ANCA-Associated Vasculitis (GPA, MPA & EGPA)

Meet the patient

A 58-year-old man arrives after a week of blood-stained nasal discharge, facial pressure unresponsive to two antibiotic courses, and a morning cough that turned frank-red yesterday. His creatinine was normal six months ago and is now 340 micromol per litre; the urine dipstick shows blood and protein, and the microscopist phones through dysmorphic red cells and red cell casts.[1][3]

This is the patient the whole page is built for. Sinusitis plus epistaxis plus haemoptysis plus a rising creatinine is a pulmonary-renal syndrome until proven otherwise, and the clock is renal — you will meet this exact picture at 3am. The two questions that decide the next 24 hours are which small-vessel disease is this? and is there an anti-GBM overlap I must not miss?[1][5]

Hold those two questions. Send the ANCA with PR3 and MPO ELISA, anti-GBM, ANA, complement, hepatitis serology and cryoglobulins, dipstick the urine yourself, and call nephrology before the creatinine doubles. Untreated severe AAV is fatal within months, and the recurring reason a salvageable kidney becomes dialysis-dependent is a biopsy booked a day too late.[1][6]

One antibody, three faces — the PR3-versus-MPO fork

AAV is one mechanism wearing three masks, and the mask is set by which neutrophil antigen the ANCA binds. The 2012 Revised International Chapel Hill Consensus Conference (CHCC) nomenclature — the document examiners quote — defines AAV as a necrotising vasculitis of small vessels (capillaries, venules, arterioles, small arteries), with few or no immune deposits (pauci-immune), associated with ANCA.[3]

The three subtypes are granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss), sitting in the small-vessel group alongside the immune-complex vasculitides — IgA vasculitis, cryoglobulinaemia, anti-GBM disease, hypocomplementaemic urticarial vasculitis.[3]

Etymology for viva gold: the eponyms are being deliberately retired, and examiners expect to hear why. Wegener was named for the German pathologist Friedrich Wegener (1939) and renamed granulomatosis with polyangiitis after evidence of his Nazi-party membership surfaced. Churg and Strauss (New York, 1951) described the eosinophilic-granulomatous pattern; the modern name EGPA keeps their initials but describes the pathology rather than the men.[3]

The split that actually drives treatment is serological, not nominal: PR3-AAV versus MPO-AAV. PR3 disease carries more granulomatous ENT and respiratory disease and a relapsing course that answers to rituximab; MPO disease is more renal-limited and indolent. The 2021 ACR/VF classification criteria and 2022 EULAR recommendations both formalise this split.[1]

The face-off — one discriminator each: GPA adds granulomas and destroys the upper airway; MPA spares the ENT but fills the urine with casts; EGPA announces itself with asthma years before the vasculitis.[1][3]

Who gets it, and why the antigen finds the vessel

AAV is uncommon but not rare, and the antigen you find predicts where the patient came from. Annual incidence is about 10 to 20 per million (prevalence 100 to 200 per million), at the higher end in Northern European populations, peaking between 65 and 75 years — though EGPA often presents younger, at 40 to 55.[1]

A striking geographic and ethnic gradient runs through the antigen: PR3-ANCA and GPA dominate in Northern European and Caucasian populations, while MPO-ANCA and MPA predominate in East Asian and African-ancestry populations. Part of that is genetic — HLA-DP with PR3 and GPA, HLA-DQ and SERPINA1 (alpha-1-antitrypsin) with MPO and MPA — and part is environmental.[1]

The environmental cofactors a candidate is expected to name: silica (mining, farming, construction, sandblasting), occupational solvents, drugs, chronic Staphylococcus aureus nasal carriage (a relapse cofactor in GPA), and smoking. The dual-hit hypothesis stitches it together — genetic predisposition plus an environmental insult exposes PR3 or MPO and lets ANCA form.[1]

How ANCA burns the vessel — priming, NETs and the C5a loop

This is the prototypic antibody-driven vasculitis, and the mechanism is taught because each step is a drug target. ANCA are IgG antibodies against neutrophil granule proteins — chiefly proteinase 3 (PR3) and myeloperoxidase (MPO). The pathogenic chain:[1]

1. Prime. Cytokines (IL-1, TNF-alpha) from infection or inflammation shift PR3 and MPO from intracellular granules onto the neutrophil surface.
2. Bind. Circulating ANCA engage surface PR3 or MPO and cross-link Fc-gamma receptors, firing a strong activation signal.
3. Degranulate. The neutrophil releases proteases (PR3, elastase), reactive oxygen species and cytokines that shred the endothelium.
4. NETosis. Neutrophils extrude neutrophil extracellular traps (NETs) — DNA webs dressed in PR3, MPO, histones and antimicrobial peptides — that propagate more ANCA, deposit in glomeruli and trigger thrombosis. Impaired NET clearance (low DNase I activity) keeps the autoantigen on display.
5. Amplify. Activated neutrophils release factors that fire the alternative complement pathway, generating C5a. C5a, through the C5a receptor (CD88) on neutrophils, recruits and primes yet more neutrophils — a self-sustaining loop. This is why the biopsy looks pauci-immune despite ferocious complement activation: the loop amplifies locally without forming detectable immune complexes. Avacopan (a C5a-receptor blocker) is the drug built to break this loop, and it is licensed for steroid-sparing induction.[1]

The phenotype follows the antigen. PR3-AAV runs granulomatous, ENT and respiratory, and relapses; MPO-AAV runs renal-limited and indolent. EGPA is pathogenically separate — a Th2-skewed process with IL-5-driven eosinophil survival, tissue eosinophilia, raised IgE (especially in the ANCA-negative eosinophilic phenotype), eosinophilic-core granulomas, and necrotising vasculitis. The ANCA-negative eosinophilic phenotype behaves like severe eosinophilic asthma with organ inflammation; the ANCA-positive MPO phenotype behaves like MPA, with renal and neuropathic disease.[2][9]

Three subtypes, three maps — read the system involved

AAV declares itself across multiple systems at once or in sequence, and the system map points straight at the subtype. Constitutional features — fever, fatigue, weight loss, myalgia, arthralgia — are common to all three and can precede organ disease by weeks or months.[1]

Granulomatosis with polyangiitis (GPA)

GPA hits the ENT, the lower respiratory tract and the kidneys, in any order.[1]

• ENT (about 90 percent at presentation, eventually nearly all): refractory sinusitis, epistaxis (often bilateral, with crusting), painless oral and nasal ulcers (unlike the painful ulcers of Behcet disease), saddle-nose deformity from cartilage collapse, subglottic tracheal stenosis (stridor — a surgical airway emergency), conductive or sensorineural hearing loss, orbital pseudotumour (proptosis, diplopia, chemosis).
• Lower respiratory tract: cough, dyspnoea, haemoptysis — the cardinal sign of alveolar haemorrhage; imaging shows cavitating pulmonary nodules, consolidations, ground-glass change, pleural effusion.
• Renal: rapidly progressive glomerulonephritis — rising creatinine, microscopic haematuria, dysmorphic red cells, red cell casts, sub-nephrotic proteinuria; untreated, this reaches ESKD within weeks.
• Other: mononeuritis multiplex, palpable purpura, scleritis or episcleritis, pericarditis, mesenteric vasculitis, prostatitis.[1]

Microscopic polyangiitis (MPA)

MPA is the archetype of pauci-immune necrotising small-vessel vasculitis with no granulomatous inflammation.[1]

• Renal (the commonest organ): idiopathic rapidly progressive pauci-immune GN — active sediment with red cell casts, rising creatinine.
• Pulmonary: pulmonary capillaritis causing diffuse alveolar haemorrhage (DAH) — haemoptysis, dyspnoea, hypoxaemia, falling haemoglobin, rising carbon monoxide transfer factor (KCO).
• Other: mononeuritis multiplex, palpable purpura, scleritis, constitutional symptoms, arthralgia.
• No destructive ENT disease — the cardinal line that separates MPA from GPA.[1]

Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss)

EGPA evolves in three phases over years — and the asthma almost always comes first.[2]

1. Prodromal (allergic) phase: adult-onset asthma (often severe and steroid-resistant), allergic rhinitis, nasal polyposis — frequently present years before vasculitis.
2. Eosinophilic phase: peripheral eosinophilia (over 10 percent or over 1.5 times ten to the ninth per litre), tissue eosinophilia, Loeffler-like fleeting pulmonary infiltrates, gastrointestinal eosinophilia (abdominal pain, diarrhoea).
3. Vasculitic phase: necrotising vasculitis — mononeuritis multiplex (the commonest vasculitic manifestation — wrist drop, foot drop), eosinophilic cardiomyopathy (heart failure, arrhythmia, endomyocardial fibrosis — the leading cause of death), mesenteric vasculitis, glomerulonephritis (more often in ANCA-positive disease), purpura and nodules.[2][9]

Atypical presentations — the ones that bite

The atypical presentations are the ones that hurt patients, because they are missed.[1]

• Elderly onset: more renal-predominant and more pulmonary haemorrhage, less ENT and granuloma; tolerate cyclophosphamide and high-dose steroids badly — favour rituximab and reduced-dose steroids (PEXIVAS supports the lower dose). Age over 65 is itself a Five Factor Score point.
• Drug-induced AAV (propylthiouracil, hydralazine, levamisole-cocaine, anti-TNF): high-titre p-ANCA plus PR3, cutaneous purpura — classically retiform, ear and necrotic in levamisole-cocaine — arthralgia, often renal-limited; remits on stopping the drug, with immunosuppression if an organ is threatened.
• Limited GPA (seronegative, ENT only): ANCA may be negative — biopsy and imaging make the call; treated with local measures, methotrexate or rituximab.
• Double-positive ANCA plus anti-GBM (Goodpasture overlap): pulmonary-renal syndrome carrying both antibodies; urgent daily plasma exchange to clear anti-GBM plus induction immunosuppression; the ANCA arm relapses, so maintenance continues.[1][5]

The killers that mimic AAV — exclude anti-GBM first

Three pivotal decisions: recognise the pulmonary-renal syndrome, exclude infection and malignancy (which immunosuppression would worsen), and consider a drug cause (which remits on withdrawal).[1]

In the wider net, name SLE (ANA, low complement, immune-complex GN), IgG4-related disease (mass-like lesions, high serum IgG4, storiform fibrosis), sarcoidosis (non-caseating granulomas, bilateral hilar lymphadenopathy), sinonasal NK or T-cell lymphoma mimicking GPA ENT disease (biopsy is mandatory in destructive sinus disease), tuberculosis and atypical infection, and cocaine-induced midline destructive lesion (no vasculitis on biopsy, no ANCA response to immunosuppression). And do not forget infectious mononucleosis in a young adult with fever, sore throat and lymphadenopathy — a classic mimic of the constitutional prodrome, and a reason to check EBV serology before blaming the ANCA.[1][7]

The bedside round — look at the nose, dip the urine

Examination rarely hands you the diagnosis; it tells you which organs are involved and how fast. Run it as a focused multi-system sweep at first contact and at every flare.[1]

ENT: nasal bridge (saddle deformity), nasal cavity (crusting, ulceration, septal perforation), oral cavity (painless palatal or gingival ulcers), otoscopy (serous otitis media, conductive loss), then look for proptosis, red eye and salivary-gland swelling.[1]

Respiratory: listen for stridor (subglottic stenosis — a surgical airway emergency), crackles or bronchial breathing in haemorrhage or pneumonia, and respiratory failure. Falling haemoglobin plus rising KCO supports diffuse alveolar haemorrhage even when there is no haemoptysis.[1]

Renal and fluids: blood pressure (hypertension in renal AAV), JVP, fluid balance, oedema — then bedside urine dipstick and microscopy for dysmorphic red cells and red cell casts, the cardinal sign of glomerular disease.[1]

Neurological: mononeuritis multiplex (asymmetric — wrist drop, foot drop, sensory loss in named nerves), sensorimotor neuropathy, cranial nerves (especially sensorineural hearing loss in GPA).[1]

Skin and abdomen: palpable non-blanching purpura on the lower limbs, nodules, digital infarcts, livedo; abdominal tenderness for mesenteric vasculitis; testicular tenderness points more to PAN.[1]

Three scores — activity, prognosis, damage

Name the trio and keep them straight: BVAS drives induction, FFS drives escalation, VDI tracks what is left behind.[1]

The Five Factor Score (FFS, 2009 revision, Guillevin) is the prognostic instrument for AAV and PAN:[1]

The Vasculitis Damage Index (VDI) records cumulative damage — non-reversible scarring from disease or treatment — and is distinct from activity. The trio mantra: BVAS equals activity, FFS equals prognosis, VDI equals damage.[1]

Two tests, then biopsy — the ANCA strategy and the gold standard

Work up AAV in stages: bloods, urine, ANCA, biopsy — each tier refining the next.[1]

First-line bloods: FBC (anaemia of chronic disease, eosinophilia in EGPA, thrombocytosis as an acute phase); ESR and CRP (raised but non-specific); U&E and creatinine; LFT (low albumin, hepatitic pattern in drug or viral overlap); serum IgG and IgE (IgE high in EGPA); creatine kinase if myositis overlaps.[1]

Urinalysis and microscopy is the single most important bedside test in suspected AAV. Look for microscopic haematuria, dysmorphic red cells and red cell casts — the cardinal sign of glomerulonephritis (AAV, anti-GBM, SLE, IgA nephritis) — and send a urine protein-to-creatinine ratio (sub-nephrotic in AAV).[1]

ANCA is a two-step test — pattern by immunofluorescence, confirmed by antigen-specific ELISA:[1]

1. Indirect immunofluorescence on ethanol-fixed neutrophils reads the pattern: c-ANCA (diffuse cytoplasmic, granular) usually means anti-PR3; p-ANCA (perinuclear) usually means anti-MPO. Atypical patterns crop up in drug-induced disease and inflammatory bowel disease.
2. Antigen-specific ELISA for anti-PR3 and anti-MPO is the diagnostic standard and the basis of the PR3-versus-MPO split.[1]

ANCA yield by subtype: PR3 in about 75 to 90 percent of GPA, MPO in about 40 to 80 percent of MPA, and MPO in about 40 percent of EGPA. ANCA can be negative in limited GPA (ENT only), in some drug-induced cases, and early in disease — a negative result does not exclude AAV, and biopsy is still diagnostic.[1]

The classic trap: ANCA titre is not a reliable flare marker in isolation. Relapse can occur without a titre rise, and titre can rise without relapse — treat the patient and the BVAS, not the number.[1]

Tissue biopsy is the diagnostic gold standard:[1]

• Renal biopsy is the highest-yield single specimen in pulmonary-renal presentation: pauci-immune necrotising crescentic glomerulonephritis — segmental fibrinoid necrosis of the capillary tuft with cellular crescents in Bowman space, little or no IgG or C3 on immunofluorescence (contrast the linear IgG of anti-GBM and the full-house pattern of lupus). The chronicity index — tubulointerstitial fibrosis and glomerular sclerosis — predicts renal recovery.
• Lung biopsy shows necrotising granulomatous inflammation with geographic necrosis and a palisading histiocyte rim — diagnostic of GPA, but rarely needed once ENT and renal biopsies have spoken.
• Sinus or nasal mucosal biopsy is often non-specific but excludes sinonasal lymphoma, squamous carcinoma, tuberculosis and cocaine-related destruction; repeat if the first is bland.
• Skin biopsy of palpable purpura shows leukocytoclastic vasculitis with nuclear debris (karyorrhexis); eosinophils suggest EGPA.[1]

Imaging: high-resolution CT chest for cavitating nodules, consolidation, ground-glass DAH, pleural effusion, tracheobronchial thickening; CT sinuses for bony destruction, septal perforation, opacification. Reserve angiography for polyarteritis nodosa (microaneurysms and beading of medium arteries) — it has no role in AAV. In DAH, bronchoscopy shows progressively bloodier lavage from serial aliquots with negative microbiology.[1]

Adjuncts to exclude mimics: anti-GBM, ANA with anti-dsDNA and C3 and C4, hepatitis B and C, HIV, cryoglobulins and serum electrophoresis, serum IgG4, blood cultures and echocardiogram (endocarditis), and QuantiFERON-TB or IGRA before immunosuppression.[1]

The pulmonary-renal emergency — resuscitate, then induce within hours

Recognise the pulmonary-renal syndrome, diffuse alveolar haemorrhage and rapidly progressive GN as emergencies. Untreated severe AAV is fatal within months; the aim is to stabilise airway, breathing and circulation, treat hypoxaemia and AKI, secure the diagnosis, and start induction within hours to days.[1]

Immediate measures:[1]

• ABC and oxygenation for hypoxaemia (DAH), lung-protective ventilation if intubated.
• IV access and cross-match — ongoing alveolar haemorrhage may need transfusion; correct hypovolaemia cautiously, because over-resuscitation worsens pulmonary haemorrhage and renal hypertension.
• Avoid nephrotoxins (NSAIDs, aminoglycosides, contrast where possible); manage fluids and electrolytes for AKI; call nephrology early for possible dialysis.
• Admit suspected severe AAV (creatinine rising fast, haemoptysis or DAH, hypoxaemia, severe neuropathy, carditis, mesenteric ischaemia) with a multidisciplinary call — nephrology, rheumatology, respiratory, ICU.
• Treat anti-GBM overlap (double-positive) with daily plasma exchange until anti-GBM is undetectable, plus induction immunosuppression.[1][5]

Investigations to send BEFORE induction — because induction is profoundly immunosuppressive:[1]

• ANCA (PR3 and MPO), anti-GBM, ANA and complement.
• Urinalysis and urine protein-to-creatinine ratio; renal biopsy within days.
• Hepatitis B and C, HIV; QuantiFERON or IGRA; HBV DNA, HBsAg and HBcore for pre-emptive antiviral therapy before rituximab or cyclophosphamide.
• Infection screen — cultures, chest imaging, urinalysis; echocardiogram if bacteraemia or endocarditis is suspected.
• Baseline FBC, U&E, LFT, glucose, lipids, bone profile for steroid and cyclophosphamide toxicity monitoring.[1]

Immediate induction (within hours of organ-threatening disease): IV methylprednisolone 500 mg to 1 g daily for 3 days, then oral prednisolone 1 mg/kg (max 60 to 80 mg daily), tapering over months. Add rituximab 375 mg per square metre weekly for 4 doses, OR cyclophosphamide 15 mg/kg IV every 2 to 4 weeks as soon as the diagnosis is secure.[1][4]

Plasma exchange is considered for creatinine over 500 micromol per litre, dialysis-dependent renal AAV, severe diffuse alveolar haemorrhage with hypoxaemia, or anti-GBM overlap. PEXIVAS (2020) showed no overall benefit on death or ESKD, so use is now selective rather than routine; many units still follow MEPEX and KDIGO guidance for the most severe renal presentations.[5][6]

Induction, maintenance and the rituximab revolution

Definitive therapy runs in four phases: induction (remission by 3 to 6 months), maintenance (sustain remission 24 to 36 months or longer), relapse management, and supportive care.[1]

Induction — steroids plus rituximab or cyclophosphamide

• Glucocorticoids: IV methylprednisolone 500 mg to 1 g daily for 3 days, then oral prednisolone 1 mg/kg (max 60 to 80 mg daily), tapered to about 10 to 15 mg by 3 months and to 5 to 7.5 mg by 6 months. PEXIVAS supports a reduced-dose glucocorticoid regimen to limit infection and steroid toxicity.[5]
• Rituximab (anti-CD20): 375 mg per square metre IV weekly for 4 doses (RAVE regimen) OR 1 g IV at day 0 and day 14. RAVE (Stone, NEJM 2010) made rituximab non-inferior to cyclophosphamide for severe AAV and superior in relapsing disease — preferred in PR3-AAV, relapsing disease, women of childbearing potential, and where cyclophosphamide toxicity is a concern.[4]
• Cyclophosphamide: IV pulse 15 mg/kg every 2 to 4 weeks (CYCLOPS regimen) OR oral 2 mg/kg daily for 3 to 6 months; pulse IV is non-inferior to daily oral at a lower cumulative dose, at the cost of slightly higher long-term relapse. Dose-reduce in the elderly and in renal impairment.[1]
• Plasma exchange (PLEX): 7 to 14 sessions of 60 mL/kg exchange over 2 to 4 weeks, with human albumin and (if bleeding or recent biopsy) fresh-frozen plasma. PEXIVAS showed no overall benefit on death or ESKD — use selectively for creatinine over 500 micromol per litre, dialysis-dependent renal AAV, severe DAH with hypoxaemia, or anti-GBM overlap.[5]
• Avacopan (C5a receptor blocker): 30 mg orally twice daily as a glucocorticoid-sparing induction agent (ADVOCATE trial, Jayne, NEJM 2021) — a licensed option for selected patients who tolerate high-dose steroids badly.[1]

Maintenance — rituximab now leads

• Rituximab (preferred, especially in PR3-AAV and relapsing disease): 1 g IV every 4 months OR 500 mg IV every 6 months for at least 24 to 36 months — longer in PR3-AAV.
• Azathioprine 2 mg/kg/day — the long-standing first-line maintenance.
• Mycophenolate mofetil 2 g/day — useful when azathioprine is not tolerated; IMPROVE (Hiemstra, JAMA 2010) showed azathioprine superior to mycophenolate for relapse-free maintenance, so mycophenolate is second-line.[8]
• Methotrexate 20 to 25 mg/week with folate — for non-severe or limited AAV only.
• Low-dose prednisolone continued for at least 12 to 18 months, then tapered under BVAS and ANCA monitoring.[1]

EGPA-specific therapy — mepolizumab for the eosinophilic phenotype

• Mepolizumab (anti-IL-5), 300 mg subcutaneously every 4 weeks, for the eosinophilic phenotype with asthma — MIRRA (Wechsler, NEJM 2017) improved remission and steroid-sparing in relapsing or refractory EGPA.[9]
• Cyclophosphamide plus glucocorticoids for severe organ-threatening EGPA (cardiac, severe neuropathy, mesenteric, renal).
• Avoid long-term high-dose steroids — cardiac and bone toxicity dominate the long game in EGPA.[2]

Relapse and limited disease

• Re-induce with rituximab (preferred) or cyclophosphamide plus glucocorticoids; consider fixed-schedule rituximab maintenance to prevent relapse in PR3-AAV.
• Cotrimoxazole (trimethoprim-sulfamethoxazole) reduces GPA relapse by clearing Staphylococcus aureus nasal carriage.
• ENT-dominant GPA: topical nasal steroids, saline irrigation, intralesional steroid for subglottic stenosis, cotrimoxazole 960 mg twice daily for staphylococcal carriage; methotrexate or mycophenolate plus rituximab increasingly used for non-severe disease.[1]

The supportive care bundle — where the preventable killers hide

• Pneumocystis jirovecii prophylaxis: cotrimoxazole 480 mg daily (or 960 mg three times weekly) on cyclophosphamide, rituximab, or sustained high-dose steroids (over 20 mg prednisolone for over 4 weeks). PJP is a preventable killer on induction — prescribe it on day one, not when the cough starts.[1]
• Bone protection: calcium and vitamin D, plus a bisphosphonate or denosumab on long-term steroids; bone densitometry.
• Gastric protection: PPI for high-risk patients on steroids (watch hypomagnesaemia with avacopan).
• Vaccination — influenza, pneumococcal, COVID-19, hepatitis B, shingles (recombinant zoster vaccine preferred if immunosuppressed) before immunosuppression where possible; avoid live vaccines during immunosuppression.
• Screening: latent TB (IGRA), hepatitis B (HBsAg, HBcore — pre-emptive entecavir or tenofovir), hepatitis C, HIV.
• Cardiovascular risk: aggressive modification — smoking cessation, statin, blood-pressure control; chronic inflammation accelerates atherosclerosis.
• VTE prophylaxis in hospital — active AAV is prothrombotic.[1]

The preventable killers — complications and the classic traps

Disease-related complications

• End-stage kidney disease: dialysis or transplant; outcome hinges on creatinine at presentation and the chronicity index.
• Saddle-nose deformity and conductive deafness: chronic structural damage from granulomatous ENT inflammation.
• Subglottic tracheal stenosis: surgical dilatation, intralesional steroid, sometimes tracheostomy.
• Peripheral neuropathy (mononeuritis multiplex): often incomplete recovery.
• EGPA cardiomyopathy: heart failure, arrhythmia, eosinophilic endomyocardial fibrosis — the leading cause of death in EGPA.
• Mesenteric vasculitis: abdominal pain, bleeding, perforation.
• Pulmonary fibrosis: after recurrent DAH.
• Venous thromboembolism: high VTE risk in active AAV — prophylax in hospital.[1]

Treatment-related complications

• Infection — the leading cause of early death: Pneumocystis jirovecii pneumonia, CMV, fungal, bacterial sepsis. Cotrimoxazole prophylaxis is mandatory on cyclophosphamide or sustained high-dose steroids.
• Cyclophosphamide: cytopenias, haemorrhagic cystitis, bladder cancer, infertility (bank sperm or oocytes for younger patients).
• Glucocorticoids: diabetes, osteoporosis, avascular necrosis, hypertension, cataract, psychosis, infection, peptic ulcer.
• Rituximab: late-onset neutropenia, hypogammaglobulinaemia (monitor IgG before each course), HBV reactivation, infusion reactions, rare PML.
• Plasma exchange: catheter infection and thrombosis, bleeding (especially without fresh-frozen plasma after biopsy), citrate hypocalcaemia.[1]

The classic traps that lose kidneys and lives

• Missing limited GPA (seronegative, ENT only): biopsy despite a negative ANCA.
• Treating the ANCA titre instead of the patient: titre is not a reliable flare marker — relapse without rise, rise without relapse.
• Missing double-positive (ANCA plus anti-GBM) disease: needs rituximab or cyclophosphamide and daily plasma exchange.
• Forgetting Pneumocystis prophylaxis: PJP is a preventable killer on induction — cotrimoxazole 480 mg daily from day one.
• Confusing DAH with infective pneumonitis: bronchoscopy and culture, with a rising KCO, tell them apart.
• Giving full-dose cyclophosphamide to the elderly without dose reduction — unacceptable toxicity.
• Calling destructive sinus disease GPA without biopsy: sinonasal lymphoma, sarcoidosis, TB and cocaine-related destruction all mimic it — tissue is essential.[1]

Prognosis — survival, relapse and the renal question

Survival has been transformed: 5-year survival in severe AAV is now about 75 to 90 percent, where the disease was fatal within months untreated. The leading causes of death are infection (early), active vasculitis (especially DAH and EGPA cardiomyopathy), cardiovascular disease (late), and ESKD.[1]

The Five Factor Score (FFS 2009) stratifies prognosis across AAV and PAN — one point each for age over 65, cardiac involvement, renal involvement (creatinine over 1.7 mg/dL or 150 micromol/L), gastrointestinal involvement, and absence of ENT involvement. Five-year mortality runs about 12 percent at FFS 0, 26 percent at FFS 1, 46 percent at FFS 2 or more. Use it to escalate therapy and to counsel risk.[1]

Relapse prediction — PR3 beats MPO. PR3-AAV relapses more (up to about 50 percent at 5 years versus 20 to 30 percent for MPO). ENT involvement, persistent PR3 positivity, and Staphylococcus aureus nasal carriage predict relapse. Rituximab maintenance cuts relapse versus azathioprine, especially in PR3-AAV.[1]

Renal outcomes: ESKD is predicted by dialysis-dependence at presentation, creatinine over 5.7 mg/dL (500 micromol/L), crescents in over 50 percent of glomeruli, severe tubulointerstitial fibrosis on biopsy, and older age. Recovery is unusual if dialysis runs beyond 12 weeks — but recovery past that window still happens, so do not prematurely label a patient ESKD.[1]

Maintenance runs at least 24 to 36 months (longer in PR3-AAV), tapered slowly under BVAS and ANCA monitoring. Premature stop risks relapse; prolonged immunosuppression risks infection. Renal transplant is offered after disease quiescence (typically 6 to 12 months of remission) — recurrence post-transplant is uncommon but possible, especially in PR3-AAV.[1]

Special populations — pregnancy, age and the dialysis patient

Pregnancy

Plan conception during remission (at least 6 months). Rituximab is acceptable early in pregnancy (avoid the third trimester — neonatal B-cell depletion, usually reversible). Avoid cyclophosphamide, mycophenolate, methotrexate and leflunomide (teratogenic); switch to azathioprine for maintenance. Use non-fluorinated steroids (prednisolone) in the first trimester; add low-dose aspirin if antiphospholipid overlaps. Active AAV in pregnancy is high-risk for mother and foetus — manage with maternal-foetal medicine.[1]

Children, the elderly and renal failure

Juvenile AAV is rare and more often GPA-phenotype — weight-based rituximab (375 mg per square metre) and cyclophosphamide, with growth, fertility and bone concerns from chronic steroids.[1]

The elderly run more MPO-AAV and renal-predominant disease, tolerate cyclophosphamide and high-dose steroids badly — favour rituximab and reduced-dose glucocorticoids (PEXIVAS-supported); age over 65 is an FFS point and predicts higher mortality.[5]

In renal impairment and dialysis, dose-adjust cyclophosphamide (creatinine-based nomograms); rituximab dosing is unchanged by renal function; avacopan helps steroid-sparing; transplant after quiescence.[1]

Infection screening before immunosuppression

Screen and pre-emptively treat latent TB (IGRA), hepatitis B (entecavir or tenofovir prophylaxis for HBsAg-positive or HBcore-positive patients throughout therapy and for 12 months after rituximab), and hepatitis C (direct-acting antivirals alongside induction where possible). Give Pneumocystis prophylaxis (cotrimoxazole 480 mg daily) and vaccinate — avoid live vaccines during immunosuppression.[1]

Anticoagulated patients

Balance the high VTE risk of active AAV against the bleeding risk of induction and PLEX — LMWH preferred in acute VTE, avoid NSAIDs in renal disease, add a PPI for gastric protection on steroids plus anticoagulation.[1]

Regional practice — UK and India

The trials that rewrote the guideline

The trials to name in a viva:[1]

• RAVE (Stone, NEJM 2010, PMID 20647199) — rituximab 375 mg per square metre weekly for 4 doses was non-inferior to cyclophosphamide (64 versus 53 percent off steroids at 6 months) and superior in relapsing disease; the trial that made rituximab standard induction.[4]
• PEXIVAS (Walsh, NEJM 2020, PMID 32053298) — a 2-by-2 factorial in 704 patients with severe AAV (creatinine over 300 micromol per litre or DAH): plasma exchange did not reduce death or ESKD at 12 months (28.4 versus 31.0 percent); reduced-dose steroid was non-inferior with fewer serious infections.[5]
• MEPEX (Jayne, JASN 2007, PMID 17582159) — plasma exchange versus IV methylprednisolone in severe renal AAV (creatinine over 500 micromol per litre): more dialysis independence at 3 months (69 versus 49 percent); underpins selective use in the worst renal presentations.[6]
• IMPROVE (Hiemstra, JAMA 2010, PMID 21060104) — azathioprine superior to mycophenolate for relapse-free maintenance after cyclophosphamide induction.[8]
• MIRRA (Wechsler, NEJM 2017, PMID 28514601) — mepolizumab 300 mg subcutaneously every 4 weeks improved remission (28 versus 3 percent on placebo) and steroid-sparing in relapsing or refractory EGPA.[9]

The mantra and the memory bank

Ward-round test

Stem 1 — The classic pulmonary-renal presentation. A 58-year-old man has epistaxis, cavitating lung nodules, a creatinine of 340 micromol per litre and red cell casts. What is the diagnosis, what three blood tests do you send now, and what is the first induction drug with its dose?[1][4]

Stem 2 — The differential trap. A 25-year-old has haemoptysis, rapidly progressive GN, a positive ANCA and a positive anti-GBM. What changes in your induction?[1][5]

Stem 3 — The preventable killer. A patient on cyclophosphamide and high-dose steroids for GPA returns at week 3 with hypoxia and a dry cough. What was missed at discharge?[1]

Stem 4 — The EGPA fork. A 44-year-old with adult-onset asthma and an eosinophil count of 2.1 times ten to the ninth per litre develops a wrist drop. Which drug, at what dose, and when is it not enough?[2][9]