PMID- 36958796 OWN - NLM STAT- MEDLINE DCOM- 20230614 LR - 20240320 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 82 IP - 7 DP - 2023 Jul TI - Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial. PG - 937-944 LID - 10.1136/ard-2022-223559 [doi] AB - OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier. CI - (c) Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. FAU - Smith, Rona M AU - Smith RM AUID- ORCID: 0000-0002-7438-5156 AD - Medicine, University of Cambridge, Cambridge, UK rms50@cam.ac.uk. FAU - Jones, Rachel B AU - Jones RB AD - Renal Medicine, Addenbrooke's Hospital, Cambridge, UK. FAU - Specks, Ulrich AU - Specks U AD - Pulmonary Medicine, Mayo Clinic, Rochester, Minnesota, USA. FAU - Bond, Simon AU - Bond S AD - Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. FAU - Nodale, Marianna AU - Nodale M AUID- ORCID: 0000-0002-0333-8918 AD - Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. FAU - Al-Jayyousi, Reem AU - Al-Jayyousi R AD - Nephrology, University Hospitals of Leicester NHS Trust, Leicester, UK. FAU - Andrews, Jacqueline AU - Andrews J AD - NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, UK. FAU - Bruchfeld, Annette AU - Bruchfeld A AD - Nephrology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden. FAU - Camilleri, Brian AU - Camilleri B AD - Nephrology, Ipswich Hospital NHS Trust, Ipswich, UK. FAU - Carette, Simon AU - Carette S AD - Rheumatology, University of Toronto, Toronto, Ontario, Canada. FAU - Cheung, Chee Kay AU - Cheung CK AD - Nephrology, University of Leicester, Leicester, UK. FAU - Derebail, Vimal AU - Derebail V AD - Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. FAU - Doulton, Tim AU - Doulton T AD - Nephrology, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK. FAU - Ferraro, Alastair AU - Ferraro A AD - Nephrology, Nottingham University Hospitals NHS Trust, Nottingham, UK. FAU - Forbess, Lindsy AU - Forbess L AD - Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA. FAU - Fujimoto, Shouichi AU - Fujimoto S AUID- ORCID: 0000-0002-0025-4030 AD - Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. FAU - Furuta, Shunsuke AU - Furuta S AUID- ORCID: 0000-0003-2482-2685 AD - Allergy and Clinical Immunology, Chiba University, Chiba, Japan. FAU - Gewurz-Singer, Ora AU - Gewurz-Singer O AD - Rheumatology, University of Michigan, Ann Arbor, Michigan, USA. FAU - Harper, Lorraine AU - Harper L AUID- ORCID: 0000-0003-1343-9234 AD - Nephrology, University of Birmingham, Birmingham, UK. FAU - Ito-Ihara, Toshiko AU - Ito-Ihara T AD - The Clinical and Translational Research Center, Kyoto Prefectural University of Medicine, Kyoto, Japan. FAU - Khalidi, Nader AU - Khalidi N AUID- ORCID: 0000-0002-8270-2617 AD - Medicine, McMaster University, Hamilton, Ontario, Canada. FAU - Klocke, Rainer AU - Klocke R AD - Rheumatology, Dudley Group of Hospitals NHS Trust, Dudley, UK. FAU - Koening, Curry AU - Koening C AD - Rheumatology, The University of Utah, Salt Lake City, Utah, USA. FAU - Komagata, Yoshinori AU - Komagata Y AD - First Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan. FAU - Langford, Carol AU - Langford C AD - Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA. FAU - Lanyon, Peter AU - Lanyon P AD - Rheumatology, Nottingham University Hospital, Nottingham, UK. FAU - Luqmani, Raashid AU - Luqmani R AD - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science (NDORMs), University of Oxford, Oxford, UK. FAU - McAlear, Carol AU - McAlear C AD - Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. FAU - Moreland, Larry W AU - Moreland LW AD - Medicine/Rheumatology, University of Pittsburg, Pittsburg, Pennsylvania, USA. FAU - Mynard, Kim AU - Mynard K AD - Vasculitis and lupus clinic, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. FAU - Nachman, Patrick AU - Nachman P AD - UNC Kidney Center, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. FAU - Pagnoux, Christian AU - Pagnoux C AD - Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. FAU - Peh, Chen Au AU - Peh CA AD - Nephrology, Royal Adelaide Hospital, Adelaide, South Australia, Australia. FAU - Pusey, Charles AU - Pusey C AD - Medicine, Imperial College London, London, UK. FAU - Ranganathan, Dwarakanathan AU - Ranganathan D AD - Medicine, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia. FAU - Rhee, Rennie L AU - Rhee RL AUID- ORCID: 0000-0002-4907-0304 AD - Rheumatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Spiera, Robert AU - Spiera R AUID- ORCID: 0000-0003-2911-6800 AD - Rheumatology, Hospital for Special Surgery, New York, New York, USA. FAU - Sreih, Antoine G AU - Sreih AG AD - Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. FAU - Tesar, Vladamir AU - Tesar V AD - Medicine, Charles University, Praha, Czech Republic. FAU - Walters, Giles AU - Walters G AUID- ORCID: 0000-0003-4854-9353 AD - Nephrology, Australian National University Medical School, Canberra, Australian Capital Territory, Australia. FAU - Wroe, Caroline AU - Wroe C AD - Nephrology, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK. FAU - Jayne, David AU - Jayne D AUID- ORCID: 0000-0002-1712-0637 AD - Medicine, Addenbrooke's Hospital, Cambridge, UK. FAU - Merkel, Peter A AU - Merkel PA AD - Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. CN - RITAZAREM co-investigators LA - eng SI - ClinicalTrials.gov/NCT01697267 GR - WT_/Wellcome Trust/United Kingdom GR - 19706/VAC_/Versus Arthritis/United Kingdom GR - U54 AR057319/AR/NIAMS NIH HHS/United States GR - U54 RR019497/RR/NCRR NIH HHS/United States PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20230323 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - MRK240IY2L (Azathioprine) RN - 4F4X42SYQ6 (Rituximab) RN - 0 (Immunosuppressive Agents) RN - 8N3DW7272P (Cyclophosphamide) RN - 0 (Antibodies, Antineutrophil Cytoplasmic) SB - IM CIN - Ann Intern Med. 2023 Aug;176(8):JC95. PMID: 37523707 MH - Humans MH - *Azathioprine/therapeutic use MH - Rituximab/therapeutic use MH - Immunosuppressive Agents/therapeutic use MH - *Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy MH - Recurrence MH - Remission Induction MH - Treatment Outcome MH - Cyclophosphamide/therapeutic use MH - Antibodies, Antineutrophil Cytoplasmic PMC - PMC10313987 OTO - NOTNLM OT - B-lymphocytes OT - granulomatosis with polyangiitis OT - rituximab OT - systemic vasculitis OT - therapeutics COIS- Competing interests: RMS reports research grant for the trial from Roche during the conduct of the study. RBJ reports contract with Roche for provision of rituximab for another trial. US reports grants from Genentech, during the conduct of the study. AB has received consulting fees from AstraZeneca, Bayer, ChemoCentryx, Fresenius, and Vifor and honoraria for lectures from AstraZeneca, Bayer, ChemoCentryx, Fresenius, and Vifor. AB sits on the Advisory Board for AstraZeneca and Bayer and is Chair of the Immunonephrology working group of ERA. BC has received honoraria from Astra Zeneca and NAPP Pharmaceuticals. SC is on an advisory board for Sanofi. CKC reports participation in an advisory board for CSL Vifor. VD reports grants from NIDDK/NIH, NIAID/NIH and NHLBI/NIH; royalties from UptoDate; consulting fees from Novartis and Forma Therapeutics; participation on advisory boards for Merck, Forma Therapeutics and Bayer. LF reports grants from Bristol Meyer Squibb and Novartis and consulting fees from Chemocentryx. S Fujimoto reports grants and honoraria from Chugai Pharmaceutical Co., Ltd. S Furuta reports honoraria from Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo, Kissei Pharma, Asahi Kasei Pharma and Eisai. NK reports grants from BMS, Abbvie and Sanofi; consulting fees from Roche and honoraria from AstraZeneca, Kataka Medical, Otsuka, GlaxoSmithKline and Mallinckrodt. CK reports honoraria from Chemocentryx. CL reports grants from Bristol-Myers Squibb, GlaxoSmithKline, AstraZeneca and National Institutes of Health and honoraria from Ohio Association of Rheumatology, McGraw Hill, California Rheumatology Alliance and American Academy of Allergy, Asthma and Immunology. PL reports a research grant from Vifor pharma and consulting fees from Pfizer and is Co-chair, Rare Autoimmune Rheumatic Disease Alliance (RAIRDA), and Rare Diseases Clinical Lead, National Disease Registration Service, NHS Digital. PN has received consulting fees from Chemocentryx and Q32. C Pagnoux has received research grants from Teva, Amgen, Pfizer and Otsuka, consulting fees from Roche, Otsuka and GlaxoSmithKline and honoraria from Roche, GlaxoSmithKline, AstraZeneca and Otsuka and participated on an advisory board for AstraZeneca. C Pusey has received research grants from Kidney Research UK, Wellcome Trust, Medical Research Council, Vasculitis UK and Imperial Health Charity; consulting fees from Vifor and Alentis; honoraria from MedUpdate and Amgen; participation in advisory boards for COMBIVAS and OBIVAS trials. RS has received research grants from Roche-Genentech, AstraZeneca, GlaxoSmithKline, Kadmon, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Novartis, Inflarx and Principia; consulting fees from GlaxoSmithKline, Boehringer Ingelheim, Regeneron, Abbvie, Sanofi, Chemocentryx, Novartis, Galderma, Vera, Chemomab and BMS; honoraria from GlaxoSmithKline, Abbvie, Sanofi, Chemocentryx, Novartis, Galderma and BMS. AS is an employee of Bristol-Myers Squibb. DJ has received grants from AstraZeneca, GlaxoSmithKline and Roche; consulting fees from Astra-Zeneca, Chemocentryx, GSK, Novartis, Otsuka, Takeda, Roche, Vifor; honoraria from GlaxoSmithKline and Vifor; participation on advisory boards for Chinook, GlaxoSmithKline and Takeda and stock options from Aurinia. PM reports research grants from AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, GlaxoSmithKline, Immagene, InfalRx, Jannsen, Jubilant, Kyverna, Magenta, MicroBio, Neutrolis, Novartis, NS Pharma, Otsuka, Q32, Regeneron, Sparrow, Takeda; royalties from UpToDate; Consulting fees from AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, GlaxoSmithKline, immagene, InfalRx, Jannsen, Jubilant, Kyverna, Magenta, MicroBio, Neutrolis, Novartis, NS Pharma, Otsuka, Q32, Regeneron, Sparrow, Takeda; meeting fees from ChemoCentryx and stock options from Kyverna. FIR - Arimura, Dr Y IR - Arimura DY FIR - Clarkson, Dr M IR - Clarkson DM FIR - Zoysa, Dr J de IR - Zoysa DJ FIR - Endo, Dr T IR - Endo DT FIR - Hamano, Dr Y IR - Hamano DY FIR - Kono, Dr H IR - Kono DH FIR - Lawman, Dr S IR - Lawman DS FIR - Muso, Dr E IR - Muso DE FIR - Hajj-Ali, Dr Rula IR - Hajj-Ali DR FIR - Sada, Dr K IR - Sada DK FIR - Smith, Dr R IR - Smith DR FIR - Suzuki, Dr K IR - Suzuki DK FIR - Tsukamoto, Dr T IR - Tsukamoto DT FIR - Uchida, Dr S IR - Uchida DS FIR - Vaglio, Dr A IR - Vaglio DA FIR - Watts, Dr R IR - Watts DR EDAT- 2023/03/24 06:00 MHDA- 2023/06/14 06:42 PMCR- 2023/07/01 CRDT- 2023/03/23 21:02 PHST- 2023/01/22 00:00 [received] PHST- 2023/03/06 00:00 [accepted] PHST- 2023/06/14 06:42 [medline] PHST- 2023/03/24 06:00 [pubmed] PHST- 2023/03/23 21:02 [entrez] PHST- 2023/07/01 00:00 [pmc-release] AID - ard-2022-223559 [pii] AID - 10.1136/ard-2022-223559 [doi] PST - ppublish SO - Ann Rheum Dis. 2023 Jul;82(7):937-944. doi: 10.1136/ard-2022-223559. Epub 2023 Mar 23.