Pulse Versus Daily Oral Cyclophosphamide for Induction of Remission in Antineutrophil Cytoplasmic Antibody—Associated Vasculitis

A Randomized Trial

  1. Kirsten de Groot, MD;
  2. Lorraine Harper, MD, PhD;
  3. David R.W. Jayne, MD, PhD;
  4. Luis Felipe Flores Suarez, MD, PhD;
  5. Gina Gregorini, MD;
  6. Wolfgang L. Gross, MD;
  7. Rashid Luqmani, MD;
  8. Charles D. Pusey, MD, PhD;
  9. Niels Rasmussen, MD;
  10. Renato A. Sinico, MD;
  11. Vladimir Tesar, MD, PhD;
  12. Philippe Vanhille, MD;
  13. Kerstin Westman, MD, PhD;
  14. Caroline O.S. Savage, MD, PhD; and
  15. for the EUVAS (European Vasculitis Study Group)
  1. From Klinikum Offenbach, Offenbach, Germany; University of Birmingham, Birmingham, United Kingdom; Addenbrooke's Hospital, Cambridge, United Kingdom; Instituto National de Ciencias Medicas y Nutrition, Mexico City, Mexico; Spedali Civili and University of Brescia, Brescia, Italy; University of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; University of Oxford, Oxford, United Kingdom; Imperial College of London, London, United Kingdom; Rigshospitalet, Copenhagen, Denmark; Ospedale San Carlo Borromeo, Milan, Italy; Charles University, Prague, Czech Republic; Centre Hospitalier, Valenciennes, France; and University Hospital Malmö, Malmö, Sweden.

    Abstract

    Background: Current therapies for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis are limited by toxicity.

    Objective: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission.

    Design: Randomized, controlled trial. Random assignments were computer-generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment.

    Setting: 42 centers in 12 European countries.

    Patients: 149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease.

    Intervention: Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone.

    Measurement: Time to remission (primary outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes).

    Results: Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87.7%). Thirteen patients in the pulse group and 6 in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11 to 22.5 g] vs. 8.2 g [interquartile range, 5.95 to 10.55 g]; P < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23 to 0.71]).

    Limitations: The study was not powered to detect a difference in relapse rates between the 2 groups. Duration of follow-up was limited.

    Conclusion: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia.

    Primary Funding Source: The European Union.

    Article and Author Information

    • Note: Drs. de Groot and Harper contributed equally to the manuscript.

    • Acknowledgment: The authors thank the trial administrator, Lucy Jayne, Cambridge, United Kingdom, and Peter Nightingale, Wellcome Trust Clinical Research Facility, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

    • Grant Support: By the European Union (European Community Systemic Vasculitis Trial project, contract nos. BMH1-CT93-1078 and CIPD-CT94-0307, and Associated Vasculitis European Randomised Trial project, contract nos. BMH4-CT97-2328 and IC20-CT97-0019).

    • Potential Financial Conflicts of Interest: None disclosed.

    • Reproducible Research Statement: Study protocol: Available at http://www.vasculitis.org/protocols/CYCLOPS.pdf. Statistical code: Available from Dr. Harper (e-mail, L.harper{at}bham.ac.uk). Data set: Available to approved individuals through written agreements with the steering committee of the EUVAS network (contact Dr. Harper; e-mail, L.harper{at}bham.ac.uk).

    • Requests for Single Reprints: Lorraine Harper, MD, PhD, School of Immunity and Infection, College of Medical and Dental Sciences, Birmingham University, Birmingham B15 2TT, United Kingdom; e-mail, L.harper{at}bham.ac.uk.

    • Current Author Addresses: Dr. de Groot: Department of Nephrology and Rheumatology, Klinikum Offenbach GmbH, Starkenburgring 66, 63069 Offenbach/Main, Germany.

    • Drs. Harper and Savage: Division of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

    • Dr. Jayne: Renal Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, United Kingdom.

    • Dr. Flores Suarez: Instituto National de Ciencias Medicas y Nutrition, Salvador Zubiran Vasco de Quiroga 15, Colonia Seccion XVI, Tlalpan C.P. 14000, Mexico D.F., Mexico.

    • Dr. Gregorini: Department of Nephrology, Spedali Civili di Brescia, Piazza le Spedali Civili, 1, 25123 Brescia, Italy.

    • Dr. Gross: Department of Rheumatology, University of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.

    • Dr. Luqmani: Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD, United Kingdom.

    • Dr. Pusey: Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, Ducane Road, London W12 0HS, United Kingdom.

    • Dr. Rasmussen: Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

    • Dr. Sinico: Renal and Clinical Immunology Unit, Ospedale San Carlo Borromeo, Via Pio II, 3 - 20153 Milan, Italy.

    • Dr. Tesar: Department of Nephrology, Charles University, Celetná 13, 116 36, Praha 1, Prague, Czech Republic.

    • Dr. Vanhille: Centre Hospitalier De Valenciennes, Avenue Désandrouin, 59300 Valenciennes, France.

    • Dr. Westman: Department of Nephrology and Transplantation, Malmö University Hospital, 205 02 Malmö, Sweden.

    • Author Contributions: Conception and design: K. de Groot, D.R.W. Jayne, R. Luqmani, C.D. Pusey, N. Rasmussen, R.A. Sinico, C.O.S. Savage.

    • Analysis and interpretation of the data: K. de Groot, L. Harper, D.R.W. Jayne, W.L. Gross, C.D. Pusey, N. Rasmussen, V. Tesar, K. Westman, C.O.S. Savage.

    • Drafting of the article: K. de Groot, L. Harper, D.R.W. Jayne, R. Luqmani, C.O.S. Savage.

    • Critical revision of the article for important intellectual content: K. de Groot, L. Harper, D.R.W. Jayne, L.F. Flores Suarez, W.L. Gross, R. Luqmani, C.D. Pusey, N. Rasmussen, R.A. Sinico, K. Westman, C.O.S. Savage.

    • Final approval of the article: K. de Groot, L. Harper, D.R.W. Jayne, L.F. Flores Suarez, G. Gregorini, W.L. Gross, R. Luqmani, C.D. Pusey, N. Rasmussen, R.A. Sinico, C.O.S. Savage.

    • Provision of study materials or patients: D.R.W. Jayne, L.F. Flores Suarez, G. Gregorini, W.L. Gross, R. Luqmani, V. Tesar, P. Vanhille, K. Westman, C.O.S. Savage.

    • Statistical expertise: D.R.W. Jayne.

    • Obtaining of funding: K. de Groot, D.R.W. Jayne, C.D. Pusey, N. Rasmussen.

    • Administrative, technical, or logistic support: K. de Groot, D.R.W. Jayne, N. Rasmussen.

    • Collection and assembly of data: K. de Groot, L. Harper, D.R.W. Jayne, L.F. Flores Suarez, R.A. Sinico.

    • ClinicalTrials.gov registration number: NCT00430105.

    Responses to this article

    • Is pulse cyclophosphamide superior to a daily regimen for induction of remission in ANCA vasculitis
      • Hiroshi Oiwa and
      • Kazuhiko Kumagai, and Eiji Sugiyama
      Ann Intern Med published online November 5, 2009
    • Re: In response
      • R. Brooks Robey
      Ann Intern Med published online October 26, 2009
    • In response
      • lorraine Harper and
      • Kirsten de groot, Caroline O. Savage
      Ann Intern Med published online October 26, 2009
    • CYCLOPS: Worth the wait?
      • R. Brooks Robey and
      • John A. Kelly, and Thomas H. Taylor
      Ann Intern Med published online October 26, 2009
      • Lee A Hebert
      Ann Intern Med published online October 26, 2009
    • Approaches on ANCA-Associated Vasculitis Therapy
      • Francisco Ramirez-Lafita and
      • Adolf Duran MD, Belinda Garcia MD (Tecnatom Medical Dept)
      Ann Intern Med published online October 26, 2009
    • Re: Daily oral cyclophosphamide in ANCA associated vasculitis
      • Stuart M. Levine
      Ann Intern Med published online October 26, 2009
    • Daily oral cyclophosphamide in ANCA associated vasculitis
      • Prasanta Padhan
      Ann Intern Med published online October 26, 2009
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