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Abstract

Background: B cell depletion therapy (BCDT) using rituximab, a monoclonal antibody targeting CD20, was first used for systemic lupus erythematosus (SLE) in 2000 for patients refractory to conventional immunosuppressants. Although the successful use of BCDT has been reported in open label studies randomized controlled trials in SLE have not met their endpoints. SLE is a heterogeneous disease and it is possible that variation in response to BCDT might be due to differences in the rate of B cell repopulation and/or serological and cellular factors in treated patients. The aim of this study was to correlate the repopulation of B cells with disease relapse after BCDT and to identify any differences in B cell numbers and phenotype between patients with active disease according to other disease parameters.

Methods: Fifty-nine patients with refractory SLE treated with BCDT using a combination of rituximab, cyclophosphamide and methylprednisolone were followed up for a minimum of 18 months or until relapse if this occurred within 18 months. Patients were assessed with the ‘classic' British Isles Lupus Assessment Group (BILAG) activity index. Relapse was defined as a new BILAG ‘A’ or two new ‘B’s in any organ system. Anti-dsDNA antibody titres, complement and leukocyte numbers were measured at baseline and relapse. B cell phenotypes were measured at relapse by flow cytometry using the markers CD19, IgD and CD27.

Results: The median time to relapse following BCDT was 16 months. During repopulation B cell numbers remained below baseline numbers for up to 9 months (p < 0.01). B cell numbers (normal range 0.11-0.50 x109 cells/L) increased more rapidly in patients that relapsed (within 18 months) compared to those that remained in remission (p < 0.01). At relapse, B cell numbers were lower than at baseline (p < 0.05). Patients that relapsed with very low B cell numbers (<0.01x109 cells/L) had the lowest B cell numbers at baseline (P < 0.05) and the highest anti-dsDNA antibody titres (normal range 0-50 IU/mL) at relapse (P < 0.05). Relapse with high anti-dsDNA antibody titres (>100 IU/mL) was associated with an increased percentage of IgD-CD27hi switched plasmablasts (p < 0.05) whereas relapse with low anti-dsDNA antibody titres was associated with an increased percentage of IgD-CD27- memory B cells (p < 0.05).

Conclusions: Whilst clinical trials have not confirmed the reported benefit of BCDT in SLE this study shows that early relapse was associated with faster rates of B cell repopulation despite similar levels of depletion. The number of B cells and the B cell phenotype found at relapse differed according to the anti-dsDNA antibody titres. This data suggest that different pathologies might exist in patients with low anti-dsDNA antibody titres compared to those with high titres, possibly governed by specific B cell subsets. Future clinical trials in SLE should take into account serological and cellular variation between patients.

Disclosure statement: D.I. has received honoraria from Roche, Vifor, GlaxoSmithKline, Teva and Merck Serono; these were donated to a local arthritis charity. All other authors have declared no conflicts of interest.

© The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
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RHEUMATOLOGY 2011 ABSTRACTS (WEDNESDAY 13 APRIL 2011)
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