The vasculitides are a heterogeneous group of systemic inflammatory disorders characterized by inflammation of blood vessels.¹ Vascular inflammation may cause vessel narrowing or occlusion leading to tissue ischemia or infarction, or may result in vessel rupture with subsequent hemorrhage. These effects underlie the significant morbidity and mortality associated with the vasculitides.

The various forms of vasculitis differ in regard to the size, type, and distribution of involved vessels. Vessel size alone is inadequate to distinguish between the vasculitides. Consequently, nomenclature and classification schemes also rely on the nature of the inflammatory lesion (e.g., granulomatous, leukocytoclastic, eosinophilic) and the organ systems that are most frequently affected (e.g., ear, nose, sinus, lung, kidney).¹ Inflammatory injury in these disorders may also occur in the absence of vasculitis.

Diagnostic Approach to Vasculitis

Even when a diagnosis of vasculitis has been clearly established on clinical and pathologic grounds, it must be determined whether the vasculitis is caused by a primary (idiopathic) vasculitic disorder or a secondary form of vasculitis. Secondary forms of vasculitis for which the etiology is known include: vasculities complicating a wide variety of viral, bacterial, mycobacterial, fungal, and other infectious agents; vasculitis caused by drug or toxin exposure; malignancies (paraneoplastic, embolic, invasive); and embolic (cholesterol) debris. Other secondary forms of vasculitis for which the etiology may lack details of factors such as vasculitis complicating other rheumatic disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren’s syndrome, and Behçet’s disease (BD) that are secondary idiopathic forms of vasculitis.

The diagnosis of vasculitis stands challenging for a number of reasons. While vasculitis must be considered in the differential diagnosis of any patient with an unexplained multisystem illness or fever of unknown origin, most of the individual forms of vasculitis are uncommon. Early diagnosis of primary vasculitis is critical to ensure that when indicated, prompt and effective immunosuppressive treatment is instituted to minimize the significant morbidity and mortality associated with these disorders. In the diagnostic process, it is also essential to consider secondary forms of vasculitis and diseases that mimic vasculitis such as infectious (e.g., infective endocarditis), neoplastic and paraneoplastic, iatrogenic, genetic (e.g., Ehler-Danlos syndrome type IV, Marfan’s syndrome), atheroembolic, vasospastic (e.g., caused by cocaine, amphetamine, and their derivatives), and other vascular disorders. Immunosuppressive therapy may have adverse and potentially fatal consequences in these disorders.

The diagnostic exercise combines information of several types: clinical phenotype, laboratory data, imaging abnormalities, and histopathologic characteristics. While histopathologic proof is often desirable, it may not be feasible as in the case of large vessel vasculitis (e.g., Takayasu’s arteritis [TAK]), coronary vasculitis (e.g., Kawasaki’s disease [KD]), or ischemic colitis in the absence of surgical indications (e.g., BD, polyarteritis nodosa [PAN], or vasculitis complicating inflammatory bowel disease).

When considering vasculitis in general, patients may present with impressive but nonspecific symptoms such as fatigue, weakness, malaise, fevers, sweats, anorexia, weight loss, arthralgias, and myalgias. More specific, although not diagnostic, features include palpable purpura, mononeuritis multiplex, and the pulmonary–renal syndrome, which raise suspicion of small–medium vessel vasculitides, and the presence of arterial tenderness (e.g., carotidynia) or asymmetry of pulses and blood pressure, which is suggestive of large vessel vasculitis. A thorough review of systems may reveal subtle but important symptoms that the patient may have overlooked. A history of drug or toxin exposure, prior illness (e.g., viral infection such as hepatitis, connective tissue disorder, remote malignancy), and family history (e.g., premature sudden death especially from vascular rupture) should also be sought. A careful physical examination is essential to assess the severity and extent of organ involvement and to help rule out other diseases. Urinalysis should be performed on all patients with evidence of a systemic inflammatory disorder, followed by careful urine microscopic examination if haematuria and/or proteinuria is detected; the presence of dysmorphic red blood cells and red blood cell casts in the urine is a sensitive indicator of glomerulonephritis and may be apparent before the onset of renal failure.

No currently available laboratory test is diagnostic for any form of vasculitis; however, some tests help to increase the degree of confidence in the presumed diagnosis. The most useful in this regard is finding an active urine sediment in the setting of multisystem disease that is not caused by sepsis. Other tests help determine the extent and severity of organ involvement. Therefore, at a minimum, complete blood count (CBC) and differential, serum creatinine, transaminases, and erythrocyte sedimentation rate (ESR) should be performed. An abnormal acute phase response is found in the majority of patients with vasculitis; however, this is not sufficiently sensitive or specific to either “rule-in” or “rule-out” a diagnosis of vasculitis. Culture of blood, tissue, and/or other specimens as indicated and serologic testing to exclude infection (especially hepatitis B and C) should be considered in most cases. Testing for antineutrophil cytoplasmic antibodies (ANCA) is useful if the pretest probability of Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), or isolated renal vasculitis is moderate to high. If SLE, Sjogren’s syndrome, or other related autoimmune disorders are suspected, antinuclear antibodies (ANA) can be helpful. Echocardiography and imaging of organs such as chest, sinuses, or central nervous system (CNS) are indicated if abnormalities are suspected in these sites.

Although biopsy proof of vasculitis in clinically involved organs or tissues provides visible evidence of vasculitis, false negatives may occur because of the small specimen size and the frequently patchy nature of the inflammation.^2,3,4 In addition, because the definitive diagnosis is the sum of clinical, laboratory, imaging, and pathologic information, biopsy alone may not be definitive in regards to final diagnosis. For patients with suspected large vessel or visceral involvement, biopsy is often not possible or may carry unacceptable risks. In such cases, angiography can be helpful. While invasive catheter-directed angiography is still the gold standard for imaging the aorta and its major branches, it is increasingly being supplanted by noninvasive angiographic techniques using magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET).^5,6,7,8 However, these noninvasive techniques do not currently provide sufficient resolution to visualize medium-sized visceral vessels; therefore, catheter-directed angiography is preferred to noninvasive angiographic approaches to visualize vessels of the caliber of the mesenteric and/or renal arteries.⁹

Overview of the Management of Primary Vasculitis

The principles of management of primary vasculitis are the judicious use of immunosuppressive therapy when indicated, accurate assessment of disease activity, and careful monitoring for disease and treatment-related complications.

The choice and intensity of immunosuppressive therapy should be individualized for each patient. This choice will be influenced by the specific form of vasculitis and general knowledge of prognosis, the extent and severity of critical organ involvement, the rate of disease progression, previous immunosuppressive therapy, the presence of infection, or other comorbid illnesses. An inadequate clinical response to immunosuppressive therapy may indicate a requirement for more aggressive therapy; however, it may also be due to the presence of an unsuspected malignancy, infectious process, or vasculitis mimic (e.g., embolic disorders, atrial myxoma, vasoactive drug use). In addition, as immunosuppressive therapy confers an increased susceptibility to infection, and the clinical features of certain infections and malignancies may transiently improve with immunosuppressive therapy, ongoing vigilance is required in patients undergoing treatment for vasculitis.

Glucocorticoids (GC) are the cornerstone of pharmacologic therapy for vasculitis. Immediate life-threatening or critical organ-threatening disease is typically treated initially with intravenous GC, at doses of up to 1 g/d of methylprednisolone (or equivalent) for 3 days, followed by oral GC therapy. Standard doses of oral GC therapy for patients with moderate to severe disease activity are prednisone 1 mg/kg/d or equivalent, up to 60 to 80 mg/d.

Although a response to treatment is frequently seen within a week, this initial dose is continued for 1 month. Thereafter, the dose should be gradually tapered. There is no evidence-based GC tapering schedule, although alternate day tapering regimens have now fallen out of favor because of concerns regarding inadequate control of disease activity. A reasonable prednisone tapering schedule is by decrements of 5 mg every week until a dose of 20 mg/d is reached, followed by decrements of 2.5 mg every 1 to 2 weeks until a dose of 10 mg/d is reached; thereafter tapering should be individualized, by decrements of 1 mg every 1 to 4 weeks depending on the particular disease and the status of the patient. Tapering should be guided by clinical assessment and acute phase reactants, which are useful but imperfect markers of disease activity. Continued tapering of therapy is contraindicated in the setting of suspected relapse. The level of acute phase reactants should not be the sole basis for the diagnosis of a relapse in a patient without symptoms nor should normality of acute phase reactants be used to rule out relapse in a patient with suggestive clinical features. Some patients would be unable to maintain disease remission without continuation of GC therapy; in such patients the aim is to reduce the occurrence of adverse events by minimizing the GC dose, if possible below prednisone 7.5 mg/d or equivalent.^10,11,12 Adverse effects of GC are listed in Table 14-1.

Combination of GC with cyclophosphamide (CYC) remains the gold standard for the treatment of severe forms of vasculitis. The currently available evidence favors the use of daily oral rather than monthly pulse intravenous CYC for systemic vasculitis. Treatment with oral CYC is typically initiated at a dose of 2 mg/kg/d. This is continued until remission induction or marked improvement, typically for 3 to 6 months, during when CYC can be switched to an alternative immunosuppressive agent to maintain remission. Dose reduction is required in the presence of renal failure. Other immunosuppressive agents such as methotrexate (MTX) and azathioprine (AZA) may also be used in the treatment of vasculitis. MTX is administered orally or parenterally once weekly; treatment is typically initiated at a dose of 15 mg and titrated upward to a maintenance dose of 20 to 25 mg as tolerated. MTX is relatively contraindicated in patients with serum creatinine >2.0 mg/dL, hepatic impairment, or bone marrow suppression. AZA is orally administered at a dose of 2 mg/kg, once or twice daily; dose reduction is required in renal failure. Adverse effects of CYC, MTX, and AZA are compared in Table 14-2.

There are some important considerations that apply to all patients undergoing immunosuppressive therapy. Because patients treated with more than 7.5 mg prednisone daily have two- to five-fold increased risk of bone fractures,¹³ unless contraindicated, calcium, vitamin D supplementation, and bisphosphonate therapy should be given to minimize bone loss. A bone density scan is also recommended to assess the risk of fracture and to monitor bone density during follow-up.

All patients treated with high-dose GC in combination with CYC or other immunosuppressive drugs should receive prophylaxis against Pneumocystis jivroveci infection by using trimethoprim-sulfamethoxazole (T/S) as one single-strength tablet daily or one double strength tablet three times per week. Alternative strategies in sulfa-allergic patients include dapsone, atovaquone, and monthly inhaled pentamidine. Dosage of immunosuppressive drugs, and CYC in particular, should be titrated to maintain a white blood cell count greater than 4 000 × 10⁶/mL; induction of leukopenia is not a goal of therapy.

To reduce the risk of bladder toxicity in patients taking CYC, they should be advised to take the recommended dose once daily in the morning after liberal fluid intake, which is to continue throughout the day. These measures help minimize the duration of exposure of the bladder mucosa to acrolein—the toxic metabolite of CYC. Patients taking MTX should be advised to abstain from alcohol because of the risk of hepatotoxicity. Concurrent administration of folic acid (1 mg daily) or folinic acid (5 mg once weekly) reduces some of the adverse effects of MTX. When starting AZA, genotyping for the enzyme that metabolizes AZA (thiopurine methyltransferase) is appropriate, as individuals with deficient thiopurine methyltransferase activity are at an increased risk of AZA toxicity and therefore require a lower starting dose of AZA, and in the case of homozygous deficient patients, an alternative agent is required. Premenopausal female patients should use reliable contraceptive measures while taking immunosuppressive therapies such as CYC, MTX, and AZA. Both male and female patients taking these agents should be advised to avoid conception during and for at least 3 months after its discontinuation. Chronic immunosuppression increases the risk for serious infections and neoplasia.

Laboratory testing includes ESR, CBC, transaminases, creatinine, and urinalysis, and should be monitored regularly. While there is no systematic comparative risk–benefit data to guide the clinician in selecting particular intervals for laboratory monitoring, for the purposes of early detection of disease flares and of treatment-related toxicities, testing as outlined above is recommended no less than once per month, even when the patient is in remission. In addition, in patients receiving CYC, for which additive toxicity over time is most common, we recommend that the CBC and urinalysis should be monitored no less than every 1 to 2 weeks.

Endovascular and surgical techniques are also a critical element in the management of large- and medium-sized-vessel vasculitis. Such interventions are generally reserved for stenotic, occlusive, or aneurysmal lesions leading to organ- or life-threatening consequences. Assessment of vessel patency after vascular procedures requires careful clinical evaluation in combination with available imaging techniques. Interventional management of vascular lesions in the vasculitides will be discussed in greater detail below.

Primary vasculitides characterized by the involvement of aorta and its major branches include giant cell arteritis (GCA) and TAK. Other vasculitides that may involve large vessels include BD, sarcoidosis, Cogan’s syndrome (CS), and KD. Less often aortitis may be a complication of rheumatic diseases such as RA, SLE, and the seronegative spondyloarthropathies as well as a number of infectious diseases, including syphilis and mycobacterial infection.

Giant Cell Arteritis

GCA is the most frequent form of vasculitis in people older than 50 years. Its annual incidence in North America and Europe ranges from 10 to 27 cases per 100 000 individuals older than 50 years.^12,14 Women are affected at least twice as often as men.¹²

Inflammatory cells in arteries of GCA patients reveal features of a delayed-type hypersensitivity reaction, with a T-cell–mediated immune response that is presumed to be directed toward uncharacterized antigens in the arterial wall (Figure 14-1).^15,16,17 Cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β and interferon-γ (IFN-γ), and a variety of chemokines and other proteins, such as matrix metalloproteinases, have been found in inflammatory lesions of GCA.^{18,19,20,21,22,23,24}

Clinical Features

The most common symptoms of GCA relate to involvement of the extracranial branches of the carotid arteries.^11,12,25 Constitutional symptoms such as fever, anorexia, weight loss, malaise, and depression are also common features. The principal clinical characteristics in GCA are listed in Table 14-3. Ischemic manifestations (Table 14-3) constitute the most feared complications at disease onset. They are derived from the vascular occlusion of distal sites leading to organ dysfunction and are presented by 15% to 25% of GCA patients.^11,12,25 The occurrence of a transient ischemic event is a predictor of permanent ischemic lesions.²⁵ A lower systemic inflammatory response at diagnosis is also associated with a higher risk of developing ischemic events.^25,26

Polymyalgia rheumatica (PMR), characterized by aching and stiffness in the neck and shoulder and hip girdles, is present in approximately 50% of GCA patients.^11,12 Polymyalgic symptoms can develop concomitantly with cranial symptoms of GCA or may precede for a number of years the appearance of clinically overt GCA. PMR can also exist as an isolated disease, without vascular involvement. When PMR occurs isolated, at least 10% of temporal artery biopsies of patients may demonstrate histologic evidence of GCA.^11,12

From 10% to 15% of GCA patients present with clinical features of large vessel involvement.^11,12 However, necropsy studies have suggested that large vessel vasculitis occurs in almost all cases.²⁷ Important findings on clinical examination include arterial tenderness, vascular bruits and diminished pulses, and asymmetry of blood pressure in the limbs. Careful physical examination is required to detect these findings since large-vessel involvement in GCA is frequently asymptomatic. When limb claudication occurs, it most commonly involves the upper extremities (Figure 14-2).^11,12 Compared with the normal population, patients with GCA have a 17- and 2.4-fold increased risk of developing thoracic and abdominal aortic aneurysms, respectively (Figure 14-2).²⁸ Several retrospective studies have described aortic aneurysms in 10% to 18% of GCA patients after a follow-up period of 2.5 months to 20 years. In half of these cases, death may occur from aortic rupture or dissection.^28,29,30 In a recent prospective study, aortic abnormalities (aneurysm or dilatation) developed in one-third of patients during a median follow-up period of 5.6 years (range 4–10.5 years).³¹ These vascular complications tend to be apparent late over the course of the disease where such patients are usually in clinical remission.³¹

Diagnosis

In the setting of a suspicious clinical picture, prominent acute phase laboratory findings play an important role in the diagnosis of GCA.^11,12 Classically the ESR is elevated, usually higher than 80 mm/h (Table 14-4). Proinflammatory cytokines, such as TNF-α and IL-6,³² some soluble adhesion molecules, and other inflammatory proteins^33,34 are also increased in sera from GCA patients.

Histologic examination of the temporal artery biopsy may provide the definitive diagnosis of GCA. Preferably, 2 to 3 cm fragment of temporal artery has to be removed from a carefully selected site and different parts of the specimen should be histologically examined. Sensibility and specificity of the surgical procedure will depend on the pretest likelihood of GCA. The inflammatory infiltrate is constituted mainly by T lymphocytes, macrophages, and dendritic cells and is frequently organized in a granulomatous pattern. Multinucleated giant cells are observed in almost half of the cases, usually located near the internal elastic lamina which is often disrupted. Varying degrees of intimal hyperplasia may lead to partial or total luminal occlusion (Figure 14-1).^4,35

If the pretest likelihood of GCA is high, a negative biopsy may still be obtained in 20% to 40% of cases. When this occurs, a contralateral temporal artery biopsy may increase the sensitivity of diagnosis by 10% to 30%. A normal temporal artery biopsy does not exclude the diagnosis of vasculitis, given the patchy distributions of the inflammatory infiltrates.^11,12 For that reason, clinical and analytical criteria for the classification of GCA have been established.³⁶ Other systemic disorders can mimic GCA. These include infections or amyloidosis.^37,38,39 On the other hand, a temporal artery biopsy may occasionally demonstrate of distinct vasculitis caused by PAN, WG, Churg-Strauss Syndrome (CSS), cryoglobulinemic vasculitis, rheumatoid vasculitis, and thromboangiitis obliterans (TAO).^{11,12,40,41,42}

If there is clinical suspicion of large vessel involvement, imaging of the aorta and major branch vessels should be undertaken. The use of newer angiographic techniques for detection of large vessel vasculitis is discussed under the following section on TAK. It has been proposed that ultrasonography (US) of the temporal artery may obviate the need for temporal artery biopsy for the diagnosis of GCA.⁴³ Proponents of US have claimed that the presence of a dark halo around the lumen of the temporal artery on color duplex US represent edema and inflammation in the vessel wall.^43,44 However, this remains an area of controversy.^12,41

Treatment

Pharmacologic Therapy. GCs are the only proven useful anti-inflammatory for GCA. After initial doses of prednisone (or corticosteroid equivalent), which range between 40 and 60 mg/d, response to treatment is usually seen within a few days.^11,12 The dose should be gradually tapered as described above after the first month. Tapering is guided by clinical features and acute phase reactants. Therefore, the level of acute phase reactants should not be the sole basis for the diagnosis of a relapse in a patient without symptoms.^11,12 Total duration of therapy varies between patients. Withdrawal of steroid treatment is achieved in less than half of cases within 2 years. Most patients require GC therapy for several years, and some indefinitely.^11,12 Patients with a strong systemic inflammatory response at disease onset are those who typically require higher cumulative GC doses and more prolonged therapy.³²

When GCA is suspected, the presence of ocular or neurologic disturbances should be considered a medical emergency necessitating immediate commencement of GC therapy. If visual loss is established, intravenous pulses of methylprednisolone of 1 g/d for 3 days are recommended by some authors.²⁶ In these situations, only the early administration of GC, within the 12 or 24 hours, appears to effect visual recovery.²⁶

The efficacy of adjunctive therapy to GC with MTX has been examined in GCA patients, but its use remains controversial.^45,46 The potential role of infliximab, a chimeric monoclonal anti-TNF-α antibody, in the treatment of GCA has been recently investigated in a multicenter, randomized, double-blind, and placebo-controlled trial. Infliximab did not improve durability of remission or reduce cumulative GC doses in newly diagnosed GCA patients.⁴⁷ Low-dose aspirin taken daily has been shown, in two retrospective studies, to reduce the risk of cranial ischemic complications in patients with GCA, without an increase of bleeding complications.^48,49 Statins have anti-inflammatory properties in cardiovascular disease; however, in one small study, statin use was not associated with clinically relevant GC-sparing effects in GCA patients.⁵⁰

In patients with GCA and symptomatic involvement of large vessels, the addition of MTX to GC has been seldom reported.⁵¹ However, this experience requires further validation in larger studies.

Endovascular and Surgical Considerations. Angioplasty or arterial bypass should be considered for symptomatic arterial stenoses. In a recent study, treatment with balloon angioplasty of arterial stenotic lesions of the upper extremities in 10 GCA patients led to a primary patency rate of 65% of the lesions. In spite of frequent restenosis, repetition of angioplasty up to three times showed an overall successful patency rate in almost 90% of vascular lesions during a mean follow-up of 2 years.⁵² Bypass was necessary for the remaining patients. Surgical intervention of aortic aneurysms needs to be considered if the aneurysm becomes symptomatic or in any case when the aneurysm exceeds 5.5 cm in diameter in abdominal aorta, or 5 and 6 cm in ascending and descending thoracic aorta, respectively. Evidence of dissection or an accelerated growth rate, more than 5 mm in 6 months, and hemodynamically significant aortic regurgitation are other indications for surgical repair.⁵³

Prognosis

Some studies have found that the overall mortality in patients with GCA is similar to that of age- and sex-matched controls.⁵⁴ However, there is no question that if GCA-related aneurysms contribute to death by dissection or rupture, in those patients mortality was increased because of GCA.^28,55

Takayasu’s Arteritis

TAK is a granulomatous vasculitis that has a predilection for the aorta and its primary branches. Sustained inflammation of involved vessels leads most often to stenotic or occlusive lesions, but may also result in aneurysm formation.⁵ Although TAK has been described in patients of all races, it occurs most frequently in Asian patients. The estimated annual incidence in North America is only 2.6 cases per million population, approximately a 100-fold lower than that in Japan⁵ females are affected up to 10 times more often than males, with the peak incidence occurring in the third decade of life.⁵

Macrophages and T lymphocytes, including cytotoxic and γ/δ T lymphocytes, are the constituents of inflammatory infiltrates in TAK.¹⁸ A potential role for TNF-α in the pathogenesis of TAK is suggested by the efficacy of anti-TNF-α therapies in patients with refractory TAK.⁵⁶ Compared to normal controls, mRNA for TNF is increased in peripheral blood mononuclear cells.^22,57,58 Serum TNF-α is similarly increased in TAK patients compared to controls.^22,57,58

Clinical Features

TAK presents with constitutional symptoms in approximately 50% of patients.⁵⁹ The most common symptoms and signs of TAK in different cohorts of patients (Americans, Italians, Mexicans, and Indians) are summarized in Table 14-5.^{5,59,60,61,62} The most commonly affected arterial territories in an American cohort are indicated in Table 14-6. Stenotic vascular lesions (Figure 14-3) are found in >90% of patients; dilatation or aneurysm formation makes up approximately 25% of lesions.^59,60 The aortic root is the most frequent location of aneurysm formation. Root dilatation leads to valvular regurgitation in approximately 20% of patients. Aortic aneurysm rupture and congestive cardiac failure caused by aortic insufficiency are two of the main causes of death in TAK patients.^5,59,60

Hypertension is a major source of disease-related morbidity, and although noted in up to 70% of patients from India, Japan, Mexico, and Korea, is present in approximately 40% of US and European patients.⁵⁹ Renal artery stenosis (Figure 14-3) occurs in 25% to 60% of patients and is the most common cause of hypertension.⁵⁹ Other causes include suprarenal aortic stenosis and diffuse aortic stiffening with loss of compliance.

Neurologic symptoms derived from stenoses of carotid or vertebral arteries are present in more than a half of patients (Table 14-5).⁵⁹ Visual disturbances, such as amaurosis fugax and permanent blindness, secondary to hypoperfusion retinopathy or derived from hypertension (hypertensive retinopathy) occur in up to 50% of TAK patients.^5,63

Although pulmonary involvement may be asymptomatic in most patients, imaging abnormalities (e.g., perfusion scan) can be detected in more than half of TAK patients.^64,65 Visceral artery stenoses can occur in up to 60% of cases, but because of abundant anastomoses clinical symptoms are infrequent.⁶⁶ Dermatologic manifestations (erythema nodosum, erythema induratum, and pyoderma gangrenosum) have been noted in up to 28% of patients.⁶⁷

Diagnosis

The diagnosis of TAK is based on clinical findings in the setting of compatible vascular imaging abnormalities. There are no serologic tests that are specific TAK diagnosis⁶⁸ and a large vessel biopsy is usually impractical. However, when a patient undergoes surgery for a vascular complication, it is recommended to obtain a specimen of an involved artery for histologic examination.⁶⁹ Distinct histopathologic patterns can be seen at different stages of TAK. Active lesions may reveal granulomatous arteritis, with transmural inflammation, and patchy destruction of medial musculoelastic lamina. Cells within the infiltrate are mainly lymphoplasmacytic infiltrate, more prominent in the media, multinucleated giant cells, and cytotoxic and γ/δ T lymphocytes.^16,35,69 Both active and healing lesions include variable degrees of intimal and adventitial fibrosis and extensive scarring of the media.³⁵ The inflammatory process leads to myointimal proliferation with subsequent vessel wall thickening and luminal stenosis, resulting in reduction or abolition of blood supply and tissue ischemia.¹⁶ Lesions that predominantly cause destruction of the muscularis and the elastica may result in vascular dilatation or aneurysms. The latter most commonly occurs in the aortic root and arch.⁶⁶

Traditionally, the gold standard for diagnosis of TAK has been the combination of an appropriate clinical phenotype with catheter-directed angiography. Such study provides not only information about the vessel shape and luminal caliber, but also enable recording of intravascular blood pressure measurements. When indicated and disease is quiescent, it also provides opportunities for intervention (e.g., angioplasty).⁵ Limitations of catheter-directed angiography include its inability to provide information about the vessel wall {per se.} It also carries risks related to arterial invasiveness, exposure to contrast agents (e.g., kidney toxicity), and high dose of ionizing radiation. Cardiovascular MRI with its two components, contrast-enhanced MRI and MRA (conventional or 3-D), is considered to have of similar diagnostic accuracy to catheter-directed angiography, and also the advantage of a better safety profile (nor radiation, risk of contrast, or vessel trauma). However, use of MRI does not allow measurement of intravascular pressure or the opportunity to carry out interventional procedures.⁶ Although MRI can provide additional information regarding the appearance of the vessel wall, the value of this data regarding prediction of vascular anatomic change is uncertain.⁷ FDG-PET has recently been demonstrated to be useful in identifying the presence or absence of inflammation within large vessels.⁸ Combinations of some of these techniques are being used with promising results (Figure 14-9). Future studies will need to define more clearly the operating characteristics of these techniques, especially in regards to whether enhanced uptake (presumed inflammation) accurately predicts later vessel anatomic change (stenosis or aneurysm formation).

Disease Activity Assessment

Acute phase reactants may be helpful in assessing disease activity. However, in many patients, they may not correlate with systemic symptoms or progressive change on imaging studies, nor do normal acute phase reactants confirm disease remission.⁵⁹ Sequential imaging evaluations have revealed disease progression (as determined by the presence of new vascular lesions) in more than 50% of patients with clinically stable profiles and normal ESR.⁵⁹ Clinical evaluation also underestimates the presence of subclinical disease activity; almost a half of TAK patients with apparent clinically quiescent disease undergoing bypass have been noted to have histopathologic evidence of vascular inflammation.⁵

In 1994, Kerr et al.⁵ defined active disease according to the existence of new or worsening of any two or more of the following parameters: (1) Signs or symptoms of vascular ischemia or inflammation; (2) Increase in sedimentation rate; (3) Angiographic features; and (4) Systemic symptoms not attributable to another disease.

These features have been demonstrated to be specific and helpful when present, but their absence does not insure disease remission. Studies that utilize these criteria in conjunction with sequential imaging modalities will better inform clinicians about the performance, characteristics of clinical features, laboratory surrogates of disease activity and enhancement per MRI or PET.

Treatment

Pharmacologic Therapy. GC therapy results in clinical improvement in almost all patients, and leads to remission in up to 90%. However, when prednisone is tapered, most patients suffer disease relapse.^59,70 Such patients require additional immunosuppressive therapy. Treatment with MTX may help achieve and maintain disease remission in patients with relapsing or GC-dependent disease.⁶⁹ However, when GC discontinuation is attempted with the aid of MTX or other cytotoxic agents, relapses still occur in most patients. Hoffman et al. showed anti-TNF-α agents to be useful in sustaining GC-free remissions in more than 60% of patients with previously refractory TAK.⁵⁶ In an extended recently published study, the same authors have recently confirmed the sustainability of anti-TNF-α therapy in maintaining disease remission for a longer follow-up period (mean >2 years, range 2 months to 6.5 years).⁷¹ Supporting these findings are several case reports of relapsing TAK that have been successfully treated with infliximab.⁷² A randomized controlled study is required to establish the efficacy and safety of anti-TNF-α therapy in TAK.

Endovascular and Surgical Management. Indications for revascularization in TAK patients include symptomatic cervicocranial or coronary artery disease, renal artery stenosis leading to renovascular hypertension, aortic aneurysm with risk of dissection or rupture; sever extremity claudication and moderate-to-severe aortic valve regurgitation or coarctation of the aorta.⁶⁹ Procedures to re-establish flow in stenotic or occluded vessels include surgical placement of synthetic grafts or autologous vessel bypass and percutaneous transluminal angioplasty. Aortic root repair or replacement are employed for aortic insufficiency.⁶⁹ Kerr et al. found that 50% (30/60) patients followed more than a mean period of 5 years required intervention for either vessel stenosis or aortic regurgitation.⁵ Revascularization procedures in TAK ideally should be performed during disease remission. Endarterectomy has been used in some cases of aortic branch vessel and coronary artery stenosis. However, this procedure is technically difficult or impossible to perform effectively, or may even be dangerous, because arterial lesions in TAK can be rigid and often involve the entire thickness of the vessel wall.⁶⁹

A longitudinal study of 30 patients having 64 revascularization procedures was recently reported from the Cleveland Clinic. All patients were followed for a mean of 3 years and re-evaluated with sequential imaging studies, with there being a mean of 4.8 months between studies. One hundred percent of the patients had stenotic lesions. All but five cases were considered to have a quiescent disease activity at the time of the vascular procedure. Twenty angioplasty procedures were performed. Two were operative failures and in 14/18 (78%) longer-term follow-up revealed restenosis. Forty-four vascular bypass/reconstruction procedures were performed, 47% following previous intervention failures. Although surgical bypass was the most successful intervention, restenosis or occlusion occurred in 36%.

Percutaneous transluminal angioplasty and stenting used alone or as a combined treatment in TAK have been recently reviewed in a study that included 11 series of TAK patients and 224 vascular lesions. Patency rate was variable among series.⁵⁹ Bypass is especially successful when autologous donor vessels are used.^5,73

Low mortality rates have been seen in American cohorts (3%–4%) more than a median follow-up periods of 3 to 5 years. However, chronic morbidity and disability is frequent in TAK.^5,59 Postoperative mortality, defined as death occurring during hospitalization, occurred in 11% of patients in a series of 106 patients with TAK.⁷⁴ Death occurred in most as a result of cardiovascular complications including congestive heart failure, aneurysm rupture, stroke, or hemorrhage.^69,75

Prognosis

Satisfactory outcomes in TAK depend on achieving and sustaining suppression of disease activity, minimizing treatment toxicity, correcting severe anatomic lesions, and effectively controlling high blood pressure when present. Recognition of hypertension is often delayed because of the high frequency of stenoses of the branches of the aortic arch, which may result in misleading low peripheral blood pressure readings in reference to pressure in the aortic root. For that reason, blood pressure should be assessed in four extremities at the onset of the disease and during follow-up visits. Vascular imaging studies will inform the examiner of which extremities have unimpeded flow from the aortic root distally. When reliability of blood pressure recordings is questionable, an invasive angiogram with central aortic pressure measurements plus recordings across stenotic lesions will discern whether any extremity provides an accurate reflection of central aortic pressure. If hypertension is clearly related to renal artery stenosis, such lesions should be surgically corrected.

Morbidity and mortality in patients with TAK are directly correlated with the vascular territories involved and the extent of disease. Additional morbidity is because of the use of GC and other immunosuppressive therapies (e.g., infections, hypertension, diabetes, osteoporosis, or cataracts). Inadequately treated or unrecognized hypertension, aortic aneurysms, aortic valve insufficiency, and coronary artery disease carry a greater risk of premature death. Sudden death may result from myocardial infarction, stroke, or rupture or dissection of an aortic aneurysm. Despite these potential life-threatening complications, 5- to 10-year survival rates have been reported to be >90%.^59,69,76

By definition, medium vessels are those muscular arteries larger than arterioles and smaller than large arteries, sized from 50 μm to 1 cm in diameter.³ Vasculitides that typically target medium-sized vessels include PAN, KD, and TAO. While PAN may affect individuals of any age, KD is seen in infants and small children. TAO is almost exclusively a disorder of adult smokers. Because chronic viral infections, especially hepatitis B, may cause a similar vasculitis to PAN, they have commonly been studied together, and will be discussed together below. It should also be appreciated that schemes based on vessel size are an over simplification. For example, illnesses that are considered “small vessel” vasculitides may also include medium-sized vessels (e.g., WG, CSS, MPA).

Polyarteritis Nodosa

PAN is a systemic necrotizing arteritis of medium-sized and small muscular arteries, and less commonly arterioles. No clear sex or race preference is observed in PAN; peak incidence is in the fifth to sixth decades. PAN is a rare disease with an annual incidence of 4.6 and 9 cases per million inhabitants in England and USA, respectively.⁹

Strictly speaking, PAN is not an immune-complex-mediated disease, making it distinct from similar disease phenotypes associated with viral infections or cryoglobulinemia.⁷⁷ A PAN-like presentation has been reported in chronic viral infections, particularly in association with hepatitis B virus (HBV). Before vaccination against HBV more than one third of cases presenting with features suggestive of PAN were associated with this viral infection, and since then, HBV- /PAN-like cases have decreased to 7%.⁹ The mechanism of vascular inflammation implicated most commonly in HBV-vasculitis is an immune complex-induced lesion.⁹

In 1994, at the Chapel Hill International Consensus Conference, PAN was differentiated from MPA. MPA was defined as a systemic small to medium-sized vessel vasculitis that typically presents with rapidly progressive glomerulonephritis (RPGN) and pulmonary involvement.¹ The absence of pulmonary and glomerular capillary involvement in PAN has become useful in distinguishing this entity from WG, MPA, or CSS. Because of the low prevalence of PAN, many of the series in the medical literature combine discussion of PAN with MPA, CSS, and viral-associated vasculitis, thereby hindering clear characterization of PAN.

Clinical Features

PAN may be indolent and mild, or severe and rapidly progressive. Clinical features in PAN include constitutional symptoms such as malaise, weight loss, fever, and musculoskeletal symptoms in the majority of patients. Skin, peripheral nerve, gastrointestinal, and renal disease occur in most patients. The range of involvement of these and less commonly affected organs is noted in Table 14-7.

Renal failure in PAN is the consequence of multiple renal infarcts, complicated in some cases by malignant hypertension.^78,80 Renal infarctions may be clinically silent and renal insufficiency may develop over the course of months to years.^78,80 Renal hematomas caused by rupture of renal microaneurysms can also occur.⁸⁰

It has traditionally been considered that patients with classic PAN rarely (<10%) suffer relapses,⁸¹ in contrast to patients with WG or MPA.⁸² However, a recent study of 10 PAN patients that strictly followed the Chapel Hill nomenclature for PAN has shown a relapse rate in PAN patients similar to that seen in those with MPA.⁸⁰

Diagnosis

The diagnosis of PAN is often delayed because of the highly variable and sometimes indolent clinical presentation. There are no laboratory markers specific for PAN. Leukocytosis and elevated ESR and CRP are common. Occasionally hypereosinophilia (>1500/mm³) is present. Testing for chronic viral infection and ANCA should also be performed as positive results strongly suggest the alternative diagnoses of viral-associated vasculitis and either WG or MPA.

Ultimately, the diagnosis is clinical–angiographic or histologic. Biopsies of vascular lesions are characteristically patchy and segmental. Active histologic lesions include necrotizing vasculitis with fibrinoid necrosis, which is often associated with thrombosis. Severe vessel wall injury may result in the formation of typical microaneurysms (Figure 14-4). The inflammatory component of the infiltrate in PAN is formed by lymphomononuclear cells and variable number of neutrophils and eosinophils. Necrotizing vasculitis, proliferative and fibrotic or healed changes may coexist.^35,83

Biopsies should be considered of symptomatic or clinically abnormal sites e.g., muscle, sural nerve, testicle, or skin). In carefully selected individuals in whom systemic vasculitis is strongly suspected, muscular biopsies from clinically affected muscles and nerves may reveal vasculitis in approximately 70% of patients.⁸⁴ In cases where biopsies of muscle and nerve are blindly performed, vasculitis can be seen in less than one-third of patients.⁸⁵ While renal biopsy may reveal arteritis of medium-sized vessels (without glomerulonephritis),⁸⁵ the presence of renal microaneurysms increases the potential for hemorrhagic complications. Therefore, closed renal biopsy is not recommended to confirm the diagnosis of PAN, and if renal biopsy is considered necessary, an open procedure should be performed.

When the histologic diagnosis of vasculitis cannot be obtained, or patients are experiencing any symptoms suggestive of abdominal, cardiac, or renal involvement, an angiographic study should be performed. In these cases, if typical angiographic changes are found the diagnosis of PAN can be established. Microaneurysms and stenoses of medium-sized vessels are commonly present in PAN (Figure 14-4). Arterial saccular or fusiform 1 to 5 mm microaneurysms are predominantly seen in the kidneys, mesentery (Figure 14-5), and liver.⁹

Treatment

The main determinants of treatment for patients with PAN or a PAN-like illness are the presence of chronic viral infection, rate of disease progression and the distribution of involved organs.⁴² In patients with PAN-like vasculitis associated with HBV infection, combination of GC with antiviral therapy, such as vidarabine, interferon-α2a, or lamivudine, and in some cases plasma exchanges, may be effective in controlling the disease, and also in facilitating viral seroconversion and preventing the development of long-term hepatic complications of HBV infection. Relapses are rare in HBV-vasculitis and never occur when viral replication has stopped and seroconversion has been obtained.⁷⁹

Milder forms of primary PAN may be treated with GC alone, typically at doses of 1 mg/kg/d. However, in the presence of critical organ- or life-threatening disease or in case of disease progression, intravenous methylprednisolone in pulses of 1000 mg/d for 1 to 3 days and cytotoxic therapy should be also initiated. CYC is used at doses of 2 mg/kg/d or as monthly intravenous doses of 0.6 g/m² for 6 to 12 months.^9,86,87 Following improvement, within 3 to 6 months, switching CYC to other maintenance immunosuppressive agents is preferred to continued use. This strategy helps to avoid long-term CYC toxicity. Initial methylprednisolone should be switched to prednisone at 1 mg/kg/d during 1 month with further tapering.^86,88 Surgical intervention may be required for complications such as bowel perforation, ischemia or hemorrhage, and hematoma or rupture of the kidney, or digital infarction.⁸⁹

Prognosis

The prognosis of PAN depends of the severity and number of organs involved and may be estimated by the five factor score (FFS). The FFS is comprised of the following items: serum creatinine ≥1.58 mg/dL, proteinuria (≥1 g/d), presence of severe gastrointestinal tract disease (defined as bleeding, perforation, infarction, and/or pancreatitis), cardiac (infarction or heart failure), and CNS involvement; each factor is scored as 1 point.^80,89 The French Vasculitis Study Group has reported a 12% mortality at 5 years for PAN patients with FFS = 0, while mortality for FFS = 1 was 26%, and, 46% when FFS ≥2. Cardiac and CNS involvement were found as independent factors predictive of early death in PAN and HBV-associated vasculitis.^81,90 The overall 7-year survival for PAN is 79%.⁹⁰