ANCA-associated vasculitis

ANCA-associated vasculitis (AAV) comprises a group of small-vessel necrotising vasculitides defined by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) and characterised by pauci-immune necrotising glomerulonephritis and/or small-vessel vasculitis. The three main clinical syndromes are granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome). AAV is a potentially life-threatening disease requiring urgent immunosuppression and early specialist involvement. Without treatment, systemic AAV carries a median survival of under 5 months. With modern immunosuppressive therapy, 5-year survival exceeds 70–80%.

ANCA antibodies directed against neutrophil granule proteins are central to AAV pathogenesis, though the mechanisms differ between GPA and MPA versus EGPA.

ANCA-Mediated Vascular Injury

• PR3-ANCA (anti-proteinase 3) and MPO-ANCA (anti-myeloperoxidase) activate primed neutrophils that adhere to vascular endothelium and release reactive oxygen species and proteolytic enzymes, causing necrotising vasculitis
• Complement activation (alternative pathway) amplifies neutrophil recruitment — this is the rationale for avacopan (C5aR1 inhibitor), a newer targeted therapy
• T cell dysregulation — granuloma formation in GPA involves CD4+ Th1 cells and macrophages; granulomas are absent in MPA
• B cell and ANCA production — B cell depletion with rituximab is highly effective, confirming the central role of B cells and ANCA in pathogenesis

EGPA Pathogenesis

• Eosinophil-driven tissue injury — eosinophilic infiltration of airways, myocardium, nerves, and skin; eosinophil cationic protein causes direct organ damage
• IL-5 is the key cytokine driving eosinophilia — mepolizumab (anti-IL-5) and benralizumab (anti-IL-5R) are emerging therapies for EGPA
• ANCA-positive EGPA (MPO-ANCA) more commonly has renal involvement and neuropathy; ANCA-negative EGPA more commonly has cardiac involvement and severe asthma

AAV can present acutely with life-threatening organ failure or subacutely with constitutional symptoms and organ involvement developing over weeks. The classic AAV triad involves upper airways, lower airways, and kidneys.

Urgent investigation is required for suspected AAV. Treatment should not be delayed while awaiting confirmatory tests when organ-threatening disease is present.

• Essential
  ANCA serology (PR3-ANCA and MPO-ANCA by ELISA)

  Positive PR3-ANCA has 90–95% specificity for GPA; positive MPO-ANCA for MPA. Combined sensitivity ~90% for systemic AAV. Negative ANCA does not exclude localised GPA or EGPA. Report as titre (higher titres correlate with active disease).
• Essential
  FBC, UEC, creatinine, urinalysis + microscopy

  Haematuria and red cell casts on urine microscopy = active glomerulonephritis. Rising creatinine = RPGN. FBC: normocytic anaemia, elevated WCC. Eosinophilia (>1.5 ×10②/L) is required for EGPA diagnosis.
• Essential
  Anti-GBM antibodies

  Exclude Goodpasture disease (anti-GBM nephritis) in pulmonary-renal syndrome. Can co-exist with ANCA (double-positive) — treat as anti-GBM disease (plasma exchange mandatory in this scenario).
• Essential
  Renal biopsy

  Gold standard for confirming pauci-immune necrotising GN in AAV. Guides prognosis (% normal vs crescent glomeruli). Mandatory before immunosuppression if renal function permits and bleeding risk acceptable. Histology also informs whether plasma exchange is appropriate.
• Essential
  CT chest, sinus CT

  Pulmonary nodules/cavities (GPA), ground-glass opacification/pulmonary haemorrhage (MPA), eosinophilic infiltrates (EGPA). Sinus CT for sinusitis/granulomatous disease in GPA. Bronchoscopy and BAL if pulmonary haemorrhage suspected.
• Recommended
  Echocardiogram (EGPA)

  Mandatory in all EGPA patients — eosinophilic myocarditis and endomyocardial fibrosis are major causes of EGPA mortality. Cardiac MRI if echo inconclusive. BNP/troponin as baseline cardiac markers.
• Recommended
  Nerve conduction studies (NCS)/EMG

  Mononeuritis multiplex is common in AAV. NCS documents extent of neuropathy. Sural nerve biopsy may confirm vasculitic neuropathy in diagnostically uncertain cases.

AAV severity is stratified using the EUVAS (European Vasculitis Study Group) categories to guide induction therapy intensity. The Birmingham Vasculitis Activity Score (BVAS) quantifies disease activity.

AAV treatment has two phases: induction of remission (high-intensity immunosuppression, typically 3–6 months) and maintenance of remission (lower-intensity immunosuppression for 18–48 months). The RAVE, RITUXVAS, and MEPEX trials established the evidence base for current regimens.

Specific organ manifestations in AAV require directed management in addition to systemic immunosuppression.

Rapidly Progressive Glomerulonephritis (RPGN)

• IV methylprednisolone 500–1000 mg/day ×3 plus CYC or RTX induction — treat urgently; delay worsens renal outcome
• Plasma exchange — PEXIVAS trial did not show mortality or ESRD benefit in unselected patients; still considered for anti-GBM co-positive AAV and severe DAH; decision made case-by-case with specialist input
• Dialysis — required in up to 25–40% of severe renal AAV at presentation; renal recovery possible even after dialysis dependence with adequate immunosuppression

Diffuse Alveolar Haemorrhage (DAH)

• ICU-level care — risk of respiratory failure requiring intubation/mechanical ventilation
• IV methylprednisolone 1000 mg/day ×3 then high-dose oral prednisolone
• Bronchoscopy (BAL) to confirm haemorrhage and exclude infection; quantify blood loss

Subglottic Stenosis (GPA)

• GPA-specific complication — not always driven by systemic disease activity; local intralesional steroid injection + tracheal dilation; tracheostomy if severe
• Systemic immunosuppression alone is often insufficient for subglottic stenosis — ENT/thoracic surgery co-management required

Infection Prophylaxis

• Pneumocystis jirovecii (PCP) prophylaxis — co-trimoxazole 960 mg three times weekly (or 480 mg daily) for all patients on CYC + prednisolone; continue during induction and while prednisolone >15 mg/day
• HBV reactivation prophylaxis — entecavir or tenofovir for HBsAg-positive patients; check HBV status before RTX
• Vaccination — influenza and pneumococcal vaccines before immunosuppression; live vaccines contraindicated during treatment

Non-pharmacological measures support recovery from organ damage and mitigate treatment-related toxicity.

Renal Protection

• Fluid balance — adequate hydration during CYC infusions to reduce haemorrhagic cystitis risk; mesna administration with IV CYC
• Avoid nephrotoxic medications (NSAIDs, contrast without pre-hydration) during active renal disease
• ACE inhibitor or ARB — proteinuria reduction and renoprotection once haematuria resolves and BP controlled

Bone Protection and Metabolic Monitoring

• Calcium, vitamin D, and bisphosphonate — all patients on long-term steroids; DEXA at baseline and 12-monthly
• Blood glucose — monthly during induction; HbA1c annually
• Cardiovascular risk — lipids, blood pressure, smoking cessation; AAV patients have significantly elevated CVD risk

Rehabilitation

• Pulmonary rehabilitation — for ILD or post-DAH respiratory impairment
• Physiotherapy — for mononeuritis multiplex and motor weakness secondary to vasculitic neuropathy

AAV requires intensive monitoring during induction therapy for treatment toxicity, disease activity, and infection risk. Monitoring is less frequent during maintenance therapy.

When to Refer Urgently

• Nephrology: Any suspected RPGN — rising creatinine, haematuria, red cell casts; arrange same-day assessment and urgent renal biopsy
• Pulmonology/ICU: Suspected diffuse alveolar haemorrhage — haemoptysis, desaturation, bilateral infiltrates in AAV patient
• Rheumatology: All new suspected AAV; any relapse; treatment-refractory disease
• ENT: Subglottic stenosis, destructive sinonasal disease in GPA

Specific patient groups with AAV require tailored management.

Fertility and Pregnancy

• Cyclophosphamide is highly gonadotoxic — discuss fertility preservation (sperm banking, embryo/oocyte cryopreservation) before commencing CYC in all patients of reproductive age; refer to fertility specialist urgently
• AAV in pregnancy is rare but high-risk — prednisolone is safe; azathioprine is used for maintenance in pregnancy; CYC, RTX, and MTX are contraindicated
• ANCA does not cross the placenta; fetal risk is primarily from disease activity and treatment toxicity

Elderly Patients

• AAV peak incidence is in the 7th decade; elderly patients have higher treatment-related mortality (predominantly infection)
• Dose-reduce CYC for age (>60 years use 12.5 mg/kg; >70 years use 10 mg/kg IV); reduce prednisolone as rapidly as tolerated
• Frailty assessment — consider less intensive regimens in frail elderly; rituximab may be preferable over CYC for reduced myelosuppression risk

Renal Transplantation in AAV

• AAV can progress to ESRD requiring renal replacement therapy; transplantation is appropriate after sustained remission (typically >12–24 months ANCA-negative)
• Post-transplant relapse risk is low but not negligible; maintain immunosuppression surveillance for ANCA titre rise

Stewardship in AAV focuses on appropriate immunosuppression intensity, infection prophylaxis, steroid minimisation, and fertility counselling prior to cyclophosphamide use.

GP Role in AAV Management

• Diagnosis trigger — any combination of haematuria/proteinuria, haemoptysis, sinusitis, peripheral neuropathy, or purpura in a patient over 40 years warrants urgent ANCA serology
• Infection surveillance — monitor for opportunistic infections (PCP, CMV) during induction; low threshold to investigate febrile illness
• Bone protection — all patients on long-term steroids; DEXA and bisphosphonate
• Relapse recognition — any new haematuria, haemoptysis, sinusitis, or neuropathy in a patient with known AAV requires urgent ANCA, UEC, and urinalysis, and referral

AAV requires long-term specialist follow-up for disease activity monitoring, maintenance therapy management, and relapse detection. GPA has a high relapse rate (up to 50% at 5 years); continued vigilance is essential.

• 01
  Jayne DRW, et al. Rituximab versus cyclophosphamide for ANCA-associated renal vasculitis (RAVE). N Engl J Med. 2010;363(3):211–220.
• 02
  Walsh M, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis (PEXIVAS). N Engl J Med. 2020;382(7):622–631.
• 03
  Jayne DRW, et al. Avacopan for the treatment of ANCA-associated vasculitis (ADVOCATE). N Engl J Med. 2021;384(7):599–609.
• 04
  Guillevin L, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis (MAINRITSAN). N Engl J Med. 2014;371(19):1771–1780.
• 05
  Wechsler ME, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis (MIRRA). N Engl J Med. 2017;376(20):1921–1932.
• 06
  Therapeutic Guidelines. Rheumatology. Melbourne: Therapeutic Guidelines Ltd; 2024.
• 07
  Pharmaceutical Benefits Scheme (PBS). Schedule of Pharmaceutical Benefits. Canberra: Department of Health; 2025.