Abstract:
INTRODUCTION: The revised shared epitope (SE) concept in rheumatoid arthritis (RA) is based on the presence (S) or
absence (X) of the SE RAA amino acid motif at positions 72 to 74 of the third hypervariable region of the various
human leucocyte antigen (HLA)-DRB1 alleles. The purpose of this study was to investigate SE subtypes on the basis
of the American College of Rheumatology 1987 revised criteria for the classification of RA in a cohort of South
African RA patients (n = 143) and their association with clinical and circulating biomarkers of disease activity
(autoantibodies, acute phase reactants and cytokines).
METHODS: Genomic DNA was analysed using high-resolution recombinant sequence-specific oligonucleotide PCR
typing of the HLA-DRB1 allele. Subtypes of the SE were classified according to the amino acids at positions 72 to
74 for the RAA sequence, and further sub-divided according to the amino acids at positions 70 and 71, which
either contribute to (S2, S3P), or negate (S1, S3D) RA susceptibility. Disease activity was assessed on the basis of (1)
Disease Activity Score in 28 joints using C-reactive protein (CRP), (2) rheumatoid factor (RF), (3) CRP and (4) serum
amyloid A by nephelometry, anticyclic citrullinated peptide antibodies (aCCP) by an immunofluorometric
procedure, and cytokines by multiplex bead array technology.
RESULTS: Of the 143 RA patients, 81 (57%) were homozygous (SS) and 50 (35%) were heterozygous (SX) for the SE
alleles with significant overexpression of S2 and S3P (respective odds ratios (ORs) 5.3 and 5.8; P < 0.0001), and 12
(8%) were classified as no SE allele (XX). Both the SS and SX groups showed a strong association with aCCP
positivity (OR = 10.2 and P = 0.0010, OR = 9.2 and P = 0.0028, respectively) relative to the XX group. Clinical scores
and concentrations of the other biomarkers of disease activity (RF, CRP and T helper cell type 1 (Th1), Th2,
macrophage and fibroblast cytokines) were also generally higher in the SS group than in the SX and XX groups.
CONCLUSIONS: RA susceptibility alleles investigated according to revised criteria for the classification of RA were
significantly increased in South African RA patients and strongly associated with aCCP in particular as well as with
circulating cytokines and disease severity.
