title: Smoking is associated with the concurrent presence of multiple autoantibodies in rheumatoid arthritis rather than with anti-citrullinated protein antibodies per se: a multicenter cohort study.
abstract: The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies.
  
  
  
  A population-based Japanese cohort (n = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n = 678), the United Kingdom (n = 761), and Sweden (n = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression.
  
  
  
  In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32-6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78-1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04-1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53-2.73).
  
  
  
  Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA.
authors.affiliation: Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands. tinekevanwesemael@gmail.com.
authors.forename: Tineke J
authors.initials: TJ
authors.lastname: van Wesemael
authors.affiliation: Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.|Rheumatology Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Ajeganova
authors.affiliation: Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Humphreys
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Center for the Promotion of Interdisciplinary Education and Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.affiliation: Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Ammar
authors.initials: A
authors.lastname: Muhammad
authors.affiliation: Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, UK.|NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Deborah P M
authors.initials: DP
authors.lastname: Symmons
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: MacGregor
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Ingiäld
authors.initials: I
authors.lastname: Hafström
authors.affiliation: Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: Trouw
authors.affiliation: Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.affiliation: Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.affiliation: Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Svensson
authors.affiliation: Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, UK.
authors.forename: Suzanne M M
authors.initials: SM
authors.lastname: Verstappen
authors.affiliation: Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Diane
authors.initials: D
authors.lastname: van der Woude
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D002956:Citrulline / Q000276:immunology; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D012217:Rheumatoid Factor / Q000276:immunology; D012907:Smoking / Q000009:adverse effects*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D010456:Peptides, Cyclic; D002956:Citrulline; D012217:Rheumatoid Factor
keywords: Anti-carbamylated protein antibodies; Anti-citrullinated protein antibodies; Rheumatoid arthritis; Rheumatoid factor; Risk factor; Smoking