{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T01:20:31Z","timestamp":1794100831784,"version":"4.8.0"},"reference-count":30,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T00:00:00Z","timestamp":1563926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004348","name":"Stockholms L\u00e4ns Landsting","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004348","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2019,9]]},"abstract":"Objective<\/jats:title>Smoking is associated with an increased risk of rheumatoid arthritis (RA<\/jats:styled-content>) in subsets of patients defined according to the presence or absence of anti\u2013citrullinated protein antibodies (ACPA<\/jats:styled-content>s) and rheumatoid factors (RF<\/jats:styled-content>s). Moreover, an interaction between smoking and the HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1 shared epitope (SE<\/jats:styled-content>) has been demonstrated to be a risk factor for seropositive RA<\/jats:styled-content>. The aim of this study was to investigate the interplay between smoking and the HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1 SE<\/jats:styled-content> with regard to risk of RA<\/jats:styled-content> in different patient subsets based on ACPA<\/jats:styled-content> and RF<\/jats:styled-content> status.<\/jats:p><\/jats:sec>Methods<\/jats:title>Incident cases of RA<\/jats:styled-content> (3,645 cases, 5,883 matched controls) were divided into 4 subgroups based on the presence or absence of RF<\/jats:styled-content> and anti\u2013cyclic citrullinated peptide 2 (anti\u2010CCP<\/jats:styled-content>2) antibodies. The influence of smoking on the risk of disease was determined in each RA<\/jats:styled-content> subgroup, using logistic regression models with calculation of odds ratios and 95% confidence intervals (95% CIs). The potential interaction between smoking and HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1 SE<\/jats:styled-content> genes was evaluated by calculating the attributable proportion due to interaction (AP).<\/jats:p><\/jats:sec>Results<\/jats:title>In the RF<\/jats:styled-content>+\/anti\u2010CCP<\/jats:styled-content>2+ subset of RA<\/jats:styled-content> patients, both smoking and the presence of the HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1 SE<\/jats:styled-content> conferred independent disease risks, and there was a strong interaction between the 2 risk factors (AP 0.4, 95% CI 0.3, 0.5). In the RF<\/jats:styled-content>\u2212\/anti\u2010CCP<\/jats:styled-content>2+ patient subset, the HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1 SE<\/jats:styled-content> conferred an increased risk of RA<\/jats:styled-content>, whereas the independent influence of smoking was limited. However, there was a significant interaction between the HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1\u00a0SE and smoking (AP 0.2, 95% CI 0.02, 0.5). In the RF<\/jats:styled-content>+\/anti\u2010CCP<\/jats:styled-content>2\u2212 patient subset, there was an increased risk of disease among smokers, which was only marginally affected by the presence of the HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1 SE<\/jats:styled-content>, and no interaction between the 2 factors was observed (AP 0.002, 95% CI \u22120.3, 0.3). In the RF<\/jats:styled-content>\u2212\/anti\u2010CCP<\/jats:styled-content>2\u2212 patient subset, neither smoking nor the presence of the HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1 SE<\/jats:styled-content> conferred an increased risk of RA<\/jats:styled-content>.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>These findings demonstrate different effects of smoking and HLA<\/jats:styled-content>\u2013DRB<\/jats:styled-content>1 in the 4 serologically defined RA<\/jats:styled-content> subsets.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40852","type":"journal-article","created":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T10:12:33Z","timestamp":1549879953000},"page":"1504-1511","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Complex Relationships of Smoking, HLA\u2013DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population\u2010Based Case\u2013Control Study"],"prefix":"10.1002","volume":"71","author":[{"given":"Anna Karin","family":"Hedstr\u00f6m","sequence":"first","affiliation":[{"name":"Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"R\u00f6nnelid","sequence":"additional","affiliation":[{"name":"Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Klareskog","sequence":"additional","affiliation":[{"name":"Karolinska Institutet at Karolinska University Hospital Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Alfredsson","sequence":"additional","affiliation":[{"name":"Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,24]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780301102"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1076"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu387"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.62.9.835"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/1756-185X.12307"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-016-0563-2"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.38"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20553"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180655"},{"key":"e_1_2_6_12_1","volume-title":"Epidemiology: an introduction","author":"Rothman KJ","year":"2002"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-005-7835-x"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-1177-9"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1699-0463.1998.tb00247.x"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40578"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40699"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201747446"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-018-0070-0"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39491"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39228"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.173.2.487"},{"key":"e_1_2_6_23_1","first-page":"379","article-title":"Simultaneous induction of rheumatoid factor\u2010 and antigen\u2010specific antibody\u2010secreting cells during the secondary immune response in man","volume":"61","author":"Tarkowski A","year":"1985","journal-title":"Clin Exp Immunol"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.21575"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex340"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2018.05.004"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38307"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402334"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204543"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212627"},{"key":"e_1_2_6_31_1","unstructured":"SCB.Statistics Sweden;2018. 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