Objectives To increase understanding of the aetiology and pathogenesis of rheumatoid arthritis (RA), genetic and environmental risk factors for RA subsets, defined by the presence or absence of different anticitrullinated protein/peptide antibodies (ACPAs) targeting citrullinated peptides from α-enolase, vimentin, fibrinogen and collagen type II, were investigated.
Methods 1985 patients with RA and 2252 matched controls from the EIRA case-control cohort were used in the study. Serum samples were assayed by ELISA for the presence of anticyclic citrullinated peptides (anti-CCP) antibodies and four different ACPA fine specificities. Cross-reactivity between ACPAs was examined by peptide absorption experiments. Genotyping was performed for HLA-DRB1 shared epitope (SE) alleles and the PTPN22 gene, while information regarding smoking was obtained by questionnaire. The association of genetic and environmental risk factors with different subsets of RA was calculated by logistic regression analysis.
Results Limited cross-reactivity was observed between different ACPA fine specificities. In total, 17 RA subsets could be identified based on their different ACPA fine specificity profiles. Large differences in association with genetic and environmental determinants were observed between subsets. The strongest association of HLA-DRB1 SE, PTPN22 and smoking was identified for the RA subset which was defined by the presence of antibodies to citrullinated α-enolase and vimentin.
Conclusion This study provides the most comprehensive picture to date of how HLA-DRB1 SE, PTPN22 and smoking are associated with the presence of specific ACPA reactivities rather than anti-CCP levels. The new data will form a basis for molecular studies aimed at understanding disease development in serologically distinct subsets of RA.
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Karin Lundberg and Camilla Bengtsson are joint first authors. Lars Alfredsson and Lars Klareskog are joint last authors.
Contributors KL had main responsibility for the study including design, experimental set-up, analyses, figures, supervising and writing the paper. CB had main responsibility for the statistical analyses and tables (association and interaction analyses). NK and ER performed ELISA assays, cross-reactivity experiments and produced figures with statistics. XJ produced the tables and, together with HK, contributed to the statistical analyses (association and interaction analyses). IP-D performed ELISA assays. LI set up the in-house ELISA assays. CK produced the Cit-C1 and C1 peptides. LP performed the HLA-DRB1 and PTPN22 genotyping. RH had main responsibility for the production of Cit-C1 and C1 peptides. LA supervised the statistical analyses (association and interaction analyses) and, together with LK, had main responsibility for the EIRA case-control study. LK and KL designed the study. All authors contributed to the final paper.
Funding The Swedish Research Council, Vinnova, the Swedish Council for Working Life and Social Research, King Gustaf V’s 80-year foundation, the Swedish Rheumatic Foundation, the EU-funded projects Gums&Joints (FP7-Health-2010-261460) and MasterSwitch (FP6-Health-2007-2.4.5-12), the IMI program BTCure (115142-2).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.