Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis.

Background: Recent evidence suggests that distinction of subsets of
rheumatoid arthritis (RA) depending on anticyclic citrullinated
peptide antibody (anti-CCP) status may be helpful in distinguishing
distinct aetiopathologies and in predicting the course of disease.
HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4
(PADI4) genotype, both of which have been implicated in anti-CCP
generation, are assumed to be associated with RA. Objectives: To
elucidate whether PADI4 affects the clinical characteristics of RA,
and whether it would modulate the effect of anti-CCPs on clinical
course. The combined effect of SE and PADI4 on autoantibody profile
was also analysed. Methods: 373 patients with RA were studied. SE,
padi4_94C.T, rheumatoid factor, anti-CCPs and antinuclear
antibodies (ANAs) were determined. Disease severity was
characterised by cumulative therapy intensity classified into
ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score.
Results: CTI was significantly associated with disease duration,
erosive disease, disease activity score (DAS) 28 and anti-CCPs. The
association of anti-CCPs with CTI was considerably influenced by
padi4_94C.T genotype (C/C: ORadj=0.93, padj=0.92; C/T: ORadj=2.92,
padj=0.093; T/T: ORadj=15.3, padj=0.002). Carriage of padi4_94T
exhibited a significant trend towards higher Steinbrocker scores in
univariate and multivariate analyses. An association of padi4_94C.T
with ANAs was observed, with noteworthy differences depending on SE
status (SE2: ORadj=6.20, padj,0.04; SE+: ORadj=0.36, padj=0.02) and
significant heterogeneity between the two SE strata (p=0.006).
Conclusions: PADI4 genotype in combination with anti- CCPs and SE
modulates clinical and serological characteristics of RA.