Background: 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 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 (SE−: 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.
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Competing interests: None.
Contributors: BH conceived and designed the study. TH, GRB, KE and BH coordinated sample acquisition and laboratory analyses. TH, TD and BH defined clinical end points, analysed and interpreted the data. BH drafted the manuscript. KE, RG, HK, AS, GRB and TD critically revised the manuscript for important intellectual content. All authors had full access to all data and approved the final version of the manuscript.
Ethics approval: Obtained.
Patient consent: Obtained.
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