Collagen Specific T-Cell Repertoire and HLA-DR Alleles: Biomarkers of Active Refractory Rheumatoid Arthritis

• In DR4 + RA patients disease activity is associated with detection of Collagen261-273-specific T cells carrying TRBV25.
• HLA-DR 04/04, 04/01 and 04/11 alleles were associated with TRBV25, DAS at the onset, and poor response to DMARDs.
• These findings could lead to tailor the treatment in the subgroup of patients with an active refractory disease.In the era of costly medical care with monoclonal antibodies and new molecules, and of an increasing request of a personalized medicine, a relevant socio-economic problem in the management of Rheumatoid Arthritis patients is the possible identification of the subgroups of poor responders to treatment. Our study aimed to detect the refractory active patients using an HLA-DR test (available in most hospital centers) combined with a relatively new biomarker of active disease expressed on the cell surface of autoreactive T cells. These tests appear complementary tools to identify the best and the poor responders to a “treat to target strategy”.

Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and associates with HLA-DRB1*04. The Collagen IIp261-273-specific T cell repertoire in the peripheral blood of DR4 + patients at the onset of the disease shows a restricted TCR-beta chain usage among which the most frequent is TRBV25.To define whether this group of DR4-restricted collagen-specific shared T cell could represent markers of active-severe disease and response to therapy, 90 subjects affected by early-RA were enrolled in the study; peripheral blood mononuclear cells were cultured with or without the human collagen II peptide p261-273 and were examined by immunoscope analysis for the usage of the previously identified shared TCR-beta chains.We report that the presence of T cells carrying rearrangement TRBV25 associated with HLA-DR haplotype and disease activity. HLA-DRB1* haplotypes 04–04, 04–01 and 04–11 were significantly associated with usage of TRBV25, higher disease activity at the onset of disease and poor response to DMARDs.Finally, the HLA-DRB1* haplotype appeared complementary with current serologic tools to predict good and poor responders in a treat to target strategy. The data reported here offer clues to predict the course of the disease and to foresee personalized treatments in RA patients.