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.

Exam domain	One-glance essentials
Definition / diagnosis	*GPA = necrotizing granulomatous inflammation of upper/lower respiratory tract + small/medium-vessel vasculitis* ^[1]^[2] Renal disease is pauci-immune necrotizing crescentic GN ^[2]
Epidemiology / risks	Usually older adults; more common in Caucasians, while MPA predominates in East Asia ^[2] Silica exposure and chronic nasal S. aureus carriage are associated with disease/relapse ^[2]
Core mechanism	Anti-PR3 binds primed neutrophils → Fc activation, degranulation/NETs → endothelial necrosis ^[2] Th1/Th17 macrophage activation produces destructive necrotizing granulomas; C5a amplifies neutrophil priming
Clinical picture	*ENT → lung → kidney*: chronic sinusitis/crusting/epistaxis, saddle nose or subglottic stenosis; nodules/cavities or DAH; RPGN ^[1]^[2] Scleritis/retro-orbital mass, palpable purpura and mononeuritis multiplex are high-yield extras
Investigations	c-ANCA/anti-PR3 strongly supports GPA but is not diagnostic; ANCA may be negative in limited disease ^[1]^[2] Urinalysis/RFT; HRCT chest and CT sinuses; biopsy is gold standard ^[2] Lung: granulomatous vasculitis; kidney: pauci-immune crescentic GN
Management	Organ-threatening disease: high-dose glucocorticoid + rituximab or cyclophosphamide; do not delay for biopsy in fulminant pulmonary-renal syndrome ^[2]^[3] Maintenance: rituximab/AZA/MTX; avacopan can reduce steroid exposure ^[3]
Complications	DAH and ESRD drive acute mortality; destructive ENT disease causes saddle nose, hearing loss and fixed subglottic stenosis ^[2]^[3] Optic compression/scleritis can blind; PR3-GPA has high relapse risk
Prevention / follow-up	Serial RFT/urine, inflammatory markers and clinical review; maintenance commonly ≥24 months ^[3] TMP-SMX for PJP (and reduced nasal S. aureus burden); vaccinate, screen HBV/TB, protect bone and fertility ^[3]
Exam traps	GPA = granulomas + destructive ENT + PR3; MPA lacks granulomas/ENT and is usually MPO ^[1] RPGN IF: pauci-immune = AAV; linear = anti-GBM; granular = immune-complex disease ^[2] Plasma exchange is reserved, not routine after PEXIVAS

References

^[1] Lecture slides: GC 053. Fingers turn white and blue.pdf (ANCA-associated vasculitis) ^[2] Senior notes: Ryan Ho Rheumatology.pdf (AAV, p. 97); Ryan Ho Urogenital.pdf (ANCA-GN, pp. 62–69) ^[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (GPA management, pp. 1772–1774)

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.

Small to medium vessels: capillaries, venules, arterioles, arteries and veins ^[1]^[2]
The Chapel Hill Consensus Conference (CHCC 2012) defines GPA as primarily a small vessel vasculitis that can also involve medium arteries

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:
1. Antibody-dependent cellular cytotoxicity (ADCC) — Fc portion recruits NK cells
2. Complement-dependent cytotoxicity (CDC) — activates complement cascade
3. 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]

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

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

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

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).

GPA Granulomatosis with Polyangiitis

References

Granulomatosis with Polyangiitis (GPA)

2. Epidemiology

4. Anatomy and Function — Organs Involved

5. Etiology and Pathophysiology

5.2 Pathophysiology — Step by Step

6. Classification

6.1 Within the Vasculitis Framework

7. Clinical Features

7.1 Symptoms (with Pathophysiological Basis)

7.2 Signs (with Pathophysiological Basis)

Active Recall - GPA (Granulomatosis with Polyangiitis)

Differential Diagnosis of GPA (Granulomatosis with Polyangiitis)

2. Differential Diagnosis by Clinical Presentation

5. Distinguishing GPA from Its Closest Mimics — Detailed Comparison

Active Recall - Differential Diagnosis of GPA

References

Diagnostic Criteria, Algorithm, and Investigations for GPA

1. Diagnostic Criteria

3. Investigation Modalities — Detailed Breakdown

3A. Blood Tests

3C. Imaging

Renal Biopsy — Histological Classification of ANCA-GN

Active Recall - Diagnosis and Investigations in GPA

References

Management of GPA (Granulomatosis with Polyangiitis)

3. Treatment Modalities — Detailed Breakdown

3A. Induction Therapy

3B. Maintenance Therapy

Active Recall - Management of GPA

References

Complications of GPA (Granulomatosis with Polyangiitis)

Active Recall - Complications of GPA

References

On this page

GPA Granulomatosis with Polyangiitis

1. Definition

2. Epidemiology

Incidence and Prevalence

Age and Sex

Geographic Variation

3. Risk Factors

4. Anatomy and Function — Organs Involved

Vessel Size Affected

Organs Classically Involved (and Why)

5. Etiology and Pathophysiology

5.1 Etiology

5.2 Pathophysiology — Step by Step

Step 1: ANCA Generation — The Central Autoantibody

Step 2: ANCA-Mediated Neutrophil Activation — "Priming and Triggering"

Step 3: Endothelial Damage and Necrotizing Vasculitis

Step 4: Granuloma Formation — The "Granulomatosis" Component

Step 5: Glomerulonephritis — "Pauci-immune RPGN"

Step 6: The Alternative Complement Pathway

6. Classification

6.1 Within the Vasculitis Framework

By the Chapel Hill Consensus Conference (CHCC 2012) [1][3][6]

GPA vs MPA vs EGPA — Comparison Table (HIGH YIELD) [1][2][3][6]

6.2 Disease Extent — Limited vs Severe/Generalised GPA

6.3 ANCA Serology Subclassification

7. Clinical Features

Overview of Organ Involvement

7.1 Symptoms (with Pathophysiological Basis)

A. Constitutional Symptoms

B. Upper Airway (ENT) Symptoms — The Hallmark of GPA

C. Lower Airway (Pulmonary) Symptoms

D. Renal Symptoms

E. Ocular Symptoms

F. Musculoskeletal Symptoms

G. Skin Symptoms

H. Neurological Symptoms

I. Cardiac Symptoms (Uncommon in GPA)

7.2 Signs (with Pathophysiological Basis)

A. ENT Signs

B. Pulmonary Signs

C. Renal Signs

D. Ocular Signs

E. Skin Signs

F. Neurological Signs

G. Musculoskeletal Signs

H. General Examination

8. Key Investigations Summary (for Context — Detailed Dx Algorithm to Follow)

9. Summary Table — ANCA-Associated Vasculitides Side-by-Side

Active Recall - GPA (Granulomatosis with Polyangiitis)

References

1. Framework for Approaching the DDx

2. Differential Diagnosis by Clinical Presentation

2A. Pulmonary-Renal Syndrome (Haemoptysis + Glomerulonephritis)

2B. RPGN / Nephritic Syndrome (Rapidly Declining Renal Function)

2C. Chronic Destructive Upper Airway / ENT Disease

2D. Cavitating Pulmonary Nodules / Masses

2E. Systemic Vasculitis (Multisystem Disease)

2F. Orbital Mass / Proptosis

3. Diagnostic Algorithm — Approaching the DDx Systematically

4. Key Serological and Immunofluorescence Discriminators

5. Distinguishing GPA from Its Closest Mimics — Detailed Comparison

5A. GPA vs MPA

5B. GPA vs EGPA

5C. GPA vs Anti-GBM Disease (Goodpasture Syndrome)

5D. GPA vs PAN (Polyarteritis Nodosa)

5E. GPA vs Sarcoidosis

6. Differential Diagnosis Summary Diagram

Active Recall - Differential Diagnosis of GPA

1. Diagnostic Criteria

1A. ACR 1990 Classification Criteria for GPA (Wegener's)

1B. 2022 ACR/EULAR Classification Criteria for GPA (Updated)

1C. CHCC 2012 Definition (Chapel Hill Consensus Conference)

1D. Practical Clinical Diagnosis — How GPA Is Actually Diagnosed

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3A. Blood Tests

i. Full Blood Count with Differential (CBC D/C)

ii. Inflammatory Markers

iii. ANCA Testing — The Serological Cornerstone

iv. Renal Function Tests (RFT)