Adding rituximab to background treatment with methotrexate (MTX) was shown to significantly improve disease control in patients with MTX-resistant rheumatoid arthritis (RA), according to a randomized, phase IIb, double-blind, placebo-controlled trial led by Paul Emery, MD, on behalf of the DANCER (Dose-Ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis) study group that was published in the May issue of Arthritis & Rheumatism.¹

"Both doses of rituximab were statistically superior to placebo," co-author Roy Fleischmann, MD, at the University of Texas Southwestern Medical Center in Dallas, told CIAOMed, adding that although "oral and IV glucocorticoids did not add to efficacy, IV glucocorticoids reduced first infusion reactions by approximately 33%."

The investigators randomized 465 patients with moderate or severe RA into nine treatment groups, each of which also included MTX at 10–25 mg/wk. The treatment arms  included placebo, two 500 mg doses of rituximab, or two 1000 mg doses of rituximab. Placebo glucocorticoids (GC), premedication IV GC, or premedication IV GC plus oral GC, were then added to each of these regimens. The premedication dosage was 100 mg methylprednisolone administered prior to rituximab or placebo infusions on days 1 and 15. The oral GC regimen was prednisone 60 mg on days 2–7 and 30 mg on days 8–14.

All patients had a lack of response or loss of response to at least one but not more than five disease-modifying antirheumatic drugs (DMARDs) other than MTX and/or to a biologic response modifier. All DMARDs other than MTX were discontinued at least 4 weeks before randomization.

The primary study endpoint was the proportion of RF-positive patients who achieved an ACR20 response at week 24. Secondary endpoints included ACR50, ACR70, Disease Activity Score (DAS28), fatigue (as measured by the Functional Assessment of Chronic Illness Therapy [FACIT-F] scale), and the Health Assessment Questionnaire Disability Index (HAQ-DI).

"The DANCER trial has confirmed that a single course of rituximab, provided as two infusions, 2 weeks apart, is highly effective over 24 weeks in the treatment of active RA in those who have shown incomplete response to MTX," the investigators write.

Dr. Fleischmann said that larger studies are underway to clarify the dose-response relationship. "It is not yet clear, but possible, that the 1000 mg x 2 schedule produces a longer duration of response and a better depth of response," he said.

Dr. Fleishmann also told CIAOMed that the responses were quite durable beyond the 24 weeks reported in the paper. "Many patients in the study did not require retreatment at 6 months and continued to have a significant clinical response for many months. Studies are currently underway to assess when it is most reasonable to retreat," he said.

Rituximab was first widely used for the treatment of non-Hodgkin's lymphoma (NHL), and RA regimens were adapted from regimens that had been successful in NHL, which included concomitant glucocorticoids. The authors conclude that the current trial "has ... established that glucocorticoids have no significant role in determining the primary endpoint of ACR20 response at 24 weeks in RA patients treated with rituximab, although they may enhance the early response (up to 4 weeks) by virtue of their anti-inflammatory properties. Consequently, the use of glucocorticoids does not appear to be a prerequisite for a clinical response to rituximab."

Reference

1. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment. Results of a phase IIb double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006;54:1390-1400.