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.

Tabs Content

Clinical Overview

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
- 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
CNS = central nervous system; ANCA = antineutrophil cytoplasmic antibodies; 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

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.

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

Recommended Use

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

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

Limitations

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

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Recommended Use

May help in ruling out infectious process

Renal Function Panel 0020144
Method: Quantitative Chemiluminescent Immunoassay/Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

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

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Recommended Use

Screen for various metabolic and kidney disorders

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Recommended Use

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)

Medical Reviewers

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, Buoncompagni A, Lazar C, Bilge I, Uziel Y, Rigante D, Cantarini L, Hilario MO, Silva CA, Alegria M, Norambuena X, Belot A, Berkun Y, Estrella AI, Olivieri AN, Alpigiani MG, Rumba I, Sztajnbok F, Tambic-Bukovac L, Breda L, Al-Mayouf S, Mihaylova D, Chasnyk V, Sengler C, Klein-Gitelman M, Djeddi D, Nuno L, Pruunsild C, Brunner J, Kondi A, Pagava K, Pederzoli S, Martini A, Ruperto N, Paediatric Rheumatology International Trials Organisation (PRINTO). EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010; 69(5): 798-806. PubMed
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013; 65(1): 1-11. PubMed
Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, Hellmich B, Holle JU, Laudien M, Little MA, Luqmani RA, Mahr A, Merkel PA, Mills J, Mooney J, Segelmark M, Tesar V, Westman K, Vaglio A, Yalçındağ N, Jayne DR, Mukhtyar C. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016; 75(9): 1583-94. PubMed

General References

Berden A, Göçeroglu A, Jayne D, Luqmani R, Rasmussen N, Bruijn JA, Bajema I. Diagnosis and management of ANCA associated vasculitis. BMJ. 2012; 344: e26. PubMed

Bossuyt X, Rasmussen N, van Paassen P, Hellmich B, Baslund B, Vermeersch P, Blockmans D, Tervaert JC, Csernok E, Damoiseaux J. A multicentre study to improve clinical interpretation of proteinase-3 and myeloperoxidase anti-neutrophil cytoplasmic antibodies. Rheumatology (Oxford). 2017; 56(9): 1533-1541. PubMed

Buggiani G, Krysenka A, Grazzini M, Vašků V, Hercogová J, Lotti T. Paraneoplastic vasculitis and paraneoplastic vascular syndromes. Dermatol Ther. 2010; 23(6): 597-605. PubMed

Caspary L. Vasculitides of large vessels. Vasa. 2011; 40(2): 89-98. PubMed

Chung SA, Seo P. Microscopic polyangiitis. Rheum Dis Clin North Am. 2010; 36(3): 545-58. PubMed

Damoiseaux J, Csernok E, Rasmussen N, Moosig F, van Paassen P, Baslund B, Vermeersch P, Blockmans D, Tervaert JC, Bossuyt X. Detection of antineutrophil cytoplasmic antibodies (ANCAs): a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of indirect immunofluorescence (IIF) versus antigen-specific immunoassays. Ann Rheum Dis. 2017; 76(4): 647-653. PubMed

de Souza AW, de Carvalho JF. Diagnostic and classification criteria of Takayasu arteritis. J Autoimmun. 2014; 48-49: 79-83. PubMed

Foster H, Brogan P. Paediatric Rheumatology. Foster H, Brogan PA, eds. Oxford Handbook of Paediatric Rheumatology. Oxford Specialist Handbooks in Paediatrics, PP. 168-222. Oxford, UK: Oxford University Press, 2012.

Harder N. Temporal arteritis: an approach to suspected vasculitides. Prim Care. 2010; 37(4): 757-66, vi-ii. PubMed

Harnden A, Tulloh R, Burgner D. Kawasaki disease. BMJ. 2014; 349: g5336. PubMed

Hellmark T, Segelmark M. Diagnosis and classification of Goodpasture's disease (anti-GBM). J Autoimmun. 2014; 48-49: 108-12. PubMed

Hernández-Rodríguez J, Alba MA, Prieto-González S, Cid MC. Diagnosis and classification of polyarteritis nodosa. J Autoimmun. 2014; 48-49: 84-9. PubMed

Holman RC, Belay ED, Christensen KY, Folkema AM, Steiner CA, Schonberger LB. Hospitalizations for Kawasaki syndrome among children in the United States, 1997-2007. Pediatr Infect Dis J. 2010; 29(6): 483-8. PubMed

Kallenberg CG. The diagnosis and classification of microscopic polyangiitis. J Autoimmun. 2014; 48-49: 90-3. PubMed

Kermani TA, Warrington KJ, Amin S. Malignancy risk in vasculitis. Ther Adv Musculoskelet Dis. 2011; 3(1): 55-63. PubMed

Kessel A, Vadasz Z, Toubi E. Cogan syndrome--pathogenesis, clinical variants and treatment approaches. Autoimmun Rev. 2014; 13(4-5): 351-4. PubMed

Lutalo PM, D'Cruz DP. Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis). J Autoimmun. 2014; 48-49: 94-8. PubMed

Mouthon L, Dunogue B, Guillevin L. Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named Churg-Strauss syndrome). J Autoimmun. 2014; 48-49: 99-103. PubMed

Piram M, Mahr A. Epidemiology of immunoglobulin A vasculitis (Henoch-Schönlein): current state of knowledge. Curr Opin Rheumatol. 2013; 25(2): 171-8. PubMed

Saguil A, Fargo M, Grogan S. Diagnosis and management of Kawasaki disease. Am Fam Physician. 2015; 91(6): 365-71. PubMed

Saulsbury FT. Henoch-Schönlein purpura. Curr Opin Rheumatol. 2010; 22(5): 598-602. PubMed

Sharma P, Sharma S, Baltaro R, Hurley J. Systemic vasculitis. Am Fam Physician. 2011; 83(5): 556-65. PubMed

Sinico RA, Radice A. Antineutrophil cytoplasmic antibodies (ANCA) testing: detection methods and clinical application. Clin Exp Rheumatol. 2014; 32(3 Suppl 82): S112-7. PubMed

Sánchez-Manubens J, Bou R, Anton J. Diagnosis and classification of Kawasaki disease. J Autoimmun. 2014; 48-49: 113-7. PubMed

Ting TV. Diagnosis and management of cutaneous vasculitis in children. Pediatr Clin North Am. 2014; 61(2): 321-46. PubMed

Weyand CM, Goronzy JJ. Clinical practice. Giant-cell arteritis and polymyalgia rheumatica. N Engl J Med. 2014; 371(1): 50-7. PubMed

Yang Y, Yu H, Chiang B. The diagnosis and classification of Henoch-Schönlein purpura: an updated review. Autoimmun Rev. 2014; 13(4-5): 355-8. PubMed

Testing Algorithms

Vasculitis in Adults Testing Algorithm

Read more about Vasculitis in Adults Testing Algorithm

Vasculitis in Children Testing Algorithm

Read more about Vasculitis in Children Testing Algorithm

Content Review:

October 2017

Last Update: August 2018


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