title: Smoking, Porphyromonas gingivalis and the immune response to citrullinated autoantigens before the clinical onset of rheumatoid arthritis in a Southern European nested case-control study.
abstract: BACKGROUND
  Antibodies to citrullinated proteins (ACPA) occur years before RA diagnosis. Porphyromonas gingivalis expresses its own peptidylarginine deiminase (PPAD), and is a proposed aetiological factor for the ACPA response. Smoking is a risk factor for both ACPA-positive RA and periodontitis. We aimed to study the relation of these factors to the risk of RA in a prospective cohort.
  
  
  METHODS
  We performed a nested case-control study by identifying pre-RA cases in four populations from the European Prospective Investigation into Cancer and nutrition, matched with three controls. Data on smoking and other covariates were obtained from baseline questionnaires. Antibodies to CCP2 and citrullinated peptides from α-enolase, fibrinogen, vimentin and PPAD were measured. Antibodies to arginine gingipain (RgpB) were used as a marker for P.gingivalis infection and validated in a separate cohort of healthy controls and subjects with periodontitis.
  
  
  RESULTS
  We studied 103 pre-RA cases. RA development was associated with several ACPA specificities, but not with antibodies to citrullinated PPAD peptides. Antibody levels to RgpB and PPAD peptides were higher in smokers but were not associated with risk of RA or with pre-RA autoimmunity. Former but not current smoking was associated with antibodies to α-enolase (OR 4.06; 95 % CI 1.02, 16.2 versus 0.54; 0.09-3.73) and fibrinogen peptides (OR 4.24; 95 % CI 1.2-14.96 versus 0.58; 0.13-2.70), and later development of RA (OR 2.48; 95 % CI 1.27-4.84 versus 1.57; 0.85-2.93), independent of smoking intensity.
  
  
  CONCLUSIONS
  Smoking remains a risk factor for RA well before the clinical onset of disease. In this cohort, P.gingivalis is not associated with pre-RA autoimmunity or risk of RA in an early phase before disease-onset. Antibodies to PPAD peptides are not an early feature of ACPA ontogeny.
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK. b.fisher@bham.ac.uk.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fisher
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. alison.cartwright@kennedy.ox.ac.uk.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cartwright
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. anne-marie.quirke@kennedy.ox.ac.uk.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Quirke
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK. P.dePablo@bham.ac.uk.
authors.forename: Paola
authors.initials: P
authors.lastname: de Pablo
authors.affiliation: School of Public Health, Imperial College London, London, UK. d.romaguera-bosch@imperial.ac.uk.|CIBER-OBN (Fisiopatología de la Obesidad y Nutrición), Madrid, Spain. d.romaguera-bosch@imperial.ac.uk.
authors.forename: Dora
authors.initials: D
authors.lastname: Romaguera
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy. spanico@unina.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy. amattiel@unina.it.
authors.forename: Amalia
authors.initials: A
authors.lastname: Mattiello
authors.affiliation: Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain. diana.gavrila@carm.es.|CIBER Epidemiología y Salud Pública (CIBERESP), Murcia, Spain. diana.gavrila@carm.es.
authors.forename: Diana
authors.initials: D
authors.lastname: Gavrila
authors.affiliation: Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain. carmen.navarro@carm.es.|CIBER Epidemiología y Salud Pública (CIBERESP), Murcia, Spain. carmen.navarro@carm.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.affiliation: Human Genetics Foundation, Turin, Italy. carlotta.sacerdote@cpo.it.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.affiliation: Human Genetics Foundation, Turin, Italy. p.vineis@imperial.ac.uk.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: Cancer Registry and Histopathology Unit, "Civic - M.P.Arezzo" Hospital, ASP Ragusa, Ragusa, Italy. rtumino@tin.it.
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.affiliation: University of Glasgow Dental School, University of Glasgow, Glasgow, UK. david.lappin@glasgow.ac.uk.
authors.forename: David F
authors.initials: DF
authors.lastname: Lappin
authors.forename: Danae
authors.initials: D
authors.lastname: Apatzidou
authors.affiliation: University of Glasgow Dental School, University of Glasgow, Glasgow, UK. dapatzidou@yahoo.co.uk.
authors.forename: Danae
authors.initials: D
authors.lastname: Apazidou
authors.affiliation: University of Glasgow Dental School, University of Glasgow, Glasgow, UK. Shauna.Culshaw@glasgow.ac.uk.
authors.forename: Shauna
authors.initials: S
authors.lastname: Culshaw
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Jan.Potempa@uj.edu.pl.|Oral Health and Systemic Research Group, School of Dentistry, University of Louisville, Louisville, USA. Jan.Potempa@uj.edu.pl.
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
authors.affiliation: School of Public Health, Imperial College London, London, UK. dominique_michaud@brown.edu.|Department of Epidemiology, Brown University School of Public Health, Providence, USA. dominique_michaud@brown.edu.
authors.forename: Dominique S
authors.initials: DS
authors.lastname: Michaud
authors.affiliation: School of Public Health, Imperial College London, London, UK. e.riboli@imperial.ac.uk.
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. patrick.venables@kennedy.ox.ac.uk.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Venables
mesh_terms: D018829:Adhesins, Bacterial / Q000276:immunology; D000328:Adult; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000276:immunology* / Q000382:microbiology; D001324:Autoantigens / Q000276:immunology; D016022:Case-Control Studies; D003546:Cysteine Endopeptidases / Q000276:immunology; D005060:Europe / Q000453:epidemiology; D005260:Female; D000080867:Gingipain Cysteine Endopeptidases; D006801:Humans; D006867:Hydrolases / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D010518:Periodontitis / Q000150:complications / Q000276:immunology; D016966:Porphyromonas gingivalis / Q000201:enzymology*; D011446:Prospective Studies; D000076342:Protein-Arginine Deiminases; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology
chemical_list: D018829:Adhesins, Bacterial; D001324:Autoantigens; D000080867:Gingipain Cysteine Endopeptidases; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D006867:Hydrolases; D003546:Cysteine Endopeptidases; D000076342:Protein-Arginine Deiminases