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.