Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis.
BACKGROUND
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.
Möller
Burkhard
B
Clinic for Rheumatology, Clinical Immunology, and Allergology, Inselspital - University Hospital of Bern, Freiburgstrasse, Bern 3010, Switzerland. burkhard.moeller@insel.ch
Aeberli
Daniel
D
Eggli
Stefan
S
Fuhrer
Martin
M
Vajtai
Istvan
I
Vögelin
Esther
E
Ziswiler
Hans-Rudolf
HR
Dahinden
Clemens A
CA
Villiger
Peter M
PM
D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000628:therapy*; D001402:B-Lymphocytes / Q000145:classification / Q000166:cytology* / Q000276:immunology*; D002452:Cell Count / Q000379:methods; D002469:Cell Separation / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007136:Immunoglobulins / Q000096:biosynthesis / Q000145:classification*; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
D007136:Immunoglobulins