Vasculitis - ANCA

Diagnosis

Indications for Testing

  • Multisystem disease presentation (including upper airway disease, renal disease, pulmonary disease, palpable purpura, urticaria, or mononeuritis multiplex)

Laboratory Testing

  • Typical test plan includes ruling out other diseases with similar presentation and assessing organ involvement
  • CBC – may have anemia, leukocytosis, thrombocytopenia
  • Erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) – usually elevated; nonspecific; lack of elevation does not rule out vasculitis
  • Urinalysis – evaluate for presence of hematuria, proteinuria, or red-cell casts (suggests glomerulonephritis)
  • Renal function tests (BUN/creatinine) – assess for renal involvement
  • Liver function tests – provide clues for hepatic involvement (most common in polyarteritis nodosa)
  • ANCA
    • Indirect immunofluorescence assay (IFA) – sensitive marker for ANCA-associated vasculitis
    • To confirm, PR3 or MPO specific assays (ELISA, Western blot or multianalyte fluorescence detection [MAFD]) required (European League Against Rheumatism [EULAR] 2009 grade A recommendation)
    • Pattern of ANCA frequently helpful – pANCA vs. cANCA
    • May be useful in combination with clinical picture in emergency setting where physician cannot wait for biopsy results
    • Absence of a positive test result does not rule out diagnosis
  • Other possible secondary testing – antinuclear antibody, rheumatoid arthritis, hepatitis B and C viruses

Histology

  • Determines size of artery involved (EULAR 2009 grade C recommendation)
  • In conjunction with clinical presentation, ANCA, urinalysis, and biopsy can usually diagnose specific vasculitis (see the Vasculitis in Adults Testing Algorithm and Vasculitis in Children Testing Algorithm)

Imaging Studies

  • Chest x-ray – nonspecific pulmonary nodules, cavitation, consolidation or pleural effusion suggest pulmonary involvement
  • Angiogram of affected area – demonstrates aneurysms and vascular occlusion
    • Magnetic resonance angiography or computed tomography angiography may be preferred
  • Echocardiography
    • 40% detection rate for Kawasaki
    • Also used in Takayasu
  • Ultrasound – for temporal artery diagnosis and monitoring
  • CT sinus – useful in Wegener granulomatosis

Other Testing

  • Nerve conduction testing if neurologic manifestations present

Differential Diagnosis

Monitoring

  • ANCA
    • Titers may decrease after induction of remission and rise secondary to relapse
      • Rising titers do not reliably predict relapse
      • Cannot use titers to guide treatment
    • Urinalysis should be performed every visit to monitor for renal involvement (EULAR 2009)
    • Inflammatory markers, renal function testing, CBC, and liver function testing should be performed every 1-3 months (EULAR 2009 grade C recommendation)

Clinical Background

The systemic vasculitides are a group of uncommon conditions characterized by inflammation and necrosis of blood vessel walls. Some of these syndromes are also characterized by the presence of antineutrophil cytoplasmic antibodies (ANCA).

Epidemiology

  • Incidence – 100/1,000,000
  • Age – peak onset is 65-74 years; unusual in children
  • Sex – M>F (minimal)

Classification

  • Based on affected blood vessel size (small, medium, or large)
  • Chapel Hill Consensus Conference Nomenclature of Systemic Vasculitis
    Nomenclature and Definitions of Vasculitis
    Proposed by the Consensus Conference on the Nomenclature of Systemic Vasculitis

    (Chapel Hill Consensus)
    • Large vessel vasculitis*
      • Giant cell arteritis
        • Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery
        • Often involves the temporal artery
        • Usually occurs in patients >50 years and often associated with polymyalgia rheumatica
      • Takayasu arteritis
        • Granulomatous inflammation of the aorta and its major branches
        • Usually occurs in patients <50 years
    • Medium-sized vessel vasculitis*
      • Polyarteritis nodosa
        • Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules
      • Kawasaki disease
        • Arteritis involving large, medium-sized and small arteries and associated with mucocutaneous lymph node syndrome
        • Coronary arteries are often involved – aorta and veins may be involved
        • Usually occurs in children
    • Small vessel vasculitis*
      • Wegener granulomatosis
        • Granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels (eg, capillaries, venules, arterioles, and arteries)
        • Necrotizing glomerulonephritis is common
      • Churg-Strauss syndrome
        • Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels and associated with asthma and blood eosinophilia
      • Microscopic polyangiitis
        • Necrotizing vasculitis with few or no immune deposits affecting small vessels (eg, capillaries, venules, or arterioles)
        • Necrotizing arteritis involving small and medium-sized arteries may be present
        • Necrotizing glomerulonephritis is very common
        • Pulmonary capillaritis often occurs
      • Henoch-Schönlein purpura
        • Vasculitis with IgA-dominant immune deposits affecting small vessels (eg, capillaries, venules, or arterioles)
        • Typically involves skin, gut, and glomeruli and is associated with arthralgias or arthritis
      • Cryoglobulinemic vasculitis
        • Vasculitis with cryoglobulin immune deposits affecting small vessels (eg, capillaries, venules or arterioles, and associated with cryoglobulins in serum)
        • Skin and glomeruli are often involved
      • Cutaneous leukocytoclastic angiitis
        • Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis
    *Large artery refers to the aorta and major branches directed toward body regions (eg, to the extremities and the head); medium-sized artery refers to main visceral arteries (eg, renal, hepatic, coronary, and mesenteric arteries); small artery refers to distal arterial radicals that connect with arterioles (small vessels include small arteries, arterioles, venules, and capillaries)

Pathophysiology

  • ANCA are directed against certain proteins in the cytoplasmic granules of neutrophils and monocytes
    • Neutrophil cytoplasmic antibodies are found in serum of >90% of patients with certain necrotizing systemic vasculitides and usually in <5% of patients with connective tissue disease or arthritis
  • ANCA are specific for enzymes in the lysosome-proteinase 3-specific (PR-3) and myeloperoxidase-specific (MPO) antibodies; ANCA have been subdivided into pANCA (perinuclear) and cANCA (cytoplasmic)
    • pANCA pattern mimics antinuclear antibodies (ANA)
      • ~90% of patients with pANCA pattern by IFA have antibodies specific for MPO
    • ~85% of patients with cANCA pattern by IFA have antibodies specific for serine proteinase 3 (PR-3)
  • Binding of ANCA may induce activation of neutrophils resulting in endothelial cell damage

Clinical Presentation

  • Nonspecific signs and symptoms early in the disease – fever, arthralgias, fatigue, weight loss, myalgias
  • Multisystem involvement later in the disease – dermatologic, ophthalmologic, renal, pulmonary, hepatic, gastrointestinal tract, vascular, central nervous system
  • Patients present with diverse organ involvement in most cases

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
ANCA-Associated Vasculitis Profile (ANCA/MPO/PR-3) with Reflex to ANCA Titer 2006480
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Differentially diagnose systemic vasculitic syndromes, such as

  • Wegener granulomatosis
  • Microscopic polyangiitis
  • Churg-Strauss syndrome
  • Necrotizing and crescentic glomerulonephritis
  • Autoimmune hepatitis
  • Primary sclerosing cholangitis

Monitor treatment of Wegener granulomatosis

If screen is positive, titer will be added

Crossreaction may occur with cationic protein 57 (CAP 57), cathepsin G, elastase, lactoferrin, and other lysosomal proteins

Test for specific disease identification including serum testing and biopsy of involved site

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Determine symptoms involved in vasculitic-like infections

   
Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Determine symptoms involved in vasculitic-like infections

   
C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Use in clinical scenarios associated with inflammation (autoimmune disease, connective tissue disease, rheumatoid arthritis, or sepsis

Do not order for cardiovascular disease risk assessment; use CRP high sensitivity

   
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential
Monitor treatment of vasculitis    
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Monitor treatment of vasculitis

Panel includes bilirubin direct; bilirubin total (serum or plasma), alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, protein total (serum or plasma), albumin (serum or plasma)

   
Renal Function Panel 0020144
Method: Quantitative Chemiluminescent Immunoassay/Quantitative Enzyme-Linked Immunosorbent Assay
Monitor treatment of vasculitis    
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
MPO/PR-3 (ANCA) Antibodies 0050707
Method: Semi-Quantitative Multiplex Bead Assay
Myeloperoxidase Antibody 0050526
Method: Semi-Quantitative Multiplex Bead Assay
Serine Protease 3 Antibody 0050527
Method: Semi-Quantitative Multiplex Bead Assay
Anti-Neutrophil Cytoplasmic Antibody, IgG 0050811
Method: Semi-Quantitative Indirect Fluorescent Antibody

Differentially diagnose systemic vasculitic syndromes such as
 

  • Wegener granulomatosis 
  • Microscopic polyangiitis
  • Churg-Strauss syndrome
  • Necrotizing and crescentic glomerulonephritis
  • Autoimmune hepatitis
  • Primary sclerosing cholangitis

If ANCA screen detects antibodies ≥1:20 dilution, titer to end point will be added

Cryoglobulin, Qualitative with Reflex to IFE Typing and Quantitative IgA, IgG, and IgM 2002403
Method: Qualitative Cold Precipitation/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

If qualitative is positive, Immunofixation Electrophoresis Typing and Quantitative IgA, IgG and IgM will be added

Glomerular Basement Membrane Antibody, IgG by Multiplex Bead Assay and IFA 2008403
Method: Semi-Quantitative Multiplex Bead Assay/Qualitative Indirect Fluorescent Antibody
Cryoglobulin, Qualitative 0050185
Method: Qualitative Cold Precipitation
Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer and MPO/PR-3 Antibodies 2002068
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay