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Vasculitis
Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis
  1. Rona M Smith1,2,
  2. Rachel Bronwen Jones2,
  3. Ulrich Specks3,
  4. Simon Bond4,
  5. Marianna Nodale4,
  6. Reem Aljayyousi5,
  7. Jacqueline Andrews6,
  8. Annette Bruchfeld7,
  9. Brian Camilleri8,
  10. Simon Carette9,
  11. Chee Kay Cheung10,
  12. Vimal Derebail11,
  13. Tim Doulton12,
  14. Lindsy Forbess13,
  15. Shouichi Fujimoto14,
  16. Shunsuke Furuta15,
  17. Ora Gewurz-Singer16,
  18. Lorraine Harper17,
  19. Toshiko Ito-Ihara18,
  20. Nader Khalidi19,
  21. Rainer Klocke20,
  22. Curry Koening21,
  23. Yoshinori Komagata22,
  24. Carol Langford23,
  25. Peter Lanyon24,
  26. Raashid Ahmed Luqmani25,
  27. Hirofumi Makino26,
  28. Carole McAlear27,
  29. Paul Monach28,
  30. Larry W Moreland29,
  31. Kim Mynard2,
  32. Patrick Nachman11,
  33. Christian Pagnoux30,
  34. Fiona Pearce31,
  35. Chen Au Peh32,
  36. Charles Pusey33,
  37. Dwarakanathan Ranganathan34,
  38. Rennie L Rhee35,
  39. Robert Spiera36,
  40. Antoine G Sreih37,
  41. Vladimir Tesar38,
  42. Giles Walters39,
  43. Michael H Weisman13,
  44. Caroline Wroe40,
  45. Peter Merkel41,
  46. David Jayne1,2
  47. RITAZAREM coinvestigators
    1. 1 University of Cambridge, Cambridge, UK
    2. 2 Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
    3. 3 Mayo Clinic, Rochester, Minnesota, USA
    4. 4 Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
    5. 5 University Hospitals of Leicester NHS Trust, Leicester, Leicester, UK
    6. 6 NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, UK
    7. 7 Department of Renal Medicine, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden
    8. 8 Ipswich Hospital NHS Trust, Ipswich, UK
    9. 9 University of Toronto, Toronto, Ontario, Canada
    10. 10 University of Leicester, Leicester, UK
    11. 11 University of North Carolina, Chapel Hill, North Carolina, USA
    12. 12 East Kent Hospitals University NHS Foundation Trust, Canterbury, Kent, UK
    13. 13 Cedars-Sinai Medical Center, Los Angeles, California, USA
    14. 14 University of Miyazaki, Miyazaki, Japan
    15. 15 Chiba University, Chiba, Japan
    16. 16 University of Michigan, Ann Arbor, Michigan, USA
    17. 17 University of Birmingham, Birmingham, UK
    18. 18 Kyoto University, Kyoto, Japan
    19. 19 McMaster University, Hamilton, Ontario, Canada
    20. 20 Dudley Group NHS Foundation Trust, Dudley, West Midlands, UK
    21. 21 University of Utah Vasculitis Center, Salt Lake City, Utah, USA
    22. 22 Kyorin University School of Medicine, Tokyo, Japan
    23. 23 Cleveland Clinic Foundation, Cleveland, Ohio, USA
    24. 24 Rheumatology, Nottingham University Hospital, Nottingham, UK
    25. 25 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science (NDORMs), University of Oxford, Oxford, UK
    26. 26 Okayama Universty Hospital, Okayama, Japan
    27. 27 Division of Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
    28. 28 Division of Rheumatology, VA Boston Healthcare System, West Roxbury, Massachusetts, USA
    29. 29 University of Pittsburg, Pittsburg, Pennsylvania, USA
    30. 30 Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
    31. 31 Nottingham University Hospitals NHS Trust, Nottingham, Nottingham, UK
    32. 32 Royal Adelaide Hospital, Adelaide, South Australia, Australia
    33. 33 Imperial College London, London, UK
    34. 34 Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
    35. 35 Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
    36. 36 HSS, New York, New York, USA
    37. 37 University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
    38. 38 Department of Nephrology, Charles University, Prague, Czech Republic
    39. 39 Canberra Hospital, Canberra, Australian Capital Territory, Australia
    40. 40 South Tees Hospitals NHS Foundation Trust, Middlesbrough, Middlesbrough, UK
    41. 41 University of Pennsylvania, Philadelphia, Pennsylvania, USA
    1. Correspondence to Dr Rona M Smith, University of Cambridge, Cambridge, UK; ronasmith{at}doctors.net.uk

    Abstract

    Objectives Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.

    Methods Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.

    Results 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.

    Conclusions This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

    • B cells
    • granulomatosis with polyangiitis
    • treatment
    • systemic vasculitis
    https://creativecommons.org/licenses/by/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

    https://doi.org/10.1136/annrheumdis-2019-216863

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      Footnotes

      • PM and DJ are joint senior authors.

      • Handling editor Josef S Smolen

      • Collaborators Additional RITAZAREM coinvestigators were: Dr Y Arimura (Kyorin University, Japan); Dr M Clarkson (Cork University Hospital, Ireland); Dr J de Zoysa (North Shore Hospital, Auckland, New Zealand); Dr T Endo (Kitano Hospital, Japan); Dr Y Hamano (Tokyo Metropolitan Geriatric Hospital, Japan); Dr H Kono (Teikyo University Hospital, Tokyo, Japan); Dr S Lawman (Brighton Royal Sussex County Hospital, UK); Dr E Muso (Kitano Hospital, Japan); Dr K Sada (Okayama University, Japan); Dr R Smith (Ipswich Hospital, UK); Dr K Suzuki (Teikyo University, Japan); Dr T Tsukamoto (Kitano Hospital, Japan); Dr S Uchida (Teikyo University Hospital, Tokyo, Japan); Dr A Vaglio (University of Parma, Iltaly); and Dr R Watts (Ipswich Hospital, UK).

      • Contributors RMS, DJ and PM conceived and designed the study. US, RBJ and SB were also involved in study design. RMS, SB, NM, DJ and PM analysed the data and interpreted the results. RMS wrote the manuscript with support from DJ and PM. All authors collected data and contributed critical appraisal to the final manuscript.

      • Funding RITAZAREM is funded by grants from Versus Arthritis (formerly Arthritis Research UK) (Grant number 18706) and Roche/Genentech (MA28150). The Vasculitis Clinical Research Consortium (VCRC) (U54 AR057319 and U01 AR5187404) is part of the United States National Institutes of Health Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Science (NCATS). The VCRC is funded through collaboration between NCATS, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and has received funding from the National Center for Research Resources (U54 RR019497). The Research Committee on Intractable Vasculitides, the Ministry of Health, Labour and Welfare of Japan. This research was also supported by the National Institute for Health Research, Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit.

      • Competing interests RMS reports grants from Roche during the conduct of the study. RBJ reports grants from GlaxoSmithKline, personal fees from ChemoCentryx outside the submitted work. US reports grants from Genentech, during the conduct of the study, grants from ChemoCentryx, grants from BMS, grants from GSK, personal fees from Astra Zeneca, outside the submitted work. AB reports grants and personal fees from Astra Zeneca, personal fees from ChemoCentryx, personal fees from Merck/MSD, personal fees from Abbvie outside the submitted work. CKC reports grants from GlaxoSmithKline, grants and consultancy fees from Retrophin outside the submitted work. CL reports grants from Genentech during the conduct of the study. NK reports personal fees and non-financial support from Roche, non-financial support from Bristol Meyers Squibb outside the submitted work. CK reports other from Genentech, other from Roche outside the submitted work. RAL reports grants from Arthritis Research UK, grants from GlaxoSmithKline, grants from MRC, grants from University of Oxford Innovation Fund, grants from Canadian Institutes of Health Research, grants from The Vasculitis Foundation, grants from Celgene, grants from Vifor, personal fees from Grunenthal, personal fees from GSK, personal fees from InflaRx, personal fees from Medpace, personal fees from MedImmune, personal fees from Roche, outside the submitted work. HM reports personal fees from AbbVie, personal fees from Boehringer-Ingelheim, personal fees from Teijin, outside the submitted work. PM reports personal fees from Kiniksa, personal fees from ChemoCentryx, personal fees from Celgene, personal fees from Insmed, outside the submitted work. PN reports other from Chemocentryx, other from InflaRx, other from Omeros, other from Aurinia outside the submitted work. CP reports grants and personal fees from Roche, personal fees from ChemoCentryx, grants and personal fees from GlaxoSmithKline, personal fees from Sanofi, personal fees from InflaRx outside the submitted work. FP reports grants from Vifor pharma outside the submitted work. RS reports grants from GlaxoSmithKline, grants from chemocentryx, grants from Roche/Genentech, grants from BIPI, personal fees from GlaxoSmithKline, personal fees from chemocentryx. RS reports personal fees from Bristol-Myers Squibb, other from Alexion outside the submitted work. VT reports other from Abbvie, other from Amgen, other from Boehringer-Ingelheim, other from Calliditas, other from Chemocentryx, other from FMC, other from Retrophin outside the submitted work. PM reports personal fees from AbbVie, grants and personal fees from AstraZeneca, personal fees from Biogen, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Boeringher-Ingelheim, grants and personal fees from Celgene, grants and personal fees from ChemoCentryx, CSL Behring, grants and personal fees from Genentech/Roche, grants and personal fees from Genzyme/Sanofi, grants and personal fees from GlaxoSmithKline, grants and personal fees from InflaRx, personal fees from Insmed, personal fees from Jannsen, personal fees from Kiniksa, grants from Kypha, personal fees from Sparrow, grants from TerumoBCT outside the submitted work. DJ reports grants from Roche/Genentech, during the conduct of the study; grants from Sanofi-Genzyme, grants and personal fees from Chemocentryx, grants and personal fees from GSK, grants from Roche/Genentech, personal fees from Takeda, personal fees from Insmed, personal fees from Astra-Zeneca, personal fees from Infla-RX, personal fees from Chugai, personal fees from Boehringer-Ingelheim outside the submitted work.

      • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

      • Patient consent for publication Not required.

      • Ethics approval An initial favourable ethical opinion was granted by NRES Committee East of England – Cambridge South: REC reference: 12/EE/0230 on 24 July 2012. US approvals: Cedars-Sinai Medical Center Institutional Review Board: Pro00031367; Cleveland Clinic Institutional Review Board: 13-666; Hospital for Special Surgery Institutional Review Board: 13114; Mount Sinai Hospital Research Ethics Board: 12-0231-A; St. Joseph's Hospital Hamilton Integrated Research Ethics Board: 13-037; University of Pittsburgh Institutional Review Board: PRO13020329; University of Pennsylvania Office of Regulatory Affairs: 816166; The Mayo Clinic, University of Michigan, University of North Carolina and the University of Utah all deferred to the University of Pennsylvania Ethics board and fall under the University of Pennsylvania approval number. Japanese ethics committee numbers: University of Miyazaki 2013-126; Chiba University 97; Kitano Hospital P14-01-002; Okayama University m05002; Kyorin University H26-031; Teikyo University 14-031; TMGH 260201.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Data availability statement Data are available on reasonable request. Deidentified participant data can be requested from the corresponding author.