Systemic vasculitis

Systemic necrotizing vasculitis (SNV)^[1] is a category of vasculitis,^[2] comprising vasculitides that present with necrosis.^[3]

Examples include giant cell arteritis,^[4] microscopic polyangiitis, and granulomatosis with polyangiitis.

ICD-10 uses the variant "necrotizing vasculopathy". ICD-9, while classifying these conditions together, doesn't use a dedicated phrase, instead calling them "polyarteritis nodosa and allied conditions".

When using the influential classification known as the "Chapel Hill Consensus Conference", the terms "systemic vasculitis" or "primary systemic vasculitides" are commonly used.^[5][6][7] Although the word "necrotizing" is omitted, the conditions described are largely the same.

Classification

Large vessel vasculitis

Giant-cell arteritis and Takayasu's arteritis have much in common,^[8] but usually affect patients of different ages,^[9] with Takayasu's arteritis affecting younger people, and giant-cell arteritis having a later age of onset.

Aortitis can also be considered a large-vessel disease.^[10]

Takayasu arteritis. Primarily affects the aorta and its main branches. At least 3 out of 6 criteria yields sensitivity and specificity of 90.5 and 97.8%:

• onset < 40 years affects young and middle -aged women (ages 15–45)
• claudication of extremities
• decreased pulsation of one or both brachial arteries
• at least 10 mmHg systolic difference in both arms
• bruit over one or both carotid arteries or abdominal aorta
• arteriographic narrowing of aorta, its primary branches, or large arteries in upper or lower extremities
• Ocular manifestation
  • visual loss or field defects
  • Retinal hemorrhages
• Neurological abnormalitis
• Treatment: steroids

Giant cell (temporal) arteritis. Chronic vasculitis of both large and medium vessels, primarily affecting cranial branches of the arteries arising from the aortic arch. At least 3 out of 5 criteria yields sensitivity and specificity of 95 and 91%:

• Age at onset ≥ 50 years
• New onset headache with localized tenderness
• Temporal artery tenderness or decreased pulsation
• Elevated ESR ≥ 50 mm/hour Westergren
• Temporal artery biopsy showing vasculitis with mononuclear cell infiltrate or granulomatous inflammation, usually with multinucleated giant cells

Medium vessel vasculitis

These conditions are sometimes considered together with the small vessel vasculitides.^[11]

Polyarteritis nodosa (PAN). Systemic necrotizing vasculitis and aneurysm formation affecting both medium and small arteries. If only small vessels are affected, it is called microscopic polyangiitis, although it is more associated with granulomatosis with polyangiitis than to classic PAN. At least 3 out of 10 criteria yields sensitivity and specificity of 82 and 87%:

• unexplained weight loss > 4 kg
• livedo reticularis
• testicular pain
• myalgias, weakness
• Abdominal pain,diarrhea,and GI bleeding
• mononeuropathy or polyneuropathy
• new onset diastolic blood pressure > 90 mmHg
• elevated serum BUN (> 40 mg/dL) or serum creatinine (> 1.5 mg/dL)
• hepatitis B infection
• arteriographic abnormalities
• arterial biopsy showing polymorphonuclear cells

Kawasaki disease. Usually in children(age<4), it affects large, medium, and small vessels, prominently the coronary arteries. Associated with a mucocutaneous lymph node syndrome. Diagnosis requires fever lasting five days or more with at least 4 out of 5 criteria:

• bilateral conjunctival injection
• injected or fissured lips, injected pharynx, or strawberry tongue
• erythema of palms/soles, edema of hands/feet, periungual desquamation
• polymorphous rash
• cervical lymphadenopathy (at least one node > 1.5 cm)

Isolated CNS vasculitis. Affects medium and small arteries over a diffuse CNS area, without symptomatic extracranial vessel involvement. Patients have CNS symptoms as well as cerebral vasculitis by angiography and leptomeningeal biopsy.

Small vessel vasculitis

There are several vasculitides that affect small vessels.^[12]

Pauci-immune

Granulomatosis with polyangiitis (GPA; formerly known as Wegener's granulomatosis). Systemic vasculitis of medium and small arteries, including venules and arterioles. Produces granulomatous inflammation of the respiratory tracts and necrotizing, pauci-immune glomerulonephritis. Most common cause of saddle nose deformity in USA (nose flattened due to destruction of nasal septum by granulomatous inflammation). Almost all patients with WG have c-ANCA, but not vice versa. Current treatment of choice is cyclophosphamide. At least 2 out of 4 criteria yields sensitivity and specificity of 88 and 92%.

• nasal or oral inflammation (oral ulcers or purulent/bloody nasal discharge, may be painful)
• abnormal CXR showing nodules, infiltrates, cavities
• microscopic hematuria or RBC casts
• vessel biopsy shows granulomatous inflammation
• Peak incidence: ages 40–60, males > females

Eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome). Affects medium and small vessels with vascular and extravascular granulomatosis. Classically involves arteries of lungs and skin, but may be generalized. At least 4 criteria yields sensitivity and specificity of 85 and 99.7%.

• asthma (history of wheezeing or presently wheezing)
• eosinophilia > 10% on CBC
• mononeuropathy or polyneuropathy
• migratory or transient pulmonary opacities on chest x-ray (CXR)
• paranasal sinus abnormalities
• vessel biopsy showing eosinophils in extravascular areas

Microscopic polyarteritis/polyangiitis. Affects capillaries, venules, or arterioles. Thought to be part of a group that includes granulomatosis with polyangiitis since both are associated with ANCA and similar extrapulmonary manifestations. Patients do not usually have symptomatic or histologic respiratory involvement.

Immune complex

Hypersensitivity vasculitis (allergic vasculitis). Usually due to a hypersensitivity reaction to a known drug. Drugs most commonly implicated are penicillin, sulphonamides and thiazide diuretics.^[13] There is presence of skin vaculitis with palpable petechiae or purpura. Biopsy of these lesions reveal inflammation of the small vessels, termed leukocytoclastic vasculitis, which is most prominent in postcapillary venules. At least 3 out of 5 criteria yields sensitivity and specificity of 71 and 84%:

• age > 16
• use of possible triggering drug in relation to symptoms
• palpable purpura
• maculopapular rash
• skin biopsy showing neutrophils around vessel

IgA vasculitis (IgAV; formerly known as Henoch-Schonlein purpura). Systemic vasculitis due to tissue deposition of IgA-containing immune complexes. Biopsy of lesions shows inflammation of small vessels. It is considered a form of hypersensitivity vasculitis but is distinguished by prominent deposits of IgA. This is the most common vasculitis in children. Presence of 3 or more criteria yielded sensitivity of 87% while less than 2 criteria yielded hypersensitivity vasculitis in 74%:

• palpable purpura (usually of buttocks & legs)
• bowel angina
• GI bleed
• hematuria
• onset < 20 years
• no new medications

Essential cryoglobulinemic vasculitis. Most often due to hepatitis C infection, immune complexes of cryoglobulins --- proteins that consists of immunoglobulins and complement and precipitate in the cold while dissolving upon rewarming --- are deposited in walls of capillaries, venules, or arterioles. Therefore, complement will be low with histology showing vessel inflammation with immune deposits.

Other/ungrouped

Vasculitis secondary to connective tissue disorders. Usually secondary to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), relapsing polychondritis, Behçet's disease, and other connective tissue disorders.

Vasculitis secondary to viral infection. Usually due to hepatitis B and C, HIV, cytomegalovirus, Epstein-Barr virus, and Parvo B19 virus.

Symptoms and signs

Patients usually present with systemic symptoms with single or multiorgan dysfunction. Common (and nonspecific) complaints include fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction. The following symptoms should raise a strong suspicion of a vasculitis:

• Mononeuritis multiplex. Also known as asymmetric polyneuropathy, in a non-diabetic this is suggestive of vasculitis.
• Palpable purpura. If patients have this in isolation, it is most likely due to cutaneous leukocytoclastic vasculitis. If the purpura is in combination with systemic organ involvement, it is most likely to be Henoch-Schonlein purpura or microscopic polyarteritis.
• Pulmonary-renal syndrome. Individuals who are coughing up blood and have kidney involvement are likely to have granulomatosis with polyangiitis, microscopic polyangiitis, or anti-GBM disease (Goodpasture's syndrome).

Diagnosis

A detailed history is important to elicit any recent medications, any risk of hepatitis infection, or any recent diagnosis with a connective tissue disorder such as systemic lupus erythematosus (SLE). A thorough physical exam is needed as usual.

• Lab tests. Basic lab tests may include a CBC, chem-7 (look for creatinine), muscle enzyme, liver function tests, ESR, hepatitis seroloties, urinalysis, CXR, and EKG. Additional, more specific tests include:
  • Antinuclear antibody (ANA) test can detect an underlying connective tissue disorder, especially SLE
  • Complement levels that are low can suggest mixed cryoglobulinemia, hepatitis C infection, and SLE, but not most other vasculitides.
  • Antineutrophil cytoplasmic antibody (ANCA) may highly suggest granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, or drug-induced vasculitis, but is not diagnostic.
• Electromyography. It is useful if a systemic vasculitis is suspected and neuromuscular symptoms are present.
• Arteriography. Arteriograms are helpful in vasculitis affecting the large and medium vessels but not helpful in small vessel vasculitis. Angiograms of mesenteri or renal arteries in polyarteritis nodosa may show aneurysms, occlusions, and vascular wall abnormalities. Arteriography are not diagnostic in itself if other accessible areas for biopsy are present. However, in Takayasu's arteritis, where the aorta may be involved, it is unlikely a biopsy will be successful and angiography can be diagnostic.
• Tissue biopsy. This is the gold standard of diagnosis when biopsy is taken from the most involved area.

Treatment

Treatment is targeted to the underlying cause. However, most vasculitis in general are treated with steroids (e.g. methylprednisolone) because the underlying cause of the vasculitis is due to hyperactive immunological damage. Immunosuppressants such as cyclophosphamide and azathioprine may also be given.

A systematic review of antineutrophil cytoplasmic antibody (ANCA) positive vasculitis identified best treatments depending on whether the goal is to induce remission or maintenance and depending on severity of the vasculitis.^[14]

References