Methotrexate-refractory patients with rheumatoid arthritis (RA) will typically get measurable relief of their symptoms following an infusion of rituximab (Rituxan), according to a multinational team of investigators who reported their findings in the June 17 issue of the New England Journal of Medicine. Rituximab is a biologic therapy typically used to treat B-cell non-Hodgkin's lymphoma.

In a randomized trial comparing oral methotrexate to rituximab monotherapy and two combinations of rituximab combination therapy, methotrexate and cyclophosphamide respectively, the patients receiving rituximab were more likely to have at least a 20 percent improvement according to the American College of Rheumatology criteria (ACR 20) and to have responses measured by the European League Against Rheumatism (EULAR) criteria. In order to be classified as responders according to EULAR criteria, patients must have a significant change in their disease activity score as well as low current disease activity.

The underlying reason for the response seems to be in rituxmab's action against B lymphocytes. "The groups receiving rituximab had profound and prolonged depletion of peripheral-blood B cells, which raises the question of whether these patients may be more susceptible to infection," the authors wrote. "However, at weeks 24 and 48, the overall incidence of infection was similar in the control group and the rituximab groups, with no obvious pattern in types of causative organism."

Although the investigators recommended careful monitoring for infection in future studies, they were also optimistic. "This study provides clear evidence that a single short course of rituximab provides significant, clinically meaningful benefits to patients with active rheumatoid arthritis," they wrote. "Rates of ACR responses were maintained over a prolonged observation period. This finding provides valuable insight into the role of B cells in this progressively disabling disease."

Lead author Jonathan C. W. Edwards, MD, noted that the findings advance the understanding of the pathogenesis of RA. "The study represents a major shift in our understanding of rheumatoid arthritis, [because it indicates] that B lymphocytes and autoantibodies play a central role," he told CiaoMed.

"B lymphocyte depletion appears to be highly effective therapy for a good proportion of patients," he added. "However, it is not clear that it can be repeated over a long period without inducing immunodeficiency. So far we have used it over a five-year period with success, but after three or four cycles antibody levels tend to fall." Dr. Edwards is a professor in connective tissue medicine at University College London in London, United Kingdom.

The investigators recruited 161 patients with active RA despite treatment with methotrexate. The patients were randomized to 1 of 4 treatments: the control therapy, which consisted of at least 10 mg of oral methotrexate per week; 1000 mg of rituximab on days 1 and 15; the study dose of rituximab plus 750 mg of cyclophosphamide on days 3 and 17; and the study doses of rituximab and methotrexate. The study protocol defined responses according to the ACR and EULAR criteria and called for an assessment at 24 and 48 weeks.

At 24 weeks, 43 percent of the patients in the rituximab-methotrexate combination had 50 percent improvement according to the ACR criteria (ACR 50). In the rituximab–cyclophosphamide combination, 41 percent had an ACR 50 response. This proportion of responses was significantly greater than that of the control arm, of which 13 percent had an ACR 50 response (P = 0.005). Further, all groups treated with rituximab had a significantly higher percent of patients with an ACR 20 response, with responses ranging from 65 to 76 percent in the rituximab groups and 38 percent in the control group (P <.025). EULAR responses ranged from 83 to 85 percent in the rituximab groups compared to 50 percent in the control group (P <.004). At week 48 the rituximab–methotrexate group's responses were sustained.

Most adverse events happened at the first rituximab infusion. At 24 weeks, the investigators documented serious infections in 1 patient in the control group (2.5 percent) and in 4 patients in the rituximab groups (3.3 percent). The patients' peripheral-blood immunoglobulin concentrations remained within the normal range throughout the study.

Rituximab should be used with caution in RA patients, Dr. Edwards stressed, and he differentiated it from antitumor necrosis factor (anti-TNF) therapies that are used as disease-modifying antirheumatic drugs (DMARDs). "There may be an increased risk of lower respiratory problems," he said. Also, "the treatment works in a completely different way from other biologics and therefore has to be managed in a completely different way. This is not like a traditional DMARD therapy. ... Physicians should understand the mechanism of B lymphocyte depletion."

For example, physicians treating RA patients need to understand that rituximab's action is confined to seropositive disease. "The treatment is completely different from anti-TNF
therapy in this regard."

The study was supported by Roche, the manufacturers of Rituxan.

Reference

Edwards JCW, Szczepanski L, Szechinski J, et al. Efficacy of B-cell–targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-2581.