Objectives: Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anti-cyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, which both have been implicated in anti-CCP generation, are assumed to be associated with RA. Aims of this study were to elucidate whether there is an impact of PADI4 on clinical characteristics of RA, and whether PADI4 would modulate the effect of anti-CCP on clinical course. Moreover, the combined effect of SE and PADI4 on autoantibody profile was analysed.
Methods: Three hundred and seventy-three RA patients were studied. SE, padi4_94C>T, rheumatoid factor, anti-CCP, and antinuclear antibodies (ANA) were determined. Disease severity was characterised by cumulative therapy intensity classified in ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score.
Results: CTI was significantly associated with disease duration, erosive disease, DAS28, and anti-CCP. Association of anti-CCP 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 ANA was observed with remarkable differences depending on SE-status (SE-: ORadj: 6.20, Padj<0.04; SE+: ORadj: 0.36, Padj=0.02) and significant heterogeneity between both SE-strata (P=0.006).
Conclusions: PADI4 genotype in combination with anti-CCP and SE modulates clinical and serological characteristics of RA.