Article
Impact of different dosages of rituximab in combination with leflunomide as retreatment on efficacy and safety measurements in patients with rheumatoid arthritis (AMARA-study)
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Authors
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Frank Behrens
- Johann Wolfgang Goethe University & Fraunhofer IME-TMP, Frankfurt, Germany, Frankfurt, Germany
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Michaela Köhm
- Abteilung Rheumatologie, Universitätsklinikum Frankfurt & Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Frankfurt/Main
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Tanja Rossmanith
- Klinische Forschung, Fraunhofer IME, Projektgruppe Translationale Medizin und Pharmakologie (TMP), Frankfurt am Main, Frankfurt am Main
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Stephanie Dauth
- Fraunhofer IME Projektgruppe TMP, Frankfurt
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Rieke H.-E. Alten
- Schlossparkklinik, Akademisches Lehrkrankenhaus der Charité - Universitätsmedizin Berlin, Innere Medizin II, Rheumatologie, klinische Immunologie und Osteologie, Berlin
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Gerd-Rüdiger Burmester
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Eugen Feist
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Martin Aringer
- Universitätsklinikum "Carl Gustav Carus" an der Technischen Universität Dresden, Medizinische Klinik III, Rheumatologie, Dresden
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Klaus Krüger
- Praxiszentrum, München
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Ulf Müller-Ladner
- Justus-Liebig-Universität Gießen, Kerckhoff-Klinik GmbH, Rheumatologie u. klinische Immunologie, Osteologie, Physikalische Therapie, Bad Nauheim
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Andrea Rubbert-Roth
- Universitätsklinikum Köln, Klinik I für Innere Medizin, Köln
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Siegfried Wassenberg
- Rheumazentrum Ratingen, Ratingen
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Hans-Peter Tony
- Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Schwerpunkt Rheumatologie und klinische Immunologie, Würzburg
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Herbert Kellner
- Schwerpunktpraxis für Rheumatologie und Gastroenterologie, München
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Marina Backhaus
- Park-Klinik Weissensee, Abteilung für Innere Medizin - Rheumatologie und Klinische Immunologie, Berlin
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Harald Louis Burkhardt
- Klinikum der Johann Wolfgang Goethe-Universität, Medizinische Klinik II, Rheumatologie, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Frankfurt/Main
| Published: | September 4, 2017 |
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Outline
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Background: In Rheumatoid Arthritis (RA) treatment with biologics such as Rituximab (RTX) is effective, but often only licensed in combination with methotrexate (MTX). Different dosing strategies for RTX-retreatment are applied in routine care. The aim of this placebo(PLA)-controlled multicenter German RCT was to demonstrate safety and efficacy of the combinational treatment of RTX and leflunomide (LEF) as well as to compare the effectiveness of different RTX-dosages as retreatment at week 24.
Methods: 189 RA-patients with active disease (DAS28>3.2 and at least 3 swollen, 3 tender joints) on stable LEF-therapy were screened for this two-parted study: Patients were randomized to receive either two times 1000mg RTX for 24-weeks (part I) followed by two times 1000mg RTX (RTX-RTXhigh) or 500mg (RTX-RTXlow; part II) or PLA (part I) followed by two times 1000mg RTX (PLA-RTX high) or 500mg (PLA-RTX low; part II) combined with ongoing LEF-treatment. Change in DAS28 at week 52 was used as primary endpoint. Disease activity was assessed at every visit. Frequency and severity of adverse events were documented.
Results: 148 patients were randomized (mean age 56 years, mean body weight 76 kg, 74% female). Baseline characteristics were similar between the treatment groups (baseline DAS28 of 5.57 for the RTX-group and 5.54 for the PLA-group). For part I ACR20 and 50 values showed superior response in the RTX vs PLA group at week 16 with 51.6% vs 23.4% and 31.2% vs 14.9%. For patients who were treated with RTX in part I and retreated with high or low doses of RTX at week 24 no differences were observed with a mean change of DAS28 at week 52 of -2.46 and -2.42. For patients of the PLA-group in part I, a clear difference in DAS28 was detected between 1000mg and 500mg RTX in part II (mean change of -2.68 and -2.32, respectively). Within the 52-week study period 372 adverse events (AEs) were observed, 14 of them classified as severe (10 in RTX and 4 in PLA).
Conclusion: Part I of this RCT demonstrated significant efficacy of RTX and LEF co-treatment compared to PLA. Retreatment with high or low doses of RTX only made a difference on efficacy in patients who received PLA in part I. No difference in efficacy levels after 52-weeks of treatment were detected within the group with high and low dosages of RTX both parts. This illustrates the importance of two times 1000mg RTX as induction therapy while retreatment with lower dose seems equally effective. The safety profile of RTX and LEF combination was reasonable.
