Vasculitis - antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis
Description
- Pauci-immune, necrotising small-vessel vasculitis (capillaries, venules, arterioles, small arteries)
- Three entities - Chapel Hill definitions
| Defining feature | ANCA | Renal | |
|---|---|---|---|
| GPA (Wegener's) | Necrotising GRANULOMATOUS inflammation of the respiratory tract + small-vessel vasculitis | PR3 (c-ANCA), ~90% positive | Common necrotising GN |
| MPA | Necrotising small-vessel vasculitis, NO granulomas | MPO (p-ANCA), ~70% positive | Very common necrotising GN; frequent pulmonary capillaritis |
| EGPA (Churg-Strauss) | Eosinophil-rich granulomatous inflammation + asthma + eosinophilia | MPO, only ~50% positive | Variable, ~50%, usually milder |
- *ANCA specificity (PR3 vs MPO) predicts phenotype, treatment response and relapse risk better than the clinical label*
- PR3: granulomatous, upper airway, relapsing, better rituximab response
- MPO: renal-limited, fibrotic, less relapsing, more ESKD
EGPA has two phenotypes
- ANCA-positive (~40%) - vasculitic: glomerulonephritis, mononeuritis multiplex, purpura, alveolar haemorrhage
- ANCA-negative (~60%) - eosinophilic: cardiomyopathy, lung infiltrates, GI disease
- *Cardiac involvement is the leading cause of death in EGPA and clusters with ANCA-negative disease*
Epidemiology
- Incidence ~20/million/yr combined; prevalence ~150-200/million
- Peak onset 55-70 yr; M=F
- Geographic split: GPA/PR3 commoner at higher latitudes (northern Europe); MPA/MPO commoner in southern Europe and Japan/Asia
- EGPA rarest (~1-3/million/yr); asthma precedes vasculitis by a median 7-9 years
Aetiopathogenesis
Mechanism - a self-perpetuating loop
- Priming (infection, cytokines) -> PR3 and MPO translocate to the neutrophil surface
- ANCA binds surface antigen -> excessive neutrophil activation
- -> degranulation: reactive oxygen species, lytic enzymes, cytokines
- -> neutrophil extracellular traps (NETs) damage endothelium
- -> NETs expose more PR3/MPO -> further ANCA formation - the loop closes
- Complement alternative pathway: C5a -> C5aR (CD88) on neutrophils amplifies priming
- *This is the target of avacopan (C5aR antagonist)*
- Result: fibrinoid necrosis, no immune deposits ("pauci-immune")
Risk factors
- Silica exposure, farming
- *Nasal Staphylococcus aureus carriage - associated with GPA relapse*
- HLA-DP/PRTN3 (PR3-ANCA); HLA-DQ (MPO-ANCA)
Drug-induced ANCA vasculitis
- *Typically very high-titre MPO-ANCA, often with anti-elastase or anti-lactoferrin, and multiple ANCA specificities*
- Propylthiouracil, carbimazole/methimazole, benzylthiouracil
- Hydralazine, levamisole-adulterated cocaine (retiform purpura of the ears), minocycline
- Allopurinol, penicillamine, phenytoin, sulfasalazine, rifampicin, nitrofurantoin, cefotaxime, anti-TNF agents
- Withdraw the drug; immunosuppression only if organ-threatening
Diagnosis
Clinical patterns
- Constitutional - fever, weight loss, night sweats, arthralgia/myalgia (present in nearly all)
- GPA - the classic triad: recurrent sinusitis + pulmonary infiltrates + glomerulonephritis
- ENT ~95%: nasal crusting, epistaxis, chronic sinusitis, saddle-nose deformity, subglottic stenosis, otitis media, sensorineural hearing loss
- Lung: nodules (often cavitating), infiltrates, alveolar haemorrhage, stridor
- Renal: active sediment, RPGN
- Eye: orbital pseudotumour/granuloma, scleritis, proptosis
- Neuro: mononeuritis multiplex, cranial nerve palsy
- MPA - renal-dominant; pulmonary capillaritis with alveolar haemorrhage; pulmonary fibrosis may precede vasculitis by years in MPO disease
- EGPA - three sequential phases
- Prodromal (2nd-3rd decade): adult-onset asthma, allergic rhinitis, nasal polyps
- Eosinophilic: peripheral eosinophilia, migratory pulmonary opacities, eosinophilic GI infiltration
- Vasculitic (3rd-4th decade): fever, weight loss; skin involvement commonest, mononeuritis multiplex ~75%, cardiac, renal
- Leukotriene receptor antagonists have been implicated but most likely just unmask disease by allowing steroid taper
Upper airway involvement by subtype
- GPA ~90% > EGPA ~50% > MPA ~35%
ANCA testing
| ANCA positive | Predominant | |
|---|---|---|
| GPA | ~90% (generalised active disease) | PR3 / c-ANCA |
| MPA | ~70% | MPO / p-ANCA |
| EGPA | ~50% only | MPO > PR3; correlates with renal and neurological disease |
- Method: indirect immunofluorescence pattern (c-ANCA/p-ANCA) + antigen-specific ELISA for PR3/MPO
- Modern practice is antigen-specific ELISA first - it outperforms IIF
- Atypical/perinuclear ANCA without PR3 or MPO specificity: IBD, autoimmune hepatitis, PSC, infective endocarditis, cocaine, drug-induced - not vasculitis
- *ANCA-negative disease exists - a negative ANCA never excludes vasculitis; biopsy where feasible*
Biopsy - the gold standard
- Kidney: pauci-immune focal necrotising and crescentic glomerulonephritis, few or no immune deposits on IF and EM
- Almost every patient with pauci-immune crescentic GN is ANCA-positive
- Berden histological classification (focal / crescentic / mixed / sclerotic) predicts renal outcome
- Lung/ENT (GPA): necrotising granulomatous inflammation with geographic necrosis and giant cells
- Nasal biopsy has low yield; open lung biopsy is the highest
- EGPA: extravascular eosinophilic granulomas + eosinophil-rich vasculitis
- Nerve/muscle: for mononeuritis multiplex
ACR criteria for EGPA - 4 of 6 (sens 85%, spec 99.7%)
- Asthma
- Eosinophils >10% on differential
- Mononeuropathy or polyneuropathy
- Migratory or transient pulmonary opacities
- Paranasal sinus abnormality
- Biopsy: extravascular eosinophil accumulation around a blood vessel
Workup on suspicion
- UEC, urinalysis with microscopy for dysmorphic RBC and red cell casts, UPCR
- FBE (eosinophil count), CRP/ESR, LFT, CK
- ANCA (PR3/MPO), anti-GBM (~5-10% double-positive - treat as anti-GBM), ANA, complement, cryoglobulins
- Hepatitis B/C, HIV, blood cultures (exclude endocarditis - it mimics everything and is ANCA-positive in up to 25%)
- CT chest, CT sinuses; nerve conduction studies; echocardiogram + cardiac MRI in EGPA
- Pulmonary-renal syndrome differential: AAV, anti-GBM, SLE, cryoglobulinaemia, severe infection, cardiac failure with AKI
Disease assessment
- BVAS (activity), VDI (damage), FFS (five-factor score) in EGPA/PAN
Management
Axis: disease severity (organ- or life-threatening vs not), then phase - induction, then maintenance. Prophylaxis runs alongside.
A. Induction - organ- or life-threatening disease (GPA/MPA)
- Glucocorticoid + EITHER rituximab OR cyclophosphamide
- Rituximab preferred for: relapsing disease, PR3-ANCA, younger patients, fertility preservation, prior cyclophosphamide exposure
- RAVE and RITUXIVAS: non-inferior to cyclophosphamide for induction; superior for relapsing disease**
- Cyclophosphamide IV pulsed preferred over oral - less leukopenia, lower cumulative dose, equal efficacy
- Rituximab preferred for: relapsing disease, PR3-ANCA, younger patients, fertility preservation, prior cyclophosphamide exposure
- Reduced-dose glucocorticoid regimen is now standard (PEXIVAS) - equal efficacy, ~27% fewer serious infections
- Pulse methylprednisolone, then oral prednisolone tapered rapidly to ~5 mg by ~5 months
- Avacopan (oral C5a receptor antagonist) - add to rituximab or cyclophosphamide to spare glucocorticoids
- ADVOCATE: superior sustained remission at 52 weeks, better eGFR recovery, less steroid toxicity
- Duration ~6-12 months; no data beyond 12 months
- Monitor LFTs; contraindicated in significant hepatic impairment
- Plasma exchange - NO LONGER ROUTINE
- *PEXIVAS: PLEX did not reduce death or ESKD in severe AAV*
- Reserve for: creatinine >500 micromol/L or dialysis-dependence (weak, individualised), concurrent anti-GBM disease, or severe diffuse alveolar haemorrhage with respiratory failure
- Dialysis-dependent at presentation is not a reason to withhold treatment - ~50% recover independent renal function
B. Induction - non-organ-threatening ("early systemic") disease
- Glucocorticoid + methotrexate, mycophenolate, or rituximab
- Avoid methotrexate if eGFR reduced
C. Maintenance - the key change from older teaching
- Rituximab is now the preferred maintenance agent, not azathioprine
- MAINRITSAN: rituximab markedly superior to azathioprine for relapse-free survival
- 500-1000 mg every 4-6 months
- Continue 24-48 months (KDIGO 18-48); longer in PR3-ANCA, relapsing disease, persistent ANCA
- Alternatives: azathioprine (~18-24 months), methotrexate (not if renal impairment), leflunomide
- *Mycophenolate is inferior for maintenance* - higher relapse rate
- Low-dose prednisolone continued or withdrawn - practice varies; withdrawal increases relapse
D. EGPA
- Induction: glucocorticoid alone achieves remission in >90% of non-severe disease
- Add cyclophosphamide or rituximab if FFS >=1, or cardiac, CNS, severe renal, GI or alveolar involvement
- Mepolizumab (anti-IL-5, 300 mg SC 4-weekly) for relapsing/refractory non-severe EGPA - MIRRA; steroid-sparing, halves relapses
- Benralizumab (anti-IL-5R) non-inferior
- These treat the eosinophilic phenotype, not vasculitic organ-threatening disease
- Rituximab increasingly used for ANCA-positive EGPA
E. Refractory disease
- Switch between rituximab and cyclophosphamide
- IVIG, plasma exchange, or (historically) infliximab/alemtuzumab
F. Adjunctive - mandatory
- PJP prophylaxis: trimethoprim-sulfamethoxazole while on cyclophosphamide, rituximab or prednisolone >=20 mg
- Also reduces GPA relapse (nasal S. aureus)
- Bone protection - calcium, vitamin D, bisphosphonate
- Fertility preservation before cyclophosphamide; consider GnRH agonist
- Bladder protection with cyclophosphamide - mesna, hydration (haemorrhagic cystitis, later urothelial carcinoma)
- Immunoglobulin monitoring with repeated rituximab - hypogammaglobulinaemia -> IVIG replacement
- Vaccination before immunosuppression; no live vaccines
- Cardiovascular risk management
- Nasal care for GPA; subglottic stenosis -> local intralesional steroid + dilatation (not systemic escalation)
G. Relapse
- A rising ANCA titre alone is NOT an indication to treat - it predicts relapse (most strongly renal relapse) but has poor positive predictive value
- Treat clinical relapse: severe -> re-induce; non-severe -> increase steroid +/- change maintenance
Associations
- Venous thromboembolism - ~7-10x risk during active disease
- Accelerated cardiovascular disease
- Subglottic and bronchial stenosis (GPA)
- Pulmonary fibrosis - may precede MPO-ANCA vasculitis by years
- Chronic sinusitis, saddle-nose deformity, nasolacrimal duct obstruction
- *Nasal S. aureus carriage* - relapse risk in GPA
- Silica and farming exposure
- Drug-induced forms - antithyroid drugs, hydralazine, levamisole/cocaine
- Anti-GBM disease (~5-10% double-positive)
- Malignancy - bladder cancer and myelodysplasia after cyclophosphamide
- Hypogammaglobulinaemia after repeated rituximab
Natural history & complications
- Untreated generalised AAV: ~80-90% mortality at 1 year - treatment transformed it into a chronic relapsing disease
- Current 5-yr survival ~75-85%
- Remission achieved in >80%; relapse in 30-50% within 5 years
- Early mortality (<1 yr) is dominated by infection and active vasculitis; late mortality by cardiovascular disease, malignancy and ESKD
Relapse risk factors
- PR3-ANCA and GPA phenotype
- Younger age
- ANCA persistence after induction, or a rising titre (most predictive of renal relapse)
- Upper respiratory tract, lung or cardiac involvement
- Preserved renal function (paradoxically - MPO renal-limited disease relapses least)
- Prior relapse
- Treatment: withdrawal of immunosuppression or prednisolone, lower cumulative cyclophosphamide dose, mycophenolate maintenance, B-cell reconstitution after rituximab
Renal outcome
- ~20-25% reach ESKD
- Predictors: creatinine at presentation, percentage of normal glomeruli / Berden sclerotic class, degree of interstitial fibrosis
- Dialysis-dependence at presentation is not futile - about half recover
Complications
- ESKD; pulmonary fibrosis; chronic respiratory failure
- Diffuse alveolar haemorrhage - the main cause of early respiratory death
- Cardiomyopathy - leading cause of death in EGPA
- Deafness, saddle-nose deformity, subglottic stenosis, blindness (orbital disease)
- Peripheral nerve deficit from mononeuritis multiplex - often permanent
- Treatment toxicity: infection (the commonest cause of death in the first year), infertility, haemorrhagic cystitis, bladder cancer, MDS, osteoporosis, diabetes, cataract
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