HLA markers and prediction of clinical course and outcome in rheumatoid arthritis

Abstract

Objective. To evaluate HLA markers as early prognostic factors for disease severity in rheumatoid arthritis (RA).Methods. HLA genotyping was carried out in a retrospective analysis of 66 RA patients and in a prospective study of 55 RA patients and 87 healthy controls using polymerase chain reaction-based methods for HLA-DRB1 specificities, DR4 alleles, and their linked DQBl alleles, as well as HLA-B27. The clinical course of RA was assessed by clinical and radiologic scores. The impact of HLA markers was evaluated by epidemiologic means in addition to modeling using multiple logistic regression analysis.Results. Shared epitope-positive (HVR3+) DR4 alleles and the HVR3 amino acid cassette QKRAA were associated with RA in both longstanding (relative risk [RR] 3.34 and 3.19) and recent-onset (RR 2.1 and 2.37) RA. In longstanding RA, radiologic evidence of severe joint destruction (Larsen score >1.62) was seen more often in HVR3 shared epitopc+positive patients than in epitope-negative patients (odds ratio [OR] = 25.67, 2 = 13.59, P = 0.0003). Moreover, rank sum analysis of Larsen indices indicated significantly higher ranking for the presence of the RA-associated HVR3 cassettes (QKRAA, QRRAA) when expressed on a DR4 allele (P < 0.0001). In the prospective study, DR4-positive pa- tients had a significantly increased risk (OR = 13.75, P = 0.00083) of developing bony erosions. In addition, HVR3 epitope-positive DR4-positive individuals had significantly higher Larsen indices than did epitopenegative patients (P = 0.0083). In particular, the presence of the HVR3 epitope on DR4 resulted in an increased a posteriori likelihood (0.91) of developing early erosive disease compared with an a priori risk of 0.62. Conversely, the likelihood decreased to a minimum of 0.35 when the HVR3 epitope was absent.

Ex Vivo Homeostatic Proliferation of CD4+ T Cells in Rheumatoid Arthritis Is Dysregulated and Driven by Membrane-Anchored TNFα

“…For quantification of T lymphocyte subpopulation in PBMC, the mAbs anti-CD28-PE (clone L293; BD Pharmingen) and CD45RA-PE (clone UCHL1; BD Pharmingen) were used. Flow Determination of HLA DRB1 alleles was performed by hybridization of DRB1 PCR products to sequence-specific oligonucleotide probes as described previously (43).…”

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis

“…It has been proposed that a conserved motif in the third hypervariable region (HVR3) of certain HLA-DR class II alleles plays a role in the presentation of "arthritogenic" antigens to T lymphocytes, the "shared epitope" (SE) hypothesis (3). Not only does carriership of SE alleles increase the risk of RA, but in RA patients, these alleles are also associated with a more severe disease type (4,5). However, since there are differences in the strength of association between SE alleles and RA, and since no convincing demonstration of the mechanisms underlying the associations is currently available, other paradigms that refine or complement the SE hypothesis have been put forward (6,7).…”

Shared Epitope and Anti-Cyclic Citrullinated Peptide Antibodies: Relationship with Age at Onset and Duration of Disease in Rheumatoid Arthritis

“…Interestingly, polymorphisms in one member of the family, PADI4, have been associated with RA in Asian populations 1 , although this association could not be reproduced in Caucasian populations 2,3 . An association has been described between the presence of the SE and anti-cyclic citrullinated peptide antibody (anti-CCP) levels, and of each variable with disease severity 4,5 . Also, anti-CCP-positive has been reported to be immunogenetically distinct from anti-CCP-negative disease, with the former subgroup being primarily responsible for association and linkage to HLA-DRB1 SE 6 .…”