Background/Purpose: Use of biologicals such as Rituximab (RTX) in Rheumatoid Arthritis (RA) is effective and often only licensed in combination with Methotrexate (MTX). In cases of contraindications to or intolerances of MTX, other cDMARDs are frequently used in routine care without data from RCTs. In addition, in daily practice different strategies for retreatment with RTX are used. The objective of this study was to demonstrate safety and efficacy of RTX in combination with Leflunomide (LEF) and compare effectiveness of therapy for different dosages of RTX as retreatment at week 24 in a multicenter randomized placebo (PLA) controlled clinical trial in Germany.

Methods: A total of 189 patients with active RA (DAS28 > 3.2 and at least 3 SJC and 3 TJC) despite stable LEF treatment were screened for a 52-weeks randomized double-blind placebo controlled multicenter clinical trial, separated into two parts: in part I, patients were randomized to receive either two times 1000mg RTX i.v. followed by two times 1000 (RTX-RTXhigh) or 500 mg (RTX-RTXlow) at week 24 or PLA, followed by a second course of RTX of either two times 1000 (PLA-RTXhigh) or 500 mg(PLA-RTXlow) at week 24 in part II. The primary endpoint of part II of the study for the retreatment was change in DAS28 at week 52. Adult patients who had inadequate response to more than one antiTNF or failed more than three cDMARDs were excluded. Disease activity as well as patient reported outcomes were measured at each visit until week 52. For safety evaluation, frequency and severity of adverse events were documented.

Results: Of 189 screened patients 148 were randomized. The mean age was 56 years; the mean body weight 76 kg and 74% were female. The disease activity (DAS28) at baseline was 5.57 for RTX and 5.54 in the PLA group. All baseline-characteristics were well balanced between the treatment groups. A superior response for ACR 20 and 50 of RTX vs PLA was seen at week 16 in Part I with 51.6% vs 23.4% (p<0.05) and 31.2% vs 14.9% (p<0.05). For retreatment in part II in patients treated with RTX (2x1000mg) (n=60) at baseline no differences were seen for both groups (RTX-RTXhigh and RTX-RTXlow) with a change in DAS 28 to week 52 of -2.46 and -2.42 respectively. In patients who initially responded to placebo and therefore entered Part II (n=24) a clear difference for two times 1000 mg (PLA-RTXhigh) vs two times 500 mg (PLA-RTX low) could be detected with changes in DAS28 to week 52 of -2.68 and -2.32 respectively. A total of 372 adverse events (AE) were observed during the one-year study period, only 14 were classified as severe (10 in RTX and 4 in PLA). 43 serious adverse events were reported, 28 of them in the RTX treatment group during the placebo controlled period.

Conclusion: Here we report for the first time data of a RCT of combination of RTX with LEF. The treatment with RTX in combination with LEF demonstrated significant efficacy compared to PLA in part I. Retreatment with two times 500mg RTX after standard first course of RTX (two times 1000mg) is comparable to two times 1000mg while clear differences were seen after PLA-treatment. This illustrates the importance of two times 1000mg as initial therapy while retreatment with the lower dose seems equally effective after regular induction therapy. The combination of RTX and LEF demonstrated a reasonable safety profile.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/effectiveness-of-different-dosages-of-retreatment-of-rituximab-in-combination-with-leflunomide-results-from-a-multicenter-randomized-placebo-controlled-investigator-initiated-clinical-trial-in-active/