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OP0173 Dominant B-cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis
  1. P-P Tak1,
  2. ME Doorenspleet2,3,
  3. M de Hair4,
  4. P Klarenbeek2,3,
  5. M Beers-Tas van5,
  6. A van Kampen6,
  7. D van Schaardenburg5,
  8. D Gerlag4,
  9. F Baas3,
  10. N de Vries2
  1. 1Department of Clinical Immunology and Rheumatology
  2. 2Amsterdam Rheumatology and Immunology Center
  3. 3Department of Genome Analysis
  4. 4Clinical Immunology and Rheumatology, Academic Medical Center
  5. 5Amsterdam Rheumatology and Immunology Center, Reade
  6. 6Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, Netherlands

Abstract

Background The onset of seropositive rheumatoid arthritis (RA) is preceded by the presence of specific autoantibodies in the absence of synovial inflammation. Only a subset of these at-risk individuals will develop clinical disease. This impedes efforts to implement early interventions that may prevent onset of clinical disease.

Objectives Here we analyze whether clonal changes in the B-cell receptor (BCR) repertoire can reliably predict onset of clinical disease.

Methods In a prospective cohort study in 21 individuals at-risk for RA, the BCR repertoire of paired peripheral blood and synovial tissue samples was analyzed using next-generation BCR sequencing. BCR clones that were expanded beyond 0.5% of the total repertoire were labeled dominant. The relative risk for onset of arthritis was assessed, using a cut-off of presence of ≥5 dominant BCR clones. Findings in peripheral blood were validated in an independent prospective cohort of 50 at-risk individuals. Based on the test cohort, individuals in the validation cohort were considered positive if peripheral blood at study entry showed ≥5 dominant BCR clones.

Results Both in the test and validation cohort, the presence of ≥5 dominant BCR clones in peripheral blood was significantly associated with arthritis development (validation cohort relative risk (RR) 6.3, 95% confidence interval (CI) 2.7 - 15, p<1*10-4). Even when adjusted for the recently described clinical prediction rule the association remained intact (relative risk 5.0, 95% CI 1.2 - 20, p=0.024). When individuals developed arthritis, dominant BCR clones disappeared from peripheral blood and appeared in synovial tissue, suggesting a direct role of these clones in disease pathogenesis.

Conclusions Dominant BCR clones in peripheral blood predict onset of clinical symptoms of RA in at-risk individuals with high accuracy. Our data suggest that during onset of RA these clones shift from peripheral blood to target tissue.

Disclosure of Interest P.-P. Tak Employee of: GlaxoSmithKline, Stevenage, United Kingdom, M. Doorenspleet: None declared, M. de Hair: None declared, P. Klarenbeek: None declared, M. van Beers-Tas: None declared, A. van Kampen: None declared, D. van Schaardenburg: None declared, D. Gerlag Employee of: Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, United Kingdom, F. Baas: None declared, N. de Vries: None declared

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