Objectives. An open study of B‐lymphocyte depletion was undertaken in rheumatoid arthritis (RA) patients to test the hypothesis that B lymphocytes may be essential to disease perpetuation.

Methods. Five patients with refractory RA were treated with a monoclonal anti‐CD20 antibody, cyclophosphamide and prednisolone and followed for 12–17 months. Patient 2 received further treatments at 8 and 12 months and patient 4 at 11 months.

Results. At 26 weeks all patients satisfied the American College of Rheumatology ACR50 and patients 1–3 the ACR70 criteria of improvement, without further therapy. Patients 1, 3 and 5 achieved ACR70 at 1 yr and rheumatoid factor (RF) levels fell to normal. In patients 3 and 5, B lymphocytes returned without relapse. Patient 2 relapsed at 28 weeks and patient 4 at 38 weeks, coincident with the return of B lymphocytes in the presence of raised RF levels. Both achieved ACR70 on retreatment. Adverse events were limited to respiratory episodes (two patients) and marginal thrombocytopenia (one patient).

Conclusions. These findings are consistent with the concept that RA is critically dependent on B lymphocytes and suggest that B‐lymphocyte depletion may be a safe and effective therapy.