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Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM\/IgG\/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5\u00a0years were investigated for different antibody-defined RA subsets.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA\/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined \u201cseronegative\u201d RA, associated with worse clinical outcome.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>\u201cSeronegative\u201d RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA\/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2\u2212\/IgM RF\u2212 patients with a high need for active treatment.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13075-020-02191-2","type":"journal-article","created":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T08:03:41Z","timestamp":1594886621000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Presence of autoantibodies in \u201cseronegative\u201d rheumatoid arthritis associates with classical risk factors and high disease activity"],"prefix":"10.1186","volume":"22","author":[{"given":"Evan","family":"Reed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Karin","family":"Hedstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Mathsson-Alm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boel","family":"Brynedal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saedis","family":"Saevarsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Cornillet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per-Johan","family":"Jakobsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikard","family":"Holmdahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Skriner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Serre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Alfredsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"R\u00f6nnelid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7625-964X","authenticated-orcid":false,"given":"Karin","family":"Lundberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,16]]},"reference":[{"issue":"9","key":"2191_CR1","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1136\/ard.2010.138461","volume":"69","author":"D Aletaha","year":"2010","unstructured":"Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology\/European League Against Rheumatism collaborative initiative. 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Ann Rheum Dis. 2017;76(2):341\u20135.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"2191_CR7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s13075-015-0611-8","volume":"17","author":"P Verschueren","year":"2015","unstructured":"Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V, et al. Patients lacking classical poor prognostic markers might also benefit from a step-down glucocorticoid bridging scheme in early rheumatoid arthritis: week 16 results from the randomized multicenter CareRA trial. Arthritis Res Ther. 2015;17(1):97.","journal-title":"Arthritis Res Ther"},{"issue":"5","key":"2191_CR8","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1136\/annrheumdis-2012-203130","volume":"73","author":"JAB van Nies","year":"2014","unstructured":"van Nies JAB, Krabben A, Schoones JW, Huizinga TWJ, Kloppenburg M, van der Helm-van Mil AHM. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? 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Ann Rheum Dis. 2013;72(5):652\u20138.","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"2191_CR17","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1136\/annrheumdis-2013-203915","volume":"74","author":"CA Wagner","year":"2015","unstructured":"Wagner CA, Sokolove J, Lahey LJ, Bengtsson C, Saevarsdottir S, Alfredsson L, et al. Identification of anticitrullinated protein antibody reactivities in a subset of anti-CCP-negative rheumatoid arthritis: association with cigarette smoking and HLA-DRB1 \u2018shared epitope\u2019 alleles. Ann Rheum Dis. 2015;74(3):579\u201386.","journal-title":"Ann Rheum Dis"},{"issue":"5","key":"2191_CR18","doi-asserted-by":"crossref","first-page":"R201","DOI":"10.1186\/ar4039","volume":"14","author":"M Hansson","year":"2012","unstructured":"Hansson M, Mathsson L, Schlederer T, Israelsson L, Matsson P, Nogueira L, et al. Validation of a multiplex chip-based assay for the detection of autoantibodies against citrullinated peptides. 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Diagnostic associations in a large and consecutively identified population positive for anti-SSA and\/or anti-SSB: the range of associated diseases differs according to the detailed serotype. Ann Rheum Dis. 2002;61(12):1090\u20134.","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"2191_CR23","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/art.1780310302","volume":"31","author":"FC Arnett","year":"1988","unstructured":"Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315\u201324.","journal-title":"Arthritis Rheum"},{"issue":"9","key":"2191_CR24","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1136\/ard.62.9.835","volume":"62","author":"P Stolt","year":"2003","unstructured":"Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, et al. 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Thermo Fisher Scientific has contributed to this consortium with in-kind contributions for the development of the microarray multiplex assay used in the current study. LMA is employed by Thermo Fischer Scientific. JR is a member of the Thermo Fisher Scientific advisory board.RH is a co-inventor of the patent US Patent 7 148 020, protecting the use of the CitC1 and C1 peptides. KS is co-inventor of patents US 13\/141,960 and EP 09799354.7, describing the diagnostic use of the hnRNP-A3 peptide epitopes. GS is co-inventor of several international patents about ACPA antigens held by BioM\u00e9rieux Cy and licenced to Eurodiagnostica Cy and Axis-Shield Cy, for commercialization of the CCP2 assays; according to French laws, part of the royalties is paid to the Toulouse III University and the University Hospital of Toulouse. KL is co-inventor of the patent US12\/524,465, describing the diagnostic use of the CEP-1 epitope.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"170"}}