Granulomatosis with Polyangiitis (GPA)

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1. Overview

Granulomatosis with Polyangiitis (GPA), formerly known as Wegener's Granulomatosis, is a primary systemic ANCA-associated vasculitis (AAV) characterised by necrotising granulomatous inflammation and vasculitis affecting predominantly small-to-medium-sized blood vessels. [1]

GPA is distinguished by a predilection for the "classic triad" of organ involvement:

1. Upper Respiratory Tract (URT): Chronic sinusitis, nasal crusting, saddle nose deformity
2. Lower Respiratory Tract (LRT): Pulmonary nodules, cavitation, alveolar haemorrhage
3. Kidneys: Pauci-immune crescentic glomerulonephritis

Key Pathophysiological Concepts

• ANCA Positivity: Strongly associated with c-ANCA (cytoplasmic pattern) targeting Proteinase 3 (PR3). [2]
• Granulomatous Inflammation: Extravascular granulomas are a hallmark, differentiating GPA from Microscopic Polyangiitis (MPA).
• Medical Emergency: Active renal or pulmonary disease requires urgent immunosuppression to prevent permanent organ failure or death.

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2. Epidemiology

Incidence and Prevalence

• Incidence: Approximately 10–20 cases per million population per year in Northern Europe and North America. [1]
• Prevalence: Estimated at 13–24 per 100,000 in European populations.
• Age: Peak onset is between 40 and 60 years, though GPA can occur at any age, including childhood and the elderly.
• Sex: Slight male predominance or equal sex distribution (approximately 1:1).
• Geography: More common in Northern European populations (Caucasian descent); rare in African and Asian populations.
• Genetics: Associations with HLA-DPB1 alleles have been identified. [2]

Risk Factors and Environmental Triggers

• Environmental: Silica exposure, farming, chronic solvent exposure, and Staphylococcus aureus nasal carriage have been implicated as potential triggers or risk factors for disease onset and relapse. [3]
• Drugs: Certain drugs (e.g., hydralazine, propylthiouracil) can induce an ANCA-associated vasculitis, though these typically present with p-ANCA/MPO positivity rather than c-ANCA/PR3.
• Infections: Upper respiratory tract infections may precede onset or relapse, suggesting a potential infectious trigger.

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3. Pathophysiology

The pathogenesis of GPA involves a complex interplay between genetic predisposition, environmental triggers, autoimmunity, and innate immune dysregulation.

The Role of ANCA

Anti-Neutrophil Cytoplasmic Antibodies (ANCA) are central to the disease process. In GPA, autoantibodies primarily target Proteinase 3 (PR3), a serine protease normally sequestered within neutrophil azurophilic granules. [2,4]

Pathogenic Mechanism of ANCA

1. Priming: Inflammatory cytokines (TNF-α, IL-1, IL-18) released during infection or other stimuli prime neutrophils, causing translocation of ANCA antigens (PR3 and MPO) from intracellular granules to the cell surface.
2. Binding: Circulating c-ANCAs bind to surface-expressed PR3 on primed neutrophils.
3. Activation: This cross-linking activates neutrophils excessively, leading to respiratory burst and degranulation.
4. Adhesion & Degranulation: Activated neutrophils adhere to vascular endothelium and release Reactive Oxygen Species (ROS), proteolytic enzymes (elastase, cathepsin G), and inflammatory mediators.
5. NETosis: Neutrophils undergo NETosis (Neutrophil Extracellular Trap formation), releasing web-like structures containing PR3, MPO, histones, and DNA. NETs further fuel the autoimmune response and directly damage endothelial cells. [4]

Granuloma Formation

• Unlike MPA (which is purely vasculitic), GPA features extravascular granulomatous inflammation.
• Granulomas are mediated by T-cell responses (Th1 and Th17 pathways) and activated macrophages.
• Granulomatous inflammation contributes to tissue destruction in the upper respiratory tract (nasal septal cartilage collapse, saddle nose deformity) and formation of mass-like lesions in the lungs (pulmonary nodules). [1]

Endothelial Injury and Vasculitis

• Vascular inflammation results from direct endothelial injury by activated neutrophils, complement activation (alternative pathway), and cytokine-mediated inflammation.
• Pauci-immune pattern: Minimal immunoglobulin and complement deposition on immunofluorescence of renal biopsies, distinguishing AAV from immune-complex-mediated GN. [5]

Genetic and Molecular Insights

• HLA-DPB1 polymorphisms confer susceptibility, particularly in PR3-ANCA-positive patients.
• SERPINA1 (alpha-1 antitrypsin deficiency) variants may increase risk.
• PR3 is constitutively expressed on a subset of neutrophils, which correlates with relapse risk (patients with high PR3-expressing neutrophils have higher relapse rates). [2]

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4. Clinical Presentation

Presentation is highly variable, ranging from indolent "localized" disease (e.g., chronic sinusitis) to fulminant, life-threatening systemic disease with pulmonary-renal syndrome.

Constitutional Symptoms

• Present in >80% of patients.
• Fever, malaise, anorexia, weight loss (often >5 kg), arthralgia, and myalgia.
• Non-specific symptoms may precede organ-specific manifestations by weeks to months.

Organ System Involvement

Upper Respiratory Tract (ENT) – 90%

The upper respiratory tract is involved in approximately 90% of patients at some point in the disease course. [1,6]

• Nasal symptoms:
  • Bloody nasal discharge, crusting, epistaxis, nasal pain.
  • Chronic purulent rhinosinusitis unresponsive to antibiotics.
• Saddle nose deformity: Due to nasal septal cartilage collapse (late manifestation).
• Sinusitis: Chronic maxillary and ethmoid sinusitis; bony erosion may occur.
• Ear involvement: Serous otitis media (conductive hearing loss), sensorineural hearing loss, auricular chondritis.
• Oral manifestations: "Strawberry gingivitis" (hyperplastic, friable gingiva; rare but characteristic), palatal ulcers, oral ulceration.

Lower Respiratory Tract (Lungs) – 60-85%

Pulmonary involvement occurs in 60-85% of patients. [1,6]

• Symptoms: Cough, haemoptysis, dyspnoea, pleuritic chest pain.
• Imaging findings:
  • Pulmonary nodules: Single or multiple; may cavitate (thick-walled cavities; "cannonball" lesions).
  • Patchy infiltrates: Ground-glass opacities (diffuse alveolar haemorrhage).
  • Masses: May mimic malignancy.
• Alveolar haemorrhage: Life-threatening complication; presents with haemoptysis, dyspnoea, hypoxia, and diffuse ground-glass opacities on imaging.
• Airway stenosis: Subglottic stenosis (tracheal narrowing below the vocal cords) causes stridor and dyspnoea; may occur independently of systemic disease activity. [7]

Renal – 75%

Renal involvement occurs in approximately 75% of patients and is often asymptomatic initially until advanced. [1,5]

• Glomerulonephritis:
  • Pauci-immune crescentic glomerulonephritis: Focal segmental necrotising GN.
  • Rapidly Progressive Glomerulonephritis (RPGN): Acute rise in creatinine; oliguria; hypertension.
  • Urinary abnormalities: Microscopic or macroscopic haematuria, proteinuria (usually sub-nephrotic range), red cell casts (active urinary sediment).
• Acute Kidney Injury (AKI): May progress to dialysis-dependent renal failure.
• Chronic Kidney Disease (CKD): Long-term sequela if treatment delayed.

Ocular – 50%

• Orbital granuloma: Proptosis, periorbital oedema, ophthalmoplegia.
• Scleritis: Painful red eye; threatens vision if untreated.
• Episcleritis: Less severe; superficial inflammation.
• Uveitis: Anterior or posterior.
• Nasolacrimal duct obstruction: Epiphora (excessive tearing).
• Corneal ulceration: Peripheral ulcerative keratitis (PUK).

Nervous System – 20-50%

• Peripheral Nervous System (PNS):
  • Mononeuritis multiplex: Asymmetric peripheral neuropathy (e.g., right foot drop + left ulnar nerve palsy).
  • Distal symmetrical polyneuropathy: Sensory or sensorimotor neuropathy.
• Central Nervous System (CNS) (rare, 2-8%):
  • Pachymeningitis: Chronic inflammation of the dura mater; headache, cranial nerve palsies.
  • Granulomatous masses: Space-occupying lesions.
  • Cerebral vasculitis: Stroke-like presentations.

Cutaneous – 40-50%

• Palpable purpura: Leukocytoclastic vasculitis (lower limbs).
• Subcutaneous nodules: Granulomatous inflammation.
• Ulcers: Chronic, non-healing ulcers.
• Livedo reticularis.

Cardiac – less than 10%

• Pericarditis: Chest pain, pericardial effusion.
• Myocarditis: Rare; can cause heart failure or arrhythmias.
• Coronary arteritis: Rare; may cause myocardial infarction.

Gastrointestinal – Rare

• Mesenteric vasculitis causing bowel ischaemia (rare; more common in PAN).

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5. Clinical Examination

A systematic examination is essential to assess the extent and severity of disease.

General Inspection

• Cachexia: Weight loss, muscle wasting.
• Pallor: Anaemia of chronic disease or renal failure.
• Vital signs: Fever (active inflammation), hypertension (renal involvement), tachypnoea/desaturation (pulmonary haemorrhage).

Ear, Nose, and Throat (ENT)

• Nose:
  • Inspect for saddle nose deformity.
  • Use a thudicum speculum or otoscope to visualise the nasal mucosa: look for crusting, ulceration, septal perforation, mucosal granulation.
• Ears: Otoscopy for serous otitis media (dull, retracted tympanic membrane), inflammation, or discharge.
• Throat: Inspect the gums for hyperplastic "strawberry gingivitis" and the palate for ulceration.

Respiratory Examination

• Inspection: Tracheal deviation (mediastinal mass or pneumothorax).
• Palpation: Tracheal position, chest expansion.
• Percussion: Dullness (consolidation, effusion) or hyper-resonance (cavitation, pneumothorax).
• Auscultation:
  • Diffuse crackles (alveolar haemorrhage, fibrosis).
  • Focal signs of consolidation.
  • Stridor: Inspiratory stridor indicates subglottic stenosis; warrants urgent ENT review.

Cardiovascular Examination

• Blood pressure: Hypertension (renal involvement).
• Heart sounds: Pericardial rub (pericarditis).
• JVP: Elevated (fluid overload in renal failure, pericardial effusion).
• Peripheral oedema: Fluid overload (renal failure, nephrotic syndrome).

Abdominal / Renal Examination

• Usually unremarkable unless advanced renal failure with uraemia.
• Check for fluid overload (ascites, peripheral oedema) if AKI/CKD.

Neurological Examination

• Peripheral Nervous System:
  • Assess power, tone, reflexes, and sensation in all limbs.
  • Look for asymmetrical weakness (mononeuritis multiplex: e.g., right foot drop [peroneal nerve] + left ulnar nerve palsy).
  • Glove-and-stocking sensory loss (distal symmetrical polyneuropathy).
• Cranial Nerve Examination: Assess for cranial nerve palsies (pachymeningitis, orbital granuloma).

Skin Examination

• Full skin examination for:
  • Palpable purpura (typically lower limbs).
  • Subcutaneous nodules.
  • Ulcers (chronic, non-healing).
  • Livedo reticularis.

Ophthalmological Examination

• External inspection: Proptosis, periorbital swelling.
• Red eye: Scleritis (deep, severe pain), episcleritis (superficial, mild pain).
• Visual acuity: Document if impaired.
• Fundoscopy: Retinal vasculitis (rare).

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6. Investigations

Urgent investigation is required to define the extent of organ involvement and confirm the diagnosis.

Bedside Tests

Urinalysis – ESSENTIAL

• Urine dipstick: Look for blood +++ and protein ++.
• Quantification: Urine protein:creatinine ratio (PCR) or albumin:creatinine ratio (ACR) to quantify proteinuria.
• Urine microscopy: Red cell casts indicate active glomerulonephritis (pathognomonic of proliferative GN).

Laboratory Investigations

Full Blood Count (FBC)

• Anaemia: Normocytic normochromic (chronic disease, renal failure, or haemorrhage).
• Leukocytosis: Neutrophilia (active inflammation).
• Thrombocytosis: Reactive (acute phase response).

Inflammatory Markers

• ESR: Typically markedly elevated (often >50 mm/hr).
• CRP: Elevated in active disease; useful for monitoring.

Renal Function

• Urea & Creatinine: Elevated creatinine indicates renal involvement.
• eGFR: Quantify renal function; RPGN shows rapidly declining eGFR.
• Electrolytes: Monitor potassium (risk of hyperkalaemia in AKI).

Liver Function

• Albumin: May be low (acute phase reaction, nephrotic syndrome).
• Transaminases: Usually normal unless hepatic involvement (rare).

ANCA Serology – KEY DIAGNOSTIC TEST

• c-ANCA (cytoplasmic pattern): Positive in >90% of generalized GPA.
• Anti-PR3 (proteinase 3): Highly specific for GPA (>90% specificity). [2,8]
• p-ANCA/MPO: May be positive in ~10% of GPA (more common in "limited" or renal-only disease).
• ANCA-negative GPA: Approximately 10% of patients are ANCA-negative (more common in localized disease). [8]

Other Serology

• Anti-GBM antibodies: Rule out concurrent anti-GBM disease (double-positive patients have worse prognosis).
• ANA, anti-dsDNA, complement (C3, C4): Rule out lupus nephritis (low C3/C4 suggests immune-complex disease, not AAV).
• Hepatitis B/C, HIV: Screen before immunosuppression.

Imaging

Chest X-Ray (CXR)

• Findings:
  • Cavitating nodules (thick-walled).
  • Patchy infiltrates.
  • Ground-glass opacities (alveolar haemorrhage).
  • Masses (may mimic malignancy).

High-Resolution CT Chest (HRCT)

• More sensitive than CXR.
• Findings:
  • Pulmonary nodules (single or multiple; may cavitate).
  • Ground-glass opacification (haemorrhage).
  • Bronchial wall thickening, airway stenosis (subglottic/endobronchial involvement). [7]
  • Tree-in-bud opacities (rare).

CT Sinuses / MRI Head and Sinuses

• CT Sinuses:
  • Mucosal thickening, opacification of sinuses.
  • Bony erosion (advanced disease).
• MRI: Superior for assessing soft tissue involvement, orbital granulomas, pachymeningitis.

Histology and Biopsy

Biopsy provides definitive diagnosis, though the classic triad of histological findings (vasculitis, necrosis, granulomatous inflammation) is seen in less than 20% of biopsies. [1]

Renal Biopsy

• Gold standard for renal involvement.
• Light microscopy:
  • Focal segmental necrotising and crescentic glomerulonephritis.
  • Fibrinoid necrosis.
  • Crescent formation (epithelial crescents).
• Immunofluorescence: Pauci-immune (negative or minimal staining for immunoglobulins and complement). [5]
• Electron microscopy: No immune-complex deposits (distinguishes from immune-complex GN).

Lung Biopsy

• Via bronchoscopy (transbronchial) or open/thoracoscopic biopsy.
• Findings:
  • Necrotising granulomatous inflammation.
  • Necrotising vasculitis.
  • Cavitation, haemorrhage.

ENT/Nasal Biopsy

• Nasal mucosal biopsy may show granulomatous inflammation, but often non-specific (mucosal necrosis, inflammation).
• Low diagnostic yield (less than 30%); does not rule out GPA if negative.

Bronchoscopy

• Indications:
  • Rule out infection (especially tuberculosis, fungal).
  • Inspect airways for stenosis, bleeding.
  • Obtain bronchoalveolar lavage (BAL): Progressively bloody BAL indicates alveolar haemorrhage (haemosiderin-laden macrophages).

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7. Diagnostic Criteria and Classification

ACR/EULAR 2022 Classification Criteria for GPA

Points are assigned based on clinical and laboratory findings. A score of ≥5 points supports a classification of GPA (sensitivity ~92%, specificity ~94%). [9]

Positive Items (increase likelihood of GPA):

• Bloody nasal discharge, ulcers, or crusting: +3 points
• Cartilaginous involvement (nasal, auricular): +2 points
• Conductive or sensorineural hearing loss: +1 point
• c-ANCA or anti-PR3 antibodies: +5 points
• Pulmonary nodules or cavities: +2 points
• Granulomatous inflammation on biopsy: +2 points
• Pauci-immune glomerulonephritis on biopsy: +1 point

Negative Items (decrease likelihood of GPA):

• Eosinophilia (≥1 × 10⁹/L): -4 points (suggests EGPA)

Differential Diagnosis

Other ANCA-Associated Vasculitides

• Microscopic Polyangiitis (MPA): p-ANCA/MPO-positive; pulmonary-renal syndrome; no granulomas.
• Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg-Strauss): Asthma, eosinophilia, p-ANCA/MPO-positive; eosinophilic granulomas.

Other Vasculitides

• Goodpasture Syndrome (Anti-GBM Disease): Anti-GBM antibodies; pulmonary-renal syndrome; linear IgG on IF.
• Polyarteritis Nodosa (PAN): Medium-vessel vasculitis; ANCA-negative; systemic symptoms, renal artery involvement, no glomerulonephritis.
• IgA Vasculitis (Henoch-Schönlein Purpura): IgA-dominant immune deposits; purpura, abdominal pain, arthritis.

Infectious and Granulomatous Diseases

• Tuberculosis: Granulomas; cavitating lung lesions; QuantiFERON/IGRA, sputum culture.
• Fungal infections (Aspergillosis, Histoplasmosis): Cavitating lesions; serology, culture.
• Sarcoidosis: Non-caseating granulomas; hilar lymphadenopathy; elevated ACE.

Malignancies

• Lymphoma (especially NK/T-cell lymphoma): Midline destructive lesions; biopsy shows malignancy.
• Lung cancer: Pulmonary nodules/masses; biopsy diagnostic.

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8. Management

Management of GPA is divided into Remission Induction (aggressive therapy to rapidly control disease) and Remission Maintenance (preventing relapse while minimizing toxicity). Co-management with Nephrology/Rheumatology is mandatory.

General Principles

• Early aggressive treatment is essential to prevent irreversible organ damage.
• Distinguish between severe/organ-threatening disease (pulmonary haemorrhage, RPGN, creatinine >150 µmol/L, CNS involvement) and non-severe/localized disease (e.g., limited ENT disease).
• Monitor for treatment-related complications (infections, malignancy, infertility).

Phase 1: Remission Induction (0-6 months)

Goal: Rapidly suppress inflammation and induce disease remission.

Severe / Organ-Threatening Disease

Definition: Creatinine >150 µmol/L, pulmonary haemorrhage, CNS involvement, scleritis, or rapidly progressive disease.

1. Corticosteroids

• Pulsed IV Methylprednisolone: 500 mg–1 g daily for 3 days (severe disease).
• Followed by oral Prednisolone: 1 mg/kg/day (max 60-80 mg/day), tapering over 3-6 months.
• Steroid-sparing goal: Reduce to ≤10 mg/day by 6 months.

2. Cyclophosphamide (CYC) or Rituximab (RTX)

Both are equally effective for induction of remission in severe AAV. [10,11]

Cyclophosphamide

• IV pulse regimen (preferred over oral due to lower cumulative dose and bladder toxicity):
  • 15 mg/kg IV every 2-3 weeks (adjust for age >60 years, renal impairment).
  • Duration: 3-6 months (typically 6 pulses).
• Oral regimen (alternative):
  • 2 mg/kg/day orally (max 200 mg/day); adjust for renal function.
  • Duration: 3-6 months.
• Adverse effects: Infertility, haemorrhagic cystitis, bladder cancer, leukopenia, infections.
• Fertility preservation: Offer gonadotropin-releasing hormone (GnRH) analogues (females), sperm banking (males).

Rituximab

• Non-inferior to CYC for induction; superior in relapsing disease. [10]
• Preferred if:
  • Relapsing disease (previous CYC exposure).
  • Fertility concerns.
  • Contraindication to CYC (e.g., bladder toxicity, malignancy history).
• Dosing:
  • 375 mg/m² IV weekly for 4 weeks, OR
  • 1 g IV on day 0 and day 14 (alternative regimen).
• Adverse effects: Infusion reactions, infections (PCP, hepatitis B reactivation), hypogammaglobulinaemia.

3. Plasma Exchange (PLEX)

• PEXIVAS trial (2020): Plasma exchange did not reduce death or ESRD in severe AAV compared to glucocorticoids alone. [12]
• Current role (controversial):
  • Consider in: Dual ANCA/anti-GBM positivity, dialysis-dependent renal failure at presentation, fulminant pulmonary haemorrhage.
  • Not routinely recommended based on PEXIVAS.

Non-Severe / Localized Disease

Definition: Limited ENT disease, no renal involvement, no organ-threatening features.

• Methotrexate + Prednisolone:
  • Methotrexate 20-25 mg once weekly (oral or subcutaneous).
  • Prednisolone 1 mg/kg/day, tapering.
• Mycophenolate Mofetil (MMF) + Prednisolone (alternative).

Phase 2: Remission Maintenance (6 months onwards)

Goal: Prevent relapse while minimizing drug toxicity.

• Start after remission achieved (typically 3-6 months).
• Duration: At least 24 months; often longer in PR3-positive patients (high relapse risk).

First-Line: Rituximab

• Superior to Azathioprine for preventing relapse (MAINRITSAN trials). [13,14]
• Dosing:
  • 500 mg IV every 6 months for at least 24 months.
• Monitoring: B-cell counts (CD19/CD20); some centres re-dose when B-cells recover rather than fixed intervals.

Second-Line: Azathioprine

• Traditional standard (now second-line after MAINRITSAN).
• Dosing: 2 mg/kg/day orally.
• Monitoring: FBC, LFTs; check TPMT activity before starting (thiopurine toxicity risk).

Alternative: Methotrexate

• If renal function allows (avoid if eGFR less than 40 mL/min).
• Dosing: 20-25 mg once weekly.
• Supplement: Folic acid 5 mg once weekly (day after MTX).

Steroid Tapering

• Goal: Withdraw prednisolone or maintain at ≤5 mg/day.
• Reduced-dose regimen: PEXIVAS trial showed reduced-dose glucocorticoid regimen was non-inferior to standard-dose and associated with fewer serious infections. [12]

Adjunctive Therapy and Supportive Care

Prophylaxis

• PCP Prophylaxis (mandatory):
  • Co-trimoxazole (Septrin) 960 mg three times weekly during CYC/RTX.
  • Alternative: Dapsone 100 mg daily, atovaquone.
• Fungal Prophylaxis: Nystatin or fluconazole if high risk.
• Gastric Protection: Proton pump inhibitor (PPI) while on high-dose steroids.
• Bone Protection: Vitamin D/Calcium supplementation + bisphosphonate (alendronate 70 mg weekly) to prevent steroid-induced osteoporosis.

Cardiovascular Risk Management

• Blood pressure control: Target less than 130/80 mmHg.
• Lipid management: Statin therapy.
• Smoking cessation.
• Antiplatelet therapy: Low-dose aspirin (if no contraindication).

Vaccinations

• Pneumococcal (PCV13 + PPV23), Influenza (annual), Hepatitis B (if non-immune).
• Avoid live vaccines during immunosuppression (MMR, VZV, yellow fever).

Renal Replacement Therapy

• Dialysis: If ESRD develops.
• Renal transplantation: Delayed until sustained remission (≥12 months); recurrence in transplant is rare.

Novel Therapies

Avacopan (C5a Receptor Inhibitor)

• ADVOCATE trial (2021): Avacopan was non-inferior to prednisone taper in inducing remission when combined with RTX or CYC. [15]
• Role: Steroid-sparing agent; reduces glucocorticoid exposure and associated toxicity.
• Dosing: 30 mg orally twice daily.
• Approval: Approved by FDA (2021) and EMA (2021) as adjunctive therapy.

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9. Complications

Disease-Related Complications

Renal

• End-Stage Renal Disease (ESRD): Requiring dialysis or transplantation.
• Chronic Kidney Disease (CKD): Permanent reduction in renal function.

Respiratory

• Subglottic Stenosis: May require repeated dilatations, laser therapy, or surgical intervention (cricotracheal resection). Often persists despite systemic remission. [7]
• Pulmonary Fibrosis: Late sequela of alveolar haemorrhage or chronic inflammation.

ENT

• Saddle Nose Deformity: Permanent cosmetic deformity from nasal septal cartilage collapse.
• Chronic Sinusitis: Persistent symptoms despite treatment.
• Hearing Loss: Permanent sensorineural or conductive hearing loss.

Neurological

• Permanent Neuropathy: Residual weakness or sensory deficits from mononeuritis multiplex.

Ocular

• Blindness: From untreated scleritis, orbital granuloma, or retinal vasculitis.

Thrombotic

• Venous Thromboembolism (VTE): High risk in active vasculitis; consider thromboprophylaxis.

Treatment-Related Complications

Infection

• Major cause of mortality in AAV.
• Opportunistic infections: Pneumocystis jirovecii pneumonia (PCP), invasive fungal infections, tuberculosis reactivation, cytomegalovirus (CMV).
• Routine bacterial infections: Pneumonia, urinary tract infections, sepsis.

Cyclophosphamide Toxicity

• Infertility: Premature ovarian failure (females), azoospermia (males); dose-dependent (cumulative dose >8-10 g increases risk).
• Haemorrhagic Cystitis: Risk reduced with IV pulse regimen, hydration, mesna.
• Bladder Cancer: Lifetime risk ~5%; risk persists >10 years post-treatment.
• Myelodysplasia / Leukaemia: Rare (1-2%).

Rituximab Toxicity

• Infusion Reactions: Fever, chills, hypotension (usually first infusion).
• Hypogammaglobulinaemia: Increases infection risk; monitor immunoglobulin levels.
• Hepatitis B Reactivation: Screen HBsAg/HBcAb before therapy; prophylaxis if positive.
• Progressive Multifocal Leukoencephalopathy (PML): Rare; JC virus reactivation.

Glucocorticoid Toxicity

• Diabetes Mellitus, osteoporosis, cataracts, glaucoma, weight gain, Cushingoid habitus, avascular necrosis (hips, knees), mood disturbance (depression, psychosis).

Azathioprine Toxicity

• Myelosuppression (TPMT deficiency).
• Hepatotoxicity.
• Increased skin cancer risk (squamous cell carcinoma).

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10. Prognosis and Outcomes

Mortality

• Untreated GPA: >90% mortality within 2 years (historical data).
• Treated GPA: 5-year survival >80%; 10-year survival ~75%. [1]
• Causes of death:
  • Infection (most common cause; ~50%).
  • Active vasculitis (pulmonary haemorrhage, renal failure).
  • Cardiovascular disease (accelerated atherosclerosis).
  • Malignancy.

Relapse

• High relapse rate: 30-50% within 5 years. [13,14]
• Predictors of relapse:
  • PR3-ANCA positivity (higher relapse than MPO-ANCA).
  • Upper respiratory tract disease (especially chronic nasal/sinus involvement).
  • Pulmonary cavitation.
  • Staphylococcus aureus nasal carriage (eradication with nasal mupirocin may reduce relapse).
• Definition of relapse:
  • Major relapse: Organ-threatening disease (requires re-induction).
  • Minor relapse: Grumbling symptoms without organ threat (increase maintenance therapy).

Long-Term Morbidity

• Damage accrual: Chronic kidney disease, hearing loss, nasal deformity, subglottic stenosis, neuropathy.
• Treatment-related morbidity: Osteoporosis, diabetes, cataracts, infertility, malignancy.
• Quality of life: Significantly impaired due to chronic disease, treatment burden, and complications.

Monitoring

During Active Disease

• Weekly: FBC, U&E, CRP/ESR, urinalysis.
• Fortnightly: After initial stabilization.

During Remission

• Every 3-6 months:
  • FBC, U&E, LFT, CRP/ESR.
  • Urinalysis (detect early relapse).
  • ANCA titres (rising titre does not always predict relapse but warrants closer monitoring).
• Annually:
  • Chest X-ray (pulmonary relapse, nodules).
  • Audiology (hearing loss).
  • Ophthalmology (if ocular involvement).

Disease Activity Scores

• Birmingham Vasculitis Activity Score (BVAS): Standardised score used in clinical trials; rates disease activity across organ systems.
• Vasculitis Damage Index (VDI): Rates permanent damage from disease or treatment.

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11. Evidence Base and Guidelines

Key Guidelines

• EULAR/ERA-EDTA Recommendations (2022): Comprehensive management of ANCA-associated vasculitis. [16]
• British Society for Rheumatology (BSR) Guidelines (2014): Management of adults with AAV. [17]
• KDIGO Glomerulonephritis Guidelines (2021): Recommendations for pauci-immune GN.

Landmark Trials

RAVE (2010)

• Design: RCT comparing rituximab vs cyclophosphamide for induction in severe AAV.
• Findings: Rituximab was non-inferior to CYC for induction; superior in relapsing disease. [10]
• Impact: Established RTX as first-line induction therapy.

PEXIVAS (2020)

• Design: RCT of plasma exchange vs no plasma exchange, and standard-dose vs reduced-dose glucocorticoids in severe AAV.
• Findings:
  • Plasma exchange did not reduce death or ESRD.
  • Reduced-dose glucocorticoid regimen was non-inferior to standard-dose and had fewer serious infections. [12]
• Impact: Reduced use of plasma exchange; adoption of reduced-dose steroid regimens.

MAINRITSAN 1 and 2

• MAINRITSAN 1 (2014): Rituximab superior to Azathioprine for preventing relapse in AAV. [13]
• MAINRITSAN 2 (2018): Fixed-interval (every 6 months) rituximab dosing superior to tailored dosing (based on ANCA/B-cell levels). [14]
• Impact: Rituximab became first-line maintenance therapy.

ADVOCATE (2021)

• Design: RCT of avacopan (C5a receptor inhibitor) vs prednisone taper, both with RTX or CYC, in active AAV.
• Findings: Avacopan was non-inferior to prednisone taper for inducing remission; steroid-sparing. [15]
• Impact: Avacopan approved as adjunctive therapy (steroid-sparing agent).

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12. Special Scenarios

Pregnancy and GPA

• Fertility: Discuss fertility preservation before cyclophosphamide (GnRH analogues, oocyte/sperm banking).
• Pregnancy outcomes:
  • Best outcomes: Stable remission for ≥6 months before conception.
  • Relapse risk: ~10-20% during pregnancy; higher if disease was active at conception.
• Medications:
  • Safe: Prednisolone, azathioprine, hydroxychloroquine.
  • Avoid: Cyclophosphamide (teratogenic), methotrexate (teratogenic), rituximab (unless critical).
• Monitoring: Frequent U&E, urinalysis; multidisciplinary care (Rheumatology, Obstetrics, Nephrology).

Paediatric GPA

• Rare: Accounts for less than 5% of GPA cases.
• Presentation: Similar to adults; growth retardation may occur.
• Management: Similar principles; involve paediatric rheumatology; cyclophosphamide dose adjusted for BSA.

Elderly Patients

• Higher infection risk: Tailor immunosuppression intensity; consider reduced-dose glucocorticoids.
• Renal function: Adjust cyclophosphamide dosing for renal impairment.

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13. Patient and Layperson Explanation

What is GPA?

Granulomatosis with Polyangiitis (GPA) is a rare autoimmune condition where the immune system mistakenly attacks small blood vessels in various parts of the body, causing inflammation and damage. It belongs to a group of diseases called "vasculitis" (inflammation of blood vessels).

Which parts of the body does it affect?

GPA typically affects the "E.L.K." areas:

• Ears, Nose, and Throat: Sinus pain, nosebleeds, blocked nose, hearing loss.
• Lungs: Cough, shortness of breath, sometimes coughing up blood.
• Kidneys: Inflammation that reduces kidney function (often no symptoms initially).

It can also affect the eyes, nerves, and skin.

Why did I get it?

The exact cause is not fully understood. It is not contagious (you cannot catch it from others), and it is not directly inherited from your parents. It likely involves a combination of:

• Genetic predisposition (your genes make you slightly more susceptible).
• Environmental triggers (such as an infection or exposure to certain chemicals) that confuse the immune system.

How is it treated?

Because GPA can cause serious damage if left untreated, we treat it aggressively:

1. Induction phase (first 3-6 months): Strong treatment to stop the inflammation:

   • Steroids (e.g., prednisolone): Powerful anti-inflammatory drugs.
   • Immune suppressors (e.g., rituximab or cyclophosphamide): Drugs that calm down the overactive immune system.

2. Maintenance phase (1-2+ years): Milder treatment to prevent the disease from coming back:

   • Rituximab or azathioprine: Keep the immune system in check.
   • Low-dose steroids: Gradually reduced or stopped.

What are the side effects of treatment?

• Infections: The immune-suppressing drugs increase your risk of infections (chest infections, urine infections). We prescribe antibiotics (co-trimoxazole) to prevent serious infections.
• Steroids: Weight gain, high blood sugar, weakened bones, mood changes. We give you bone protection and taper the dose as soon as possible.
• Cyclophosphamide: Can affect fertility (we discuss fertility preservation before starting).

What is the outlook?

• With modern treatment, most people achieve remission (disease becomes inactive) and live normal, full lives.
• However, GPA can come back (relapse) in about 30-50% of patients, so you will need:
  • Regular blood and urine tests to spot early signs of relapse.
  • Long-term follow-up with your rheumatology or nephrology team.

What should I watch out for?

Contact your doctor urgently if you develop:

• Coughing up blood (haemoptysis).
• Severe shortness of breath.
• Passing very little urine or dark urine.
• Fever with chills (possible infection).
• Sudden weakness or numbness in arms/legs.
• Severe eye pain or vision loss.

Can I live a normal life?

Yes, many people with GPA live full, active lives. The key is:

• Taking your medications as prescribed.
• Attending regular check-ups.
• Reporting new symptoms early.
• Maintaining a healthy lifestyle (balanced diet, exercise, no smoking).

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14. Examination Viva Scenarios

Viva 1: Differentiating ANCA-Associated Vasculitides

Question: A 50-year-old male presents with pulmonary-renal syndrome, haemoptysis, and rapidly rising creatinine. He is c-ANCA/PR3 positive. How do you differentiate GPA from Microscopic Polyangiitis (MPA) and Goodpasture syndrome?

Model Answer:

• GPA vs MPA:
  • GPA: c-ANCA/PR3-positive (>90%); granulomatous inflammation on biopsy; upper respiratory tract involvement (chronic sinusitis, nasal crusting, saddle nose); pulmonary nodules/cavities.
  • MPA: p-ANCA/MPO-positive; pulmonary-renal syndrome; no granulomas; no upper respiratory tract involvement; diffuse alveolar haemorrhage (ground-glass on CT).
• GPA/MPA vs Goodpasture:
  • Goodpasture (Anti-GBM Disease): Anti-GBM antibodies positive; pulmonary-renal syndrome; linear IgG deposition on renal biopsy immunofluorescence (vs pauci-immune in AAV); ANCA may co-exist (10-30% dual-positive; worse prognosis).

Viva 2: Management of Severe GPA

Question: A 45-year-old female presents with haemoptysis, creatinine 350 µmol/L, and urinary red cell casts. She is diagnosed with GPA (c-ANCA/PR3-positive). How would you manage her?

Model Answer:

1. Immediate:
   • Admit to hospital (medical emergency).
   • Assess for pulmonary haemorrhage: Oxygen saturation, CXR/CT chest, arterial blood gas.
   • IV access, bloods (FBC, U&E, CRP, clotting, G&S).
2. Induction therapy:
   • Pulsed IV methylprednisolone: 500 mg-1 g daily for 3 days.
   • Rituximab or Cyclophosphamide (discuss with patient; RTX preferred if fertility concerns or relapsing disease):
     • Rituximab: 375 mg/m² IV weekly × 4 weeks.
     • Cyclophosphamide: 15 mg/kg IV pulse every 2-3 weeks.
   • Plasma exchange: Consider if dual ANCA/anti-GBM positive or dialysis-dependent (though PEXIVAS showed no benefit overall).
3. Adjunctive:
   • Co-trimoxazole 960 mg TDS weekly (PCP prophylaxis).
   • PPI (gastric protection).
   • Calcium/Vitamin D + bisphosphonate (bone protection).
   • Monitor for infection (FBC, CRP, clinical vigilance).
4. Renal support:
   • Involve nephrology; may need dialysis if anuric or uraemic.
5. Transition to maintenance (after 3-6 months remission):
   • Rituximab 500 mg IV every 6 months × 24 months.

Viva 3: Relapsing GPA

Question: A patient with GPA achieved remission on cyclophosphamide + prednisolone and is now on azathioprine maintenance. Six months later, he develops recurrent nasal crusting, haemoptysis, and rising ANCA titres. How would you manage?

Model Answer:

1. Assess severity of relapse:
   • Major relapse (organ-threatening): Haemoptysis, rising creatinine, new GN → requires re-induction.
   • Minor relapse (grumbling symptoms): Nasal crusting only, stable renal function → increase maintenance therapy.
2. Investigations:
   • FBC, U&E, CRP/ESR, urinalysis (for haematuria, proteinuria, red cell casts).
   • ANCA titre (quantify).
   • Chest X-ray or CT chest (new nodules, infiltrates).
3. Management (assuming major relapse with haemoptysis):
   • Re-induction: Rituximab preferred (previous CYC exposure; RTX superior in relapsing disease per RAVE trial).
     • Rituximab 1 g IV day 0 and day 14, or 375 mg/m² weekly × 4.
   • Increase prednisolone (e.g., 0.5-1 mg/kg/day), then taper.
   • Stop azathioprine (switch to rituximab maintenance after remission).
4. Relapse prevention:
   • Rituximab maintenance (superior to azathioprine per MAINRITSAN).
   • Eradicate Staph aureus nasal carriage (nasal mupirocin, consider co-trimoxazole long-term).
   • Optimize adherence, monitor closely.

Viva 4: Subglottic Stenosis

Question: A patient with GPA in remission develops progressive dyspnoea and stridor. What is the likely diagnosis and management?

Model Answer:

• Diagnosis: Subglottic stenosis (SGS) – narrowing of the trachea below the vocal cords due to granulomatous inflammation and scarring.
• Key point: SGS can occur independently of systemic disease activity (i.e., patient may be in systemic remission but still develop/worsen SGS).
• Investigations:
  • CT neck/chest: Assess degree and extent of stenosis.
  • Bronchoscopy: Direct visualization; measure stenosis diameter.
  • Check systemic disease activity (CRP, ANCA, urinalysis) – may be normal.
• Management:
  • ENT referral (urgent if severe stridor).
  • Airway management:
    • Mild: Observation, optimize systemic immunosuppression.
    • Moderate-severe: Bronchoscopic dilatation (balloon or bougie), laser therapy, intralesional corticosteroid injection.
    • Refractory: Surgical resection (cricotracheal resection).
  • Systemic therapy: May increase immunosuppression (e.g., RTX, methotrexate) but often limited efficacy for established fibrotic SGS.
  • Long-term: Many patients require repeated dilatations; some have permanent tracheostomy.

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15. Key Learning Points

Clinical Pearl: Red Flags in GPA:

• Pulmonary haemorrhage (haemoptysis, hypoxia, ground-glass on CXR/CT)
• Rapidly progressive glomerulonephritis (rising creatinine, oliguria, active urinary sediment)
• Subglottic stenosis (stridor, dyspnoea)
• Scleritis (painful red eye threatening vision)
• Mononeuritis multiplex (asymmetric neuropathy)
• Pachymeningitis (headache, cranial nerve palsies)

Clinical Pearl: ANCA Testing in GPA:

• c-ANCA/PR3: Highly specific (>90%) for GPA.
• p-ANCA/MPO: May be positive in ~10% of GPA (more common in "limited" disease).
• ANCA-negative: ~10% of GPA; more common in localized disease.
• Dual ANCA/anti-GBM positive: Worse prognosis; consider plasma exchange.

Clinical Pearl: Induction Therapy: CYC vs RTX:

• Rituximab: Non-inferior to CYC; superior in relapsing disease; preferred if fertility concerns.
• Cyclophosphamide: Equally effective; more experience; lower cost.
• PEXIVAS trial: Plasma exchange did not reduce death/ESRD; reduced-dose glucocorticoids non-inferior and safer.

Clinical Pearl: Maintenance Therapy:

• Rituximab: Superior to azathioprine (MAINRITSAN); 500 mg IV every 6 months.
• Duration: Minimum 24 months; often longer in PR3-positive patients (high relapse risk).
• Relapse predictors: PR3-ANCA, upper respiratory tract disease, pulmonary cavitation, Staph aureus carriage.

Clinical Pearl: Complications to Monitor:

• Infection: Leading cause of death; PCP prophylaxis (co-trimoxazole) mandatory during CYC/RTX.
• Infertility: Cyclophosphamide dose-dependent; discuss fertility preservation before starting.
• Bladder cancer: Lifetime risk ~5% with CYC; monitor for haematuria long-term.
• Osteoporosis: Steroid-induced; give bone protection (calcium/vitamin D + bisphosphonate).

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Last updated: 2026-01-07