A RANDOMISED DOUBLE-BLIND PLACEBO CONTROLLED TRIAL ON THE EFFECTS OF INCREASED DOSE RITUXIMAB IN PATIENTS WITH INITIAL INCOMPLETE DEPLETION – THE EXTENDED TREATMENT WITH RITUXIMAB IN RHEUMATOID ARTHRITIS (EXTRRA) TRIAL

Background: Rituximab is licensed for rheumatoid arthritis but a significant proportion fail to achieve a EULAR response after standard therapy of 2 x 1g. Using highly sensitive flow cytometry (HSFC), we have previously shown that 95% of patients without EULAR response at 6 months have incomplete B cell depletion after the first infusion of rituximab and often after both [1]. Objectives: To assess the effect of an additional 1g dose of rituximab at 4 weeks in patients with incomplete depletion during standard therapy. Methods: Patients with active RA (DAS28 > 3.2) despite methotrexate who had received an initial dose of 1g RTX were evaluated at 2 weeks using HSFC as previously described. Patients with persistent circulating B cells were randomised 1:1 to either 2 further infusions of 1g RTX or 1 infusion of 1g RTX and 1 infusion of placebo. All patients received 100mg methylprednisolone prior to the first 2 infusions only. Clinical response was assessed using DAS28 and EULAR criteria and B cells were measured by HSFC at weeks 0, 2, 8, 12, 16, 28, 40. Patients that relapsed (rise in DAS28 > 0.6) were retreated and categorised as non-responders at subsequent timepoints. Continuous variables were compared using Mann Whitney U, and categorical variables using Chi Square test. Results: 12 patients received 3g and 13 received 2g. Efficacy and safety data is available from all patients up to 9 months. At baseline mean DAS28 was 5.75, mean HAQ 1.57, mean methotrexate dose 20mg, mean previous DMARDs 2.94 and 28% of patients had previously received anti-TNF agents. There were no substantive differences in these characteristics between groups. B cell depletion: B cell numbers were lower at all timepoints after rituximab in patients that received 3g. The proportions of patients with detectable B cells by HSFC (>0.0001 x 109/L) for 2g and 3g RTX groups respectively were 77 and 50% at 8wks, 54 and 33% at 12wks, 84 and 33% at 16wks (p=0.009); 100 and 92% at both 28wks and 40wks. Clinical Response: Patients that received 3g RTX had significantly higher EULAR response rate at 40wks. Mod/Good response was achieved by 10/13(77%) and 11/12 (92%) after 2g and 3g respectively at 26 wks (ns), and 7/13(54%) and 11/12(92%) at 40wks (p = 0.035). 12 month data are available from 20 patients and show EULAR mod/good response in 3/11(27%) and 6/9 (67%) after 2g and 3g respectively (p = 0.078). Safety: At 9 months there were a total of 46 and 40 AEs in the 2g and 3g groups respectively. There was 1 SAE (fracture, 3g). There was no significant difference in immunoglobulin titres between groups and no patient had IgG below lower limit of normal. Conclusion: In patients with incomplete B cell depletion, as determined by HSFC, clinical response is improved by a higher dose of rituximab than is currently standard. These results indicate that not only is B cell depletion important in determining clinical response, but it can be enhanced by increasing the dose of rituximab. HSFC enables targeting of therapy by adjusting doses to individual patients for better responses to B cell depletion. References: 1. Dass S et al. Arthritis Rheum. 2008 Oct;58(10):2993-9. Disclosure of Interest: E. Vital Grant/Research Support from: Roche, Speakers Bureau: Roche, S. Dass Grant/Research Support from: Roche, Speakers Bureau: Roche, M. Buch Grant/Research Support from: Roche, Speakers Bureau: Roche, F. Atzeni: None Declared, F. Ponchel: None Declared, A. Rawstron: None Declared, P. Emery Grant/Research Support from: Roche, Consultant for: Roche, Speakers Bureau: RocheCitation: Annals of the Rheumatic Diseases, volume 69, supplement 3, year 2010, page 147Session: Update on non-antiTNF biologic treatment in RA (Oral Presentations )