Benjamin A. Fisher and Alison J. Cartwright contributed equally to this work.
An erratum to this article can be found at http://dx.doi.org/10.1186/s12891-016-0916-z.
The authors have no competing interests.
PJV, ER, DM, BF and DR designed the study. AC and AQ ran ELISAs. PP undertook statistical analysis. DL, DA and SC collected the periodontitis cohort and ran PCR analyses. JP provided RgpB. All other authors participated in identification of RA cases and controls. BF drafted the manuscript. All authors read and approved the final manuscript.
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.
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.
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.
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.
Gerlag DM, Raza K, van Baarsen LG, Brouwer E, Buckley CD, Burmester GR, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis. 2012;71(5):638–41. PubMedCentralCrossRefPubMed
van der Woude D, Rantapaa-Dahlqvist S, Ioan-Facsinay A, Onnekink C, Schwarte CM, Verpoort KN, et al. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann Rheum Dis. 2010;69(8):1554–61. CrossRefPubMed
Quirke AM, Lugli EB, Wegner N, Hamilton BC, Charles P, Chowdhury M, et al. Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Ann Rheum Dis. 2014;73(1):263–9. PubMedCentralCrossRefPubMed
Montgomery AB, Kopec J, Shrestha L, Thezenas ML, Burgess-Brown NA, Fischer R et al. Crystal structure of Porphyromonas gingivalis peptidylarginine deiminase: implications for autoimmunity in rheumatoid arthritis. Ann Rheum Dis 2015, doi: 10.1136/annrheumdis-2015-207656.
Konig MF, Paracha AS, Moni M, Bingham CO, III, Andrade F. Defining the role of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) in rheumatoid arthritis through the study of PPAD biology. Ann Rheum Dis. 2015;74(11):2054-61.
Kokkonen H, Brink M, Hansson M, Lassen E, Mathsson-Alm L, Holmdahl R, et al. Associations of antibodies against citrullinated peptides with human leukocyte antigen-shared epitope and smoking prior to the development of rheumatoid arthritis. Arthritis Res Ther. 2015;17:125. doi: 10.1186/s13075-015-0638-x. 125–0638. PubMedCentralCrossRefPubMed
Hensvold AH, Magnusson PK, Joshua V, Hansson M, Israelsson L, Ferreira R, et al. Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins. Ann Rheum Dis. 2015;74(2):375-80.
Arlestig L, Mullazehi M, Kokkonen H, Rocklov J, Ronnelid J, Dahlqvist SR. Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden. Ann Rheum Dis. 2012;71(6):825–9. PubMedCentralCrossRefPubMed
de Smit M, van de Stadt LA, Janssen KM, Doornbos-van der Meer B, Vissink A, van Winkelhoff AJ, et al. Antibodies against Porphyromonas gingivalis in seropositive arthralgia patients do not predict development of rheumatoid arthritis. Ann Rheum Dis. 2014;73(6):1277-9
Mikuls TR, Payne JB, Yu F, Thiele GM, Reynolds RJ, Cannon GW et al. Periodontitis and Porphyromonas gingivalis in Patients with Rheumatoid Arthritis. Arthritis Rheum. 2014;66(5)1090-100
Ferucci ED, Darrah E, Smolik I, Choromanski TL, Robinson DB, Newkirk MM, et al. Prevalence of anti-peptidylarginine deiminase type 4 antibodies in rheumatoid arthritis and unaffected first-degree relatives in indigenous North American Populations. J Rheumatol. 2013;40(9):1523–8. PubMedCentralCrossRefPubMed
- 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
Benjamin A. Fisher
Alison J. Cartwright
Paola de Pablo
David F. Lappin
Dominique S. Michaud
Patrick J. Venables
- BioMed Central
Neu im Fachgebiet Orthopädie und Unfallchirurgie
Mail Icon II