Repeated B-cell depletion with rituximab in rheumatoid arthritis

Thirty-seven patients have been recruited to a programme of repeated B-cell depletion therapy for rheumatoid arthritis. Protocols have been based on rituximab, combined with cyclophosphamide initially. Sixty-two treatments have been given over 4.5 years. Patients were withdrawn for inadequate response (< ACR20), for successful reintroduction of disease-modifying antirheumatic drug (DMARD) or for toxicity.

Twenty-five patients continue on the programme with evidence of response, and a further three patients have regained control on reintroduction of DMARD (methotrexate, sulphasalazine). All four IgM rheumatoid factor-negative patients failed to respond. One seropositive patient achieved no benefit, and two achieved benefit of 5 months or less. Two patients have been lost to follow-up. The mean period of benefit (> ACR20) was 15 months, with a maximum of 35 months. One patient showed inadequate depletion. Secondary failure of clinical response or depletion was not observed in up to four repeat treatments. Coexistent psoriasis on three patients showed no change.

B-cell depletion protocols were well tolerated. Eight febrile episodes with pulmonary symptoms occurred in 85 patient-years of follow-up. All settled rapidly on antibiotic. Although most were assumed infective, at least four may have been late reactions to therapy or been disease associated. One suspected joint prosthesis infection was sterile on culture. Three patients who received rituximab in combination with cyclophosphamide have developed breast carcinoma (two patients) or carcinoma in situ (one patient), although in one case there was evidence that this predated therapy. (No increase in the incidence of carcinoma has been reported in surveillance of rituximab usage elsewhere.) In three cases who have received three courses of therapy in rapid succession, serum IgM levels have fallen to undetectable during the period of depletion. Falls in IgG levels have been modest and antibacterial antibody levels well maintained.

In summary, experience with repeated B-cell depletion therapy in rheumatoid arthritis suggests that approximately 80% of seropositive patients may become susceptible to continuing control of disease, but seronegative disease appears unresponsive. Secondary resistance appears not to be a problem over 2–4 years. Susceptibility to chest infection may be increased. Cumulative effects on immunoglobulin levels may occur with frequently repeated usage.