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Abstract
Background Rituximab (RTX) is an effective treatment for patients with Rheumatoid Arthritis (RA). 1000mg (1 × 1000mg or 2 × 500mg) has similar 6-month efficacy as the registered dose of 2 × 1000mg. Based on several case reports and a case series even lower doses might be sufficient for maintenance treatment, potentially improving safety and decreasing costs.(1)
Objectives To compare effectiveness of RTX retreatment with ultra-low doses (1 × 500mg or 1 × 200mg) to standard low dose (1 × 1000mg).
Methods A 6-month double-blind randomised controlled non-inferiority trial (REDO study (2)) was performed in 5 centres in the Netherlands. Patients with RA responding well to RTX (based on DAS28-CRP<2.9 or clinical judgement) were randomised (1:2:2) to 1 × 1000mg, 1 × 500mg or 1 × 200mg RTX respectively. DAS28-CRP and peripheral CD19+ B-cells were measured at baseline, 3 and 6 months. Primary analysis (per protocol with LOCF) consisted of a hierarchical testing procedure comparing ultra-low doses (1 × 500mg at 3 and 6 months, then 1 × 200mg at 3 and 6 months) to 1 × 1000mg using a non-inferiority margin of 0.6 (on DAS28-CRP). DAS28-CRP change of study groups was compared using linear regression, adjusted for baseline DAS28-CRP, RF/ACPA status and concomitant csDMARD use.
Results The projected inclusion was met (n=142, table 1a). In both ultra-low dose groups 2 patients received an extra dose of 1000mg RTX due to a flare. The 500mg dose was non-inferior to 1000mg at 3 months (-0.04 (95% CI -0.39 to 0.30)), but not at 6 months (0.31 (95% CI -0.05 to 0.68). The 200mg dose was non-inferior to 1000mg at both time points. Because of our pre-defined hierarchical testing, non-inferiority could not formally be inferred for the 200mg dose. Mean DAS28-CRP scores remained low in all groups throughout the study, and B-cell counts decreased similarly at 3 months (figure 1). In the 200mg group, more patients received intramuscular corticosteroid injection(s) compared to the 1000mg group (table 1b).
Conclusion Non-inferiority of retreatment with 1 × 500mg or 1 × 200mg rituximab versus 1 × 1000mg after 6 months could not formally be established. However, ultra-low doses appear similarly effective in the majority of RA patients, judged by DAS28-CRP course over time and B-cell results, with use of slightly more co-medication.
References [1] Shenoy et al. Arthritis Rheumatol 2015;67(suppl 10).
[2] Den Broeder et al. Trials 2017;30;18(1):403.
Disclosure of Interests L.M. Verhoef: None declared, Nathan den Broeder: None declared, R.M. Thurlings Grant/research support from: Congress invitations: Roche, Abbvie, Cellgene, W.H. van der Laan: None declared, W. van der Weele: None declared, Marc Kok: None declared, H.J. Bernelot Moens: None declared, Thasia Woodworth: None declared, Bart van den Bemt Grant/research support from: UCB, Pfizer, Abbvie, Bristol-Myers Squibb, Consultant for: UCB, Novartis and Pfizer, Speakers bureau: Pfizer, AbbVie, UCB, Biogen, Sandoz, Frank van den Hoogen Grant/research support from: Grants, speakers fee, advisory boards: AbbVie, Actelion, Amgen, Boehringer Ingelheim, Biogen, BMS, Celgene, Celltrion Healthcare, Corbus, Janssen, Eli Lilly, Mundipharma, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme., Alfons den Broeder Grant/research support from: Congress invitations: Roche, Cellgene, Abbvie, Biogen, Consultant for: Expert Witness for Fresenius, BI, BMS, Amgen