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The peripheral blood is the only compartment that matters for B cell depletion

The peripheral blood is the only compartment that matters for B cell depletion. Dr Edward Vital University of Leeds, Leeds Teaching Hospitals Trust, Leeds, UK. Introduction. Rituximab effective in RA, but responses variable

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The peripheral blood is the only compartment that matters for B cell depletion

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  1. The peripheral blood is the only compartment that matters for B cell depletion Dr Edward Vital University of Leeds,Leeds Teaching Hospitals Trust, Leeds, UK

  2. Introduction • Rituximab effective in RA, but responses variable • Roles of B cells in RA include production of pathogenic antibodies and/or interaction with T cells • Autoantibody positivity required for response, but significance of reduction titres unclear • Explanation for variable responses needed: • To select patients for treatment • To guide strategies to treat non-responding patients • To guide future therapy development

  3. Breedveld F et al. J Clin Pharmacol 2007;47:1119-28

  4. Synovial B cell depletion is incomplete All patients with synovial depletion hada EULAR response Synovial CD20 score Before rituximab 6 months after rituximab Dass S et al. Arthritis Rheum 2008;58:2993-9

  5. Synovial biopsy studies • Thurlings et al. • Biopsies at 0, 4 and 16 weeks • Reduction in synovial B cells precedes clinical response and changes in other cells types • B cells significantly reduced, but not completely depleted • Plasma cells persisted in non-responders • Kavanaugh et al. • Biopsies at 0 and 8 weeks • B cells significantly reduced but not completely depleted • Trend to more reduction in responders • Teng et al. • Biopsies at 0 and 12 weeks • Complete synovial CD20cy depletion • Patients with good response had lower CD79a and CD138 at baseline Thurlings RM et al. Ann Rheum Dis 2008;67:917-25; Kavanaugh A et al. Ann Rheum Dis 2008;67:402-8; Teng YK et al. Arthritis Rheum 2007;56:3909-18

  6. What represents complete depletion of B cells? • If not <0.005 x 109/L, are standard approaches insufficiently sensitive to measure B cell depletion? B cells = 0.005 x 109/L 10 000 events Dass S et al. Arthritis Rheum 2008;58:2993-9

  7. What represents complete depletion of B cells? • Are standard approaches sufficiently sensitive to measure B cell depletion? B cells = 0.005 x 109/L 500 000 events Dass S et al. Arthritis Rheum 2008;58:2993-9

  8. High sensitivity flow cytometry: Six-colour approach Dass S et al. Arthritis Rheum 2008;58:2993-9

  9. B cell response to rituximab therapy Conventional flow cytometry Highly Sensitive flow cytometry Absolute count (109/L) 1 1 0.1 0.1 0.01 0.01 0.005 0.001 Before treatment Before 2nd infusion After treatment Before treatment Before 2nd infusion After treatment 0.0001 Dass S et al. Arthritis Rheum 2008;58:2993-9

  10. Highly sensitive flow cytometry reveals incomplete depletion in more patients Conventional flow Highly sensitive flow 100 80 60 Patients (%) 40 20 0 2 weeks 6 weeks 3 months 6 months 9 months 12 months Pretreatment Dass S et al. Arthritis Rheum 2008;58:2993-9

  11. Initial depletion predicts clinical response (1) EULAR moderate or good response rate 100 90 80 70 Depletion after first infusion 60 Patients (%) Complete depletion 50 Partial depletion 40 30 20 10 0 3 months 6 months 9 months 12 months Dass S et al. Arthritis Rheum 2008;58:2993-9

  12. Fast depletion Slow depletion Incomplete depletion Initial depletion predicts clinical response (2) EULAR moderate or good response rate 100 Depletion after first infusion 90 80 70 60 50 Patients (%) 40 30 20 10 0 3 months 6 months 9 months 12 months Dass S et al. Arthritis Rheum 2008;58:2993-9

  13. Summary SYNOVIUM • Incomplete B cell depletion • Persistence of B lineage cells in non-responders PERIPHERAL BLOOD • Conventional flow cytometry: 100% complete depletion • Highly sensitive flow cytometry: • Variable depletion • Correlates with synovial B cells • 95% non-responders have incomplete B cell depletion REPOPULATION • 85% of patients have B cells by 6 months • Always precedes relapse

  14. Conclusions • Failure to respond to rituximab is explained by failure to deplete B lineage cells in blood and synovium • Highly sensitive flow cytometry is a useful tool to interpret response to rituximab therapy • In clinical practice may assume that B cells are present in all patients who • Fail to respond to rituximab • Relapse after an initial response • Initial non-responders to rituximab benefit from retreatment • Depletion enhanced • Clinical responses enhanced

  15. Acknowledgements B cell group Ed Vital Shouvik Dass Maya Buch Andy Rawstron Frederique Ponchel Paul Emery Study Coordination Christine Thomas Flow Cytometry Karen Henshaw Clinical Support Domini Bryer

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