Granulomatosis with Polyangiitis (Wegener)

Granulomatosis with Polyangiitis (Wegener)

Surya V. Seshan, MD

GPA in a kidney shows irregular necrotizing granulomatous inflammation with palisading and giant cells image and a neutrophil-rich infiltrate with lymphocytes and epithelioid cells.

Periodic acid-Schiff shows glomerular tuft mostly compressed by a cellular crescent in the Bowman space mixed with inflammatory cells, typical lesion of GPA, and other ANCA-mediated vasculitides.



  • Granulomatosis with polyangiitis (GPA)


  • Wegener granulomatosis (WG)

  • Rhinogenic granulomatosis


  • Chapel Hill Consensus Conference

    • GPA is granulomatous inflammation of respiratory tract and necrotizing vasculitis of small to medium-sized vessels (capillaries, venules, arterioles, and arteries), commonly with necrotizing glomerulonephritis (GN) with no or very few deposits (“pauci-immune crescentic GN”)

  • Americal College of Rheumatology (ACR) criteria

    • Nasal or oral inflammation with purulent discharges or oral ulcers

    • Abnormal chest radiograph

      • Cavitating or noncavitating nodules

      • Infiltrates

    • Abnormal urinary finding (e.g., microhematuria)

    • Granulomatous inflammation in vessel wall, perivascular or interstitial locations

    • Any 2 or more of the above have high diagnostic specificity and sensitivity


Antineutrophil Cytoplasmic Antibody (ANCA)-mediated Small Vessel Vasculitis

  • Autoantibodies to proteinase 3 (PR3) in most patients (> 75%)

    • ANCAs react to peptide sequences in complementary PR3-molecule

    • These sequences have significant homology with infectious agents, e.g., Staphylococcus

    • Minority (< 25%) have antimyeloperoxidase (MPO) ANCA

    • Proteinase-3 (PR3)

      • Serine proteinase related to neutrophil elastase (55% homology)

      • Inactivated by combining with α-1-antitrypsin

    • Neutrophil activation via feedback loop with ANCA

      • Activated neutrophils express PR3 on surface

      • Neutrophils activated via binding of ANCA

      • Release of oxygen radicals, lytic enzymes, and inflammatory cytokines

      • Alternative pathway complement activation and mediation by C5a

    • Increased adhesion of neutrophils to previously activated endothelium and transmigration

      • Mediate endothelial damage and vascular inflammation

    • Disease activity related to inhibition of PR3-α-1-antitrypsin complex formation

  • Other antibodies

    • Antiendothelial antibodies identified

      • Lysosomal membrane protein-2, on surface of endothelial cells

  • T cells, B cells needed to promote autoimmune response

Genetic Risk Factors

  • MHC class II gene HLA-DRB1*0401

    • Odds ratio 2-3

    • Retinoid X receptor B (RXRB) polymorphism (nearby on chromosome 6p21.3)

    • HLA-DRB1*0401 not associated with Churg-Strauss syndrome or microscopic polyangiitis

  • DNAM-1 polymorphism (Gly307Ser)

    • Codes for CD226, DNAX accessory protein

    • Also in type I diabetes, multiple sclerosis, Graves disease

  • Limited evidence for other gene polymorphisms

    • SERPINA1 (α-1-antitrypsin), PTPN22 (protein tyrosine phosphatase), CTLA4, PD-1 gene (also Kawasaki disease), FCGR3B (FcγRIIIb)

Potential Triggers of Autoantibody Response

  • Possible triggers of ANCA formation include infections (bacteria, viral)

    • GPA onset more common in winter

  • Exposure to allergens

  • Exposure to dust, heavy metal, respiratory toxins

Animal Model

  • Passive transfer of ANCA (anti-MPO) causes glomerulonephritis with crescents in immunodeficient mice (RAG1 knockout)



  • Incidence

    • 30-60/1,000,000

    • Higher incidence in North America and northern Europe; lower in Asia

    • Increased reporting in last 2 decades due to increased awareness of the disease

  • Age

    • GPA can develop at any age

    • Peak age at onset: 30-50 years

    • Mean: 40 years

    • Can also occur in children and the elderly

  • Gender

    • Slight male predominance

  • Ethnicity

    • No ethnic predilection


  • Multisystemic involvement, often preceded by constitutional symptoms

    • Kidney, upper airway, and lung involvement in 90% of cases

    • A pulmonary renal syndrome

  • 2 phases of disease

    • Granulomatous disease of upper respiratory tract

    • Vasculitic phase

  • Renal

    • Renal symptoms usually follow but sometimes precede respiratory disease up to several years

    • Macroscopic or microscopic hematuria

    • Red blood cell casts

    • Oliguria

    • Rapidly progressive or acute renal failure

    • Sometimes insidious onset of renal insufficiency with proteinuria &/or hematuria

    • Mass lesion (rare)

    • Occasionally presents with renal mass

Laboratory Tests

  • Hematuria, proteinuria, elevated BUN, Cr

  • Anemia, elevated ESR

  • ˜ 95% positive for ANCA

    • ELISA: Anti-PR3 ANCA (˜ 75%) or anti-MPO (˜ 25%)

    • Indirect IF: c-ANCA (PR3) or p-ANCA (MPO)

  • Rheumatoid factor positive (20-30%)


  • Steroids combined with cyclophosphamide

  • Plasmapheresis is beneficial in severe disease

  • Maintenance therapies have oral cyclophosphamide, cyclosporine, azathioprine, or mycophenolate mofitel

  • Clinical trials to assess benefit of

    • Anti-CD20, targets B cells

    • Blocking tumor necrosis factor-α


  • 20% renal morbidity and end-stage renal disease

    • Lack of treatment or late diagnosis leads to ESRD

  • Trend toward improved renal and patient survival is observed

  • Clinical factors of poor prognosis

    • Older age

    • High creatinine level at initial presentation

    • High serum titer of ANCA (anti-PR3)

    • Severity of initial vascular damage

    • Multisystem involvement

      • Concomitant lung involvement or hemorrhage

    • Increased relapse rate (10-50%)

  • Clinical factors of good prognosis

    • Close to normal baseline renal function

Renal Transplantation

  • Patient and graft survival rates are comparable to those observed in non-ANCA patients

  • Both renal and extrarenal relapses occur after renal transplantation (though uncommon)

    • Recurrent disease or relapses are managed effectively by cyclophosphamide therapy


Radiographic Findings

  • Chest x-ray shows shifting infiltrates in lungs

  • Single or multiple nodular lung lesions

  • Diffuse pulmonary infiltrates suggesting hemorrhage



  • Usually normal in size or slightly enlarged

  • In acute phase, small scattered infarcts and petechial hemorrhages in cortex and medulla

  • Larger vessels appear grossly normal

  • Aneurysms or thrombi are rare

  • Focal or diffuse papillary necrosis


Histologic Features

  • Glomeruli

    • Wide range and extent of glomerular lesions with crescents

    • Segmental to severe capillary tuft thrombosis

      • Fibrinoid necrosis with rupture of basement membranes

      • Accumulation of neutrophils and karyorrhexis of cells in areas of necrosis

    • Crescents in different stages of healing (such as cellular, fibrocellular, and fibrous types) may be seen in same biopsy

      • Cellular crescent is composed of mainly parietal epithelial cells and exuded inflammatory cells (more than 2-3 layers thick)

      • Segmental/small to large, sometimes circumferential cellular crescents in Bowman space

      • A few crescents acquire granulomatous appearance with epithelioid and giant cells

      • Varying degrees of glomerular tuft compression

    • Acute and subacute periglomerular inflammation due to disruption of Bowman capsule

    • No intraglomerular cell proliferation

    • Later glomerulosclerosis, residual disruption of Bowman capsule

  • Tubulointerstitium

    • Mild to marked active interstitial inflammation may accompany glomerular crescentic lesions

    • Sometimes necrotizing neutrophilic granulomatous interstitial nephritis with palisading histiocytes (geographic pattern) or mass lesion

      • Occasional interstitial (extravascular) granulomas

    • Plasma cells can be prominent

    • Focal microscopic interstitial hemorrhages

    • Tubular red blood cells and RBC casts

    • Active tubulitis and epithelial cell injury

    • Peritubular capillaritis

    • Tubular atrophy and interstitial fibrosis

  • Vessels

    • Interlobular arteries are usual site affected by vasculitis

      • Segmental or circumferential fibrinoid necrosis

      • Cellular reaction composed of neutrophils, histiocytes, and sometimes prominent eosinophils

      • Occasional granulomatous inflammation

    • Smaller arteries down to pre- and postglomerular arterioles and venules involved

    • Isolated or concomitant medullary inflammation, capillaritis, and interstitial hemorrhages

    • Progressive vascular sclerosis with variable loss of elastic lamina by EVG stain

  • General comments

    • Vascular lesions and granulomata are more difficult to find in renal biopsies than in larger samples or autopsy kidneys

    • Small vessel vasculitis and capillaritis also seen in skin, lung, and other organs similar to other small vessel or ANCA-associated vasculitides

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Granulomatosis with Polyangiitis (Wegener)
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