Systemic Vasculitis
Kitty Kelly
Diagnostic clues to this confusing array of diseases
Thomas M. Bush, MD
VOL 103 / NO 2 / FEBRUARY 1998 / POSTGRADUATE MEDICINE
Preview: Systemic vasculitis can be difficult to recognize because of
the many types of the disease and the conditions that can mimic it.
However, early identification and initiation of treatment (often
empirical) are important to avoid severe morbidity. In this symposium
article, Dr Bush clearly describes the most common types of vasculitis
according to current nomenclature based on the size of affected vessels.
Illustrations of common signs of the various types of vasculitis are
also included.
Systemic vasculitides are characterized by aberrant immune responses
that result in inflammation and necrosis of blood vessels. The immune
dysfunction may be triggered by infection, autoimmune disease, or
exposure to a drug; often the cause is unknown. The categorization of
vasculitis by the size of the involved blood vessels is a useful guide
to diagnosis and therapy(1-3) (table 1). The most recent nomenclature
for vasculitis was developed by a multispecialty panel at the Chapel
Hill Consensus Conference on the Nomenclature of Systemic Vasculitis
(3).
This article presents a review of the chief types of vasculitis with an
emphasis on important diagnostic features.
Table 1. Classification of systemic vasculitis
Small vessels
Leukocytoclastic angiitis
Schönlein-Henoch purpura
Mixed cryoglobulinemia
Small to medium vessels
Wegener's granulomatosis
Churg-Strauss syndrome
Microscopic polyangiitis
Medium vessels
Polyarteritis nodosa
Kawasaki syndrome
Large vessels
Temporal arteritis
Takayasu's arteritis
Vasculitis related to connective tissue disease
Diagnostic clues
Vasculitis should be suspected in any patient presenting with a
multisystem disease that is not readily explained by an infectious or
malignant process. The challenge of diagnosis is heightened by the
rarity of the various types of vasculitis: Estimated incidences range
from 4 cases per million for Wegener's granulomatosis to 170 per million
for giant cell arteritis (4).
Hallmarks of vasculitis include renal dysfunction, skin rashes (palpable
purpura, necrotic ulcers), and neurologic involvement, especially
footdrop and wristdrop (figure 1: not shown). Malaise, arthralgia, and
anemia are also common.
Before workup for vasculitis is initiated, consideration should be given
to conditions that may mimic vasculitis (table 2) (5). Also,
antiphospholipid antibody syndrome should be considered in patients who
have a history of venous or arterial thrombi, thrombocytopenia, or
multiple miscarriages.
Table 2. Conditions that may mimic systemic vasculitis
Drug exposure
Cocaine
Amphetamines
Antibiotics
Ergotamine derivatives
Infections
HIV
Subacute bacterial endocarditis
Malignant disease
Cardiac myxoma
Cholesterol emboli
Antiphospholipid antibody syndrome
Initial evaluation in patients in whom vasculitis is suspected should
include a detailed history of drug exposures and risk factors for
hepatitis B, hepatitis C, and HIV infection. In addition, identification
of an underlying rheumatic disease (eg, rheumatoid arthritis, systemic
lupus erythematosus) may have important therapeutic implications. Some
clinical features, such as fever and renal disease, are common to both
systemic lupus erythematosus and systemic vasculitis.
However, systemic lupus erythematosus usually can be distinguished by a
history of pleuritis or pericarditis or the presence of a positive
antinuclear antibody response, malar rash, photosensitivity, or
polyarthritis.
Small-vessel vasculitis
Small-vessel vasculitis typically involves the venules, capillaries, and
arterioles located in the skin, kidneys, and gastrointestinal tract (6).
The hallmark of the disease is palpable purpura, a slightly raised,
nonblanching eruption that usually begins in the lower extremities
(figure 2: not shown). Occasionally, the rash is vesicular or slightly
ulcerated. Skin biopsy reveals a leukocytoclastic vasculitis
characterized by disruption of the postcapillary venule walls with
nuclear debris from polymorphonuclear cells, fibrinoid necrosis, and
extravasation of red blood cells.
An experienced clinician can identify palpable purpura on visual
examination, although skin biopsy may be useful when the diagnosis is
uncertain. Renal manifestations include proteinuria and renal
insufficiency. Colicky abdominal pain or melena may develop in patients
with gastrointestinal disease.
Patients should undergo evaluation for a drug exposure or an underlying
infection or malignant disease. Many drugs have been reported to cause
palpable purpura, most commonly antibiotics (penicillins, sulfa drugs),
anticonvulsants, isoniazid (Laniazid, Nydrazid), and cardiac
medications. Typical infectious agents include streptococcus and
viruses.
Occasionally, an underlying malignancy or collagen vascular disease is
implicated. All patients should undergo a complete physical examination
and urinalysis, and a chest film and blood cultures should be obtained.
More extensive evaluation may be indicated in patients with history or
physical examination findings suggestive of underlying disease.
Most patients do not need treatment, because small-vessel vasculitis is
usually self-limited. Occasionally, however, the disease is persistent
or progressive. Patients should undergo serial examination of the urine
and the abdomen to detect development of renal or intestinal
involvement. Therapy with prednisone and other immunosuppressant
medications may be indicated in patients with significant renal or
gastrointestinal manifestations.
Two types of small-vessel vasculitis warrant special attention:
Schönlein-Henoch purpura and mixed cryoglobulinemia.
Schönlein-Henoch purpura is common in children after a viral or
streptococcal upper respiratory tract infection, often with coincident
antibiotic exposure (7). Pathologic specimens of involved blood vessels
reveal IgA-dominant immune complex deposition. Patients present with
lower extremity purpura, arthralgia, and abdominal pain. Mild renal
involvement develops in 40% of patients and progresses to chronic
nephritis in 10%.
Most cases remit spontaneously and do not require immunosuppressive
therapy.
Over the last decade a link has been discovered between cryoglobulinemia
and hepatitis C (8). Cryoglobulins are antigen-antibody complexes that
precipitate in the cold. They can be detected in various chronic
inflammatory conditions (eg, in 36% of cases of hepatitis C (9).
Occasionally, patients with cryoglobulins have a syndrome of palpable
purpura that includes arthralgia, nephritis, and hepatitis in 60% of
cases. In some patients, the syndrome may progress to life-threatening
renal or pulmonary disease.
A previous therapeutic approach involving immunosuppression and
plasmapheresis was only temporarily effective. Current trials with
antiviral agents such as interferon alfa-2b (Intron-A) have been more
successful. Testing for hepatitis C should be considered in all patients
with palpable purpura. If the result is positive, they should undergo
evaluation for cryoglobulinemia. Patients with progressive disease may
be candidates for interferon alfa-2b therapy.
Small- to medium-vessel vasculitis
Another group of vasculitides affects small to medium vessels of the
skin, upper respiratory tract, lungs, and kidneys.
Included in this group are Wegener's granulomatosis, Churg-Strauss
syndrome, and microscopic polyangiitis.
Wegener's granulomatosis
Wegener's granulomatosis involves vessels of the upper respiratory
tract, lungs, and kidneys (10). Initial symptoms are often common and
seemingly benign. Sinusitis, nasal ulcers, otitis media, or hearing loss
occurs initially in 70% of patients. Eye disease (eg, conjunctivitis,
scleritis, proptosis) is seen in 50% of patients. Wegener's
granulomatosis is usually recognized after pulmonary and renal disease
has become apparent.
Pulmonary infiltrates or nodules, or both, develop in 85% of patients.
Eighty percent of patients have a focal necrotizing glomerulonephritis
that can rapidly progress to renal failure.
Traditionally, the diagnosis has been established on the basis of tissue
examination. Pathologic findings include a necrotizing vasculitis of
medium-sized arteries with associated extravascular granulomas. Open
lung biopsy, the most definitive diagnostic test, reveals positive
findings in 90% of cases (10).
Transbronchial lung biopsy has a lower yield. Sinus biopsies are
diagnostic in only 30% of cases because inflammatory findings are
nonspecific. Renal biopsy is also relatively nonspecific.
Antineutrophil cytoplasmic antibodies (ANCA) develop in more than 90% of
patients with Wegener's granulomatosis (11). Cytoplasmic (c) ANCA are
present in 80% of cases and perinuclear (p) ANCA in 20%. c-ANCA are
antibodies to proteinase-3, and p-ANCA are antibodies to
myeloperoxidase, lactoferrin, and elastase, the proinflammatory enzymes
found in neutrophils. Release of these enzymes after exposure to ANCA
may result in local tissue necrosis. Although a tissue biopsy is usually
obtained to confirm the diagnosis of Wegener's granulomatosis, some
clinicians may choose to forego the procedure in patients with a classic
presentation and positive c-ANCA titers.
Therapy for Wegener's granulomatosis consists of prednisone, 1 mg/kg per
day, and cyclophosphamide (Cytoxan, Neosar), 2 mg/kg per day. Prednisone
therapy is tapered rapidly over the first few months, and
cyclophosphamide is gradually tapered after 1 year in patients with no
disease activity. The 1-year mortality rate is 90% without therapy, 50%
with corticosteroid therapy, and 10% with combined corticosteroid and
cytotoxic therapy. Methotrexate (Folex, Rheumatrex Dose Pack) may have a
role as a less toxic replacement for cyclophosphamide in patients with a
stable disease course (12).
Churg-Strauss syndrome
Onset of this eosinophilic vasculitis is usually preceded by severe
allergic rhinitis and asthma (13). Patients present with eosinophilia
and lung or gastrointestinal tract involvement. Palpable purpura and
skin nodules are present in 75% of cases, and cardiac, neurologic, or
mild renal involvement is found in 50%. The diagnosis is established on
the basis of biopsy of involved organs. Pathologic findings include
panarteritis with eosinophilic infiltrates and extravascular granulomas
consisting of eosinophils and giant cells. In addition to prednisone,
cytotoxic agents are needed in many patients to control the vasculitis.
Microscopic polyangiitis
This vasculitis involves small to medium vessels in the skin, lungs,
gastrointestinal tract, and kidneys (14). Patients commonly present with
palpable purpura, hemoptysis, abdominal pain, or renal insufficiency.
Microscopic polyangiitis lacks the immune complex deposition in the
blood vessels seen in
Schönlein-Henoch purpura and the upper airway involvement and
granulomas present in Wegener's granulomatosis. Also, unlike in
polyarteritis nodosa, no aneurysms are detected on angiography. The
diagnosis is confirmed on biopsy of the involved organ. Half of patients
have positive titers of ANCA (of both the c-ANCA and p-ANCA type).
Treatment of microscopic polyangiitis is the same as that of Wegener's
granulomatosis, and patient prognosis in the two diseases is similar.
Medium-vessel vasculitis
Two types of vasculitis affect medium-sized arteries: Polyarteritis
nodosa can affect the kidneys, intestines, and peripheral nerves, while
Kawasaki syndrome primarily involves the coronary arteries.
Polyarteritis nodosa
This potentially lethal necrotizing vasculitis can be difficult to
diagnose (15). Patients usually have an elevated erythrocyte
sedimentation rate and a history of subacute fever, myalgia, and
arthralgia. Renal disease develops in 60% of patients, and cardiac or
gastrointestinal involvement that can progress to heart failure or bowel
necrosis in 40% (16).
Peripheral neuropathy, occasionally with footdrop or wristdrop from
mononeuritis multiplex, occurs in 60%. Lesions of the eye, testicle,
lung, or central nervous system are present in 20% of patients.
Occasionally, a necrotic skin ulcer or gangrene of the digits develops.
Evaluation of polyarteritis nodosa usually requires an invasive
procedure (17). Arteriography or biopsy is needed to verify the
diagnosis. An arteriogram of the abdominal vessels shows multiple
aneurysms, beading, or tapering of vessels in about 60% of patients. One
drawback of arteriography is the increased risk of contrast-induced
acute renal failure in patients with renal insufficiency.
Compared with arteriography, tissue biopsy is more specific for
polyarteritis nodosa but often less sensitive because of the patchy
distribution of lesions. Tissue biopsies reveal panarteritis involving
focal destruction of the walls of small to medium arteries, fibrinoid
necrosis, and gradual healing accompanied by fibrosis.
Biopsy of the gastrocnemius muscle (figure 5) and the sural nerve is
positive in 60% of patients with peripheral neuropathy or myopathy but
in only 30% of those with no overt neuromuscular disease.
Electromyography and nerve conduction velocity study of the lower
extremities are advisable when polyarteritis nodosa is first suspected.
If results of these studies are abnormal, biopsy of the gastrocnemius
muscle and sural nerve would be the next best step. If the results are
normal, angiography or biopsy of other involved organs is advised.
Renal, gastrointestinal, or testicular biopsies are occasionally
warranted in symptomatic patients.
Antinuclear antibody response is usually negative in patients with
polyarteritis nodosa. p-ANCA is positive in 20% of patients and c-ANCA
in 10%. An association with hepatitis B has been reported in 6% to 30%
of cases (4). Prognosis for this subset of patients is worse than for
those without hepatitis B-associated disease.
Therapy consists of high-dose prednisone (1 mg/kg per day) given for 1
to 2 months, then gradually tapered. Patients with life-threatening
disease should also be given cyclophosphamide (2 mg/kg per day). The
dose can be tapered after 1 year of quiescent disease. Historically, the
5-year survival rate is 12% without therapy, 48% with corticosteroid
treatment, and 80% with combined corticosteroid and cytotoxic
therapy.(16)
Plasma exchange accompanied by therapy with vidarabine (Vira-A) and
interferon alfa-2b is useful in patients with hepatitis B-associated
disease (18).
Kawasaki syndrome
Kawasaki syndrome is a febrile illness generally seen in children under
the age of 5 years (19). The first 1 to 2 weeks of illness are
characterized by bilateral conjunctival injection; dry, fissured lips; a
strawberry-colored tongue; and edema or erythema of the hands and feet.
A truncal rash and lymphadenopathy also may develop--hence the
descriptive name "mucocutaneous lymph node syndrome." The initial
symptoms clear after several weeks and are sometimes followed by
arthritis and desquamation of the hands and feet. Coronary arteritis,
which can lead to fatal myocardial infarction, may develop late in 25%
of patients who go untreated.
The cause of Kawasaki syndrome is not clear. On the basis of clinical
and epidemiologic factors, many investigators have suspected infection,
but no causative agent has been identified. Aspirin and high-dose
intravenous immunoglobulin are effective for reducing acute symptoms as
well as risk of subsequent coronary arteritis.
Large-vessel vasculitis
Large vessels are involved in two types of vasculitis: Temporal
arteritis affects the extracranial, ophthalmic, and aortic arch vessels
(20), and Takayasu's arteritis affects vessels of the aortic arch and
its branches (21).
Temporal arteritis
Almost all patients with temporal arteritis are over the age of 50
years, and more than 90% have a markedly elevated erythrocyte
sedimentation rate.(22) A history of temporal or occipital headache is
common. Visual loss due to central retinal artery occlusion, anterior
ischemic optic retinitis, or occipital cortex infarction develops in up
to 36% of patients. When loss of vision occurs in one eye, the patient
has a 27% risk of loss in the other eye. Jaw claudication or ischemia of
the tongue is seen in 30% of patients.
Claudication of the upper extremities occasionally develops as a result
of involvement of the aortic arch and its branches. Temporal arteritis
is accompanied by polymyalgia rheumatica in one half of cases. Affected
patients have aching and stiffness in the shoulder and limb girdles
without demonstrable weakness or an elevated creatine kinase level.
When temporal arteritis is suspected, high doses of prednisone should be
given immediately to prevent visual loss. All patients should undergo a
temporal artery biopsy involving excision and careful inspection of at
least 4 cm of artery. Results are positive in about 90% (22).
Many experts recommend biopsy of the opposite temporal artery if results
of the initial biopsy are negative. Sections of the temporal artery
reveal lymphocytic infiltrate with giant cells in the media and
adventitia and with fragmentation of the internal elastic lamina.
Initial treatment with prednisone, 1 mg/kg per day, can be tapered to
about 15 mg/day after 4 to 6 weeks in patients in stable condition. The
dose can be subsequently decreased by 1 mg/month in asymptomatic
patients. Monitoring for recurrence of symptoms or marked elevation of
erythrocyte sedimentation rate is important during therapy.
Occasionally, treatment with methotrexate or azathioprine (Imuran) in
addition to prednisone is needed.
Takayasu's arteritis
This disease usually affects women 20 to 30 years of age. Early
manifestations include malaise, arthralgia, and myalgia and an elevated
erythrocyte sedimentation rate. Later in the course of disease, patients
often present with claudication or hypertension but few inflammatory
symptoms. Bruits and an absence of peripheral pulses are noted on
physical examination (hence the term "pulseless disease").
The diagnosis is established on the basis of an angiogram showing
arterial cutoffs and stenosis of major branches of the aorta. All
hypertensive patients should be aggressively treated with calcium
channel blockers or angiotensin-converting enzyme inhibitors. Prednisone
(30 to 60 mg/day) is given to suppress inflammation when the erythrocyte
sedimentation rate is elevated or progressive vascular disease is
present. Methotrexate (7.5 to 15 mg given once weekly) is effective in
patients who have an incomplete response to prednisone (23).
Surgical revascularization may be necessary in patients with
renovascular hypertension or ischemic symptoms. Percutaneous
transluminal angioplasty has been successfully used to open occluded
vessels (24). Long-term symptomatic relief and graft patency have been
reported with graft bypass of arterial occlusions or aneurysms (25).
Vasculitis related to connective tissue disease
Vasculitis affecting small, medium, or large vessels occasionally
develops in patients with systemic lupus erythematosus, rheumatoid
arthritis, or Sjögren's syndrome. Prompt identification of the
underlying connective tissue disease expedites the workup for vasculitis
and allows exclusion of other diagnostic considerations (eg, infection,
malignant disease). Treatment is similar to that for other types of
vasculitis, but long-term immunosuppressive therapy for the underlying
connective tissue disease may also be required.
Conclusion
Systemic vasculitides can be highly morbid, even fatal, and often
require risky diagnostic and therapeutic interventions. The various
types of vasculitis may present with a myriad of clinical findings.
Initial evaluation is often directed at more common infectious or
neoplastic conditions. Once vasculitis is suspected, evaluation must be
expedient and therapy often empirical until results of diagnostic tests
are available.
Primary care physicians have a crucial role in diagnosis and treatment
of vasculitis. They may be the first to recognize early warning signs
(eg, headache, unexplained malaise, anemia). Prompt consultation with a
rheumatologist is generally warranted to assist in thorough diagnostic
workup and initiation of therapy. Primary care physicians also have an
essential role in long-term management. Careful monitoring is needed to
manage secondary complications, such as hypertension and chronic renal
failure. In addition, close observation for an extended period after
discontinuation of treatment is necessary to detect recurrence.
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Dr. Bush is chief, division of rheumatology, Santa Clara Valley Medical
Center, San Jose, and clinical associate professor of medicine, Stanford
University School of Medicine, Stanford, California. Correspondence:
Thomas M. Bush, MD, Department of Medicine, Santa Clara Valley Medical
Center, 750 S Bascom Ave, San Jose, CA 95128.
Copyright (C) 1998. The McGraw-Hill Companies. All Rights Reserved