Randomized Controlled Trial

. 2023 Jul;82(7):937-944.

doi: 10.1136/ard-2022-223559. Epub 2023 Mar 23.

Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial

Rona M Smith¹, Rachel B Jones², Ulrich Specks³, Simon Bond⁴, Marianna Nodale⁴, Reem Al-Jayyousi⁵, Jacqueline Andrews⁶, Annette Bruchfeld⁷, Brian Camilleri⁸, Simon Carette⁹, Chee Kay Cheung¹⁰, Vimal Derebail¹¹, Tim Doulton¹², Alastair Ferraro¹³, Lindsy Forbess¹⁴, Shouichi Fujimoto¹⁵, Shunsuke Furuta¹⁶, Ora Gewurz-Singer¹⁷, Lorraine Harper¹⁸, Toshiko Ito-Ihara¹⁹, Nader Khalidi²⁰, Rainer Klocke²¹, Curry Koening²², Yoshinori Komagata²³, Carol Langford²⁴, Peter Lanyon²⁵, Raashid Luqmani²⁶, Carol McAlear²⁷, Larry W Moreland²⁸, Kim Mynard²⁹, Patrick Nachman³⁰, Christian Pagnoux³¹, Chen Au Peh³², Charles Pusey³³, Dwarakanathan Ranganathan³⁴, Rennie L Rhee³⁵, Robert Spiera³⁶, Antoine G Sreih²⁷, Vladamir Tesar³⁷, Giles Walters³⁸, Caroline Wroe³⁹, David Jayne⁴⁰, Peter A Merkel⁴¹; RITAZAREM co-investigators

Collaborators, Affiliations

Collaborators

RITAZAREM co-investigators:
Dr Y Arimura, Dr M Clarkson, Dr J de Zoysa, Dr T Endo, Dr Y Hamano, Dr H Kono, Dr S Lawman, Dr E Muso, Dr Rula Hajj-Ali, Dr K Sada, Dr R Smith, Dr K Suzuki, Dr T Tsukamoto, Dr S Uchida, Dr A Vaglio, Dr R Watts

Affiliations

¹ Medicine, University of Cambridge, Cambridge, UK rms50@cam.ac.uk.
² Renal Medicine, Addenbrooke's Hospital, Cambridge, UK.
³ Pulmonary Medicine, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Nephrology, University Hospitals of Leicester NHS Trust, Leicester, UK.
⁶ NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, UK.
⁷ Nephrology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
⁸ Nephrology, Ipswich Hospital NHS Trust, Ipswich, UK.
⁹ Rheumatology, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Nephrology, University of Leicester, Leicester, UK.
¹¹ Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹² Nephrology, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK.
¹³ Nephrology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹⁴ Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹⁵ Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
¹⁶ Allergy and Clinical Immunology, Chiba University, Chiba, Japan.
¹⁷ Rheumatology, University of Michigan, Ann Arbor, Michigan, USA.
¹⁸ Nephrology, University of Birmingham, Birmingham, UK.
¹⁹ The Clinical and Translational Research Center, Kyoto Prefectural University of Medicine, Kyoto, Japan.
²⁰ Medicine, McMaster University, Hamilton, Ontario, Canada.
²¹ Rheumatology, Dudley Group of Hospitals NHS Trust, Dudley, UK.
²² Rheumatology, The University of Utah, Salt Lake City, Utah, USA.
²³ First Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
²⁴ Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
²⁵ Rheumatology, Nottingham University Hospital, Nottingham, UK.
²⁶ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science (NDORMs), University of Oxford, Oxford, UK.
²⁷ Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
²⁸ Medicine/Rheumatology, University of Pittsburg, Pittsburg, Pennsylvania, USA.
²⁹ Vasculitis and lupus clinic, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
³⁰ UNC Kidney Center, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
³¹ Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
³² Nephrology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
³³ Medicine, Imperial College London, London, UK.
³⁴ Medicine, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
³⁵ Rheumatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁶ Rheumatology, Hospital for Special Surgery, New York, New York, USA.
³⁷ Medicine, Charles University, Praha, Czech Republic.
³⁸ Nephrology, Australian National University Medical School, Canberra, Australian Capital Territory, Australia.
³⁹ Nephrology, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK.
⁴⁰ Medicine, Addenbrooke's Hospital, Cambridge, UK.
⁴¹ Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 36958796
PMCID: PMC10313987
DOI: 10.1136/ard-2022-223559

Randomized Controlled Trial

Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial

Rona M Smith et al. Ann Rheum Dis. 2023 Jul.

. 2023 Jul;82(7):937-944.

doi: 10.1136/ard-2022-223559. Epub 2023 Mar 23.

Authors

Collaborators

RITAZAREM co-investigators:
Dr Y Arimura, Dr M Clarkson, Dr J de Zoysa, Dr T Endo, Dr Y Hamano, Dr H Kono, Dr S Lawman, Dr E Muso, Dr Rula Hajj-Ali, Dr K Sada, Dr R Smith, Dr K Suzuki, Dr T Tsukamoto, Dr S Uchida, Dr A Vaglio, Dr R Watts

Affiliations

¹ Medicine, University of Cambridge, Cambridge, UK rms50@cam.ac.uk.
² Renal Medicine, Addenbrooke's Hospital, Cambridge, UK.
³ Pulmonary Medicine, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Nephrology, University Hospitals of Leicester NHS Trust, Leicester, UK.
⁶ NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, UK.
⁷ Nephrology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
⁸ Nephrology, Ipswich Hospital NHS Trust, Ipswich, UK.
⁹ Rheumatology, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Nephrology, University of Leicester, Leicester, UK.
¹¹ Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹² Nephrology, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK.
¹³ Nephrology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹⁴ Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹⁵ Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
¹⁶ Allergy and Clinical Immunology, Chiba University, Chiba, Japan.
¹⁷ Rheumatology, University of Michigan, Ann Arbor, Michigan, USA.
¹⁸ Nephrology, University of Birmingham, Birmingham, UK.
¹⁹ The Clinical and Translational Research Center, Kyoto Prefectural University of Medicine, Kyoto, Japan.
²⁰ Medicine, McMaster University, Hamilton, Ontario, Canada.
²¹ Rheumatology, Dudley Group of Hospitals NHS Trust, Dudley, UK.
²² Rheumatology, The University of Utah, Salt Lake City, Utah, USA.
²³ First Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
²⁴ Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
²⁵ Rheumatology, Nottingham University Hospital, Nottingham, UK.
²⁶ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science (NDORMs), University of Oxford, Oxford, UK.
²⁷ Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
²⁸ Medicine/Rheumatology, University of Pittsburg, Pittsburg, Pennsylvania, USA.
²⁹ Vasculitis and lupus clinic, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
³⁰ UNC Kidney Center, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
³¹ Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
³² Nephrology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
³³ Medicine, Imperial College London, London, UK.
³⁴ Medicine, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
³⁵ Rheumatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁶ Rheumatology, Hospital for Special Surgery, New York, New York, USA.
³⁷ Medicine, Charles University, Praha, Czech Republic.
³⁸ Nephrology, Australian National University Medical School, Canberra, Australian Capital Territory, Australia.
³⁹ Nephrology, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK.
⁴⁰ Medicine, Addenbrooke's Hospital, Cambridge, UK.
⁴¹ Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 36958796
PMCID: PMC10313987
DOI: 10.1136/ard-2022-223559

Abstract

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.

Keywords: B-lymphocytes; granulomatosis with polyangiitis; rituximab; systemic vasculitis; therapeutics.

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Conflict of interest statement

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.

Figures

**Figure 1**
Consort Diagram for the RITAZAREM trial. ¹Patients not eligible for randomisation remain under long-term follow-up, unless they withdraw consent. ²The full analysis population includes all randomised patients, including those subsequently withdrawn.

**Figure 2**
Probability of relapse-free survival: rituximab compared with azathioprine. Black arrows represent 1000 mg dose of rituximab. Dashed vertical line indicates end of maintenance treatment period and start of the follow-up period per protocol. Shaded areas represent 95% CIs.

**Figure 3**
Multivariate model of clinical predictors for relapse in the RITAZAREM trial. Induction regimen refers to glucocorticoid dose. 1A—1 mg/kg/day starting dose (maximum 60 mg daily); 1B—0.5 mg/kg/day starting dose (maximum 30 mg daily). PR3, proteinase 3; MPO, myeloperoxidase. The estimates are from a multiple regression model that simultaneously adjusts for the treatment and all covariates.

See this image and copyright information in PMC

Comment in

In relapsing AAV with rituximab-induced remission, maintenance rituximab vs. azathioprine reduced relapse at ≥32 mo.
Pisetsky DS. Pisetsky DS. Ann Intern Med. 2023 Aug;176(8):JC95. doi: 10.7326/J23-0057. Epub 2023 Aug 1. Ann Intern Med. 2023. PMID: 37523707

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Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial

Collaborators

Affiliations

Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial

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Abstract

Conflict of interest statement

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