Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis

Abstract

Objectives: ACPA is a highly specific marker for RA. It was recently reported that ACPA can be used to classify RA into two disease subsets, ACPA-positive and ACPA-negative RA. ACPA-positive RA was found to be associated with the HLA-DR shared epitope (SE), but ACPA negative was not. However, the suspicion remained that this result was caused by the ACPA-negative RA subset containing patients with non-RA diseases. We examined whether this is the case even when possible non-RA ACPA-negative RA patients were excluded by selecting only patients with bone erosion.

Methods: We genotyped HLA-DRB1 alleles for 574 ACPA-positive RA, 185 ACPA-negative RA (including 97 erosive RA) and 1508 healthy donors. We also tested whether HLA-DR SE is associated with RF-negative or ANA-negative RA.

Results: ACPA-negative RA with apparent bone erosion was not associated with SE, supporting the idea that ACPA-negative RA is genetically distinct from ACPA-positive RA. We also tested whether these subsets are based on autoantibody-producing activity. In accordance with the ACPA-negative RA subset, the RF-negative RA subset showed a clearly distinct pattern of association with SE from the RF-positive RA. In contrast, ANA-negative as well as ANA-positive RA was similarly associated with SE, suggesting that the subsets distinguished by ACPA are not based simply on differences in autoantibody production.

Conclusions: ACPA-negative erosive RA is genetically distinct from ACPA-positive RA.

Fig. 1

Association of number of SE alleles and titre of ACPA, RF or ANA. ACPA-positive (A), RF-positive (B) or ANA-positive (C) RA patients were selected from the Kyoto University cohort, and the serum ACPA titre (A), RF titre (B) or ANA titre (C) was plotted stratified by the number of SE alleles present. The P-values were calculated by Jonckheere–Terpstra trend test.

Fig. 2

Association of HLA-DRB1*0405 allele number and ACPA titre. Only ACPA-positive RA samples were selected from the Kyoto University cohort, and ACPA titres and the number of HLA-DRB1*0405 alleles (the most popular SE allele in Japanese subjects) in each sample are box plotted. The P-value by Jonckheere–Terpstra trend test for this association is 0.000127.