title: Association of smoking with the constitution of the anti-cyclic citrullinated peptide response in the absence of HLA-DRB1 shared epitope alleles.
abstract: OBJECTIVE
  Smoking is a risk factor for anti-cyclic citrullinated peptide (anti-CCP) antibody-positive rheumatoid arthritis (RA) in patients with HLA-DRB1 shared epitope (SE) alleles. It is unknown whether smoking influences not only the presence of these antibodies, but also other characteristics of the anti-CCP response, such as isotype usage. The aim of this study was to determine the influence of smoking on anti-CCP isotypes in RA patients, and to determine whether this influence is observed in the presence and/or absence of SE alleles.
  
  
  METHODS
  IgA, IgM, and IgG subclasses of anti-CCP antibodies were measured by enzyme-linked immunosorbent assay in serum obtained at the first visit to the Leiden Early Arthritis Clinic from 216 patients with anti-CCP-positive RA whose smoking habits were also assessed. HLA genotyping data were available for 202 of these patients.
  
  
  RESULTS
  IgA and IgM anti-CCP were more frequent in RA patients who were smokers than in those who were nonsmokers (odds ratio 2.8 and 1.8, respectively). In addition, levels of all isotypes of anti-CCP, except IgG3, were significantly higher (P < 0.05) in smokers. The number of anti-CCP isotypes was higher in smokers compared with nonsmokers, both in SE-negative RA (P = 0.04) and in SE-positive RA (P = 0.07).
  
  
  CONCLUSIONS
  Patients with anti-CCP-positive RA who have a current or former tobacco exposure display a more extensive anti-CCP isotype usage in general, and IgA and IgM in particular, compared with patients with anti-CCP-positive RA who have never smoked. In contrast to its influence on the incidence of anti-CCP positivity, the influence of tobacco exposure on the constitution of the anti-CCP response is significant in SE-negative RA. These findings suggest a differential effect of tobacco exposure on the induction as compared with the propagation of the anti-CCP antibody response.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands. K.N.Verpoort@lumc.nl
authors.forename: K N
authors.initials: KN
authors.lastname: Verpoort
authors.forename: E A M
authors.initials: EA
authors.lastname: Papendrecht-van der Voort
authors.forename: A H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.forename: C M
authors.initials: CM
authors.lastname: Jol-van der Zijde
authors.forename: M J D
authors.initials: MJ
authors.lastname: van Tol
authors.forename: J W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: F C
authors.initials: FC
authors.lastname: Breedveld
authors.forename: R R P
authors.initials: RR
authors.lastname: de Vries
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: R E M
authors.initials: RE
authors.lastname: Toes
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D000939:Epitopes; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D010456:Peptides, Cyclic / Q000276:immunology*; D012907:Smoking / Q000276:immunology*
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide