Background/Purpose:

Rheumatoid arthritis
(RA) is characterized by autoimmunity to citrullinated proteins. Porphyromonas
gingivalis (Pg) has been proposed as an epidemiologic link between
RA and periodontitis (PD) and expresses peptidylarginine deiminase (PPAD).  In
addition to catalyzing citrullination, PPAD itself can be citrullinated.  Reports
have demonstrated a heightened immune response to cit-PPAD that is specific to
RA and that might serve as a potential mechanism for breaching immunologic
tolerance. There have been no studies examining the association of
anti-cit-PPAD antibody with RA risk factors or measures of disease severity. 
The objective of the present study was to examine the association of anti-cit-PPAD
antibody with known RA risk factors and disease severity. 

Methods:

Patients with
RA (n=285) were studied in a post-hoc analysis of a case-control study that
included standardized full-mouth examination to assess PD status. ACPA specific
to CCP, cit-enolase, and cit-H2A (histone) and antibody to the immunodominant
peptide of cit-PPAD (CPP3) were measured using ELISA.  Anti-CPP3 was defined as
concentrations ≥2.5 SD above the mean in 330 osteoarthritis controls, while
anti-cit-enolase and anti-cit-H2A were defined as concentrations ≥2 SD
above the control mean.  Associations of RA risk factors (smoking, PD, and
HLA-DRB1 shared epitope [SE]) with anti-CPP3 positivity were examined using the
chi-square test; associations with disease activity and radiographic severity
(hand films and oral panoramic films) were examined using Wilcoxon rank-sum
tests.  Associations of anti-CPP3 with ACPA concentrations were examined using
Spearman rank correlations.

 Results:

Anti-CPP3 positivity
was observed in 100 RA cases (35%) with positivity nearly exclusive to anti-CCP
antibody positive RA; only 3 of 43 anti-CCP negative RA cases were positive for
anti-CPP3.  Associations of anti-CPP3 antibody with patient factors and RA
disease severity measures are shown in Table 1, with significant associations between
anti-CPP3 antibody and HLA-DRB1 SE status, erosion score on hand films,
alveolar bone loss, and RF.  There were significant correlations of anti-CPP3
antibody concentrations with ACPA concentrations including anti-CCP (r 0.54; p
< 0.001), anti-cit-enolase (r 0.63; p < 0.001), and anti-cH2A (r 0.41; p
< 0.001).

Conclusion:

As previously
observed with ACPA, antibody to citrullinated PPAD is increased in RA and is
associated with worse oral and joint radiographic damage in RA in addition to
HLA-DRB1 SE and higher titers of RF.  Moreover, anti-CPP3 antibody is strongly
correlated with circulating ACPA, supporting a potential pathogenic role for Pg
expressed PPAD in RA disease pathogenesis and progression.

Table 1: Associations of anti-CPP3 antibody with patient factors
and measures of disease activity / severity