A 42-year-old Indian woman presents with a 2-month history of progressive dyspnea, hemoptysis, and constitutional symptoms. Chest X-ray shows bilateral pulmonary infiltrates with cavitation. ANCA serology is positive for c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies) with anti-PR3 specificity. Serum creatinine is 3.2 mg/dL, and urinalysis shows dysmorphic RBCs with RBC casts. What is the most likely diagnosis?

Explanation

## Diagnosis: Granulomatosis with Polyangiitis (GPA) ### Clinical Presentation This patient presents with the classic **triad of GPA**: 1. **Upper respiratory involvement:** Not explicitly stated, but hemoptysis suggests lower respiratory tract 2. **Lower respiratory tract disease:** Bilateral infiltrates with cavitation (highly suggestive of GPA) 3. **Glomerulonephritis:** Elevated creatinine, dysmorphic RBCs, RBC casts (pauci-immune crescentic GN) ### ANCA Serology | Vasculitis | ANCA Pattern | Antigen Specificity | Notes | |---|---|---|---| | **GPA** | **c-ANCA (70–90%)** | **Anti-PR3 (proteinase-3)** | Highly specific for GPA; cavitary lung lesions | | MPA | p-ANCA (60–80%) | Anti-MPO (myeloperoxidase) | No upper respiratory involvement; no cavitation | | EGPA | p-ANCA (40–60%) | Anti-MPO | Asthma, eosinophilia, neuropathy | | AABMD | — | Anti-GBM | Linear IgG on IF; no ANCA | **Key Point:** **c-ANCA + anti-PR3 is virtually pathognomonic for GPA.** This is the most specific ANCA pattern–antigen pair in clinical practice. **High-Yield:** The presence of **cavitary lung lesions** is a distinguishing feature of GPA and is rare in other ANCA-associated vasculitides (MPA and EGPA typically show non-cavitary infiltrates). ### Pathophysiology & Histology ```mermaid flowchart TD A[c-ANCA/anti-PR3 positive]:::outcome --> B[Activation of neutrophils]:::action B --> C[Release of PR3 and other proteases]:::action C --> D[Necrotizing vasculitis of small/medium vessels]:::action D --> E[Three target organs]:::outcome E --> F[Upper respiratory: sinusitis, granulomas]:::outcome E --> G[Lower respiratory: cavitary infiltrates, hemoptysis]:::outcome E --> H[Kidneys: pauci-immune crescentic GN]:::outcome ``` **Mnemonic — GPA Triad:** **CRY** - **C**avitary lung lesions (lower respiratory) - **R**espiratory upper tract (sinusitis, nasal granulomas) - **Y**ellow-green sputum (hemoptysis from cavitation) ### Diagnostic Confirmation 1. **Tissue biopsy** (lung or kidney): Necrotizing granulomatous inflammation + necrotizing vasculitis 2. **ANCA serology:** c-ANCA/anti-PR3 (sensitivity ~90% in generalized GPA) 3. **Pauci-immune crescentic GN on renal biopsy:** Minimal or absent immune deposits on immunofluorescence (distinguishes from AABMD, which shows linear IgG) ### Why Not the Other Options? **Microscopic Polyangiitis (MPA):** - p-ANCA/anti-MPO pattern (not c-ANCA/anti-PR3) - No upper respiratory involvement - No cavitary lung lesions; infiltrates are typically non-cavitary - Glomerulonephritis is present but less common than in GPA **Eosinophilic Granulomatosis with Polyangiitis (EGPA):** - p-ANCA/anti-MPO pattern (not c-ANCA/anti-PR3) - Requires **asthma and eosinophilia** (not mentioned here) - Pulmonary infiltrates are non-cavitary - Neuropathy is common **Anti-Glomerular Basement Membrane (AABMD) Disease:** - **ANCA-negative** (this patient is c-ANCA positive) - Linear IgG on immunofluorescence (not pauci-immune) - Pulmonary hemorrhage + rapidly progressive GN (Goodpasture syndrome) - No upper respiratory involvement ### Management **Induction therapy:** Corticosteroids + cyclophosphamide or rituximab **Maintenance:** Azathioprine or rituximab [cite:Harrison 21e Ch 378; Robbins 10e Ch 11]