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Overview of Vasculitis

by Carmen E. Gota, MD

Vasculitis is inflammation of blood vessels, often with ischemia, necrosis, and organ inflammation. Vasculitis can affect any blood vessel—arteries, arterioles, veins, venules, or capillaries. Clinical manifestations of specific vasculitic disorders are diverse and depend on the size and location of the involved vessels and the degree of the organ dysfunction and inflammation.

Etiology

Vasculitis may be primary or secondary. Primary vasculitis results from an inflammatory response that targets the vessel walls and has no known cause. Secondary vasculitis may be triggered by an infection, a drug, or a toxin or may occur as part of another inflammatory disorder or cancer.

Pathophysiology

Histologic description of an affected vessel should include the following:

  • A description of vessel wall damage (eg, type and location of inflammatory infiltrate, extent and type of damage, presence or absence of fibrinoid necrosis)

  • A description of healing responses (eg, intimal hypertrophy, fibrosis)

Certain features (eg, predominant inflammatory cells, location of inflammation) suggest particular vasculitic processes and may aid in the diagnosis (see Histologic Clues to Diagnosis of Vasculitic Disorders). For example, in many acute lesions, the predominant inflammatory cells are PMNs; in chronic lesions, lymphocytes predominate.

Inflammation may be segmental or involve the entire vessel. At sites of inflammation, varying degrees of cellular inflammation and necrosis or scarring occur in one or more layers of the vessel wall. Inflammation in the media of a muscular artery tends to destroy the internal elastic lamina.

Leukocytoclastic vasculitis is a histopathologic term used to describe findings in small-vessel vasculitis. It refers to breakdown of inflammatory cells that leaves small nuclear fragments (nuclear debris) in and around the vessels. Inflammation is transmural and nongranulomatous. PMNs predominate early; later, lymphocytes predominate. Resolution of the inflammation tends to result in fibrosis and intimal hypertrophy. Intimal hypertrophy or secondary clot formation can narrow the vessel lumen and cause tissue ischemia or necrosis.

Histologic Clues to Diagnosis of Vasculitic Disorders

Findings

Possible Diagnoses

Predominantly nonnecrotizing granulomatous inflammatory infiltrate with lymphocytes, macrophages, and multinucleated giant cells

Giant cell arteritis

Primary angiitis of the CNS (certain types)

Takayasu arteritis

Fibrinoid vascular necrosis of the vessel wall with a mixed infiltrate consisting of various combinations of leukocytes and lymphocytes

EGPA (formerly Churg-Strauss syndrome)

GPA (formerly Wegener granulomatosis)

Immune complex–associated vasculitis

Microscopic polyangiitis

Polyarteritis nodosa

RA

IgA deposits*

Immunoglobulin A–associated vasculitis (formerly Henoch-Schönlein purpura)

Scant or complete absence of immunoglobulins and complement deposition in the vessel walls* ,†

EGPA

GPA

Microscopic polyangiitis

*These findings are detected using immunofluorescence staining.

Disorders thus characterized are called pauci-immune vasculitic disorders.

EGPA = eosinophilic granulomatosis with polyangiitis; GPA = granulomatosis with polyangiitis.

Classification

Vasculitic disorders can be classified according to the size of the predominant vessel affected. However, there is often substantial overlap (see Classification of Vasculitic Disorders).

Classification of Vasculitic Disorders

Size of Affected Vessels

Disorders

Symptoms and Signs

Large

Behçet syndrome

Giant cell arteritis

Polymyalgia rheumatica

Takayasu arteritis

Limb claudication

Unequal BP measurements or unequal pulse strength/absent pulse in the limbs

CNS ischemic symptoms (eg, strokes)

Medium

Cutaneous vasculitis

Polyarteritis nodosa

Symptoms of tissue infarction in affected organs, such as

  • Muscles: Myalgias

  • Nerves: Mononeuritis multiplex

  • GI tract: Mesenteric ischemia

  • Kidneys: New-onset hypertension

  • Skin: Ulcers, nodules, and livedo reticularis

Small

Eosinophilic granulomatosis with polyangiitis (formerly called Churg-Strauss syndrome)

Cyroglobulinemic vasculitis

Granulomatosis with polyangiitis (formerly called Wegener granulomatosis)

Immunoglobulin A–associated vasculitis (formerly called Henoch-Schönlein purpura)

Microscopic polyangiitis

Small-vessel cutaneous vasculitis

Symptoms of tissue infarction in affected organs similar to those for medium-sized vessels, except skin lesions more likely to be purpuric

Symptoms and Signs

Size of the affected vessels helps determine clinical presentation (see Classification of Vasculitic Disorders).

Regardless of the size of the vessels involved, patients can present with symptoms and signs of systemic inflammation (eg, fever, night sweats, fatigue, anorexia, weight loss, arthralgias, arthritis). Some manifestations are life- or organ-threatening and require immediate treatment. They include alveolar hemorrhage, rapidly progressive glomerulonephritis, mesenteric ischemia, and vision loss in patients with giant cell arteritis. Small- and medium-sized vasculitides often manifest with skin lesions such as palpable purpura, urticaria, ulcers, livedo reticularis, and nodules.

Diagnosis

  • Clinical evaluation

  • Basic laboratory tests to detect inflammation or organ dysfunction (eg, CBC, ESR or C-reactive protein, serum albumin and total protein, AST and ALT, BUN and creatinine, urinalysis)

  • Laboratory tests to diagnose the type of vasculitis (eg, antineutrophil cytoplasmic antibodies [ANCA])

  • Laboratory and imaging studies that determine the cause of vasculitis and extent of organ involvement

  • Biopsy

Systemic vasculitis is suspected in patients with the following:

  • Symptoms or signs suggestive of vasculitis (eg, temporal headache and jaw claudication suggesting giant cell arteritis)

  • Ischemic manifestations (eg, ischemic stroke, limb claudication, mesenteric ischemia) out of proportion to a patient's risk factors for atherosclerosis

  • Unexplained combinations of symptoms in more than one organ system that are compatible with vasculitis (eg, hypertension, myalgias), particularly when symptoms of a systemic illness are present

Primary vasculitic disorders are diagnosed based on the presence of characteristic symptoms, physical findings, compatible laboratory test results, and exclusion of other causes (ie, secondary vasculitis). Histologic examination is done whenever possible and may point to a particular vasculitic disorder (see Histologic Clues to Diagnosis of Vasculitic Disorders).

Routine laboratory tests are done first. Most results are nonspecific but can help support the diagnosis. Tests usually include CBC, ESR or C-reactive protein, serum albumin and total protein, AST, and ALT. Often, patients present with elevated ESR or C-reactive protein, anemia due to chronic inflammation, elevated platelets, and low serum albumin. Freshly voided urine must be tested for RBCs, RBC casts, and protein to identify renal involvement. Serum creatinine levels should be checked and monitored. Leukopenia and thrombocytopenia are not typical of vasculitis and suggest an alternate diagnosis.

Detection of ANCA may support the diagnosis of granulomatosis with polyangiitis (GPA—formerly known as Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA—formerly known as Churg-Strauss syndrome), or microscopic polyangiitis (sometimes called collectively ANCA-associated vasculitides). Standardized tests for ANCA include immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Immunofluorescence staining of ethanol-fixed neutrophils can detect the cytoplasmic pattern of c-ANCA or the perinuclear pattern of p-ANCA. Then ELISA is used to check for antibodies specific for the major autoantigens: proteinase-3 (PR3), which produces the c-ANCA staining pattern, or myeloperoxidase (MPO), which produces the p-ANCA staining pattern seen on ethanol-fixed neutrophils. Because ANCA-associated vasculitides are rare, ANCA testing should be done only when the pretest probability for ANCA-associated vasculitis is at least moderately high.

Other useful laboratory tests include hepatitis B and C serologic testing, serum and urine protein electrophoresis, antinuclear antibody and anti-extractable nuclear antigens panel, testing for the presence of cryoglobulins, and complement levels to diagnose viral vasculitis, cryoglobulinemic vasculitis, lymphoproliferative disorders, or vasculitis secondary to other autoimmune diseases.

Further testing is determined by clinical findings. If indicated based on clinical findings, a chest x-ray should be done to check for infiltrates, but high-resolution noncontrast CT of the chest may be needed to check for subtle findings, such as small nodules or cavities. Bilateral diffuse infiltrates suggest possible alveolar hemorrhage, which requires immediate diagnosis and treatment. Other imaging tests may be required. For example, magnetic resonance angiography of large blood vessels and the aorta is useful for diagnosis and monitoring when such vessels appear affected. If symptoms suggest mononeuritis multiplex, electromyography may be helpful.

Because vasculitic disorders are rare and treatment may have severe adverse effects, tissue biopsy is done to confirm the diagnosis whenever possible. Clinical findings suggest the best site for biopsy. Biopsy results are most likely to be positive if taken from affected lung, skin, and kidney tissue. Blind biopsies of organs without clinical manifestations or laboratory suggestion of involvement have a low likelihood of providing positive results.

Treatment

  • Induction of remission for life- or organ-threatening vasculitis with corticosteroids plus cyclophosphamide or rituximab

  • Induction of remission for less severe vasculitis with corticosteroids plus a less potent immunosuppressant (eg, methotrexate, azathioprine, mycophenolate mofetil) or rituximab

  • Maintenance of remission with methotrexate, azathioprine, or rituximab, plus tapering of corticosteroids

Treatment depends on the etiology and extent and severity of disease. For secondary vasculitic disorders, removing the cause (eg, infection, drug, cancer) can help.

For primary vasculitic disorders, treatment aims to induce and maintain remission. Remission is induced by using cytotoxic immunosuppressants and high-dose corticosteroids, usually for 3 to 6 mo, until remission occurs or disease activity is acceptably reduced. The duration of remission is hard to predict and may depend on the type of vasculitis. For many patients, maintaining remission requires continuation of immunosuppressive therapy with or without a low dose of corticosteroids. During this period, the goal is to eliminate corticosteroids or reduce their dose and to use less potent (and less toxic) immunosuppressants as long as needed.

Induction of remission

For less severe forms of vasculitis, low doses of corticosteroids and less potent immunosuppressants (eg, methotrexate, azathioprine, mycophenolate mofetil) or rituximab may be used.

Severe, rapidly progressive and life- or organ-threatening vasculitis (eg, causing alveolar hemorrhage, rapidly progressive glomerulonephritis, or mesenteric ischemia) is a medical emergency requiring hospital admission and immediate treatment. Treatment typically consists of the following:

  • Corticosteroids: High-dose corticosteroids (also called pulse corticosteroids) are often prescribed. Methylprednisolone 15 mg/kg or 1 g IV once/day for 3 days may be used, followed by 1 mg/kg prednisone or methylprednisolone po once/day for about 4 wk. The dose is then tapered slowly, as tolerated, usually by 10 mg every week to 40 mg/day, by 5 mg every 2 wk to 20 mg/day, by 2.5 mg every 2 wk to 10 mg/day, and by 1 mg every month from there on until the drug is stopped. Changes in this tapering schedule may be necessary if the patient fails to improve or relapses.

  • Cyclophosphamide: A dose of 2 mg/kg po once/day is usually recommended for at least 3 mo or until remission occurs. The WBC count must be closely monitored, and the dose must be adjusted to avoid leukopenia. (WBC count should be maintained at > 3500/µL.) Less often, a higher dose IV cyclophosphamide regimen of 0.5 to 1 g/m2 at 2- to 4-wk intervals is used. The dose should be reduced in patients with significant renal insufficiency, and WBC counts should be monitored frequently. Patients taking cyclophosphamide should also be given prophylactic treatment against Pneumocystis jirovecii.

  • Mesna: Mesna is mixed with IV cyclophosphamide to bind acrolein, a product of cyclophosphamide degradation that is toxic to the bladder epithelium and can lead to hemorrhagic cystitis and sometimes transitional cell carcinoma of the bladder. Long-term use of cyclophosphamide increases the risk of bladder cancer. One milligram of mesna is added for each milligram of cyclophosphamide. Recurrence of hematuria, especially without casts and dysmorphic red cells, should prompt a referral for urologic evaluation. Cystoscopy and renal imaging should be done to exclude cancer.

  • Rituximab: Rituximab, a B cell-depleting anti-CD20 monoclonal antibody, has been shown to be noninferior to cyclophosphamide in inducing remission of severe ANCA-associated vasculitis. Rituximab is given as 375 mg/m 2 IV once/wk for 4 wk. A widely used alternative regimen is two 1000-mg infusions given 2 wk apart.

Remission maintenance

Corticosteroids are tapered to zero or to the lowest dose that can maintain remission. Usually, weekly methotrexate (with folate) or daily azathioprine is prescribed to replace cyclophosphamide because these drugs have a better adverse effects profile. Periodic IV rituximab may also be used to maintain remission. The duration of this treatment varies, from one year to several years, depending on the patient, specific diagnosis, and propensity for relapse. Patients with frequent relapses may need to take immunosuppressants indefinitely.

Long-term use of corticosteroids can have significant adverse effects. Patients who are taking such therapy should be given Ca and vitamin D supplements and bisphosphonates to help prevent or minimize osteoporosis; bone density should be monitored.

Key Points

  • Vasculitis can be a primary disorder or secondary to other causes.

  • Clinical manifestations can be systemic and/or organ-specific, depending on how vessels are affected.

  • Vasculitis tends to affect small-, medium-, or large-sized vessels, each with certain patterns of organ involvement.

  • Do blood tests, imaging studies, and tissue biopsy as indicated to determine the cause of vasculitis (including disorders such as infections and cancer) and extent of organ involvement.

  • Treat with corticosteroids and immunosuppressants.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CYTOXAN (LYOPHILIZED)
  • IMURAN
  • RITUXAN
  • OTREXUP
  • MEDROL
  • MESNEX
  • RAYOS

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