Systemic Vasculitis

Systemic or necrotizing vasculitides are a group of rare diseases characterized by inflammation of diverse blood vessel walls. Diseases are categorized by blood vessel size, namely small, medium, or large vessel vasculitis. Some vasculitides are associated with the presence of antineutrophil cytoplasmic antibodies (ANCA), or so-called ANCA-associated vasculitides. Vasculitis can occur in association with other conditions, including infections, drug reactions, inflammatory bowel disease, and malignancy.

Quick Answers for Clinicians

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Diagnosis

Indications for Testing

  • General presentation
    • Fever
    • Joint pain and inflammation
    • Malaise, weight loss
  • Large vessel vasculitides
    • Aortic dilation
    • Asymmetric or absent pulses
    • Bruits
    • Pain due to claudication
    • Stroke-like symptoms
  • Medium vessel vasculitides
    • Mononeuritis multiplex
    • Skin signs (eg, livedo reticularis, nodules)
    • Digital necrosis
    • Microaneurysms
    • Abdominal pain
    • Gastrointestinal ulcers
  • Small vessel vasculitides
    • Alveolar hemorrhage
    • Glomerulonephritis
    • Skin signs (eg, purpura, splinter hemorrhages)
    • Uveitis
    • Episcleritis
    • Purpura
    • Urticaria 

Laboratory Testing

  • Useful testing for the evaluation of vasculitis
    • Antineutrophil cytoplasmic antibody (ANCA) – most useful for differentiating ANCA(+) vasculitis from other vasculitis
      • Indirect fluorescent antibody (IFA) test – preferred screening method for ANCA-associated vasculitis with 2 main patterns: C-ANCA and P-ANCA
      • Proteinase 3 (PR3) or myeloperoxidase (MPO) specific assays (by enzyme-linked immunosorbent assay [ELISA], Western blot, or multianalyte fluorescence detection [MAFD]) can confirm positive C-ANCA or P-ANCA result
        • C-ANCA is associated with PR3 antibodies
        • P-ANCA is associated with MPO antibodies
      • Absence of a positive test result does not rule out vasculitis
    • C-reactive protein (CRP)
      • Often elevated in active disease; nonspecific marker suggestive of systemic inflammation
      • If CRP not available, erythrocyte sedimentation rate (ESR) may be used
    • CBC – may demonstrate
      • Normochromic normocytic anemia – chronic inflammation
      • Eosinophilia – eosinophilic granulomatosis with polyangiitis
      • Leukocytosis – inflammation
      • Reactive thrombocytosis – inflammation
    • Peripheral smear
    • Renal function tests – evaluate type and extent of kidney damage
      • Urinalysis – evaluate for hematuria, proteinuria, red blood cell casts, nitrates, and leukocytes
      • Serum kidney function tests (blood urea nitrogen [BUN]/creatinine)
      • Spot urine albumin/creatinine
      • Estimated glomerular filtration rate
  • Evaluation for other vasculitis associations
    • Liver function tests
    • Immunoglobulin levels/complement levels and functional assay/cryoglobulins
    • Antiglomerular basement membrane (anti-GBM) testing – detect GBM antibodies in suspected or established anti-GBM disease (Goodpasture Syndrome)
      • By IFA and/or multiplex bead assay
    • Coagulation and synthetic function testing
      • Prothrombin time
    • Infectious vasculitis testing
      • Rickettsia rickettsii
      • Hepatitis C and B – cryoglobulinemic vasculitis
      • Treponema pallidum
      • HIV
      • Varicella zoster virus (VZV)
    • Autoimmune rheumatic systemic disease testing – lupus, rheumatoid arthritis, antiphospholipid antibody syndrome (APS)
      • Antinuclear antibody (ANA)
      • Double-stranded DNA (dsDNA)
      • Extractable nuclear antigen (ENA) antibodies panel
      • Angiotensin converting enzyme (ACE)
      • Rheumatoid factor (RF)
      • Anticardiolipin antibodies, lupus anticoagulant

Histology

  • Biopsy required to confirm or rule out diagnosis
    • ANCA has a sensitivity of ~85% in active Wegener granulomatosis (WG)
  • Assess damage and characterize disease
  • Size of blood vessels involved (small, medium, large)
  • IgA deposition for IgA vasculitis
  • Evaluation for eosinophils in eosinophilic granulomatosis with polyangiitis

Imaging Studies

  • Chest X-ray – nonspecific pulmonary nodules, cavitation, consolidation, or pleural effusion suggest pulmonary involvement
  • Angiogram of affected area – cardiac, central nervous system (CNS)
    • May demonstrate aneurysms and vascular occlusion
    • Magnetic resonance angiography or computed tomography angiography may be preferred
  • Echocardiography
    • Use to evaluate extent of disease in large and medium vessel vasculitis
    • 40% detection rate for Kawasaki
    • Also used in Takayasu arteritis
  • Ultrasound – for giant cell arteritis diagnosis and monitoring
  • Computed tomography (CT) scan
    • Sinus – useful in granulomatosis with polyangiitis (GPA)
    • Chest – useful to detect pulmonary involvement

Other Testing

Differential Diagnosis

Monitoring

  • Antineutrophil cytoplasmic antibody (ANCA) – if positive in initial evaluation
    • Titers may decrease after induction of remission and elevation may herald relapse
      • Rising titers do not reliably predict relapse
      • Titers cannot be used to guide treatment
  • Urinalysis – perform every visit to monitor for infection or renal involvement (European League Against Rheumatism [EULAR]/European Renal Association-European Dialysis and Transplant Association [ERA-EDTA], 2016)
  • Inflammatory markers and renal function testing – perform every 1-3 months (EULAR/ERA-EDTA, 2016)
  • Malignancy evaluation – higher risk for cancer in Wegener’s granulomatosis and microscopic polyangiitis, specifically for bladder, skin, and hematologic malignancies (Kermani, 2011)
    • Consider careful monitoring

Background

Epidemiology

  • Incidence – 100/million
  • Age
    • Peak onset is 65-74 years
    • Unusual in children
  • Sex – M>F; minimal

Nomenclature

  • Based on affected blood vessel size – small, medium, or large
  • Chapel Hill Consensus Conference Nomenclature of Systemic Vasculitis (Revised 2012)
    Revised Systemic Vasculitis Nomenclature

    Large vessel vasculitis

    Takayasu arteritis

    Giant cell arteritis

    Medium vessel vasculitis

    Polyarteritis nodosa

    Kawasaki disease

    Small vessel vasculitis

    ANCA-associated SVV

    • Microscopic polyangiitis
    • Granulomatosis with polyangiitis
    • Eosinophilic granulomatosis with polyangiitis

    Immune complex SVV

    Variable vessel vasculitis

    Behçet’s syndrome vasculitis

    Cogan’s syndrome vasculitis

    Single organ vasculitis

    Cutaneous leukocytoclastic angiitis

    Cutaneous arteritis

    Primary CNS vasculitis

    Isolated aortitis

    Vasculitis associated with systemic disease

    Lupus vasculitis

    Rheumatoid vasculitis

    Sarcoid vasculitis

    Vasculitis associated with probable etiology

    Hepatitis C virus-associated cryoglobulinemic vasculitis

    Hepatitis B virus-associated vasculitis

    Syphilis-associated aortitis

    Drug-associated ANCA-associated vasculitis

    Cancer-associated vasculitis

    ANCA, antineutrophil cytoplasmic antibodies; CNS, central nervous system; SVV, small vessel vasculitis

    Source: International Chapel Hill Consensus 2012

Clinical Presentation

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

Pediatrics

Vasculitis in pediatrics is categorized by the predominant size of the blood vessels affected; most vasculitides can affect a range of sizes (overlap) (Foster, 2012). The most common pediatric vasculitides are immunoglobulin A (IgA) vasculitis and Kawasaki disease; eosinophilic granulomatosis with polyangiitis is extremely rare in children, and giant cell arteritis is not seen. Laboratory testing and other evaluation with confirmation by biopsy is similar to adult testing. See Diagnosis for adult testing recommendations.

Epidemiology

  • IgA vasculitis (formerly Henoch-Schönlein purpura) (Piram, 2013)
    • Incidence – 3-27/100,000 children and infants ≤18 years
      • 2-33 times more common in children than adults
    • Age – predilection for children 3-12 years
    • M>F
    • Autumn-winter predominance
  • Kawasaki disease (Holman, 2010)
    • Incidence – 20/100,000 U.S. children <5 years
      • Highest incidence in Japan
    • Age – peak incidence <1 year
    • M>F
    • Winter-spring predominance

ARUP Lab Tests

Preferred reflex panel for the workup of suspected vasculitis

For patients with a history of vasculitis, refer to the antineutrophil cytoplasmic antibodies (ANCA) reflex panel that includes a titer, and myeloperoxidase MPO) and proteinase 3 (PR3) antibodies

Individual antibody tests are available; refer to PR3 antibody or MPO antibody tests

Initial test in conjunction with autoimmune liver disease with reflex to smooth muscle antibody for evaluation of autoimmune liver disease

All interpretation of antibody patterns must be done in conjunction with clinical presentation

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

Panel includes ANCA, IgG; MPO antibodies, IgG; and serine PR3, IgG

Reflex pattern: if the ANCA screen detects antibodies at a 1:20 dilution or greater, then a titer to end point will be added

May help in ruling out infectious process

Evaluate for kidney dysfunction in patients with known risk factors (eg, hypertension, diabetes, obesity, family history of kidney disease)

Monitor treatment of vasculitis

Panel includes albumin, calcium, carbon dioxide, creatinine, chloride, glucose, phosphorous, potassium, sodium, blood urea nitrogen (BUN), and a calculated anion gap value

Screen for various metabolic and kidney disorders

Initial screening for hepatobiliary inflammation

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)

Related Tests

Nonspecific test used to detect inflammation associated with infections, cancers, and autoimmune diseases

Monitor previously established myeloperoxidase (MPO)/proteinase 3 (PR3) antibodies or confirm an indirect fluorescent antibody (IFA) antineutrophil cytoplasmic antibodies (ANCA) positive test result

Test does not include ANCA testing by IFA

For ANCA testing, refer to the available panel tests

For the workup of suspected vasculitis, refer to ANCA-associated vasculitis profile (ANCA/MPO/PR3) with reflex to ANCA titer

For patients with history of vasculitis, refer to ANCA reflex to titer and MPO/PR3 antibodies

When used in conjunction with other autoantibody tests (ANCA, PR3), may assist in evaluating suspected immune-mediated vasculitis, especially microscopic polyangiitis (MPA)

May be useful when monitoring MPA disease and/or treatment response

Panel tests are available for the workup of suspected vasculitis; refer to ANCA-associated vasculitis profile (ANCA/MPO/PR3) with reflex to ANCA titer, and for patients with a history of vasculitis, refer to the ANCA reflex to titer and MPO/PR3 antibodies

When used in conjunction with other autoantibody tests (ANCA, MPO), may assist in differentiating suspected Wegener granulomatosis (WG) from other vasculitides

May be useful when monitoring patients with PR3 antibodies

Panel tests are available for the workup of suspected vasculitis; refer to ANCA-associated vasculitis profile (ANCA/MPO/PR3) with reflex to ANCA titer, and for patients with a history of vasculitis, refer to the ANCA reflex to titer and MPO/PR3 antibodies

First-line screening test for ANCA-associated vasculitis

For the workup of suspected vasculitis, refer to ANCA-associated vasculitis profile (ANCA/MPO/PR3) with reflex to ANCA titer

Recommended in the differential evaluation of autoimmune diseases with renal involvement (systemic lupus erythematosus [SLE] and antiglomerular basement membrane [anti-GBM] disease)

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

Preferred reflex panel for managing patients with a known diagnosis of vasculitis

May be assistive in evaluating suspected vasculitis

For the workup of suspected vasculitis, the preferred panel is ANCA-associated vasculitis profile (ANCA/MPO/PR3) with reflex to ANCA titer

Panel includes ANCA, IgG; MPO antibody; and PR3 antibody

Reflex pattern: if screen is positive, then titer and MPO/PR3 antibodies will be added to aid in antibody determination

Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold

Reflex pattern: if qualitative is positive, immunofixation electrophoresis typing and quantitative IgA, IgG, and IgM will be added

Detect GBM antibodies in suspected or established anti-GBM disease

Panel includes GBM antibody, IgG by multiplex bead assay and IFA

Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold

Initial test for suspected bleeding disorder

Preferred test for acute or convalescent phase of disease

Acute and convalescent titers often necessary

Order to evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

Panel includes hepatitis A virus (HAV) IgM, hepatitis B virus (HBV) core antibody IgM, HBV surface antigen, hepatitis C virus (HCV) antibody

2014 CDC Recommended Algorithm for Laboratory Diagnosis of HIV infection

This 4th generation test screens for HIV-1 p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2

Repeatedly reactive HIV-1/2 antigen/antibody screening results are confirmed with an HIV-1/HIV-2 antibody differentiation test

Negative or indeterminate results for HIV-1/2 antibody differentiation are confirmed with a quantitative NAAT test

CDC recommended test for the screening and diagnosis of syphilis

For rapid plasma reagin (RPR) test that follows reverse algorithm, refer to RPR test with reflex to RPR titer or Treponema pallidum antibody

May aid in diagnosing acute infections and detecting past exposure and/or vaccination

Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold

Preferred antinuclear antibodies (ANA) screening test for connective tissue disease

Secondary screening for systemic lupus erythematosus (SLE) based on ANA results

Recommended for the differential diagnosis of SLE and Sjögren syndrome

Preferred panel for the workup of suspected rheumatoid arthritis or undifferentiated inflammatory arthritides

Acceptable initial test when antiphospholipid syndrome (APS) is strongly suspected

Acceptable initial test when APS is strongly suspected

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References

Additional Resources
  • 23318735

    Piram M, Mahr A. Curr Opin Rheumatol. 2013; 25 (2): 171-8.
    PubMed