Granulomatosis with Polyangiitis (GPA)
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Granulomatosis with Polyangiitis (GPA), formerly known as Wegener's Granulomatosis, is a primary systemic ANCA-associated vasculitis (AAV). It predominantly affects small-to-medium-sized blood vessels and is characterised by necrotising granulomatous inflammation.
Crucially, GPA is defined by a predilection for the "classic triad" of organ involvement:
- Upper Respiratory Tract (URT): Sinusitis, nasal crusting, saddle nose deformity.
- Lower Respiratory Tract (LRT): Pulmonary nodules, cavitation, alveolar haemorrhage.
- Kidneys: Pauci-immune crescentic glomerulonephritis.
Key Pathophysiological Concepts
- ANCA Positivity: Strongly associated with c-ANCA (cytoplasmic pattern) targeting Proteinase 3 (PR3).
- Granulomas: Extravascular granulomatous inflammation is a hallmark, differentiating it from Microscopic Polyangiitis (MPA).
- Medical Emergency: Active renal or pulmonary disease requires urgent immunosuppression to prevent permanent organ failure or death.
Clinical Scenario: The Persistent 'Sinusitis'
A 55-year-old male presents with 3 months of recurrent nasal congestion, bloody nasal discharge, and fatigue. He has been treated with multiple courses of antibiotics for 'sinusitis' without effect. Recently, he developed a cough and noticed his hearing is muffled. Urine dipstick in clinic shows Blood +++ and Protein ++.
Key Teaching Points
- Chronic sinusitis unresponsive to antibiotics is a red flag for GPA or fungal disease.
- Systemic symptoms (fatigue) + local symptoms suggest a systemic aetiology.
- Urinary findings (haematuria/proteinuria) are critical; they imply renal vasculitis (renal-pulmonary syndrome risk).
- Referral to Rheumatology/Nephrology is urgent.
- Incidence: Approximately 10–20 cases per million population per year in Europe/North America.
- Prevalence: Estimated at 13–24 per 100,000.
- Age: Peak onset is between 40 and 60 years, but it can occur at any age, including childhood and the elderly.
- Sex: Slight male predominance or equal sex distribution (1:1).
- Geography: More common in Northern European populations (Caucasian descent).
- Genetics: Associations with HLA-DPB1 alleles.
Risk Factors
- Environmental: Silica exposure, farming, solvent exposure, and Staphylococcus aureus nasal carriage have been implicated as potential triggers for relapse.
- Drugs: Certain drugs (e.g., hydralazine, propylthiouracil) can induce an ANCA-associated vasculitis, though typically p-ANCA/MPO positive.
The pathogenesis involves a complex interplay between genetic predisposition, environmental triggers, and immune dysregulation.
The Role of ANCA
Anti-Neutrophil Cytoplasmic Antibodies (ANCA) are central to the disease process. In GPA, the autoantibodies primarily target Proteinase 3 (PR3), a neutrophil granule enzyme.
- Priming: Cytokines (TNF-alpha, IL-1) released during an infection prime neutrophils, causing translocation of ANCA antigens (PR3) to the cell surface.
- Binding: Circulating c-ANCAs bind to PR3 on the neutrophil surface.
- Activation: This cross-linking activates the neutrophils excessively.
- Adhesion & Degranulation: Activated neutrophils adhere to the endothelium and release Reactive Oxygen Species (ROS) and lytic enzymes.
- NETosis: Neutrophils release Neutrophil Extracellular Traps (NETs), which contain PR3 and MPO, further fuelling the autoimmune response and damaging endothelial cells.
Granuloma Formation
- Unlike MPA, GPA features granulomatous inflammation.
- T-cell mediated (Th1 and Th17 responses).
- Granulomas may contribute to tissue destruction in the URT (cartilage collapse) and masses in the lungs (pulmonary nodules).
Presentation is highly variable, ranging from indolent "sinusitis" to fulminant pulmonary-renal failure.
Constitutional Symptoms
organ System Involvement
ENT (Upper Respiratory Tract) - 90%
Lungs (Lower Respiratory Tract) - 60-85%
Renal - 75%
Other Systems
A systematic examination is required to assess extent of disease.
General
- Assess for cachexia, pallor (chronic disease anaemia/renal failure).
- Vital signs: Fever? Hypertension (renal)? Tachypnoea/Desaturation (pulmonary)?
ENT
- Nose: Inspect for saddle deformity. Use a thudicum speculum or otoscope to look for crusting, ulceration, or septal perforation.
- Ears: Otoscopy for serous otitis media or red tympanic membranes.
- Throat: Check the gums (hyperplastic 'strawberry' gingivitis) and palate.
Respiratory
- Inspection: Tracheal deviation?
- Auscultation: Diffuse crackles (haemorrhage/fibrosis) or localised signs of consolidation. Stridor warrants immediate ENT review (subglottic stenosis).
Renal / Abdominal
- Usually unremarkable unless advanced. Check for fluid overload if AKI is present.
Neurological
- PNS: Test sensation and power in peripheries. Look for asymmetrical weakness (mononeuritis multiplex – e.g., right foot drop + left ulnar nerve palsy).
- CNS: Cranial nerve exam.
Skin
- Full skin check for purpura (typically lower limbs), nodules, or necrotic ulcers.
Urgent investigation is required to define organ involvement and confirm diagnosis.
Bedside
- Urinalysis: Essential. Look for Blood +++ and Protein ++.
- Quantification: Urine PCR or ACR to quantify proteinuria.
- Microscopy: Active urinary sediment (red cell casts) indicates glomerulonephritis.
Laboratory
- FBC: Anaemia (normocytic normochromic), Leukocytosis (neutrophilia), Thrombocytosis (reactive).
- ESR/CRP: Usually significantly elevated in active disease.
- U&Es: Creatinine may be elevated. Monitor Potassium.
- Liver Profile: Albumin may be low (acute phase protein/nephrotic).
- ANCA Serology:
- c-ANCA (cytoplasmic) positive.
- Anti-PR3 (proteinase 3) positive (>90% specificity for GPA).
- Note: 10% may be ANCA negative or p-ANCA/MPO positive.
Imaging
- CXR: Cavitating nodules, infiltrates.
- CT Chest (High Resolution): More sensitive. Nodules, cavities, ground glass (haemorrhage), airway stenosis.
- CT Sinuses / MRI Head: Mucosal thickening, bony destruction, orbital masses.
Procedures / Histology
- Biopsy is the gold standard for confirmation.
- Renal Biopsy: Pauci-immune (negative immunofluorescence) focal segmental necrotising crescentic glomerulonephritis.
- Lung/ENT Biopsy: Granulomatous inflammation + Necrotising vasculitis.
- Bronchoscopy: To rule out infection and inspect airways (stenosis, bleeding).
Diagnostic Criteria (ACR/EULAR 2022 Classification Criteria for GPA)
Points based on clinical and lab findings. A score of ≥5 supports a classification of GPA.
- Positive items: Bloody nasal discharge/ulcers/crusting (+3), Cartilaginous involvement (+2), Conductive/Sensorineural hearing loss (+1), c-ANCA/PR3 (+5), Pulmonary nodules/cavities (+2), Granuloma on biopsy (+2), Pauci-immune GN (+1).
- Negative items: Eosinophilia (-4, suggests EGPA).
Management is divided into Remission Induction (aggressive) and Remission Maintenance (preventing relapse). Co-management with Nephrology/Rheumatology is mandatory.
Phase 1: Remission Induction
Goal: Rapidly suppress inflammation and save organs.
Severe / Organ-Threatening Disease (Creatinine >150, Pulmonary Haemorrhage)
- Corticosteroids:
- Pulsed IV Methylprednisolone: 500mg–1g daily for 3 days.
- Followed by high-dose oral Prednisolone (e.g., 1mg/kg), tapering over months.
- Cyclophosphamide (CYC) or Rituximab (RTX):
- Cyclophosphamide: IV pulse usually preferred over oral due to lower cumulative dose (bladder toxicity).
- Rituximab: Non-inferior to CYC (RAVE trial). Preferred if fertility concerns, previous CYC toxicity, or relapsing disease.
- Plasma Exchange (PLEX):
- Controversial (PEXIVAS trial showed no benefit in death/ESRD for all comers).
- Still considered in: Anti-GBM positivity overlap, fulminant pulmonary haemorrhage, or extremely rapidly rising creatinine (dialysis dependent).
Non-Organ Threatening (e.g., localized ENT only)
- Methotrexate + Steroids.
- Mycophenolate Mofetil (MMF) + Steroids.
Phase 2: Remission Maintenance
Goal: Prevent relapse while minimizing drug toxicity.
- Start after remission achieved (usually 3–6 months).
- Rituximab: Superior to Azathioprine for maintenance (MAINRITSAN trials). Dosed every 6 months.
- Azathioprine: Traditional standard.
- Methotrexate: Alternative if renal function allows.
- Duration: At least 24 months, often longer in PR3-positive patients (high relapse risk).
- Steroid Taper: Aim to withdraw prednisolone if possible, or maintain on low dose (≤5mg).
Adjunctive Therapy
- PCP Prophylaxis: Co-trimoxazole (Septrin) 960mg thrice weekly (mandatory during CYC/RTX).
- Fungal Prophylaxis: Nystatin/Fluconazole if high risk.
- Gastric Protection: PPI.
- Bone Protection: Vit D/Calcium + Bisphosphonate.
- Cardiovascular Risk: Manage BP strict (<130/80), lipids, smoking cessation.
- Vaccines: Pneumococcal, Influenza (avoid live vaccines on immunosuppression).
Disease-Related
- Renal Failure (ESRD): Requiring dialysis or transplant.
- Subglottic Stenosis: May require dilatation or surgery. Scarring can be permanent.
- Saddle Nose: Cosmetic deformity.
- Hearing Loss: Permanent sensorineural/conductive loss.
- Venous Thromboembolism (VTE): High risk in active vasculitis.
Treatment-Related
- Infection: Major cause of mortality. Pneumonia, sepsis.
- Infertility: Cyclophosphamide causes premature ovarian failure/azoospermia.
- Malignancy: Bladder cancer (Cyclophosphamide), Skin cancer (Azathioprine).
- Steroid Effects: Diabetes, Osteoporosis, Cataracts, Cushingoid habitus.
- Haemorrhagic Cystitis: Cyclophosphamide.
- Untreated: >90% mortality within 2 years.
- Treated: 5-year survival is >80%.
- Relapse: High rate (30–50% within 5 years), especially in PR3-ANCA patients and those with ENT disease/lung cavities.
- Morbidity: High burden of damage (CKD, hearing loss, nasal deformity) and treatment toxicity.
Monitoring
- Regular FBC, U&E, LFT, CRP, ESR.
- Urinalysis (detect proliferative relapse).
- ANCA titres (rising titre does not always predict relapse but warrants closer monitoring).
- Birmingham Vasculitis Activity Score (BVAS) used in trials/specialist centres.
Key Guidelines
- EULAR/ERA-EDTA Recommendations (2022): Management of ANCA-associated vasculitis.
- BSR Guidelines: Management of adults with AAV.
- KDIGO: Glomerulonephritis guidelines.
Landmark Trials
- RAVE (2010): Rituximab non-inferior to Cyclophosphamide for severe AAV induction; superior for relapsing disease.
- PEXIVAS (2020): Plasma Exchange did not reduce death/ESRD in severe AAV. Reduced-dose steroid regimen was non-inferior to standard-dose (less infections).
- MAINRITSAN: Rituximab superior to Azathioprine for maintenance.
- ADVOCATE: Avacopan (C5a receptor inhibitor) non-inferior to prednisone taper in induction (steroid-sparing agent).
What is GPA? Granulomatosis with Polyangiitis (GPA) is a rare autoimmune condition where the immune system attacks blood vessels, causing inflammation. It belongs to a group of diseases called "vasculitis".
Which parts of the body does it affect? It typically affects the "E.L.K." areas:
- Ears, Nose and Throat (sinus pain, nosebleeds, hearing loss).
- Lungs (cough, shortness of breath).
- Kidneys (inflammation reducing kidney function).
Why did I get it? It is not fully known. It is not an infection you can catch, and it's not directly inherited from parents. It likely involves a mix of your genes and an environmental trigger (like a virus) that confuses the immune system.
How is it treated? Because it can be serious, we treat it strongly to stop the inflammation ("induction"):
- Steroids: Powerful anti-inflammatories.
- Immune Suppressors: Drugs like Rituximab or Cyclophosphamide to calm the immune system. Once the disease is quiet ("remission"), we switch to milder drugs for 1-2 years to stop it coming back.
What is the outlook? With modern treatment, most people attain remission and live normal lives. However, the condition can come back (relapse), so you will need regular blood and urine tests for a long time to spot any meaningful changes early.
- Boerner A, et al. 2022 Update of the EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2023.
- Stone JH, et al. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE). N Engl J Med. 2010;363:221-232.
- Walsh M, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS). N Engl J Med. 2020;382:622-631.
- Jayne D, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis (ADVOCATE). N Engl J Med. 2021;384:599-609.
- Exley A, et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford). 2014;53(12):2306-2309.
- Jennette JC, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.