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08.21 Dominant b-cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis
  1. Paul-Peter Tak1,*,
  2. Marieke E Doorenspleet2,3,
  3. Marjolein J.H. de Hair1,
  4. Paul L Klarenbeek2,3,
  5. Marjan H van Beers-Tas4,
  6. Antoine HC van Kampen5,
  7. Dirkjan van Schaardenburg4,
  8. Danielle M Gerlag1,6,
  9. Frank Baas3,
  10. Niek de Vries2
  1. 1Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
  2. 2Amsterdam Rheumatology and Immunology Centre | Academic Medical Centre, Amsterdam, The Netherlands
  3. 3Department of Genome Analysis, Academic Medical Centre, Amsterdam, The Netherlands
  4. 4Amsterdam Rheumatology and Immunology Centre | Reade, Amsterdam, The Netherlands
  5. 5Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands
  6. 6Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, UK
  7. *currently also: Cambridge University, Cambridge, UK, Ghent University, Ghent, Belgium and GlaxoSmithKline, Stevenage, UK

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. Here we analyse 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 analysed using next-generation BCR sequencing. BCR clones that were expanded beyond 0.5% of the total repertoire were labelled 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.

Conclusion 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.

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