Classification, diagnosis and treatment of ANCA-associated vasculitis

Table 1 Randomized controlled trials in patients with antineutrophil cytoplasmic antibody-associated vasculitis[51]

Trial (n)	Inclusion criteria	Treatment groups (dose)	Primary end-points	Outcome
Induction of remission
NORAM (100)	New diagnosis of GPA or MPA, and creatinine < 150 μmol/L	Methotrexate (0.3 mg/kg once weekly) vs daily oral cyclophosphamide	Remission Time to relapse	Methotrexate not inferior to cyclophosphamide Time to relapse shorter with methotrexate
CYCLOPS (149)	New diagnosis of GPA, MPA, or relapse with renal involvement, creatinine 150-500 μmol/L	Intravenous pulse cyclophosphamide (15 mg/kg) vs daily oral cyclophosphamide (2 mg/kg)	Remission Time to relapse	Pulse cyclophosphamide not inferior to oral cyclophosphamide Less leucopenia and trend towards more relapses with pulse cyclophosphamide
RITUXVAS (44)	New diagnosis of AAV and severe renal involvement	Rituximab (four 375 mg/m² infusions) plus two intravenous pulses of cyclophosphamide, vs intravenous pulse cyclophosphamide only	Sustained remission	Rituximab not inferior to pulse cyclophosphamide
RAVE (198)	New or relapsing GPA or MPA	Rituximab (4 × 375 mg/m² infusions) vs daily oral cyclophosphamide	Complete remission and cessation of glucocorticoids at 6 mo	Rituximab not inferior to oral cyclophosphamide Rituximab better in patients with relapse than after first diagnosis
MEPEX (137)	New diagnosis of GPA or MPA and creatinine > 500 μmol/L	Plasma exchange and oral cyclophosphamide vs 3 × intravenous methylprednisolone pulse and oral cyclophosphamide	Renal survival at 3 mo	Better renal survival with plasma exchange 24% risk reduction for ESRD with plasma exchange
MYCYC (140)	New diagnosis of GPA, MPA and major organ involvement	Mycophenolate mofetil (2-3 g daily) vs intravenous pulse cyclophosphamide (15 mg/kg)	Remission at 6 mo Relapse	Preliminary data: noninferiority not proven for mycophenolate mofetil vs pulse cyclophosphamide
CORTAGE (104)	New diagnosis of MPA, GPA, EGPA, PAN and age > 65 yr	Rapid glucocorticoid tapering and reduced-dose intravenous pulse cyclophosphamide (500 mg) vs standard intravenous pulse cyclophosphamide (500 mg/m²)	Severe adverse events	Preliminary data: less severe adverse events with reduced immunosuppression, no difference in remission and relapse rates
Maintenance of remission
CYCAZAREM (144)	GPA, MPA or relapse and renal or vital organ involvement	Oral azathioprine (2 mg/kg) vs oral cyclophosphamide (1.5 mg/kg daily)	Relapse Adverse events	No difference in relapse
IMPROVE (165)	New diagnosis of GPA or MPA	Oral mycophenolate mofetil (2 g daily) vs oral azathioprine (2 mg/kg)	Time without relapse Adverse events	More relapses with mycophenolate mofetil than azathioprine, trend towards more adverse events with azathioprine
WEGENT (126)	GPA or MPA and renal or multiorgan involvement	Methotrexate (0.3 mg/kg once weekly) vs azathioprine (2 mg/kg)	Adverse events with consecutive treatment cessation or death	No difference between groups in primary end point and relapses
LEM (54)	Generalized GPA and creatinine < 1.3 mg/dL	Leflunomide (30 mg daily) vs methotrexate (up to 20 mg per week)	Relapse	More relapses with methotrexate than leflunomide, trend towards more adverse events with leflunomide
WGET (174)	GPA and BVAS > 3	Etanercept and methotrexate or cyclophosphamide vs placebo and methotrexate or cyclophosphamide	Sustained remission for > 6 mo	No benefit with etanercept, more cancers in etanercept group

AAV: Antineutrophil cytoplasmic antibody-associated vasculitis; BVAS: Birmingham vasculitis activity score; EGPA: Eosinophilic granulomatosis with polyangiitis; ESRD: End-stage renal disease; GPA: Granulomatosis with polyangiitis; MPA: Microscopic polyangiitis; PAN: Polyarteriitis nodosa.