Current and future prospects in the management of granulomatosis with polyangiitis (Wegener’s granulomatosis)

Figures & data

Table 1 Evidence for immunosuppression in GPA, based on disease severity

Clinical phenotype	Immunosuppressive (plus corticosteroids)	Evidence
Early systemic	Methotrexate (minor disease only), or cyclophosphamide or rituximab, plus cotrimoxazole if nasal involvement	NORAM^Citation59,Citation60 RAVE^Citation62,Citation64 Cotrimoxazole^Citation96,Citation97
Generalized	Cyclophosphamide or rituximab	CYCAZAREM^Citation56 CYCLOPS^Citation57,Citation58 RAVE^Citation62,Citation64 RITUXVAS^Citation63
Severe	Cyclophosphamide or rituximab (given with 2 doses of cyclophosphamide in RITUXVAS trial) plus plasma exchange	RITUXVAS^Citation63 MEPEX^Citation69,Citation70
Major relapse	Cyclophosphamide or rituximab (rituximab more effective in RAVE trial)	RAVE^Citation62,Citation64
Refractory disease	Rituximab Intravenous immunoglobulin	Roll et al^Citation73 Jayne et al^Citation74; Martinez et al^Citation75
	Infliximab	Booth et al^Citation78; Lamprecht et al^Citation127
	Alemtuzumab	Walsh et al^Citation76
	Mycophenolate mofetil	Joy et al^Citation79
	15-deoxyspergualin	Birck et al^Citation77
Maintenance therapy	Azathioprine or methotrexate (or rituximab – currently under evaluation) mycophenolate mofetil, leflunomide	CYCAZAREM^Citation56 IMPROVE^Citation84 WEGENT^Citation85 German Network Study^Citation87 MAINRITSAN^Citation90

Abbreviations: GPA, granulomatosis with polyangiitis; CYCAZAREM, Cyclophosphamide vs azathioprine for early remission phase of vasculitis; CYCLOPS, Randomized trial of daily oral versus pulse cyclophosphamide as therapy for ANCA-associated systemic vasculitis; MEPEX, Methylprednisolone versus Plasma Exchange; NORAM, Nonrenal wegener’s Granulomatosis Treated Alternatively with Methotrexate; RAVE, Rituximab in ANCA-Associated Vasculitis; RITUXVAS, Rituximab Versus Cyclophosphamide in ANCA-Associated Vasculitis; ANCA, anti-neutrophil cytoplasm antibody; MAINRITSAN, Efficacy Study of Two Treatments in the Remission of Vasculitis; WEGENT, Wegener’s Granulomatosis-entretien/Maintenance; ANCA, anti-neutrophil cytoplasm antibody; IMPROVE, international Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides.

Table 2 Short-term side effects and long-term damage associated with treatment in GPA

Drug	Short-term side effects	Long-term damage (% affected at long-term follow-up)
Corticosteroids	Weight gain	Hypertension, 41.5%*
	Skin thinning	Osteoporosis, 14.1%*
	Purpura	Avascular necrosis, 0.7%*
	Striae	Cataract, 9.3%*
	Muscle weakness	Angina/CABG, 8.1%*
	Diabetes	Stroke, 3.7%*
	Insomnia	Muscle atrophy, 7.4%*
	Mood disturbance
	Psychosis
	Bacterial infection
Cyclophosphamide	Neutropenia	Gonadal failure, 4.1%*
	Lymphopenia	Bone marrow failure, 3%*
	Bacterial infection	Hypogammaglobulinemia^Citation128
	Pneumocystis jirovecii pneumonia	Bladder cancer (SIR 2.4)^Citation47
	Hemorrhagic cystitis	Myeloid leukemia (SIR 3.2)^Citation47
	Teratogenicity	Nonmelanoma skin cancer (SIR 2.8)^Citation47
Rituximab	Infection	Progressive multifocal leukoencephalopathy (rare <1:10,000)^Citation92
	Allergic reactions
	Reactivation of hepatitis B (check status before starting)	Hypogammaglobulinemia (repeated dosesor prior immunosuppression)^Citation128
Azathioprine (check TPMT before starting)	Lymphopenia	Associated with nonmelanoma skin cancer^Citation108,Citation109
	Liver blood test abnormalities
	Rash
	Infection
Methotrexate (avoid if eGFR <30 mL per minute)	Nausea/gastrointestinal side effects	Lung injury (<1%)^Citation129
	Abnormal liver blood tests	Liver injury (unusual if liver tests monitored and action taken if abnormal)
	Macrocytosis
	Leukopenia
	Infection
	Teratogenicity
Mycophenolate mofetil	Gastrointestinal upset	Not clear whether risk of skin or lymphoproliferative malignancy increased
	Leukopenia
	Infection
	Teratogenicity

Note:

* Evidence from the European Vasculitis Study Group trial data.⁴⁸

Abbreviations: CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; GPA, granulomatosis with polyangiitis; SIR, standardized incidence ratio; TPMT, thiopurine methyltransferase.

Table 3 Completed multicenter randomized controlled studies of induction therapy in AAV

Induction trials	Indication	Induction (trial)	Induction (control)	Maintenance	Primary endpoint	Brief results
NORAM^Citation59,Citation60	Newly diagnosed GPA or MPA, with early systemic involvement	Oral Mtx + Pred (n=51)	Oral Cyc + Pred (n=49)	Oral Cyc/Mtx + Pred	Remission at 6 months	Mtx noninferior to oral Cyc. Later follow-up showed more relapses and more corticosteroid treatment in the Mtx group
CYCLOPS^Citation57,Citation58	GPA or MPA with renal involvement but serum creatinine <500 μmol/L	iv Cyc + Pred (n=76)	Oral Cyc + Pred (n=73)	Aza + Pred	Time to remission	IV Cyc non inferior to oral Cyc. Later results showed higher relapse rates with IV Cyc but no difference in mortality
MEPEX^Citation69,Citation70	Severe renal GPA or MPA with serum creatinine >500 μmol/L	Plex + oral Cyc + Pred (n=70)	Methyl Pred + oral Cyc + Pred (n=67)	Aza + Pred	Dialysis independence at 3 months	Renal survival better with Plex, but no difference in long-term mortality
RITUXVAS^Citation63	Newly diagnosed GPA or MPA with renal involvement	Rtx + Pred + IV Cyc × 2 doses (n=33)	IV Cyc + Pred (n=11)	Pred alone or Aza + Pred	Sustained remission at 12 months and adverse event rates	Rtx noninferior to IV Cyc; no difference in adverse event rate
RAVE^Citation62,Citation64	New or relapsing GPA or MPA (excluding serum creatinine >4.0 mg/dL, or PH	Rtx + Pred (n=99)	Oral Cyc + Pred (n=98)	Nil or Aza without Pred	Remission without Pred at 6 months	Rtx noninferior to oral Cyc. Rtx more effective than Cyc in relapsing patients

Abbreviations: AAV, anti-neutrophil cytoplasm antibody-associated small vessel vasculitides; Mtx, methotrexate; Cyc, cyclophosphamide; Pred, oral prednisone or prednisolone; Methyl pred, methylprednisolone; IV, intravenous; Aza, azathioprine; Rtx, rituximab; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; Plex, plasma exchange; CYCLOPS, Randomized trial of daily oral versus pulse cyclophosphamide as therapy for ANCA-associated systemic vasculitis; MEPEX, Methylprednisolone versus Plasma Exchange; NORAM, Nonrenal Wegener’s Granulomatosis Treated Alternatively with Methotrexate; RAVE, Rituximab in ANCA-Associated Vasculitis; RITUXVAS, Rituximab Versus Cyclophosphamide in ANCA-Associated Vasculitis; ANCA, anti-neutrophil cytoplasm antibody; PH, pulmonary hemorrhage.

Table 4 Trials of induction therapy in AAV in progress or completed and not yet published

Trial	Indication (total projected n)	Induction (trial)	Induction (control)	Primary endpoint	Trial number
Induction trials
MYCYC^Citation61	New onset GPA or MPA (n=140)	MMF and Pred (n=70)	IV Cyc and Pred (n=70)	Remission at 6 months	NCT00414128
PEXIVAS^Citation66	Renal MPA or GPA (GFR <60 mL per minute) or pulmonary hemorrhage (n=500)	Plex + standard or reduced Pred + Cyc or Rtx (n=250)	Plex + standard or reduced Pred + Cyc or Rtx (n=250)	Composite of all-cause mortality and ESRD	NCT00987389
CLEAR^Citation67	Renal GPA or MPA (GFR >25mL per minute, n=60)	CCX168 + Cyc + half dose or no Pred	Cyc + standard Pred	Safety of CCX168 (secondary corticosteroid use)	NCT01363388
SPARROW^Citation130	Relapsed GPA (n=216)	Gusperimus and Pred	Cyc and Pred or rituximab and Pred or MTX and Pred	Proportion of patients in complete or partial remission	NCT01446211
ALEVIATE^Citation118	Refractory GPA or MPA (n=24)	Alemtuzumab 30 mg on day 1 and 2 at 0 and 6 months (high dose)	Alemtuzumab 15 mg on day 1 and 2 at 0 and 6 months (low dose)	Proportion of patients in complete or partial remission	NCT01405807

Abbreviations: AAV, anti-neutrophil cytoplasm antibody-associated small vessel vasculitides; CCX168, C5a receptor antagonist; ESRD, end-stage renal disease; GFR, glomerular filtration rate; IV, intravenous; Plex, plasma exchange; Pred, prednisone or prednisolone; Cyc, cyclophosphamide; MMF, mycophenolate mofetil; MTX, methotrexate; Rtx, rituximab; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MYCYC, A randomized clinical trial of mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis; PEXIVAS; An international Randomized Controlled Clinical Trial Assessing Plasma Exchange and Steroid Dosing in the Treatment of Severe Anti-Neutrophil Cytoplasm Antibody (ANCA) Associated Vasculitis; CLEAR, C5aR inhibitor on Leukocytes Exploratory ANCA-associated Renal Vasculitis; SPARROW, SPAnidin in Relapsing gRanulomatosis with pOlyangiitis; ALEVIATE, Alemtuzumab for ANCA-Associated Refractory Vasculitis; ANCA, anti-neutrophil cytoplasm antibody.

Table 5 Completed multicenter randomized controlled trials of remission maintenance therapy in AAV

Maintenance trials	Indication	Induction	Maintenance (trial)	Maintenance (control)	Primary endpoint	Brief results
CYCAZAREM^Citation56	Newly diagnosed GPA or MPA, with renal or multiorgan involvement	Oral Cyc + Pred	Aza + Pred (n=71)	Oral Cyc + Pred (n=73)	Relapse rate	No difference in relapse rate at 18 months
IMPROVE^Citation84	Newly diagnosed GPA or MPA	Cyc + Pred	MMF + Pred (n=76)	Aza + Pred (n=80)	Relapse-free survival	MMF less effective than Aza in maintaining remission. No difference in adverse events
WEGENT^Citation85	GPA or MPA with renal or multiorgan involvement	IV Cyc + Pred	Mtx + Pred (n=63)	Aza + Pred (n=63)	Adverse event causing treatment cessation or death	No difference in adverse events or relapse
WGET^Citation86	GPA and BVAS >3	IV Cyc/oral Mtx + Pred ± Etn	Aza or Mtx plus Etn (n=89)	Aza or Mtx (n=92)	Remission for >6 months	Etn failed to improve sustained remission rates. No difference in adverse events.
German Network of Rheumatic Diseases study^Citation87	GPA and creatinine <1.3 mg/dL	Oral Cyc + Pred	Lef + pred (n=26)	Mtx + pred (n=28)	Relapse	Lef at 30 mg/day more effective than Mtx in maintaining remission but with more adverse events

Abbreviations: AAV, anti-neutrophil cytoplasm antibody-associated small vessel vasculitides; BVAS, Birmingham Vasculitis Activity Index; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; Aza, azathioprine; Cyc, cyclophosphamide; Mtx, methotrexate; MMF, mycophenolate mofetil; Pred, prednisolone or prednisone; Lef, leflunomide; Etn, etanercept; IV, intravenous; CYCAZAREM, Cyclophosphamide vs azathioprine for early remission phase of vasculitis; IMPROVE, International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides; WEGENT, Wegener’s Granulomatosis-Entretien/Maintenance; WGET, Wegener’s Granulomatosis Etanercept Trial.

Table 6 Trials of maintenance therapy in AAV in progress or completed and not yet published

Trial	Indication	Induction	Maintenance (trial)	Maintenance (control)	Primary endpoint	Trial number
Maintenance trials
REMAIN^Citation131	GPA or MPA patients who remain c-ANCA positive in remission (n=180)	Cyc + Pred	Aza for 48 months	Aza for 18 months	Disease-free survival during 48 months of follow-up	NCT00128895
MAINRITSAN^Citation90	New or relapsed GPA or MPA within a month of remission (n=117)	Cyc + Pred	Rtx 0.5 mg every 6 months with last dose at month 18	Aza 2 mg/kg tapering from 12 months to zero at 22 months	Number of major relapses (BVAS >10) within 28 months	NCT00748644
RITAZAREM^Citation91	Relapsing GPA or MPA (n=190)	Rtx + Pred	Rtx 1 g every 4 months for 2 years then monitor for 2 years	Aza for 2 years, then monitor for 2 years	Time to first relapse	NCT01697267
BREVAS^Citation132	ANCA-positive GPA or MPA in remission treated for active disease in past 26 weeks (n=400)	Cyc + Pred or Rtx + Pred	Belimumab plus Aza 2 mg/kg	Placebo plus Aza 2 mg/kg	Time to first relapse	NCT01663623

Abbreviations: AAV, anti-neutrophil cytoplasm antibody-associated small vessel vasculitides; Cyc, cyclophosphamide; Pred, prednisone or prednisolone; Rtx, rituximab; Aza, azathioprine; BVAS, Birmingham Vasculitis Activity Index; REMAIN, Randomized trial of prolonged remission-maintenance therapy in systemic vasculitis; MAINRITSAN, Efficacy Study of Two Treatments in the Remission of Vasculitis; RITAZAREM, Rituximab Vasculitis Maintenance Study; BREVAS, Belimumab in Remission of VASculitis; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; ANCA, anti-neutrophil cytoplasm antibody.

Figure 1 A selection of biologics and small molecule inhibitors targeting the autoimmune response and effector responses that may be important in GPA.

Note: *Of these agents, only rituximab is currently licensed for the treatment of GPA, but some of the others are currently undergoing clinical trial evaluation.
Abbreviations: ANCA, anti-neutrophil cytoplasm antibody; GPA, granulomatosis with polyangiitis; IL, interleukin; CCX168, C5a receptor antagonist; BlyS, B cell activating factor; TNF, tumor necrosis factor; CD, cluster of differentiation; ANCA, Anti-neutrophil cytoplasm antibody; SYK, spleen tyrosine kinase.

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