The influence of HLA-DRB1 alleles encoding the DERAA amino acid motif on radiological outcome in rheumatoid arthritis

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Abstract
Objectives. To investigate the influence of HLA-DRB1 alleles encoding the QK/RRAA shared epitope (SE) on radiological outcome in rheumatoid arthritis (RA), and to determine whether it is modulated by alleles carrying the putative rheumatoid arthritis-protective (RAP) sequence DERAA. Patients and methods. The association between erosive damage and HLA-DRB1 status was examined in 315 RA patients with a disease duration of 5–30 yr. Radiological outcome was measured by scoring X-rays of the hands and feet using the standard radiographs of Larsen (Larsen score). HLA-DRB1 typing was carried out using polymerase chain reaction methodology. Results. Patients with two alleles encoding the QK/RRAA SE had significantly higher Larsen scores than SE-negative patients (96.9 vs 83.3; P=0.04, after correction for multiple testing), with DRB1*0401/*0401 homozygotes demonstrating the greatest radiological damage (99.9). The lowest Larsen score (65.6) was observed in patients carrying the DERAA motif without an accompanying SE allele (RAP+/SE−). This was significantly lower than in patients with RAP+/SE+ (105.6; P=0.04), RAP−/SE− (88.2; P=0.05) and RAP−/SE+ (95.8; P=0.009), after correction for multiple testing. There was no evidence that the RAP sequence was modulating the effect of the SE since radiological outcome in RAP+/SE+ patients was not significantly different to that in RAP−/SE+ individuals. Conclusions. Our data support a possible role for DRB1 alleles encoding the DERAA motif in protection against severe erosive damage in patients lacking the QK/RRAA SE, but not in patients heterozygous for the SE. This suggests that DRB1 alleles encoding the SE have a dominant influence over `protective alleles' and are not merely `non-protective'.