AUTHOR INFORMATION	Section 1 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Author: Christine Hom, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Rheumatology, New York Medical College

Christine Hom, MD, is a member of the following medical societies: American College of Rheumatology, American Medical Association, and Arthritis Foundation

Editor(s): Barry L Myones, MD, Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital at Houston; Associate Professor, Departments of Pediatrics & Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Thomas JA Lehman, MD, Clinical Professor of Pediatrics, Weill-Cornell University; Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Hospital for Special Surgery; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Norman T Ilowite, MD, Professor of Pediatrics, Albert Einstein College of Medicine; Chief, Department of Pediatrics, Division of Rheumatology, Schneider Children's Hospital

Disclosure

	INTRODUCTION	Section 2 of 11
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Background: Vasculitis is a descriptive term associated with a heterogeneous group of diseases that results in inflammation of blood vessels. Arteries and veins of any size in any organ may be affected, leading to ischemic damage to organs. The pattern of vessel involvement is highly variable, leading to innumerable clinical presentations. The most common vasculitides of childhood are Henoch-Schönlein purpura and Kawasaki disease. See articles on Kawasaki Disease, Infantile Polyarteritis Nodosa, Polyarteritis Nodosa, and Takayasu Arteritis.

For the clinician, diagnosing the cause of vasculitis is a difficult task that involves distinguishing disease entities with possibly overlapping clinical presentations. Classification criteria have been established for a number of distinct clinical syndromes, but these are less useful in making a diagnosis in patients who do not meet all the criteria of any one disease. While groups of patients with unifying features can be identified, a patient with vasculitis often presents initially with nonspecific constitutional findings. Diagnosis may not be made until more specific organ involvement occurs. Making a diagnosis in a patient with vasculitis is an evolving process because later organ system involvement may suggest revision of the initial diagnosis. Diagnosis must be flexible, following the course of the illness over time.

Primary systemic vasculitis is relatively rare, so the physician must eliminate other known causes of vasculitis, including infection, malignancy, collagen vascular disease, hypocomplementemic urticarial vasculitis, drug hypersensitivity, inflammatory bowel disease, and sarcoidosis. Many other infectious and inflammatory conditions mimic the signs and symptoms of vasculitis and must be ruled out.

Consider vasculitis in patients with constitutional symptoms in conjunction with multisystem disease, palpable purpura, unexplained neurologic symptoms, decreased pulses, bruits, or elevated inflammatory indices. Conversely, physical findings may be scant, without explanation for the presenting symptoms. A high index of suspicion may lead to early and aggressive treatment, with better outcomes for previously fatal diseases.

Various classification schemes for vasculitis have been proposed, most recently by an international consensus conference in Chapel Hill, North Carolina in 1994. This classification is as follows:

• Large-sized vessel vasculitis
  • Temporal arteritis - Granulomatous arteritis of the aorta and major branches, especially the extracranial branches of the carotid artery that usually occurs in patients older than 50 years

  • Takayasu arteritis - Granulomatous arteritis of the aorta and major branches that usually occurs in patients younger than 50 years

• Medium-sized vessel vasculitis
  • Polyarteritis nodosa - Necrotizing vasculitis of medium- or small-sized arteries without involvement of large arteries, veins, or venules; renal involvement without glomerulonephritis

  • Kawasaki disease - Medium- and small-sized arteritis of childhood associated with mucocutaneous lymph node syndrome; most commonly affects coronary arteries, although veins and aorta may be involved (Lesions of the aorta have been found on autopsy.)

• Small-sized vessel vasculitis
  • Wegener granulomatosis - Granulomatous inflammation of small- to medium-sized vessels involving the respiratory tract; necrotizing glomerulonephritis common

  • Churg-Strauss syndrome - Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis of small- to medium-sized vessels; associated with asthma and eosinophilia (Under the classification of the American College of Rheumatology and traditional classifications, Wegener granulomatosis and Churg-Strauss syndrome are grouped together with polyarteritis nodosa under medium-sized vessel vasculitis.)

  • Microscopic polyangiitis (MPA) - Pauci-immune necrotizing vasculitis involving small- and medium-sized vessels; necrotizing glomerulonephritis common; pulmonary capillaritis frequent

  • Henoch-Schönlein purpura: Small-vessel vasculitis with immunoglobulin A (IgA) immune deposits; involvement of skin, gut, and glomeruli typical; associated with arthritis or arthralgia

  • Essential cryoglobulinemic vasculitis - Vasculitis with cryoglobulin immune deposits affecting arterioles and venules; associated with serum cryoglobulins; skin and glomeruli often involved

  • Cutaneous leukocytoclastic vasculitis - Isolated cutaneous vasculitis without systemic vasculitis or glomerulonephritis

  • Possible thrombophlebitis, or superficial venous thrombosis - Resulting from vasculitic lesions with endothelial activation; in children, more often due to hypercoagulable states or catheter instrumentation

A practical, more comprehensive classification was proposed by Lie in 1994:

Primary vasculitides

• Affecting large, medium, and small blood vessels
  • Takayasu arteritis

  • Temporal arteritis

  • Isolated angiitis of the central nervous system

• Affecting medium and small blood vessels
  • Polyarteritis nodosa

  • Churg-Strauss syndrome

  • Wegener granulomatosis

• Affecting small vessels
  • Microscopic polyangiitis

  • Henoch-Schönlein purpura

  • Cutaneous leukocytoclastic angiitis

• Miscellaneous conditions
  • Buerger disease

  • Cogan syndrome

  • Kawasaki disease

Secondary vasculitides

• Infection-related vasculitis

• Vasculitis secondary to connective tissue disease

• Drug hypersensitivity-related vasculitis

• Vasculitis secondary to mixed essential cryoglobulinemia

• Malignancy-related vasculitis

• Hypocomplementemic urticaria vasculitis

• Post organ transplant vasculitis

• Pseudovasculitic syndromes (myxoma, endocarditis, Sneddon syndrome)

Pathophysiology: Because the vasculitides comprise a group of different diseases, no single disease process explains the common final pathway of vessel wall inflammation. Immune complex disease, antibody-dependent cellular cytotoxicity (ADCC), endothelial activation, and coagulopathy have been invoked in models of inflammatory disease of the vasculature.

In immune complex disease, small (19S) immune complexes reach the vessel wall through increased vascular permeability and are deposited in the wall where Fc portions of immunoglobulin G (IgG) and immunoglobulin M (IgM) activate complement and initiate T- and B-cell responses with cytokine activation and recruitment of neutrophils. Levels of interferon-alpha and interleukin-2 (IL-2) are highly elevated in patients with polyarteritis nodosa. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta are moderately elevated in polyarteritis nodosa.

In antibody-mediated disease, endothelial cell cytolysis follows binding of specific antibodies to granulocytic cells with subsequent activation of natural killer cells. B cells may also play a role; patients with Wegener granulomatosis had increased levels of B-cell activating factor of the TNF family (BAFF); levels decreased with treatment to control levels. B-cell targeted therapies have been used anecdotally in treatment of Wegener granulomatosis; an NIH funded randomized controlled trial of rituximab (anti-CD20) is in progress.

Antineutrophil cytoplasmic antibodies (ANCAs) have been implicated as pathogenic in Wegener granulomatosis, MPA, and polyarteritis nodosa. These antibodies, directed against proteins in the cytoplasm, were first described in 1985. In vitro, ANCAs activate neutrophils with up-regulation of adhesion molecules. The activated neutrophils adhere to endothelium and stimulate lysis of endothelial cells in the presence of TNF-alpha. Activated neutrophils express membrane-bound proteinase 3 (PR3; normally a cytosolic protein), the target antigen of cytoplasmic pattern ANCA (c-ANCA). Perinuclear ANCAs (p-ANCAs) are directed against myeloperoxidase, as well as other antigens, including elastase and lactoferrin. ANCAs identify a subset of small-vessel vasculitis with pulmonary and renal disease with poorer prognosis; rapidly rising ANCA titers have been associated with disease flare. ANCAs bind to membrane PR3 and trigger degranulation of neutrophils, endothelial cell injury, and necrotizing vasculitis with granuloma formation.

Antiendothelial cell antibodies (AECAs) are found in primary vasculitis, as well as in infection-related vasculitis, so they are not helpful in differentiating primary vasculitis. In vitro, these antibodies demonstrate complement-dependent cytotoxicity against endothelial cells. The antibodies may play a role in vascular damage as an end pathway in multiple vasculitis syndromes. Bound to endothelial cells, AECAs may also potentiate injury by neutrophils via Fc receptor binding on neutrophils.

The endothelium plays an active role in physiologic function, controlling vascular permeability and cell-adhesion molecules. In addition, the endothelium secretes a large range of proinflammatory cytokines, including prostaglandins, nitric oxide, adenosine nucleotides, and platelet-activating factor, in response to cellular injury. Endothelium can also be stimulated to express major histocompatibility complex II (MHC II) molecules and can present antigen to T cells with subsequent proliferation of T-cell populations.

Superantigen-mediated activation of B-cell subsets has been proposed as a mechanism for Kawasaki disease. The seasonal pattern of Kawasaki disease suggests an infectious etiology; a vigorous IgA response in the respiratory tract and medium vessels of patients with Kawasaki disease suggests a respiratory pathogen. Parvovirus B19, Chlamydia pneumoniae, Epstein-Barr virus, and toxin-producing staphylococcal or streptococcal infections have been proposed as putative etiologic agents but have not been substantiated. Most recently, a New Haven coronavirus has been associated with Kawasaki disease (8/11 vs 1/22 controls positive for PCR), but only 1/48 patients with Kawasaki disease tested positive for the coronavirus on nasopharyngeal swab in a subsequent series.

In thrombophlebitis, a complex interaction of endothelial activation, thrombogenic nidus, and hypercoagulability leads to thrombosis and vessel inflammation.

Frequency:

• In the US: Henoch-Schönlein purpura occurs in 10,000 children per year, with an estimated incidence of 13.5 cases per 100,000 children. Kawasaki disease occurs in 1-3 per 10,000 children. Takayasu arteritis occurs much less frequently, with a total incidence of 2.6 cases per million people. Polyarteritis nodosa has a reported incidence of 0.7 cases per 100,000 people. Wegener granulomatosis is similarly rare, with an incidence of 1-3 cases per 100,000 adults.

• Internationally: In Japan, Kawasaki disease occurs in as many as 1 in 1000 children younger than 5 years.

  In the United Kingdom, the annual incidence of MPA is 3.6 cases per million population; incidence of polyarteritis nodosa is 2.4 cases per million population. The combined annual incidence of MPA and polyarteritis nodosa in Kuwait is reported as 45 cases per million population.

Mortality/Morbidity: Morbidity and mortality of these syndromes is highly variable, from the self-limited course of uncomplicated Henoch-Schönlein purpura to fulminant Wegener granulomatosis. Overall, morbidity and mortality are determined by the extent of end-organ renal, pulmonary, cardiac, or CNS disease and ischemic disease caused by thrombosis. Children with renal and pulmonary involvement have a poorer outcome.

Aggressive early treatment is essential in a number of vasculitis syndromes. Untreated, Wegener granulomatosis carries a 100% mortality rate with a mean survival time of 5 months. Treatment of Wegener granulomatosis has resulted in an 87% remission rate, but with a 53% relapse rate. In a 1998 series by Valentini, renal failure occurred in only one seventh (14%) of pediatric patients treated with cyclophosphamide and corticosteroids for ANCA-positive glomerulonephritis. In patients with polyarteritis nodosa, the mortality rate at 5 years decreased from 85% to 20% with cytotoxic and glucocorticoid therapy. Most deaths due to uncontrolled vasculitis occur in the first 6 months. Additional morbidity and, ultimately, mortality occurs because of cytotoxic and immunosuppressive therapies used to control the disease.

In contrast, cutaneous polyarteritis nodosa is a relapsing and often painful disease limited to the skin with nodules or ulceration, and prognosis is excellent.

Patients with vasculitis secondary to hepatitis B become chronic viral carriers, and many progress to hepatic cirrhosis and esophageal varices.

Venous thrombophlebitis may lead to chronic vasculopathy, known as postphlebitic syndrome, with venous insufficiency, swelling, pain, and ulceration.

Race: The vasculitides are observed in people of all races and ethnicities, but they are not equally distributed. Children of Japanese descent have a higher incidence of Kawasaki disease. Young women of Japanese and Indian descent are affected more often with Takayasu arteritis. Non-Hispanic whites living in Turkey and other areas of the Middle East have an increased incidence of Behçet disease.

Sex:

• Henoch-Schönlein purpura - Male-to-female ratio of 1.5:1

• Kawasaki disease - Male-to-female ratio of 1.5:1

• Polyarteritis nodosa - Male-to-female ratio of up to 2:1 (some demonstrate no preponderance)
  
  
• Takayasu arteritis - Primarily affects adolescent and young adult females, with a male-to-female ratio of 1:8
  
  
• Wegener granulomatosis - Male-to-female ratio of 2:1

Age:

• Henoch-Schönlein purpura: Peak age of onset is 5-15 years.

• Kawasaki disease: Mean age of onset is 1.5 years. Eighty percent of cases occur in children younger than 5 years.

• Polyarteritis nodosa: Peak age of onset is 40-60 years.
  
  
• Takayasu arteritis: Peak age of onset is 20-30 years. Twenty percent of patients are aged 19 years or younger.
  
  
• Wegener granulomatosis: Peak age of onset is 40-50 years. Only 1-3% of cases occur in people younger than 20 years.

	CLINICAL	Section 3 of 11
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History: Obtain a comprehensive history and full review of systems in all patients in whom vasculitis is suspected. The complete clinical picture often suggests the diagnosis. History should address any medications or herbal remedies, recent or recurrent upper respiratory illness, rashes, skin ulcerations, constitutional symptoms, and central and peripheral neurologic symptoms. Also seek other conditions, such as asthma, anemia, malignancy, and inflammatory bowel disease. Family history may help to identify patients with coagulopathy, antiphospholipid antibody syndrome, or other autoimmune diseases.

Classification criteria for vasculitis have been established by the American College of Rheumatology. These clinical guidelines are not meant for diagnostic purposes but are used to define uniform and distinct patient groups for definition and analysis of study populations for clinical research studies and treatment protocols.

Clinical information for several vasculitides is provided below:

• Henoch-Schönlein purpura: Up to 50% of patients may report a history of preceding upper respiratory tract infection or pharyngitis. The triad of abdominal pain, palpable purpura, and periarticular inflammation, swelling, or both may be incomplete at presentation. Abdominal symptoms include severe colicky abdominal pain, nausea, vomiting, and hematochezia or diarrhea. The initial presentation of rash may be a bluish discoloration of the ankles, urticaria, or a maculopapular rash before progressing to the characteristic palpable purpura. Nephritis is a late finding, but if present initially, it portends a worse renal outcome. American College of Rheumatology criteria include the following:

• Palpable purpura

• Age of onset younger than 20 years

• Abdominal pain or bowel angina

• Positive wall granulocytes on biopsy sample of arteriole or venule

• Kawasaki disease: Diagnosis requires high fever for more than 5 days and 4 out of the 5 criteria below. Additional findings include history of irritable behavior, hydrops of the gallbladder, myocarditis, and coronary artery aneurysms. In the presence of aneurysms, diagnosis may be made at day 4 of fever.

• Polymorphous rash

• Enlarged cervical lymph node

• Mucous membrane changes (eg, erythema, swelling, crusting) of the lips, oropharynx, or both

• Nonpurulent conjunctivitis

• Peripheral extremity changes (eg, erythema, edema, desquamation)

• Takayasu arteritis: The presence of 3 out of the 6 American College of Rheumatology criteria provide 90% sensitivity and 97.8% specificity. Criteria are as follows:

• Extremity claudications, especially the upper extremities

• Age younger than 40 years

• Decreased brachial artery pulses

• Blood pressure difference greater than 10 mm Hg in the arms

• Abnormal findings on arteriography

• Bruit over subclavian artery or aorta

• Other frequent findings - Fever, weight loss, abdominal pain

• Polyarteritis nodosa

• American College of Rheumatology criteria include the following:
  • Weight loss of more than 4 kg

  • Livedo reticularis

  • Testicular tenderness

  • Myalgias or arthralgias

  • Mononeuropathy or polyneuropathy

  • Diastolic blood pressure greater than 90 mm Hg

  • Elevated BUN or creatinine

  • Hepatitis B infection

  • Abnormal findings on arteriography

  • Positive polymorphonuclear lymphocytes on artery biopsy

  • 3 of 10 criteria provide 82.2% sensitivity and 86.6% specificity

• Renal involvement without glomerulonephritis is present. A cutaneous form is limited to the skin only and has an excellent prognosis. In addition, criteria for the diagnosis of polyarteritis nodosa in children were proposed by Ozen et al in 1992 (these have not been validated). The presence of 5 of the minor criteria and 1 major criterion is proposed to be highly suggestive of polyarteritis nodosa in children, and therapy should be instituted pending other diagnostic procedures. Major criteria include musculoskeletal or renal involvement. Minor criteria include the following:
  • Cutaneous findings

  • Gastrointestinal involvement

  • Peripheral neuropathy

  • Central nervous system involvement

  • Hypertension

  • Cardiac involvement

  • Lung involvement

  • Constitutional symptoms

  • Presence of acute-phase reactants

  • Presence of hepatitis B surface antigen

• Wegener granulomatosis: Patients have fever, weight loss, recurrent sinusitis, pneumonias, cough, and hemoptysis. Pulmonary nodules or cavities are found. Glomerulonephritis and renal insufficiency are frequent. Additional symptoms may include saddle-nose deformity or other cartilaginous destruction, proptosis, and painful oral lesions. A strong association with c-ANCA (anti-PR3) exists. The presence of 2 of the 4 American College of Rheumatology criteria yields 88% sensitivity and 92% specificity. Criteria include the following:

• Nasal or oral inflammation

• Abnormal findings with fixed infiltrates on chest radiography

• Microhematuria

• Granulomatous inflammation of artery wall biopsy

• Churg-Strauss disease: Asthma or atopic diathesis is always present first. In adults, the onset of asthma is late, occurring at age 30 years, in contrast to children. Fever, weight loss, myalgia, and skin lesions are observed. Serum eosinophilia is above 1500/mm³. When renal lesions are present, they usually consist of glomerulonephritis and hypertension. The presence of 4 of the 6 American College of Rheumatology criteria yields 85% sensitivity and 99.7% specificity. Criteria include the following:

• Asthma

• Eosinophilia

• Mononeuropathy or polyneuropathy

• Migratory or transitory pulmonary infiltrates

• Paranasal sinus pain or tenderness

• Extravascular eosinophilia

• MPA: Patients present with fever, rash, weight loss, glomerulonephritis, and pulmonary capillaritis. A strong association with p-ANCA (anti-MPO) exists.

• Essential cryoglobulinemia: Essential cryoglobulinemia is associated with fever, skin abscesses, arthralgias, myalgias, and Raynaud syndrome, Sjögren syndrome, or both. Glomerulonephritis and peripheral neuropathy are frequent. Type I is associated with such malignancies as Waldenström macroglobulinemia or multiple myeloma. Type II is essential, and type III is polyclonal and associated with hepatitis C infection.

• Behçet syndrome: This syndrome is associated with oral ulcerations, genital ulcerations, uveitis, erythema nodosum, papulopustular lesions, arthritis, and pulmonary artery aneurysms.

Physical: A careful complete examination is required when a vasculitis is suspected.

• Constitutional symptoms

• Fever

• Hypertension

• Blood pressure difference between arms greater than 30 mm Hg

• Head, ears, eyes, nose, and throat (HEENT) findings

• Conjunctivitis

• Chemosis

• Proptosis

• Saddle-nose deformity

• Paranasal sinus tenderness

• Painful aphthous ulcers

• Palatal ulcerations

• Cheilosis

• Injected swollen lips

• Strawberry tongue

• Hearing loss

• Chest findings

• Wheezing

• Stridor or decreased breath sounds

• Cardiovascular manifestations

• Bruits over subclavian vessels or aorta

• Diminished or absent pulses

• Abdominal findings

• Abdominal tenderness

• Hypoactive bowel sounds

• Dermal manifestations

• Palpable purpura

• Erythema nodosum

• Tender subcutaneous nodules

• Livedo reticularis

• Digital ulcers or peripheral gangrene

• Genital ulcerations

• Musculoskeletal manifestations - Arthritis or periarthritis and muscle pain, especially bilateral calf pain

• Findings on examination of the extremities

• Pedal edema

• Decreased pulses

• Neurologic manifestations

• Peripheral neuropathy, especially sensory

• Mononeuritis multiplex, common

• Cranial nerve palsies, common

• Localizing neurologic findings suggesting central nervous system lesions due to thrombosis or hemorrhage

• Irritability typical in Kawasaki disease

• Funduscopic examination findings

• Cotton-wool exudates (cytoid bodies)

• Retinal hemorrhages

• Optic atrophy

• Anterior or posterior uveitis

• Genital manifestations
  • Testicular swelling and pain

  • Vaginal ulcers or scars of old ulcers

Causes:

• Examples of infectious causes of vasculitis include the following:

• Syphilitic aortitis

• Lemierre syndrome (internal jugular vein thrombosis complicating pharyngeal infection)

• Pylephlebitis (mesenteric vein thrombosis associated with appendicitis or appendiceal abscess)

• Viral etiologies, such as hepatitis B and C, HIV, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Parvovirus B19

• Vasculitis also occurs secondary to the following:

• Malignancy

• Polyarticular and systemic juvenile rheumatoid arthritis

• Systemic lupus erythematosus

• Sjögren syndrome

• Drug reactions

• Inflammatory bowel disease

• Polyposis

• Sarcoidosis

• Juvenile dermatomyositis

	DIFFERENTIALS	Section 4 of 11
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Anti-GBM Antibody Disease
Antiphospholipid Antibody Syndrome
Behcet Syndrome
Coronary Artery Anomalies
Endocarditis, Bacterial
Endocarditis, Fungal
Goodpasture Syndrome
Hematuria
Hepatitis B
Hepatitis C
Infantile Polyarteritis Nodosa
Kawasaki Disease
Mixed Connective Tissue Disease
Polyarteritis Nodosa
Proteinuria
Sarcoidosis
Sjogren Syndrome
Systemic Lupus Erythematosus
Takayasu Arteritis
Thrombasthenia
Thromboembolism
Weber-Christian Disease
Wegener Granulomatosis

Other Problems to be Considered:

Atrial myxoma
Atrial thrombus
Churg-Strauss disease
Cogan syndrome
Erythema nodosum
Henoch-Schönlein purpura
Lemierre syndrome
Mucha-Habermann syndrome
MPA
Panniculitis
Rheumatoid vasculitis
Thrombophlebitis
Glomerulonephritis