Vasculitis - ANCA

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)
- Small – Wegener granulomatosis, microscopic polyangiitis, renal vasculitis, Henoch Schönlein purpura
- Medium – polyarteritis nodosa, Churg-Strauss syndrome, Kawasaki disease
- Large – Cogan syndrome, Takayasu arteritis, giant cell (temporal) arteritis

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 is 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 anti-nuclear 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 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 is 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

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
  - M. tuberculosis
  - T. pallidum
Medium vessel/small vessel
- Other vasculitis
  - Cogan syndrome
  - Behcet syndrome
- Autoimmune disease
  - Systemic lupus erythematosus, rheumatoid arthritis, scleroderma
- Neoplasm
  - Lymphoma, leukemia (ALL, AML), plasma cell dyscrasias, paraneoplastic syndrome
- Infection
  - HIV, hepatitis C virus, hepatitis B virus, herpes simplex virus, endocarditis
- Glomerulonephritis
- Sickle cell disease
- Hypercoagulable states
  - Antiphospholipid syndrome
  - Thrombotic thrombocytopenic purpura (TTP)
- Mycotic aneurysms
- Hereditary disorders
  - Ehlers Danlos syndrome
  - Neurofibromatosis
  - Grange syndrome
- Fibromuscular dysplasia
- Drugs
  - Cocaine
  - Amphetamines
  - Hypersensitivity reactions
Central nervous system vasculitis
- Sarcoidosis
- Infection
  - Bacterial
  - Fungal (yeasts and molds)
  - Viral (progressive multifocal leukoencephalopathy)
  - Parasitic
- Malignancy
  - Glioma
  - Angiocentric lymphoma
- Hypercoagulable states
  - TTP
  - Antiphospholipid syndrome
- Stroke-like syndromes
  - Sickle cell disease
  - Migraine headaches
  - Fabry disease
- Cerebral hemorrhage
- Embolic disease
  - Myxoma
  - Endocarditis

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)

Tests generally appear in the order most useful for common clinical situations

Test name: Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer & MPO/PR-3 Antibodies

ARUP #: 2002068

Methodology: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multi-Analyte Fluorescent Detection

Use:

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

Limitations:

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

Follow-up:

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

Test name: Urinalysis, Complete

ARUP #: 0020350

Methodology: Reflective Photometry/Microscopic by Yellow IRIS

Use:

Determine symptoms involved in vasculitic-like infections

Test name: Sedimentation Rate, Westergren (ESR)

ARUP #: 0040325

Methodology: Westergren

Use:

Determine symptoms involved in vasculitic-like infections

Test name: C-Reactive Protein

ARUP #: 0050180

Methodology: Quantitative Immunoturbidimetric

Use:

Nonspecific test to check for inflammation

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use: Monitor treatment of vasculitis

Test name: Hepatic Function Panel

ARUP #: 0020416

Methodology: Refer to individual components.

Use:

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)

Test name: Renal Function Panel

ARUP #: 0020144

Methodology: Refer to individual components

Use: Monitor treatment of vasculitis

Additional Tests Available

Test name: MPO/PR-3 (ANCA) Antibodies

ARUP #: 0050707

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Comments:

Test name: Myeloperoxidase Antibody

ARUP #: 0050526

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection