Abstract
IntroductionReconstitution 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).MethodsThirty-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.ResultsSix 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.ConclusionsThe 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.
Highlights
Reconstitution of peripheral blood (PB) B cells after therapeutic depletion with the chimeric anti-CD20 antibody rituximab (RTX) mimics lymphatic ontogeny
The present data support the hypothesis that control of adaptive immune processes involving germinal centrederived, antigen, and T-cell-dependently matured B cells is essential for successful RTX treatment
After 12 months, median C-reactive protein (CRP) concentrations as well as erythrocyte sedimentation rate (ESR) were in the same range as baseline values
Summary
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). B-cell depletion with the chimeric anti-human CD20 IgG1 antibody rituximab (RTX) represents a novel target-specific treatment option [1,2,3] for active rheumatoid arthritis (RA). Despite its specific mode of action on B cells, clinical response to RTX is not restricted to rheumatoid factor (RF)-positive or otherwise autoantibody-positive RA patients [2]. CCP: cyclic citrullinated peptide; CRP: C-reactive protein; DAS28: 28-joint disease activity score; DMARD: disease-modifying antirheumatic drug; ESR: erythrocyte sedimentation rate; EULAR: European League Against Rheumatism, GC: germinal centre; Ig: immunoglobulin; IQR: interquartile range; MemB: memory B cell; PB: peripheral blood; RA: rheumatoid arthritis; RF: rheumatoid factor; RTX: rituximab; TNF: tumour necrosis factor
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