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

Table 2

Maintenance therapy trials of ANCA-associated vasculitis discussed in this article.

	Trial	Therapy	Study type	Population	Doses	Outcomes
CYC	CYCAZAREM trial (2003) [45]	CYC vs. AZA	RCT	Newly diagnosed generalized ANCA-associated vasculitis after induction with GC and oral CYC. ()	CYC: 1.5 mg/kg/day for 12 months; AZA: 2 mg/kg/day for 12 months; Both arms received after AZA until month 12	No difference in relapse and adverse events at 18 months of follow-up
MMF	IMPROVE trial (2010) [47]	AZA vs. MMF	RCT	Newly diagnosed GPA or MPA after induction with GC and CYC. ()	AZA: 2 mg/kg/day for 12 months, then 1.5 mg/kg/day for 6 months, and 1 mg/kg/day until month 42; MMF: 2000 mg/day for 12 months, then 1500 mg for 6 months, and 1000 mg until month 42	At median follow-up of 39 months: increased incidence of first relapse in the MMF group compared to AZA; increased incidence of first major relapse in the MMF group compared to AZA
MTX	WEGENT trial (2008) [43]	MTX vs. AZA	RCT	Newly diagnosed GPA or MPA with positive serologic or histological ANCA, after induction with GC and CYC	AZA: 2 mg/kg/day for 12 months; MTX: 0.3 mg/kg/week (oral or subcutaneous), progressively increasing to 25 mg/week for 12 months	At median follow-up of 29 months: No difference in adverse reactions and relapses ()
	WEGENT trial—long term (2016) [44]					At 10 years: no significant difference in relapse-free survival ()
AZA	REMAIN trial (2017) [46]	Prolonged AZA treatment for maintenance	RCT	Newly diagnosed GPA or MPA or renal-limited vasculitis after induction with GC and CYC ()	Maintenance with AZA and prednisone low dose for 24 vs. 48 months	Significant reduction of relapse with 48 months of treatment compared to 24 months; ANCA positivity at randomization associated with relapse risk
Rituximab	MAINRITSAN trial (2014) [52]	RTX vs. AZA	RCT	Newly diagnosed or relapse of severe GPA or MPA or renal-limited vasculitis in complete remission after induction therapy with GC and CYC ()	RTX: 500 mg IV at days 0 and 14 and then at months 6, 12, and 18 (total 18 months); AZA: 2 mg/kg/day for 12 months, 1.5 mg/kg/day for 6 months, and then 1 mg/kg/day for 4 months (total: 22 months)	At 28 months of follow-up: less relapses with RTX
	MAINRITSAN-1—60 months (2018) [53]					At 60 months: improved survival and increased major relapse-free survival with RTX
	MAINRITSAN-2 (2018) [54]	Fixed RTX vs. individualized	RCT	Newly diagnosed or relapsing severe GPA or MPA in complete remission after induction therapy with GC and CYC or RTX ()	Fixed: 500 mg IV at days 0 and 14 and then at 6, 12, and 18 months; Individualized: 500 mg IV at randomization and then reinfusion only if reappearance of CD19 or ANCA or increased titer of ANCA; measured every 3 months, until month 18	Median of 5 vs. 3 infusions in 2 years, respectively; At 28 months of follow-up: no significant difference in relapse rate; ANCA and CD19 measured every 3 months do not predict relapse
	MAINRITSAN-3 (2020) [55]	RTX 2 vs. 4 years	RCT	Newly diagnosed or relapsing severe GPA or MPA in complete remission following the completion of MAINRITSAN-2 trial ()	Four additional 500 mg IV doses of RTX: at inclusion, months 34, 40, and 46 vs. placebo	At 56 months: relapse-free survival rates superior with RTX with no difference in severe adverse events
	RITAZAREM; Abstract (2019) [56]	RTX vs. AZA	RCT	Maintenance therapy after a major relapse of GPA or MPA after induction with GC+RTX ()	RTX: 1000 mg IV every 4 months x 5 doses; AZA: 2 mg/kg/day	At 24 months of follow-up: RTX superior to AZA to prevent relapses
Belimumab	BREVAS trial (2019) [58]	Belimumab vs. placebo	RCT	Newly diagnosed or relapsing severe GPA or MPA after induction with GC and either CYC or RTX ()	All patients: AZA (2 mg/kg/day) and low-dose GC; Belimumab: 10 mg/kg IV on days 0, 14, and 28 and then every 28 days vs. placebo of belimumab	At 12 months: no difference in vasculitis relapse; No relapsing disease in patients receiving RTX followed by belimumab
	COMBIVAS	Belimumab+RTX vs. RTX alone	RCT	Patients with PR3-positive AAV ()	Rituximab: 1 g IV x 2 doses (all patients); Belimumab group: 200 mg sc q week	Results expected in 2023
Prednisone	TAPIR trial	Low-dose prednisone	Open label	GPA in remission ()	All patients tapered to 5 mg of daily prednisone and then randomized; Prednisone: 5 mg daily; No prednisone: taper to 0 mg	Results pending; Endpoint: rate of relapse being the endpoint at 6 months after randomization
	MAINEPSAN trial	Low-dose prednisone	RCT	Patients with GPA or MPA in remission, 12 months following induction therapy	Prednisone: continue 5 mg daily for 12 months; No prednisone: taper to 0 mg in 1 month	Recruiting in France

Abbreviations: ANCA = antineutrophil cytoplasmic antibody; AZA = azathioprine; CYC = cyclophosphamide; GC = glucocorticoids; GPA = granulomatosis with polyangiitis; GFR = glomerular filtration rate; GN = glomerulonephritis; IV = intravenous; MMF = mycophenolate mofetil; MPA = microscopic polyangiitis; q = every; RCT = randomized controlled trial; RTX = rituximab; sc = subcutaneous.