Hierarchy of risk of childhood onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope

Rheumatoid arthritis (RA), which is estimated to affect ~1% of the adult population, is the most common form of inflammatory arthritis in the world. A substantial majority of individuals with RA have rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA), and the presence of these antibodies has been associated with a worse prognosis. Some children with juvenile idiopathic arthritis (JIA) have a disease that phenotypically resembles RA, characterized by chronic inflammatory arthritis and the presence of the characteristic biomarkers seen in RA including RF and ACPA Such JIA patients presumably represent a subset of RA patients with childhood onset of RA (CORA), but it is unclear if CORA shares the same risk factors associated with adult-onset RA, which has its peak age of onset in the fifth decade, or if patients with CORA have additional risk factors that, once identified, will offer important insight into the etiopathogenesis of RA. Both genetic and environmental factors have been associated with the risk of developing RA in adults. A recent meta-analysis of genome-wide associations studies of RA brought the total number of loci with confirmed genetic association to 31(1). The strongest association observed to date has been with a subset of alleles encoding the class II Human leukocyte antigens (HLA). RA associated HLA-DRB1 alleles encode DRβ1 chains with conserved amino acid sequence in positions 70-74. The molecular structure encoding the susceptibility residues is termed the shared epitope (SE)(2). While associations between SE and risk of RA are well established, some alleles (e.g. HLA-DRB1*0401) appear to confer a greater degree of risk than others (HLA-DRB1*0101)(3). Tezenas Du Montcel et al proposed a classification based on the amino acid sequence at positions 70-74, and suggested that some classes of SE alleles conferred greater susceptibility than others (4, 5). While SE alleles have been evaluated in childhood cases of RA, often referred to in the literature as “seropositive juvenile rheumatoid arthritis” or “polyarticular RF+ juvenile idiopathic arthritis”, most prior cohorts were small, used low resolution HLA typing, and thus have been limited to evaluation of the presence or absence of SE (6-11). Our objectives were to investigate the association between SE-encoding HLA-DRB1 alleles and CORA, and to explore a possible hierarchy of risk conferred by SE alleles based on the amino-acid sequence in position 70-74, in a large cohort of CORA patients. We also sought to compare the frequencies of SE genotypes in children with CORA versus published frequencies in adults with RA.