Laboratory tests - ANCA

What it is and how it is tested

Antibodies against cytoplasmic granule constituents of neutrophils and monocytes
Two testing methods, and the modern practice has reversed the old order

Method	Result	Note
Indirect immunofluorescence (IIF) on ethanol-fixed neutrophils	c-ANCA (cytoplasmic granular) or p-ANCA (perinuclear)	The perinuclear pattern is an ethanol-fixation artefact - MPO redistributes around the nucleus
Antigen-specific immunoassay (ELISA/multiplex)	PR3-ANCA or MPO-ANCA	Now the recommended primary screening method - it outperforms IIF

*The antigen specificity, not the clinical label, is what predicts phenotype, treatment response and relapse*

ANCA-associated vasculitis incidence ~20/million/yr
PR3/GPA predominates at higher latitudes (northern Europe); MPO/MPA predominates in southern Europe, Japan and Asia
Positive predictive value depends entirely on pre-test probability - in an unselected population most positives are false

PR3 and MPO are normally intracellular in azurophilic granules
Priming by infection or cytokines -> translocation to the neutrophil surface
ANCA binding -> excessive neutrophil activation, degranulation, reactive oxygen species, NET formation
NETs expose more PR3/MPO -> further ANCA production - a self-perpetuating loop
Alternative complement pathway amplification via C5a/C5aR - the target of avacopan
Result: pauci-immune necrotising small-vessel vasculitis with no immune deposits

	Predominant	ANCA-positive
GPA	PR3 (c-ANCA)	~90% in active generalised disease
MPA	MPO (p-ANCA)	~70%
EGPA	MPO > PR3	only ~50%
Anti-GBM disease	MPO in ~30% (double-positive)
Drug-induced vasculitis	Very high-titre MPO, often multiple specificities

	PR3-ANCA	MPO-ANCA
Typical syndrome	GPA	MPA (and EGPA)
Histology	Granulomas present	No granulomas
Renal	More acute, more crescentic	More chronic, more fibrotic, more sclerosed glomeruli
Upper airway	Common	Rare
Lung	Nodules, cavities	Fibrosis (may precede vasculitis by years)
Relapse	Higher	Lower
Rituximab	Possibly superior to cyclophosphamide	Similar to cyclophosphamide

Glomerulonephritis, especially rapidly progressive GN
Pulmonary haemorrhage, especially pulmonary-renal syndrome
Cutaneous vasculitis with systemic features
Multiple lung nodules (with or without cavitation)
Chronic destructive upper airway disease; long-standing sinusitis or otitis
Subglottic or tracheal stenosis
Mononeuritis multiplex or unexplained peripheral neuropathy
Retro-orbital mass
Also: unexplained constitutional illness with raised inflammatory markers and multi-organ involvement

Atypical p-ANCA without PR3 or MPO specificity (targets lactoferrin, elastase, cathepsin G, BPI)
- Inflammatory bowel disease (especially UC), autoimmune hepatitis, primary sclerosing cholangitis, rheumatoid arthritis, SLE
- Cystic fibrosis and bronchiectasis (anti-BPI)
- *Not vasculitis - do not treat*
Infective endocarditis - ANCA-positive in up to 25%, often with low complement, purpura and glomerulonephritis
- *The single most important mimic - blood cultures and echocardiography before immunosuppression*
Drug-induced: propylthiouracil, carbimazole/methimazole, hydralazine, minocycline, levamisole-adulterated cocaine, allopurinol, penicillamine, TNF inhibitors
- Suggested by very high MPO titre, multiple ANCA specificities, anti-elastase or anti-lactoferrin positivity
TB, HIV, hepatitis C, malaria, amoebiasis

*A positive ANCA does not diagnose vasculitis, and a negative ANCA does not exclude it*
- ~10% of GPA and ~30% of MPA are ANCA-negative; ~50% of EGPA is ANCA-negative
- Localised/limited GPA is frequently ANCA-negative
Biopsy remains the gold standard where feasible - kidney, lung, nerve, skin, ENT
Always send anti-GBM at the same time - ~5-10% are double-positive and behave like anti-GBM disease (urgent plasma exchange)
Take a drug history and blood cultures before starting immunosuppression

A rising ANCA titre predicts relapse but has poor positive predictive value
- Most strongly predictive of RENAL relapse
- *A rising titre alone is NOT an indication to treat* - treat clinical relapse
ANCA persistence after induction is a relapse risk factor and supports longer maintenance
Serial monitoring is reasonable in PR3 disease to inform maintenance duration, not to trigger therapy

GPA, MPA, EGPA - the ANCA-associated vasculitides
Anti-GBM disease (double-positive)
Inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis - atypical p-ANCA
Infective endocarditis, TB, HIV, hepatitis C
Drug-induced vasculitis - antithyroid drugs, hydralazine, minocycline, cocaine/levamisole
Cystic fibrosis and bronchiectasis (anti-BPI)
Rheumatoid arthritis, SLE - atypical patterns
Pulmonary fibrosis preceding MPO-ANCA vasculitis

ANCA can precede clinical vasculitis by months to years
Titres generally fall with successful induction and rise before relapse - but with too much noise to drive therapy alone
PR3-ANCA persistence after induction is the strongest serological predictor of relapse
MPO-ANCA disease relapses less but reaches ESKD more often - the chronic fibrotic renal lesion is already established at presentation
Atypical p-ANCA in IBD or autoimmune liver disease persists indefinitely and carries no vasculitic risk

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