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Open Access Research article

Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity

YK Onno Teng1*, Gillian Wheater2, Vanessa E Hogan3, Philip Stocks3, EW Nivine Levarht1, Tom WJ Huizinga1, Rene EM Toes1 and Jacob M van Laar3

Author Affiliations

1 Department of Rheumatology, C1-R, Leiden University Medical Center, PO Box 9600, NL-2300 RC Leiden, The Netherlands

2 Department of Biochemistry, The James Cook University Hospital, Marton Road, Middlesbrough, Cleveland, TS4 3BW, UK

3 Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor Cookson Building, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

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Arthritis Research & Therapy 2012, 14:R57  doi:10.1186/ar3770

Published: 12 March 2012

Abstract

Introduction

B-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA). Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial. The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells.

Methods

In this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients.

Results

Fixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium. Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella). This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion.

Conclusion

By studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion. This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells.