Laboratory Tests
Histopathology typically exhibits extravascular granuloma-tous inflammation, with a prominent eosinophilic infiltrate and vasculitis. Vasculitis in a given tissue section may be granulo-matous or nongranulomatous. Granulomas can be found in tissue at areas separate from the demonstrable vasculitis. Eosinophilic infiltrates are more striking than in WG. Neither abundant eosinophils, granulomas, nor giant cells are found in classic polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA). The pathology of the nodules is not by itself sufficient to make a diagnosis of CSS, because similar pathology can be seen in lymphoma and sarcoidosis. Glomerulonephritis is frequently not as severe as in WG, but when present, it is usually focal and segmental and indistinguishable from other forms of so-called pauci-immune glomerulonephritis (i.e., glomerulonephritis that is without significant tissue deposition of immune complexes).
Treatment
CSS is generally responsive to corticosteroid therapy. Most patients are able to be withdrawn from steroids. However, bronchial asthma and sinus disease may require ongoing therapy, even if the vasculitic component of the disease has remitted. Patients with severe or refractory visceral organ involvement are empirically treated with additional agents such as cy-clophosphamide, methotrexate, or azathioprine; the cortico-steroids are tapered after remission is achieved [see Table 2].
Polyarteritis Nodosa and Microscopic Polyangiitis
Classification
Attempts to separate PAN and MPA, two forms of necrotiz-ing small to medium-sized vessel arteritis, have not been universally accepted. A recent international conference proposed that the diagnosis of these disorders be based on the absence of granulomatous inflammation in both and by involvement of ar-terioles, capillaries, venules, and glomerular capillaries in MPA but not in PAN. Older studies of patients with PAN did not uniformly make this distinction. Even more important, patients with viral hepatitis B or C were not excluded from older studies. The recognition of viral hepatitis is crucially important because chronic hepatitis B or C2,15 can elicit a secondary vasculitic syndrome indistinguishable from PAN or MPA in presentation but distinct in response to therapy.16 MPA involves vessels ranging in size from capillaries and venules to medium-sized arteries [see Figure 1].17 Clinically, MPA can mimic WG, although some authors have arbitrarily defined MPA as excluding involvement of the upper airway.
Diagnosis
Clinical Manifestations
Glomerulonephritis, particularly rapidly progressive glomer-ulonephritis, and alveolar hemorrhage are common in MPA and absent, by definition, in classic PAN.
PAN affects the medium-sized muscular arteries and, like MPA, is associated with peripheral neuropathy and bowel is-chemia.18-20 Azotemia and hypertension in PAN may occur because of arteritis of the renal arteries but not because of glomeru-lonephritis. Microaneurysm formation in medium-sized visceral arteries may be striking, and they may rupture.
Constitutional symptoms such as fever, asthenia, and myalgias are common in both PAN and MPA. Elevated acute-phase reactants, thrombocytosis, leukocytosis, and the anemia of inflammatory disease are common, although they are not uniformly present.
When the clinical syndrome of PAN or MPA is suspected, bacterial infection (e.g., endocarditis) and viral infection (e.g., hepatitis B or C) must be excluded. The association with hepatitis B or C infection may not dramatically alter the presentation of the PAN or MPA syndrome, except that membranous glomeru-lonephritis, cryoglobulinemia, immune complex-associated glomerulonephritis, hepatic failure, and thrombocytopenia are more likely to occur with viral hepatitis-associated vasculitis.
Antiphospholipid antibody syndrome (APLS) can mimic PAN by presenting as mesenteric ischemia or renal insufficiency caused by thrombotic occlusion of mesenteric and renal vessels.21 Features of APLS and arteritis affecting muscular arteries include livedo reticularis [see Figure 5]. Glomerulonephritis cryo-globulinemia, immune complex-associated glomerulonephritis, and peripheral neuropathy are not expected in APLS unless the patient also has SLE. Thrombocytopenia can occur with APLS but is not expected in PAN. Cholesterol embolization should also be considered as a cause of livedo, renal insufficiency, eosinophilia, and constitutional symptoms22; the clinical history of a recent vascular procedure and the performance of a biopsy will help confirm the diagnosis.
Laboratory Tests
The diagnosis of MPA and PAN should ideally be based on histopathologic demonstration of arteritis and the clinical pattern of disease. A biopsy specimen of clinically involved, non-necrotic tissue that demonstrates the presence of arteritis of muscular arteries is the ideal supportive finding for the diagnosis of arteritis of a medium-sized vessel, but such a biopsy is not always possible. The presence of serum p-ANCA with an-timyeloperoxidase specificity (in 60% of MPA patients) supports the clinical diagnosis of MPA, but p-ANCA is not specific for this disease. ANCAs are not characteristic of PAN. MPA is a form of pauci-immune glomerulonephritis; that is, the renal biopsy tissue in MPA, as in WG and CSS, does not contain extensive immune complexes on immunofluorescent staining and electron microscopy. Lung biopsy in the setting of pulmonary infiltrates or hemorrhage reveals capillaritis, a histopathologic pattern that can also be seen in WG, SLE, and anti-glomerular basement membrane disease. Biopsy is most useful in ruling out alternative pulmonary diagnoses; open lung and thoraco-scopic techniques have a higher yield for demonstrating vas-culitis than transbronchial biopsy. Classic PAN does not cause glomerulonephritis or pulmonary parenchymal disease.
The demonstration of arteritis in PAN may be difficult, especially in the setting of dominant constitutional symptoms and the absence of easily accessible, disease-affected tissue. Biopsy efforts should be directed toward tissue that is abnormal as demonstrated by symptoms or objective testing. Sural nerve biopsy has become a popular option when attempting to diagnose an arteritis that is affecting medium-sized muscular vessels. The sural nerve is an accessible pure sensory nerve, and its vasa nervorum contains small as well as medium-sized muscular arteries. Nerve conduction studies can identify a diseased is-chemic sural nerve before the appearance of clinical symp-toms.23 Multiple reports have emphasized the low diagnostic yield from the biopsy of asymptomatic and electrically normal nerve. Even nerves exhibiting abnormal conduction have reportedly showed no diagnostic pathology 46% of the time.24 There is notable morbidity associated with sural nerve biopsy; 13 of 60 patients experienced wound infections or delayed healing, and three patients suffered from new pain in the distribution of the sural nerve that underwent biopsy.24 Biopsy of clinically uninvolved tissue (i.e., asymptomatic muscle) has a diagnostic yield of less than 30%.
Figure 5 Livedo reticularis is characterized by reddish-blue mottling of the extremities caused by occlusion of the deep dermal arterioles.
Abdominal angiography is frequently utilized in the evaluation of patients who may have medium-sized vessel arteritis when biopsy has been unrewarding or is not an option. Arteries affected by polyarteritis nodosa and other disorders of medium-sized muscular arteries may develop microaneurysms or stenoses that can be visualized by angiography. When angiography is used in an effort to diagnose systemic necrotizing vasculitis in the absence of pathologic evidence of the disease, several caveats must be noted. Angiography has limited spatial resolution; smaller vessels are not well seen. In patients with primarily smaller vessel disease, the angiogram will not likely be diagnostic. In one study, angiograms were diagnostic in only four of 30 patients with MPA, a disease that affects both small and medium-sized arteries.17 Different investigators have reported aneu-rysms in 60% to 90% of patients with PAN. Aneurysms take time to develop and may not be present early in the course of the illness. In addition to being associated with aneurysms, arteritis may be associated with stenoses, which may be longer and smoother than typical atherosclerotic lesions or occlusion. To maximize the yield from the procedure, angiography should include the celiac, renal, and mesenteric vessels. Lack of clinical involvement of an organ (i.e., no intestinal ischemia) does not exclude the possibility of finding abnormal vessels on angiography. It has been suggested that the visualization of aneurysms in PAN denotes more severe disease; it is unclear whether their presence may alternatively relate to the actual duration of the untreated illness. Aneurysms may resolve with successful treatment of primary or viral hepatitis-associated disease. The presence of visceral microaneurysms is not diagnostic of PAN. They have also been anecdotally described in patients with WG and MPA, likely representing medium-sized muscular artery involvement in these diseases. Microaneurysms also occur in nonvasculitic disorders. Isolated case reports have described aneurysms in patients with atrial myxoma, bacterial endocarditis, peritoneal car-cinomatosis, or severe arterial hypertension and after metham-phetamine abuse. Inadequate data are available to assess the sensitivity and specificity or the predictive value of abdominal angiography in the diagnosis of necrotizing arteritis. As is the case when interpreting a biopsy result of suspected vasculitis, imaging studies must be considered in the light of the entire clinical profile. Angiography is generally avoided in the setting of progressive or significant renal insufficiency.
Treatment
Treatment of both PAN and MPA is empirical25 [see Table 2]. Corticosteroids in high doses (1 mg/kg daily of prednisone or its equivalent) remain the initial mainstay of therapy for both disorders in the acutely ill patient. Use of corticosteroids alone may be sufficient in patients who do not have critical organ involvement, defined as renal insufficiency, gastrointestinal ischemia, cardiomyopathy, or dense peripheral neuropathy. Therapy with corticosteroids alone may fail more frequently in MPA than in PAN, given the tendency for frequent relapses in MPA.17 Patients who require long-term corticosteroid therapy for disease control or patients who have clinical markers of severe disease are usually treated with glucocorticoids and an additional immunosuppressive agent such as cyclophosphamide. The indications for initial combination therapy have not been adequately studied.
When active hepatitis B or C infection is present, a relatively short course of steroids should be considered on the basis of disease severity and the organs at acute risk for failure, in conjunction with aggressive antiviral therapy.
Kawasaki Disease
Kawasaki disease (KD) was first described in 1967 as mucocutaneous lymph node syndrome.26 It typically affects infants and young children, causing dominant cutaneous manifestations, fever, and coronary arteritis. It can on rare occasions affect adults.
Diagnosis
The presence of characteristic clinical features has permitted the establishment of diagnostic criteria for KD [see Table 4]. Vas-culitis may involve vessels ranging in size from venules to the aorta. Prominent inflammation is noted in the larger coronary arteries, which results in aneurysm formation in approximately 25% of untreated patients. The immediate and delayed life-threatening cardiac complications of the disease, coupled with its unique therapy (aspirin and intravenous y-globulin), mandates prompt clinical diagnosis. Biopsy is generally not necessary, nor is it likely to yield a specific diagnosis.
High, spiking fevers may persist for 1 to 2 weeks if left untreated. Rapid defervescence is usually observed with initiation of appropriate therapy. Nonexudative conjunctivitis often appears with the fever. Aseptic (lymphocytic) meningitis is common. Oral involvement includes erythema, dryness and fissur-ing of the lips, nonexudative pharyngitis, and tongue erythema with very prominent papillae. Mucosal ulcerations are not characteristic of this illness. Distal limb swelling may appear days after the fever, with erythema and tenderness that are not limited to the joints. Desquamation, often in sheets, may begin days to a few weeks after the onset of fever. When desquamation occurs early in KD, it may appear concurrently with a truncal rash and eye and lip changes; it may mimic a drug reaction or Stevens-Johnson syndrome. The rash is usually diffuse and polymorphous, with urticarial, morbilliform, annular, or plaque components, but it is not vesicular. Adenopathy, which is present in 75% of patients, is most apparent in the cervical region.
The morbidity and mortality (< 3%) of KD is overwhelmingly associated with the development of inflammatory coronary artery aneurysms, most of which are asymptomatic at the time of formation. Aneurysms may be detected by echocardiography. Thrombosis can occur in the aneurysms, resulting in direct or embolic coronary artery occlusion. Coronary events may occur weeks or even many years after the febrile illness. A baseline echocardiogram should be obtained at the time of the acute illness and repeated 2 and 6 weeks later. Early recognition of the disease and treatment with intravenous immunoglobulin and aspirin have significantly decreased the frequency of aneurysm formation and thrombotic coronary events.
Treatment
Treatment of KD should be initiated with intravenous im-munoglobulin (2 g/kg as a single dose) and aspirin (80 to 100 mg/kg/day every 6 hours) as soon as the disease is seriously suspected.27 Aspirin is more effective than corticosteroids in preventing aneurysms. Corticosteroid therapy is usually unnecessary, and some authors feel that it is relatively contraindi-cated. Symptoms tend to respond within several days after the institution of aspirin and intravenous immunoglobulin. In resistant cases, however, corticosteroids are frequently added to the above therapies.
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Table 4 Diagnostic Criteria for Kawasaki Disease |
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Persistent fever (> 5 days) plus |
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Four of the following five conditions: |
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Nonpurulent bilateral conjunctivitis |
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Oral mucosal involvement |
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Erythematous pharynx |
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Red or fissured lips |
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Strawberry tongue |
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Soft tissue abnormalities of hands and feet |
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Edema/erythema |
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Desquamation |
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Polymorphous, nonvesicular rash |
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Cervical adenopathy |
Figure 6 Angiograms of a patient with Takayasu aortitis demonstrating long, smooth stenotic lesions of the left subclavian artery and involvement of other branches of the aortic arch vessels.
Large Vessel Arteritis
Temporal, or giant cell, arteritis (GCA) of the elderly and Takayasu arteritis (TA) are the most common inflammatory diseases of the aorta and its major branches. Similar vascular targeting may occur in Behcet disease, Cogan syndrome, and sarcoidosis. The last two conditions are recognized by the pattern of extra-aortic organ involvement. It is uncertain whether TA and GCA are distinct disorders or are the same disorder with modified expression in different age groups.
Temporal or giant cell arteritis
GCA generally affects individuals older than 50 years.28,29 In many patients, it is associated with the syndrome of polymyal-gia rheumatica (PMR). PMR is characterized by proximal muscle pain, with nocturnal and early morning worsening. There may be a subjective sense of weakness, without true weakness on examination and without elevation of serum muscle enzyme levels.
GCA is variably associated with fever, scalp tenderness, headache, masticatory muscle claudication, peripheral vascular disease, inflammatory aortic aneurysms, and retinal ischemic syndromes. Oligoarticular arthritis, often in the upper extremity, and acute carpal tunnel syndrome can occur. The ischemic symptoms and signs may be clinically indistinguishable from those occurring in arteriosclerotic obliterative disease.
Examination for disparate four-extremity blood pressure readings, abdominal aneurysms, and bruits must be part of the routine follow-up visits of patients with GCA or PMR. Pathologic findings of GCA can occur in superficial temporal arteries of patients with PMR, even without any symptoms of GCA. However, routine biopsy of the superficial temporal arteries in patients with PMR, without any other symptoms of GCA, is not warranted.
Levels of acute-phase reactants are elevated in more than 80% of patients. Definitive diagnosis of GCA is generally made by biopsy of the superficial temporal artery. Pathology in GCA usually reveals chronic mononuclear cell infiltrates; destruction of the internal elastic lamina; and giant cells. The presence of giant cells is not requisite to make the diagnosis. The presence of characteristic clinical features such as new headache and jaw claudication, especially with concurrent PMR, may allow for a presumptive diagnosis in the absence of a biopsy or even when the superficial temporal artery biopsy is negative. However, because other conditions can mimic GCA, including atherosclerosis, an attempt to diagnose GCA by biopsy is warranted in most patients.30 Corticosteroid therapy will not rapidly affect the biopsy results and should not be withheld from a patient strongly suspected of having GCA who is awaiting biopsy. Bilateral superficial temporal artery biopsy increases the diagnostic yield.
Takayasu arteritis
Takayasu arteritis (pulseless disease) is a chronic inflammatory disease affecting the aorta and its major branches.31 Usually diagnosed in younger, predominantly female patients of reproductive age, TA can also occur in young children and older patients of either sex. TA is more commonly associated with stenoses and aneurysms of the aorta and aortic branch vessel than is GCA.
The presenting clinical syndrome may include a prolonged flulike illness, including a polymyalgia rheumatica pattern of muscle pain. Many patients initially present with symptoms of limb, cerebral, or cardiac ischemia in the absence of any constitutional features. The characteristic features of the disease reflect the ischemia produced by the inflammatory stenoses of the aorta and its major branches. Renal ischemia can elicit high renin hypertension. Predominant sites of stenosis are the aortic arch vessels, particularly the subclavian arteries [see Figure 6]. Arm claudication with bruits is common. Superficial artery pain and tenderness (e.g., carotidynia) may be found on examination but are not diagnostic of TA. Severe central hypertension caused by renal artery stenosis may not be recognized because of coexistent arm artery stenosis; thus, four-extremity blood pressure readings must be evaluated initially and monitored on a frequent basis. Occasionally, stenoses exist in all major vessels of the extremities, and cuff monitoring may be an unreliable measure of central aortic pressures. Stroke is not uncommon and is often related to undetected central hypertension. It is extremely difficult to assess the activity of TA; the presence or absence of constitutional features or elevated acute-phase reactants are poor measures of disease activity. This impression is supported by vessel histopathology obtained during reconstructive surgery. Over 40% of vascular specimens from patients thought to be in remission revealed active inflammation.
Diagnosis of TA is usually made by arteriographic demonstration of stenotic lesions; aneurysms are less commonly observed. The entire arch, as well as the abdominal aorta and renal vessels, should be evaluated. It is of paramount importance that central arterial pressure be routinely obtained at the time of angiography and compared with simultaneously obtained arm and leg cuff pressures. The role of sequential vascular magnetic resonance imaging in the evaluation and follow-up of these patients is currently under investigation.32 This technique may reveal therapy-related changes in vessel wall thickness and edema as well as changes in lumen size. Pathologic documentation is difficult to obtain in TA, but the histopathol-ogy, usually obtained at the time of bypass surgery, is similar to that for GCA. Preoperative discussion with the vascular surgeon is mandatory to ensure that appropriate tissue samples are obtained if possible.
Treatment of gca and ta
Corticosteroids are the initial treatment for both TA and GCA. GCA is generally very responsive to steroid therapy, although the most appropriate initial dose remains controversial. Initial daily doses of between 20 mg and 1 mg/kg have been advocated, with tapering over 8 to 12 months. It is generally recommended (without the support of data from controlled trials) that patients with any symptoms of ocular ischemia be initially treated with high-dose corticosteroids (at least 1 mg/kg of prednisone or its equivalent, with some authors suggesting I.V. methylprednisolone in doses of up to 1 g daily for several days). A significant proportion of patients with GCA require several years of therapy. Measurement of acute-phase reactants provides an imperfect index of disease activity and should not be the sole guide for adjustment of steroid dosing. If significant steroid side effects occur or if patients experience relapses during tapering, a second-line agent such as methotrexate is often added on an empirical basis to the corticosteroid therapy. However, the value of adjunctive steroid-sparing agents in GCA is currently unproved. A recent large prospective, randomized trial was unable to demonstrate a positive effect from methotrexate therapy.33 Vascular reconstructive surgery, angio-plasty, and stent placement are adjunctive therapeutic options in some patients. Although very preliminary experience suggests a high degree of stent failure, the frequent involvement of the subclavian vessels in TA must be taken into consideration when choosing the graft implantation site for coronary or carotid bypass procedures. High-dose corticosteroid therapy, especially in the elderly, has potentially dangerous side effects. Special attention must be paid to the prevention of opportunistic infections, osteoporosis, glaucoma, hyperglycemia, and hy-perlipidemia.
