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RF in the role of antibody to immune complexes (ICs) appears to be involved in activation of the complement system and in the production of chemotactic and inflammatory mediators, creating a condition that can be sustained and reinitiated. In the synovial cavity, a state of nonresolving inflammation is produced with the formation of citrullinated protein antigen\u2013antibody complexes or other forms of ICs. This is followed by a second wave of IC production in the form of RF acting as antibody reactive with the initial ICs. Both of these processes are associated with complement consumption and production of inflammatory mediators. We present a model of an initiation phase of RA that might represent an example of repetitive formation of ICs and complement-mediated inflammation. Targeting therapy at this phase of RA to break the cycles of recurrent inflammation might be a novel approach to aid in further control of the disease.<\/jats:p>","DOI":"10.1084\/jem.20160792","type":"journal-article","created":{"date-parts":[[2016,9,12]],"date-time":"2016-09-12T14:07:31Z","timestamp":1473689251000},"page":"1937-1950","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":99,"title":["Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor"],"prefix":"10.1084","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8711-3248","authenticated-orcid":false,"given":"Eng M.","family":"Tan","sequence":"first","affiliation":[{"name":"The Scripps Research Institute, La Jolla, CA 92037 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-8877","authenticated-orcid":false,"given":"Josef S.","family":"Smolen","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 1090 Vienna, Austria 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,9,12]]},"reference":[{"key":"2023072608541938100_bib1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/1756-0500-2-44","article-title":"Assessment of anti-cyclic citrullinated peptide in psoriatic arthritis","volume":"2","author":"Abdel Fattah","year":"2009","journal-title":"BMC Res. 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