Update in the Management of ANCA-Associated Vasculitis: Recent Developments and Future Perspectives

Table 1

Induction therapy studies of ANCA-associated vasculitis discussed in this article.

	Trial	Treatment	Study type	Population	Treatment	Outcomes
CYC	CYCLOPS trial (2009) [25]	CYC daily oral vs. CYC IV	RCT	Newly diagnosed severe GPA or MPA with renal involvement	IV CYC: 15 mg/kg weeks 0, 2, and 4 then q3 weeks continued for 3 months after remission (maximum 1200 mg IV/dose); Oral CYC: 2 mg/kg/day until remission then 1.5 mg/kg/day x 3 months (maximum oral dose of 200 mg)	At 9 months: no difference in time to remission with a lower rate of leukopenia and reduced cumulative dose with IV CYC ()
	CYCLOPS trial—long term (2012) [26]					At 4.3 years of median follow-up: significantly lower relapses with oral CYC; no difference in mortality or renal survival ()
MTX	NORAM study (2005) [40]	MTX vs. CYC	RCT	Newly diagnosed GPA or MPA without critical organ manifestations ()	Oral CYC: 2 mg/kg/day until remission (3-6 months) and then 1.5 mg/kg/day until month 10 and discontinued by month 12; Oral MTX: 20-25 mg/week for 12 months and then discontinued	At 6 months: MTX noninferior for remission rate; delayed remission in patients with more extensive disease; At 18 months: increased relapses with MTX
MMF	MYCYC (2019) [42]	CYC vs. MMF	RCT	Newly diagnosed GPA or MPA excluding severe disease ()	CYC: IV pulse CYC 15 mg/kg q2-3 weeks for 6 months; MMF: 2 g/day increased to 3 g/day (if required) for 3-6 months; Both groups received AZA 2 mg/kg daily as maintenance therapy	At 6 months: MMF noninferior for remission; At 18 months: more disease relapses with MMF compared to CYC, especially in PR3-ANCA patients
Rituximab	RITUXVAS trial (2010) [28]	RTX vs. CYC	RCT	Newly diagnosed generalized GPA or MPA with renal involvement; ()	RTX: 375 mg/m^2 IV weekly x 4 (patients received IV CYC 15 mg/kg x 2 doses at weeks 0 and 3); CYC: 15 mg/kg IV × 3 to 6 months and then AZA	At 12 months: no significant difference in sustained remissions, SAE, and deaths
	RAVE trial (2010) [29]	RTX vs. CYC	RCT	Newly diagnosed or severe relapse of GPA or MPA with positive ANCA ()	RTX: 375 mg/m^2 IV q week x 4; Oral CYC: 2 mg/kg/day x 3-6 months until remission and then AZA (2 mg/kg/day)	At 6 months: RTX noninferior for remission ( and successful completion of prednisone tapering); At 6 months: RTX superior for relapsing vasculitis or PR3-positive patients
	RAVE trial—long term (2013) [30]					At 18 months: RTX noninferior for remission ()
Reduced GC	Glucocorticoid (Pepper et al.) (2018) [22]	Standard vs. reduced GC	Multicenter cohort study	Active MPO- or PR3-ANCA vasculitis or ANCA-negative pauci-immune GN ()	Induction therapy with two doses of RTX and three months of low-dose pulse IV CYC followed by short course (1 to 2 weeks) of GC	Similar outcomes to a matched population from the EUVAS trials, with lower exposure to CYC and GC
	CycLowVas (2019) [20]	CYC+RTX+reduced GC	Single-center cohort study	Renal ANCA-associated vasculitis (excluding alveolar hemorrhage, cerebral vasculitis, ) ()	RTX: 1000 mg IV at day 0 and day 14; CYC: 10 mg/kg IV weekly for 2 weeks, followed by 500 mg IV weekly for 4 weeks (total of 6 doses); Reduced prednisone: rapid taper reaching 12.5 mg/day at week 12	At median follow-up of 56 months: reduced risk of death, progression to ESRD, and reduced relapses
Plasma exchange	MEPEX trial (2007) [34, 63]	PLEX vs. MP	RCT	Newly diagnosed severe renal GPA or MPA ()	PLEX: 7 treatments (60 mL/kg) in 14 days followed by standard therapy (CYC+prednisone); MP: 1000 mg IV per day x 3 days followed by standard therapy	At 3 and 12 months: more survivors free of dialysis with plasma exchange; No difference in long-term survival at 3 months, 12 months, and 4 years
	PEXIVAS trial (2020) [19]	PLEX and reduced GC	RCT	Newly diagnosed or severe relapse of GPA or MPA with positive ANCA ()	Four study groups in a 2-by-2 factorial design receiving; (i)-PLEX (7 treatments in 14 days) vs. no PLEX; (ii)-Standard GC doses (PEXIVAS) vs. reduced GC (PEXIVAS-reduced)	Up to 7 years of follow-up, no difference in death from any cause or ESRD
Avacopan	CLEAR trial (2017) [37]	Avacopan vs. prednisone	RCT	Newly diagnosed or relapsing GPA or MPA ()	All groups: standard induction therapy (CYC or RTX); Control group: avacopan placebo+prednisone 60 mg daily; Study group: avacopan 30 mg twice daily+prednisone 20 mg daily; Study group: avacopan 30 mg twice daily, no prednisone	At 12 weeks: avacopan treatment with or without prednisone was noninferior to the control group in achieving disease remission
	ADVOCATE trial; Abstract (2020) [39]	Avacopan vs. prednisone	RCT	ANCA MPA or GPA patients receiving RTX or CYC/AZA; ()	All patients: RTX (375 mg/m^2 weekly for 4 weeks) or CYC orally (2 mg/kg daily for 14 weeks) or IV (15 mg/kg every 2 to 3 weeks for 13 weeks, maximum of 1.2 g/dose), followed by 1 to 2 mg/kg of AZA at week 15; Prednisone: 60 mg (taper over 21 weeks); Avacopan: 30 mg orally twice daily for 52 weeks	At week 26: noninferior remission rate in the avacopan group compared to prednisone; At 52 weeks: noninferiority and superiority for sustained remission in the avacopan arm
Abatacept	ABROGATE	Abatacept vs. placebo	RCT	Relapsing nonsevere GPA ()	Abatacept: 125 mg sc q week vs. abatacept placebo	Results expected in 2023

Abbreviations: ad = until; ANCA = antineutrophil cytoplasmic antibody; AZA = azathioprine; CYC = cyclophosphamide; ESRD = end-stage renal disease; GC = glucocorticoid; GFR = glomerular filtration rate; GN = glomerulonephritis; GPA = granulomatosis with polyangiitis; IV = intravenous; MMF = mycophenolate mofetil; MP = methylprednisolone; MPA = microscopic polyangiitis; MTX = methotrexate; q = every; PLEX = plasma exchange; RCT = randomized controlled trial; RTX = rituximab; SAE = severe adverse events; sc = subcutaneous; vs. = versus; x = times.