Transient B cell depletion with the monoclonal anti‐CD20 antibody rituximab has resulted in favorable clinical responses in patients with rheumatoid arthritis (RA). However, little is known about the regeneration profile of different peripheral B cell subpopulations. The aim of this study was to delineate the regeneration profile of different B cell subsets in the peripheral blood after selective anti‐CD20–mediated B cell depletion.

Seventeen patients with RA refractory to standard therapy were treated with rituximab. Patients 1–6 received 4 weekly infusions of rituximab at a dose of 375 mg/m², and patients 7–17 received 2 infusions of rituximab (1,000 mg), 2 weeks apart. Four‐color staining was performed at several time points, using CD38, IgD, and CD27 in addition to other cell surface markers. In one patient, the mutational status of the immunoglobulin receptor was examined.

The analysis revealed a distinct pattern of B cell regeneration. The first wave of repopulating B cells were immature B cells (CD38^high,IgD+,CD10+,CD24^high), the immunoglobulin receptors of which were not yet somatically mutated. In parallel, a recirculation of plasma cells was observed. Later, the number of naive B cells increased, and these cells predominated in the peripheral blood B cell pool. CD27+ memory B cells showed a slow and delayed repopulation, and the level of these cells stayed significantly reduced (<50%) compared with baseline values, for more than 2 years.

Our findings provide evidence for a characteristic regeneration pattern of B cell subpopulations, with long‐lasting modulation of B cell subset composition, after selective anti‐CD20–mediated B cell depletion.