ANCA-associated vasculitis

Meet the patient

A 62-year-old man presents with three months of nasal crusting and epistaxis, two months of arthralgia and weight loss, and one week of dark urine. His creatinine has risen to 320 µmol/L with microscopic haematuria and red cell casts, ANCA returns strongly c-ANCA with anti-PR3 positivity, and a chest CT shows two cavitating nodules in the right lung.^[1]

Two questions decide his next hour, and they are the two that decide every AAV case: is a critical organ failing — kidney, lung, heart, or nerve? (decides induction intensity and whether plasma exchange joins the bundle) and which subtype is this? (the antigen plus the phenotype decide drug choice, relapse risk, and prognosis). Hold those two questions and the whole disease slots into place.^[1][3]

Three masks, one antigen — the face-off that earns the marks

AAV is one pauci-immune necrotising vasculitis read through the ANCA antigen, and the three subtypes part cleanly on a single feature each. Granulomatosis with polyangiitis (GPA, formerly Wegener) carries PR3-ANCA / c-ANCA in 75 to 90 percent with the classic ENT, pulmonary, and renal granulomatous triad. Microscopic polyangiitis (MPA) carries MPO-ANCA / p-ANCA in 40 to 80 percent with renal-predominant disease and no granulomas. Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss) carries MPO-ANCA in about 40 percent and is defined by asthma, eosinophilia, and neuropathy.^[1][2]

^[1]

One-line discriminator beneath the table: nose plus nodules plus PR3 is GPA; renal plus neuropathy plus MPO with no nose is MPA; asthma plus eosinophils plus a dropped foot is EGPA.^[1]

The classic trap: the conceptual shift since 2020 is from immunofluorescence-pattern classification (c-ANCA/p-ANCA) toward antigen-based classification (PR3-AAV / MPO-AAV), because the antigen specificity predicts relapse rate, organ involvement, and response to therapy better than the pattern label does. PR3-AAV relapses more; MPO-AAV carries a higher chronic-damage burden on renal biopsy.^[1]

Why the biopsy is "pauci-immune" despite complement involvement

AAV is an ANCA-driven, neutrophil-mediated endothelial injury with amplificatory loops — NETosis and the alternative complement pathway — but without significant immune-complex deposition. That paradox is the whole reason the biopsy reads "pauci-immune", and it is worth being able to explain at viva depth.^[2]

Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, C5a) prime neutrophils, translocating PR3 and MPO from cytoplasmic granules to the plasma membrane. Circulating IgG ANCA then binds via its Fab region to the membrane antigen while its Fc region engages FcγRIIa and FcγRIIIb, cross-linking and activating the neutrophil.^[1]

Activated neutrophils degranulate (releasing PR3, MPO, elastase), generate reactive oxygen species, and extrude neutrophil extracellular traps (NETs) — chromatin webs decorated with PR3 and MPO that damage the endothelium and perpetuate autoimmunity. The result is fibrinoid necrosis of the vessel wall, microvascular thrombosis, and — in the glomerulus — the cellular crescent of pauci-immune crescentic GN.^[1]

Why "pauci-immune" if complement is involved? The alternative pathway amplifies inflammation at the tissue level without depositing large immune complexes — there is little immunoglobulin, and complement fragments act as anaphylatoxins (C3a, C5a) rather than as membrane attack complexes on the basement membrane. Hence the paradox. The C5a feed-forward loop is the rationale for avacopan, the oral C5a-receptor antagonist that steroid-spares induction.^[1]

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Clinical presentation — the system-by-system read

AAV presents with a combination of constitutional, organ-specific, and cutaneous features, and the phenotype dictates both the ANCA expected and the urgency of induction. A comprehensive review of systems is mandatory at first contact — the patient who describes "sinus trouble, cough, dark urine, and tingling feet" is a textbook GPA; the asthmatic who develops a foot drop with new eosinophilia is a textbook EGPA.^[1][3][4]

GPA is the prototypical relapsing AAV. ENT disease (refractory sinusitis, nasal crusting, epistaxis, saddle-nose deformity, subglottic stenosis, orbital pseudotumour) hits about 90 percent; lower-respiratory disease (cavitating nodules, diffuse alveolar haemorrhage) about 70 to 80 percent; and renal rapidly progressive glomerulonephritis about 70 to 80 percent. Skin shows palpable purpura, nodules, ulcers, and digital infarcts in 35 to 50 percent.^[1]

MPA is the renal-pulmonary-neuropathy AAV without granulomas — the absence of sinusitis or nasal crusting at presentation is a high-yield clue distinguishing it from GPA. Renal disease hits about 90 percent, pulmonary capillaritis with or without diffuse alveolar haemorrhage 30 to 50 percent, and mononeuritis multiplex 30 to 60 percent.^[1]

EGPA classically unfolds in three overlapping phases — allergic (adult-onset asthma, allergic rhinitis, nasal polyposis), eosinophilic (peripheral eosinophilia greater than 1.5 × 10⁹/L, transient pulmonary infiltrates), and vasculitic (mononeuritis multiplex, cardiomyopathy — the leading cause of death, glomerulonephritis). The ANCA status partitions it: ANCA-positive is the vasculitic phenotype; ANCA-negative is the eosinophilic and cardiac phenotype.^[5][6]

The cutaneous signature and the constitutional opener

Palpable purpura on dependent areas is the most common cutaneous lesion across all three subtypes — leukocytoclastic vasculitis on biopsy — and it is the dermatology exam's route into AAV. Crops of non-blanching papules on the lower legs and ankles, often over weeks, are the classic presentation; subcutaneous nodules, ulcers with undermined violaceous borders, livedo reticularis, and digital infarcts complete the picture.^[8]

Constitutional features — fever, weight loss, night sweats, myalgia, arthralgia — attend nearly every patient at presentation. Strawberry gingivitis is pathognomonic of GPA when present, and scleritis with peripheral ulcerative keratitis is sight-threatening and needs ophthalmology within 24 hours. Venous thromboembolism is increased two- to three-fold during active disease and the first six months of immunosuppression.^[1][8]

Drug-induced AAV deserves a named line because it is a contemporary entity. Levamisole-adulterated cocaine produces sudden AAV with very high-titre p-ANCA and PR3-ANCA, characteristic ear-pinna necrosis, retiform purpura, neutropenia, and a positive ANA with anti-histone antibodies. Propylthiouracil, hydralazine, minocycline, allopurinol, and anti-TNF agents are the other culprits — stop the drug first.^[1][4]

The bedside round and the activity instruments

A structured bedside examination supports the diagnosis, gauges severity, and identifies the biopsy site. Begin with the vital signs — a falling SpO2 with bloodstained sputum is diffuse alveolar haemorrhage until proven otherwise — and inspect the skin on dependent areas, photographing each lesion for serial comparison.^[1]

Examine the ENT and the often-neglected oral cavity: anterior rhinoscopy for crusting and septal perforation, inspection for saddle nose and proptosis, the oral cavity for strawberry gingivitis, and fibreoptic nasendoscopy for subglottic stenosis in hoarse or stridulous patients. The neurological exam maps named peripheral nerves — foot drop (common peroneal), wrist drop (radial), sural and ulnar sensory loss.^[1]

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The Five Factor Score (FFS, 2009 revision) is prognostic, not activity: one point each for age over 65, cardiac involvement, renal involvement (creatinine over 150 µmol/L), gastrointestinal involvement, and absence of ENT involvement; score 0 versus 1 versus 2 or more stratifies 5-year mortality at roughly 12, 26, and 46 percent. The Vasculitis Damage Index (VDI) measures cumulative irreversible damage, separate from current activity.^[1]

Investigations — serology, biopsy, and the mimics to exclude

A diagnosis of AAV rests on a triad of serology (ANCA), histology (biopsy), and organ involvement — no single test is definitive, and a negative ANCA does not exclude AAV if the clinical phenotype is typical. The standard approach is a two-step strategy: indirect immunofluorescence to identify the pattern, then a confirmatory antigen-specific ELISA for PR3 and MPO.^[1]

^[1]

The renal biopsy is the gold standard for renal AAV — pauci-immune necrotising crescentic GN with focal and segmental fibrinoid necrosis of the glomerular tuft, cellular crescents, disrupted basement membrane, and little or no IgG, IgM, IgA, C3, or C1q on immunofluorescence. Skin biopsy of a purpuric lesion shows leukocytoclastic vasculitis with neutrophilic infiltrate and fibrinoid necrosis, and no immune deposits on direct immunofluorescence.^[1][8]

^[1]

Before immunosuppression, exclude the mimics that would change the plan: anti-GBM antibody (Goodpasture and double-positive overlap), ANA and dsDNA with C3 and C4 (SLE), hepatitis B and C and HIV (mandatory before rituximab or cyclophosphamide), and cryoglobulins with low C4. Interpret ANCA in context — a small rise with a flat pattern in renal failure is chronic injury, not acute infarction.^[1]

Differential — the pulmonary-renal and the ANCA-negative mimics

The differential of AAV is wide, and any exam answer should triage pauci-immune necrotising vasculitis plus ANCA before going to alternatives. Two mimics recur in every viva and reward a single discriminator each.^[1][8]

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Management — resuscitation, then the induction-and-maintenance spine

AAV becomes a medical emergency when renal function is deteriorating rapidly, when alveolar haemorrhage is producing hypoxaemia, when mononeuritis multiplex is acutely disabling, or when cardiac involvement is producing heart failure. The immediate bundle secures the airway (subglottic stenosis is fragile — avoid nasal intubation in severe GPA), gives cautious fluids, cross-matches for haemorrhage, and screens for infection before profound immunosuppression begins.^[1][3]

High-dose glucocorticoids are the immediate induction backbone for organ-threatening or life-threatening disease: EULAR recommends high-dose glucocorticoids combined with either rituximab or cyclophosphamide for remission induction, tapering to a target of 5 mg prednisolone equivalent per day within 4 to 5 months. Renal biopsy and ANCA testing establish the diagnosis; do not delay induction in the critically ill patient to obtain the biopsy.^[3]

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Definitive treatment runs in two phases — induction (three to six months, high-intensity) and maintenance (24 to 48-plus months, lower-intensity). The pivotal modern trials are RAVE, RITUXVAS, CYCLOPS, MAINRITSAN, IMPROVE, MEPEX, PEXIVAS, MIRRA, and ADVOCATE.^[1]

Induction — rituximab equals cyclophosphamide

Rituximab and cyclophosphamide are equivalent first-line induction partners for severe AAV, and the choice turns on relapse history, antigen, age, and fertility. RAVE (Stone, NEJM 2010) randomised 197 ANCA-positive patients with severe Wegener's granulomatosis or microscopic polyangiitis to rituximab 375 mg per square metre of body-surface area weekly for 4 weeks versus oral cyclophosphamide 2 mg per kilogram per day, both over a tapering glucocorticoid course; rituximab was non-inferior for remission without prednisone at 6 months (64 versus 53 percent) and superior in relapsing disease (67 versus 42 percent).^[9]

^{[9] [13]}

Rituximab is first-line in relapsing AAV, in PR3-AAV (higher relapse, rituximab maintenance is particularly effective), and in women of childbearing age where cyclophosphamide threatens fertility. Screen and prophylax hepatitis B before the first dose; watch for hypogammaglobulinaemia with repeated dosing and late-onset neutropenia two to three months after infusion. In renal AAV, RITUXVAS (Jones, NEJM 2010) combined rituximab 375 mg per square metre weekly for four weeks with two intravenous cyclophosphamide pulses: 76 percent sustained remission at twelve months, no better than intravenous cyclophosphamide (82 percent) — rituximab-based induction holds its own in severe renal disease.^[1][17]

Cyclophosphamide — give MESNA with each IV bolus and encourage hydration to protect the bladder from haemorrhagic cystitis and urothelial carcinoma; bank sperm and eggs before therapy because the gonadal toxicity is cumulative-dose dependent; reduce the dose in renal impairment and in the elderly. CYCLOPS showed pulse IV was non-inferior to oral with a lower cumulative dose but a slightly higher relapse rate long-term.^[1]

Glucocorticoids are the third pillar — and PEXIVAS showed that less is just as safe: in severe AAV a reduced-dose oral glucocorticoid regimen was non-inferior to the standard-dose regimen for death or end-stage kidney disease (27.9 versus 25.5 percent) and caused fewer serious infections at 1 year (incidence rate ratio 0.69) (Walsh, NEJM 2020). EULAR pairs this with an explicit taper target of 5 mg prednisolone equivalent per day within 4 to 5 months.^[10][3]

Plasma exchange and avacopan — when to add them

Plasma exchange is selective, not routine, since PEXIVAS showed no overall mortality or ESKD benefit — reserve it for the genuinely severe.^[1][3][10]

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Avacopan — the oral selective C5a-receptor antagonist — targets the alternative-complement amplification loop directly. ADVOCATE (Jayne, NEJM 2021) randomised 331 patients to avacopan 30 mg orally twice daily versus a tapering prednisone schedule, both on background rituximab or cyclophosphamide: avacopan was non-inferior for remission at week 26 (72.3 versus 70.1 percent) and superior for sustained remission at week 52 (65.7 versus 54.9 percent) — remission achieved in place of the oral prednisone taper. EULAR allows avacopan as part of a strategy to reduce glucocorticoid exposure in GPA and MPA.^[11][3]

EGPA-specific therapy — screen the heart, target the eosinophil

EGPA is the subtype where cardiac involvement is the leading cause of death, so every patient gets a cardiac screen at diagnosis and on follow-up — ECG, troponin, BNP, transthoracic echo, and cardiac MRI for subclinical myocarditis.^[5][6]

^{[16] [3] [7]}

Mepolizumab works better in the ANCA-negative, eosinophilic group; cyclophosphamide works better in the vasculitic group — the phenotypic split tracks both prognosis and treatment response.^[5][7]

Maintenance — after three to six months of induction

Relapse, not refractory disease, is the long-term problem — so maintenance is where the modern trials earn their keep. Rituximab is the EULAR-preferred maintenance agent for GPA and MPA: MAINRITSAN (Guillevin, NEJM 2014) found rituximab 500 mg on days 0 and 14 and at months 6, 12, and 18 left only 5 percent with a major relapse at month 28, versus 29 percent on azathioprine; EULAR lists azathioprine and methotrexate as the non-biologic alternatives.^[12][3]

^{[12] [15] [3]}

Azathioprine is the standard non-biologic maintenance — started at 2 mg/kg per day, it kept more patients relapse-free than mycophenolate mofetil in IMPROVE (30 of 80 versus 42 of 76 relapsed over a median 39 months). Co-trimoxazole 960 mg twice daily for 24 months reduced relapses in Wegener's granulomatosis in remission (82 versus 60 percent relapse-free at two years) and cut respiratory-tract infections (Stegeman, NEJM 1996).^[15][18]

The follow-through bundle — what EULAR adds after induction

^{[3] [7] [12] [18]}

Complications and the pitfalls that fail candidates

The preventable-harm list in AAV is short and unforgiving — every item is a case-losing error if missed.^[1]

• Treating the ANCA titre, not the patient. A rising PR3 titre predicts but does not equal relapse; MAINRITSAN defined major relapse as renewed clinical disease activity with a BVAS greater than 0 and organ involvement.^[12]
• Confusing diffuse alveolar haemorrhage with pneumonia. Haemoptysis plus falling haemoglobin plus diffuse ground-glass opacities plus a rising KCO is DAH until proven otherwise; the bronchoalveolar lavage is progressively bloodier.^[1]
• Missing the EGPA heart. Cardiomyopathy is the leading cause of death in EGPA — screen every patient with ECG, troponin, echo, and cardiac MRI.^[5][6]
• Skipping Pneumocystis prophylaxis. Cotrimoxazole is mandatory on cyclophosphamide, rituximab, and sustained high-dose steroids.^[1]
• Treating double-positive AAV as anti-GBM alone. Add plasma exchange plus AAV induction; higher relapse risk if anti-GBM persists.^[1]
• Ignoring fertility in cyclophosphamide exposure — discuss sperm and egg banking before therapy.^[1]

Prognosis, guidelines, and regional differences

Modern induction therapy has transformed AAV from a fatal illness to a chronic relapsing-remitting disease — 5-year survival is now 75 to 90 percent in severe disease. The leading causes of death are infection in the first two years, active vasculitis (especially DAH), cardiovascular disease, and end-stage kidney disease.^[1]

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PR3-AAV relapses in up to 50 percent at five years; MPO-AAV in 20 to 30 percent. Predictors of relapse: PR3-ANCA, ENT involvement at presentation, persisting PR3 positivity after induction, chronic nasal S. aureus carriage, and prior relapse. Predictors of ESKD: dialysis at presentation, creatinine over 500 µmol/L, crescents in over 50 percent of glomeruli, and severe tubulointerstitial fibrosis. Dialysis-dependent patients should be considered for renal transplant after one to two years of quiescent disease; recurrence post-transplant is uncommon.^[1]

^{[1] [3]}

The mantra, and the mnemonic

The mantra: PR3 plus nose plus nodules is GPA; MPO plus renal plus neuropathy is MPA; asthma plus eosinophils plus a dropped foot is EGPA — and in EGPA the heart kills first. Induce with rituximab or cyclophosphamide plus steroids, maintain with rituximab, and never treat the ANCA titre instead of the patient.^[1][3]

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Ward-round test

Stem 1 — A 62-year-old man has three months of nasal crusting and epistaxis, weight loss, a creatinine rising to 320 µmol/L with red cell casts, a strong c-ANCA with anti-PR3 positivity, and cavitating pulmonary nodules on chest CT. What is the diagnosis, and what is the induction?^[1]

AnswerShowHide

This is granulomatosis with polyangiitis (GPA, PR3-AAV) — the ENT plus pulmonary plus renal triad with PR3-ANCA is the classic pattern. Induction is high-dose glucocorticoids plus rituximab or cyclophosphamide (EULAR): rituximab 375 mg per square metre weekly for four weeks was non-inferior to oral cyclophosphamide 2 mg per kilogram per day in RAVE, and pulse cyclophosphamide 15 mg/kg every 2 to 3 weeks is the CYCLOPS alternative. Taper glucocorticoids toward the 5 mg per day target within 4 to 5 months. Renal biopsy and ANCA testing confirm the diagnosis; plasma exchange is no longer routine — PEXIVAS found no reduction in death or ESKD, though EULAR allows considering it in rapidly progressive glomerulonephritis.^{[3][9][13][10]}

Stem 2 — A 45-year-old asthmatic develops a left foot drop, a right wrist drop, and an eosinophil count of 2.8 × 10⁹/L. What is the diagnosis, what must you screen urgently, and why?^[5]

AnswerShowHide

This is eosinophilic granulomatosis with polyangiitis (EGPA) — asthma plus blood eosinophilia plus mononeuritis multiplex is the classic triad. Assess the heart: cardiomyopathy dominates the ANCA-negative, eosinophilic subset (lung infiltrates, cardiomyopathy), while ANCA-positive disease drives the vasculitic manifestations (glomerulonephritis, purpura, mononeuritis multiplex). For relapsing or refractory disease, EULAR recommends mepolizumab 300 mg subcutaneously every 4 weeks — in MIRRA it delivered at least 24 weeks of accrued remission in 28 versus 3 percent, and let 44 versus 7 percent of patients reach a prednisone dose of 4.0 mg per day or less.^[7][3][16]

Stem 3 — A registrar wants to re-induce a patient whose PR3-ANCA titre has risen but who is clinically well, in remission with a BVAS of 0 and stable renal function. What is the right call?^[11]

AnswerShowHide

Do not re-induce on the titre alone. MAINRITSAN defined a major relapse clinically — renewed disease activity with a BVAS greater than 0 plus major-organ involvement — so a laboratory shift by itself is not a relapse, and a positive ANCA at a single time point marks heightened relapse risk rather than a mandate to treat. Continue maintenance, intensify surveillance, and re-induce only on clinical reactivation. Treating the number instead of the patient is the recurring trainee error.^[12][18]

Stem 4 — An ANCA-positive patient with rapidly progressive glomerulonephritis is also anti-GBM positive, with pulmonary haemorrhage. What is the diagnosis, and what changes in the management?^[1]

AnswerShowHide

This is anti-GBM and ANCA double-positive disease — a pulmonary-renal syndrome with both antibodies. The change is to add daily plasma exchange until the anti-GBM antibody is undetectable, alongside full AAV induction (rituximab or cyclophosphamide plus corticosteroids). Treat as anti-GBM with the addition of the AAV immunosuppression protocol; the relapse risk is higher if anti-GBM persists, so long-term surveillance is essential.^[1]

References18ShowHide

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2. [2]Kitching AR, Anders HJ, Basu N, et al. ANCA-associated vasculitis Nat Rev Dis Primers, 2020.PMID 32855422
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13. [13]de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial Ann Intern Med, 2009.PMID 19451574
14. [14]Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis J Am Soc Nephrol, 2007.PMID 17582159
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16. [16]Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis N Engl J Med, 2017.PMID 28514601
17. [17]Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis N Engl J Med, 2010.PMID 20647198
18. [18]Stegeman CA, Tervaert JW, de Jong PE, et al. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis N Engl J Med, 1996.PMID 8637536