Research article

Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis

Burkhard Möller¹ , Daniel Aeberli¹ , Stefan Eggli² , Martin Fuhrer¹ , Istvan Vajtai³ , Esther Vögelin⁴ , Hans-Rudolf Ziswiler¹ , Clemens A Dahinden⁵ and Peter M Villiger¹

¹  Clinic for Rheumatology, Clinical Immunology, and Allergology, Inselspital – University Hospital of Bern, Freiburgstraße, Bern 3010, Switzerland

²  Department of Orthopaedic Surgery, Inselspital – University Hospital of Bern, Freiburgstraße, Bern 3010, Switzerland

³  Section of Neuropathology, Institute of Pathology, University of Bern, Murtenstraße 31, Bern 3010, Switzerland

⁴  Department of Orthopaedic, Plastic and Reconstructive and Hand Surgery, Inselspital – University Hospital of Bern, Freiburgstraße, Bern 3010, Switzerland

⁵  Institute of Immunology, Inselspital – University Hospital of Bern, Freiburgstraße, Bern 3010, Switzerland

author email corresponding author email

Arthritis Research & Therapy 2009, 11:R62doi:10.1186/ar2686

Published:	6 May 2009

Abstract

Introduction

Reconstitution of peripheral blood (PB) B cells after therapeutic depletion with the chimeric anti-CD20 antibody rituximab (RTX) mimics lymphatic ontogeny. In this situation, the repletion kinetics and migratory properties of distinct developmental B-cell stages and their correlation to disease activity might facilitate our understanding of innate and adaptive B-cell functions in rheumatoid arthritis (RA).

Methods

Thirty-five 'RTX-naïve' RA patients with active arthritis were treated after failure of tumour necrosis factor blockade in an open-label study with two infusions of 1,000 mg RTX. Prednisone dose was tapered according to clinical improvement from a median of 10 mg at baseline to 5 mg at 9 and 12 months. Conventional disease-modifying antirheumatic drugs were kept stable. Subsets of CD19⁺ B cells were assessed by flow cytometry according to their IgD and CD27 surface expression. Their absolute number and relative frequency in PB were followed every 3 months and were determined in parallel in synovial tissue (n = 3) or synovial fluid (n = 3) in the case of florid arthritis.

Results

Six of 35 patients fulfilled the European League Against Rheumatism criteria for moderate clinical response, and 19 others for good clinical response. All PB B-cell fractions decreased significantly in number (P < 0.001) after the first infusion. Disease activity developed independently of the total B-cell number. B-cell repopulation was dominated in quantity by CD27^-IgD⁺ 'naïve' B cells. The low number of CD27⁺IgD^- class-switched memory B cells (MemB) in the blood, together with sustained reduction of rheumatoid factor serum concentrations, correlated with good clinical response. Class-switched MemB were found accumulated in flaring joints.

Conclusions

The present data support the hypothesis that control of adaptive immune processes involving germinal centre-derived, antigen, and T-cell-dependently matured B cells is essential for successful RTX treatment.