Last updated: November 3, 2014

Definition: The major histocompatibility complex locus designated HLA-DR4 was first associated with RA in studies reported by Stastny in 1978. Using the technique of mixed lymphocyte culture, patients with RA were found to be more alike than were normal individuals, suggesting the presence of a shared cell-associated antigen. This shared antigen was later identified on chromosome 6 as a member of the major histocompatability complex D locus, designated HLA-DR4. The DR molecule consists of two transmembrane chains, designated α and β. The β chain shows extensive polymorphisms and is used to identify subtypes of DR4.

Normal Values: The prevalence of HLA-DR4 is highest in northern European whites and lowest in those of Mediterranean ancestry.

Increased in: Studies in diverse ethnic groups show that the incidence of HLA-DR4 is significantly higher in patients with RA than in the matched normal control population. In white populations of North America, most published series indicate that 60% to 65% of patients with RA are positive for HLA-DR4, which is more than twice the incidence of this allele in the normal population. Moreover, the presence of this allele seems to define a more aggressive variant of RA, with a greater incidence of articular erosions, rheumatoid nodules, secondary Sjögren’s syndrome, and other extraarticular features of RA. Molecular techniques have been used to identify subtypes of the serologically identified HLA-DR4 molecule that are associated with a significantly elevated risk of RA. These include the HLA-DR4 alleles designated DRB1*0401 and DRB1*0404 as well as the closely related alleles of HLA-DR1 designated DRB1*0101.

• Sequence analyses have further demonstrated that these alleles known to be associated with increased susceptibility and severity of RA also share a common amino acid sequence at positions 67, 70, 71, and 74 in the β chain of the DR4 molecule. This common sequence has been called the “shared epitope”. Identification of the antigen recognized by the shared motif carries the potential to reveal the causative antigen in RA. Furthermore, interference with the pathogenetic binding site through production of blocking antibodies or peptides may offer therapeutic benefit. Studies examining the feasibility of this ap- proach are currently in progress.
• The association of HLA-DR with other arthropathies is weaker but, when present, seems to define individuals with a greater risk of chronic, severe polyarthritis (e.g., Lyme disease, psoriatic arthritis).

Clinical Applications: At present, HLA typing is not useful in the clinical management of patients with RA. It appears that patients with DR4, especially those with two copies of the disease-related shared epitope, have more severe disease than patients with RA without any shared epitope alleles. Nonetheless, patients show significant variability in clinical course, and no predictive or prognostic value has been demonstrated. Therefore, therapeutic decisions should be made based on the clinical disease features, not the HLA type.

Cost: HLA-DR4 (DRβ1), $170—230.

Olsen NJ, Callahan LF, Brooks RH, et al. Associations of HLA-DR4 with rheumatoid factor and radiographic severity in rheumatoid arthritis. Am J Med 1988;84:257–264. PMID:3261537
Weyand CM, Hicok KC, Conn DL, et al. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med 1992;117:801–806.PMID:1416553
Winchester R. Genetic determination of susceptibility and severity in rheumatoid arthritis. Ann Intern Med 1992;117:869–871.PMID:1416564


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