SYSTEMIC VASCULITIS
Vasculitis is a nonspecific term that encompasses a large and heterogeneous
group of disorders that are characterized by inflammation of blood vessels. The term
"systemic necrotizing vasculitis" describes a systemic process in which blood vessel
architecture has been destroyed by inflammatory cells.
As described by Mandell and Hoffman,1 vasculitis-induced injury to blood vessels
may lead to increased vascular permeability, vessel weakening that causes aneurysm
formation or hemorrhage, and intimal proliferation and thrombosis that result in
obstruction and local ischemia. Because systemic vasculitis can affect vessels of all
sizes and distributions, it has a wide spectrum of clinical features. Knowing the size
of the vessels affected in a particular patient is important, since vessel size carries
implications for the diagnosis, treatment and prognosis of the disease.
It is critical to distinguish vasculitis occurring as a primary autoimmune
disorder from vasculitis secondary to infection, drugs, malignancy or
connective tissue disease such as systemic lupus erythematosus (SLE) or
rheumatoid arthritis. Immunosuppressive therapy, which is sometimes used
in the treatment of certain types of vasculitis, can have catastrophic
consequences in the face of a systemic infection, as can delayed or
inappropriate treatment of primary systemic vasculitis. Consequently, much
of the diagnostic work-up in a patient with suspected vasculitis is directed at
excluding secondary causes or conditions that can mimic vasculitis. When
systemic vasculitis is suspected, the first step in the evaluation is to exclude
other processes such as infection, thrombosis or neoplasia.
Classification of Vasculitis
Vasculitis may be classified by the size and type of vessel involvement, by the
histopathologic features (leukocytoclastic, granulomatous vasculitis, etc.) or by the
pattern of clinical features.
Identifying the type of vasculitis is important, since certain types may be selflimited, whereas others may require corticosteroid therapy, with or without a
cytotoxic agent, or other modalities such as plasmapheresis. Initially in the work-up,
however, determining the extent of visceral organ involvement is more important
than identifying the type of vasculitis, so that organs at risk of damage are not
jeopardized if treatment is delayed or inadequate.
The clinical features of primary vasculitis syndromes often overlap, and many
patients do not fit neatly into a well-defined type of vasculitis. These patients may be
described as having "undifferentiated systemic vasculitis." Such cases require close
follow-up, looking for signs of involvement in other organs or signs that may lead to
a specific diagnosis.
Clinical Features and Primary Treatment of the Major Systemic Vasculitis
Syndromes
Systemic vasculitis Common presenting
syndrome
features
Vasculitis of small
vessels
Hypersensitivity
Palpable purpura
vasculitis
Henoch-Schönlein Palpable purpura,
purpura
arthritis,
glomerulonephritis,
intestinal ischemia
Cryoglobulinemia Arthritis, Raynaud's
phenomenon,
glomerulonephritis,
palpable purpura
Vasculitis of small
and medium-sized
vessels
Polyarteritis
Peripheral neuropathy,
nodosa
mononeuritis multiplex,
intestinal ischemia, renal
ischemia, testicular pain,
livedo reticularis
Microscopic
Pulmonary hemorrhage,
polyangiitis
glomerulonephritis
Primary treatment
Often self-limited if
offending agent is removed.
If isolated to skin, may not
require therapy. In more
severe cases, moderate- to
high-dose corticosteroid
therapy may be needed.
Often self-limited and
requires no treatment.
Steroid therapy for some
cases of gastrointestinal or
renal involvement.
Corticosteroids;
plasmapheresis for severe
involvement. Antiviral
therapy required if
associated with hepatitis C.
High-dose corticosteroids,
often with cytotoxic agents
(e.g., cyclophosphamide
[Cytoxan])
High-dose corticosteroids,
often with cytotoxic agents
(e.g., cyclophosphamide)
Churg-Strauss
vasculitis
Wegener's
granulomatosis
Kawasaki disease
Allergic rhinitis, asthma,
eosinophilia, pulmonary
infiltrates, coronary
arteritis, intestinal
ischemia
Recurrent epistaxis or
sinusitis, pulmonary
infiltrates and/or
nodules,
glomerulonephritis,
ocular involvement
Fever, conjunctivitis,
lymphadenopathy,
desquamating rash,
mucositis, arthritis,
coronary artery
aneurysms
High-dose corticosteroids,
often with cytotoxic agents
(e.g., cyclophosphamide)
High-dose corticosteroids
and cyclophosphamide.
Corticosteroids and
methotrexate may be used
for less severe involvement.
High-dose aspirin and
intravenous immune
globulin
Vasculitis of large
vessels
Giant cell, or
Headache, polymyalgia High-dose corticosteroids
temporal, arteritis rheumatica, jaw or
tongue claudication,
scalp tenderness, fever,
vision disturbances
Takayasu's arteritis Extremity claudication, High-dose corticosteroids
athralgias, constitutional
symptoms, renal
ischemia
When to Suspect Systemic Vasculitis
In particular, two types of presentation should alert the clinician to the possibility
of systemic vasculitis: unexplained ischemia, such as claudication, limb ischemia,
angina, transient ischemic attack, stroke, mesenteric ischemia and cutaneous
ischemia, particularly in a young patient or a patient without risk factors for
atherosclerosis and multiple organ dysfunction in a systemically ill patient, especially
in the presence of other suggestive clinical features.
Clinical Features That Raise Suspicion of Vasculiti
General clinical
feature
Signs or presenting
disorder
Constitutional
symptoms
Polymyalgia
rheumatica
Type of vasculitis
Fever, fatigue, malaise,
Any type of vasculitis
anorexia, weight loss
Proximal muscle pain with Giant cell arteritis; less
morning stiffness
commonly, other
vasculitides
Nondestructive
Joint swelling, warmth,
Polyarteritis, Wegener's
oligoarthritis
painful range of motion
granulomatosis, ChurgStrauss vasculitis
Skin lesions
Livedo reticularis, necrotic Polyarteritis, Churglesions, ulcers, nodules,
Strauss vasculitis,
digital tip infarcts
Wegener's
granulomatosis,
hypersensitivity vasculitis
Palpable purpura
Any type of vasculitis
except giant cell arteritis
and Takayasu's arteritis
Multiple
Injury to two or more
Polyarteritis, Churgmononeuropathy separate peripheral nerves Strauss vasculitis,
(mononeuritis
(e.g., patient presents with Wegener's
multiplex)
both right foot drop and granulomatosis,
left wrist drop)
cryoglobulinemia
Renal involvement Ischemic renal failure
Polyarteritis, Takayasu's
related to arteritis
arteritis; less commonly,
Churg-Strauss vasculitis
and Wegener's
granulomatosis
Glomerulonephritis
Microscopic polyangiitis,
Wegener's
granulomatosis,
cryoglobulinemia, ChurgStrauss vasculitis,HenochSchönlein purpura
General Approach to Diagnosis
When systemic vasculitis is suspected, the diagnostic work-up can be approached in
a stepwise fashion:
1. Attempt to exclude other processes, particularly infection, thrombosis and
neoplasia, that can cause secondary vasculitis or can have features that
mimic vasculitis. This must be done quickly to provide appropriate therapy
for a potentially life-threatening condition. In addition, anti-inflammatory and
immunosuppressive therapy of the systemic vasculitides is potentially toxic
and may mask certain disorders, such as infection or a perforated viscus.
Conditions That Can Mimic Primary Systemic Vasculitis
Embolic disease
Endocarditis
Atrial myxoma
Cholesterol embolization
Vessel stenosis or "spasm"
Atherosclerosis
Fibromuscular dysplasia
Drug-induced vasospasm (e.g., ergots, cocaine,
phenylpropanolamine)
Intravascular lymphoma
Vessel thrombosis
Disseminated intravascular coagulopathy
Thrombotic thrombocytopenic
purpura
Antiphospholipid antibody
syndome
Heparin- or warfarin-induced
thrombosis
Systemic infection
Malignancy
Other connective tissue
disorders
2. Consider the patient's age, sex and ethnic origin, since certain vasculitis
syndromes occur more commonly in specific populations.
Demographic Associations of the Vasculitides
Age
group
Male-tofemale ratio
Child
M=F
M>F
Young
adult
M=F
Middle
age
Elderly
F>M
M>F
F>M
Ethnic origin
Type of vasculitis
Any
Asian > white >
others
Middle Eastern >
others
Asian >> others
Any
Henoch-Schönlein purpura
Kawasaki disease
Caucasian >>
others
Behçet's disease
Takayasu's arteritis
Wegener's granulomatosis, polyarteritis,
Churg-Strauss vasculitis
Giant cell arteritis
3. Determine which organs are involved and estimate the size of vessel
involvement. The type and extent of organ involvement in vasculitis can be
helpful in determining the specific type of vasculitis and the degree of
urgency in initiating treatment. The clinical features in a given patient can be
used to discern the size of the vessels affected by vasculitis. It should be
recognized that the terms "small," "medium" and "large" to describe vessel
size have different meanings for a pathologist, an angiographer and a
clinician.
Clues for Identifying the type of Vessel Involvement in Vasculitis
Clinical feature
Cutaneous
Palpable purpura
Skin ulcers
Gangrene in an extremity
Gastrointestinal tract
Abdominal pain or
mesenteric ischemia
Gastrointestinal bleeding
Renal
Glomerulonephritis
Ischemic renal failure
Pulmonary
Pulmonary hemorrhage
Most likely affected Most commonly associated systemic
vessel
vasculitis
Postcapillary venules Any type of vasculitis except giant
cell arteritis and Takayasu's arteritis
Arterioles to small Polyarteritis, Churg-Strauss vasculitis,
arteries
Wegener's granulomatosis,
hypersensitivity vasculitis
Small to mediumPolyarteritis, Churg-Strauss vasculitis,
sized arteries
Wegener's granulomatosis
Small to mediumsized arteries
Capillaries to
medium-sized
arteries
Henoch-Schönlein purpura,
polyarteritis, Churg-Strauss vasculitis
Henoch-Schönlein purpura,
polyarteritis, Churg-Strauss vasculitis
Capillaries
Microscopic polyangiitis, Wegener's
granulomatosis, cryoglobulinemia,
Churg-Strauss vasculitis, HenochSchönlein purpura
Polyarteritis, Takayasu's arteritis; less
commonly, Churg-Strauss vasculitis
and Wegener's granulomatosis
Small to mediumsized arteries
Capillaries; less
commonly small to
medium-sized
arteries
Microscopic polyangiitis, Wegener's
granulomatosis
Pulmonary infiltrates or
cavities
Neurologic
Peripheral neuropathy
Stroke
Small to mediumsized arteries
Churg-Strauss vasculitis, microscopic
polyangiitis
Small arteries
Polyarteritis, Churg-Strauss vasculitis,
Wegener's granulomatosis,
cryoglobulinemia
Small, medium-sized Giant cell arteritis, SLE-associated
or large arteries
vasculitis
4. Attempt to distinguish the specific type of vasculitis on the basis of the above
information and the pattern of the clinical features.
Laboratory Testing
Although occasionally helpful in classifying vasculitis, laboratory testing is
most important in determining organ involvement and excluding the presence of
other diseases. Important routine tests include complete blood cell count,
urinalysis, blood urea nitrogen, creatinine and liver enzyme levels. Leukocytosis,
anemia of chronic disease, a high erythrocyte sedimentation rate (ESR) and an
elevated C-reactive protein level are commonly found in most types of vasculitis.
Although ESR is almost always elevated in vasculitis, a normal ESR does not rule
out systemic vasculitis.1 If the patient has renal failure or proteinuria and
hematuria on urinalysis, a fresh-spun urine sample should be evaluated for red
blood cell casts or dysmorphic red cells that would suggest the presence of a
glomerulonephritis.
Laboratory Tests to Consider in the Evaluation of Systemic Vasculitis
Laboratory test
Purpose or interpretation
Routine tests (including complete
blood cell count, liver enzymes,
creatinine, urinalysis)
Blood cultures
Erythrocyte sedimentation rate
C-reactive protein
Rheumatoid factor
Evaluate for hematologic, renal and other organ
involvement
Rule out infection
High value suggests inflammatory disease
High value suggests inflammatory disease
Very high titers in rheumatoid arthritis,
Antinuclear antibody
Complements (C3, C4, CH50)
Cryoglobulins
ANCA
Creatine phosphokinase
RPR/VDRL
Serum protein electrophoresis
Hepatitis B and C serology
HIV
Anti-glomerular basement
membrane
Sjögren's syndrome and cryoglobulinemiaassociated vasculitis
Screen for SLE and Sjögren's syndrome
Low complement levels suggest consumption by
immune complexes, which are commonly found
in SLE and cryoglobulinemia
Must be present to diagnose mixed essential
cryoglobulinemia but can be found in any
primary or secondary vasculitis
Cytoplasmic ANCA pattern specific for
Wegener's granulomatosis; perinuclear ANCA
pattern may occur in other vasculitides
Elevation suggests myositis, which can occur in
many vasculitis syndromes
Rule out syphilis
Evaluate for plasma cell dyscrasias
Rule out hepatitis B or hepatitis C infection
Rule out HIV infection
Rule out Goodpasture's syndrome, which can
mimic vasculitis and cause pulmonary
hemorrhage and glomerulonephritis
SLE = systemic lupus erythematosus; ANCA = anti-neutrophil cytoplasmic antibodies; RPR =
rapid plasmin reagin; HIV = human immunodeficiency virus.
Chest radiographs may reveal asymptomatic pulmonary involvement. If findings
suggestive of peripheral neuropathy or muscle inflammation are noted on the
history and physical examination, nerve conduction velocity and electromyographic
testing can help confirm these suspicions and serve as a guide for biopsy.
Although rheumatoid factor can be present in any inflammatory disease, it is
more often found in rheumatoid arthritisassociated vasculitis, Sjögren's syndrome
and mixed cryoglobulinemia. Hepatitis B, hepatitis C and human immunodeficiency
virus (HIV) serologies should be obtained, since these infections are sometimes
associated with vasculitis.8-10 While complement levels (C3, C4 and CH50) are often
normal or high in other types of vasculitis, they tend to be low in SLE-associated
vasculitis, cryoglobulinemia and hepatitis B and Cassociated vasculitis, reflecting
consumption by circulating immune complexes.
Cryoglobulins can be present in malignancy (plasma cell dyscrasias, lymphoma
and leukemia), chronic infections (hepatitis B, hepatitis C and endocarditis),
inflammatory rheumatic disease (Sjögren's syndrome, SLE and rheumatoid arthritis)
or in the syndrome of mixed essential cryoglobulinemia. Mixed essential
cryoglobulinemia is now known to be strongly associated with hepatitis C.
Cryoglobulins are antibodies that reversibly precipitate in cold. They should be
collected in a warmed tube and kept warm on transport to the laboratory.
There are two staining patterns for anti-neutrophil cytoplasmic antibodies
(ANCA). Cytoplasmic ANCA (C-ANCA) most often represents antibody to proteinase 3
and is present in up to 90 percent of patients with active, diffuse Wegener's
granulomatosis and quite specific in the appropriate clinical setting. Perinuclear
ANCA (P-ANCA), which is often caused by anti-myeloperoxidase antibody, is less
specific but is often present when vasculitis affects small to medium-sized arteries.
Arteriography and Biopsy
Confirmation of a clinical suspicion of vasculitis usually requires arteriography,
biopsy, or both. Evaluation should be directed toward establishing a tissue diagnosis,
if possible. In general, because "blind" biopsy of asymptomatic sites or organs
generally has a low yield,2 it is best to "go where the money is." For example, if a
patient is over age 50 and presents with a new, unexplained headache and elevated
ESR, with or without a tender or abnormal temporal artery, a temporal artery biopsy
would be indicated. Similarly, in a patient who presents with a multisystem illness
and testicular pain and swelling, a testicular biopsy should be considered. Sural
nerve biopsy may be indicated in a patient with numbness and tingling in a lower
extremity. If the urine sediment is abnormal, a renal biopsy might be obtained.
If a biopsy is impractical, an angiogram may be diagnostic. An angiogram should
be obtained in cases of suspected large-vessel vasculitis, such as of the branches of
the aorta, which may be manifested as extremity ischemia or claudication. A patient
with abdominal pain may have mesenteric or renal vasculitis. If visceral involvement
is suspected (and in the absence of a surgical abdomen), a visceral angiogram to
include the celiac, mesenteric, renal and, perhaps, hepatic arteries should be
performed.