An extra dose of rituximab improves clinical response in rheumatoid arthritis patients with initial incomplete B cell depletion: a randomised controlled trial

Objectives Since clinical non-response to 2x1000mg rituximab has previously been found to be associated with incomplete B cell depletion, we determined, in a randomised controlled proof of concept study, whether patients with initial incomplete B cell depletion would benefit from an additional infusion of rituximab at week 4. Methods Patients with active rheumatoid arthritis despite methotrexate received a first infusion of rituximab 1000mg and were tested for persistent B cells using highly sensitive flow cytometry on day 15. All received a second infusion of 1g (according to license), but patients with persistent B cells were subsequently randomised double-blind to receive, 2weeks later, either a third infusion of 1000mg rituximab or placebo. Clinical response was determined by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) criteria. Results Baseline characteristics were balanced between groups. Treatment with 3x1000mg rituximab resulted in significantly greater depletion (lower B cell and plasmablast numbers between 8 and 28weeks) paralleled by significantly better EULAR and ACR20 response rates at 40weeks (p=0.035 and p=0.027, respectively) and 52weeks (p=0.021 and p=0.043, respectively) compared with 2x1000mg. Immunoglobulin titres remained stable in both arms, and adverse event rates were balanced. Conclusions In rituximab-treated patients with incomplete B cell depletion (predictive of poor response), an extra 1000mg infusion of rituximab at 4weeks produced both better depletion and clinical responses than placebo with no worsening of safety. Degree of depletion is an important, but modifiable, determinant of response.