Systemic Vasculitis

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
    • 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

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
  • See Vasculitis in Adults Testing Algorithm and Vasculitis in Children Testing Algorithm

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
    • Systemic lupus erythematosus
    • Rheumatoid arthritis
    • Scleroderma
  • 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
    • Antiphospholipid syndrome (APS)
    • 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
    • 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
• 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	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