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.
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
- Antineutrophil cytoplasmic antibody (ANCA) – most useful for differentiating ANCA(+) vasculitis from other vasculitis
- Evaluation for other vasculitis associations
- Liver function tests
- Evaluate hepatic involvement – most common in polyarteritis nodosa
- 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
- Liver function tests
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
- Nerve conduction testing if neurologic manifestations present
- Combination of patient’s presentation, history, laboratory, imaging, and clinical findings are critical to optimal classification of systemic vasculitis
Differential Diagnosis
- Large vessel
- Mycotic aneurysms
- Atherosclerosis
- Congenital – aortic coarctation
- Hereditary disorders
- Marfan syndrome
- Ehlers-Danlos syndrome (type IV)
- Loeys-Dietz syndrome
- Fibromuscular dysplasia
- Postradiation syndrome
- Chronic aortic aneurysm
- Chronic infection
- Mycobacterium tuberculosis
- Treponema pallidum
- Medium vessel/small vessel
- Vasculitis
- Cogan syndrome
- Behçet syndrome
- Autoimmune disease
- Neoplasm
- Lymphoma
- Leukemia (acute lymphocytic leukemia [ALL], acute myeloid leukemia [AML])
- Plasma cell dyscrasias
- Paraneoplastic syndrome
- Infection
- HIV
- Hepatitis C virus
- Hepatitis B virus
- Herpes simplex virus
- Endocarditis
- Glomerulonephritis – acute, infectious, other etiologies
- Sickle cell disease
- Hypercoagulable states
- Mycotic aneurysms
- Hereditary disorders
- Ehlers-Danlos syndrome
- Neurofibromatosis
- Grange syndrome
- Fibromuscular dysplasia
- Drugs
- Cocaine
- Amphetamines
- Hypersensitivity reactions
- Vasculitis
- Central nervous system vasculitis
- Sarcoidosis
- Infection
- Bacterial
- Fungal – yeasts and molds
- Viral – progressive multifocal leukoencephalopathy
- Parasitic
- Malignancy
- Glioma
- Angiocentric lymphoma
- Hypercoagulable states
- TTP
- APS
- Stroke-like syndromes
- Sickle cell disease
- Migraine headaches
- Fabry disease
- Cerebral hemorrhage
- Embolic disease
- Myxoma
- Endocarditis
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
- Titers may decrease after induction of remission and elevation may herald relapse
- 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
- Antiglomerular membrane disease
- Cryoglobulinemia vasculitis
- IgA vasculitis (Henoch-Schönlein)
- Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)
Variable vessel vasculitis
Cogan 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
- Incidence – 3-27/100,000 children and infants ≤18 years
- 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
- Incidence – 20/100,000 U.S. children <5 years
ARUP Laboratory Tests
Preferred first-line reflex panel for the evaluation of ANCA-associated vasculitis
Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay
Evaluate for kidney dysfunction in patients with known risk factors (eg, hypertension, diabetes, obesity, family history of kidney disease)
Monitor treatment of vasculitis
Quantitative Chemiluminescent Immunoassay/Quantitative Enzyme-Linked Immunosorbent Assay
Panel includes albumin, calcium, carbon dioxide, creatinine, chloride, glucose, phosphorous, potassium, sodium, blood urea nitrogen (BUN), and a calculated anion gap value
Initial screening for hepatobiliary inflammation
Monitor treatment of vasculitis
Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Panel includes bilirubin, direct; bilirubin, total (serum or plasma); alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; protein, total (serum or plasma); albumin (serum or plasma)
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
Semi-Quantitative Multiplex Bead Assay
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
Semi-Quantitative Multiplex Bead Assay
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
Semi-Quantitative Multiplex Bead Assay
Not a recommended first-line screening test for ANCA-associated vasculitis
Semi-Quantitative Indirect Fluorescent Antibody
Comprehensive panel for the evaluation of ANCA-associated vasculitis
Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay
Components: ANCA, IgG; MPO antibody; and PR3 antibody
Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold
Qualitative Cold Precipitation/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry
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
Semi-Quantitative Multiplex Bead Assay/Qualitative Indirect Fluorescent Antibody
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
Qualitative Cold Precipitation
Initial test for suspected bleeding disorder
Electromagnetic Mechanical Clot Detection
Preferred test for acute or convalescent phase of disease
Acute and convalescent titers often necessary
Semi-Quantitative Indirect Fluorescent Antibody
Use to evaluate for a viral etiology in symptomatic individuals with acute hepatitis
Not recommended for screening asymptomatic individuals
Qualitative Chemiluminescent Immunoassay/Quantitative Transcription-Mediated Amplification
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
Qualitative Chemiluminescent Immunoassay/Qualitative Immunoassay/Quantitative Transcription-Mediated Amplification
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
Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Particle Agglutination
May aid in diagnosing acute infections and detecting past exposure and/or vaccination
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Chemiluminescent Immunoassay
Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold
Semi-Quantitative Indirect Fluorescent Antibody
Preferred antinuclear antibodies (ANA) screening test for connective tissue disease
Qualitative Cold Precipitation
Secondary screening for systemic lupus erythematosus (SLE) based on ANA results
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Recommended for the differential diagnosis of SLE and Sjögren syndrome
Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Multiplex Bead Assay
Preferred panel for the workup of suspected rheumatoid arthritis or undifferentiated inflammatory arthritides
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Immunoturbidimetry
Acceptable initial test when antiphospholipid syndrome (APS) is strongly suspected
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Acceptable initial test when APS is strongly suspected
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Cytochemical Stain
Quantitative Enzymatic Assay
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Medical Experts
Peterson

Components: ANCA, IgG; MPO, IgG; PR3, IgG