Vasculitis, ANCA-Related



Vasculitis, ANCA-Related


Monica P. Revelo, MD, PhD





Key Facts


Terminology



  • Systemic vasculitis involving small to medium-sized vessels associated with or caused by ANCA


  • Kidney involvement is characterized by prominent crescents and scant or no immunoglobulin deposition


Clinical Issues



  • Overall, AAV vasculitis is rare in children


  • Whites and females more commonly involved


  • MPO ANCA (p-ANCA) is most common in PIGN, MPA and CSS


  • PR3 ANCA (c-ANCA) is most common in GPA


Microscopic Pathology



  • Glomerular lesions are similar in all PIGN


  • Fibrinoid necrosis and capillary basement membrane disruption


  • Crescents: Cellular/fibrocellular (in active phase) and fibrous (chronic phase) involving most of glomeruli present, usually > 50%


  • Minimal cellular proliferation (endocapillary/mesangial) may be seen


  • Bowman capsule rupture and periglomerular inflammation in severe cases


  • Segmental scars in healing/chronic phase


  • Segmental/circumferential fibrinoid necrosis and perivascular inflammation


  • Eosinophils are more prominent in CSS


Ancillary Tests



  • In all types of PIGN, there are minimal (< 1-2+) or no deposits of immunoglobulins and complement




TERMINOLOGY



Abbreviations



  • Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)


Synonyms



  • Pauci-immune glomerulonephritis (PIGN)


  • Pauci-immune crescentic glomerulonephritis


  • Rapidly progressive glomerulonephritis (RPGN)



Definitions



  • Systemic vasculitis involving small to medium-sized vessels associated with or caused by ANCA



    • Kidney involvement is characterized by prominent crescents and scant or no immunoglobulin deposition


    • Includes: Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and limited pauci-immune glomerulonephritis


ETIOLOGY/PATHOGENESIS


Autoimmunity



  • Autoantibodies made to neutrophil lysosomal components (PR3 or MPO)


  • Antigens expressed on surface of activated neutrophils


  • ANCA augments neutrophil-mediated cytotoxicity


  • ANCA initiates signal transduction pathways for cell activation, FcR participation


  • Neutrophils activate alternative complement pathway


  • Leukocyte activation and adhesion to primed endothelial cells, resulting in cell damage


  • Trigger for ANCA production unknown



    • Presumed immune dysregulation


    • Evidence of molecular mimicry


    • Can be precipitated by drugs (propylthiouracil, hydralazine, penicillamine, minocycline)


  • Cell-mediated immune mechanisms with T-lymphocytes, neutrophils, and histiocytes are necessary for crescentic glomerulonephritis development


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Overall, AAV is rare in children



      • GPA: 3.2:100,000 children/year


      • GPA > MPA in some studies


      • CSS very rare in children


  • Gender



    • F > M


  • Ethnicity



    • Whites more commonly involved


    • MPA most common small vessel vasculitis in Japan, China, Spain, and Kuwait


Presentation



  • Systemic manifestations



    • Malaise, fever, weight loss (89%)


  • Lung symptoms



    • Shortness of breath, chronic cough, hemoptysis/alveolar hemorrhage, nodules, abnormal pulmonary function, fixed pulmonary infiltrates (80%)


  • Ear, nose, and throat symptoms



    • Nasal involvement, sinusitis, otitis/mastoiditis, subglottic involvement, hearing loss, oral ulcers (80%)


  • Renal symptoms



    • Abnormal urinalysis (hematuria, proteinuria), biopsy-proven pauci-immune crescentic glomerulonephritis, elevated serum creatinine (75.4%)


  • Other symptoms




    • Conjunctivitis, scleritis, palpable purpura, abdominal pain, arthralgias/myalgia, arthritis, severe headache, dizziness


Laboratory Tests



  • Positive ANCA test by indirect immunofluorescence and ELISA



    • Myeloperoxidase (MPO) ANCA (p-ANCA) is most common in PIGN, MPA, and CSS


    • Proteinase 3 (PR3) ANCA (c-ANCA) is most common in GPA


Natural History



  • With treatment, clinical remission is possible, but relapses are common


  • Progression to end-stage renal disease may occur (˜ 10%)



Treatment



  • Surgical approaches



    • Renal transplantation


  • Drugs



    • Induction treatment



      • Pulse of methylprednisolone and cyclophosphamide


      • Plasma exchange


    • Maintenance treatment; although no validated studies are available, the following drugs have been used



      • Steroids


      • Azathioprine/mycophenolate mofetil


      • Methotrexate


    • Relapse



      • Pulse of methylprednisolone and cyclophosphamide


      • Rituximab


Prognosis



  • Remission of kidney and systemic manifestations can be accomplished with current therapy



    • Reported remission rate: 80-84%


    • Low mortality


  • Relapses are common after discontinuation of therapy


  • Prognostic factors of poor outcome include



    • Decreased glomerular filtration rate at presentation


    • Chronic lesions in renal biopsy


    • Nephrotic range proteinuria


  • Serum creatinine has been inversely correlated with kidney survival


Diagnostic Criteria for GPA (EULAR/PRINTO/PRES)



  • At least 3 criteria are necessary for diagnosis of GPA in childhood



    • Upper airway involvement


    • Laryngeo-tracheal-bronchial stenoses


    • Pulmonary involvement


    • Renal involvement


    • Granulomatous inflammation within arterial wall or perivascular/extravascular area


    • ANCA positivity


MICROSCOPIC PATHOLOGY


Histologic Features



  • Glomerular lesions are similar in all PIGN



    • Fibrinoid necrosis and capillary basement membrane disruption


    • Crescents: Cellular/fibrocellular (in active phase) and fibrous (chronic phase) involving most of glomeruli present, usually > 50%


    • Neutrophils can be seen within capillary loops


    • Minimal cellular proliferation (endocapillary/mesangial) may be seen


    • Bowman capsule rupture and periglomerular inflammation in severe cases


    • Segmental scars in healing/chronic phase


  • Tubules and interstitium



    • Significant mixed interstitial inflammatory infiltrate (neutrophils, mononuclear cells, and eosinophils) in acute phase



      • In GPA, interstitial inflammation may show granulomatous features



      • True granulomas are unusual in kidney biopsies, but their presence favors GPA


      • Eosinophils are more prominent in CSS and less prominent in MPA


    • Interstitial hemorrhage


    • Tubular necrosis with tubulitis may be seen


  • Vessels



    • Type of vessel involved



      • Interlobular/small arteries, arterioles, capillaries, and venules are affected in GPA


      • Arteries, arterioles, and capillaries in MPA


      • Arteries, arterioles, and, rarely, capillaries in CCS


    • Segmental/circumferential fibrinoid necrosis and perivascular inflammation



      • Eosinophils are more prominent in CSS


    • Progressive vascular sclerosis with loss of elastic in healing phase


    • Renal medullary capillaritis can be seen in GPA and MPA

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Vasculitis, ANCA-Related

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