Granulomatosis with Polyangiitis (Wegener)



Granulomatosis with Polyangiitis (Wegener)


Surya V. Seshan, MD





Key Facts


Etiology/Pathogenesis



  • Form of ANCA-mediated small vessel vasculitis


  • Usually due to anti-PR3 antibodies (˜ 75%), others to MPO


Clinical Issues



  • Peak age at onset: 30-50 years


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


  • Present with acute or rapidly progressive renal failure


  • Steroids combined with cyclophosphamide; plasmapheresis beneficial in severe disease


  • Poor prognostic factors



    • High initial creatinine, concomitant lung disease


    • Frequency of renal relapses


    • Few preserved glomeruli


Microscopic Pathology



  • Fibrinoid necrosis, crescents (cellular, fibrocellular, and fibrous types)


  • Occasional interstitial (extravascular) granulomas


  • Interlobular and smaller arteries affected by vasculitis


  • Granulomatous inflammation in vessel wall, perivascular or interstitial locations


  • Isolated or concomitant medullary capillaritis


Ancillary Tests



  • Pauci-immune with little or no immunoglobulins or complement components by IF


Top Differential Diagnoses



  • ANCA(+) vasculitides (Churg-Strauss syndrome, microscopic polyangiitis), anti-GBM disease, HSP, drug-induced vasculitis







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.


TERMINOLOGY


Abbreviations



  • Granulomatosis with polyangiitis (GPA)


Synonyms



  • Wegener granulomatosis (WG)


  • Rhinogenic granulomatosis


Definitions



  • 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


ETIOLOGY/PATHOGENESIS


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)


CLINICAL ISSUES


Epidemiology



  • 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


Presentation



  • 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%)


Treatment



  • 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


Prognosis



  • 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


IMAGE FINDINGS


Radiographic Findings



  • Chest x-ray shows shifting infiltrates in lungs


  • Single or multiple nodular lung lesions


  • Diffuse pulmonary infiltrates suggesting hemorrhage


MACROSCOPIC FEATURES


Kidney



  • 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


MICROSCOPIC PATHOLOGY


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


Other Organs

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

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