Systemic Vasculitis

Am Fam Physician. 2011 Mar 1;83(5):556-565.

The systemic vasculitides are characterized by inflammation of blood vessel walls. Vessels of any type, in any organ can be affected, resulting in a broad spectrum of signs and symptoms. The heterogenous nature of vasculitides presents a diagnostic challenge. The American College of Rheumatology classification criteria and the Chapel Hill Consensus Conference nomenclature are the most widely used to distinguish different forms of vasculitis. The Chapel Hill Consensus Conference nomenclature defines 10 primary vasculitides based on vessel size (large, medium, and small). The diagnosis relies on the recognition of a compatible clinical presentation supported by specific laboratory or imaging tests and confirmatory histology. Antineutrophilic cytoplasmic antibody testing has been of particular benefit in defining a subgroup of small vessel vasculitides. Treatment is based on clinical presentation and the pattern of organ involvement. Glucocorticoids are the primary treatment for many forms of vasculitis. Additional immunosuppressive agents, including methotrexate and cyclophosphamide, are sometimes required. Newer approaches, such as the use of anti-tumor necrosis factor or B cell therapies, are being tried in resistant cases. Patients can experience considerable treatment-related toxicity, especially infection from immunosuppressive therapy and adverse effects from steroids (e.g., osteoporosis, diabetes mellitus, cataract). Vitamin D and calcium prophylaxis are recommended in patients on long-term steroid therapy.

Vasculitis refers to a heterogenous group of disorders in which there is inflammation and damage in blood vessel walls, leading to tissue necrosis. These are relatively uncommon disorders, with a reported annual incidence of 40 to 54 cases per 1 million persons.1 The incidence appears to be affected by geography, age, and seasonal challenges. Vasculitis may be limited to skin or other organs, or may be a multisystem disorder with multiple manifestations.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

The American College of Rheumatology classification criteria and the Chapel Hill Consensus Conference nomenclature may be used to distinguish different forms of vasculitis.

C

26

The Birmingham Vasculitis Activity Score can be used to monitor the activity of the specific condition during treatment.

C

9

A definitive diagnosis of systemic vasculitis should be made by the presence of characteristic symptoms and signs of vasculitis and at least one of the following: histologic evidence of vasculitis, positive serology for antineutrophilic cytoplasmic antibody, or specific indirect evidence of vasculitis.

C

1016

For patients with localized and early vasculitis, treatment with steroids and methotrexate or cyclophosphamide is recommended for induction of remission.

C

1820, 23

Steroids and cyclophosphamide are recommended for initial treatment of generalized organ-threatening vasculitis.

C

1820

Patients presenting with severe life-threatening vasculitis (severe renal failure or pulmonary hemorrhage) should be treated with cyclophosphamide (pulsed intravenous or continuous oral) and steroids, with adjuvant plasma exchange.

C

1823


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

The American College of Rheumatology classification criteria and the Chapel Hill Consensus Conference nomenclature may be used to distinguish different forms of vasculitis.

C

26

The Birmingham Vasculitis Activity Score can be used to monitor the activity of the specific condition during treatment.

C

9

A definitive diagnosis of systemic vasculitis should be made by the presence of characteristic symptoms and signs of vasculitis and at least one of the following: histologic evidence of vasculitis, positive serology for antineutrophilic cytoplasmic antibody, or specific indirect evidence of vasculitis.

C

1016

For patients with localized and early vasculitis, treatment with steroids and methotrexate or cyclophosphamide is recommended for induction of remission.

C

1820, 23

Steroids and cyclophosphamide are recommended for initial treatment of generalized organ-threatening vasculitis.

C

1820

Patients presenting with severe life-threatening vasculitis (severe renal failure or pulmonary hemorrhage) should be treated with cyclophosphamide (pulsed intravenous or continuous oral) and steroids, with adjuvant plasma exchange.

C

1823


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

Classification

Numerous classifications of vasculitis have been proposed. The American College of Rheumatology has classification criteria for seven primary vasculitides: polyarteritis nodosa, Churg-Strauss syndrome, Wegener granulomatosis, hypersensitivity vasculitis, Henoch-Schönlein purpura, giant cell arteritis, and Takayasu arteritis.2 Microscopic polyangiitis is not included in the classification criteria. The American College of Rheumatology criteria were designed for research studies, but are often used for diagnosis, and do not include antineutrophilic cytoplasmic antibody (ANCA) testing for the diagnosis of small vessel vasculitis or require biopsy or angiography for vasculitis classification. The criteria have poor reliability when applied as diagnostic criteria.3

In 1994, the Chapel Hill Consensus Conference proposed a nomenclature defining 10 primary vasculitides based on vessel size (large, medium, and small; Table 1).4 The nomenclature includes microscopic polyangiitis and defines it as vasculitis involving microscopic vessels (arterioles, venules, and small capillaries). Microscopic polyangiitis is distinguished from polyarteritis nodosa by the presence of microscopic vessel involvement. Polyarteritis nodosa must have no involvement of microscopic vessels, including no glomerulonephritis. The nomenclature also stresses the importance of ANCA testing in the diagnosis of vasculitis, particularly in differentiating Wegener granulomatosis and microscopic polyangiitis in persons with pulmonary and renal involvement. The advantage of the Chapel Hill Consensus Conference nomenclature is its clarity and simplicity. However, the usefulness of this nomenclature as diagnostic criteria has been questioned.5,6

There is no recommended diagnostic standard for vasculitis. In the absence of validated diagnostic criteria, the American College of Rheumatology classification criteria and the Chapel Hill Consensus Conference nomenclature are most widely used in clinical practice to distinguish different forms of vasculitis.

Table 1.

Classification of Primary Systemic Vasculitis (Chapel Hill Consensus Conference Nomenclature)

Vasculitis Description

Small vessel

Churg-Strauss syndrome

Eosinophil-rich and granulomatous inflammation involving the respiratory tract; necrotizing vasculitis of small to medium vessels; associated with asthma

Cutaneous leukocytoclastic angiitis

Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis

Essential cryoglobulinemic vasculitis

Vasculitis, with cryoglobulin immune deposits, affecting capillaries, venules, or arterioles; associated with serum cryoglobulins; skin and glomeruli are often involved

Henoch-Schönlein purpura

Immunoglobulin A–dominant immune deposits, affecting capillaries, venules, or arterioles; typically involves skin, gut, and glomeruli; associated with arthralgias or arthritis

Microscopic polyangiitis

Necrotizing vasculitis, with few or no immune deposits, affecting capillaries, venules, or arterioles, but may involve small and medium arteries; necrotizing glomerulonephritis is very common; pulmonary capillaritis often occurs

Wegener granulomatosis

Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting capillaries, venules, arterioles, and arteries; necrotizing glomerulonephritis is common

Medium vessel

Kawasaki disease

Arteritis involving coronary arteries, but aorta and veins may be involved; associated with mucocutaneous lymph node syndrome

Polyarteritis nodosa

Necrotizing inflammation of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules

Large vessel

Giant cell (temporal) 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; associated with polymyalgia rheumatica

Takayasu arteritis

Granulomatous inflammation of the aorta and its major branches


Adpated with permission from Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):189.

Table 1.   Classification of Primary Systemic Vasculitis (Chapel Hill Consensus Conference Nomenclature)

View Table

Table 1.

Classification of Primary Systemic Vasculitis (Chapel Hill Consensus Conference Nomenclature)

Vasculitis Description

Small vessel

Churg-Strauss syndrome

Eosinophil-rich and granulomatous inflammation involving the respiratory tract; necrotizing vasculitis of small to medium vessels; associated with asthma

Cutaneous leukocytoclastic angiitis

Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis

Essential cryoglobulinemic vasculitis

Vasculitis, with cryoglobulin immune deposits, affecting capillaries, venules, or arterioles; associated with serum cryoglobulins; skin and glomeruli are often involved

Henoch-Schönlein purpura

Immunoglobulin A–dominant immune deposits, affecting capillaries, venules, or arterioles; typically involves skin, gut, and glomeruli; associated with arthralgias or arthritis

Microscopic polyangiitis

Necrotizing vasculitis, with few or no immune deposits, affecting capillaries, venules, or arterioles, but may involve small and medium arteries; necrotizing glomerulonephritis is very common; pulmonary capillaritis often occurs

Wegener granulomatosis

Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting capillaries, venules, arterioles, and arteries; necrotizing glomerulonephritis is common

Medium vessel

Kawasaki disease

Arteritis involving coronary arteries, but aorta and veins may be involved; associated with mucocutaneous lymph node syndrome

Polyarteritis nodosa

Necrotizing inflammation of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules

Large vessel

Giant cell (temporal) 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; associated with polymyalgia rheumatica

Takayasu arteritis

Granulomatous inflammation of the aorta and its major branches


Adpated with permission from Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):189.

Pathogenesis

The pathogenesis of vasculitides is poorly understood. Three possible mechanisms of vascular damage are immune complex deposition, ANCAs (humoral response), and T-lymphocyte response with granuloma formation (cell-mediated).7,8 The end result of these various pathways is endothelial cell activation, with subsequent vessel obstruction and ischemia of dependent tissue. This may cause hemorrhage in the surrounding tissues and, in some cases, weakening of the vessel wall, which leads to the formation of aneurysms. For almost all forms of vasculitis, the triggering event initiating and driving this inflammatory response is unknown. Many small vessel vasculitides have a paucity of vascular immune deposits and, therefore, other mechanisms have been sought for these so-called pauci-immune vasculitides.

Clinical Features

Patients with vasculitis typically have prodromal symptoms, constitutional disturbances, and organ-specific manifestations. Patients can present to the family physician with nonspecific signs or symptoms (e.g., fever, rash, myalgia, arthralgia, malaise, weight loss) or to the emergency department with life-threatening features (e.g., massive hemoptysis, renal failure). Manifestations vary, depending on the size, site, and extent of vessels involved. Clinical manifestations of various forms of vasculitis are discussed in Table 2.

Table 2.

Clinical Features of Major Systemic Vasculitides

Vasculitis Organ involvement Age (years) Clinical features

Small vessel

Churg-Strauss syndrome

Respiratory tract, heart

50 to 60

Allergic rhinitis, asthma, peripheral eosinophilia

Cryoglobulinemic vasculitis

Skin, kidney

40 to 50

Recurrent palpable purpura, polyarthralgia, glomerulonephritis

Cutaneous leukocytoclastic angiitis

Skin

Any age

Palpable purpura, cutaneous infarcts, necrotic papules, urticaria

Henoch-Schönlein purpura

Skin, gastrointestinal tract, kidney, joint

3 to 8

Purpura, arthritis, abdominal pain, gastrointestinal bleeding, glomerulonephritis

Microscopic polyangiitis

Skin, lung, heart, kidney, liver, gastrointestinal tract

50 to 60

Palpable purpura, pulmonary hemorrhage, glomerulonephritis

Wegener granulomatosis

Upper and lower respiratory tracts, kidney

40 to 50

Pneumonitis with bilateral nodular and cavitary infiltrates, mucosal ulceration of nasopharynx, chronic sinusitis, glomerulonephritis

Medium vessel

Kawasaki disease

Coronary arteries, aorta and its branches

2 to 4

Fever, conjunctivitis, desquamating skin rash, enlarged cervical lymph nodes

Polyarteritis nodosa

Renal and visceral organs, spares lung

30 to 40

Fever, weight loss, hypertension, abdominal pain, melena, peripheral neuritis, renal ischemia

Large vessel

Giant cell arteritis

Extracranial branches of carotid artery, often involves temporal artery

50 to 60

Fever, visual disturbances, facial pain and headache (often along the course of superficial temporal artery)

Takayasu arteritis

Aorta and its major branches

30 to 40

More common in young Asian women

Markedly lower blood pressure and weaker pulse in upper extremities, with coldness and numbness of fingers, visual disturbances, hypertension, neurologic deficit

Table 2.   Clinical Features of Major Systemic Vasculitides

View Table

Table 2.

Clinical Features of Major Systemic Vasculitides

Vasculitis Organ involvement Age (years) Clinical features

Small vessel

Churg-Strauss syndrome

Respiratory tract, heart

50 to 60

Allergic rhinitis, asthma, peripheral eosinophilia

Cryoglobulinemic vasculitis

Skin, kidney

40 to 50

Recurrent palpable purpura, polyarthralgia, glomerulonephritis

Cutaneous leukocytoclastic angiitis

Skin

Any age

Palpable purpura, cutaneous infarcts, necrotic papules, urticaria

Henoch-Schönlein purpura

Skin, gastrointestinal tract, kidney, joint

3 to 8

Purpura, arthritis, abdominal pain, gastrointestinal bleeding, glomerulonephritis

Microscopic polyangiitis

Skin, lung, heart, kidney, liver, gastrointestinal tract

50 to 60

Palpable purpura, pulmonary hemorrhage, glomerulonephritis

Wegener granulomatosis

Upper and lower respiratory tracts, kidney

40 to 50

Pneumonitis with bilateral nodular and cavitary infiltrates, mucosal ulceration of nasopharynx, chronic sinusitis, glomerulonephritis

Medium vessel

Kawasaki disease

Coronary arteries, aorta and its branches

2 to 4

Fever, conjunctivitis, desquamating skin rash, enlarged cervical lymph nodes

Polyarteritis nodosa

Renal and visceral organs, spares lung

30 to 40

Fever, weight loss, hypertension, abdominal pain, melena, peripheral neuritis, renal ischemia

Large vessel

Giant cell arteritis

Extracranial branches of carotid artery, often involves temporal artery

50 to 60

Fever, visual disturbances, facial pain and headache (often along the course of superficial temporal artery)

Takayasu arteritis

Aorta and its major branches

30 to 40

More common in young Asian women

Markedly lower blood pressure and weaker pulse in upper extremities, with coldness and numbness of fingers, visual disturbances, hypertension, neurologic deficit

The Birmingham Vasculitis Activity Score is a checklist of signs and symptoms that are consistent with the diagnosis of systemic vasculitis and can be used to monitor the activity of the specific condition during treatment (Table 3).9

Table 3.

Birmingham Vasculitis Activity Score

Feature None Active disease

General

Arthralgia or arthritis

Fever ≥ 100°F (38°C)

Myalgia

Weight loss ≥ 4 lb (2 kg)

Cutaneous

Gangrene

Infarct

Other skin vasculitis

Purpura

Ulcer

Mucous membranes/eyes

Adnexal inflammation

Blepharitis/keratitis

Blurred vision

Genital ulcers

Mouth ulcers/granulomata

Red eye conjunctivitis/retinal hemorrhages

Red eye (epi)scleritis

Retinal vasculitis

Significant proptosis

Sudden vision loss

Thrombosis/retinal exudates

Uveitis

Ears, nose, throat

Bloody nasal discharge/nasal crusts/conductive hearing loss

Paranasal sinus involvement

Sensorineural hearing loss

Subglottic stenosis

Ulcers or granulomata

Chest

Endobronchial involvement

Hemorrhage

Infiltrate

Massive hemoptysis/alveolar nodules or cavities

Pleural effusion/pleurisy

Respiratory failure

Wheeze

Cardiovascular

Cardiomyopathy

Congestive cardiac failure

Ischemic cardiac pain

Loss of pulses

Pericarditis

Valvular heart disease

Abdominal

Bloody diarrhea

Ischemic abdominal pain

Peritonitis

Renal

Creatinine 1.41 to 2.82 mg per dL (125 to 249 μmol per L)

Creatinine 2.83 to 5.64 mg per dL (250 to 499 μmol per L)

Creatinine ≥ 5.65 mg per dL (500 μmol per L)

Creatinine clearance decrease of > 25 percent

Hematuria (≥ 10 red blood cells per high-power field)

Hypertension

Proteinuria > 1+

Nervous system

Cord lesion

Cranial nerve palsy

Headache

Meningitis

Motor mononeuritis multiplex

Seizures (not hypertensive)

Sensory peripheral neuropathy

Stroke

Other

___________________

___________________

___________________

___________________

Persistent disease only All the above abnormalities are caused by low-grade disease and not new or worse disease


note: Check box only if abnormality represents active disease. If there are no abnormalities in a system, please check the “none” box. If all the abnormalities recorded represent smoldering or low-grade disease, and there are no new or worse features, check the box at the bottom right corner.

Adapted with permission from Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87(11):678.

Table 3.   Birmingham Vasculitis Activity Score

View Table

Table 3.

Birmingham Vasculitis Activity Score

Feature None Active disease

General

Arthralgia or arthritis

Fever ≥ 100°F (38°C)

Myalgia

Weight loss ≥ 4 lb (2 kg)

Cutaneous

Gangrene

Infarct

Other skin vasculitis

Purpura

Ulcer

Mucous membranes/eyes

Adnexal inflammation

Blepharitis/keratitis

Blurred vision

Genital ulcers

Mouth ulcers/granulomata

Red eye conjunctivitis/retinal hemorrhages

Red eye (epi)scleritis

Retinal vasculitis

Significant proptosis

Sudden vision loss

Thrombosis/retinal exudates

Uveitis

Ears, nose, throat

Bloody nasal discharge/nasal crusts/conductive hearing loss

Paranasal sinus involvement

Sensorineural hearing loss

Subglottic stenosis

Ulcers or granulomata

Chest

Endobronchial involvement

Hemorrhage

Infiltrate

Massive hemoptysis/alveolar nodules or cavities

Pleural effusion/pleurisy

Respiratory failure

Wheeze

Cardiovascular

Cardiomyopathy

Congestive cardiac failure

Ischemic cardiac pain

Loss of pulses

Pericarditis

Valvular heart disease

Abdominal

Bloody diarrhea

Ischemic abdominal pain

Peritonitis

Renal

Creatinine 1.41 to 2.82 mg per dL (125 to 249 μmol per L)

Creatinine 2.83 to 5.64 mg per dL (250 to 499 μmol per L)

Creatinine ≥ 5.65 mg per dL (500 μmol per L)

Creatinine clearance decrease of > 25 percent

Hematuria (≥ 10 red blood cells per high-power field)

Hypertension

Proteinuria > 1+

Nervous system

Cord lesion

Cranial nerve palsy

Headache

Meningitis

Motor mononeuritis multiplex

Seizures (not hypertensive)

Sensory peripheral neuropathy

Stroke

Other

___________________

___________________

___________________

___________________

Persistent disease only All the above abnormalities are caused by low-grade disease and not new or worse disease


note: Check box only if abnormality represents active disease. If there are no abnormalities in a system, please check the “none” box. If all the abnormalities recorded represent smoldering or low-grade disease, and there are no new or worse features, check the box at the bottom right corner.

Adapted with permission from Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87(11):678.

General Diagnostic Approach

The primary systemic vasculitides are difficult to diagnose because the clinical manifestations mimic several infectious, neoplastic, and autoimmune conditions (Table 4). Attempts should first be made to exclude the malignant and infectious processes. The patient's age, sex, and demographic or ethnic origin are also important. Finally, type and extent of organ involvement and the size of the vessels involved should be determined. Certain organ-specific symptoms, not otherwise explained, may be clues leading to a more specific diagnosis (Table 2). A definitive diagnosis of systemic vasculitis should be made by the presence of characteristic symptoms and signs of vasculitis and at least one of the following: histologic evidence of vasculitis; positive serology for ANCA; or specific indirect evidence of vasculitis.1016 It is important to ascertain that no other diagnosis accounts for the presenting symptoms and signs.

Table 4.

Selected Conditions Mimicking Primary Systemic Vasculitis

Antiphospholipid syndrome

Atheroembolic disease

Atheromatous vascular disease

Cocaine and amphetamine abuse

Hypersensitivity reactions

Infective endocarditis

Multiple myeloma

Paraneoplastic syndromes

Secondary causes of vasculitis (rheumatoid arthritis, systemic lupus erythematosus, scleroderma, hepatitis B and C infection, lymphoma, and solid organ malignancy)

Sickle cell disease

Table 4.   Selected Conditions Mimicking Primary Systemic Vasculitis

View Table

Table 4.

Selected Conditions Mimicking Primary Systemic Vasculitis

Antiphospholipid syndrome

Atheroembolic disease

Atheromatous vascular disease

Cocaine and amphetamine abuse

Hypersensitivity reactions

Infective endocarditis

Multiple myeloma

Paraneoplastic syndromes

Secondary causes of vasculitis (rheumatoid arthritis, systemic lupus erythematosus, scleroderma, hepatitis B and C infection, lymphoma, and solid organ malignancy)

Sickle cell disease

Laboratory Testing

Laboratory testing is important to determine the organs involved, to exclude other diseases, and to monitor the disease and treatment toxicity. A typical plan of investigation for a patient with vasculitis is summarized in Table 5.

Table 5.

Diagnostic and Monitoring Tests in the Evaluation of Systemic Vasculitis

Test Indication Use

Chemistry

Blood urea nitrogen, creatinine, electrolyte measurements

Proteinuria, hematuria, suspicion of glomerulonephritis

Diagnosis, disease and treatment toxicity monitoring

Liver function

Fever, fatigue, suspicion of infection, monitoring patients treated with hepatotoxic drugs (e.g., methotrexate, azathioprine [Imuran])

Diagnosis, disease and treatment toxicity monitoring

Hematology

Clotting screen

Bleeding or thrombosis

Diagnosis, disease monitoring

Complete blood count

Fever, fatigue, symptoms of bone marrow suppression

Diagnosis, disease and treatment toxicity monitoring

C-reactive protein, erythrocyte sedimentation rate

Arthralgia, fever, suspicion of giant cell arteritis

Diagnosis, disease monitoring

Imaging

Angiography

Suspicion of Takayasu arteritis, polyarteritis nodosa, or Kawasaki disease

Diagnosis, disease monitoring

Chest or organ-specific computed tomography, magnetic resonance imaging

Guided by organ-specific clinical symptoms

Chest computed tomography is diagnostic and used for monitoring of Takayasu arteritis and Kawasaki disease

Computed tomography can be used for monitoring Wegener granulomatosis

Chest radiography

Pulmonary infiltrates, nodules, patchy consolidation, pleural effusion, cardiomegaly

Diagnosis and monitoring of Wegener granulomatosis, Takayasu arteritis, Kawasaki disease

Echocardiography

Suspicion of Kawasaki disease

Diagnosis of coronary artery abnormality in Kawasaki disease

Microbiology

Hepatitis B and C serology, human immunodeficiency virus testing

Hepatitis or immunodeficiency

Diagnosis of hepatitis B virus–related polyarteritis nodosa and hepatitis C virus–related cryoglobulinemic vasculitis

Urine culture

Abnormal urinalysis

Disease monitoring

Serology

Anticardiolipin antibodies

Bleeding, thrombosis, fetal loss

Diagnosis,* disease monitoring

Antineutrophilic cytoplasmic antibodies, and if positive, specific target antigen(proteinase 3 or myeloperoxidase)

Suspicion of microscopic polyangiitis, Churg-Strauss syndrome, or Wegener granulomatosis

Diagnosis, disease monitoring

Antinuclear antibody

Arthralgia, myalgia

Diagnosis,* disease monitoring

Complement (C3 and C4)

Arthralgia, myalgia

Disease monitoring

Cryoglobulins

Purpura, arthritis, hepatitis C

Diagnosis of cryoglobulinemic vasculitis

Immunoglobulins and protein electrophoresis

Arthralgia, bone lesions, defective immune status

Diagnosis*

Rheumatoid factor

Arthralgia, myalgia

Diagnosis*

Tissue biopsy

Biopsy of involved organ or tissue

Guided by organ-specific clinical symptoms(e.g., skin, sinuses, lung, artery, nerve, kidney)

Definitive diagnosis in some vasculitides, such as Wegner granulomatosis and giant cell arteritis

Urinalysis

Analysis and microscopy

Fever, leukocytosis, suspicion of cystitis or renal involvement

Diagnosis, disease and treatment toxicity monitoring

Other

Nerve conduction test, electromyographic test

Motor and sensory neuropathy

Diagnosis, disease monitoring


*—These tests assist in differential diagnosis of vasculitis.

Table 5.   Diagnostic and Monitoring Tests in the Evaluation of Systemic Vasculitis

View Table

Table 5.

Diagnostic and Monitoring Tests in the Evaluation of Systemic Vasculitis

Test Indication Use

Chemistry

Blood urea nitrogen, creatinine, electrolyte measurements

Proteinuria, hematuria, suspicion of glomerulonephritis

Diagnosis, disease and treatment toxicity monitoring

Liver function

Fever, fatigue, suspicion of infection, monitoring patients treated with hepatotoxic drugs (e.g., methotrexate, azathioprine [Imuran])

Diagnosis, disease and treatment toxicity monitoring

Hematology

Clotting screen

Bleeding or thrombosis

Diagnosis, disease monitoring

Complete blood count

Fever, fatigue, symptoms of bone marrow suppression

Diagnosis, disease and treatment toxicity monitoring

C-reactive protein, erythrocyte sedimentation rate

Arthralgia, fever, suspicion of giant cell arteritis

Diagnosis, disease monitoring

Imaging

Angiography

Suspicion of Takayasu arteritis, polyarteritis nodosa, or Kawasaki disease

Diagnosis, disease monitoring

Chest or organ-specific computed tomography, magnetic resonance imaging

Guided by organ-specific clinical symptoms

Chest computed tomography is diagnostic and used for monitoring of Takayasu arteritis and Kawasaki disease

Computed tomography can be used for monitoring Wegener granulomatosis

Chest radiography

Pulmonary infiltrates, nodules, patchy consolidation, pleural effusion, cardiomegaly

Diagnosis and monitoring of Wegener granulomatosis, Takayasu arteritis, Kawasaki disease

Echocardiography

Suspicion of Kawasaki disease

Diagnosis of coronary artery abnormality in Kawasaki disease

Microbiology

Hepatitis B and C serology, human immunodeficiency virus testing

Hepatitis or immunodeficiency

Diagnosis of hepatitis B virus–related polyarteritis nodosa and hepatitis C virus–related cryoglobulinemic vasculitis

Urine culture

Abnormal urinalysis

Disease monitoring

Serology

Anticardiolipin antibodies

Bleeding, thrombosis, fetal loss

Diagnosis,* disease monitoring

Antineutrophilic cytoplasmic antibodies, and if positive, specific target antigen(proteinase 3 or myeloperoxidase)

Suspicion of microscopic polyangiitis, Churg-Strauss syndrome, or Wegener granulomatosis

Diagnosis, disease monitoring

Antinuclear antibody

Arthralgia, myalgia

Diagnosis,* disease monitoring

Complement (C3 and C4)

Arthralgia, myalgia

Disease monitoring

Cryoglobulins

Purpura, arthritis, hepatitis C

Diagnosis of cryoglobulinemic vasculitis

Immunoglobulins and protein electrophoresis

Arthralgia, bone lesions, defective immune status

Diagnosis*

Rheumatoid factor

Arthralgia, myalgia

Diagnosis*

Tissue biopsy

Biopsy of involved organ or tissue

Guided by organ-specific clinical symptoms(e.g., skin, sinuses, lung, artery, nerve, kidney)

Definitive diagnosis in some vasculitides, such as Wegner granulomatosis and giant cell arteritis

Urinalysis

Analysis and microscopy

Fever, leukocytosis, suspicion of cystitis or renal involvement

Diagnosis, disease and treatment toxicity monitoring

Other

Nerve conduction test, electromyographic test

Motor and sensory neuropathy

Diagnosis, disease monitoring


*—These tests assist in differential diagnosis of vasculitis.

COMPLETE BLOOD COUNT

Patients with active vasculitis often have leukocytosis, anemia, and thrombocytopenia. Eosinophilia is a prominent feature in Churg-Strauss syndrome. A complete blood count is important to look for the bone marrow suppression that may result from vasculitis treatment.

ACUTE PHASE REACTANTS

An increased erythrocyte sedimentation rate and an elevated C-reactive protein level are common in patients with vasculitis, but are nonspecific and can occur in many settings, particularly infection. A normal erythrocyte sedimentation rate and C-reactive protein level can occur in vasculitis when the disease is inactive, and should not exclude the diagnosis. In patients with giant cell arteritis, an increased erythrocyte sedimentation rate can suggest the diagnosis and can be useful for disease monitoring when combined with compatible clinical features.

RENAL FUNCTION TESTS AND URINALYSIS

Blood urea nitrogen and serum creatinine measurements should be obtained, and urinalysis should be performed in any patient with suspected vasculitis. Proteinuria and hematuria suggest the possibility of glomerulonephritis. Monitoring creatinine and the urinalysis is useful to detect changes in disease activity. It may be helpful to identify bladder toxicity in patients treated with cyclophosphamide.

LIVER FUNCTION TESTS

Serum bilirubin and liver enzyme levels (aspartate and alanine transaminase, alkaline phosphatase, γ-glutamyltransferase) can provide clues for vasculitis that affects the liver, such as polyarteritis nodosa. Serial liver function tests are also important in monitoring patients treated with hepatotoxic drugs, such as methotrexate and azathioprine (Imuran).

ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES

Serum from many patients with vasculitis shows the presence of ANCAs, which are a heterogeneous group of autoantibodies directed against enzymes found in neutrophils. There are two types of ANCAs based on indirect immunofluorescence patterns: cytoplasmic and perinuclear. The most common corresponding antigens identified by enzyme immunoassay are proteinase 3 for cytoplasmic ANCA and myeloperoxidase for perinuclear ANCA. All positive ANCA results based on immunofluorescence should be confirmed by enzyme immunoassay.10,11

The disorders characterized by circulating ANCAs are called ANCA-associated vasculitides, and include Churg-Strauss syndrome, microscopic polyangiitis, and Wegener granulomatosis. Either type of ANCA may occur in a patient with ANCA-associated small vessel vasculitis, but cytoplasmic ANCA is typically found in Wegener granulomatosis, and perinuclear ANCA is typically found in microscopic polyangiitis and Churg-Strauss syndrome. ANCAs are useful quantitative markers for these conditions, and the level reflects the degree of inflammation.12 As such, ANCAs increase during recurrence and are useful in monitoring response to treatment.13,14 Persistence of ANCAs is a predictor of poor response to treatment. Approximately 10 percent of patients with Wegener granulomatosis or microscopic polyangiitis have negative assays for ANCAs; therefore, a negative result does not completely rule out these diseases.17 In addition, ANCAs have been reported in other conditions, such as infections, inflammatory bowel disease, and drug-induced vasculitis.

Imaging

CHEST RADIOGRAPHY

Nonspecific abnormalities that can be seen on chest radiography include infiltrates, nodules, patchy consolidation, pleural effusion, and cardiomegaly. These findings can occur in many settings, but if unexplained, may raise the suspicion of vasculitis.

ANGIOGRAPHY

Angiography can show vascular occlusion and aneurysm. A diagnosis of polyarteritis nodosa can be confirmed by detection of aneurysms in mesenteric and renal arteries. Although conventional angiography is still accepted as the recommended diagnostic modality, computed tomography angiography and magnetic resonance angiography may be superior because they can provide valuable information regarding intraluminal pathology and thickening of the vessel wall. These techniques have been used for diagnosis and monitoring of Takayasu arteritis and Kawasaki disease.

ECHOCARDIOGRAPHY

Transthoracic echocardiography detects coronary artery abnormality in Kawasaki disease. Approximately 40 percent of children with Kawasaki disease have coronary artery lesions (ectasia or aneurysm) on echocardiography.15 Echocardiography is used for assessing coronary artery blood flow and the degree of coronary stenosis in patients with Takayasu arteritis.16

ULTRASONOGRAPHY

Ultrasonography may be useful for diagnosis and monitoring of large vessel vasculitis. Patients with giant cell arteritis may have stenosis, occlusion, or halo sign (a dark area around the artery from vessel wall edema) of the superficial temporal artery.

COMPUTED TOMOGRAPHY

Computed tomography is of diagnostic value in patients with sinonasal Wegener granulomatosis. Findings include thickening of nasal mucosa and punctate bony destruction, mainly in the midline. Nodules or masses can be seen on chest computed tomography in approximately 90 percent of patients with Wegener granulomatosis.18

Other Testing

NERVE CONDUCTION TESTING

Motor and sensory neuropathy can occur in the context of systemic vasculitis when the vasa nervorum are affected (e.g., polyarteritis nodosa, Wegener granulomatosis, Churg-Strauss syndrome). Nerve conduction testing should be used for the evaluation of neurologic manifestations.

TISSUE BIOPSY

The definitive diagnosis of vasculitis is established by biopsy of the involved tissue (e.g., skin, sinuses, lung, artery, nerve, kidney), which determines the pattern of vessel inflammation. The presence of immunoglobulins and complement found by immunofluorescence on the tissue section may be helpful in elucidating the specific type of vasculitis. Biopsies are particularly valuable in ruling out other causes, but a negative biopsy does not rule out vasculitis.

Treatment

The initial presentation may be to the family physician or any number of subspecialists, including a dermatologist, rheumatologist, nephrologist, otolaryngologist, or pulmonologist. Most patients are treated by a rheumatologist experienced with these diseases. The rheumatologist works with the patient's family physician, who monitors the disease progression and complications of treatment.

The treatment includes three phases: induction of remission, maintenance, and treatment of relapse. The severity and extent of the disease divides patients into three groups: those with localized or early disease, those with generalized disease with threatened organ involvement, and those with severe or life-threatening disease. For patients with localized and early disease, treatment with steroids and methotrexate or cyclophosphamide is recommended for induction of remission.1820 Methotrexate may be associated with a higher relapse rate.21,22 Evidence of relapse or disease progression despite treatment with methotrexate requires the use of cyclophosphamide. Initial treatment of generalized organ-threatening disease should include steroids and cyclophosphamide.1820 Cyclophosphamide can be administered as an intravenous infusion every two weeks (and later every three weeks), or as a daily low-dose oral treatment. There is no difference in remission rates or relapse risk between oral and intravenous regimens. Steroids are given as daily oral prednisone (1 mg per kg, up to 60 mg daily). Pulsed intravenous steroids can be given just before or with the first two intravenous pulses of cyclophosphamide. Patients presenting with severe life-threatening disease (severe renal failure or pulmonary hemorrhage) should be treated with cyclophosphamide (pulsed intravenous or continuous oral) and steroids, with adjuvant plasma exchange.19,23

Maintenance therapy with either azathioprine or methotrexate is initiated if remission has occurred after three to six months of induction therapy. Steroid dosage is tapered during this phase. Patients may need to continue maintenance treatment for up to 24 months.24 Maintenance treatment for up to five years is recommended in patients with Wegener granulomatosis and patients who remain ANCA-positive.19 Some patients may require treatment indefinitely. Disease relapse may occur anytime after the remission. Serial measurements of ANCA are not closely associated with disease activity; therefore, treatment should not be solely guided on the basis of an increase in ANCA.25 Relapsing disease can be managed with an increase in steroid dose, optimization of the current immunosuppressant, or combination of an immunosuppressant with an increased dose of steroid.

Novel biologic therapies targeted against specific components of the immune system are being used for systemic vasculitis, particularly for patients in whom conventional therapy has failed. Agents such as infliximab (Remicade; human chimeric anti-tumor necrosis factor [TNF]-α monoclonal antibody), etanercept (Enbrel; fusion protein of the p75 TNF-α receptor and immunoglobulin G1), adalimumab (Humira; fully humanized IgG1 anti-TNF-α monoclonal antibody), rituximab (Rituxan; anti-CD20 chimeric mouse/human monoclonal antibody), anakinra (Kineret; recombinant interleukin-1 receptor antagonist), and intravenous immune globulins may be used in refractory disease.26,27

Patients with systemic vasculitis are at increased risk of comorbidities resulting from disease-related end organ damage and immunosuppressive therapy. The immunosuppressive medications used for the treatment of systemic vasculitis cause serious adverse effects during the first year of therapy. Steroids and cyclophosphamide predispose patients to life-threatening infections. Cyclophosphamide can cause hemorrhagic cystitis, ovarian and testicular failure, and bladder cancer. Diagnosis and treatment of these complications are coordinated with the family physician. Recommendations regarding detecting and preventing these complications include use of mesna (Mesnex) for protecting against urothelial toxicity of cyclophosphamide, antifungal prophylaxis, prophylaxis against Pneumocystis jiroveci, consideration for Staphylococcus aureus treatment, screening for cervical malignancy, and counseling about infertility with cyclophosphamide. Adverse effects of long-term steroid use (e.g., diabetes mellitus, osteoporosis, cataract) should be assessed. Vitamin D and calcium prophylaxis are recommended in patients on long-term therapy with steroids. Table 6 summarizes the drugs and treatments for systemic vasculitis.23

Table 6.

Summary of Drugs and Treatments Used for Systemic Vasculitis

Vasculitis Drug/treatment Indication

Small vessel

Antineutrophilic cytoplasmic antibody–associated small vessel vasculitis (Churg-Strauss syndrome, microscopic polyangiitis, Wegener granulomatosis)

Prednisolone

First-line therapy in conjunction with cyclophosphamide in generalized disease; first-line therapy in localized/early disease

Methylprednisolone

Severe vasculitis with rapidly progressive glomerulonephritis

Methotrexate

First-line therapy in conjunction with steroids in localized/early disease

Cyclophosphamide

First-line therapy in generalized disease, aggressive local disease, and life-threatening disease

Plasmapheresis

Progressive severe renal disease

Intravenous immune globulin

Refractory disease

Azathioprine (Imuran)

Refractory or relapsing disease

Biologic therapy used alone or in combination with standard treatment (infliximab [Remicade], rituximab [Rituxan], antithymocyte globulin)

Refractory or relapsing disease

Intravenous immune globulin

Refractory or relapsing disease

Interferon alfa

Refractory or relapsing disease

Trimethoprim/sulfamethoxazole (Bactrim, Septra)

In conjunction with prednisolone and cyclophosphamide for Pneumocystis jiroveci

Prophylaxis

Bisphosphonate

Bone protection with long-term steroid

Cutaneous leukocytoclastic angiitis

Antihistaminics plus nonsteroidal anti-inflammatory drugs

Symptom control in absence of systemic disease

Prednisolone

Severe cutaneous or systemic disease

Essential cryoglobulinemic vasculitis

Interferon alfa plus oral ribavirin

Hepatitis C–related cryoglobulinemic vasculitis

Therapy same as antineutrophilic cytoplasmic antibody–associated vasculitis

Nonviral-related cryoglobulinemic vasculitis

Henoch-Schönlein purpura

Steroids plus cyclophosphamide

Henoch-Schönlein purpura with nephritis (most cases without renal involvement resolve spontaneously)

Medium vessel

Kawasaki disease

Intravenous immune globulin with aspirin

First-line therapy

Intravenous immune globulin plus heparin infusion

Second-line therapy in patients who do not initially respond to intravenous immune globulin and aspirin combination

Methylprednisolone followed by prednisolone

Second-line therapy

Polyarteritis nodosa

Prednisolone

First-line therapy

Methylprednisolone

Fulminant disease

Cyclophosphamide

First-line therapy (used in combination with steroids in non–hepatitis B-associated polyarteritis nodosa)

Antiviral agents (interferon alfa plus lamivudine [Epivir])

Hepatitis B–associated polyarteritis nodosa

Plasmapheresis

Hepatitis B–associated polyarteritis nodosa

Bisphosphonate

Bone protection with long-term steroid

Large vessel

Giant cell arteritis and Takayasu arteritis

Prednisolone

First-line in active Takayasu arteritis and in giant cell arteritis without eye symptoms

Methylprednisolone

Consider in giant cell arteritis with significant visual disturbance

Methotrexate

Adjunct to steroids for maintenance therapy

Reduces risk of first or second relapse

Decreased cumulative dose of steroids

Allows earlier discontinuation of steroids

Azathioprine

Adjunct to prednisolone for maintenance therapy

Bisphosphonate

Bone protection with long-term steroid

Aspirin

In conjunction with maintenance therapy for prevention of cerebrovascular and cardiovascular ischemic events


Information from reference 23.

Table 6.   Summary of Drugs and Treatments Used for Systemic Vasculitis

View Table

Table 6.

Summary of Drugs and Treatments Used for Systemic Vasculitis

Vasculitis Drug/treatment Indication

Small vessel

Antineutrophilic cytoplasmic antibody–associated small vessel vasculitis (Churg-Strauss syndrome, microscopic polyangiitis, Wegener granulomatosis)

Prednisolone

First-line therapy in conjunction with cyclophosphamide in generalized disease; first-line therapy in localized/early disease

Methylprednisolone

Severe vasculitis with rapidly progressive glomerulonephritis

Methotrexate

First-line therapy in conjunction with steroids in localized/early disease

Cyclophosphamide

First-line therapy in generalized disease, aggressive local disease, and life-threatening disease

Plasmapheresis

Progressive severe renal disease

Intravenous immune globulin

Refractory disease

Azathioprine (Imuran)

Refractory or relapsing disease

Biologic therapy used alone or in combination with standard treatment (infliximab [Remicade], rituximab [Rituxan], antithymocyte globulin)

Refractory or relapsing disease

Intravenous immune globulin

Refractory or relapsing disease

Interferon alfa

Refractory or relapsing disease

Trimethoprim/sulfamethoxazole (Bactrim, Septra)

In conjunction with prednisolone and cyclophosphamide for Pneumocystis jiroveci

Prophylaxis

Bisphosphonate

Bone protection with long-term steroid

Cutaneous leukocytoclastic angiitis

Antihistaminics plus nonsteroidal anti-inflammatory drugs

Symptom control in absence of systemic disease

Prednisolone

Severe cutaneous or systemic disease

Essential cryoglobulinemic vasculitis

Interferon alfa plus oral ribavirin

Hepatitis C–related cryoglobulinemic vasculitis

Therapy same as antineutrophilic cytoplasmic antibody–associated vasculitis

Nonviral-related cryoglobulinemic vasculitis

Henoch-Schönlein purpura

Steroids plus cyclophosphamide

Henoch-Schönlein purpura with nephritis (most cases without renal involvement resolve spontaneously)

Medium vessel

Kawasaki disease

Intravenous immune globulin with aspirin

First-line therapy

Intravenous immune globulin plus heparin infusion

Second-line therapy in patients who do not initially respond to intravenous immune globulin and aspirin combination

Methylprednisolone followed by prednisolone

Second-line therapy

Polyarteritis nodosa

Prednisolone

First-line therapy

Methylprednisolone

Fulminant disease

Cyclophosphamide

First-line therapy (used in combination with steroids in non–hepatitis B-associated polyarteritis nodosa)

Antiviral agents (interferon alfa plus lamivudine [Epivir])

Hepatitis B–associated polyarteritis nodosa

Plasmapheresis

Hepatitis B–associated polyarteritis nodosa

Bisphosphonate

Bone protection with long-term steroid

Large vessel

Giant cell arteritis and Takayasu arteritis

Prednisolone

First-line in active Takayasu arteritis and in giant cell arteritis without eye symptoms

Methylprednisolone

Consider in giant cell arteritis with significant visual disturbance

Methotrexate

Adjunct to steroids for maintenance therapy

Reduces risk of first or second relapse

Decreased cumulative dose of steroids

Allows earlier discontinuation of steroids

Azathioprine

Adjunct to prednisolone for maintenance therapy

Bisphosphonate

Bone protection with long-term steroid

Aspirin

In conjunction with maintenance therapy for prevention of cerebrovascular and cardiovascular ischemic events


Information from reference 23.

Management of systemic vasculitis is complicated. Educating patients about signs and symptoms, and monitoring typical adverse effects are helpful. Many patients will have a relatively benign, self-limited course, especially if the disease is limited to the skin; however, for patients with aggressive disease, such as ANCA-associated small vessel vasculitis, it is imperative to begin treatment without delay. The multisystem involvement in systemic vasculitis necessitates a multidisciplinary team approach to patient care. Recent advances in therapy have led to considerably better outcomes in patients with vasculitis.

The Authors

POONAM SHARMA, MBBS, is an associate professor at Creighton University Medical Center in Omaha, Neb.

SANJEEV SHARMA, MD, is an associate professor at Creighton University Medical Center.

RICHARD BALTARO, MD, is an associate professor at Creighton University Medical Center.

JOHN HURLEY, MD, is an associate professor at Creighton University Medical Center.

Address correspondence to Poonam Sharma, MBBS, Creighton University Medical Center, 601 N. 30th St., Omaha, NE 68131. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. Reinhold-Keller E, Herlyn K, Wagner-Bastmeyer R, Gross WL. Stable incidence of primary systemic vasculitides over five years: results from the German vasculitis register. Arthritis Rheum. 2005;53(1):93–99.

2. Bloch DA, Michel BA, Hunder GG, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Patients and methods. Arthritis Rheum. 1990;33(8):1068–1073.

3. Rao JK, Allen NB, Pincus T. Limitations of the 1990 American College of Rheumatology classification criteria in the diagnosis of vasculitis. Ann Intern Med. 1998;129(5):345–352.

4. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187–192.

5. Sørensen SF, Slot O, Tvede N, Petersen J. A prospective study of vasculitis patients collected in a five year period: evaluation of the Chapel Hill nomenclature. Ann Rheum Dis. 2000;59(6):478–482.

6. Basu N, Watts R, Bajema I, et al. EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis. Ann Rheum Dis. 2010;69(10):1744–1750.

7. Sneller MC, Fauci AS. Pathogenesis of vasculitis syndromes. Med Clin North Am. 1997;81(1):221–242.

8. Danila MI, Bridges SL Jr. Update on pathogenic mechanisms of systemic necrotizing vasculitis. Curr Rheumatol Rep. 2008;10(6):430–435.

9. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87(11):671–678.

10. Merkel PA, Polisson RP, Chang Y, Skates SJ, Niles JL. Prevalence of anti-neutrophil cytoplasmic antibodies in a large inception cohort of patients with connective tissue disease. Ann Intern Med. 1997;126(11):866–873.

11. Roggenbuck D, Buettner T, Hoffmann L, Schmechta H, Reinhold D, Conrad K. High-sensitivity detection of autoantibodies against proteinase-3 by a novel third-generation enzyme-linked immunosorbent assay. Ann N Y Acad Sci. 2009;1173:41–46.

12. Savige J, Pollock W, Trevisin M. What do antineutrophil cytoplasmic antibodies (ANCA) tell us? Best Pract Res Clin Rheumatol. 2005;19(2):263–276.

13. Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med. 2005;143(9):621–631.

14. Pagnoux C, Hogan SL, Chin H, et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum. 2008;58(9):2908–2918.

15. Baer AZ, Rubin LG, Shapiro CA, et al. Prevalence of coronary artery lesions on the initial echocardiogram in Kawasaki syndrome. Arch Pediatr Adolesc Med. 2006;160(7):686–690.

16. Espinola-Zavaleta N, Soto ME, Bauk L, et al. Coronary reserve in Takayasu's arteritis: transesophageal echocardiographic analysis. Echocardiography. 2005;22(7):593–598.

17. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med. 1997;337(21):1512–1523.

18. Nataraja A, Mukhtyar C, Hellmich B, Langford C, Luqmani R. Outpatient assessment of systemic vasculitis. Best Pract Res Clin Rheumatol. 2007;21(4):713–732.

19. Lapraik C, Watts R, Bacon P, et al.; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology (Oxford). 2007;46(10):1615–1616.

20. Yazici Y. Systemic vasculitis treatment and monitoring update, 2008. Bull NYU Hosp Jt Dis. 2008;66(3):228–230.

21. Metzler C, Miehle N, Manger K, et al.; German Network of Rheumatic Diseases. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis. Rheumatology (Oxford). 2007;46(7):1087–1091.

22. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52(8):2461–2469.

23. Chan M, Luqmani R. Pharmacotherapy of vasculitis. Expert Opin Pharmacother. 2009;10(8):1273–1289.

24. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005;352(4):351–361.

25. Stegeman CA. Predictive value of antineutrophil cytoplasmic antibodies in small-vessel vasculitis: is the glass half full or half empty? J Rheumatol. 2005;32(11):2075–2077.

26. Langford CA. Drug insight: anti-tumor necrosis factor therapies for the vasculitic diseases. Nat Clin Pract Rheumatol. 2008;4(7):364–370.

27. Eleftheriou D, Melo M, Marks SD, et al. Biologic therapy in primary systemic vasculitis of the young. Rheumatology (Oxford). 2009;48(8):978–986.


Copyright © 2011 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions


Article Tools

  • Download PDF
  • Print page
  • Share this page
  • AFP CME Quiz

Information From Industry

More in Pubmed

Navigate this Article