{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:11:05Z","timestamp":1790363465089,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,3,28]],"date-time":"2014-03-28T00:00:00Z","timestamp":1395964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000738","name":"US Department of Veterans Affairs","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases)","award":["R01-AR-0636763"],"award-info":[{"award-number":["R01-AR-0636763"]}]},{"name":"NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases)","award":["U01-AI-101981"],"award-info":[{"award-number":["U01-AI-101981"]}]},{"name":"Arthritis Foundation Innovative Research Award"},{"name":"Rheumatology Research Foundation Within Our Reach Awards"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The co\u2010occurrence of rheumatoid factor (RF) and anti\u2013citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA\u2010associated inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double\u2010negative (anti\u2013cyclic citrullinated peptide [anti\u2010CCP]\u2212\/RF\u2212), anti\u2010CCP+\/RF\u2212, anti\u2010CCP\u2212\/RF+, or double\u2010positive (anti\u2010CCP+\/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM\u2010RF, and tumor necrosis factor \u03b1 production measured as a readout of macrophage activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with the double\u2010negative subgroup (as well as each single\u2010positive subgroup), the double\u2010positive subgroup exhibited higher disease activity as well as higher levels of C\u2010reactive protein and inflammatory cytokines (all\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM\u2010RF significantly increased macrophage tumor necrosis factor \u03b1 production (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.003 versus ACPA ICs alone).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The combined presence of ACPAs and IgM\u2010RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM\u2010RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.38307","type":"journal-article","created":{"date-parts":[[2014,1,27]],"date-time":"2014-01-27T14:12:48Z","timestamp":1390831968000},"page":"813-821","source":"Crossref","is-referenced-by-count":209,"title":["Rheumatoid Factor as a Potentiator of Anti\u2013Citrullinated Protein Antibody\u2013Mediated Inflammation in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"66","author":[{"given":"Jeremy","family":"Sokolove","sequence":"first","affiliation":[{"name":"VA Palo Alto Health Care System, Palo Alto, California, and Stanford University School of Medicine Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dannette S.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Jackson VA Medical Center and University of Mississippi Jackson"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren J.","family":"Lahey","sequence":"additional","affiliation":[{"name":"VA Palo Alto Health Care System, Palo Alto, California, and Stanford University School of Medicine Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona A.","family":"Wagner","sequence":"additional","affiliation":[{"name":"VA Palo Alto Health Care System, Palo Alto, California, and Stanford University School of Medicine Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danye","family":"Cheng","sequence":"additional","affiliation":[{"name":"VA Palo Alto Health Care System, Palo Alto, California, and Stanford University School of Medicine Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey M.","family":"Thiele","sequence":"additional","affiliation":[{"name":"Omaha VA Medical Center and University of Nebraska Medical Center Omaha"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaleb","family":"Michaud","sequence":"additional","affiliation":[{"name":"Omaha VA Medical Center and University of Nebraska Medical Center Omaha"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harlan","family":"Sayles","sequence":"additional","affiliation":[{"name":"Omaha VA Medical Center and University of Nebraska Medical Center Omaha"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas M.","family":"Reimold","sequence":"additional","affiliation":[{"name":"Dallas VA Medical Center and Texas Southwestern University Medical Center Dallas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liron","family":"Caplan","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs, Denver and University of Colorado School of Medicine Denver"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant W.","family":"Cannon","sequence":"additional","affiliation":[{"name":"George E. Wahlen VA Medical Center and University of Utah Salt Lake City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"Kerr","sequence":"additional","affiliation":[{"name":"Washington DC VA Medical Center and Georgetown University Washington DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ted R.","family":"Mikuls","sequence":"additional","affiliation":[{"name":"Omaha VA Medical Center and University of Nebraska Medical Center Omaha"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H.","family":"Robinson","sequence":"additional","affiliation":[{"name":"VA Palo Alto Health Care System, Palo Alto, California, and Stanford University School of Medicine Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,3,28]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-68-16375"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.105.5.425"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780040602"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2005.035691"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-146-11-200706050-00008"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1313.031"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-007-0601-6"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.122739"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.62.9.870"},{"key":"e_1_2_6_12_1","first-page":"S59","article-title":"Autoantibodies in early arthritis: advances in diagnosis and prognostication","volume":"21","author":"Hueber W","year":"2003","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30081"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23284"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60975"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25422"},{"key":"e_1_2_6_17_1","first-page":"1480","article-title":"The association of race and ethnicity with disease expression in male US veterans with rheumatoid arthritis","volume":"34","author":"Mikuls TR","year":"2007","journal-title":"J Rheumatol"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380107"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3190"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(199910)42:10<2220::AID-ANR26>3.0.CO;2-5"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.21778"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035296"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.2741\/E379"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.091062498"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830120206"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965"},{"key":"e_1_2_6_28_1","doi-asserted-by":"crossref","first-page":"985","DOI":"10.4049\/jimmunol.93.6.985","article-title":"Effects of the rheumatoid factor and antigen\u2010antibody complexes on the vessels of the rat mesentery","volume":"93","author":"Baum J","year":"1964","journal-title":"J Immunol"},{"key":"e_1_2_6_29_1","first-page":"91","article-title":"Immunological properties of isolated IgG and IgM anti\u2010\u03b3\u2010globulins (rheumatoid factors)","volume":"17","author":"Bianco NE","year":"1974","journal-title":"Clin Exp Immunol"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780250208"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780271008"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.173.2.487"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.054924"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30213"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.1.94"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.151.7.3840"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar622"}],"container-title":["Arthritis &amp; 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