ANCA-Associated Vasculitis

The contract between this chapter and the reader.

1. 1. Define ANCA-associated vasculitis and its three forms.
2. 2. Explain the ANCA-mediated mechanism of injury.
3. 3. Recognise the systemic and renal manifestations.
4. 4. Diagnose with ANCA serology and renal biopsy.
5. 5. Distinguish PR3 from MPO disease and the mimics.
6. 6. Treat induction with glucocorticoids plus rituximab or cyclophosphamide.
7. 7. Decide on plasma exchange and reduced-dose glucocorticoids.
8. 8. Manage maintenance and relapse.
9. 9. Appraise the evidence and the prognosis.

A sixty-second reading. Each bullet stands alone.

• ANCA-associated vasculitis is a small-vessel vasculitis with anti-neutrophil cytoplasmic antibodies.
• Its forms are granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic GPA.
• ANCA activate primed neutrophils, injuring small vessels and causing focal necrosis and crescents.
• The renal lesion is a pauci-immune necrotizing crescentic glomerulonephritis causing rapidly progressive GN.
• It presents systemically (ENT, lung, skin, nerve) and renally (hematuria, RBC casts, rising creatinine).
• Pulmonary-renal syndrome — lung hemorrhage with glomerulonephritis — is a feared presentation.
• ANCA serology (PR3 or MPO) supports the diagnosis; biopsy confirms it and guides prognosis.
• Anti-GBM disease can coexist (double-positive) and must be excluded.
• Induction is glucocorticoids plus rituximab or cyclophosphamide.
• Rituximab is non-inferior to cyclophosphamide and preferred in relapsing or younger patients.
• Plasma exchange gives no overall benefit but may be considered for severe renal or pulmonary disease.
• A reduced-dose glucocorticoid regimen is non-inferior and causes less infection.
• Maintenance (rituximab or azathioprine) is continued for years because relapse is common, especially in PR3 disease.

The medical core. An expert should agree ANCA-associated vasculitis is fully covered here.

Why it matters at the bedside

ANCA vasculitis is a disease where days matter. It can destroy kidneys and fill lungs with blood within a week, yet — caught early and treated — even a dialysis-dependent patient may recover renal function. The art is to recognise it fast, prove it with serology and biopsy, and immunosuppress decisively while not killing the patient with infection in the process.

What it is and its forms

• ANCA-associated vasculitis is a small-vessel vasculitis defined by anti-neutrophil cytoplasmic antibodies. It comes in three forms: granulomatosis with polyangiitis (GPA — ENT, lung, and kidney, with granulomas, usually PR3-ANCA), microscopic polyangiitis (MPA — kidney and lung without granulomas, usually MPO-ANCA), and eosinophilic GPA (EGPA — asthma and eosinophilia, ANCA-positive in a minority). The kidney behaves similarly across them.

The mechanism

• The injury is antibody-driven but not deposited. ANCA bind antigens (proteinase-3 or myeloperoxidase) on primed neutrophils, activating them to degranulate, generate a respiratory burst, and release neutrophil extracellular traps — which injure the small-vessel endothelium directly. In the glomerulus this produces focal necrosis and crescents with little or no immune-complex deposition, the ‘pauci-immune’ pattern that defines the renal lesion.

Systemic and renal manifestations

• Systemically it is protean: constitutional symptoms, ENT disease in GPA (sinusitis, nasal crusting, the saddle-nose deformity, subglottic stenosis), pulmonary involvement (haemorrhage, nodules, infiltrates), purpuric skin, mononeuritis multiplex, and scleritis. Renally it causes haematuria with red-cell casts, proteinuria, and a rising creatinine — a rapidly progressive glomerulonephritis. The combination of lung haemorrhage and glomerulonephritis — pulmonary-renal syndrome — is the most feared presentation.

Diagnosis: serology and biopsy

• ANCA serology supports the diagnosis: PR3 or MPO antibodies by ELISA, corresponding to the cytoplasmic (c-ANCA) and perinuclear (p-ANCA) patterns on immunofluorescence. But the biopsy is the gold standard — a pauci-immune necrotizing crescentic glomerulonephritis confirms the diagnosis and, through its balance of active (cellular crescents, necrosis) and chronic (sclerosis, fibrosis) lesions, predicts the potential for renal recovery.

PR3 versus MPO and the mimics

• The serotype carries prognostic weight: PR3-ANCA disease (typically GPA) relapses more often than MPO-ANCA disease (typically MPA), which shapes the duration of maintenance. Crucially, ANCA-positive patients must also be tested for anti-GBM antibody, because double-positive disease occurs and behaves badly; lupus and infection are the other mimics to exclude.

Induction treatment

• Organ- or life-threatening disease is treated urgently with induction: glucocorticoids plus either rituximab or cyclophosphamide. Rituximab (anti-CD20) is non-inferior to cyclophosphamide and is preferred in relapsing disease, younger patients, and where fertility matters; cyclophosphamide remains an alternative. The aim is rapid control of the necrotizing inflammation before the kidneys are lost.

Plasma exchange and reduced-dose steroids

• Two practice-changing trial results define the adjuncts. Plasma exchange, once routine for severe disease, gave no overall benefit on death or end-stage kidney disease in a large trial — so it is now used selectively, considered for severe renal disease (especially dialysis-requiring) or pulmonary haemorrhage rather than for all. And a reduced-dose glucocorticoid regimen proved non-inferior to standard high doses while causing less serious infection, so lower steroid dosing is now favoured.

Maintenance and relapse

• After remission, maintenance immunosuppression — scheduled rituximab (preferred) or azathioprine — is continued for years, because relapse is common, particularly in PR3-ANCA/GPA. Glucocorticoids are tapered. A rising ANCA titre predicts relapse only imperfectly, so it informs rather than dictates decisions.

Avacopan and steroid-sparing

• The newest strand is steroid-sparing: avacopan, an oral C5a-receptor antagonist that blocks complement-mediated neutrophil priming, has been shown to sustain remission while markedly reducing glucocorticoid exposure — part of a broader move to limit the steroid toxicity that has long accompanied treatment of this disease.

Evidence and prognosis

• The evidence base is strong and still moving: rituximab non-inferior to cyclophosphamide (RAVE, RITUXVAS), plasma exchange without overall benefit and reduced-dose steroids non-inferior (PEXIVAS), and avacopan steroid-sparing (ADVOCATE). The disease relapses and remits, PR3/GPA relapsing more; renal recovery is possible even from dialysis dependence if treated promptly; and infection — from the immunosuppression itself — is a leading cause of early death, which is precisely why steroid minimisation and prophylaxis matter.

Five fully-built tables.

Table A — The three forms

Table B — Manifestations

Table C — Diagnosis

Table D — Induction and adjuncts

Table E — Maintenance and relapse

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — ANCA to crescent

ANCA bind primed neutrophils → activation, degranulation, and NETs → small-vessel endothelial injury → necrotizing crescentic GN → ACTION: immunosuppress to halt the inflammation.

Chain 2 — The pauci-immune signature

Injury is antibody-driven but not deposited → little/no immune complexes → a pauci-immune pattern on immunofluorescence → ACTION: biopsy with IF/EM to distinguish it from immune-complex GN.

Chain 3 — The relapse tendency

PR3-ANCA / GPA → a higher relapse rate → disease recurs after remission → ACTION: give longer maintenance, favouring rituximab.

Chain 4 — Double trouble

ANCA and anti-GBM can coexist → double-positive disease → worse outcomes → ACTION: test both antibodies and treat (with plasma exchange) accordingly.

Chain 5 — The cost of treatment

Intense immunosuppression (especially high-dose steroids) → impaired defence → serious infection (a leading early death) → ACTION: use reduced-dose steroids and infection prophylaxis.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Five cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Patient Decisions

Outcomes as natural frequencies. Figures are representative; the direction of effect is given where precise numbers are uncertain.

Apply & Test

Copy-paste chart notes that map to the real decisions in this chapter.

Template 1 — AAV diagnosis note

• Presentation: systemic (ENT/lung/skin/nerve) and renal (RPGN) features ___.
• Serology: PR3 / MPO ___; anti-GBM (double-positive?) ___.
• Biopsy: pauci-immune necrotizing crescentic GN; active vs chronic lesions ___.
• Form: GPA / MPA / EGPA; organ/life-threatening? ___.
• Mimics excluded (lupus, infection): ___.

Template 2 — Induction / maintenance plan note

• Induction: reduced-dose glucocorticoids + rituximab / cyclophosphamide ___.
• Plasma exchange (severe renal/pulmonary)? rationale ___.
• Prophylaxis: Pneumocystis (co-trimoxazole); others ___.
• Maintenance: rituximab / azathioprine; planned duration (longer if PR3/GPA) ___.
• Monitoring: renal function, ANCA, relapse watch ___.

Pre-rounds compression. Rules only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Metacognition anchored to this chapter's tensions. No answers provided.

1. 1. Plasma exchange has no overall benefit yet may help the sickest; how do you decide when an unproven adjunct is worth using in the patient in front of you?
2. 2. Reduced-dose steroids match high-dose with less infection; how readily should a single landmark trial change a long-standing habit?
3. 3. A rising ANCA predicts relapse imperfectly; how do you act on a marker that informs but does not decide?
4. 4. Treatment can salvage a dialysis-dependent kidney but can also kill with infection; how do you weigh aggressive immunosuppression against its own lethality?
5. 5. Maintenance duration trades relapse prevention against cumulative drug harm; in a relapse-prone PR3 patient, where do you draw the line?

Nine items, each anchored in this chapter. At least one per objective.