title: Rheumatoid arthritis-associated autoantibodies in non-rheumatoid arthritis patients with mucosal inflammation: a case-control study.
abstract: BACKGROUND
  Rheumatoid arthritis-associated autoantibodies (RA-AAB) can be present in serum years before clinical onset of rheumatoid arthritis (RA). It has been hypothesized that initiation of RA-AAB generation occurs at inflamed mucosal surfaces, such as in the oral cavity or lungs. The aim of this study was to assess systemic presence of RA-AAB in patients without RA who had oral or lung mucosal inflammation.
  
  
  METHODS
  The presence of RA-AAB (immunoglobulin A [IgA] and IgG anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), IgM and IgA rheumatoid factor (RF), IgG anti-carbamylated protein antibodies and IgG and IgA anti-citrullinated peptide antibodies against fibrinogen, vimentin and enolase) were determined in sera of non-RA patients with periodontitis (PD, n = 114), bronchiectasis (BR, n = 80) or cystic fibrosis (CF, n = 41). Serum RA-AAB levels were compared with those of periodontally healthy controls (n = 36). Patients with established RA (n = 86) served as a reference group. Association of the diseases with RA-AAB seropositivity was assessed with a logistic regression model, adjusted for age, sex and smoking.
  
  
  RESULTS
  Logistic regression analysis revealed that IgG anti-CCP seropositivity was associated with BR and RA, whereas the association with PD was borderline significant. IgA anti-CCP seropositivity was associated with CF and RA. IgM RF seropositivity was associated with RA, whereas the association with BR was borderline significant. IgA RF seropositivity was associated with CF and RA. Apart from an influence of smoking on IgA RF in patients with RA, there was no influence of age, sex or smoking on the association of RA-AAB seropositivity with the diseases. Anti-CarP levels were increased only in patients with RA. The same held for IgG reactivity against all investigated citrullinated peptides.
  
  
  CONCLUSIONS
  Although overall levels were low, RA-AAB seropositivity was associated with lung mucosal inflammation (BR and CF) and may be associated with oral mucosal inflammation (PD). To further determine whether mucosal inflammation functions as a site for induction of RA-AAB and precedes RA, longitudinal studies are necessary in which RA-AAB of specifically the IgA isotype should be assessed in inflamed mucosal tissues and/or in their inflammatory exudates.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. k.m.j.janssen@umcg.nl.
authors.forename: Koen M J
authors.initials: KM
authors.lastname: Janssen
authors.affiliation: Center for Dentistry and Oral Hygiene, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. m.j.de.smit@umcg.nl.
authors.forename: Menke J
authors.initials: MJ
authors.lastname: de Smit
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, PO Box 30.001, 9700, RB, Groningen, The Netherlands. e.brouwer@umcg.nl.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brouwer
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, PO Box 30.001, 9700, RB, Groningen, The Netherlands. fennedekok@gmail.com.
authors.forename: Fenne A C
authors.initials: FA
authors.lastname: de Kok
authors.affiliation: Department of Pulmonology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. j.kraan@umcg.nl.
authors.forename: Jan
authors.initials: J
authors.lastname: Kraan
authors.affiliation: Department of Pulmonary Diseases, Medical Center Alkmaar, Alkmaar, The Netherlands. j.altenburg@mca.nl.
authors.forename: Josje
authors.initials: J
authors.lastname: Altenburg
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. m.k.verheul@lumc.nl.
authors.forename: Marije K
authors.initials: MK
authors.lastname: Verheul
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. l.a.trouw@lumc.nl.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: Trouw
authors.affiliation: Center for Dentistry and Oral Hygiene, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. a.j.van.winkelhoff@umcg.nl.|Department of Medical Microbiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. a.j.van.winkelhoff@umcg.nl.
authors.forename: Arie Jan
authors.initials: AJ
authors.lastname: van Winkelhoff
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. a.vissink@umcg.nl.
authors.forename: Arjan
authors.initials: A
authors.lastname: Vissink
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, PO Box 30.001, 9700, RB, Groningen, The Netherlands. johanna.westra@umcg.nl.
authors.forename: Johanna
authors.initials: J
authors.lastname: Westra
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001987:Bronchiectasis / Q000097:blood / Q000276:immunology*; D016022:Case-Control Studies; D003550:Cystic Fibrosis / Q000097:blood / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010518:Periodontitis / Q000097:blood / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology; D055815:Young Adult
chemical_list: D001323:Autoantibodies