GPA Granulomatosis with Polyangiitis
Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis of small- and medium-sized vessels characterized by granulomatous inflammation of the respiratory tract, necrotizing glomerulonephritis, and association with c-ANCA (anti-PR3) antibodies.
Granulomatosis with Polyangiitis (GPA)
Granulomatosis with polyangiitis (GPA) — formerly known as Wegener's granulomatosis (renamed in 2011 by the ACR/EULAR to remove the eponym due to Friedrich Wegener's Nazi associations) — is a systemic ANCA-associated small vessel vasculitis characterised by two cardinal pathological processes:
- Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract [1][2][3]
- Necrotizing vasculitis affecting predominantly small to medium vessels (capillaries, venules, arterioles, small arteries and veins), with necrotizing glomerulonephritis being common [1][2]
Breaking down the name from first principles:
- Granulomatosis = formation of granulomas (organised aggregates of activated macrophages/epithelioid cells ± giant cells), indicating a chronic immune-mediated process
- Polyangiitis = "poly" (many) + "angiitis" (vessel inflammation) → inflammation of multiple blood vessels
- This is a pauci-immune vasculitis — meaning that on immunofluorescence, there is minimal or absent deposition of immunoglobulins/complement in vessel walls, despite severe tissue destruction [1][4]. This distinguishes it from immune complex-mediated vasculitides (e.g., IgA vasculitis, lupus nephritis).
Key Defining Features — Triad of GPA
The classic triad is:
- Upper airway granulomatous disease (ENT involvement)
- Lower airway granulomatous disease (pulmonary nodules/cavities)
- Pauci-immune glomerulonephritis (renal vasculitis)
Not all three need to be present simultaneously. GPA can present in "limited" forms (e.g., ENT-only or lung-only without renal involvement).
2. Epidemiology
- Annual incidence: ~5–10 per million population in Northern European/Caucasian populations [2]
- Prevalence: ~25–160 per million (varies by geography and ethnicity)
- More common in Caucasians [2] — relatively less common in Asian populations including Hong Kong, though certainly encountered
- In Hong Kong, MPA tends to be more common than GPA among the ANCA-associated vasculitides (a pattern also seen in Japan, China, and Korea), whereas in Western countries GPA predominates [5]
- Occurs at any age but typically between 65–74 years old [2]
- Peak incidence in the 5th–7th decades of life
- Slight male predominance (M:F ≈ 1.5:1) in most series
- Can occur in children and young adults, though uncommonly
- Higher incidence at higher latitudes (Northern Europe, Scandinavia, UK, Northern USA)
- Lower incidence in equatorial/tropical regions and East Asian populations
- In Hong Kong, clinicians should maintain a high index of suspicion but recognise that MPA with anti-MPO/p-ANCA predominates over GPA with anti-PR3/c-ANCA in the local population
GPA is an idiopathic autoimmune disease — there is no single definitive risk factor, but several associations have been identified:
| Risk Factor | Mechanism / Rationale |
|---|---|
| Caucasian ethnicity | Genetic predisposition; HLA associations (HLA-DPB104:01, HLA-B08, HLA-DRB1*15) |
| Silica exposure | Chronic inhalation of silica dust → airway epithelial injury → abnormal immune activation → ANCA generation |
| Infections (Staphylococcus aureus nasal carriage) | Chronic nasal S. aureus carriage is strongly associated with GPA relapse; molecular mimicry and superantigen-mediated T-cell activation are proposed mechanisms |
| Certain medications | Propylthiouracil (PTU), hydralazine, minocycline → drug-induced ANCA-positive vasculitis (usually anti-MPO, but relevant differentially) |
| Smoking | Chronic airway inflammation may serve as a trigger for granuloma formation in genetically susceptible individuals |
| Genetic factors | SERPINA1 (α1-antitrypsin gene — encodes proteinase-3's natural inhibitor), PRTN3, CTLA-4 polymorphisms |
High Yield — S. aureus and GPA Relapse
Chronic nasal carriage of Staphylococcus aureus is found in ~60–70% of GPA patients and is an independent risk factor for disease relapse. Prophylactic trimethoprim-sulfamethoxazole (TMP-SMX / co-trimoxazole) has been used to reduce relapse rates in limited GPA — partly through reducing S. aureus colonisation and partly via mild immunomodulatory effects.
4. Anatomy and Function — Organs Involved
GPA is a systemic disease. Understanding which vessels and organs are affected is critical for understanding the clinical features.
| Organ System | Structures Affected | Why This Organ? |
|---|---|---|
| Upper airway (ENT) | Nasal mucosa, sinuses, middle ear, subglottis, trachea | Richly vascularised mucosa with constant antigen exposure → granuloma formation |
| Lower airway (Lungs) | Pulmonary parenchyma, bronchi, pulmonary capillaries | Extensive capillary bed and alveolar vasculature are targets for necrotizing vasculitis |
| Kidneys | Glomerular capillaries | Glomeruli are essentially tufts of capillaries (small vessels) → pauci-immune crescentic GN |
| Eyes | Sclera, episclera, orbit (retro-orbital space), lacrimal glands | Dense vascular supply; orbital pseudotumour from granulomatous extension |
| Skin | Dermal small vessels | Cutaneous vasculitis → palpable purpura, ulcers |
| Nervous system | Vasa nervorum (small vessels supplying peripheral nerves) | Vasculitis of vasa nervorum → ischaemic nerve injury → mononeuritis multiplex |
| Joints | Synovial membrane vasculature | Inflammatory arthralgia/arthritis |
| Heart | Coronary arteries (less common), pericardium | Uncommon in GPA (cf. EGPA where cardiac involvement is the major killer) |
5. Etiology and Pathophysiology
The exact cause of GPA remains unknown (idiopathic). Current understanding is that it results from an aberrant autoimmune response in genetically susceptible individuals, likely triggered by environmental factors:
5.2 Pathophysiology — Step by Step
This is the key section. Let's walk through the disease mechanism from first principles.
- c-ANCA (cytoplasmic pattern) = anti-proteinase-3 (anti-PR3) — positive in approximately 85–90% of GPA patients [1][2][3][6]
- p-ANCA (perinuclear pattern) = anti-myeloperoxidase (anti-MPO) — positive in approximately 10–20% of GPA patients [1]
"GPA = c-ANCA/anti-PR3 (85%); p-ANCA/anti-MPO (10%)" [1][2][3][6]
Why anti-PR3?
- Proteinase-3 (PR3) is a serine protease stored in the azurophilic granules of neutrophils and also expressed on the neutrophil surface
- In normal individuals, PR3 is sequestered inside neutrophils and not "seen" by the immune system
- In GPA, tolerance to PR3 breaks down → B cells produce anti-PR3 (c-ANCA) antibodies
What triggers loss of tolerance?
- S. aureus nasal carriage: bacterial products may act as superantigens that non-specifically activate T cells → helper T cells drive B cells to produce anti-PR3
- Molecular mimicry: microbial peptides that resemble PR3 → cross-reactive immune response
- Complementary PR3 theory: antibodies against the antisense peptide of PR3 (complementary PR3) may generate anti-idiotypic antibodies that are, in fact, anti-PR3
- Neutrophil extracellular traps (NETs): during infections, neutrophils release NETs containing PR3 and MPO → these autoantigens are presented to the immune system in an inflammatory context
This is a two-hit model:
Hit 1 — Priming:
- During infection or inflammation, pro-inflammatory cytokines (TNF-α, IL-1, IL-8) are released
- These cytokines cause neutrophils to translocate PR3 from intracellular granules to the cell surface
- Simultaneously, endothelial cells upregulate adhesion molecules (P-selectin, E-selectin, ICAM-1)
Hit 2 — ANCA Binding and Full Activation:
- Circulating anti-PR3 antibodies (c-ANCA) bind to surface-expressed PR3 on primed neutrophils
- ANCA also engages Fc receptors on the neutrophil surface
- This dual engagement causes full neutrophil activation:
- Degranulation → release of reactive oxygen species (ROS), proteolytic enzymes (PR3, elastase, cathepsins)
- Firm adhesion to endothelium
- Release of NETs → further autoantigen exposure and endothelial damage
- Production of pro-inflammatory cytokines → amplification loop
- Activated neutrophils adhere to and damage endothelial cells of small vessels
- Direct endothelial toxicity from released enzymes and ROS
- ANCA can also directly bind to endothelial cells expressing PR3 → endothelial activation and injury
- This leads to fibrinoid necrosis of the vessel wall — the hallmark of necrotizing vasculitis
- Vascular lumen occlusion → downstream ischaemic injury to supplied tissues
This is what distinguishes GPA from MPA (which has vasculitis but NO granulomas):
- Cell-mediated immunity (Th1/Th17) is strongly activated
- Macrophages activated by Th1 cytokines (IFN-γ, IL-12) → transform into epithelioid cells and multinucleated giant cells
- These cells organise into necrotizing granulomas — collections of activated macrophages surrounded by lymphocytes
- The granulomas are destructive — they cause local tissue necrosis (unlike sarcoidosis granulomas which are non-caseating and typically non-destructive)
- In the upper airway: granulomas destroy nasal cartilage (→ saddle nose deformity), invade sinuses, and erode bone
- In the lungs: granulomas form nodules that can cavitate (central necrosis creates a cavity)
- In the orbit: granulomatous tissue forms a retro-orbital mass → proptosis
- Necrotizing glomerulonephritis is common (80% of GPA patients) [2]
- Pauci-immune focal and segmental necrotizing and rapidly progressive (crescentic) glomerulonephritis (RPGN) [2][4]
- Deposition of immune complex in vessel wall is minimal or absent [2]
Why "pauci-immune"?
- Unlike IgA nephropathy or lupus nephritis, the glomerular injury in GPA is NOT driven by immune complex deposition
- Instead, it's driven by direct neutrophil-mediated endothelial damage in glomerular capillaries
- On immunofluorescence: minimal or no staining for IgG, IgA, IgM, or complement (hence "pauci" = "few")
- On light microscopy: segmental fibrinoid necrosis of glomerular tufts + crescent formation (proliferation of parietal epithelial cells in Bowman's space)
Why crescents?
- Severe injury to glomerular capillary walls → rupture → leakage of fibrin and plasma proteins into Bowman's space
- This triggers proliferation of parietal epithelial cells and influx of macrophages → cellular crescents
- If untreated, cellular crescents organise into fibrous crescents (irreversible)
- Crescentic GN → RPGN = rapid loss of renal function over days to weeks [4]
In the RPGN classification, ANCA-associated GN is Type III (pauci-immune, negative staining on IF) [4]
- Recent evidence shows that the alternative complement pathway plays a role in ANCA-mediated vasculitis
- Activated neutrophils release C5a (via the alternative pathway), which further primes more neutrophils → amplification loop
- This is the basis for the novel drug avacopan (C5a receptor inhibitor), now used in GPA/MPA treatment
Pathophysiology Summary — The ANCA-Vasculitis Cascade
- Genetic susceptibility + environmental trigger (S. aureus, silica) → loss of tolerance to PR3
- Anti-PR3 (c-ANCA) production by B cells
- Priming: infection/cytokines translocate PR3 to neutrophil surface
- ANCA binding to surface PR3 + Fc receptors → full neutrophil activation
- Degranulation → ROS, proteases → endothelial damage → necrotizing vasculitis
- Th1-mediated macrophage activation → granuloma formation (destructive, necrotizing)
- In glomeruli: pauci-immune crescentic GN (RPGN Type III)
- Alternative complement (C5a) amplification loop potentiates disease
6. Classification
6.1 Within the Vasculitis Framework
GPA is classified under several overlapping frameworks:
Classification of primary vasculitis:
| Vessel Size | Disease |
|---|---|
| Large vessel vasculitis | Giant cell arteritis; Takayasu's arteritis |
| Medium / small vessel vasculitis | Polyarteritis nodosa (PAN) (Viral hepatitis B related); Kawasaki disease |
| Granulomatosis with polyangiitis (Wegener's granulomatosis) (ANCA related) | |
| Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (ANCA related) | |
| Microscopic polyangiitis (ANCA related) | |
| IgA vasculitis (Henoch-Schönlein Purpura) | |
| Immune complex small vessel vasculitis | IgA vasculitis, Cryoglobulinemic vasculitis, Anti-GBM disease |
[6] GC slide: "Classification of primary vasculitis — Large vessel disease: Giant cell arteritis, Takayasu's arteritis; Medium/small vessel disease: PAN (Viral hepatitis B related), Kawasaki disease, GPA (Wegener's, ANCA related), EGPA (Churg-Strauss, ANCA related), MPA (ANCA related), IgA vasculitis (HSP)"
| Feature | GPA | MPA | EGPA |
|---|---|---|---|
| Granuloma | +ve | -ve | +ve |
| Renal involvement | 80% | 90% | 45% |
| Pulmonary involvement | 90% (+ ENT) | 50% | 70% |
| Asthma | -ve | -ve | +ve |
| ANCA +ve | 90% | 70% | 40–50% |
| ANCA type | Anti-PR3 (c-ANCA) | Anti-MPO (p-ANCA) | Anti-MPO (p-ANCA) |
| ENT | Necrotising lesions (saddle nose, sinusitis, epistaxis) | Similar to GPA but uncommon (35%) | Allergic rhinitis, polyposis |
| Histology | Necrotizing epithelioid granuloma | No granuloma | Eosinophilic necrotizing granuloma |
| Major cause of death | Pulmonary and renal | Pulmonary and renal | Cardiac |
| Eosinophilia | Minimal | Minimal | > 10% of peripheral WCC |
[6] GC slide: "ANCA related vasculitis — pANCA (perinuclear) = Anti-myeloperoxidase [MPO] Ab; cANCA (cytoplasmic) = Anti-proteinase 3 [PR3] Ab"
[6] GC slide table: "GPA: Anti-PR3 85%, Anti-MPO 10%; EGPA: Anti-PR3 10%, Anti-MPO 66%; MPA: Anti-PR3 15-45%, Anti-MPO 45-80%"
Exam Pearl — Differentiating GPA from MPA
The key differences are:
- GPA has granulomas; MPA does NOT
- GPA has prominent ENT/upper airway involvement; MPA does NOT
- GPA = c-ANCA/anti-PR3; MPA = p-ANCA/anti-MPO
- Both cause pauci-immune RPGN and pulmonary haemorrhage
- Think of MPA as "GPA minus the granulomas and ENT disease"
This classification is clinically important because it guides treatment intensity:
| Category | Definition | Key Features |
|---|---|---|
| Limited (localised) GPA | Disease confined to upper/lower airways WITHOUT life-threatening organ involvement | No renal involvement; no alveolar haemorrhage; serum creatinine normal |
| Early systemic GPA | Systemic disease without organ-threatening or life-threatening disease | Constitutional symptoms + non-critical organ involvement |
| Generalised (severe) GPA | Organ-threatening or life-threatening disease | Renal involvement (GN, rising creatinine), pulmonary haemorrhage, mononeuritis multiplex |
| Severe/Rapidly progressive | Renal failure or other vital organ failure | Creatinine > 500 μmol/L; pulmonary-renal syndrome |
| Refractory GPA | Progressive disease unresponsive to standard induction therapy | Requires second-line agents (rituximab if CYC-refractory, or vice versa) |
| ANCA Pattern | Target Antigen | Association |
|---|---|---|
| c-ANCA (cytoplasmic) | Anti-proteinase-3 (anti-PR3) | GPA (85%) |
| p-ANCA (perinuclear) | Anti-myeloperoxidase (anti-MPO) | MPA (45-80%), EGPA (66%), GPA (10%) |
| Atypical ANCA | Various (non-specific) | Drug-induced vasculitis, IBD, other conditions |
Why is the ANCA pattern different?
- c-ANCA: when ethanol-fixed neutrophils are used for indirect immunofluorescence, anti-PR3 antibodies produce a diffuse cytoplasmic staining pattern (because PR3 is distributed throughout the cytoplasm)
- p-ANCA: anti-MPO antibodies produce a perinuclear staining pattern (because during ethanol fixation, the positively charged MPO redistributes to the negatively charged nuclear membrane — this is an artefact of fixation, not the true intracellular location)
7. Clinical Features
GPA is a multisystem disease. The clinical presentation depends on which organs are affected and the disease extent.
Frequency of organ involvement:
- Upper airway (ENT): ~90% (most common initial presentation)
- Lower airway (Lungs): ~90%
- Kidney: ~80%
- Joints: ~60%
- Eye: ~50%
- Skin: ~40%
- Nervous system: ~15–20%
- Heart: uncommon (cf. EGPA)
7.1 Symptoms (with Pathophysiological Basis)
| Symptom | Pathophysiological Basis |
|---|---|
| Fever | Systemic inflammation → pro-inflammatory cytokines (IL-1, IL-6, TNF-α) → hypothalamic PGE2 → fever |
| Malaise / fatigue | Chronic inflammation → cytokine-mediated sickness behaviour; anaemia of chronic disease |
| Weight loss | Catabolic state from chronic inflammation (TNF-α = "cachectin"); anorexia from cytokines |
| Night sweats | Fever-related autonomic thermoregulation |
| Myalgia / arthralgia | Systemic inflammation → joint synovitis and muscle inflammation |
"S/S: begins in URT → trachea/lungs → spread to other systems" [5] "Upper airway: rhinosinusitis, recurrent epistaxis, nasal crusting/ulcers, saddle nose deformity" [1][2]
| Symptom | Pathophysiological Basis |
|---|---|
| Chronic rhinosinusitis (bloody/purulent nasal discharge, nasal congestion) | Necrotizing granulomatous inflammation of nasal mucosa and paranasal sinuses → mucosal oedema, obstruction, secondary infection |
| Recurrent epistaxis | Granulomatous destruction of nasal mucosal vasculature → friable, ulcerated mucosa → bleeding |
| Nasal crusting | Mucosal ulceration with dried blood and necrotic debris forming crusts |
| Oral/nasal ulcers | Direct granulomatous destruction of mucosal epithelium |
| Anosmia | Destruction of olfactory epithelium by granulomatous inflammation |
| Otitis media / otalgia / hearing loss | Granulomatous inflammation of middle ear mucosa and/or obstruction of Eustachian tube → serous/suppurative otitis media → conductive hearing loss; sensorineural hearing loss from vasculitis of cochlear vessels |
| Otorrhoea (ear discharge) | Middle ear granulomatous inflammation with secondary infection |
| Hoarseness / stridor | Subglottic tracheal stenosis → subglottic granuloma formation + scarring narrows the airway below the vocal cords → causes inspiratory stridor and voice change |
| Sore throat | Pharyngeal/laryngeal mucosal granulomatous inflammation |
GC slide: "GP ENT features — Necrotising lesions" [6] "Necrotizing ENT masses (saddle nose deformity)" [3]
Why Does GPA Cause Saddle Nose Deformity?
The necrotizing granulomas destroy the nasal septal cartilage (specifically the quadrangular cartilage forming the anterior nasal septum). As the cartilage is destroyed, the dorsum of the nose loses its structural support and collapses — producing the characteristic saddle-shaped depression of the nasal bridge. This is analogous to the saddle of a horse. Similar septal perforation can occur.
This is a late and destructive finding — it indicates longstanding uncontrolled upper airway disease [5].
| Symptom | Pathophysiological Basis |
|---|---|
| Cough | Airway mucosal inflammation; granulomatous lesions in bronchi; irritation from pulmonary nodules |
| Haemoptysis | Diffuse alveolar haemorrhage (DAH) from necrotizing vasculitis of pulmonary capillaries → blood leaks into alveolar spaces; OR cavitating nodules eroding into vessels |
| Dyspnoea | DAH → impaired gas exchange; airway stenosis; pleural effusion |
| Chest pain (pleuritic) | Pleural inflammation (pleuritis) from adjacent parenchymal disease |
"LRT: cough, haemoptysis, chest pain" [5] GC slide: "GP pulmonary involvement — 90% (+ ENT)" [6]
| Symptom | Pathophysiological Basis |
|---|---|
| Haematuria (often microscopic) | Glomerular capillary necrosis → red blood cells leak through damaged capillary walls into urine |
| Proteinuria (usually sub-nephrotic) | Glomerular basement membrane disruption; however, proteinuria is often modest because the severely reduced GFR limits total protein filtration |
| Oliguria / anuria (late) | Severe crescentic GN → > 50% glomeruli affected → critical loss of filtration capacity |
| Oedema (late) | Fluid retention from renal failure |
| Hypertension | Reduced renal perfusion → RAAS activation; fluid overload |
"Renal: pauci-immune focal and segmental necrotizing and rapidly progressive (crescentic) glomerulonephritis (RPGN)" [2] "Hematuria/proteinuria, T3 RPGN (classical)" [3]
High Yield — RPGN in GPA
GPA-associated GN can progress to ESRD within days to weeks if untreated. The renal disease is often clinically silent in the early stages — patients may feel well despite a rapidly rising creatinine. Always check urinalysis and RFT in any patient with suspected GPA, even if they have no urinary symptoms.
RPGN Type III (pauci-immune) = ANCA-associated = most common cause of RPGN overall [4].
| Symptom | Pathophysiological Basis |
|---|---|
| Scleritis (deep boring eye pain, red eye) | Necrotizing vasculitis of scleral vessels → scleral inflammation; can cause scleromalacia perforans |
| Episcleritis (mild discomfort, red eye) | Inflammation of superficial episcleral vessels (less severe than scleritis) |
| Proptosis (eye bulging forward) | Retro-orbital granulomatous mass → pushes the globe forward [1][2][3] |
| Diplopia | Retro-orbital mass compressing extraocular muscles or their cranial nerves (CN III, IV, VI) |
| Visual loss | Optic nerve compression by retro-orbital mass, or ischaemic optic neuropathy from vasculitis |
| Epiphora (excessive tearing) | Lacrimal duct obstruction from granulomatous inflammation |
"Eye: scleritis, retro-orbital mass" [1] "Retro-orbital mass (proptosis, diplopia, optic n. compression)" [3]
| Symptom | Pathophysiological Basis |
|---|---|
| Arthralgia / non-erosive arthritis | Synovial inflammation from systemic vasculitis; typically non-deforming, migratory, polyarticular |
| Myalgia | Systemic inflammatory cytokines; occasionally granulomatous myositis |
"Others: arthritis" [5]
| Symptom | Pathophysiological Basis |
|---|---|
| Palpable purpura | Leukocytoclastic vasculitis of dermal small vessels → RBC extravasation → non-blanching, raised (palpable) purple lesions, typically on lower limbs |
| Skin ulcers | Ischaemic necrosis from vasculitis of dermal vessels |
| Subcutaneous nodules | Granulomatous inflammation in subcutaneous tissue |
"Skin: Cutaneous vasculitis — palpable purpura" [1]
| Symptom | Pathophysiological Basis |
|---|---|
| Mononeuritis multiplex | Vasculitis of vasa nervorum (the small blood vessels that supply peripheral nerves) → nerve ischaemia → sudden-onset focal neuropathy in the distribution of individual named nerves (e.g., foot drop from peroneal nerve, wrist drop from radial nerve) |
| Cranial neuropathy | Granulomatous inflammation extending from sinuses/skull base → compression of cranial nerves; or vasculitis of cranial nerve blood supply |
| Headache | Sinusitis; dural/meningeal granulomatous involvement (pachymeningitis) |
"Neuro: Mononeuritis multiplex — peripheral neuropathy" [1] "Neuro uncommon (15%)" [3]
Causes of Mononeuritis Multiplex — Mnemonic: WARD SPLC
Wegener's granulomatosis (GPA) Amyloidosis Rheumatoid arthritis Diabetes mellitus SLE Polyarteritis nodosa Leprosy Carcinomatosis and Churg-Strauss syndrome [7]
| Symptom | Pathophysiological Basis |
|---|---|
| Pericarditis (chest pain, pericardial rub) | Pericardial vasculitis/granulomatous inflammation |
| Myocarditis | Rarely, granulomatous infiltration of myocardium |
| Conduction abnormalities | Granulomatous involvement of conduction system |
Cardiac involvement is uncommon in GPA (contrast with EGPA where cardiac disease is the "major cause of death" [3][6])
7.2 Signs (with Pathophysiological Basis)
| Sign | Pathophysiological Basis |
|---|---|
| Saddle nose deformity | Destruction of nasal septal cartilage by necrotizing granulomas → loss of dorsal nasal support → concave nasal bridge [1][2][3][5] |
| Nasal septal perforation | Granulomatous necrosis eroding through the full thickness of the nasal septum |
| Nasal mucosal ulceration / crusting | Visible on anterior rhinoscopy — friable, inflamed, crusted mucosa |
| Strawberry gingival hyperplasia | Granulomatous hypertrophy of gingival tissue → characteristic red, granular ("strawberry-like") appearance — pathognomonic for GPA |
| Middle ear effusion | Serous otitis media from Eustachian tube obstruction |
| Subglottic stenosis | Granulomatous inflammation and fibrosis below the vocal cords → narrowed subglottic airway → stridor |
| Sign | Pathophysiological Basis |
|---|---|
| Crackles / reduced breath sounds | Alveolar haemorrhage → fluid-filled alveoli → inspiratory crackles; consolidation |
| Signs of respiratory failure (tachypnoea, desaturation) | Diffuse alveolar haemorrhage with extensive V/Q mismatch |
| Pleural effusion signs (dullness, reduced breath sounds, reduced vocal resonance) | Pleural inflammation from adjacent parenchymal disease |
| Sign | Pathophysiological Basis |
|---|---|
| Hypertension | RAAS activation from reduced renal perfusion; fluid overload |
| Peripheral oedema | Renal failure → sodium and water retention |
| Uraemic signs (in advanced disease): asterixis, pericardial rub, uraemic frost | Accumulation of uraemic toxins from severely impaired GFR |
| Sign | Pathophysiological Basis |
|---|---|
| Proptosis (unilateral or bilateral) | Retro-orbital granulomatous mass — this is relatively specific for GPA among the vasculitides |
| Scleral injection (deep violaceous hue) | Necrotizing scleritis — NOT blanched by phenylephrine (cf. episcleritis which blanches) |
| Restricted eye movements | Retro-orbital mass compressing extraocular muscles |
| Conjunctivitis / keratitis | Ocular surface inflammation |
| Sign | Pathophysiological Basis |
|---|---|
| Palpable purpura (lower limbs predominantly) | Leukocytoclastic vasculitis of dermal venules → RBC extravasation → raised, non-blanching purple lesions |
| Livedo reticularis (less common) | Vasculitis/occlusion of dermal arterioles → mottled, net-like purplish discolouration |
| Ulcers | Full-thickness skin necrosis from vasculitis |
| Sign | Pathophysiological Basis |
|---|---|
| Focal motor/sensory deficits in named nerve distributions | Mononeuritis multiplex — e.g., foot drop (common peroneal nerve), wrist drop (radial nerve) |
| Cranial nerve palsies | Granulomatous compression or vasculitic ischaemia of cranial nerves |
| Sign | Pathophysiological Basis |
|---|---|
| Swollen, tender joints | Non-erosive synovitis, typically large joints |
| No deformity (cf. RA) | GPA arthritis is non-erosive and non-deforming |
| Sign | Pathophysiological Basis |
|---|---|
| Fever | Systemic inflammation |
| Cachexia (late disease) | Chronic systemic inflammation → TNF-α-mediated catabolism |
| Lymphadenopathy (uncommon) | Reactive lymphadenopathy from chronic inflammation |
This section provides an overview of the investigation rationale to bridge clinical features to diagnosis. (Full diagnostic workup, criteria, and algorithm will be covered in the next response.)
| Investigation Category | Tests | Rationale |
|---|---|---|
| Bloods | CBC D/C (anaemia, leukocytosis, ↑↑ESR/CRP) | Chronic inflammation; eosinophil count helps distinguish from EGPA |
| Serology | ANCA (c-ANCA/anti-PR3) | Diagnostic cornerstone; 85-90% sensitivity in active generalised GPA |
| Renal | RFT (urea, creatinine) + urinalysis (haematuria, proteinuria, RBC casts) | Detect glomerulonephritis; rising creatinine = urgency |
| Imaging | CXR → HRCT chest | Multiple nodules and cavitations [5]; ground-glass opacities (DAH) |
| Biopsy | Tissue biopsy of involved organ (nasal mucosa, lung, kidney) | Gold standard: necrotizing granulomas + necrotizing vasculitis [1][5] |
| Urinalysis | Microscopy for dysmorphic RBCs, RBC casts | Indicates glomerular origin of haematuria |
"Investigations: CBC D/C, ↑↑ESR/CRP, ANCA, RFT & urinalysis; Skin biopsy: histology & direct IF; Biopsy of involved organs: kidney, vessels" [1] "CXR may show multiple nodules and cavitations; Tissue biopsy shows necrotizing granulomas and necrotizing vasculitis" [5]
This is one of the most high-yield comparison tables for exams:
| GPA | MPA | EGPA | |
|---|---|---|---|
| Former name | Wegener's | — | Churg-Strauss |
| Pathology | Necrotizing granulomatous vasculitis | Necrotizing non-granulomatous vasculitis | Eosinophil-rich necrotizing vasculitis |
| ANCA | c-ANCA/anti-PR3 (85%) | p-ANCA/anti-MPO (45-80%) | p-ANCA/anti-MPO (66%) |
| ENT | Necrotizing lesions, saddle nose | Uncommon | Allergic rhinitis, polyposis |
| Lungs | Nodules, cavities, DAH (90%) | DAH, capillaritis (50%) | Migratory infiltrates, asthma (>90%) |
| Renal | Pauci-immune RPGN (80%) | Pauci-immune RPGN (90%) | Uncommon (45%) |
| Asthma | No | No | Yes (almost always) |
| Eosinophilia | Minimal | Minimal | >10% WCC |
| Peripheral nerves | Mononeuritis multiplex (15%) | Mononeuritis multiplex (70%) | Mononeuritis multiplex (up to 75%) |
| Cardiac | Uncommon | Uncommon | Major cause of death (50%) |
| Histology | Necrotizing epithelioid granuloma | No granuloma | Eosinophilic necrotizing granuloma |
| Major cause of death | Pulmonary and renal | Lung/renal and infection | Cardiac |
| Disease phases | No distinct phases | No distinct phases | 3 phases: (1) Asthma/atopy → (2) Eosinophilic infiltration → (3) Vasculitis |
GC slide: "EGPA: ENT = Rhinitis, polyposis; Allergy/bronchial asthma = Frequent; Renal = Uncommon; Eosinophilia = >10% of peripheral white cells; ANCA = pANCA (anti-MPO) 66%; Histology = Eosinophilic necrotising granuloma; Major cause of death = Cardiac" [6] GC slide: "GP: ENT = Necrotising lesions; Allergy/bronchial asthma = Similar to general population; Eosinophilia = Minimally elevated; ANCA = cANCA (anti-PR3) 85%; Histology = Necrotising epithelioid granuloma; Major cause of death = Pulmonary and renal" [6]
High Yield Summary
Definition: GPA is a systemic ANCA-associated small vessel vasculitis characterised by necrotizing granulomatous inflammation of the upper and lower respiratory tract + necrotizing vasculitis + pauci-immune crescentic GN.
Epidemiology: More common in Caucasians, peak age 65-74, slight male predominance. In Hong Kong, MPA > GPA.
ANCA: c-ANCA/anti-PR3 positive in ~85-90% of GPA (the most important serological marker).
Classic Triad: (1) Upper airway granulomatous disease, (2) Pulmonary nodules/cavities, (3) Pauci-immune RPGN.
Key Clinical Features:
- ENT: Sinusitis, epistaxis, nasal crusting, saddle nose deformity, subglottic stenosis, otitis media
- Lungs: Nodules, cavitating lesions, diffuse alveolar haemorrhage, cough, haemoptysis
- Kidneys: Pauci-immune RPGN (Type III) — can progress to ESRD in days/weeks
- Eyes: Scleritis, retro-orbital mass → proptosis
- Skin: Palpable purpura
- Nerves: Mononeuritis multiplex (uncommon, ~15%)
Distinguishing Features from Other AAVs:
- GPA vs MPA: GPA has granulomas + ENT involvement; MPA does not
- GPA vs EGPA: EGPA has asthma, eosinophilia, and cardiac involvement as major killer; GPA does not
- GPA = c-ANCA/PR3; MPA & EGPA = p-ANCA/MPO
Pathophysiology: Anti-PR3 antibodies bind to primed neutrophils → neutrophil activation → degranulation → endothelial damage → necrotizing vasculitis. Th1/Th17-mediated granuloma formation destroys tissue (nasal cartilage, lung parenchyma). Pauci-immune GN = minimal IF staining.
Key Investigations: ANCA (c-ANCA/anti-PR3), RFT + urinalysis, CXR (nodules/cavities), tissue biopsy (necrotizing granuloma + vasculitis).
Active Recall - GPA (Granulomatosis with Polyangiitis)
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology section, p.331 — ANCA-associated vasculitis, GPA/MPA/EGPA comparison table) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1770–1772 — GPA overview, epidemiology, comparison table) [3] Senior notes: Ryan Ho Rheumatology.pdf (p.97 — ANCA-associated vasculitis comparison table, clinical features, treatment, prognosis) [4] Senior notes: Ryan Ho Fundamentals.pdf (p.359, 361 — RPGN classification, Type III pauci-immune, ANCA-associated vasculitis in GN context) [5] Senior notes: Ryan Ho Respiratory.pdf (p.139–140 — Pulmonary vasculitides, Wegener's granulomatosis clinical features and investigations) [6] Lecture slides: GC 053. Fingers turn white and blue.pdf (p.79–80, 91, 94 — Classification of primary vasculitis, ANCA-related vasculitis table, EGPA vs GP comparison) [7] Senior notes: Ryan Ho Neurology.pdf (p.180 — Causes of mononeuritis multiplex mnemonic)
Differential Diagnosis of GPA (Granulomatosis with Polyangiitis)
The differential diagnosis of GPA is broad because GPA is a multisystem disease. A patient rarely walks in and announces "I have GPA." Instead, they present with a clinical syndrome — chronic sinusitis, haemoptysis, renal failure, palpable purpura — and your job is to work through an organised differential. The DDx must be structured around the dominant presenting organ system, because the list changes depending on whether you're approaching this from the ENT angle, the pulmonary-renal angle, or the vasculitis angle.
Let's think about this systematically.
GPA can masquerade as many things. The key clinical entry points are:
- Pulmonary-renal syndrome (haemoptysis + GN)
- RPGN / nephritic syndrome (rapidly declining renal function + active sediment)
- Chronic destructive upper airway disease (sinusitis, saddle nose, subglottic stenosis)
- Cavitating pulmonary nodules / masses
- Systemic vasculitis (multisystem disease with constitutional symptoms)
- Orbital disease (proptosis, retro-orbital mass)
The DDx is best organised by asking: "What else could produce this particular clinical pattern?"
2. Differential Diagnosis by Clinical Presentation
This is the most acute and dangerous presentation. The differential is narrow but critical.
"Triad of sinusitis, pulmonary infiltrates and nephritis suggest Wegener's" [4][8] "Haemoptysis suggest pulmonary haemorrhage (pulmonary vasculitis)" [4][8]
| Condition | Key Distinguishing Features | Why It's in the DDx |
|---|---|---|
| GPA | c-ANCA/anti-PR3 +ve; necrotizing granulomas; upper airway (ENT) involvement | The classic cause of pulmonary-renal syndrome with granulomas |
| MPA (Microscopic polyangiitis) | p-ANCA/anti-MPO +ve; NO granulomas; NO ENT involvement [1][2][3] | Pauci-immune RPGN + DAH, but lacks granulomatous upper airway disease |
| Goodpasture syndrome (Anti-GBM disease) | Anti-GBM antibody +ve; linear IF staining; typically younger males; smoking is a trigger for pulmonary involvement [9][10][11] | Pulmonary haemorrhage + RPGN, but NO vasculitis, NO granulomas, NO ENT disease |
| SLE (Lupus nephritis + DAH) | ANA/anti-dsDNA +ve; ↓complement; granular IF staining; characteristic rash, arthritis, serositis | DAH + GN can occur in severe lupus; but full-blown SLE features are present |
| EGPA (Churg-Strauss) | p-ANCA/anti-MPO +ve; asthma almost always present; eosinophilia > 10%; cardiac involvement is the major killer [1][2][3][6] | Can cause pulmonary infiltrates + renal involvement, but asthma and eosinophilia are the hallmarks |
High Yield — Pulmonary-Renal Syndrome DDx by IF Pattern
The immunofluorescence (IF) pattern on renal biopsy is the most helpful investigation for narrowing the DDx [4][8][9][10]:
| IF Pattern | RPGN Type | Diagnosis |
|---|---|---|
| Pauci-immune (minimal/no staining) | Type III | ANCA-associated vasculitis: GPA, MPA, EGPA |
| Linear staining | Type I | Anti-GBM disease / Goodpasture syndrome |
| Granular staining | Type II | Immune complex-mediated: SLE, IgAN, PSGN, cryoglobulinemia |
This is how nephrology differentiates the causes of RPGN — always ask for the IF pattern. [4][8][9][10]
When GPA presents primarily with renal disease (haematuria, proteinuria, rising creatinine), the full DDx of RPGN must be considered. The complement level is a powerful discriminator [4][8]:
"Serum complement level: important in helping narrow the differential diagnosis. ↓C3/4 generally indicates IC-mediated GN. Normal C3/4 generally indicates non-IC-mediated GN (except IgAN)" [4][8]
| Complement Level | DDx | Key Distinguishing Features |
|---|---|---|
| Normal C3/C4 | GPA, MPA, EGPA | Pauci-immune; ANCA +ve |
| Anti-GBM disease / Goodpasture | Anti-GBM +ve; linear IF | |
| IgA nephropathy / IgA vasculitis (HSP) | IgA deposits on IF; normal complement (IgA-IgG immune complex does NOT activate complement [8]) | |
| Polyarteritis nodosa (PAN) | Medium vessel; ANCA usually -ve; no GN (renal artery involvement instead) | |
| ↓C3/C4 | SLE (Lupus nephritis) | ANA, anti-dsDNA, ↓complement; granular IF |
| Post-streptococcal GN (PSGN) | URTI 7-10 days before; ASLO +ve; ↓C3 | |
| Membranoproliferative GN (MPGN) | HBV/HCV association; granular IF | |
| Cryoglobulinemia | HCV association; cryoglobulins +ve | |
| Infective endocarditis | Persistent fever, murmur, positive blood cultures |
[8] "Serology for relevant conditions: ANCA and its subtypes for ANCA-vasculitis; ANA, anti-dsDNA for lupus nephritis; anti-GBM autoAb for anti-GBM disease; ASLO for PSGN; anti-HCV, HBV for HBV/HCV-related MPGN"
[10] "Differential diagnosis according to IF pattern: ANCA-associated GN (Pauci-immune) — GPA, EGPA, MPA; Anti-GBM diseases (Linear) — Goodpasture syndrome, Anti-GBM disease; Immune complex diseases (Granular) — normal C3: IgAN/HSP; ↓C3: SLE, IE, cryoglobulinemia, MPGN"
When the dominant presentation is chronic sinusitis, nasal crusting, epistaxis, saddle nose deformity, or subglottic stenosis, the DDx includes:
| Condition | Key Distinguishing Features | Why It's in the DDx |
|---|---|---|
| GPA | c-ANCA +ve; necrotizing granulomas; systemic vasculitis (renal, lung) | The classic cause |
| Cocaine abuse ("Cocaine-induced midline destructive lesion") | History of cocaine use; often p-ANCA positive (anti-human neutrophil elastase); midline nasal destruction can mimic GPA exactly | Cocaine causes nasal septal perforation and destructive midline lesions — a critical DDx especially in younger patients |
| Relapsing polychondritis | Auricular chondritis (red, swollen ears sparing earlobes); saddle nose; tracheal involvement; no ANCA | Cartilage destruction in nose and trachea can mimic GPA |
| NK/T-cell lymphoma (Lethal midline granuloma) | Destructive nasal/palatal mass; associated with EBV; more common in Asian populations (including Hong Kong) | Causes midline facial destruction that can look identical to GPA on initial presentation |
| Sarcoidosis | Non-caseating granuloma; ↑ACE; hypercalcemia; bilateral hilar lymphadenopathy [12] | Nasal mucosal granulomas, but non-destructive; no ANCA; different histology |
| Tuberculosis | AFB +ve; caseating granulomas; positive Mantoux/IGRA; endemic in Hong Kong | Nasal TB is rare but causes granulomatous destruction; always exclude TB in Hong Kong |
| Tertiary syphilis (Gummatous) | RPR/VDRL +ve; gummatous destruction of nasal septum | Rare but classic cause of saddle nose |
| Fungal infection (Mucormycosis / Aspergillosis) | Immunocompromised host; tissue invasion by fungal hyphae | Nasal destruction in immunocompromised patients |
Exam Pearl — Cocaine vs GPA
Cocaine-induced midline destructive lesion is a critical differential for GPA, especially in younger patients with saddle nose and nasal septal perforation. Cocaine can even cause a positive p-ANCA (though the target antigen is typically anti-human neutrophil elastase, NOT anti-MPO or anti-PR3). Always take a drug history — failure to do so is a common exam error.
When GPA presents with pulmonary nodules or cavities on CXR/CT, the DDx broadens to include malignancy and infections:
| Condition | Key Distinguishing Features |
|---|---|
| GPA | Multiple bilateral nodules that cavitate; c-ANCA +ve; upper airway + renal involvement |
| Lung cancer (Primary or metastatic) | Solitary or multiple masses; risk factors (smoking, age); no ANCA; tissue biopsy shows malignant cells |
| Pulmonary TB | Upper lobe cavities; AFB stain/culture +ve; IGRA +ve; endemic in HK |
| Lung abscess | Fever, foul-smelling sputum; air-fluid level in cavity; often polymicrobial on culture; associated with aspiration risk |
| Septic emboli | Multiple bilateral peripheral nodules ± cavitation; source of endocarditis (positive blood cultures, vegetation on echo) |
| Rheumatoid nodules (Caplan syndrome) | Known RA; RF/anti-CCP +ve; coal workers → pneumoconiosis + rheumatoid lung nodules |
| Fungal infections (Aspergillosis, Histoplasmosis, Coccidioidomycosis) | Immunocompromised; fungal serology/culture +ve |
When a patient presents with multisystem inflammatory disease (fever, rash, neuropathy, renal impairment, pulmonary disease), the DDx includes all vasculitides and connective tissue diseases:
| Condition | Vessel Size | Key Distinguishing Features |
|---|---|---|
| GPA | Small-medium | c-ANCA/anti-PR3; granulomas; ENT + lung + kidney |
| MPA | Small | p-ANCA/anti-MPO; NO granulomas; NO ENT; lung + kidney [1][2][3] |
| EGPA | Small-medium | p-ANCA/anti-MPO; asthma; eosinophilia > 10%; cardiac death [1][2][3][6] |
| PAN (Polyarteritis nodosa) | Medium | ANCA usually negative; NO glomerulonephritis; orchitis; HBV association; livedo reticularis; mononeuritis multiplex (up to 70%) [1][13] |
| SLE | Small | ANA +ve; anti-dsDNA +ve; ↓complement; characteristic rash, arthritis, serositis |
| Cryoglobulinemic vasculitis | Small | HCV association; cryoglobulins +ve; purpura, neuropathy, GN |
| IgA vasculitis (HSP) | Small | IgA deposits; palpable purpura + GI pain + arthritis; typically children/young adults |
| Anti-GBM disease | Small (capillaries) | Anti-GBM +ve; linear IF; pulmonary haemorrhage + RPGN; no ENT; no systemic vasculitis |
[6] "Classification of primary vasculitis: Large vessel — Giant cell arteritis, Takayasu's arteritis; Medium/small vessel — PAN (Viral hepatitis B related), Kawasaki disease, GPA (Wegener's, ANCA related), EGPA (Churg-Strauss, ANCA related), MPA (ANCA related), IgA vasculitis (HSP)"
[6] "ANCA related vasculitis: pANCA = Anti-myeloperoxidase [MPO] Ab; cANCA = Anti-proteinase 3 [PR3] Ab"
When GPA presents with a retro-orbital granulomatous mass causing proptosis:
| Condition | Key Distinguishing Features |
|---|---|
| GPA | Bilateral possible; c-ANCA +ve; associated sinusitis and systemic vasculitis |
| Thyroid eye disease (Graves' orbitopathy) | Bilateral proptosis; lid retraction; anti-TSH receptor Ab +ve; hyperthyroidism features |
| Orbital lymphoma | Usually painless, progressive; tissue biopsy diagnostic |
| IgG4-related disease | Lacrimal gland enlargement; ↑serum IgG4; storiform fibrosis on biopsy |
| Orbital cellulitis | Acute, febrile; usually post-sinusitis; CT shows orbital fat stranding |
| Sarcoidosis | Lacrimal gland involvement; non-caseating granulomas; ↑ACE |
The following algorithm shows how to approach a patient with suspected GPA and work through the differentials:
This table is one of the highest yield DDx tools for exams — it integrates serology, complement, and IF pattern to narrow the differential:
| Investigation | GPA | MPA | EGPA | Anti-GBM | SLE | IgAN/HSP | PSGN |
|---|---|---|---|---|---|---|---|
| ANCA | c-ANCA/PR3 (85%) | p-ANCA/MPO (70%) | p-ANCA/MPO (40-50%) | Usually -ve (10-50% +ve) | Usually -ve | -ve | -ve |
| Anti-GBM | -ve | -ve | -ve | +ve | -ve | -ve | -ve |
| ANA | -ve | -ve | -ve | -ve | +ve | -ve | -ve |
| Complement (C3/C4) | Normal | Normal | Normal | Normal | ↓↓ | Normal | ↓C3 |
| Renal IF | Pauci-immune | Pauci-immune | Pauci-immune | Linear | Granular ("full house") | Granular (IgA dominant) | Granular |
| Eosinophilia | Minimal | Minimal | > 10% WCC | -ve | -ve | -ve | -ve |
[4][8] "Complement: ↓C3/4 generally indicates IC-mediated GN; Normal C3/4 generally indicates non-IC-mediated GN (except IgAN)"
5. Distinguishing GPA from Its Closest Mimics — Detailed Comparison
This is the most common comparison tested in exams.
| Feature | GPA | MPA |
|---|---|---|
| Granulomas | Present (necrotizing epithelioid granuloma) | Absent [1][2][3] |
| ENT involvement | Prominent (saddle nose, sinusitis, epistaxis, subglottic stenosis) | Uncommon or absent [1][2][3] |
| ANCA | c-ANCA/anti-PR3 (85%) | p-ANCA/anti-MPO (45-80%) [1][2][3] |
| Renal | RPGN in 80% | RPGN in 90% (more frequent and often more severe) |
| Pulmonary | Nodules/cavities (90%) | DAH/capillaritis (50%) |
| Relapse rate | Higher relapse rate | Lower relapse rate |
| Histology | Necrotizing epithelioid granuloma | No granuloma on histology [3] |
Think of it this way: MPA is essentially "GPA minus the granulomas and ENT disease." Both cause pauci-immune RPGN and can cause DAH. The presence of destructive upper airway granulomatous disease is what tips you towards GPA.
| Feature | GPA | EGPA |
|---|---|---|
| Asthma | Absent (same as general population) | Almost always present (> 90%) [3][6] |
| Eosinophilia | Minimally elevated | > 10% of peripheral WCC [3][6] |
| ENT | Necrotising lesions | Allergic rhinitis, polyposis [3][6] |
| Cardiac | Uncommon | Major cause of death (50%) [3][6] |
| ANCA | cANCA/anti-PR3 (85%) | pANCA/anti-MPO (66%) [3][6] |
| Renal | 80% | 45% (uncommon) |
| Disease phases | No distinct phases | Three phases: (1) Asthma/atopy → (2) Eosinophilic infiltration → (3) Vasculitis [1] |
[6] "EGP: Allergy, bronchial asthma = Frequent; Renal involvement = Uncommon; Eosinophilia = > 10% of peripheral white cells; Major cause of death = Cardiac. GP: Allergy, bronchial asthma = Similar to general population; Eosinophilia = Minimally elevated; Major cause of death = Pulmonary and renal"
| Feature | GPA | Anti-GBM / Goodpasture |
|---|---|---|
| Autoantibody | c-ANCA / anti-PR3 | Anti-GBM (against NC1 domain of α3 chain of collagen IV) [9] |
| IF pattern | Pauci-immune (minimal staining) | Linear IgG/C3 staining along GBM [9][10] |
| ENT | Prominent | Absent |
| Granulomas | Present | Absent |
| Pulmonary haemorrhage | Can occur (DAH) | Can occur (especially in smokers — smoking "exposes" pulmonary basement membrane Ag [9]) |
| RPGN | Yes | Yes (very severe; > 90% death or dialysis if untreated [9]) |
| Treatment | Immunosuppression | Immunosuppression + plasmapheresis (to remove circulating anti-GBM antibodies [4][9]) |
| Overlap | 10-50% of anti-GBM patients may also be ANCA +ve → "double-positive" disease [9] | — |
"Anti-GBM disease: linear staining in immunofluorescence; requires pulse steroids + cyclophosphamide (or rituximab) ± plasma exchange" [10]
Double-Positive Disease (ANCA + Anti-GBM)
About 10-50% of patients with anti-GBM disease are also ANCA-positive. These "double-positive" patients tend to have a clinical course that is intermediate between pure anti-GBM disease and pure ANCA vasculitis. They are more likely to respond to treatment than pure anti-GBM disease and may have a higher relapse rate (a feature more typical of ANCA vasculitis). Always check both ANCA and anti-GBM in any patient presenting with RPGN or pulmonary-renal syndrome [9].
| Feature | GPA | PAN |
|---|---|---|
| Vessel size | Small (predominantly) | Medium arteries [1][13] |
| ANCA | c-ANCA +ve (85%) | ANCA usually negative (15% p-ANCA) [1][13] |
| Glomerulonephritis | Pauci-immune RPGN (80%) | No glomerulonephritis (renal involvement is due to renal artery vasculitis → HTN, renal infarction) [1][13] |
| ENT / Granulomas | Prominent | Absent |
| Orchitis | Rare | Orchitis (testicular pain) — relatively specific for PAN [1] |
| HBV association | No | HBV (HBsAg included in ACR criteria) [1] |
| Skin | Palpable purpura | Livedo reticularis, digital ulcers/gangrene, subcutaneous nodules [1] |
| Mononeuritis multiplex | ~15% | Up to 70% [13] |
The key difference: PAN affects medium arteries and does NOT cause glomerulonephritis (because glomeruli are capillaries — small vessels). PAN causes renal artery vasculitis leading to hypertension and renal infarction, NOT crescentic GN.
Both cause granulomatous disease, but they are fundamentally different:
| Feature | GPA | Sarcoidosis |
|---|---|---|
| Granuloma type | Necrotizing (destructive) granuloma | Non-caseating granuloma (non-destructive) [12] |
| ANCA | c-ANCA/anti-PR3 +ve | Negative |
| ACE level | Normal | ↑ACE [12] |
| Calcium | Normal | Hypercalcemia/hypercalciuria (granulomas produce 1α-hydroxylase → excess 1,25-OH vitamin D) [12] |
| Lymphadenopathy | Uncommon | Bilateral hilar lymphadenopathy (pathognomonic on CXR) [12] |
| Renal | Pauci-immune RPGN | Nephrolithiasis (from hypercalciuria); interstitial nephritis; no GN |
| Pulmonary | Nodules, cavities, DAH | ILD (reticular pattern), hilar LAD, pulmonary hypertension |
| Destructive ENT | Yes (saddle nose, septal perforation) | No (nasal mucosal granulomas are non-destructive) |
High Yield Summary — Differential Diagnosis of GPA
Approach: Organise the DDx by the dominant presenting syndrome:
- Pulmonary-renal syndrome: GPA vs MPA vs Anti-GBM/Goodpasture vs SLE vs EGPA
- RPGN: Classify by IF pattern — Type I (linear = anti-GBM), Type II (granular = immune complex), Type III (pauci-immune = ANCA)
- Destructive sinonasal disease: GPA vs cocaine vs NK/T-cell lymphoma vs relapsing polychondritis vs TB/syphilis
- Cavitating lung nodules: GPA vs cancer vs TB vs abscess vs septic emboli
Key discriminators:
- ANCA type: c-ANCA/PR3 → GPA; p-ANCA/MPO → MPA/EGPA
- Complement: Normal → ANCA-associated, anti-GBM, IgAN; Low → SLE, PSGN, MPGN, cryoglobulinemia, IE
- IF pattern: Pauci-immune → ANCA; Linear → anti-GBM; Granular → immune complex
- Asthma + eosinophilia: Absent in GPA, always present in EGPA
- Granulomas: Present in GPA/EGPA, absent in MPA
- ENT destruction: Present in GPA, absent in MPA; always exclude cocaine and NK/T-cell lymphoma (especially in HK/Asian populations)
Active Recall - Differential Diagnosis of GPA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — ANCA-associated vasculitis comparison table, PAN) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1770–1772 — GPA overview, comparison table) [3] Senior notes: Ryan Ho Rheumatology.pdf (p.97 — ANCA-associated vasculitis comparison table) [4] Senior notes: Ryan Ho Fundamentals.pdf (p.359–361 — RPGN classification, evaluation of nephritic syndrome) [6] Lecture slides: GC 053. Fingers turn white and blue.pdf (p.79–80, 91, 94 — Vasculitis classification, ANCA table, EGPA vs GP comparison) [8] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.324–326 — Nephritic syndrome evaluation, complement-based DDx, RPGN classification) [9] Senior notes: Ryan Ho Urogenital.pdf (p.64, 67–69 — RPGN, Anti-GBM disease, ANCA-associated GN pathogenesis and classification) [10] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.413, 421 — RPGN DDx by IF pattern) [11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1006 — RPGN DDx by IF pattern) [12] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.231 — Sarcoidosis features, ILD classification) [13] Senior notes: Ryan Ho Rheumatology.pdf (p.159 — PAN clinical features, mononeuritis multiplex)
Diagnostic Criteria, Algorithm, and Investigations for GPA
1. Diagnostic Criteria
GPA does not have a single universally accepted "diagnostic criteria" set in the way that, say, SLE has the SLICC criteria. Instead, there are classification criteria (designed for research, to categorise patients who already have a diagnosis of vasculitis) and clinical diagnostic approaches (used to make the diagnosis in practice). Understanding this distinction matters.
These are the original classification criteria. They were designed to classify a patient already known to have vasculitis into the GPA subtype, NOT to make a de novo diagnosis of GPA. However, they are still widely cited in exams.
≥ 2 of 4 criteria → classifies as GPA (sensitivity 88%, specificity 92%):
| Criterion | Definition | Why This Criterion? |
|---|---|---|
| 1. Nasal or oral inflammation | Oral ulcers OR purulent/bloody nasal discharge | Reflects upper airway granulomatous disease |
| 2. Abnormal CXR | Nodules, fixed infiltrates, or cavities | Reflects lower airway granulomatous disease |
| 3. Urinary sediment | Microhaematuria ( > 5 RBC/HPF) or RBC casts | Reflects glomerulonephritis |
| 4. Granulomatous inflammation on biopsy | Histological changes showing granulomatous inflammation within the wall of an artery or in the perivascular/extravascular area | The pathological hallmark |
Limitation of ACR 1990 Criteria
The ACR 1990 criteria were published before ANCA testing was widely available. Notably, ANCA is NOT included in these criteria. They also don't distinguish well between GPA and MPA. For modern clinical practice, ANCA testing and tissue biopsy are the cornerstones of diagnosis.
The 2022 revised criteria represent a significant update. They use a weighted scoring system applied AFTER a patient has been diagnosed with AAV (i.e., you first confirm this is ANCA-associated vasculitis, then classify it as GPA vs MPA vs EGPA).
Score ≥ 5 → classifies as GPA (rather than MPA or EGPA):
| Item | Score |
|---|---|
| Bloody nasal discharge, nasal crusting, nasal ulcers, sinonasal congestion | +3 |
| Cartilaginous involvement (nasal septal perforation/saddle nose, conducting hearing loss) | +2 |
| Subglottic/tracheal stenosis | +5 |
| p-ANCA/anti-MPO positive | −1 (negative item — this favours MPA over GPA) |
| c-ANCA/anti-PR3 positive | +5 |
| Pulmonary nodules, masses, or cavitation on imaging | +2 |
| Granuloma, extravascular granulomatous inflammation, or giant cells on biopsy | +3 |
| Pauci-immune GN on biopsy | +1 |
| Positive test for c-ANCA or anti-PR3 by ELISA | +5 (if applicable, often combined with IIF above) |
The key point: the 2022 criteria include ANCA testing and give the highest individual weight to c-ANCA/anti-PR3 positivity (+5) and subglottic stenosis (+5) — both are highly specific for GPA.
The CHCC provides a pathological definition rather than clinical criteria:
"Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels. Necrotizing glomerulonephritis is common." [2]
This definition emphasises the two cardinal pathological features: granulomatous inflammation + necrotizing vasculitis.
In clinical reality, the diagnosis of GPA is made by combining clinical features + serology + histopathology. No single test is 100% diagnostic.
The practical diagnostic approach requires ALL THREE legs of the diagnostic tripod:
- Compatible clinical features (upper/lower airway disease, GN, vasculitic skin/nerve disease)
- Positive ANCA (c-ANCA/anti-PR3 in ~85-90%)
- Tissue biopsy showing necrotizing granulomatous vasculitis (gold standard but often technically difficult to obtain)
"Serum ANCA: suggestive but not diagnostic (can have both FP or FN)" [9] "Biopsy of affected organ: gold-standard, e.g. renal biopsy, lung biopsy" [9]
High Yield — ANCA Is Suggestive But NOT Diagnostic
A positive c-ANCA/anti-PR3 in the right clinical context is strongly supportive of GPA, but it is neither 100% sensitive nor 100% specific. About 10% of GPA patients are ANCA-negative (especially in limited/localised disease). False positives can occur in infections, other autoimmune diseases, and even cocaine use. Tissue biopsy remains the gold standard — but biopsy yield varies by site (lung > kidney > nasal mucosa). [9]
The following algorithm integrates the clinical, serological, and histopathological approach to diagnosing GPA:
"Triad of sinusitis, pulmonary infiltrates and nephritis suggest Wegener's" [4][8]
Key Principle — Do NOT Wait for Biopsy If Life-Threatening
In a patient presenting with fulminant pulmonary-renal syndrome (DAH + RPGN), treatment with empirical pulse IV methylprednisolone should be started BEFORE biopsy results return. The rationale: waiting days for biopsy results while the patient's creatinine doubles daily risks irreversible renal damage or death from alveolar haemorrhage. [4][9]
"Can give empirical pulse IV methylprednisolone before renal Bx if indicated" [4][9]
3. Investigation Modalities — Detailed Breakdown
3A. Blood Tests
| Finding | Interpretation / Mechanism |
|---|---|
| Normochromic normocytic anaemia (NcNc) | Anaemia of chronic disease — chronic inflammation → hepcidin upregulation → impaired iron utilisation; also possible iron deficiency from chronic haemoptysis (DAH) |
| Leukocytosis (↑WBC) | Systemic inflammation; neutrophilia from cytokine-driven bone marrow stimulation |
| Thrombocytosis | Reactive thrombocytosis from chronic inflammation (IL-6 stimulates thrombopoietin production) |
| Eosinophil count | Minimally elevated in GPA (cf. EGPA where eosinophilia > 10% WCC is expected) [3] — this helps distinguish GPA from EGPA |
"CBC: NcNc anaemia with ↓Hct ± ↑WBC" [4][8] "CBC D/C, ↑↑ESR/CRP" [1]
| Test | Expected Finding | Why? |
|---|---|---|
| ↑ ESR | Often markedly elevated ( > 100 mm/hr in severe disease) | ESR reflects fibrinogen levels — high in chronic active inflammation |
| ↑ CRP | Elevated | Direct marker of IL-6-driven hepatic acute phase response |
"Serum inflammatory markers: ↑ ESR and CRP" [2]
This is the single most important serological test. Two methods are used:
Step 1: Indirect Immunofluorescence (IIF) — the screening test
- Ethanol-fixed neutrophils are incubated with patient serum
- The staining pattern is observed:
- c-ANCA (cytoplasmic pattern): diffuse granular cytoplasmic staining → most commonly due to anti-PR3
- p-ANCA (perinuclear pattern): perinuclear staining → most commonly due to anti-MPO (artefact of ethanol fixation redistributing MPO to nuclear membrane)
- Atypical ANCA: neither purely cytoplasmic nor perinuclear → non-specific
Step 2: Antigen-specific immunoassay (ELISA / chemiluminescence) — the confirmatory test
- Identifies the specific target antigen: anti-PR3 or anti-MPO
- This step is essential because IIF patterns can be misleading (e.g., ANA can cause a false p-ANCA pattern on IIF)
"Anti-neutrophil cytoplasmic antibodies (ANCA): presents in 90% of patients with Wegener's granulomatosis. Cytoplasmic ANCA (C-ANCA) (Anti-PR3) in 80% of patients. Perinuclear ANCA (P-ANCA) (Anti-MPO) in 20% of patients" [2]
"ANCA related vasculitis: pANCA (p = perinuclear) = Anti-myeloperoxidase [MPO] Ab; cANCA (c = cytoplasmic) = Anti-proteinase 3 [PR3] Ab" [6]
| ANCA Result | Interpretation in GPA Context |
|---|---|
| c-ANCA/anti-PR3 positive | Strongly supports GPA (85-90% of active generalised GPA) |
| p-ANCA/anti-MPO positive | Supports AAV but more typical of MPA or EGPA; ~10-20% of GPA |
| ANCA negative | Does NOT exclude GPA — ~10% of GPA is ANCA-negative (especially limited/localised disease). Still pursue biopsy |
| Rising ANCA titre | May correlate with disease relapse (controversial — not used alone to guide treatment changes, but raises clinical suspicion) |
[6] "GPA: Anti-PR3 85%, Anti-MPO 10%"
2017 International Consensus — ANCA Testing Algorithm
Current international guidelines (2017 revised international consensus) recommend that high-quality antigen-specific immunoassays (anti-PR3 and anti-MPO ELISA) can be used as the primary screening test WITHOUT mandatory IIF first — a departure from the older two-step approach. In many modern labs, both IIF and ELISA are run simultaneously. The key point for exams: know that both the IIF pattern AND the specific antigen must be reported for a complete ANCA result.
| Test | Expected Finding | Interpretation |
|---|---|---|
| ↑ Urea and creatinine | Rising creatinine indicates declining GFR | Reflects active glomerulonephritis; rate of rise indicates severity (RPGN can double creatinine in days) |
| eGFR | Decreased | Calculated from creatinine; quantifies degree of renal impairment |
| Electrolytes | Hyperkalaemia, metabolic acidosis possible | Consequences of acute kidney injury from GN |
"RFT: ↑ Urea and creatinine level" [2]
| Finding | Significance |
|---|---|
| Normal C3 and C4 | Expected in GPA (pauci-immune disease — complement is NOT consumed by immune complex deposition) [4][8] |
This is a critical DDx discriminator:
- Normal complement → ANCA-associated vasculitis, anti-GBM, IgAN/HSP
- Low complement → SLE, PSGN, MPGN, cryoglobulinemia, IE
"Serum complement level: important in helping narrow the differential diagnosis. Normal C3/4 generally indicates non-IC-mediated GN" [4][8]
| Test | Purpose |
|---|---|
| Anti-GBM antibody | Exclude anti-GBM disease / Goodpasture (linear IF on biopsy) [4][8][10] |
| ANA, anti-dsDNA | Exclude SLE / lupus nephritis [4][8][10] |
| ASLO titre | Exclude post-streptococcal GN (if recent URTI) [4][8] |
| HBV/HCV serology | Exclude HBV/HCV-associated MPGN or PAN [4][8] |
| Cryoglobulins | Exclude cryoglobulinemic vasculitis [4][8] |
| Blood cultures | Exclude infective endocarditis (if persistent fever ± murmur) [4][8] |
"Serology for relevant conditions: ANCA and its subtypes for ANCA-vasculitis; ANA, anti-dsDNA for lupus nephritis; anti-GBM autoAb for anti-GBM disease; ASLO for PSGN; anti-HCV, HBV for HBV/HCV-related MPGN; cryocrit for cryoglobulinemia; blood culture for infection" [4][8]
"Anti-neutrophil cytoplasmic antibody (ANCA): Screen for vasculitis such as GPA, MPA and EGPA" [10]
| Test | Expected Finding | Interpretation |
|---|---|---|
| Urine dipstick | Haematuria (blood +ve), proteinuria | Screen for glomerulonephritis |
| Urine microscopy | Dysmorphic RBCs, RBC casts | Dysmorphic RBCs = glomerular origin (RBCs deformed passing through damaged GBM); RBC casts = pathognomonic for glomerulonephritis (RBCs trapped in Tamm-Horsfall protein within tubules) [2][4][8] |
| WBCs | Sterile pyuria possible | Inflammatory infiltrate without infection |
| 24h urine protein or spot ACR | Usually sub-nephrotic proteinuria | Proteinuria is limited by severely reduced GFR in RPGN; massive proteinuria should raise suspicion of a concurrent glomerular disease [9] |
"Urinalysis: Screen for glomerulonephritis. Look for proteinuria, haematuria, sediment with RBC casts and dysmorphic RBCs" [2]
High Yield — Active Urinary Sediment is a Medical Emergency
Finding dysmorphic RBCs and RBC casts on urine microscopy in a patient with rising creatinine = active glomerulonephritis until proven otherwise. In the context of a positive c-ANCA, this combination is virtually diagnostic of ANCA-associated RPGN and demands urgent treatment (pulse steroids ± renal biopsy). Do not dismiss haematuria as "UTI" without examining the urine sediment. [4][8]
3C. Imaging
| Finding | Interpretation / Mechanism |
|---|---|
| Pulmonary nodules | Granulomatous masses within lung parenchyma [2][5] |
| Cavitation | Central necrosis of granulomatous nodules → cavity formation; a hallmark of GPA [2][5] |
| Pulmonary infiltrates (diffuse bilateral opacities) | Diffuse alveolar haemorrhage (DAH) — blood filling alveolar spaces; or consolidation from granulomatous pneumonitis [2][5] |
| Pleural effusion | Pleuritis from adjacent parenchymal disease |
"CXR: Pulmonary infiltrates, pulmonary nodules, cavitation in the lung parenchyma" [2] "CXR may show multiple nodules and cavitations" [5]
HRCT provides far more detail than CXR and is the preferred imaging modality:
| Finding | Interpretation |
|---|---|
| Multiple bilateral nodules (variable size, may be > 3 cm) | Granulomatous inflammation within parenchyma |
| Thick-walled cavities | Necrotic core of granulomatous nodules |
| Ground-glass opacification (GGO) — diffuse bilateral | DAH — active alveolar haemorrhage |
| Consolidation | Haemorrhage or granulomatous pneumonia |
| Airway wall thickening / subglottic stenosis | Granulomatous inflammation and fibrosis of trachea/bronchi |
| Bronchial stenosis | Endobronchial granulomas |
| Finding | Interpretation |
|---|---|
| Mucosal thickening / opacification of sinuses | Granulomatous sinusitis |
| Bony erosion / destruction | Advanced granulomatous disease eroding sinus walls — distinguishes GPA from simple chronic sinusitis |
| Nasal septal perforation | Direct visualisation of cartilage destruction |
"CT scan of sinuses: Look for evidence of sinusitis and bone erosions" [2]
| Finding | Interpretation |
|---|---|
| ↑ DLCO (paradoxically increased) | In active DAH, haemoglobin in the alveolar space absorbs CO during the DLCO test, falsely elevating the result. This is a classic finding. |
| ↓ DLCO | If pulmonary fibrosis has developed (late/chronic disease) |
"CXR, CT thorax, DLCO for pulmonary involvement if cough ± haemoptysis" [4][8]
| Modality | Indication | Findings |
|---|---|---|
| MRI orbits | Retro-orbital mass / proptosis | Well-defined soft tissue mass in retro-orbital space; involvement of extraocular muscles |
| PET-CT | Assess extent of disease; identify biopsy targets | FDG-avid lesions in affected organs (not specific but helps map disease burden) |
| Renal ultrasound | Before renal biopsy | Assess kidney size (normal or slightly enlarged in active GN; small kidneys suggest chronic damage and may preclude biopsy) |
| CT/MRI brain | Suspected CNS involvement | Pachymeningitis (dural thickening), cranial nerve enhancement |
| Echocardiogram | If cardiac involvement suspected | Pericardial effusion; valvular vegetations (to exclude endocarditis as a DDx) |
"Biopsy of involved organs: Presence of necrotizing granulomatous inflammation of arterioles, venules and capillaries" [2] "Tissue biopsy shows necrotizing granulomas and necrotizing vasculitis" [5] "Biopsy of affected organ: gold-standard" [9]
Biopsy is the definitive diagnostic step, but its yield varies by site:
| Biopsy Site | Yield | Key Histological Findings | Advantages / Limitations |
|---|---|---|---|
| Lung biopsy (open/thoracoscopic) | Highest yield (~90%) for demonstrating both granulomas AND vasculitis | Necrotizing granulomatous vasculitis — epithelioid granulomas with multinucleated giant cells surrounding necrotic zones; fibrinoid necrosis of small vessel walls [5] | Most definitive; but invasive (VATS or open thoracotomy needed — transbronchial biopsy often insufficient due to small sample size) |
| Renal biopsy | High yield for GN (~80%) but does NOT usually show granulomas | Pauci-immune focal segmental necrotizing crescentic GN; IF: minimal or absent staining for Ig/complement ("pauci-immune") [2][9] | Less invasive than lung biopsy; confirms renal involvement and predicts prognosis based on histological class |
| Nasal / sinus mucosal biopsy | Lowest yield (~50%) for definitive histology | May show granulomatous inflammation, but often shows only non-specific chronic inflammation due to superficial sampling and concurrent infection | Least invasive; often performed first but frequently non-diagnostic |
| Skin biopsy | Variable | Leukocytoclastic vasculitis; direct IF for Ig deposition around blood vessels (usually pauci-immune in GPA) [1] | Useful when skin lesions are present |
| Orbital biopsy | Moderate | Granulomatous inflammation of orbital tissue | Performed when orbital pseudotumour is the presenting feature |
Renal Biopsy — Histological Classification of ANCA-GN
The renal biopsy classification system (Berden et al., 2010) predicts prognosis:
| Class | Definition | Prognosis |
|---|---|---|
| Focal | ≥ 50% glomeruli normal | Best prognosis |
| Crescentic | ≥ 50% glomeruli with crescents (cellular or fibrotic) | Intermediate — depends on cellular vs fibrous |
| Mixed | % normal, crescentic, sclerotic all < 50% | Intermediate |
| Sclerotic | ≥ 50% glomeruli are globally sclerotic | Worst prognosis (irreversible damage) |
"LM: variable inflammation ± granulomatous changes in GPA. Focal: ≥50% glomeruli normal. Crescentic: ≥50% glomeruli with crescents. Mixed: all < 50%. Sclerotic: ≥50% glomeruli are globally sclerotic. This classification was shown to predict 1 and 5-year outcome" [9]
"IF: unremarkable ('pauci-immune')" [9]
Critical Concept — Cellular vs Fibrous Crescents
Cellular crescents (composed of proliferating epithelial cells + macrophages) are potentially reversible with aggressive immunosuppression.
Fibrous crescents (fibroblast proliferation replacing the cellular component) are irreversible — they represent scarred, non-functional glomeruli that will NOT respond to treatment.
This is why early biopsy and early treatment are paramount — the window to save glomeruli is narrow. [4][9]
| Investigation | Indication | Key Finding |
|---|---|---|
| Nerve conduction studies / EMG | Suspected mononeuritis multiplex | Axonal neuropathy pattern in individual named nerve distributions |
| Audiometry | Hearing loss | Conductive (middle ear) or sensorineural (cochlear vasculitis) loss |
| Nasal endoscopy | ENT assessment | Mucosal ulceration, crusting, septal perforation; guides biopsy site |
| Bronchoscopy + BAL | DAH assessment | BAL progressively bloodier with sequential aliquots (diagnostic of DAH); haemosiderin-laden macrophages confirm alveolar haemorrhage |
| Pulmonary function tests | Baseline assessment | May show restrictive pattern (if ILD/fibrosis); DLCO as above |
| Ophthalmological examination | Eye involvement | Slit-lamp for scleritis, fundoscopy, B-scan ultrasound or MRI orbits for retro-orbital mass |
Once diagnosed, disease activity is quantified using the BVAS (Birmingham Vasculitis Activity Score for Wegener's Granulomatosis). This is used to:
- Classify disease severity (mild vs severe)
- Guide treatment intensity
- Monitor response to therapy
"BVAS = Birmingham Vasculitis Activity Score for Wegener's granulomatosis" [2] "Mild disease (ABSENCE of end-organ damage; BVAS score 0–3): Corticosteroids + Methotrexate. Severe disease (Presence of end-organ damage, e.g. RPGN / Pulmonary hemorrhage; BVAS score > 3): High-dose corticosteroids + Rituximab / Cyclophosphamide" [2]
| Organ System | Items Assessed |
|---|---|
| General | Myalgia, arthralgia/arthritis, fever, weight loss |
| Cutaneous | Purpura, ulcers, gangrene |
| Mucous membranes / Eyes | Mouth ulcers, eye inflammation (scleritis, proptosis) |
| ENT | Bloody nasal discharge, sinus involvement, subglottic stenosis, hearing loss |
| Chest | Wheeze, nodules/cavities, DAH, respiratory failure |
| Cardiovascular | Heart failure, pericarditis, ischaemia |
| Abdominal | Peritonitis, bloody diarrhoea |
| Renal | Haematuria, proteinuria, creatinine rise, RPGN |
| Nervous system | Cranial nerve palsy, mononeuritis multiplex, sensorimotor neuropathy, stroke |
BVAS helps distinguish limited from generalised/severe disease, which directly determines whether to use milder (MTX-based) or aggressive (CYC/rituximab-based) induction.
| Category | Tests | Key Findings in GPA |
|---|---|---|
| Bloods | CBC D/C | NcNc anaemia, leukocytosis, thrombocytosis, minimal eosinophilia |
| ESR, CRP | Markedly elevated | |
| ANCA (IIF + ELISA) | c-ANCA / anti-PR3 positive (~85-90%) | |
| RFT | ↑ Urea, ↑ Creatinine | |
| Complement C3/C4 | Normal (pauci-immune — no complement consumption) | |
| Anti-GBM, ANA, anti-dsDNA | Negative (to exclude mimics) | |
| Urine | Urinalysis + microscopy | Haematuria, proteinuria, dysmorphic RBCs, RBC casts |
| 24h urine protein / spot ACR | Usually sub-nephrotic | |
| Imaging | CXR | Nodules, cavitations, infiltrates |
| HRCT chest | Nodules, thick-walled cavities, GGO (DAH), airway wall thickening | |
| CT sinuses | Mucosal thickening, bone erosion | |
| DLCO | ↑ in acute DAH; ↓ if fibrosis | |
| MRI orbits | Retro-orbital mass if proptosis | |
| Biopsy | Lung biopsy | Necrotizing granulomatous vasculitis (highest yield) |
| Renal biopsy | Pauci-immune crescentic GN; IF: minimal staining | |
| Nasal/sinus biopsy | Granulomas possible but often non-specific | |
| Other | NCS/EMG | Axonal neuropathy (mononeuritis multiplex) |
| BAL | Progressively bloody aliquots (DAH); haemosiderin-laden macrophages | |
| BVAS score | Disease activity quantification |
"Investigations: CBC D/C, ↑↑ESR/CRP, ANCA, RFT & urinalysis. Skin biopsy: histology & direct IF. Biopsy of involved organs: kidney, vessels" [1]
High Yield Summary — Diagnosis of GPA
Diagnostic tripod: (1) Compatible clinical features, (2) Positive c-ANCA/anti-PR3, (3) Tissue biopsy showing necrotizing granulomatous vasculitis.
ANCA: c-ANCA/anti-PR3 in ~85-90% of active generalised GPA. Suggestive but NOT diagnostic alone — can have false positives and false negatives.
Biopsy: Gold standard. Lung biopsy has highest yield for full histological picture. Renal biopsy shows pauci-immune crescentic GN (IF: minimal staining). Nasal biopsy is often non-diagnostic.
CXR/HRCT: Nodules, cavities, infiltrates (DAH). CT sinuses shows mucosal thickening and bone erosion.
Key discriminating investigations: Complement (normal in GPA), ANCA subtype (c-ANCA/PR3 for GPA; p-ANCA/MPO for MPA/EGPA), IF pattern on renal biopsy (pauci-immune = Type III RPGN).
Severity: BVAS score — mild (BVAS 0-3): corticosteroids + MTX; severe (BVAS > 3, end-organ damage): high-dose steroids + CYC/rituximab.
Do not delay treatment: Empirical pulse methylprednisolone can be given before biopsy if clinical suspicion is high and RPGN/DAH is present.
Active Recall - Diagnosis and Investigations in GPA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — ANCA-associated vasculitis, investigations) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1770–1774 — GPA overview, diagnosis, treatment, BVAS) [3] Senior notes: Ryan Ho Rheumatology.pdf (p.97 — ANCA-associated vasculitis comparison table) [4] Senior notes: Ryan Ho Fundamentals.pdf (p.359–361 — RPGN classification, evaluation of nephritic syndrome, complement-based DDx) [5] Senior notes: Ryan Ho Respiratory.pdf (p.139–140 — Pulmonary vasculitides, CXR findings, tissue biopsy) [6] Lecture slides: GC 053. Fingers turn white and blue.pdf (p.91 — ANCA related vasculitis table, anti-PR3/anti-MPO) [8] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.324–326 — Nephritic syndrome evaluation, serology panel, complement-based DDx) [9] Senior notes: Ryan Ho Urogenital.pdf (p.62–69 — ANCA-associated GN pathogenesis, histological classification, diagnosis, management) [10] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.413–421 — RPGN DDx by IF, GN investigation panel)
Management of GPA (Granulomatosis with Polyangiitis)
Managing GPA is conceptually straightforward once you understand the logic. There are two phases and one overriding principle:
The overriding principle: GPA is a lethal disease if untreated (90% mortality within 2 years without treatment). Management is therefore aggressive immunosuppression balanced against treatment toxicity [2][3].
The two phases:
- Induction of remission — hit hard and fast with potent immunosuppression to extinguish active inflammation and prevent organ destruction (typically 3–6 months)
- Maintenance of remission — switch to less toxic agents to keep the disease quiet and prevent relapse (typically 24–48 months, sometimes longer)
The intensity of induction depends on disease severity:
"Mild disease (ABSENCE of end-organ damage; BVAS score 0–3): Corticosteroids + Methotrexate. Severe disease (Presence of end-organ damage, e.g. RPGN / Pulmonary hemorrhage; BVAS score > 3): Induction of remission — High-dose corticosteroids + Rituximab / Cyclophosphamide. Maintenance of remission — Low-dose corticosteroids + Rituximab / Azathioprine / Methotrexate / MMF" [2]
GPA treatment: "Induction: high-dose steroid + cyclophosphamide / rituximab (± plasma exchange if severe). Maintenance: azathioprine / rituximab / methotrexate" [3]
3. Treatment Modalities — Detailed Breakdown
3A. Induction Therapy
Mechanism of action (from first principles):
- Glucocorticoids bind to intracellular glucocorticoid receptors → translocate to nucleus → suppress NF-κB and AP-1 transcription factors → ↓production of pro-inflammatory cytokines (IL-1, IL-6, TNF-α), chemokines, adhesion molecules, and prostaglandins
- Also induce lymphocyte apoptosis and inhibit T-cell activation
- Net effect: rapid and broad suppression of both innate and adaptive immune responses
Regimens:
| Severity | Regimen | Rationale |
|---|---|---|
| Severe / organ-threatening | Pulse IV methylprednisolone 500–1000 mg/day for 3 days → then oral prednisolone 1 mg/kg/day (max 60–80 mg), tapered over 3–6 months [2][3][10] | IV pulses rapidly achieve supra-physiological immunosuppression to halt active vasculitis/GN immediately |
| Limited disease | Oral prednisolone 0.5–1 mg/kg/day, taper over 3–6 months | Lower intensity matches lower disease burden |
"Requires pulse steroids (IV methylprednisolone 1 g/day for 3 days) + cyclophosphamide (or rituximab) ± plasma exchange" [10][11]
Key points on steroid tapering:
- Modern guidelines (PEXIVAS, LoVAS trials) favour rapid glucocorticoid tapering (reduced-dose regimen) — typically reaching < 10 mg prednisolone by 3–5 months and aiming to stop by 6–12 months if possible
- Rationale: prolonged high-dose steroids contribute significantly to morbidity (infections, osteoporosis, diabetes, cataracts, AVN) without necessarily improving outcomes compared to faster tapers when combined with effective induction agents
Contraindications / Cautions:
| Contraindication | Explanation |
|---|---|
| Active untreated infection (relative) | Steroids suppress immune defence; however, in life-threatening GPA, treatment may still proceed with concurrent antimicrobials |
| Uncontrolled diabetes (relative) | Steroids cause hyperglycaemia via hepatic gluconeogenesis and insulin resistance; tight glucose monitoring required |
| Active peptic ulcer disease (relative) | Steroids ↑ gastric acid secretion and impair mucosal healing; co-prescribe PPI |
| Severe osteoporosis (relative) | Long-term steroids ↓ osteoblast function + ↑ osteoclast activity; co-prescribe calcium, vitamin D, ± bisphosphonate |
Name breakdown: "cyclo" = ring, "phosph" = phosphorus, "amide" = nitrogen-containing group. It is a nitrogen mustard-derived alkylating agent that cross-links DNA strands, preventing cell replication.
Mechanism of action:
- Alkylates DNA at the guanine N-7 position → interstrand cross-links → prevents DNA unwinding and replication → cell death
- Particularly effective against rapidly dividing cells (lymphocytes, including autoreactive B and T cells)
- Suppresses both humoral (B cell → antibody) and cellular (T cell) immunity
Regimens:
| Route | Regimen | Advantages | Disadvantages |
|---|---|---|---|
| IV pulse CYC (preferred) | 15 mg/kg (max 1.2 g) every 2–3 weeks × 3–6 months (CYCLOPS protocol) | Lower cumulative dose; fewer bladder/gonadal side effects; better compliance | Requires hospital visits |
| Daily oral CYC (alternative) | 2 mg/kg/day (max 200 mg) for 3–6 months | Continuous exposure may be marginally more effective in some severe cases | Higher cumulative dose → more toxicity |
Side effects (critical for exams):
| Side Effect | Mechanism | Prevention |
|---|---|---|
| Haemorrhagic cystitis | Acrolein (CYC metabolite) is directly toxic to bladder urothelium | Mesna (2-mercaptoethane sulfonate sodium) — binds and neutralises acrolein in the urinary tract; also ensure adequate hydration |
| Bone marrow suppression (leukopenia, neutropenia) | Alkylation of haematopoietic stem cells | Monitor CBC regularly; dose-adjust for WCC nadir; hold if WCC < 4 × 10⁹/L |
| Gonadal toxicity (infertility) | Alkylation of germ cells — especially cumulative damage | Discuss sperm/oocyte cryopreservation before starting; prefer IV pulse (lower cumulative dose); GnRH agonists may offer ovarian protection |
| Increased malignancy risk | DNA damage in non-target cells → ↑ risk of bladder cancer, lymphoma, leukaemia, skin cancer | Limit cumulative dose; surveillance |
| Infections (especially opportunistic) | Profound immunosuppression | TMP-SMX prophylaxis for PCP; monitor for infections |
| Nausea / vomiting | Direct GI mucosal irritation + CNS emetogenic zone stimulation | Anti-emetics (ondansetron); give IV pulses with pre-hydration |
Contraindications:
| Absolute | Relative |
|---|---|
| Active severe infection | Severe renal impairment (dose-adjust for eGFR) |
| Pregnancy (teratogenic) | Leukopenia (WCC < 4 × 10⁹/L) |
| Known hypersensitivity | Active malignancy |
High Yield — Mesna with Cyclophosphamide
Mesna (etymology: 2-mercaptoethane sulfonate) neutralises acrolein, the toxic metabolite of CYC that causes haemorrhagic cystitis. Mesna is given with EACH dose of IV CYC. Think of it as "CYC's bodyguard for the bladder." Adequate IV hydration before and after CYC is also essential to dilute acrolein in urine.
Name breakdown: "ri-" prefix, "tuxi-" from chimeric, "-mab" = monoclonal antibody. Rituximab is a chimeric (mouse-human) anti-CD20 monoclonal antibody.
Mechanism of action:
- CD20 is a surface antigen expressed on pre-B cells and mature B cells (but NOT on plasma cells or very early pro-B cells)
- Rituximab binds CD20 → depletes B cells via:
- Antibody-dependent cellular cytotoxicity (ADCC) — Fc portion recruits NK cells
- Complement-dependent cytotoxicity (CDC) — activates complement cascade
- Direct apoptosis induction
- Depletes the B cell pool that would otherwise replenish short-lived plasma cells producing anti-PR3 antibodies
- Also removes B cells that act as antigen-presenting cells to autoreactive T cells
Clinical evidence:
- The RAVE trial (2010) and RITUXVAS trial (2010) demonstrated that rituximab is non-inferior to cyclophosphamide for induction of remission in severe ANCA-associated vasculitis
- Rituximab was shown to be superior to CYC for relapsing disease (RAVE trial)
- This was a landmark finding because it provided an effective alternative without CYC's cumulative toxicity (infertility, bladder cancer)
Regimen:
| Protocol | Dose |
|---|---|
| RAVE protocol | 375 mg/m² IV weekly × 4 doses |
| RA protocol (increasingly used for convenience) | 1000 mg IV on Day 1 and Day 15 |
Indications (why choose RTX over CYC?):
| Favour Rituximab | Favour Cyclophosphamide |
|---|---|
| Relapsing disease (RTX superior in RAVE) | First presentation of severe disease (both are options) |
| Young patients — avoids gonadal toxicity | Patients who cannot access rituximab (cost/availability) |
| Prior CYC exposure — avoids cumulative alkylating toxicity | Concomitant anti-GBM disease |
| Patient preference — no bladder cancer risk |
Side effects:
| Side Effect | Mechanism |
|---|---|
| Infusion reactions (fever, chills, rigors, urticaria, bronchospasm) | Cytokine release from lysed B cells; prevented by pre-medication (paracetamol, diphenhydramine, methylprednisolone) |
| Hypogammaglobulinaemia (↓IgG) | Depletion of B cells → reduced immunoglobulin production over time (especially with repeated courses) → ↑ infection risk |
| Late-onset neutropenia | Mechanism unclear; usually self-limiting |
| Progressive multifocal leukoencephalopathy (PML) | Very rare; JC virus reactivation in severely immunosuppressed patients |
| HBV reactivation | B cell depletion removes immune control over latent HBV → screen HBsAg/anti-HBc before starting |
Contraindications:
| Contraindication | Explanation |
|---|---|
| Active severe infection | Further immunosuppression is dangerous |
| HBV positive without antiviral prophylaxis | Risk of fulminant HBV reactivation; must give antiviral cover (entecavir/tenofovir) if HBsAg+ |
| Severe hypogammaglobulinaemia (IgG < 3 g/L) | Already immunocompromised; further B cell depletion may be harmful |
| Known hypersensitivity | Anaphylaxis risk |
Mechanism:
- Physically removes circulating ANCA (anti-PR3/anti-MPO) antibodies, complement components, and inflammatory cytokines from the blood
- Patient's plasma is separated from cellular components and replaced with albumin or FFP
Indications in GPA:
- Life-threatening disease: severe DAH, severe RPGN with creatinine > 500 μmol/L [3][10][11]
- The PEXIVAS trial (2020) showed that plasma exchange did NOT reduce the composite endpoint of death or ESRD in AAV overall. However, it may still benefit patients with severe AKI (Cr > 500 μmol/L) or life-threatening DAH where rapid antibody removal is needed as a bridge while immunosuppression takes effect
- Current 2024 KDIGO / ACR guidelines: plasma exchange is considered but not routinely recommended — reserved for the most severe cases
"± plasma exchange if severe" [3]
Regimen: 7 exchanges over 14 days using albumin (or FFP if coagulopathic/recent biopsy/active bleeding)
Mechanism:
- Inhibits dihydrofolate reductase → blocks purine/pyrimidine synthesis → suppresses rapidly dividing immune cells
- At low doses, also has anti-inflammatory effects via adenosine accumulation (inhibits AICAR transformylase → ↑ extracellular adenosine → anti-inflammatory)
Indication in GPA:
"Mild disease (ABSENCE of end-organ damage; BVAS score 0–3): Corticosteroids + Methotrexate — Methotrexate as a less toxic alternative induction agent in patients with non-organ-threatening disease" [2]
Key points:
- Used for limited/non-organ-threatening GPA (e.g., ENT-limited disease, arthritis, skin vasculitis without renal/pulmonary involvement)
- NOT suitable for severe/organ-threatening disease (RPGN, DAH)
- Typical dose: 15–25 mg orally or SC once weekly + folic acid supplementation (5 mg, given 24h after MTX to reduce mucosal/marrow toxicity without antagonising the therapeutic effect)
Contraindications:
- Renal impairment (MTX is renally excreted — ↑ toxicity if GFR is reduced)
- Liver disease
- Pregnancy (teratogenic — causes neural tube defects)
- Significant lung disease (MTX can itself cause pneumonitis)
3B. Maintenance Therapy
Once remission is achieved (usually 3–6 months after induction), the goal switches from "putting out the fire" to "preventing it from reigniting" — using less toxic agents for a prolonged period.
"Maintenance of remission: Low-dose corticosteroids + Rituximab / Azathioprine / Methotrexate / MMF" [2] "Maintenance: azathioprine / rituximab / methotrexate" [3] "Maintenance: non-GC non-CYC immunosuppressant × 18 months, taper GC" [1]
- The MAINRITSAN trial (2014) demonstrated that rituximab maintenance (500 mg IV every 6 months × 4 doses) was superior to azathioprine for preventing relapse in AAV
- The RITAZAREM trial (2019) confirmed rituximab's superiority over azathioprine specifically in relapsing AAV
- Current recommendation: rituximab is now considered the preferred maintenance agent, especially in PR3-ANCA/GPA (which has a higher relapse rate than MPO-ANCA disease)
- Dose: typically 500 mg IV every 6 months for at least 24 months (some centres extend further)
Name breakdown: "aza" = nitrogen-containing (azole ring), "thio" = sulfur, "prine" = purine analogue. Azathioprine is a pro-drug converted to 6-mercaptopurine.
Mechanism:
- 6-Mercaptopurine is incorporated into DNA → inhibits purine synthesis → suppresses lymphocyte proliferation (particularly T cells)
- Less potent than CYC but much less toxic for long-term use
Key details:
- Typical dose: 2 mg/kg/day orally
- Must check TPMT (thiopurine methyltransferase) genotype/activity before starting — patients with low/absent TPMT have impaired drug metabolism → severe myelosuppression risk
- Standard alternative to rituximab for maintenance
Side effects: Bone marrow suppression, hepatotoxicity, GI upset, pancreatitis, ↑ infection risk, small ↑ lymphoma risk
- Can be used for maintenance in patients with limited disease who were induced with MTX
- Dose: 15–25 mg/week + folic acid
- Avoid in patients with renal impairment (drug accumulates)
Mechanism:
- Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis → selectively suppresses lymphocyte proliferation (lymphocytes are uniquely dependent on de novo pathway, unlike most cells that can use the salvage pathway)
Role in GPA:
- Second-line maintenance agent
- The IMPROVE trial showed MMF was inferior to azathioprine for maintaining remission in AAV → higher relapse rate
- Used when azathioprine/rituximab are contraindicated or not tolerated
Dose: 1–2 g/day in divided doses
Contraindications: Pregnancy (teratogenic), severe GI disease, severe leukopenia
- Prednisolone is gradually tapered during maintenance
- Goal: reach ≤ 5 mg/day by 3–6 months, and ideally discontinue by 12 months
- Prolonged steroid use is associated with significant morbidity without proven benefit over steroid-free maintenance with RTX/AZA
| ANCA Type | Relapse Risk | Recommended Duration |
|---|---|---|
| Anti-PR3 / c-ANCA (GPA) | Higher relapse rate (~50% at 5 years) | At least 24–48 months; many experts advocate indefinite or extended maintenance |
| Anti-MPO / p-ANCA (MPA) | Lower relapse rate | 24 months may be sufficient in some patients |
"↑ relapse risk cf GPA" [3] — this refers to GPA having a higher relapse risk than MPA, justifying longer maintenance
Name breakdown: "ava" + "copan" (complement-related). Avacopan is an oral C5a receptor antagonist.
Mechanism:
- Blocks the C5a complement receptor (C5aR1) on neutrophils
- In ANCA vasculitis, activated neutrophils release C5a → C5a binds C5aR1 on other neutrophils → primes them for ANCA binding → amplification loop
- Avacopan breaks this amplification loop, reducing neutrophil activation without broad immunosuppression
Clinical evidence:
- ADVOCATE trial (2021): avacopan (30 mg orally BID) was non-inferior to prednisone taper as adjunctive to standard CYC or RTX induction, and superior at sustaining remission at 52 weeks
- Avacopan allows steroid-sparing or steroid-free induction regimens → reduces steroid side effects (diabetes, osteoporosis, infections)
- FDA-approved (2021) for adjunctive treatment of severe active AAV in combination with standard therapy
Role: Used as an adjunct to replace or reduce glucocorticoids during induction, NOT as monotherapy
Side effects: Hepatotoxicity (monitor LFTs), GI upset, nasopharyngitis, headache
GPA has a high relapse rate — approximately 50% within 5 years, especially in PR3-ANCA positive patients.
Approach to relapse:
- Major relapse (organ-threatening): re-induce with same protocol as initial induction (pulse steroids + CYC or RTX)
- If initially induced with CYC → switch to RTX for re-induction (and vice versa)
- Rituximab may be preferred for relapse based on RAVE trial data
- Minor relapse (non-organ-threatening): increase maintenance immunosuppression ± short course of higher-dose steroids
Refractory disease = progressive disease despite standard induction therapy
| Strategy | Rationale |
|---|---|
| Switch CYC ↔ RTX | If one fails, try the other |
| IV immunoglobulin (IVIG) | Immunomodulatory; used as bridging in refractory cases or when infections preclude further immunosuppression |
| Mepolizumab / other biologics | Experimental; limited data in GPA (more data for EGPA) |
| Clinical trial enrolment | For truly refractory cases |
These are as important as the immunosuppressive agents themselves. Infection is a leading cause of death in treated GPA [3].
| Measure | Rationale | Details |
|---|---|---|
| Trimethoprim-sulfamethoxazole (TMP-SMX) | Dual role: (1) Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) during immunosuppression; (2) Reduces S. aureus nasal carriage → may reduce GPA relapse | TMP-SMX 960 mg (double strength) 3× per week OR 480 mg daily; continue throughout induction and for ≥3 months into maintenance |
| PPI (e.g., omeprazole) | Gastroprotection during high-dose steroids | Especially if on concomitant NSAIDs or anticoagulants |
| Bone protection | Prevent glucocorticoid-induced osteoporosis | Calcium 1000–1200 mg + Vitamin D 800–1000 IU daily; DEXA scan; bisphosphonate (e.g., alendronate) if prolonged steroid use or T-score ≤ -1.5 |
| Pre-treatment screening | Prevent reactivation of latent infections under immunosuppression | HBV serology (HBsAg, anti-HBc, anti-HBs) — antiviral prophylaxis if positive; HCV; TB screening (IGRA/Mantoux + CXR) — INH prophylaxis if latent TB; HIV |
| Vaccinations | Immunosuppression ↑ infection risk | Pneumococcal (PCV13 + PPSV23), Influenza (annually), COVID-19, HBV (if non-immune). Avoid live vaccines during immunosuppression (e.g., MMR, varicella, BCG, oral polio) |
| Infection surveillance | Infection is the leading cause of early mortality in treated AAV | Low threshold for investigating fever/new symptoms; monitor WCC regularly during CYC; CMV surveillance if profound immunosuppression |
| ACEI/ARB | Renoprotection in patients with proteinuria / CKD | ↓ intraglomerular pressure → ↓ proteinuria → ↓ rate of GFR decline [14] |
| Fertility preservation | CYC causes gonadal toxicity | Discuss sperm banking / oocyte cryopreservation before CYC initiation; consider GnRH agonists for ovarian protection |
"Pneumococcal vaccinations: indicated for ALL as pneumococcal infection is common" [14]
High Yield — TMP-SMX in GPA: Two Birds, One Stone
TMP-SMX serves a dual purpose in GPA:
- PCP prophylaxis — mandatory during induction with CYC or RTX
- S. aureus eradication — chronic nasal S. aureus carriage is associated with disease relapse; TMP-SMX reduces nasal colonisation
In limited GPA (e.g., ENT-only disease without organ-threatening features), some older studies suggested TMP-SMX alone could help maintain remission, though this is NOT a substitute for proper immunosuppressive induction.
| Organ/Issue | Specific Management | Why? |
|---|---|---|
| Subglottic stenosis | May require intralesional steroid injection + endoscopic dilatation ± stenting; sometimes unresponsive to systemic immunosuppression alone because fibrotic (not active inflammation) | Subglottic stenosis can be a fixed, fibrotic complication that does not resolve with systemic therapy — it is a structural problem requiring a mechanical solution |
| Retro-orbital mass | Systemic immunosuppression (steroids + RTX/CYC); do NOT surgically debulk unless vision-threatening and unresponsive to medical therapy | Responds well to aggressive medical therapy; surgery risks damaging orbital structures |
| Scleritis | Systemic steroids + immunosuppressants (usually prednisolone 1 mg/kg/day + rituximab or CYC for necrotizing forms) [15] | Scleritis in GPA is not just an eye problem — it reflects systemic vasculitis activity requiring systemic treatment |
| Mononeuritis multiplex | Systemic induction therapy (steroids + CYC/RTX) | Nerve ischaemia from vasculitis; responds to treatment but recovery may be incomplete if axonal damage is established |
| Dialysis-dependent RPGN | Systemic induction still given but renal prognosis is poor; those requiring immediate dialysis are unlikely to recover renal function | Renal biopsy showing > 50% sclerotic glomeruli = irreversible |
| DAH (life-threatening) | Pulse steroids + CYC/RTX + consider plasma exchange; ICU care; may need mechanical ventilation | Haemoptysis can be massive; supportive care includes correction of coagulopathy and transfusion |
| Parameter | Frequency | Why |
|---|---|---|
| CBC (D/C) | Every 1–2 weeks during CYC; monthly during maintenance | Detect bone marrow suppression (neutropenia) — hold CYC if WCC < 4 × 10⁹/L |
| RFT + urinalysis | Every 1–4 weeks during induction; every 1–3 months during maintenance | Monitor renal function trajectory; detect relapse early |
| ESR/CRP | Each visit | Disease activity markers |
| ANCA titre | Every 3–6 months | Rising titre may herald relapse (though not used alone to change therapy) |
| LFTs | Regular if on MTX, AZA, or avacopan | Hepatotoxicity screening |
| Immunoglobulin levels (IgG) | Every 6–12 months if on rituximab | Detect hypogammaglobulinaemia → ↑ infection risk; consider IVIG replacement if IgG < 3 g/L with recurrent infections |
| Glucose | Regular during steroid therapy | Steroid-induced diabetes |
| DEXA scan | Baseline + every 1–2 years | Glucocorticoid-induced osteoporosis |
| Category | Definition | Induction | Maintenance |
|---|---|---|---|
| Limited / non-organ-threatening | BVAS 0–3; no renal, pulmonary, or neuro involvement | Glucocorticoids + Methotrexate [2] | AZA or MTX or RTX + taper steroids |
| Severe / organ-threatening | BVAS > 3; RPGN, DAH, scleritis, mononeuritis multiplex | Pulse IV methylprednisolone + Rituximab OR Cyclophosphamide [2][3] | Rituximab OR AZA or MTX or MMF + taper steroids [2][3] |
| Life-threatening | Severe RPGN (Cr > 500), life-threatening DAH | Pulse steroids + RTX/CYC + Plasma exchange [3][10][11] | RTX or AZA + taper steroids |
| Relapsing | Recurrence after remission | Re-induction: switch CYC ↔ RTX preferred | RTX preferred for relapsing disease |
| Refractory | Progressive despite standard therapy | Switch agents; IVIG; clinical trials | Individualised |
Comparison across AAVs — GPA: "Induction: high-dose steroid + cyclophosphamide / rituximab (± plasma exchange if severe). Maintenance: azathioprine / rituximab / methotrexate." MPA: same induction but RTX/AZA maintenance. EGPA: "Induction: high-dose steroid ± cyclophosphamide. Maintenance: azathioprine / methotrexate / leflunomide." [3]
| Parameter | Detail |
|---|---|
| Untreated | ~90% mortality within 2 years (historically, before immunosuppressive era) |
| Treated | 4–10 year survival 56–95% [3] |
| Major cause of death | Pulmonary and renal disease; infection (treatment-related) [3] |
| Relapse rate | GPA has a higher relapse rate compared to MPA (~50% at 5 years for PR3-ANCA) [3] |
| Poor prognostic factors | Older age, renal impairment at diagnosis, high BVAS, pulmonary haemorrhage, sclerotic class on renal biopsy |
High Yield Summary — Management of GPA
Two phases: Induction (3–6 months) → Maintenance (≥ 24–48 months).
Induction:
- Limited disease (BVAS 0–3): Glucocorticoids + MTX
- Severe disease (BVAS > 3): Pulse IV methylprednisolone + RTX or CYC
- Life-threatening: Add plasma exchange
Maintenance: Rituximab (preferred, especially for PR3-ANCA) OR Azathioprine OR MTX OR MMF + taper steroids.
Key drugs:
- CYC: Alkylating agent; effective but toxic (haemorrhagic cystitis — give mesna; infertility — offer cryopreservation; myelosuppression)
- RTX: Anti-CD20 mAb; non-inferior to CYC; superior for relapse; avoids CYC toxicity (infusion reactions, hypogammaglobulinaemia)
- Avacopan: C5a receptor inhibitor; steroid-sparing adjunct (ADVOCATE trial)
Supportive: TMP-SMX (PCP prophylaxis + S. aureus eradication), bone protection, PPI, vaccinations, pre-treatment HBV/TB screening, fertility counselling.
Prognosis: 4–10y survival 56–95%; major causes of death: pulmonary/renal failure and infection. GPA has higher relapse rate than MPA.
Active Recall - Management of GPA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — AAV management: induction + maintenance, non-CYC immunosuppressant x 18 months) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1772–1774 — GPA treatment: mild vs severe, BVAS score, induction + maintenance) [3] Senior notes: Ryan Ho Rheumatology.pdf (p.97 — GPA/MPA/EGPA comparison table including treatment and prognosis) [9] Senior notes: Ryan Ho Urogenital.pdf (p.68–69 — ANCA-associated GN management approach, early Tx and better prognosis) [10] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1006 — ANCA +ve vasculitis treatment: pulse steroids + CYC/RTX ± plasma exchange) [11] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.413 — RPGN treatment: pulse steroids + CYC/RTX ± plasma exchange) [14] Senior notes: Ryan Ho Fundamentals.pdf (p.368 — General GN management: ACEI/ARB, pneumococcal vaccination, anti-proteinuric therapy) [15] Senior notes: Ryan Ho Ophthalmology.pdf (p.29 — Scleritis management: systemic steroids + immunosuppressant for necrotizing forms)
Complications of GPA (Granulomatosis with Polyangiitis)
Complications of GPA fall into two broad categories that you must think about in parallel:
- Disease-related complications — direct consequences of uncontrolled or inadequately treated vasculitis and granulomatous inflammation destroying organs
- Treatment-related complications — iatrogenic harm from the intensive immunosuppressive therapy required to control GPA
Both contribute to morbidity and mortality. In the modern era, treatment-related infections have become as important a cause of death as the disease itself.
"4–10y survival 56–95%. Lung/renal and infection as major cause of death" [3] GC slide: "GP — Major cause of death: Pulmonary and renal" [6]
1. Disease-Related Complications
These complications result from the two pathological hallmarks of GPA — necrotizing granulomatous inflammation and necrotizing vasculitis — causing progressive, irreversible organ damage if treatment is inadequate or delayed.
| Complication | Pathophysiological Explanation |
|---|---|
| End-stage renal disease (ESRD) | The most feared renal complication. Pauci-immune crescentic GN (RPGN Type III) destroys glomeruli. Cellular crescents → fibrous crescents → sclerotic glomeruli → irreversible nephron loss. Once > 50% of glomeruli are globally sclerotic, renal recovery is essentially impossible, even with aggressive immunosuppression [9]. The patient becomes dialysis-dependent. |
| Chronic kidney disease (CKD) | Even patients who respond to treatment often do not recover baseline renal function completely. The degree of residual CKD depends on how many glomeruli were already sclerosed at the time of treatment initiation — this is why early treatment is paramount [9]. |
| Relapsing GN | GPA has a high relapse rate (~50% at 5 years for PR3-ANCA positive disease [3]). Each relapse episode destroys more glomeruli, progressively accumulating irreversible renal damage even if each individual flare is treated. This "stepwise" decline is a major driver of long-term ESRD. |
"Renal-limited vasculitis are considered part of MPA/GPA spectrum because many may eventually exhibit extrarenal manifestations" [9] "Those who require immediate dialysis are unlikely to be dialysis-free in long term" [9]
Why Early Treatment Matters — The Fibrous Crescent Window
Cellular crescents (macrophages + epithelial cells proliferating in Bowman's space) are potentially reversible with immunosuppression — the inflammatory cells can be eliminated and the glomerulus may partially recover. But once fibroblasts replace the cellular crescent with a fibrous crescent, the damage is permanent. This transition can happen within weeks. Every day of delay in treatment converts more cellular crescents into fibrous ones, permanently closing the window of opportunity for renal recovery.
| Complication | Pathophysiological Explanation |
|---|---|
| Diffuse alveolar haemorrhage (DAH) | Necrotizing vasculitis of pulmonary capillaries → capillary wall disruption → blood floods into alveolar spaces. Can be massive and life-threatening, presenting as acute respiratory failure with haemoptysis. Requires ICU admission, mechanical ventilation, and emergency immunosuppression ± plasma exchange [2][3][5] |
| Pulmonary fibrosis | Chronic or recurrent alveolar haemorrhage and granulomatous inflammation → fibroblast proliferation → progressive interstitial fibrosis → restrictive lung disease → chronic respiratory failure [2] |
| Cavitary nodule complications | GPA's characteristic cavitating nodules can become secondarily infected (bacterial abscess, mycobacteria, or Aspergillus — the cavity provides a nidus). Cavities may also → massive haemoptysis if granulomatous erosion breaches a pulmonary artery branch |
| Subglottic/tracheal stenosis | Granulomatous inflammation of the subglottic region → acute mucosal oedema + chronic cicatricial fibrosis → progressive narrowing of the airway. Unlike most GPA manifestations, subglottic stenosis is often refractory to systemic immunosuppression because the stenosis is partly fibrotic (structural) rather than purely inflammatory. May require endoscopic dilatation, intralesional steroid injection, or stenting [3][5] |
| Bronchial stenosis | Endobronchial granulomas → segmental/lobar bronchial narrowing → post-obstructive atelectasis or pneumonia |
"LRT: cough, haemoptysis, chest pain" [5] "Pulmonary hemorrhage; Pulmonary capillary alveolitis; Pulmonary fibrosis" [2]
Subglottic Stenosis — The Exception to the Rule
Most GPA complications respond to systemic immunosuppression. Subglottic stenosis is the notable exception. It frequently persists or recurs despite adequate systemic treatment because the stenosis has a significant fibrotic (non-inflammatory) component. Patients present with progressive stridor, hoarseness, and dyspnoea. Management is often local: repeated endoscopic balloon dilatation, intralesional corticosteroid or mitomycin C injection, and occasionally tracheal stenting. Severe cases may require tracheostomy.
| Complication | Pathophysiological Explanation |
|---|---|
| Saddle nose deformity | Necrotizing granulomas destroy nasal septal cartilage → loss of dorsal nasal support → permanent cosmetic disfigurement. Once cartilage is destroyed, it is irreversible — even if disease is brought into remission [5] |
| Nasal septal perforation | Full-thickness destruction of the nasal septum by granulomatous necrosis → whistling sound on breathing, crusting, epistaxis |
| Chronic sinusitis / secondary infections | Granulomatous mucosal damage impairs mucociliary clearance → bacterial superinfection of sinuses → chronic sinusitis cycle requiring antibiotics |
| Hearing loss | Conductive: granulomatous obstruction of Eustachian tube → serous/suppurative otitis media → conductive hearing loss. Sensorineural: vasculitis of cochlear blood supply (labyrinthine artery) → cochlear ischaemia → irreversible sensorineural hearing loss [3][5] |
| Oral/nasal ulceration | Granulomatous mucosal destruction → painful, recurrent ulceration |
"ENT: Nasal crusting, epistaxis, sinusitis; OM, otalgia, hearing loss; Necrotizing ENT masses (saddle nose deformity)" [3] "Saddle nose deformity is due to damage to nasal septum by the necrotizing granulomas" [5]
| Complication | Pathophysiological Explanation |
|---|---|
| Blindness / visual loss | (1) Retro-orbital granulomatous mass → compresses optic nerve → compressive optic neuropathy → irreversible visual loss if not treated urgently. (2) Necrotizing scleritis → scleral thinning → scleromalacia perforans → globe perforation. (3) Vasculitis of retinal/optic nerve vessels → ischaemic optic neuropathy [3] |
| Scleromalacia perforans | Progressive necrotizing scleritis → scleral melting and thinning → underlying dark uveal tissue becomes visible → risk of globe rupture (ocular emergency) |
| Proptosis with diplopia | Retro-orbital granuloma physically pushes the globe forward and restricts extraocular muscle movement → misalignment of visual axes → diplopia |
| Nasolacrimal duct obstruction | Granulomatous inflammation obstructs the nasolacrimal duct → chronic epiphora (tearing) → risk of dacryocystitis (lacrimal sac infection) |
| Corneal ulceration / peripheral ulcerative keratitis (PUK) | Extension of scleral inflammation to the adjacent cornea → corneal melting → risk of perforation |
"Eye: scleritis, retro-orbital mass" [1] "Retro-orbital mass (proptosis, diplopia, optic n. compression)" [3]
| Complication | Pathophysiological Explanation |
|---|---|
| Mononeuritis multiplex | Vasculitis of vasa nervorum → nerve ischaemia and infarction → sudden-onset focal neuropathy (e.g., foot drop from common peroneal nerve, wrist drop from radial nerve). Recovery may be incomplete if axonal damage is severe — axonal regeneration occurs at ~1 mm/day but is often imperfect [7] |
| Cranial neuropathies | Granulomatous invasion from sinuses or skull base compresses cranial nerves (especially CN II, III, VI, VII). Direct vasculitis of cranial nerve blood supply can also cause ischaemic neuropathy |
| Hypertrophic pachymeningitis | Granulomatous inflammation of the dura mater → dural thickening → headache, cranial nerve entrapment, seizures. Rare but characteristic of GPA |
| Cerebral vasculitis (very rare) | Vasculitis of CNS vessels → stroke, seizures, encephalopathy. Unlike PAN and SLE, CNS vasculitis is uncommon in GPA (~2–8%) |
"Mononeuritis multiplex: simultaneous or sequential occurrence of mononeuropathies affecting multiple non-contiguous nerve trunks. Cause: axonal due to nerve infarction from small-to-medium arterial diseases" [7] "Neuro uncommon (15%)" [3]
| Complication | Pathophysiological Explanation |
|---|---|
| Pericarditis | Pericardial vasculitis or granulomatous inflammation → pericardial effusion → chest pain, pericardial rub; rarely tamponade |
| Coronary arteritis | Small-vessel vasculitis of coronary arteries (rare) → myocardial ischaemia |
| Cardiomyopathy | Very rare granulomatous myocarditis → dilated cardiomyopathy |
Note: cardiac involvement is uncommon in GPA. This contrasts sharply with EGPA, where cardiac disease is the major cause of morbidity and mortality (myocarditis, pericarditis, arrhythmias) [3][6]. GC slide: "EGP — Major cause of death: Cardiac. GP — Major cause of death: Pulmonary and renal" [6]
| Complication | Mechanism |
|---|---|
| Non-healing skin ulcers | Vasculitis-mediated dermal ischaemia → tissue necrosis → chronic ulceration, sometimes requiring skin grafting |
| Digital gangrene (rare) | Severe small vessel vasculitis → critical digital ischaemia → gangrene |
| Secondary skin infection | Immunosuppression + disrupted skin barrier → cellulitis, abscess |
| Complication | Mechanism |
|---|---|
| Chronic arthralgia | Persistent low-grade synovial inflammation; usually non-erosive but can be debilitating |
| Avascular necrosis (AVN) of femoral head | Primarily a treatment complication (glucocorticoids) rather than disease itself — steroids impair blood supply to femoral head → osteonecrosis |
| Factor | Detail |
|---|---|
| Relapse rate | GPA has a higher relapse rate compared to MPA — approximately 50% at 5 years for PR3-ANCA positive disease [3] |
| Risk factors for relapse | PR3-ANCA positivity (vs MPO-ANCA); persistent ANCA positivity after induction; chronic S. aureus nasal carriage; upper airway involvement (ENT-dominant disease); premature withdrawal of maintenance therapy |
| Consequence | Each relapse → further cumulative organ damage (especially kidneys and lungs) → stepwise decline in organ function |
| Monitoring | Serial ANCA titres, ESR/CRP, urinalysis, RFT every 3–6 months during and after maintenance |
2. Treatment-Related Complications
These are complications of the immunosuppressive drugs used to treat GPA. In the modern era, infection is a leading cause of death in treated GPA — rivalling or even exceeding the disease itself as a cause of mortality [3].
| Infection Type | Why It Occurs | Key Examples |
|---|---|---|
| Opportunistic infections | Profound immunosuppression from CYC, RTX, and high-dose steroids depletes neutrophils, lymphocytes, and immunoglobulins | Pneumocystis jirovecii pneumonia (PCP) — prevented by TMP-SMX prophylaxis; CMV reactivation; Aspergillus (especially in cavitary lung disease); Herpes zoster reactivation |
| Bacterial infections | Neutropenia (CYC-induced) + steroid-mediated impaired phagocytosis + hypogammaglobulinaemia (RTX) | Pneumonia, urinary tract infections, line sepsis, skin/soft tissue infections |
| HBV reactivation | RTX depletes B cells that control HBV → loss of immune surveillance → fulminant hepatitis | Mandatory HBV screening before RTX; antiviral prophylaxis (entecavir/tenofovir) if HBsAg or anti-HBc positive |
| TB reactivation | High-dose steroids + immunosuppressants → reactivation of latent TB (especially relevant in Hong Kong where TB is endemic) | IGRA/Mantoux + CXR screening before immunosuppression; isoniazid prophylaxis if latent TB detected |
"Lung/renal and infection as major cause of death" [3]
Infections in Treated GPA — The Other Side of the Coin
Students often focus on controlling the vasculitis and forget that the treatment itself can kill. In the first year of treatment, infection is the most common cause of death — not the vasculitis. This is why:
- TMP-SMX prophylaxis (PCP + S. aureus) is mandatory
- Pre-treatment screening for HBV, HCV, TB, HIV is essential
- Monitoring WCC during CYC prevents life-threatening neutropenia
- IgG levels should be checked during RTX — replace with IVIG if IgG < 3 g/L with recurrent infections
These are dose- and duration-dependent. High-dose steroids are necessary for induction, but prolonged use causes significant morbidity.
| Complication | Mechanism |
|---|---|
| Glucocorticoid-induced osteoporosis | Steroids ↓ osteoblast function + ↑ osteoclast activity + ↓ intestinal calcium absorption → bone loss → fractures (especially vertebral compression fractures). Prevented with calcium/vitamin D ± bisphosphonate |
| Steroid-induced diabetes mellitus | Steroids → hepatic gluconeogenesis + peripheral insulin resistance → hyperglycaemia. Monitor glucose regularly |
| Avascular necrosis (AVN) | Steroids cause fat embolisation and endothelial damage in end-arteries of bone → ischaemic necrosis, classically of the femoral head → hip pain, limp. May require joint replacement |
| Cushingoid features | Central obesity, moon face, buffalo hump, striae, skin thinning — cosmetically distressing and metabolically harmful |
| Cataracts (posterior subcapsular) | Steroid-induced changes in lens protein metabolism → lens opacification |
| Peptic ulcer disease | Steroids ↑ gastric acid and impair mucosal defence. Co-prescribe PPI |
| Adrenal suppression | Exogenous steroids suppress the HPA axis → iatrogenic adrenal insufficiency if abruptly discontinued. Must taper slowly |
| Mood disturbance / psychosis | Steroid-induced psychiatric effects (insomnia, agitation, mania, depression, psychosis) |
| Impaired wound healing | Steroids inhibit fibroblast proliferation and collagen synthesis |
| Increased infection susceptibility | Broad immunosuppressive effect (see above) |
| Complication | Mechanism | Prevention |
|---|---|---|
| Haemorrhagic cystitis | Acrolein (CYC metabolite) toxic to bladder urothelium | Mesna + hydration |
| Bladder cancer | Chronic acrolein exposure → DNA damage to urothelial cells → transitional cell carcinoma (risk increases with cumulative dose — especially with > 36 g lifetime dose) | Limit cumulative dose; urine cytology surveillance |
| Gonadal failure / infertility | Alkylation of germ cells (oocytes, spermatogonia) → premature ovarian failure / azoospermia. More common with cumulative dose | Pre-treatment fertility counselling; sperm/oocyte cryopreservation; IV pulse regimen (lower cumulative dose vs daily oral); GnRH agonist for ovarian protection |
| Myelodysplastic syndrome / leukaemia | Alkylating agent-related secondary malignancy | Limit cumulative dose |
| Bone marrow suppression | Direct toxicity to haematopoietic stem cells → leukopenia, neutropenia → ↑ infection risk | Monitor CBC; dose-adjust for WCC nadir |
| Complication | Mechanism |
|---|---|
| Hypogammaglobulinaemia | Prolonged B cell depletion → ↓ immunoglobulin production (especially IgG) → ↑ sinopulmonary infections. Monitor IgG levels every 6–12 months; IVIG replacement if IgG < 3 g/L with recurrent infections |
| Infusion reactions | Cytokine release from B cell lysis → fever, rigors, urticaria, hypotension, bronchospasm. Prevented by pre-medication |
| Late-onset neutropenia | Mechanism unclear; usually transient; occurs weeks to months after infusion |
| Progressive multifocal leukoencephalopathy (PML) | Very rare; JC virus reactivation in severely immunocompromised patients → fatal demyelinating disease of CNS |
| HBV reactivation | Loss of B cell-mediated immune surveillance → viral rebound → fulminant hepatitis |
| Complication | Mechanism |
|---|---|
| MTX pneumonitis | Idiosyncratic hypersensitivity reaction → acute interstitial pneumonitis (fever, cough, dyspnoea, diffuse infiltrates). NOT dose-dependent. Must stop MTX immediately |
| Hepatotoxicity / liver fibrosis | Cumulative hepatocyte injury from impaired folate metabolism |
| Bone marrow suppression | Folate antagonism → megaloblastic pancytopenia (especially if renal impairment slows drug clearance). Prevented by folic acid supplementation and dose adjustment for eGFR |
| Mucosal ulceration | Rapidly dividing mucosal epithelial cells are susceptible to folate antagonism → stomatitis, GI ulcers |
| Complication | Mechanism |
|---|---|
| Severe myelosuppression (if TPMT deficient) | TPMT is the enzyme that metabolises 6-mercaptopurine (active metabolite of AZA). Patients with low/absent TPMT accumulate toxic metabolite levels → life-threatening pancytopenia. Must check TPMT before starting AZA |
| Hepatotoxicity | Direct hepatocellular injury and cholestasis |
| Pancreatitis | Idiosyncratic; occurs in ~3–5% of patients |
| Increased malignancy risk | Small ↑ risk of lymphoma and non-melanoma skin cancer with long-term use |
| Organ | Disease-Related | Treatment-Related |
|---|---|---|
| Kidney | ESRD, CKD, relapsing GN | — |
| Lung | DAH, pulmonary fibrosis, cavitary superinfection, subglottic stenosis | PCP, opportunistic pneumonia, MTX pneumonitis |
| ENT | Saddle nose, septal perforation, hearing loss, chronic sinusitis | — |
| Eye | Blindness, scleromalacia perforans, proptosis, PUK | Steroid-induced cataracts, glaucoma |
| Nerve | Mononeuritis multiplex, cranial neuropathies, pachymeningitis | PML (very rare, RTX) |
| Cardiovascular | Pericarditis (uncommon) | Steroid-induced diabetes, hypertension, AVN |
| Bone | — | Glucocorticoid-induced osteoporosis, AVN |
| Infection | Cavitary superinfection | Leading cause of early death: PCP, CMV, HBV reactivation, TB, bacterial sepsis |
| Bladder | — | Haemorrhagic cystitis, bladder cancer (CYC) |
| Gonadal | — | Infertility (CYC) |
| Haematological | — | Myelosuppression (CYC, AZA, MTX), MDS/leukaemia (CYC) |
| Relapse | ~50% at 5y (PR3-ANCA); stepwise organ damage | — |
| Factor | Detail |
|---|---|
| Untreated GPA | ~90% mortality within 2 years (median survival 5 months historically) |
| Treated GPA | 4–10 year survival 56–95% [3] |
| Major causes of death | Pulmonary and renal failure (disease-related) + Infection (treatment-related) [3][6] |
| Comparison with EGPA | GPA: death from lung/renal; EGPA: death from cardiac [3][6] |
| Comparison with MPA | GPA has higher relapse risk than MPA; both have similar overall mortality [3] |
| Poor prognostic factors | Older age at diagnosis, renal impairment at presentation (especially dialysis-dependent), high BVAS score, sclerotic class on renal biopsy, DAH requiring ventilation, anti-PR3/c-ANCA positivity (higher relapse risk) |
| Good prognostic factors | Young age, limited disease, early treatment, achievement of sustained remission |
High Yield Summary — Complications of GPA
Disease-related complications (from uncontrolled vasculitis/granulomas):
- Kidney: ESRD from crescentic GN — the most critical; each relapse causes stepwise, irreversible nephron loss
- Lung: DAH (acute, life-threatening), pulmonary fibrosis (chronic), subglottic stenosis (often refractory to systemic Tx)
- ENT: Saddle nose deformity (irreversible cartilage destruction), septal perforation, hearing loss
- Eye: Blindness (optic nerve compression from retro-orbital mass, scleromalacia perforans)
- Nerve: Mononeuritis multiplex from vasa nervorum vasculitis
- Relapse: ~50% at 5 years for PR3-ANCA; major long-term challenge
Treatment-related complications (from immunosuppression):
- Infection is the #1 iatrogenic killer — PCP, CMV, HBV reactivation, TB (especially in HK); prevented by TMP-SMX, HBV/TB screening
- CYC: Haemorrhagic cystitis (mesna), infertility (cryopreservation), bladder cancer, myelosuppression
- RTX: Hypogammaglobulinaemia, HBV reactivation, infusion reactions
- Steroids: Osteoporosis, diabetes, AVN, cataracts, infections, Cushing's, peptic ulcers
Major cause of death: Pulmonary and renal failure + infection (contrast with EGPA where cardiac is the major killer).
Active Recall - Complications of GPA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — GPA clinical features: eye scleritis, retro-orbital mass) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1774 — MPA/GPA clinical manifestations: pulmonary hemorrhage, pulmonary fibrosis, mononeuritis multiplex) [3] Senior notes: Ryan Ho Rheumatology.pdf (p.97 — GPA comparison table: prognosis 4-10y survival, major cause of death pulmonary/renal and infection, relapse risk) [5] Senior notes: Ryan Ho Respiratory.pdf (p.139–140 — GPA: URT features including saddle nose deformity, subglottic stenosis, LRT features, CXR findings) [6] Lecture slides: GC 053. Fingers turn white and blue.pdf (p.94 — EGPA vs GP comparison: GP major cause of death = Pulmonary and renal) [7] Senior notes: Ryan Ho Neurology.pdf (p.180 — Mononeuritis multiplex: definition, causes including Wegener's granulomatosis, mechanism of nerve infarction) [9] Senior notes: Ryan Ho Urogenital.pdf (p.68–69 — ANCA-GN histological classification predicting outcome, renal-limited vasculitis prognosis, dialysis-dependent outcomes)
High Yield Summary
Definition: GPA is a systemic ANCA-associated small vessel vasculitis characterised by necrotizing granulomatous inflammation of the upper and lower respiratory tract + necrotizing vasculitis + pauci-immune crescentic GN.
Epidemiology: More common in Caucasians, peak age 65-74, slight male predominance. In Hong Kong, MPA > GPA.
ANCA: c-ANCA/anti-PR3 positive in ~85-90% of GPA (the most important serological marker).
Classic Triad: (1) Upper airway granulomatous disease, (2) Pulmonary nodules/cavities, (3) Pauci-immune RPGN.
Key Clinical Features:
- ENT: Sinusitis, epistaxis, nasal crusting, saddle nose deformity, subglottic stenosis, otitis media
- Lungs: Nodules, cavitating lesions, diffuse alveolar haemorrhage, cough, haemoptysis
- Kidneys: Pauci-immune RPGN (Type III) — can progress to ESRD in days/weeks
- Eyes: Scleritis, retro-orbital mass → proptosis
- Skin: Palpable purpura
- Nerves: Mononeuritis multiplex (uncommon, ~15%)
Distinguishing Features from Other AAVs:
- GPA vs MPA: GPA has granulomas + ENT involvement; MPA does not
- GPA vs EGPA: EGPA has asthma, eosinophilia, and cardiac involvement as major killer; GPA does not
- GPA = c-ANCA/PR3; MPA & EGPA = p-ANCA/MPO
Pathophysiology: Anti-PR3 antibodies bind to primed neutrophils → neutrophil activation → degranulation → endothelial damage → necrotizing vasculitis. Th1/Th17-mediated granuloma formation destroys tissue (nasal cartilage, lung parenchyma). Pauci-immune GN = minimal IF staining.
Key Investigations: ANCA (c-ANCA/anti-PR3), RFT + urinalysis, CXR (nodules/cavities), tissue biopsy (necrotizing granuloma + vasculitis).
High Yield Summary — Differential Diagnosis of GPA
Approach: Organise the DDx by the dominant presenting syndrome:
- Pulmonary-renal syndrome: GPA vs MPA vs Anti-GBM/Goodpasture vs SLE vs EGPA
- RPGN: Classify by IF pattern — Type I (linear = anti-GBM), Type II (granular = immune complex), Type III (pauci-immune = ANCA)
- Destructive sinonasal disease: GPA vs cocaine vs NK/T-cell lymphoma vs relapsing polychondritis vs TB/syphilis
- Cavitating lung nodules: GPA vs cancer vs TB vs abscess vs septic emboli
Key discriminators:
- ANCA type: c-ANCA/PR3 → GPA; p-ANCA/MPO → MPA/EGPA
- Complement: Normal → ANCA-associated, anti-GBM, IgAN; Low → SLE, PSGN, MPGN, cryoglobulinemia, IE
- IF pattern: Pauci-immune → ANCA; Linear → anti-GBM; Granular → immune complex
- Asthma + eosinophilia: Absent in GPA, always present in EGPA
- Granulomas: Present in GPA/EGPA, absent in MPA
- ENT destruction: Present in GPA, absent in MPA; always exclude cocaine and NK/T-cell lymphoma (especially in HK/Asian populations)
High Yield Summary — Diagnosis of GPA
Diagnostic tripod: (1) Compatible clinical features, (2) Positive c-ANCA/anti-PR3, (3) Tissue biopsy showing necrotizing granulomatous vasculitis.
ANCA: c-ANCA/anti-PR3 in ~85-90% of active generalised GPA. Suggestive but NOT diagnostic alone — can have false positives and false negatives.
Biopsy: Gold standard. Lung biopsy has highest yield for full histological picture. Renal biopsy shows pauci-immune crescentic GN (IF: minimal staining). Nasal biopsy is often non-diagnostic.
CXR/HRCT: Nodules, cavities, infiltrates (DAH). CT sinuses shows mucosal thickening and bone erosion.
Key discriminating investigations: Complement (normal in GPA), ANCA subtype (c-ANCA/PR3 for GPA; p-ANCA/MPO for MPA/EGPA), IF pattern on renal biopsy (pauci-immune = Type III RPGN).
Severity: BVAS score — mild (BVAS 0-3): corticosteroids + MTX; severe (BVAS > 3, end-organ damage): high-dose steroids + CYC/rituximab.
Do not delay treatment: Empirical pulse methylprednisolone can be given before biopsy if clinical suspicion is high and RPGN/DAH is present.
High Yield Summary — Management of GPA
Two phases: Induction (3–6 months) → Maintenance (≥ 24–48 months).
Induction:
- Limited disease (BVAS 0–3): Glucocorticoids + MTX
- Severe disease (BVAS > 3): Pulse IV methylprednisolone + RTX or CYC
- Life-threatening: Add plasma exchange
Maintenance: Rituximab (preferred, especially for PR3-ANCA) OR Azathioprine OR MTX OR MMF + taper steroids.
Key drugs:
- CYC: Alkylating agent; effective but toxic (haemorrhagic cystitis — give mesna; infertility — offer cryopreservation; myelosuppression)
- RTX: Anti-CD20 mAb; non-inferior to CYC; superior for relapse; avoids CYC toxicity (infusion reactions, hypogammaglobulinaemia)
- Avacopan: C5a receptor inhibitor; steroid-sparing adjunct (ADVOCATE trial)
Supportive: TMP-SMX (PCP prophylaxis + S. aureus eradication), bone protection, PPI, vaccinations, pre-treatment HBV/TB screening, fertility counselling.
Prognosis: 4–10y survival 56–95%; major causes of death: pulmonary/renal failure and infection. GPA has higher relapse rate than MPA.
High Yield Summary — Complications of GPA
Disease-related complications (from uncontrolled vasculitis/granulomas):
- Kidney: ESRD from crescentic GN — the most critical; each relapse causes stepwise, irreversible nephron loss
- Lung: DAH (acute, life-threatening), pulmonary fibrosis (chronic), subglottic stenosis (often refractory to systemic Tx)
- ENT: Saddle nose deformity (irreversible cartilage destruction), septal perforation, hearing loss
- Eye: Blindness (optic nerve compression from retro-orbital mass, scleromalacia perforans)
- Nerve: Mononeuritis multiplex from vasa nervorum vasculitis
- Relapse: ~50% at 5 years for PR3-ANCA; major long-term challenge
Treatment-related complications (from immunosuppression):
- Infection is the #1 iatrogenic killer — PCP, CMV, HBV reactivation, TB (especially in HK); prevented by TMP-SMX, HBV/TB screening
- CYC: Haemorrhagic cystitis (mesna), infertility (cryopreservation), bladder cancer, myelosuppression
- RTX: Hypogammaglobulinaemia, HBV reactivation, infusion reactions
- Steroids: Osteoporosis, diabetes, AVN, cataracts, infections, Cushing's, peptic ulcers
Major cause of death: Pulmonary and renal failure + infection (contrast with EGPA where cardiac is the major killer).
Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)
Eosinophilic granulomatosis with polyangiitis is an ANCA-associated small- and medium-vessel vasculitis characterized by asthma, peripheral eosinophilia, and extravascular eosinophilic granulomas affecting multiple organ systems.
IgA Vasculitis (Henoch-Schoenlein Purpura)
IgA vasculitis (Henoch-Schönlein purpura) is a small-vessel vasculitis caused by IgA immune complex deposition, characterized by palpable purpura, arthralgia, abdominal pain, and glomerulonephritis, most commonly affecting children.