Antineutrophil cytoplasmic antibody associated vasculitides with renal involvement: Open challenges in the remission induction therapy

Table 1 Randomized controlled trials for induction of remission in antineutrophil cytoplasmic antibody associated vasculitides with renal involvement and cyclophosphamide-sparing regimens

Name of the Trial (number of patients)	Inclusion criteria	Treatment groups (drug dose)	Primary end points	Outcome
CYCLOPS[7] (149)	New diagnosis of GPA, MPA, or relapse with renal involvement, creatinine 150–500 μmol/L (1.7- 5.66 mg/dL)	Intravenous pulse CYC (15 mg/kg) vs Daily oral CYC (2 mg/kg)	Remission, Time to relapse	Pulse CYC not inferior to oral CYC Less leucopenia and trend towards more relapses with pulse CYC
CORTAGE[8] (104)	New diagnosis of MPA, GPA, EGPA, PAN and age > 65 yr	Rapid CCS tapering and reduced-dose intravenous pulse CYC (500 mg) vs Standard intravenous pulse CYC (500 mg/m²)	Severe adverse events	Less severe adverse events with reduced immunosuppression, no difference in remission and relapse rates
RAVE[10] (197)	New or relapsing GPA or MPA creatinine ≤ 353.6 μmol/L (4 mg/dL)	RTX (4 × 375 mg/m² infusions) vs Daily oral CYC	Complete remission and cessation of CCS at 6 mo	RTX not inferior to oral CYC, RTX better in patients with relapse than after first diagnosis
RITUXVAS[11] (44)	New diagnosis of AAV and severe renal involvement	RTX (4 × 375 mg/m² infusions) plus two intravenous pulses of CYC vs intravenous pulse CYC only	Sustained remission	RTX not inferior to pulse CYC

AAV: Antineutrophil cytoplasmic antibody associated vasculitides; CYC: Cyclophosphamide; RTX: Rituximab; CCS: Corticosteroids; GPA: Granulomatosis with polyangiitis; MPA: Microscopic polyangiitis; EGPA: Eosinophilic granulomatosis with polyangiitis; PAN: Polyarteritis nodosa.

Table 2 Current guidelines in the remission induction therapy for antineutrophil cytoplasmic antibody associated vasculitides with severe renal involvement

KDIGO recommendations[23]

Initial treatment of pauci-immune focal and segmental necrotizing GN with or without systemic vasculitis, and with or without circulating ANCA:

We recommend that CYC and CCS be used as initial treatment (1A) We recommend that RTX and CCS be used as an alternative initial treatment in patients without severe disease or in whom CYC is contraindicated (1B) We recommend the addition of PLEX for patients requiring dialysis or with rapidly increasing sCr (1C)

Treatment of relapse

We recommend treating patients with severe relapse of ANCA vasculitis (life- or organ threatening) according to the same guidelines as for the initial therapy (1C)

EULAR/ERA-EDTA recommendations[26]

For remission-induction of new-onset organ-threatening or life threatening AAV we recommend treatment with a combination of CCS and either CYC or RTX

CYC: Level of evidence 1A for GPA and MPA; grade of recommendation A; strength of vote 100%

RTX: Level of evidence 1B for GPA and MPA; grade of recommendation A; strength of vote 82%

For a major relapse of organ-threatening or life-threatening disease in AAV we recommend treatment as per new disease with a combination of CCS and either CYC or RTX

CYC: Level of evidence 1A for GPA and MPA; grade of recommendation A; strength of vote 88%

RTX: Level of evidence 1B for GPA and MPA; grade of recommendation A; strength of vote 94%

PLEX should be considered for patients with AAV and a serum creatinine level of > 500 mmol/L (5.7 mg/dL) due to rapidly progressive glomerulonephritis in the setting of new or relapsing disease. Level of evidence 1B; grade of recommendation B; strength of vote 77%

AAV: Antineutrophil cytoplasmic antibody associated vasculitides; KDIGO: Kidney disease improving global outcomes; EULAR: European league against rheumatism; ERA-EDTA: European renal association-european dialysis and transplant association; GN: Glomerulonephritis; GPA: Granulomatosis with polyangiitis; MPA: Microscopic polyangiitis; CYC: Cyclophosphamide; RTX: Rituximab; CCS: Corticosteroids; PLEX: Plasma exchange.

Table 3 Trials for induction of remission in antineutrophil cytoplasmic antibody associated vasculitides with renal involvement and corticosteroids-sparing regimens

Name of the Trial (number of patients)	Inclusion criteria	Treatment groups (drug dose)	Primary end points	Outcome
LoVAS[71] (140)	New clinical diagnosis of MPA or GPA, Age > 20 yr, eGFR > 15 mL/min	Low-dose CCS (0.5 mg/kg per day tapered and off within 6 mo) plus RTX vs High-dose CCS (1.0 mg/kg per day tapered to 10 mg/d within 6 mo) plus RTX	Proportion of the patients achieving remission at 6 mo (BVAS = 0 and CCS < 10 mg)	Ongoing trial (NCT02198248)
PEXIVAS[69] (704)	New or previous clinical diagnosis of MPA or GPA, Age > 15 yr, eGFR < 50 mL/min	without PLEX: normal versus reduced CCS vs with PLEX: normal versus reduced CCS (reduced dose regimen provides approximately 55% of the standard dose regimen over the first 6 mo)	All-cause mortality and ESRD at 2 yr	Ongoing trial (NCT00987389)
CLEAR[73] (67)	New or previous clinical diagnosis of MPA or GPA, Age > 18 yr, eGFR > 20 mL/min	Placebo plus 60 mg prednisone vs Avacopan (30 mg x 2/d) plus 20 mg prednisone vs Avacopan (30 mg x 2/d) without prednisone	Safety of Avacopan in subjects with AAV over the 12-wk treatment period	Avacopan can replace high-dose CCS efficiently and safely in patients with newly diagnosed or relapsing AAV
ADVOCATE[75] (300)		Avacopan in combination with RTX or CYC/AZA vs Prednisone in combination with RTX or CYC/AZA	The proportion of patients achieving disease remission at 26 wk	Ongoing trial (NCT02994927)

AAV: Antineutrophil cytoplasmic antibody associated vasculitides; GPA: Granulomatosis with polyangiitis; MPA: Microscopic polyangiitis; CYC: Cyclophosphamide; AZA: Azathioprine; RTX: Rituximab; CCS: Corticosteroids; PLEX: Plasma exchange; eGFR: Estimated glomerular filtration rate; ESRD: End-stage renal disease; BVAS: Birmingham vasculitis activity score.

Table 4 New agents investigated in preclinical models and clinical trials in humans for antineutrophil cytoplasmic antibody associated vasculitides with renal involvement

Agent	Therapeutic target	Preclinical models	Human trials
Avacopan	Complement C5a receptor inhibitor	Mice[72]	CLEAR, a phase II trial, Status: Completed[73] CLASSIC, a phase II trial, Status: Completed[74] ADVOCATE, a phase III trial, Status: Recruiting (NCT02994927)[75]
Bortezomib	Proteasome inhibitor	Mice[76]	Not available
Fostamatinib	Spleen tyrosine kinase (Syk) inhibitor	Mice[79]	Not available
Anakinra	Interleukin-1 receptor antagonist (IL-1Ra)	Mice[80]	Not available
Gusperimus	NF-κB translocalization inhibition in leucocytes IFNγ, IL-6, IL-10 production reduction	Mice[82]	Phase II trials[83-85] Status: Completed
Alemtuzumab	Anti-CD52 humanized antibody inducing T-cell and macrophages depletion	Not available	Phase II trial[86] Status: Completed