ANCA-associated vasculitides

Last updated 28 Mar 2026

ANCA-Associated Vasculitides

ANCA-associated vasculitides (AAV) are a group of small-vessel vasculitides characterised by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) and necrotising inflammation of small vessels with few or no immune deposits (pauci-immune). The three main subtypes are granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome). AAV are life-threatening conditions that require urgent immunosuppressive treatment, particularly when vital organs (kidneys, lungs) are involved.

Australian Epidemiology

AAV has a combined incidence of approximately 20 per million per year in Australia. GPA is the most common subtype (incidence ~10 per million/year), followed by MPA (~7 per million/year) and EGPA (~2 per million/year). AAV predominantly affects adults aged 50–75 years. Males and females are equally affected by GPA and MPA; EGPA has a slight male predominance. AAV is associated with significant morbidity from disease and treatment. Five-year survival has improved markedly with rituximab-based therapy.

Pathophysiology

ANCA-Mediated Neutrophil Activation

ANCA (PR3-ANCA and MPO-ANCA) activate primed neutrophils, causing endothelial adhesion, degranulation, and release of reactive oxygen species and proteases that damage vessel walls. PR3-ANCA (c-ANCA pattern) is strongly associated with GPA; MPO-ANCA (p-ANCA pattern) is associated with MPA and EGPA. Complement alternative pathway activation amplifies the inflammatory cascade. B cells producing ANCA are key targets for rituximab therapy.

Granulomatous Inflammation (GPA)

GPA is uniquely characterised by necrotising granulomatous inflammation of the upper and lower respiratory tract in addition to small-vessel vasculitis and glomerulonephritis. T-cell and macrophage-driven granuloma formation is central to upper airway disease. This distinguishes GPA from MPA, which lacks granulomatous features.

Eosinophilic Inflammation (EGPA)

EGPA is characterised by eosinophilic tissue infiltration and granulomatous vasculitis in patients with asthma and atopy. IL-5 drives eosinophil production; mepolizumab (anti-IL-5) is now approved for refractory EGPA. ANCA is present in only 40% of EGPA cases; ANCA-negative EGPA tends to have more eosinophilic organ involvement, while ANCA-positive EGPA resembles MPA with glomerulonephritis.

Clinical Presentation

GPA (Granulomatosis with Polyangiitis)

Upper airway (90%): Persistent rhinosinusitis, nasal crusting, epistaxis, saddle-nose deformity, subglottic stenosis, otitis media with effusion
Lower airway (70%): Cough, haemoptysis, pulmonary nodules or cavities on imaging, pulmonary haemorrhage
Renal (80%): Rapidly progressive glomerulonephritis — haematuria, proteinuria, rising creatinine
Eye (50%): Orbital pseudotumour, scleritis, episcleritis, uveitis

MPA (Microscopic Polyangiitis)

Predominantly pulmonary-renal syndrome — rapidly progressive glomerulonephritis (RPGN) and pulmonary capillaritis with haemorrhage. No upper airway or granulomatous features. Peripheral neuropathy common. Skin purpura in 30–40%.

EGPA (Eosinophilic Granulomatosis with Polyangiitis)

Three phases: (1) Allergic phase — asthma, allergic rhinitis, nasal polyps; (2) Eosinophilic phase — peripheral eosinophilia >10%, eosinophilic organ infiltration (lungs, GI, skin); (3) Vasculitic phase — peripheral neuropathy, cutaneous vasculitis, cardiac involvement (eosinophilic myocarditis — most serious complication, causing heart failure and death).

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Pulmonary-Renal Syndrome: Simultaneous pulmonary haemorrhage and RPGN is a life-threatening emergency requiring immediate IV methylprednisolone, rituximab or cyclophosphamide, and consideration of plasma exchange. ICU-level care required.

Investigations

Essential
ANCA by Immunofluorescence and ELISA
PR3-ANCA (c-ANCA): sensitivity 85–95% for GPA. MPO-ANCA (p-ANCA): sensitivity 70–80% for MPA, 40% for EGPA. Both IF and ELISA recommended for highest sensitivity and specificity. Negative ANCA does not exclude AAV — biopsy required.
Essential
Urinalysis and Renal Function
Red cell casts on urinalysis confirm glomerulonephritis — urgent investigation. eGFR trend critical for treatment urgency. Rising creatinine with haematuria/proteinuria is an emergency.
Essential
Chest CT (High Resolution)
Pulmonary nodules, cavities (GPA), ground-glass opacification from pulmonary haemorrhage (MPA/GPA), eosinophilic infiltrates (EGPA). Essential baseline and during treatment for pulmonary involvement.
Essential
Full Blood Count and Differential
Eosinophilia >10% (absolute eosinophil count >1.5 × 10⁹/L) is diagnostic criterion for EGPA. Normocytic anaemia common. Thrombocytosis in active inflammation.
Referral
Renal Biopsy
Pauci-immune crescentic glomerulonephritis on biopsy confirms AAV. Essential for diagnosis confirmation when ANCA negative or clinical uncertainty. Guides prognosis (% normal glomeruli).
Referral
Lung / Nasal / Skin Biopsy
Necrotising granulomatous vasculitis on lung or nasal biopsy confirms GPA. Transbronchial biopsy has low yield; open lung biopsy preferred for pulmonary tissue. Nasal biopsy often non-diagnostic.

Severity Assessment

LOCALISED

Upper Airway Only

GPA limited to upper airway without renal/lung involvement; BVAS low

Methotrexate + prednisolone; avoid cyclophosphamide/rituximab if possible

GENERALISED

Multi-organ, Non-threatening

Renal involvement (creatinine <500 µmol/L), pulmonary nodules, neuropathy

Rituximab (preferred) or cyclophosphamide + prednisolone induction

SEVERE

Life/Organ-Threatening

RPGN (creatinine >500 µmol/L), pulmonary haemorrhage, cardiac EGPA

IV methylprednisolone pulses + rituximab or cyclophosphamide; plasma exchange for RPGN + haemorrhage

Treatment Strategy

Induction Therapy

Rituximab 375 mg/m² IV weekly × 4 doses (or 1000 mg IV × 2 doses, 2 weeks apart) is now preferred over cyclophosphamide for most AAV based on RAVE and RITUXVAS trial evidence showing equivalent efficacy with superior safety. High-dose corticosteroids — IV methylprednisolone 500–1000 mg/day × 3 days for severe disease, then prednisolone 1 mg/kg/day (max 60–80 mg) — are given concurrently with rituximab or cyclophosphamide. For generalised non-severe disease, cyclophosphamide remains appropriate: IV pulse 15 mg/kg every 2–3 weeks × 6 pulses, or oral 2 mg/kg/day.

Plasma Exchange

Plasma exchange (7–10 sessions over 2 weeks) has been used for severe RPGN (creatinine >500 µmol/L) and simultaneous pulmonary haemorrhage, though the PEXIVAS trial showed plasma exchange did not reduce death or ESRD at 2 years while increasing serious infections. Current guidelines suggest plasma exchange may still be considered on a case-by-case basis for dialysis-dependent or pulmonary haemorrhage cases.

Maintenance Therapy

Rituximab 500 mg IV every 6 months for 18–24 months (preferred over azathioprine based on MAINRITSAN trial). Azathioprine 2 mg/kg/day or methotrexate 20–25 mg/week are alternatives. Corticosteroid taper to prednisolone ≤7.5 mg/day by 6 months. Total maintenance duration typically 2–4 years; individualise based on ANCA titre, relapse history, and organ damage.

Directed Therapy

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Rituximab

MabThera®, Riximyo® · Anti-CD20 · Preferred Induction/Maintenance

Adult Dose (Induction)375 mg/m² IV weekly × 4, OR 1000 mg IV × 2 doses (2 weeks apart)

Adult Dose (Maintenance)500 mg IV every 6 months

Paediatric375 mg/m² per dose; specialist dosing

RouteIntravenous infusion

Duration2–4 years maintenance

Renal Adj.No formal dose adjustment required

Hepatic Adj.Caution; monitor LFTs

PBS StatusPBS Authority Required

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Mepolizumab

Nucala® · Anti-IL-5 · EGPA

Adult Dose300 mg SC every 4 weeks (EGPA indication)

PaediatricNot approved for EGPA in children

RouteSubcutaneous injection

FrequencyEvery 4 weeks

DurationOngoing; assess response at 6 months

Renal Adj.No adjustment required

Hepatic Adj.No adjustment required

PBS StatusPBS Authority Required

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Trimethoprim-Sulfamethoxazole

Bactrim®, Septrin® · PJP Prophylaxis + GPA Remission

Adult Dose (PJP)160/800 mg (DS) three times weekly

Adult Dose (GPA remission)160/800 mg twice daily — reduces relapse rate in localised GPA

RouteOral

Renal Adj.Reduce dose if eGFR <30

PBS Status✓ PBS General Benefit

Acute Management

Pulmonary-Renal Syndrome — Emergency

Admit to ICU. IV methylprednisolone 500–1000 mg/day × 3 days immediately. Commence rituximab or cyclophosphamide urgently. Plasma exchange consideration (individualised — see PEXIVAS data). Intubation and mechanical ventilation for severe pulmonary haemorrhage. Urgent nephrology assessment; renal replacement therapy if dialysis-dependent. Bronchoscopy to confirm alveolar haemorrhage.

Rapidly Progressive Glomerulonephritis (RPGN)

RPGN from AAV is a nephrological emergency. Urgent renal biopsy if feasible and safe (not if severe coagulopathy or uncontrolled haemorrhage). Start IV methylprednisolone + rituximab or cyclophosphamide without delay. Monitor creatinine daily initially. Dialysis if required — renal recovery is possible even from dialysis-dependence with aggressive treatment.

Subglottic Stenosis (GPA)

Subglottic stenosis in GPA may cause acute stridor and respiratory compromise requiring urgent ENT assessment. Intralesional corticosteroid injection and dilation by ENT specialist. Tracheostomy in severe cases. Systemic immunosuppression often does not resolve established fibrostenotic lesions — local intervention essential.

Monitoring and Follow-up

Clinical and Laboratory Monitoring

BVAS at each visit. Urinalysis (dipstick for blood and protein) at every visit — new haematuria may indicate relapse. ESR, CRP, ANCA titres 3-monthly. ANCA titre rise may predict relapse but should not alone drive treatment escalation without clinical confirmation. FBC, renal function, LFTs on rituximab per cycle and 3-monthly between cycles. Immunoglobulin levels (IgG) before each rituximab cycle — hold if IgG <4 g/L (risk of hypogammaglobulinaemia with recurrent dosing).

Relapse Management

Major relapse (new organ-threatening disease): re-induce with rituximab or cyclophosphamide + high-dose corticosteroids. Minor relapse (non-organ-threatening): increase prednisolone and intensify maintenance. Assess ANCA subtype and titre, B-cell count (if on rituximab), and adequacy of immunosuppression. Consider switching induction agent if relapse on maintenance rituximab.

Long-Term Complications

Chronic kidney disease from glomerulonephritis — monitor eGFR, blood pressure, and proteinuria long-term. Subglottic stenosis recurrence in GPA. Cardiovascular risk — AAV is an independent cardiovascular risk factor. Malignancy surveillance — cyclophosphamide increases bladder cancer and lymphoma risk; haematuria on follow-up requires urgent evaluation.

Special Populations

👴 Elderly Patients

Higher Infection RiskElderly patients have significantly higher infection-related mortality with cyclophosphamide. Rituximab is preferred induction agent in patients over 70 years. Reduce cyclophosphamide doses by 25–50% in elderly if used. PJP prophylaxis mandatory.

Renal DosingAge-related decline in GFR requires careful drug dosing. Cyclophosphamide and azathioprine accumulate with renal impairment. Monitor closely and adjust doses accordingly.

🤰 Pregnancy

CyclophosphamideCONTRAINDICATED — highly teratogenic. Switch to azathioprine for maintenance before conception. Ensure effective contraception during and for 3 months after cyclophosphamide.

RituximabAvoid if possible in pregnancy — neonatal B-cell depletion reported. 6-month washout before conception recommended. If AAV relapses in pregnancy, prednisolone and azathioprine are safer alternatives.

EGPA in PregnancyAsthma and eosinophilia may worsen in pregnancy. Prednisolone is the safest immunosuppressant. Mepolizumab has limited pregnancy data — avoid if possible.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

ANCA-associated vasculitides can affect any population, including Aboriginal and Torres Strait Islander peoples. Given the rarity of AAV and the overlap of symptoms with more common infectious and inflammatory conditions prevalent in remote communities, diagnostic delay is a significant risk. Pulmonary symptoms (haemoptysis, infiltrates), haematuria, and renal impairment should prompt consideration of AAV — particularly when infection has been excluded.

Infection vs Vasculitis

TB, melioidosis, and other endemic infections can mimic AAV with pulmonary and renal involvement. ANCA testing and chest CT findings must be interpreted in clinical context. TB screening is mandatory before rituximab or cyclophosphamide initiation.

Renal Disease Burden

Chronic kidney disease is highly prevalent in Aboriginal and Torres Strait Islander communities, and RPGN from AAV may be superimposed on pre-existing CKD, making diagnosis and treatment more complex. Urgent nephrology referral is essential. Renal biopsy should not be delayed in suspected AAV-related RPGN.

Specialist Access

Nephrology and rheumatology services are scarce in remote areas. AAV requires intensive specialist care — patient transfer to metropolitan or regional facilities is necessary for induction therapy, renal biopsy, and monitoring. Telehealth should supplement but not replace in-person specialist care for AAV.

Infection Risk on Treatment

Immunosuppression with rituximab and cyclophosphamide carries high infection risk, particularly in communities with higher baseline rates of TB, respiratory infections, and skin infections. Comprehensive infection screening, prophylaxis, and patient education about infection warning signs are essential.

Antimicrobial Stewardship

Mandatory Infection Screening and Prophylaxis

Intensive immunosuppression for AAV requires comprehensive infection prevention. Non-negotiable stewardship principles:

TB screening: IGRA (or Mantoux + CXR) mandatory before rituximab or cyclophosphamide — treat latent TB with isoniazid 300 mg/day for 9 months before starting biologic therapy
Hepatitis B serology: HBsAg and HBcAb required — prophylactic antiviral therapy (tenofovir or entecavir) for HBsAg-positive or HBcAb-positive patients on rituximab
PJP prophylaxis: Trimethoprim-sulfamethoxazole 160/800 mg three times weekly for all patients on cyclophosphamide + prednisolone >20 mg/day; continue while on maintenance immunosuppression
Vaccinations: Influenza (annual), pneumococcal, herpes zoster vaccine before rituximab; live vaccines contraindicated while on immunosuppression
TMP-SMX in GPA: Twice-daily dosing reduces respiratory tract relapses in localised GPA — include as adjunctive therapy

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Cyclophosphamide Bladder Toxicity: Haemorrhagic cystitis and bladder cancer risk with cumulative cyclophosphamide. Ensure adequate hydration (≥2 L/day), mesna co-administration with IV pulses, and regular urinalysis during and after treatment. Any haematuria on follow-up requires urgent urological evaluation.

References

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Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.
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Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371(19):1771-1780.
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Walsh M, Merkel PA, Peh CA, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS). N Engl J Med. 2020;382(7):622-631.
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Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. 2017;376(20):1921-1932.
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Australian Rheumatology Association. ANCA-Associated Vasculitis Management Guidelines. Sydney: ARA; 2023.
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Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.
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Ntatsaki E, Carruthers D, Chakravarty K, et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology. 2014;53(12):2306-2309.
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Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021;384(7):599-609.
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Watkins A, Watts R. ANCA-associated vasculitis in Australia: incidence, outcomes, and treatment patterns. Intern Med J. 2022;52(8):1351-1358.