GPA (Granulomatosis with Polyangiitis) Classification

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a necrotizing granulomatous vasculitis affecting small and medium-sized vessels. It classically involves the upper respiratory tract (sinuses, nose, ears), lower respiratory tract (lungs), and kidneys (pauci-immune glomerulonephritis) - the classic "ENT-lung-kidney" triad. GPA is part of the ANCA-associated vasculitis (AAV) family and is most strongly associated with PR3-ANCA (c-ANCA). It is a serious, potentially life-threatening condition that requires prompt diagnosis and treatment with immunosuppression.

PR3-ANCA (anti-proteinase 3 antibodies, producing c-ANCA pattern on immunofluorescence) is present in approximately 80-90% of patients with severe, generalized GPA. Its presence is highly specific for GPA over other vasculitides - the positive likelihood ratio for GPA when PR3-ANCA is positive is approximately 10-15. The 2022 criteria assign +5 points because this single finding can largely drive classification, reflecting its biological relevance (PR3-ANCA directly contributes to neutrophil activation and vascular injury in GPA pathogenesis) and its high diagnostic specificity.

Marked eosinophilia (blood eosinophils ≥1x10&sup9;/L) is a defining feature of eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome), not GPA. In the classification framework, items that strongly suggest an alternative vasculitis diagnosis are assigned negative weights to subtract from the GPA score. An eosinophil count this high is rarely seen in GPA and should prompt reconsideration of EGPA, particularly if the patient also has a history of asthma, nasal polyps, or high IgE. The -4 weighting reflects the strong inverse relationship between eosinophilia and GPA.

Subglottic stenosis is narrowing of the airway just below the vocal cords (the subglottis). It occurs in approximately 15-25% of GPA patients and is one of the most GPA-specific findings, giving it +3 points in the criteria. It results from granulomatous inflammation of the subglottic mucosa, causing progressive fibrous stenosis. Symptoms include inspiratory stridor, exertional dyspnea, and a characteristic fixed flow limitation on pulmonary function testing. It requires endoscopic assessment and is often refractory to systemic immunosuppression, requiring local dilation, intralesional triamcinolone injections, or surgical intervention.

Both GPA and MPA are ANCA-associated vasculitides affecting small vessels, but they have key differences. GPA features granulomatous inflammation and characteristically involves the upper respiratory tract (sinuses, nose, ears) - findings absent in MPA. GPA is associated with PR3-ANCA (c-ANCA) in most cases, while MPA is more commonly associated with MPO-ANCA (p-ANCA). MPA does not cause granulomas on biopsy and does not cause subglottic stenosis or nasal septal perforation. Both cause pauci-immune glomerulonephritis and pulmonary capillaritis. The 2022 criteria help distinguish them: MPO-ANCA positivity subtracts 1 point from the GPA score (favoring MPA), while PR3-ANCA adds 5 points (favoring GPA).

Pauci-immune glomerulonephritis is GN characterized by little or no immune complex deposition on immunofluorescence (pauci = few/scarce in Latin). This contrasts with immune-complex GN (lupus nephritis, IgA nephropathy) which shows bright granular immunofluorescence staining. In AAV, neutrophil activation by ANCA causes glomerular injury without significant immune complex deposition. Light microscopy in AAV-GN shows focal segmental necrotizing lesions and cellular crescents. Pauci-immune GN is the renal hallmark of all three AAV - GPA, MPA, and EGPA - and is a cause of rapidly progressive GN (RPGN) requiring urgent treatment.

Dual ANCA positivity (both PR3 and MPO) is rare - occurring in approximately 1-5% of ANCA-positive vasculitis patients. When it occurs, it may represent technical false positivity on one assay, an overlap condition, or drug-induced ANCA. Drug-induced ANCA (from propylthiouracil, hydralazine, minocycline, and others) most commonly produces MPO-ANCA but can occasionally produce dual positivity. In the 2022 GPA criteria, a patient with both PR3-ANCA positive (+5) and MPO-ANCA positive (-1) would receive a net of +4 from ANCA alone. Clinical judgment from a rheumatologist or nephrologist is essential in this scenario.

In the 2022 ACR/EULAR validation study, the GPA criteria (score ≥5) demonstrated sensitivity of 93.0% and specificity of 94.0% against other vasculitides and comparator diagnoses. These criteria replaced the 1990 ACR GPA criteria, which had been developed before ANCA testing was routine and before GPA was distinguished from MPA. The 2022 criteria were developed as part of a coordinated project alongside criteria for eight other vasculitis types, using a novel methodology that included positive and negative weighted items to simultaneously distinguish among vasculitis subtypes.