Granulomatosis with Polyangiitis (Wegener)

• Antineutrophil cytoplasmic antibody (ANCA) formation and neutrophil activation: The pathogenic hallmark involves autoantibodies directed against cytoplasmic ANCA (c-ANCA) recognizing proteinase-3 (PR3), a serine protease found in azurophilic granules of neutrophils and monocytes. These anti-PR3 antibodies bind to PR3-expressing cells and crosslink Fcγ receptors on neutrophils, triggering robust activation characterized by production of reactive oxygen species (ROS), degranulation releasing proteolytic enzymes, and increased expression of adhesion molecules. This activation cascade primes neutrophils to extravasate and infiltrate tissue, where they deposit their proteolytic cargo causing direct endothelial damage and vessel wall necrosis. Approximately 90% of generalized GPA cases are c-ANCA/PR3-positive, with the remaining cases being perinuclear ANCA (p-ANCA)/myeloperoxidase (MPO)-positive or ANCA-negative. The anti-PR3 titer correlates imperfectly with disease activity, though rising titers may herald relapse.

• Cellular immunity and granuloma formation: GPA involves aberrant T-cell and B-cell responses with preferential Th1 and Th17 differentiation. Activated CD4+ T cells produce interferon-gamma (IFN-γ) and interleukin-17 (IL-17), which enhance macrophage activation and promote granuloma formation. Macrophages accumulate in affected tissues (particularly upper and lower respiratory tracts) where they undergo activation and multinucleation to form granulomas—a defining histological feature. These granulomas represent an attempt at local immune containment but paradoxically drive tissue destruction through release of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and matrix metalloproteinases. B cells produce pathogenic ANCA, exhibit abnormal selection checkpoints, and undergo preferential activation in gut-associated lymphoid tissue and secondary lymphoid organs.

• Endothelial dysfunction and necrotizing vasculitis: Neutrophil infiltration and ANCA-mediated activation trigger endothelial cell injury through multiple mechanisms: direct neutrophil-endothelial contact, release of neutrophil elastase and other serine proteases that degrade endothelial surface molecules, deposition of immune complexes (though GPA is typically pauci-immune), and increased endothelial expression of ANCA antigens rendering them vulnerable to autoantibody attack. The resulting necrotizing vasculitis affects small arteries, arterioles, capillaries, and occasionally medium-sized vessels. Vascular necrosis is characterized by fibrinoid necrosis—a pathognomonic histological finding—with destruction of the vessel wall architecture, infiltration by neutrophils and fibrin deposition. In the kidney, this manifests as rapidly progressive pauci-immune crescentic glomerulonephritis where glomerular capillary necrosis occurs with minimal or absent immune complex deposition (hence "pauci-immune"), distinguishing it from post-streptococcal or lupus-mediated vasculitis.

• Respiratory tract involvement and geographic clustering: The upper and lower respiratory tracts appear uniquely susceptible to GPA pathology, potentially because of enhanced local ANCA antigen expression, localized dysbiosis, or chronic respiratory infections triggering B-cell activation. Nasal, paranasal sinus, and pulmonary tissues develop necrotizing granulomas with vasculitis, leading to mucosal ulceration, hemorrhage, and tissue necrosis. Geographic factors and potential infectious triggers (though no definitive pathogen identified) may contribute to disease initiation, explaining apparent clustering in certain populations and seasonal variation in some cohorts.

• Genetic predisposition: While GPA is not strictly genetic, multiple susceptibility loci have been identified including HLA-DPβ1 and SERPINA1 variants. Defective regulatory T cell (Treg) function and impaired apoptosis of autoreactive B cells contribute to loss of self-tolerance. Environmental triggers in genetically predisposed individuals likely precipitate disease, though the precise triggers remain incompletely understood.

• No single infectious pathogen identified, but evidence of molecular mimicry: Unlike post-streptococcal vasculitis with clear causative organisms, GPA lacks a definitively proven single etiologic agent. However, several observations support an infectious trigger model: upper respiratory infections frequently precede symptom onset, and certain pathogens (including Staphylococcus aureus, Klebsiella pneumoniae, and various respiratory viruses) share epitopes with PR3 and may trigger cross-reactive anti-PR3 responses through molecular mimicry. Chronic Staph. aureus nasal colonization is more prevalent in GPA patients and may perpetuate disease. Nevertheless, infection alone is insufficient for GPA development, as antibodies to PR3 occur in approximately 0.5–1% of the general population without causing disease.

• Genetic predisposition and HLA associations: The HLA-DPβ1 locus (particularly alleles encoding specific DPβ1 residues) shows strong association with both anti-PR3 and anti-MPO ANCA development, suggesting that certain HLA molecules present PR3-derived peptides more efficiently to autoreactive T cells. SERPINA1 variants affecting alpha-1 antitrypsin (which modulates neutrophil elastase activity) and other genetic polymorphisms affecting immune tolerance increase disease susceptibility. Family clustering is rare, and monozygotic concordance is low, indicating that genetic factors alone are insufficient and environmental triggers are critical.

• Environmental factors and occupational exposures: Silica dust exposure has been epidemiologically associated with increased GPA risk in some populations, possibly through enhanced respiratory tract inflammation and innate immune activation. Heavy smoking and chronic respiratory infections may perpetuate pulmonary disease. Drug exposures including hydralazine and levamisole (contaminant of street cocaine) can induce ANCA-associated vasculitis distinct from idiopathic GPA but clinically overlapping.

Upper respiratory tract involvement (85–90% of patients)

• Chronic rhinosinusitis and nasal symptoms: Patients experience persistent nasal congestion, chronic sinusitis refractory to standard antibiotics, and recurrent sinusitis. Nasal mucosa appears inflamed with potential for ulceration, crusting, and bloody drainage. The pathophysiology involves granulomatous infiltration of nasal and paranasal sinus mucosa causing mucosal thickening, edema, and eventual necrosis. Imaging reveals opacification of sinuses, but sinus involvement alone distinguishes GPA from infectious sinusitis because the granulomatous process persists despite antibiotic therapy.
• Epistaxis: Necrotizing granulomas erode into nasal blood vessels causing recurrent nosebleeds, sometimes severe.
• Nasal deformity: Chronic necrotizing inflammation and ulceration of the nasal septum and cartilage can result in collapse of the nasal bridge and "saddle nose deformity"—a classic finding (though not pathognomonic) that develops insidiously over months to years as cartilage is destroyed.
• Otitis media and conductive hearing loss: Granulomatous infiltration of the middle ear and Eustachian tube causes otitis media with effusion and sensorineural hearing loss.

Lower respiratory tract involvement (50–80% of patients)

• Pulmonary nodules and cavitary disease: Chest imaging reveals nodules or masses, often multiple and bilateral, frequently with cavitation—a key distinguishing feature from other vasculitides. These represent granulomatous infiltrates and necrotizing inflammation. The nodules are typically 1–4 cm and may cavitate in 25% of cases, creating confusion with tuberculosis or malignancy. Cavitary lesions may hemorrhage into the airway.
• Pulmonary hemorrhage and hemoptysis: Necrotizing vasculitis affecting pulmonary capillaries can cause alveolar hemorrhage manifesting as hemoptysis, dyspnea, and hypoxemia. The pathophysiology involves ANCA-mediated capillary destruction with extravasation of red blood cells into alveolar spaces. This represents a medical emergency requiring rapid intervention as massive hemoptysis can be rapidly fatal.
• Dyspnea and cough: Patients develop progressive dyspnea due to pulmonary nodules, granulomas, and vasculitis. A nonproductive or minimally productive cough is common. When hemoptysis occurs, it signals more severe alveolar involvement.

Glomerulonephritis and renal manifestations (50–75% of patients)

• Asymptomatic hematuria and proteinuria: The kidney involvement often initially presents silently with discovery of hematuria and/or proteinuria on screening urinalysis. The pathophysiology involves necrotizing vasculitis of glomerular capillaries with fibrinoid necrosis and formation of "crescent" lesions—proliferation of Bowman's capsule epithelial cells surrounding areas of glomerular necrosis. These are crescentic glomerulonephritis lesions where ANCA-mediated pauci-immune vasculitis predominates (minimal immunoglobulin deposition on immunofluorescence unlike post-streptococcal GN).
• Rapidly progressive glomerulonephritis (RPGN): Some patients develop rapid rise in serum creatinine over days to weeks indicating acute proliferative glomerulonephritis. This represents a medical emergency as untreated RPGN progresses to end-stage renal disease requiring dialysis within weeks.
• Renal dysfunction and acute kidney injury: Progressive hematuria and proteinuria lead to declining renal function, manifesting as rising creatinine and reduced glomerular filtration rate. The presence of dysmorphic RBCs and RBC casts on urinalysis indicates glomerular origin rather than lower urinary tract pathology.

Systemic and constitutional manifestations

• Arthralgia and arthritis: Occurs in 60–70% of patients, typically affecting large joints (knees, ankles, shoulders) in an asymmetric oligoarticular pattern. The arthritis is usually nonerosive and seronegative (negative rheumatoid factor and anti-CCP). The mechanism likely involves synovial vasculitis and immune complex deposition. Joint inflammation may precede other manifestations by weeks to months.
• Constitutional symptoms: Fever, night sweats, malaise, and weight loss reflect systemic inflammation and TNF-α and IL-6 production. These symptoms are often mistaken for infection or malignancy, delaying diagnosis.
• Skin manifestations: Palpable purpura (typically lower extremities and buttocks) reflecting small vessel vasculitis occurs in 40–50%. Nodules, ulcers, and vesiculitis occur less commonly. Histopathology of skin lesions shows necrotizing vasculitis of small vessels.
• Neurological involvement: Occurs in 20–50% of patients through multiple mechanisms—granulomatous inflammation (mononeuritis multiplex affecting peripheral nerves), vasculitis of the vasa nervorum (causing peripheral neuropathy), or granulomatous infiltration of the central nervous system (CNS) causing seizures, stroke, or cranial nerve palsies.
• Ocular involvement: Scleritis, uveitis, and orbital pseudotumor from granulomatous infiltration occur in 15–20% of patients and may lead to vision loss if untreated.
• Cardiac involvement: Myocarditis from granulomatous infiltration, coronary vasculitis, and valvular disease are less common but potentially catastrophic.

Physical examination findings

• Nasal ulceration, crusting, or saddle nose deformity on inspection
• Sinusitis on sinus percussion
• Lung crackles or wheezes on auscultation (though lungs may be clear despite radiographic findings)
• Elevated blood pressure from renal involvement
• Rashes (palpable purpura)
• Evidence of peripheral neuropathy or mononeuritis multiplex

Laboratory studies

• ANCA serology and subtyping: c-ANCA/PR3-specific antibodies are detected in 85–90% of generalized GPA cases but in only 50–60% of limited disease (upper/lower respiratory without systemic vasculitis). The test is performed using indirect immunofluorescence microscopy (showing a cytoplasmic staining pattern) confirmed by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay for anti-PR3 specificity. p-ANCA/MPO-specific antibodies are found in 10–15% of GPA cases and are associated with more indolent disease and higher risk of late relapses. Approximately 5–10% of biopsy-proven GPA cases are ANCA-negative ("seronegative GPA") and require histological confirmation. ANCA serology sensitivity for limited GPA is lower (~50%), and some patients remain seronegative throughout disease course, emphasizing the need for tissue diagnosis. Rising ANCA titers may herald impending relapse, though serial monitoring is not recommended as a sole indicator of relapse risk without clinical correlation.

• Complete blood count (CBC): Normochromic, normocytic anemia of chronic disease is common (hemoglobin typically 9–11 g/dL). Leukocytosis (WBC 12,000–18,000 cells/μL) reflects systemic inflammation. Thrombocytosis may be present. If thrombocytopenia develops, consider alternative diagnoses or complications.

• Comprehensive metabolic panel and renal function:
• Serum creatinine and glomerular filtration rate (GFR): Baseline renal function is essential for prognostic assessment and dosing of immunosuppressive agents. Creatinine >1.5 mg/dL at presentation indicates more severe disease with poorer prognosis. GFR <50 mL/min/1.73m² at diagnosis is associated with higher mortality and higher risk of end-stage renal disease despite treatment.
• Blood urea nitrogen (BUN): Elevations indicate reduced glomerular filtration; BUN-to-creatinine ratio >20:1 may suggest prerenal azotemia.
• Electrolytes: Hypokalemia may develop from tubulointerstitial disease. Hyponatremia may occur with severe systemic disease.

• Urinalysis with microscopy: Hematuria (dysmorphic RBCs, RBC casts) and proteinuria are hallmarks of glomerulonephritis. RBC casts are pathognomonic for glomerulonephritis and distinguish upper from lower urinary tract involvement. Proteinuria typically ranges from 0.5–2 g/day but can exceed 3.5 g/day, rarely approaching nephrotic syndrome levels. Absence of hematuria does not exclude GPA but makes generalized disease less likely.

• Inflammatory markers: Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP

Immediate stabilisation (organ- or life-threatening disease)

• Airway and oxygenation: diffuse alveolar hemorrhage or subglottic stenosis may demand ICU admission, intubation, and bronchoscopy; hemoglobin may fall without visible hemoptysis.
• Empiric pulse glucocorticoids: IV methylprednisolone is started for suspected rapidly progressive glomerulonephritis or alveolar hemorrhage before biopsy results return — waiting costs nephrons. Dialysis is initiated for the usual indications and does not preclude immunosuppression.

Remission induction — severe disease (ACR/Vasculitis Foundation 2021 ANCA-Associated Vasculitis guideline)

• Anti-CD20 monoclonal antibody: rituximab plus glucocorticoids is preferred over cyclophosphamide, especially for relapsing disease, in women and men of reproductive age, and in children, because it spares gonadal toxicity and malignancy risk.
• Alkylating agent: cyclophosphamide (IV or oral) plus glucocorticoids remains an accepted alternative; give with mesna and generous hydration.
• Reduced-dose glucocorticoid taper is favored over standard high-dose regimens; the oral C5a receptor antagonist avacopan is an option as a steroid-sparing adjunct.
• Plasma exchange: not routine. ACR/VF conditionally recommends against it for most patients, reserving consideration for severe kidney involvement or coexisting anti-GBM antibody disease.

Adjunctive and surgical

• Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole, bone protection, hepatitis B screening before rituximab, and fertility preservation counselling before cyclophosphamide.
• Subglottic stenosis: endoscopic dilation with intralesional glucocorticoid rather than systemic escalation; nasal reconstruction and kidney transplantation are deferred until sustained remission.

Disease-related — emergencies

• Diffuse alveolar hemorrhage: capillaritis with red cells extravasating into alveoli; signalled by falling hemoglobin, new diffuse ground-glass opacities, hypoxemia, and progressively bloodier sequential bronchoalveolar lavage aliquots — hemoptysis may be absent.
• Rapidly progressive glomerulonephritis / ESRD: crescent formation obliterates Bowman space; signalled by creatinine doubling over days with RBC casts. Dialysis dependence at presentation is the strongest predictor of renal non-recovery.
• Subglottic stenosis: circumferential granulomatous scarring below the cords; signalled by biphasic stridor, hoarseness, and flattening of both limbs of the flow–volume loop. Can obstruct acutely.
• Scleritis/orbital pseudotumor: granulomatous mass in the orbit causing proptosis, diplopia, and optic nerve compression — threatens permanent vision loss.

Disease-related — non-emergent but disabling

• Saddle nose deformity and septal perforation from cartilage necrosis; conductive or sensorineural hearing loss from middle-ear granuloma.
• Mononeuritis multiplex from vasa nervorum occlusion — asymmetric wrist/foot drop.
• Venous thromboembolism: active vasculitis is prothrombotic; unexplained DVT/PE during a flare is characteristic.
• Relapse, more frequent in PR3-ANCA disease than MPO-ANCA disease.

Treatment-related

• Infection, the leading cause of early death: Pneumocystis jirovecii pneumonia, bacterial sepsis, and herpes zoster from combined steroid plus B-cell or alkylator therapy.
• Cyclophosphamide: acrolein-mediated hemorrhagic cystitis, later urothelial carcinoma, myelodysplasia/leukemia, and premature gonadal failure.
• Rituximab: hypogammaglobulinemia with recurrent sinopulmonary infection, hepatitis B reactivation, rarely progressive multifocal leukoencephalopathy.
• Glucocorticoids: hyperglycemia, osteoporotic fracture, avascular necrosis of the hip, adrenal suppression.
• Avacopan: transaminase elevation requiring liver enzyme monitoring.

• The triad the stem is built on: chronic "sinusitis that will not respond to antibiotics" + cavitary lung nodules + hematuria with RBC casts. Upper airway, lower airway, kidney — that combination is GPA until proven otherwise.
• Serology: c-ANCA / anti-PR3 is the tested association. Anti-MPO/p-ANCA points instead toward microscopic polyangiitis or EGPA, and a minority of GPA is ANCA-negative — so a negative ANCA never excludes the diagnosis.
• Best next step when the stem is diagnostic-flavored: obtain tissue. Renal biopsy showing pauci-immune necrotizing crescentic glomerulonephritis (negative immunofluorescence) is the highest-yield confirmatory test; nasal biopsies are often non-diagnostic.
• Best next step when the stem is sick: pulse IV methylprednisolone immediately for alveolar hemorrhage or rising creatinine — do not wait for biopsy or ANCA. Then rituximab plus glucocorticoids as ACR/Vasculitis Foundation–preferred induction.
• Buzzwords: saddle nose deformity, stridor from subglottic stenosis, mononeuritis multiplex, and cavitating nodules that mimic tuberculosis or malignancy.
• The discriminators examiners love:
• EGPA (Churg–Strauss): asthma + peripheral eosinophilia + MPO-ANCA; no destructive upper-airway granulomas.
• Microscopic polyangiitis: pulmonary–renal syndrome with no granulomas and no cavitary nodules.
• Anti-GBM disease: linear IgG on immunofluorescence, not pauci-immune.
• Common distractors to avoid: do not chase a cavitary nodule as TB or lung cancer when sinus and urinary findings are present; do not escalate or de-escalate therapy on a rising ANCA titer alone without clinical relapse; and remember that plasma exchange is no longer routine for ANCA vasculitis after PEXIVAS.
• Treatment-side trap: new gross hematuria in a patient on cyclophosphamide is acrolein-induced hemorrhagic cystitis or bladder cancer, not necessarily a vasculitis flare — and pregnancy excludes cyclophosphamide, methotrexate, and rituximab.