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

Nephrol Dial Transplant. 2016 Sep;31(9):1453-9. doi: 10.1093/ndt/gfw211. Epub 2016 May 30.


Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT 00128895.

Trial registration: ClinicalTrials.gov NCT00128895.

Keywords: ANCA; maintenance therapy; proteinase 3; relapse; vasculitis.

Publication types

  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / drug therapy*
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / epidemiology
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / immunology*
  • Antibodies, Antineutrophil Cytoplasmic / immunology*
  • Azathioprine / therapeutic use*
  • Cyclophosphamide / therapeutic use
  • Female
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Incidence
  • Male
  • Middle Aged
  • Myeloblastin / immunology*
  • Netherlands / epidemiology
  • Recurrence
  • Remission Induction
  • Standard of Care
  • Young Adult


  • Adrenal Cortex Hormones
  • Antibodies, Antineutrophil Cytoplasmic
  • Immunosuppressive Agents
  • Cyclophosphamide
  • Myeloblastin
  • Azathioprine

Associated data

  • ClinicalTrials.gov/NCT00128895