title: Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: a randomized clinical trial.
abstract: Cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) positivity at remission has been associated with an increased relapse rate in patients with proteinase 3 anti-neutrophil cytoplasmic antibody-associated vasculitis (PR3-AAV) after a switch to azathioprine maintenance therapy. We therefore hypothesized that extended azathioprine maintenance therapy could reduce the incidence of relapse in this setting.
  
  
  
  Patients newly diagnosed with PR3-AAV at 12 centres in The Netherlands during 2003-11 who received a standardized induction regimen consisting of oral cyclophosphamide and corticosteroids were enrolled (n = 131). Patients were randomized to standard or extended azathioprine maintenance therapy when C-ANCA was positive at the time of stable remission. Standard maintenance treatment consisted of azathioprine (1.5-2.0 mg/kg) until 1 year after diagnosis and subsequent tapering to 25 mg every 3 months. Extended azathioprine maintenance therapy (1.5-2.0 mg/kg) was continued until 4 years after diagnosis and tapered thereafter. The primary endpoint was relapse-free survival at 4 years after diagnosis.
  
  
  
  In patients with PR3-AAV who were C-ANCA positive at the time of stable remission, relapse-free survival at 4 years after diagnosis did not differ significantly between standard azathioprine (n = 24) and extended azathioprine (n = 21) maintenance therapy (P = 0.40). There was also no significant difference in relapse-free survival between patients receiving standard azathioprine (n = 106) versus extended azathioprine maintenance therapy (n = 21; P = 0.94). In addition, there was no difference in the relapse rate between patients with PR3-AAV who were C-ANCA positive (n = 45) at the time of remission versus patients who became C-ANCA negative at the time of remission (n = 82; P = 0.62).
  
  
  
  This randomized trial suggests that extended azathioprine maintenance therapy has only a limited effect on the prevention of relapse in patients with PR3-AAV at 4 years after diagnosis. Moreover, positive C-ANCA status at stable remission was not associated with an increased rate of relapse.
  
  
  
  ClinicalTrials.gov NCT 00128895.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan-Stephan F
authors.initials: JS
authors.lastname: Sanders
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Anoek A E
authors.initials: AA
authors.lastname: de Joode
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ruud G
authors.initials: RG
authors.lastname: DeSevaux
authors.affiliation: Medical Center Leeuwarden, Leeuwarden, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Broekroelofs
authors.affiliation: VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
authors.affiliation: Maastricht University, Maastricht, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: van Paassen
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.affiliation: Maastricht University, Maastricht, The Netherlands.
authors.forename: Jan Willem Cohen
authors.initials: JW
authors.lastname: Tervaert
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Coen A
authors.initials: CA
authors.lastname: Stegeman
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology*; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D001379:Azathioprine / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin / Q000276:immunology*; D009426:Netherlands / Q000453:epidemiology; D012008:Recurrence; D012074:Remission Induction; D059039:Standard of Care; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D019268:Antibodies, Antineutrophil Cytoplasmic; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D053146:Myeloblastin; D001379:Azathioprine
keywords: ANCA; maintenance therapy; proteinase 3; relapse; vasculitis