolwijk","year":"2016","journal-title":"Arthritis Care Res"},{"key":"2025090313373366000_8.1.e002302.8","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780270301"},{"key":"2025090313373366000_8.1.e002302.9","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780280107"},{"key":"2025090313373366000_8.1.e002302.10","doi-asserted-by":"publisher","DOI":"10.1002\/art.20990"},{"key":"2025090313373366000_8.1.e002302.11","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.108233"},{"key":"2025090313373366000_8.1.e002302.12","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.108217"},{"key":"2025090313373366000_8.1.e002302.13","doi-asserted-by":"publisher","DOI":"10.1002\/acr2.11044"},{"key":"2025090313373366000_8.1.e002302.14","doi-asserted-by":"publisher","DOI":"10.1002\/art.37803"},{"key":"2025090313373366000_8.1.e002302.15","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202073"},{"key":"2025090313373366000_8.1.e002302.16","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-015-0535-y"},{"key":"2025090313373366000_8.1.e002302.17","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780270401"},{"key":"2025090313373366000_8.1.e002302.18","unstructured":"Cronbach L , Gleser G , Nanda H . The dependability of behavioural measurements: theory of generalisability for scores and profiles. New York: Wiley, 1972."},{"key":"2025090313373366000_8.1.e002302.19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1167\/iovs.61.6.3","article-title":"Genomewide association study of acute anterior uveitis identifies new susceptibility loci","volume":"61","author":"Huang","year":"2020","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2025090313373366000_8.1.e002302.20","doi-asserted-by":"crossref","unstructured":"Li Z , Wu X , Leo PJ . Polygenic risk scores have high diagnostic capacity in ankylosing spondylitis. Ann Rheum Dis 2021.doi:10.1136\/annrheumdis-2020-219446","DOI":"10.1136\/annrheumdis-2020-219446"},{"key":"2025090313373366000_8.1.e002302.21","doi-asserted-by":"crossref","DOI":"10.1136\/annrheumdis-2021-222083","article-title":"Factors predicting axial spondyloarthritis among first-degree relatives of probands with ankylosing spondylitis: a family study spanning 35 years","author":"van der Linden","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"2025090313373366000_8.1.e002302.22","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1977.03270510035017"},{"key":"2025090313373366000_8.1.e002302.23","doi-asserted-by":"publisher","DOI":"10.1002\/acr.21688"},{"key":"2025090313373366000_8.1.e002302.24","unstructured":"Kellgren J , Jeffrey M , Ball J . The epidemiology of chronic rheumatism. Blackwell: Oxford, 1963."},{"key":"2025090313373366000_8.1.e002302.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)03219-5"},{"key":"2025090313373366000_8.1.e002302.26","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1017\/S0080456800012163","article-title":"XV.\u2014The correlation between relatives on the supposition of Mendelian inheritance","volume":"52","author":"Fisher","year":"1919","journal-title":"Transactions of the Royal Society of Edinburgh"},{"key":"2025090313373366000_8.1.e002302.27","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204835"},{"key":"2025090313373366000_8.1.e002302.28","doi-asserted-by":"publisher","DOI":"10.1002\/art.24585"},{"key":"2025090313373366000_8.1.e002302.29","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.060293"},{"key":"2025090313373366000_8.1.e002302.30","doi-asserted-by":"crossref","DOI":"10.1007\/s11926-018-0744-2","article-title":"Gender differences in axial spondyloarthritis: women are not so lucky","volume":"20","author":"Rusman","year":"2018","journal-title":"Curr Rheumatol Rep"},{"key":"2025090313373366000_8.1.e002302.31","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1007\/s10067-019-04885-8","article-title":"Presence of active MRI lesions in patients suspected of non-radiographic axial spondyloarthritis with high disease activity and chance at conversion after a 6-month follow-up period","volume":"39","author":"Rusman","year":"2020","journal-title":"Clin Rheumatol"},{"key":"2025090313373366000_8.1.e002302.32","doi-asserted-by":"crossref","DOI":"10.1007\/s11926-017-0654-8","article-title":"Ankylosing spondylitis: HLA-B*27-Positive versus HLA-B*27-Negative disease","volume":"19","author":"Akko\u00e7","year":"2017","journal-title":"Curr Rheumatol Rep"},{"key":"2025090313373366000_8.1.e002302.33","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s41584-020-0450-0","article-title":"Biomarker development for axial spondyloarthritis","volume":"16","author":"Brown","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"2025090313373366000_8.1.e002302.34","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1186\/s13075-020-02337-2","article-title":"Differences between men and women with nonradiographic axial spondyloarthritis: clinical characteristics and treatment effectiveness in a real-life prospective cohort","volume":"22","author":"Neuenschwander","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"2025090313373366000_8.1.e002302.35","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.160958"},{"key":"2025090313373366000_8.1.e002302.36","doi-asserted-by":"crossref","first-page":"493","DOI":"10.3109\/03009742.2014.918173","article-title":"Efficacy and drug survival of anti-tumour necrosis factor-alpha therapies in patients with non-radiographic axial spondyloarthritis: an observational cohort study from southern Sweden","volume":"43","author":"Gulfe","year":"2014","journal-title":"Scand J Rheumatol"},{"key":"2025090313373366000_8.1.e002302.37","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-eular.5566"},{"key":"2025090313373366000_8.1.e002302.38","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201766"},{"key":"2025090313373366000_8.1.e002302.39","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1002\/art.39257","article-title":"A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis","volume":"67","author":"Sieper","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"2025090313373366000_8.1.e002302.40","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204231"},{"key":"2025090313373366000_8.1.e002302.41","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.081048"},{"key":"2025090313373366000_8.1.e002302.42","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1002\/art.27571","article-title":"The diagnostic utility of magnetic resonance imaging in spondylarthritis: an international multicenter evaluation of one hundred eighty-seven subjects","volume":"62","author":"Weber","year":"2019","journal-title":"Arthritis & Rheumatism"},{"key":"2025090313373366000_8.1.e002302.43","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1007\/s10067-019-04824-7","article-title":"Mri compared with low-dose CT scanning in the diagnosis of axial spondyloarthritis","volume":"39","author":"Ye","year":"2020","journal-title":"Clin Rheumatol"},{"key":"2025090313373366000_8.1.e002302.44","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1002\/art.40475","article-title":"Magnetic resonance imaging of the Sacroiliac joints indicating sacroiliitis according to the assessment of spondyloarthritis International Society definition in healthy individuals, runners, and women with postpartum back pain","volume":"70","author":"de Winter","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"2025090313373366000_8.1.e002302.45","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1002\/art.40429","article-title":"Frequency and anatomic distribution of magnetic resonance imaging features in the sacroiliac joints of young athletes: exploring \"background noise\" toward a data-driven definition of sacroiliitis in early spondyloarthritis","volume":"70","author":"Weber","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"2025090313373366000_8.1.e002302.46","doi-asserted-by":"publisher","DOI":"10.1136\/ard.62.6.519"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2022-002302","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T20:37:39Z","timestamp":1756931859000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2022-002302"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,5,6]]},"published-print":{"date-parts":[[2022,5]]}},"alternative-id":["10.1136\/rmdopen-2022-002302"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2022-002302","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5]]}}}