title: Treatment of systemic necrotizing vasculitides in patients aged sixty-five years or older: results of a multicenter, open-label, randomized controlled trial of corticosteroid and cyclophosphamide-based induction therapy.
abstract: OBJECTIVE
  To investigate a new therapeutic strategy, with rapid corticosteroid dose tapering and limited cyclophosphamide (CYC) exposure, for older patients with systemic necrotizing vasculitides (SNVs; polyarteritis nodosa [PAN], granulomatosis with polyangiitis [Wegnener's] [GPA], microscopic polyangiitis [MPA], or eosinophilic GPA [Churg-Strauss] [EGPA]).
  
  
  METHODS
  A multicenter, open-label, randomized controlled trial comprising patients ≥65 years old and newly diagnosed as having SNV was conducted. The experimental treatment consisted of corticosteroids for ∼9 months and a maximum of six 500-mg fixed-dose intravenous (IV) CYC pulses, every 2-3 weeks, then maintenance azathioprine or methotrexate. The control treatment included ∼26 months of corticosteroids for all patients, combined with 500 mg/m(2) IV CYC pulses, every 2-3 weeks until remission, then maintenance for all patients with GPA or MPA and for those with EGPA or PAN with a Five-Factors Score (FFS) of ≥1. Randomization used a 1:1 ratio computer-generated list and was performed centrally with sealed opaque envelopes. The primary outcome measure was ≥1 serious adverse event (SAE) occurring within 3 years of followup. Secondary outcome measures included remission and relapse rates.
  
  
  RESULTS
  Among the 108 patients randomized, 4 were excluded (early consent withdrawal or protocol violation). Mean ± SD age at diagnosis was 75.2 ± 6.3 years. Analysis at 3 years included 53 patients (21 GPA, 21 MPA, 8 EGPA, and 3 PAN) in the experimental arm and 51 patients (15 GPA, 23 MPA, 6 EGPA, and 7 PAN) in the conventional arm. In total, 32 (60%) versus 40 (78%) had ≥1 SAE (P = 0.04), most frequently infections; 6 (11%) versus 7 (14%) failed to achieve remission (P = 0.71); 9 (17%) versus 12 (24%) died (P = 0.41); and 20 (44%) of 45 versus 12 (29%) of 41 survivors in remission experienced a relapse (P = 0.15).
  
  
  CONCLUSIONS
  For older SNV patients, an induction regimen limiting corticosteroid exposure and with fixed low-dose IV CYC pulses reduces SAEs in comparison to conventional therapy, and does not affect the remission rate. Three-year relapse rates remain high for both arms.
authors.affiliation: National Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Hôpital Cochin, AP-HP, and Université Paris Descartes, Paris,, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Pagnoux
authors.forename: Thomas
authors.initials: T
authors.lastname: Quéméneur
authors.forename: Jacques
authors.initials: J
authors.lastname: Ninet
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Diot
authors.forename: Xavier
authors.initials: X
authors.lastname: Kyndt
authors.forename: Benoît
authors.initials: B
authors.lastname: de Wazières
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Reny
authors.forename: Xavier
authors.initials: X
authors.lastname: Puéchal
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: le Berruyer
authors.forename: Olivier
authors.initials: O
authors.lastname: Lidove
authors.forename: Philippe
authors.initials: P
authors.lastname: Vanhille
authors.forename: Pascal
authors.initials: P
authors.lastname: Godmer
authors.forename: Olivier
authors.initials: O
authors.lastname: Fain
authors.forename: Daniel
authors.initials: D
authors.lastname: Blockmans
authors.forename: Boris
authors.initials: B
authors.lastname: Bienvenu
authors.forename: Florence
authors.initials: F
authors.lastname: Rollot
authors.forename: Séverine
authors.initials: S
authors.lastname: Aït el Ghaz-Poignant
authors.forename: Alfred
authors.initials: A
authors.lastname: Mahr
authors.forename: Pascal
authors.initials: P
authors.lastname: Cohen
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
authors.forename: Elodie
authors.initials: E
authors.lastname: Perrodeau
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravaud
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillevin
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D012074:Remission Induction / Q000379:methods*; D056647:Systemic Vasculitis / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D003520:Cyclophosphamide; D001379:Azathioprine; D008727:Methotrexate