++
++
Key Clinical Questions
When should a diagnosis of vasculitis be considered?
How is a diagnosis of vasculitis made or excluded?
What are the appropriate strategies for triage, consultation, and follow-up for vasculitis?
What treatment and staging for vasculitis should be initiated in the hospital?
In a patient with established vasculitis, how should new symptoms of illness be evaluated?
++
The diagnosis of vasculitis is considered far more often than these diseases are actually seen—appropriately, since these rare diseases have diverse presentations, are dangerous and often rapidly progressive, yet are treatable. All vasculitides feature inflammation of the walls of blood vessels, with symptoms and findings attributable to the size(s) and locations of the involved vessels. Vessel size, epidemiology, and/or a constellation of typical clinical features have proved useful for classifying the vasculitides, with key points summarized in (Table 257-1).
++
++
The classification of vasculitis remains imprecise with more than one system in use. “Primary” systemic vasculitides are further sorted by the sizes of the predominant arteries involved, leading to sets of small-, medium-, and large-vessel vasculitides. There are also several “secondary” forms of vasculitis associated with infections, drug exposure, or another form of systemic disease such as systemic lupus erythematosis or rheumatoid arthritis.
++
All of the primary, idiopathic vasculitides are rare diseases, each categorized as an “orphan” disease in the United States (prevalence of <200,000 persons). However, as a group, and especially among patients with initially unexplained systemic disease who are ill enough to be hospitalized, vasculitis is common enough that hospitalists will likely encounter cases.
++
The pathophysiology of the primary vasculitides is poorly understood. They are all considered immune mediated, based on histologic and serologic studies and by analogy to the many cases of vasculitis that have occurred secondary to infections or drug exposure. Since no pathogens have been found, the primary vasculitides are suspected to be autoimmune, with the humoral and cellular branches of the adaptive immune system involved to different degrees in different diseases.
+++
NOTES ON INDIVIDUAL FORMS OF VASCULITIS
++
It is impractical to describe each of the vasculitides in detail in a single chapter, but short summaries of most of the vasculitides are provided as reference points for the subsequent discussion.
++
Giant cell arteritis (GCA) only affects adults over the age of 50, and incidence markedly increases with age, to about 1:2000 per year among Caucasians of Northern European descent by age 80. Headache is the most common symptom (80%), with scalp tenderness, jaw claudication, constitutional symptoms, and polymyalgia rheumatica (pain and stiffness in the shoulders, hips, and/or neck) each seen in 40% to 70% of patients. The presentation of GCA is often insidious and diagnosed during outpatient care, but sometimes is acute and leads to hospitalization. GCA has also been reported to be an important cause (about 10%) of fever of unknown origin in the elderly, and since the aorta and its major branches are involved in more than 15% of cases, GCA is also an important consideration in cases of claudication, loss of pulse, and asymmetric blood pressure measurements in the elderly. (See the section on laboratory testing [acute phase reactants], imaging [angiography, ultrasound], and biopsy [temporal artery]).
++
Takayasu arteritis is a rare disease (prevalence <1:100,000), usually presenting in young adults, and 90% of patients are female. Patients often present with claudication, dizziness, abnormal blood pressure readings, and/or bruits. Diagnosis is confirmed by angiography. The types of presentation more likely to lead to hospitalization (eg, symptoms of coronary artery disease or cerebrovascular disease) carry a broad differential diagnosis, so suspicion for or against Takayasu may initially be gained by checking pulses and blood pressures and listening for bruits. (See the section on laboratory testing [acute phase reactants] and imaging [angiography, ultrasound]).
+++
Granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis
++
Granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA), often grouped together as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), are small-vessel vasculitides that together affect ~1:20,000 persons. AAV is high in the differential diagnosis of patients presenting with pulmonary hemorrhage, acute renal disease, or acute peripheral neuropathy, and is also an important consideration in patients with palpable purpura, inflammatory eye disease (scleritis or episcleritis), acute sensorineural hearing loss, cutaneous ulcers, or digit ischemia. Renal disease in AAV often leads to elevated serum creatinine and presence of urinary RBC casts; however, in the early stages of renal disease with AAV patients may only have microscopic hematuria and modest proteinuria. GPA usually (70%-80% at initial presentation) also features granulomatous inflammation of the upper airway, with nasal discharge and crusting, epistaxis, facial pain, and/or hearing loss, and the presence of these symptoms often facilitates the diagnosis of GPA. GPA is an important consideration in cases of subglottic stenosis, orbital mass with proptosis, or pulmonary nodule(s). However, many patients with AAV, particularly MPA, present only with nonspecific symptoms of malaise, myalgias, and arthralgias. The role of testing for ANCA in diagnosing AAV is discussed in detail below. (See section on laboratory testing [autoimmune serologies, acute phase reactants, tests of renal function], imaging [chest imaging, sinus imaging], and biopsy [skin, nasal cavity and sinuses, kidney, lung, peripheral nerve and muscle]).
+++
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
++
Eosinophilic granulomatosis with polyangiitis (EGPA) is worth considering in a patient who is ill with what might be vasculitis, has a history of asthma (often severe or poorly controlled), and has eosinophilia. The presentations of EGPA most likely to lead to hospitalization are asthma exacerbation, pulmonary infiltrates, or acute peripheral neuropathy, but constitutional symptoms, nasal polyps, rash, and arthralgias are also common. Myocarditis, gastrointestinal inflammation or ischemia, stroke, and renal involvement (similar to AAV) are less common but important presentations. Positive tests for ANCA are present in 40% of patients and EGPA is considered part of the spectrum of ANCA-associated vasculitis. (See section on laboratory testing [autoimmune serologies, acute phase reactants, tests of renal function, and complete blood count (CBC)], imaging [chest imaging and sinus imaging], and biopsy [skin, nasal cavity, and sinuses, kidney, lung, peripheral nerve, and muscle]).
+++
Antiglomerular-basement-membrane disease
++
In contrast to AAV, symptoms of antiglomerular-basement-membrane (GBM) disease are limited to the kidneys and/or lungs (if both = Goodpasture syndrome), with rapidly progressive glomerulonephritis and/or pulmonary hemorrhage as manifestations. In the right setting, a positive test for serum antiglomerular-basement-membrane (anti-GBM) antibodies is diagnostic for this disorder, as is demonstration of the characteristic pattern of antibody deposition by immunofluorescence on kidney tissue obtained by biopsy. Testing for anti-GBM antibodies should be rapidly obtained for any patient for whom anti-GBM disease is possible, since the disease can lead to irreversible kidney damage or death from pulmonary hemorrhage. (See section on laboratory testing [autoimmune serologies, tests of renal function], and imaging [chest imaging], biopsy [kidney, lung]).
++
The most common features of polyarteritis nodosa (PAN) are livedo reticularis (a lacy pattern of cutaneous blood vessels on extremities that is more commonly due to benign conditions rather than vasculitis), painful cutaneous nodules or ulcers, hypertension, abdominal pain, myalgias, peripheral neuropathy, testicular pain, and digit ischemia. There is a strong association between hepatitis B virus (HBV) infection and PAN, but only in areas where HBV is endemic; the incidence of PAN has markedly declined in countries with high rates of HBV vaccination. PAN is probably the most challenging type of vasculitis to diagnose, because (1) it is particularly rare (in regions where HBV infection is also rare), (2) it features the least specific array of symptoms and findings among the vasculitides, and (3) there are no helpful diagnostic blood tests analogous to ANCA, cryoglobulins, or even eosinophil count. Biopsy or angiography is usually required for the diagnosis of PAN. For all of these reasons, PAN is contemplated much more often than it is diagnosed. (See section on laboratory testing [acute phase reactants, tests of renal function, selected testing for infectious diseases], imaging [angiography], and biopsy [skin, kidney, peripheral nerve and muscle, other organs]).
++
The manifestations of Behçet disease (BD) that may lead to hospitalization are extraordinarily diverse: vision loss or a red and painful eye, deep vein thrombosis (including dural sinus thrombosis or Budd-Chiari syndrome), colitis resembling inflammatory bowel disease, meningoencephalitis, or pulmonary artery rupture leading to massive hemorrhage. Considering the diagnosis of BD in these settings requires recognition of the various milder but more common features of BD that may be concurrently present or reported by the patient, including recurrent oral ulcers (required for diagnosis), genital ulcers, erythema nodosum, acneiform skin lesions, inflammatory arthritis, and superficial thrombophlebitis. The diagnosis or exclusion of BD is always made on clinical grounds since there are no specific blood tests or biopsy features of the disease.
+++
Primary angiitis of the central nervous system
++
This rare disease is limited to the central nervous system (CNS) and presents with symptoms of encephalopathy, multiple small strokes, and often headache. Angiography may be normal since the disease often affects only small vessels. Furthermore, angiography cannot easily distinguish vasculitis from atherosclerosis or from cerebral vasospasm (which usually presents with a severe headache of sudden onset). Thus, diagnosis of CNS vasculitis is ideally made by brain biopsy. (See section on imaging [angiography], and biopsy [brain]).
+++
Cryoglobulinemic vasculitis
++
Cryoglobulinemia encompasses a variety of clinical syndromes associated with circulating immune complexes that precipitate at cold temperatures. The majority of cases of cryoglobulinemia (~70%) are associated with chronic hepatitis C virus infection, with plasma cell malignancies and systemic rheumatic diseases accounting for most other cases. Cryoglobulinemia associated with chronic hepatitis C virus infection or systemic rheumatic disease causes a small-vessel vasculitis that typically involves skin (palpable purpura and/or ulcers), commonly involves peripheral nerves or kidneys (glomerulonephritis), and less commonly involves a wide range of internal organs. (See section on laboratory testing [tests of renal function, paraproteins, selected testing for infectious diseases], and biopsy [skin, kidney, peripheral nerve and muscle]).
+++
IgA vasculitis (Henoch-Schönlein)
++
IgA vasculitis (Henoch-Schönlein purpura, IgAV) is much more common among children than adults. It is usually self-limited and presents with palpable purpura, often in association with inflammatory arthritis and abdominal pain. A minority of patients has severe renal involvement, and the presence or absence of significant proteinuria or elevated creatinine is often used to determine whether to treat with immunosuppressive agents; however, the usefulness of such treatment has not been firmly established. (See section on laboratory testing [tests of renal function] and biopsy [skin, kidney]).
++
Kawasaki disease (KD) is almost exclusively a disease of young children, and it is not rare in its characteristic age group (incidence 1:10,000 in the United States). The syndrome classically includes fever persisting for at least 5 days, erythematous rash with desquamation in the hands and feet, conjunctivitis, oral mucosal inflammation, and lymphadenopathy. However, many patients present without all of these features and, since a consequence of untreated KD is life-threatening coronary artery aneurysms, the diagnosis is considered in almost any young child with a fever lasting 5 days.
+++
Vasculitis associated with other autoimmune diseases
++
Systemic lupus, rheumatoid arthritis, Sjögren syndrome, and inflammatory bowel disease have all been associated with vasculitis, mostly involving small vessels (palpable purpura, ulcers, neuropathy), but occasionally medium-sized vessels (analogous to PAN). Inflammatory bowel disease, relapsing polychondritis, and Cogan syndrome are each rarely associated with large-vessel vasculitis similar to Takayasu arteritis. (See section on laboratory testing [autoimmune serologies and tests of renal function]).
+++
DIAGNOSIS: DOES THIS PATIENT HAVE VASCULITIS?
++
Vasculitis is commonly in the differential diagnosis for any patient with an unexplained systemic illness or any patient with one or more specific findings suggestive of vasculitis. It is important to realize that vasculitis is rare. Nonetheless, being open to the possibility of vasculitis is critical for reducing delays in diagnosis. There are many “red flags” that should alert clinicians that vasculitis must be considered (Table 257-2). Some of these findings merit urgent diagnostic testing and sometimes even empiric treatment for vasculitis, pending the results of testing.
++
++
Not shown in Table 257-2 are syndromes that could be caused by vasculitis but have other causes in the vast majority of cases such as fever of unknown origin, lower-extremity ulcers, abdominal pain, arthralgias, myalgias, and other nonspecific symptoms.
++
Since vasculitis is rare, nonvasculitic causes of red-flag symptoms remain more common than vasculitis in many cases. A broad range of infectious, autoimmune, toxic, malignant, thromboembolic, vasospastic, and atherosclerotic disorders can mimic many of the characteristic features of vasculitis, as outlined in general terms in Table 257-2.
+++
DIAGNOSTIC TESTING FOR SUSPECTED VASCULITIS
++
The method for diagnosing vasculitis generally depends on the size of vessels involved. Small-vessel vasculitis is usually diagnosed by biopsy, but sometimes the combination of a typical clinical syndrome and a laboratory test (see preceding section) is sufficient. Medium-vessel vasculitis (PAN) is diagnosed by biopsy or angiography. GCA is usually diagnosed by biopsy (temporal arteritis) but occasionally by angiography if the aorta or its major branches are involved. Takayasu is diagnosed by angiography. CNS vasculitis is usually diagnosed by biopsy but sometimes by angiography. Behçet disease and Kawasaki disease are diagnosed based on the clinical syndrome.
++
The uses of laboratory testing, diagnostic imaging, and biopsy for diagnosing vasculitis are outlined below.
+++
LABORATORY TESTING FOR EVALUATION OF SUSPECTED VASCULITIS
++
Although individual laboratory tests on their own are almost never diagnostic for vasculitis, such tests are essential in the evaluation of a patient in whom vasculitis is being considered, for several reasons: (1) in the proper setting, selected serologic tests may confirm a diagnosis of vasculitis; (2) laboratory testing may identify organ systems involved in the disease process (especially for renal disease); (3) laboratory tests may establish a diagnosis other than vasculitis.
+++
Autoimmune serologies
++
Testing for various autoantibodies plays a key role in the evaluation of patients suspected of having vasculitis, but over-reliance on such testing often leads to delayed or missed diagnoses.
+++
Antineutrophil cytoplasmic antibodies
++
The widespread availability of testing for ANCA has had a striking impact on the evaluation of patients with suspected small-vessel vasculitis. The current standard of care for ANCA testing includes combining tests for ANCA by immunoflourescence and tests for specific ANCA autoantibodies by ELISA. Only two combinations of test results constitute a truly “positive” ANCA test: the cytoplasmic (C-ANCA) immunoflourescence pattern combined with antiproteinase 3 (PR3) antibodies by ELISA, or the perinuclear (P-ANCA) immunoflourescence pattern combined with antimyeloperoxidase (MPO) antibodies by ELISA. In the proper clinical settings, positive ANCA testing (C/anti-PR3 or P/anti-MPO) is highly specific for the diagnosis of AAV (>95%) and may preclude the need for biopsy or at least support initiation of treatment with glucocorticoids pending a biopsy. However, ANCA testing is presumed to have lower specificity in the setting of nonspecific symptoms such as malaise, myalgias, and arthralgias—a relatively common initial presentation of AAV. The sensitivity of ANCA testing is ~90% in patients with systemic GPA or MPA and is considerably lower (70%) in patients with GPA limited to the airway, so a patient may still have GPA even if the ANCA test is negative. Thus, ANCA testing is extremely useful diagnostically but must be used in the context of supportive clinical and other data.
+++
Antiglomerular-basement-membrane antibodies
++
In the setting of renal insufficiency and/or pulmonary hemorrhage, anti-GBM antibodies are highly specific for the diagnosis of anti-GBM disease/Goodpasture disease as long as the initial anti-GBM antibody screening test is confirmed by Western blot. Because the treatment of choice for anti-GBM disease is the combination of high-dose glucocorticoids and plasma exchange, it is crucial to establish the diagnosis as early as possible. Antibody testing can play a central role in this process, but sometimes immunoflourescence staining of a kidney biopsy can make the diagnosis more rapidly.
+++
Antinuclear antibodies
++
Testing for antinuclear antibodies (ANA) is quite useful when there is suspicion of systemic lupus erythematosus (SLE), either underlying vasculitis or as an alternative diagnosis for pulmonary hemorrhage and/or acute renal failure. ANA testing is >95% sensitive for the diagnosis of lupus; therefore, a negative test essentially rules out lupus as a diagnosis, unless a patient has clear pathognomonic features.
+++
Acute phase reactants
++
Although the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are usually elevated in patients with untreated vasculitis, and ESR and CRP are often ordered when evaluating patients with suspected vasculitis, these tests have a surprisingly low value diagnostically. ESR or CRP are neither sensitive nor specific enough to be considered as screening tests to make or exclude a diagnosis of vasculitis, except, in a limited way, as part of a diagnostic algorithm for GCA. Even for new-onset GCA, the ESR or CRP may be normal in ~15% of cases, and both are normal in ~4% of cases. Therefore, a normal ESR is only helpful in ruling out GCA and avoiding the need for a temporal artery biopsy in a low-probability patient (atypical headache only), but not in a patient with additional cranial, arthritic, or constitutional symptoms. These tests may have selected roles in evaluation for persistent or recurrent disease but still must be interpreted cautiously. Furthermore, ESR and/or CRP are often elevated in the major mimics of vasculitis, especially infections (either acute or chronic) and malignancies.
+++
Tests of renal function and other chemistry laboratory testing
++
Prompt assessment of renal function is an essential part of the evaluation of any patient suspected of having vasculitis. Renal disease can be either insidious or fulminant, and renal injury is usually asymptomatic until symptoms of end-stage renal disease arise. Serum creatinine with estimate of glomerular filtration rate should be done immediately in all patients and compared with prior measurements. Even subtle rises in creatinine levels within the “normal” range may be indicative of serious disease.
++
If urinary dipstick testing demonstrates the presence of any blood or protein, then a microscopic examination of the urine sediment on a freshly collected specimen must be performed for any patient suspected of having vasculitis. However, it is essential that the urinalysis be performed by someone experienced in evaluating patients with glomerulonephritis, usually a nephrologist or rheumatologist. It is the norm for hospital-based and reference laboratories to miss evidence of an “active” urinary sediment since casts are often destroyed by the time the specimens are processed, and laboratory personnel are simply not trained to detect these changes. The presence of red blood cell casts and, to a lesser extent, “dysmorphic” red cells in a urine specimen are strong indicators of glomerular disease. However, patients can still have highly active glomerulonephritis or other renal disease in vasculitis (eg, aneurysms in PAN) and not have urinary casts present.
++
Other routine chemistry panels, including measurements of electrolytes and liver function tests, are of limited value in diagnosing vasculitis per se and provide more useful information about nonvasculitic conditions.
++
Urine or serum toxicology screens for commonly used legal and illegal drugs of abuse may be appropriate for some clinical situations in which vasculitis is suspected. For example, both cocaine and methamphetamines have been associated with vasculitis and/or arterial vasospasm, and levamisole is now a common adulterant of cocaine and can cause a form of AAV.
++
A complete blood count (CBC) should be conducted on all patients suspected of having vasculitis but is usually of limited diagnostic value. Many, but by no means all, patients with active vasculitis have anemia and/or thrombocytosis, but neither finding is sensitive or specific for the diagnosis. The one diagnostic use of the CBC in vasculitis concerns EGPA; although an elevated eosinophil count is nonspecific, a normal eosinophil count (in a patient who has not received glucocorticoids) usually rules out this diagnosis.
+++
Paraproteins (abnormal immunoglobulins)
++
Abnormal immunoglobulins that can be associated with vasculitis include both those that precipitate at room temperature (cryoglobulins) and other clonal immunoglobulins that may cause small-vessel vasculitis. Cryoglobulins results in vasculitis are most closely associated with chronic infection with hepatitis C virus. Testing for cryoglobulins requires careful attention to specimen handling and processing with incorrect practice at any of several steps resulting in uninterpretable findings (ie, high false-negative rate due to poor processing). Similarly, standard serum protein electrophoresis testing (SPEP) may not pick up some immunoglobulin clones; immunofixation electrophoresis (IFE) is a more comprehensive screen for clonal immunoglobulins. Similar issues exist for urine protein electrophoresis (UPEP) versus urine immunofixation electrophoresis (UFE). The great majority of patients with cryoglobulinemic vasculitis tests positive for rheumatoid factor (RF) and/or has low levels of circulating complement proteins (C4 more so than C3), ~80% each for RF or low C4. RF has poor specificity, but results are obtained faster and more reliably than are tests for cryoglobulins.
+++
Selected testing for infectious diseases
++
Hepatitis B, hepatitis C, and HIV virus infections are associated with vasculitis and tests for these viruses should be sent for all patients suspected of having a small- or medium-vessel vasculitis. Blood cultures are appropriate when bacteremia may be a possible cause of vasculitis. Several other infections may cause signs and symptoms mimicking vasculitis and serologic tests or cultures specific to those diseases are useful on a case-by-case basis.
+++
DIAGNOSTIC IMAGING FOR EVALUATION OF SUSPECTED VASCULITIS
++
The major forms of vasculitis that involve the lung are AAV (including GPA, MPA, and EGPA) and anti-GBM disease. A chest x-ray is therefore prudent in any patient with acute renal failure and an active urine sediment, and one should have a low threshold for performing a computed tomography (CT) test (noncontrast, but ideally with high-resolution cuts). However, the appearances of AAV on CT imaging—solitary or multiple nodules, multifocal or diffuse infiltrates—are not sufficiently specific to be diagnostic. For a patient with known vasculitis, comparison of abnormal findings on chest imaging to prior studies is essential.
++
A patient in whom GPA or EGPA is being considered due to prominent symptoms of nasal inflammation should have a CT (a noncontrast study is usually sufficient) performed to assess for sinus, mastoid, and retro-orbital involvement.
++
Angiography, whether conventional or performed using CT (CTA) or magnetic resonance (MRA) techniques, is essential for the diagnosis of large-vessel vasculitis (Takayasu arteritis, GCA, and others) and many cases of medium-vessel vasculitis (PAN). For Takayasu and GCA involving the major branches of the aorta, either MRA or CTA is often sufficient. Angiography (CTA or conventional) is usually unable to differentiate between CNS vasculitis, vasospasm, and atherosclerosis.
++
Catheter-based conventional angiography is still considered the “gold standard” for arterial imaging and is considerably more sensitive for disease of smaller arteries. Furthermore, catheter-based angiography allows for measurement of blood pressures and selective sampling of specific arterial areas.
++
Ultrasound of certain large arteries (particularly the carotids) can be helpful in diagnosing large-vessel vasculitis (GCA or Takayasu), since wall thickness as well as luminal diameter can be measured. Ultrasound of the temporal arteries for diagnosis of GCA has performed well in research studies at specialized centers but is not yet recommended for routine clinical use. Echocardiography, which allows visualization of the major coronary arteries in children, has an important role in the diagnosis and management of Kawasaki disease.
+++
Positron emission tomography
++
Positron emission tomography (PET) scanning has been reported to identify areas of inflammation in large-vessel vasculitis in small studies, but the diagnostic usefulness of this modality for vasculitis has not been established.
+++
BIOPSY FOR EVALUATION OF SUSPECTED VASCULITIS
++
Biopsy is required for the diagnosis of vasculitis in many cases, although there are important exceptions. Behçet disease and IgA vasculitis (Henoch-Schönlein) (in children) are diagnosed on clinical grounds. Kawasaki disease is diagnosed on clinical grounds, often with confirmation by imaging showing evidence of coronary artery aneurysm(s). Large-vessel vasculitis is diagnosed by angiography in patients with Takayasu and a subset of patients with GCA. Some patients with small-vessel vasculitides (GPA, MPA, EGPA, and cryoglobulinemia) can be diagnosed confidently on the basis of symptoms, signs, and laboratory and imaging findings but biopsy remains the best evidence for these diseases.
++
The usefulness of biopsy either in diagnosing vasculitis or in diagnosing a particular type of vasculitis depends on the organ system. Consideration of the need for biopsy is one of the main reasons for prompt consultation of the appropriate specialist.
++
Skin biopsies are simple, have low morbidity, and should be strongly considered in any patient with new-onset purpura or other lesions suspected to be due to vasculitis. Assuming lesions are due to vasculitis is a common clinical error. Cutaneous small-vessel vasculitis usually presents as palpable purpura, but other presentations include flat and angular (retiform) purpura, nodules, ulcers, and bullae. Vasculitis is probably the most common cause of palpable purpura, but there are others, and thus biopsy is usually indicated. The typical pathologic finding is leukocytoclastic vasculitis (LCV), which is quite helpful for confirming the presence of vasculitis but does nothing to address the many potential causes of this pathology. Immunofluorescence staining can be of additional value, especially if IgA vasculitis (Henoch-Schönlein) (associated with strong staining for IgA) is suspected.
++
It is important to realize that patients with LCV on skin biopsy may have one of the named primary vasculitides or any of several other conditions, including another named systemic rheumatic disease, a concurrent or recent infection, or drug/toxin exposure. Some patients will have vasculitis apparently limited to the skin and without any clear exposure. Thus, it is important to interpret the skin biopsy in the context of a compulsive search for other findings by history, examination, laboratory tests, and imaging.
++
A full-thickness skin biopsy that includes larger vessels and subdermal tissue may be necessary for some forms of vasculitis or related disease, such as PAN, panniculitis, and others.
+++
Nasal cavity and sinuses biopsy
++
Although the sinonasal mucosa is frequently involved in either GPA or EGPA, biopsies of these readily accessible tissues are of limited diagnostic value since the three characteristic features of granulomatous inflammation, necrosis, and vasculitis are often not present; however, if seen in the right setting, then such biopsy findings are supportive of a diagnosis of vasculitis. Sinonasal biopsies and cultures may be useful to establish a diagnosis of infection or malignancy.
+++
Temporal artery biopsy
++
Biopsy of the temporal artery is safe and ~85% sensitive for diagnosing GCA, so one should have a low threshold for having it performed in an elderly patient who has either a new and persistent headache and a high ESR or CRP, or a constellation of features suggestive of GCA regardless of the ESR and CRP. Performing bilateral biopsies improves sensitivity by ~5%. The specificity of finding vasculitis in temporal arteries is high for a diagnosis of GCA; however, other forms of vasculitis can rarely involve the temporal arteries.
++
Kidney biopsy is quite valuable for diagnosing AAV and remains one gold standard for the diagnosis. However, in some settings of acute renal insufficiency with an active urine sediment, other features suggestive of GPA or MPA, and a positive test for serum anti-PR3 or anti-MPO antibodies, kidney biopsy may not be necessary. Kidney biopsy is also quite valuable for diagnosing anti-GBM disease. Kidney pathology in IgA vasculitis (Henoch-Schönlein) and cryoglobulinemia are both distinct from the other vasculitides and in many settings is therefore diagnostic. Kidney biopsy is rarely helpful in diagnosing PAN involving the kidneys since the vessels involved are often too large and/or too patchily distributed to be detected on biopsy, and PAN does not cause glomerular disease. Of course, kidney biopsies are extremely helpful in diagnosing nonvasculitic causes of renal disease or a coexisting second pathology in patients with vasculitis.
++
Brain biopsy is considered to be essential for the confident diagnosis of CNS vasculitis, since vasospastic disease has a similar angiographic appearance, and a variety of infectious, inflammatory, or malignant diseases can cause the type of multifocal small abnormalities that are usually seen on brain MRI in CNS vasculitis.
++
Lung biopsy has a high diagnostic yield for AAV for nodules or infiltrates (including eosinophilic infiltrates in EGPA). Similarly, small-vessel vasculitis with capillaritis can be diagnosed by lung biopsy, but the bronchoscopic evidence of diffuse alveolar hemorrhage in the right clinical and laboratory setting often makes biopsy unnecessary. Lung biopsy can also be important in a patient with known GPA who develops a new lung lesion to help differentiate vasculitis from infection or malignancy.
+++
Peripheral nerve and muscle biopsy
++
Peripheral nerves are frequently involved in PAN, EGPA, GPA, and MPA, and biopsy of the sural nerve, particularly with simultaneous biopsy of the nearby muscle, has fairly good sensitivity for diagnosing vasculitis. Nerve biopsy is rarely performed on a clinically uninvolved sural nerve and probably has lower sensitivity. However, sural nerve biopsy often leaves the patient with a permanent sensory deficit in the innervated area, and occasionally with neuropathic pain.
+++
Biopsy of other organs
++
Vasculitis has been reported to occur in almost every organ either as part of a named systemic vasculitis or in cases of “single organ” vasculitis. Thus, biopsy of organs other than those listed above may be useful. More common is the situation in which vasculitis is found in surgical specimens for patients thought to have other medical problems. Such findings then appropriately stimulate a full evaluation of possible systemic vasculitis.
+++
ILLNESS IN A PATIENT WITH KNOWN VASCULITIS
++
A new illness in a patient already diagnosed with vasculitis still frequently presents diagnostic and therapeutic challenges. Many of the vasculitides involve diverse symptoms and findings, and the features during flare do not always resemble the features at initial diagnosis. Patients receiving immunosuppressive medications for vasculitis are at risk for both conventional and opportunistic infections. Noninfectious side effects of medications are also common. Importantly, permanent damage from prior episodes of vasculitis (eg, from neuropathy, nasal septal perforation, or stenosis of a large artery) can produce chronic symptoms that fluctuate in severity and mimic active vasculitis or infection.
++
An example of the complexity of evaluating new clinical problems in a patient with vasculitis is that of dyspnea in a patient with GPA. This problem could indicate pulmonary hemorrhage, subglottic stenosis, pulmonary nodules (with or without superinfection), pericarditis, pulmonary embolism, bacterial pneumonia, atypical pneumonia (particularly due to pneumocystis jeruvicii [carinii]), or glucocorticoid-induced myopathy, all problems for which a patient treated for GPA would be at relatively high risk. Distinguishing a manifestation of recurrent vasculitis from an infection or a medication side effect can be quite difficult, so the most appropriate general advice is to think broadly: resist the temptation to assume that vasculitis is the cause of symptoms, consider the possibility that infection may coexist with active vasculitis, consider the possibility that the original diagnosis of vasculitis may have been wrong, and have a low threshold for hospitalization and consultation.
++
PRACTICE POINT
Think broadly in order to distinguish a manifestation of recurrent vasculitis from an infection or a medication side effect.
Do not assume that vasculitis is the cause of symptoms.
The original diagnosis of vasculitis may have been wrong.
Infection may coexist with active vasculitis.
Have a low threshold for hospitalization and consultation.
+++
TRIAGE AND CONSULTATION
++
The decision whether to hospitalize a patient who has or may have vasculitis depends on the severity of illness. Sometimes the need for admission is obvious: pulmonary hemorrhage, hematuria with elevated creatinine, or vision loss. Admission may also be indicated for other manifestations that may appear less serious but are often indicators of severe disease with the potential to cause permanent organ damage (peripheral neuropathy, hematuria, or new hypertension with normal creatinine), or to facilitate rapid evaluation. In patients who appear safe to return home, arrangement for close outpatient follow-up remains critical. For example, a patient with a moderate or high probability of having GCA may be discharged from the emergency room after receiving a first dose of glucocorticoids, but only with a prescription for prednisone (40-80 mg/d) and scheduling within 1 week for a temporal artery biopsy and follow-up with a primary care provider or rheumatologist.
++
Urgent rheumatologic consultation on either an inpatient or outpatient basis is usually indicated for patients suspected of having vasculitis and is influenced by the organ system(s) involved and the need for biopsy or advanced imaging. Consultations with specialists with expertise in particular clinical skills and diagnostic procedures (eg, ophthalmology, otolaryngology, pulmonary, nephrology, gastroenterology, dermatology, or neurology) may well also be indicated. Since syndromes that include vasculitis in the differential diagnosis often include infectious diseases and/or malignancies, it is common, and usually appropriate, for a patient with a severe illness of mysterious cause to require “pan-consults”. In such situations, the hospitalist has the challenge of facilitating and prioritizing the evaluations and communicating to the patient and concerned family members the recommendations of numerous specialists.
++
Clinicians should expect their consultants, particularly rheumatologists or nephrologists, to guide treatment for vasculitis. Hospitalists may, however, be faced with the decision of whether to start high-dose glucocorticoids in advance of consultation, and play an important role in monitoring for the many potential side effects of treatment.
++
Glucocorticoids are the cornerstone of treatment for all severe forms of vasculitis and are often started in the hospital. If suspicion is high for organ-threatening vasculitis (eg, GCA or acute renal failure with active sediment), then it is often wise to start glucocorticoids while the diagnostic workup is in progress. For less urgent clinical situations in which vasculitis is one of several considerations, particularly if severe infection is a possibility, then it is advisable to forgo glucocorticoid treatment until the diagnosis is confirmed. Vasculitis causing compromise to vital organs (eg, pulmonary hemorrhage, glomerulonephritis, acute peripheral neuropathy, vision loss, angina, or digit ischemia) is often treated with high-dose IV methylprednisolone, 1000 mg daily for 1 to 3 days, followed by oral prednisone 1 mg/kg/d. Starting with oral prednisone is usually appropriate for disease that is potentially severe but not actively damaging organs such as GCA with headache, Takayasu with new arterial lesions, or GPA with nasal disease and a pulmonary nodule.
++
Another urgent inpatient treatment decision is whether a patient requires plasma exchange. This procedure is considered standard care in anti-GBM disease. Plasma exchange is also used in some centers for treatment of fulminant AAV, particularly with rapidly progressive renal failure, but the value of this approach is under active investigation. The decision for or against plasma exchange is always an urgent one and is a major reason why it is appropriate to push for renal biopsy with immunofluorescence staining and rapid serologic testing for anti-GBM, anti-PR3 ANCA, and anti-MPO ANCA.
++
Additional immunosuppressive drugs are widely used in vasculitis, with the choice of agent dependent on the disease and its severity. Cyclophosphamide, azathioprine, methotrexate, and rituximab are all used for various types and stages of vasculitis. Unlike glucocorticoids or plasma exchange, the effects of these other drugs are not rapid, and the decision to start them can await evaluation by a consultant with expertise in vasculitis and in the use of these medications.
++
Physicians caring for patients being treated for vasculitis should be attentive to common side effects of glucocorticoids including diabetes mellitus, osteoporosis, osteonecrosis, glaucoma, cataracts, psychosis and mania, myopathy, infection, and other problems. Prophylaxis against pneumocystis jeruvicii (carinii) is widely considered indicated for any patient receiving cyclophosphamide or for any patient receiving both high-dose glucocorticoids and another immunosuppressive agent. Trimethoprim-sulfamethoxazole, either a double-strength tablet three times per week or single-strength tablet daily, is considered the drug of choice for such prophylaxis for patients who are not sulfa-allergic; dapsone (first screen for G6PD deficiency) and atovaquone are alternatives.
+++
DISCHARGE CONSIDERATIONS
++
Patients with vasculitis or those in whom results of key diagnostic tests such as temporal artery biopsy are pending need to be seen quickly after hospital discharge by a rheumatologist and/or another specialist, rather than relying on the patient’s primary care provider. Patients may leave the hospital with multiple new medications, often including high doses of prednisone that have a diverse range of side effects. One should also anticipate that the receipt of a new diagnosis of a dangerous and previously unheard-of disease will likely produce understandable psychological stress for both the patient and family members.
++
Hospitals need systems to allow for rapid processing of selected tests that can establish a diagnosis of vasculitis and lead to initiation of time-critical therapies, including testing for ANCA and anti-GBM antibodies, measurement of cryoglobulins and partially surrogate tests for cryoglobulins (rheumatoid factor and complement components), temporal artery and renal biopsies, and angiography.
++
Hospitals should develop a multidisciplinary team comfortable with the many aspects of the evaluation and management of these challenging multisystem diseases.
++
The major factor that delays the correct diagnosis of vasculitis is a delay in even considering the diagnosis. Efforts must be made to educate clinicians that the presence of any of the red flags mentioned in this chapter should rapidly prompt evaluation for possible vasculitis and initiation of appropriate consultations.
+
Kissin
EY, Merkel
PA. Diagnostic imaging in Takayasu’s arteritis.
Curr Opin Rheumatol. 2004;16:31–37.
[PubMed: 14673386]
+
Merkel
PA. Drug-induced vasculitis.
Rheum Dis Clin North Am. 2001;27:849–862.
[PubMed: 11723768]
+
Mukhtyar
C, Guillevin
L, Cid
M,
et al, for the European Vasculitis Study Group. EULAR recommendations for the management of large vessel vasculitis. Annals Rheum Dis. 2009;68:103–106.
+
Mukhtyar
C, Guillevin
L, Cid
M,
et al, for the European Vasculitis Study Group. EULAR recommendations for the management of primary small and medium vessel vasculitis. Annals Rheum Dis. 2009;68:310–317.