Giant Cell Arteritis

Giant-cell arteritis, also commonly known as temporal arteritis and described in detail in Chapter 43, is the most common of the idiopathic vasculitides.^4,5 Giant-cell arteritis affects men and women aged 50 and older but is especially prevalent after age 70. Many vascular and systemic manifestations are seen in this disease. Vascular disease occurs in the aorta and its branches, with predilection for the branches of the carotid arteries, especially the ophthalmic artery, with resulting headaches, jaw claudication, and visual impairment. Rapid-onset irreversible monocular blindness is the most feared complication, but stroke, limb ischemia, and aortic disease can occur, the latter more common than generally appreciated, especially several years after the initial presentation. Common systemic manifestations include fever, anemia, proximal arthralgias (polymyalgia rheumatica), and fatigue. Diagnosis is often established on finding arteritis on temporal artery biopsy, but this is not required for a diagnosis. Elevated acute phase reactants are seen in 90% of cases. Treatment with high-dose glucocorticoids is highly effective but often results in significant drug-related morbidity.

Takayasu’s Arteritis

Takayasu’s arteritis, described in detail in Chapter 42, is a vasculitis that involves the aorta and all its major branches and the pulmonary arteries, including but not limited to the brachiocephalic, carotid, vertebral, subclavian, renal, femoral, and coronary arteries. This disease often results in stenoses, occlusions, and ischemic damage to end organs and limbs.^4,6 Stroke, myocardial infarction (MI), limb claudication, and severe renovascular hypertension are all complications well known to occur in this disease. It is mostly seen in women and usually first presents clinically in the second or third decade, but it can occur at older ages. Many patients have associated systemic symptoms of fever, arthralgias, and malaise. The disease has a waxing and waning course, and delay in diagnosis is common. Treatment involves glucocorticoids in almost all patients and often the addition of immunosuppressive medications. Surgical bypass procedures may be necessary in some cases.

Behçet’s Disease

Behçet’s disease is a systemic inflammatory disease with multiple mucocutaneous manifestations, especially including genital and oral ulcers and often severe sight-threatening inflammatory eye disease.⁷ Arthritis, gastrointestinal disease (including mucosal lesions), epididymitis, and secondary amyloidosis can also occur. Although its prevalence is markedly increased in countries in the Eastern Mediterranean, Middle East, and East Asia and descendents of people from these regions, Behçet’s disease is found in populations worldwide.

Vasculitis occurs in up to one third of patients with Behçet’s disease and is unique among the inflammatory vasculitides for the relatively common clinical involvement of venous disease. Both arterial and venous manifestations may occur in the same patients. Venous involvement includes superficial phlebitis, varices, and thromboses of deep veins, vena cava, cerebral sinuses, and other major veins.

The arterial lesions in Behçet’s disease are often in large vessels and frequently result in aneurysms, stenoses, or rupture. The most common sites of arteritis are the aorta and its branches and the pulmonary arteries; however, Behçet’s disease may also involve medium and small vessels.

Behçet’s disease can involve a huge range of different types of histopathologies, consistent with the protean disease manifestations. The oral and genital ulcers do not have specific pathognomonic features. Similarly, biopsy specimens of the gastrointestinal lesions cannot differentiate Behçet’s disease from inflammatory bowel disease. Although the vascular lesions can include large and small arteries as well as veins, these lesions are similar to those of other vasculitides.

Treatment of Behçet’s disease varies with the manifestation being addressed and may range from colchicine and topical glucocorticoids for aphthous ulcers to large doses of glucocorticoids for many problems including mucocutaneous, vascular, and eye lesions. The uveitis is treated with long-term immunosuppressive agents, including cyclosporine, azathioprine, chlorambucil, and cyclophosphamide. Inhibitors of tumor necrosis factor (TNF)-α are now also used to treat this disorder. Many treatment protocols are based on expert opinion, but in recent years an increasing number of controlled clinical trials have been performed, especially involving eye disease. Behçet’s disease can be a highly aggressive form of vasculitis that frequently results in significant morbidity and mortality.

Relapsing Polychondritis

Relapsing polychondritis is a rare connective tissue disease that predominantly affects the cartilaginous structures of the eyes, ears, nose, and subglottis/trachea, but may also affect a wide variety of other organ systems and is associated with vasculitis, especially of large vessels.⁸ The cardinal feature of polychondritis is auriculitis, inflammation of the outer ear, usually sparing the noncartilaginous lobe. Auriculitis, which is also a feature of GPA and CSS but virtually of no other diseases, is readily treated with glucocorticoids and can result in disfigurement if allowed to go untreated. Other common manifestations include inflammatory eye disease that can lead to blindness, destruction of nasal cartilage leading to internal derangement and external disfigurement, sensorineural hearing loss and vertigo, arthritis, and subglottic inflammation with resulting stenosis, a life-threatening condition. Each of these features can also be seen in GPA, although auriculitis is rare in this disease, and relapsing polychondritis is not associated with parenchymal pulmonary manifestations.

The vasculitis seen in relapsing polychondritis can affect vessels of any size, but large-vessel vasculitis is the most common. Aortitis with associated aortic valvular dysfunction and accompanied by thoracic or abdominal aortic aneurysms is fairly common and can lead to heart failure, aneurysmal rupture or dissection, and involvement of branch arteries. Small-vessel disease can affect nerves, eyes, kidneys, and other systems.

The histopathology of relapsing polychondritis includes destructive inflammation of various types of cartilage, necrotizing aortitis, vasculitis in small vessels (e.g., skin, glomeruli), and direct inflammatory infiltration of eye structures, heart valves, pericardium, skin, and other tissues.

Relapsing polychondritis has been associated with various other primary autoimmune diseases, such as inflammatory bowel disease, lupus, and others. The rarity of this syndrome has precluded comprehensive research that might help both better differentiate cases from other conditions and learn more about the pathophysiology. Treatment almost always involves systemic glucocorticoids, and immunosuppressive agents are frequently prescribed for this often rapidly progressive disease.

Cogan’s Syndrome

Cogan’s syndrome is a rare disorder characterized by inflammatory eye and inner ear/vestibular disease that can also involve inflammatory vasculitis.⁹ It is a disease of young adults, usually first affecting patients before age 40, although both children and older patients have also been affected.

The characteristic clinical manifestations of Cogan’s syndrome are interstitial keratitis, sensorineural hearing loss, and vestibulatory dysfunction. Although interstitial keratitis is the most common eye problem in Cogan’s syndrome, uveitis, scleritis, and many other types of ophthalmological inflammation can occur. The eye and ear damage is often permanent and can be quite debilitating. The combination of inflammatory eye disease and inner ear problems is required for a diagnosis of Cogan’s syndrome, but these findings can occur in other diseases as well, such as infections, malignancies, sarcoidosis, and various autoimmune diseases, including other vasculitides (e.g., GPA, relapsing polychondritis, Behçet’s disease). Other organ systems are less commonly involved.

Vasculitis occurs in up to 15% of patients with Cogan’s syndrome and is mostly large-vessel disease, with some medium-vessel manifestations reported. The large-vessel disease in Cogan’s syndrome is similar to that of TA and includes aortitis with aortic insufficiency, stenoses of the carotid and subclavian and other aortic branch arteries, and even coronary artery disease (CAD). Treatment of Cogan’s syndrome includes both glucocorticoids and immunosuppressive drugs, appropriate rehabilitation (e.g., vestibular retraining), surgical correction of eye damage, and use of hearing aides or surgical correction of hearing loss.

Idiopathic Aortitis

Aortitis may be found in the absence of any other manifestations of a systemic inflammatory disease.^10–12 These cases often come to the attention of vascular medicine specialists when patients undergoing surgical repair of aortic aneurysms and dissections are found to have inflammation consistent with aortitis on pathological specimens. Autopsies and studies of large numbers of surgical specimens have demonstrated that noninfectious aortitis occurs in 4% to 15% of cases. Although on detailed investigation, many of these patients are retrospectively found to have had evidence of GCA, TA, relapsing polychondritis, GPA, or another definable vasculitis, it is common among these cases to find no evidence of more systemic inflammatory disease. The majority of cases of so-called idiopathic aortitis involve thoracic lesions, in contrast to the overall predominance of abdominal aortic lesions for noninflammatory disease.

It is possible that cases of isolated inflammatory aortic aneurysms will be increasingly identified earlier as magnetic resonance imaging (MRI) technology continues to improve and helps demonstrate inflammation in the arterial wall. It can, however, be difficult to differentiate inflammation due to true idiopathic aortitis and vasculitis from the vascular and periaortic inflammations seen in association with atherosclerotic disease. Currently, in the absence of pathological specimens or other evidence of a vasculitis, MRI alone is not diagnostic for inflammation. The emergence of positron emission tomography (PET) scanning for large-vessel disease may also help in the evaluation of such patients.

The approach to treatment of idiopathic aortitis is unclear; many patients never develop other findings of vasculitis. However, new aneurysms and significant vascular disease do occur in some cases.¹¹ Comprehensive evaluation of evidence of systemic disease is necessary and should include a detailed physical examination, diagnostic imaging, laboratory studies, and other approaches outlined later in this chapter. Appropriate treatment should be given if inflammatory disease other than that seen in the surgical specimen is found, but not all patients require glucocorticoids, especially in the postoperative period. Furthermore, regular follow-up of such patients by a specialist knowledgeable about vasculitis is imperative because lesions may develop subtly and only years after the initial pathological diagnosis is made.

Miscellaneous Forms of Large-Vessel Vasculitis

Although large-vessel vasculitis is only rarely seen with other systemic inflammatory conditions, it is important to recognize these potential associations. Aortitis is rarely associated with long-standing seronegative spondyloarthropathies (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease) and can result in aortic insufficiency. Retroperitoneal fibrosis, a rare disease of proliferating fibroblasts usually causing ureteral obstruction and at times aortic stenosis and periaortitis, is also associated with true inflammatory aortitis. There have been a few case reports of large-vessel vasculitis in patients with rheumatoid arthritis, systemic lupus erythematosus (SLE), and GPA.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is among the “purer” vasculitides in that most of its manifestations are due to true vascular inflammation.¹³ With the identification of other types of vasculitis, the spectrum of what is now diagnosed as PAN has narrowed over the past 50 years. Although characterized as a medium-vessel disease, PAN may also involve small vessels such as those in the skin. Polyarteritis nodosa frequently involves inflammation leading to multiple small aneurysms that often appear angiographically as a “string of beads.” Ischemia and infarction of kidneys, intestines, and skin are common in PAN, with arthralgias, myalgias, and fevers also frequently seen. Diagnosis is based on angiographic appearance (Fig. 41-2) or tissue pathology, often from surgical specimens such as a resected ischemic bowel segment. Interestingly, PAN in one subset of patients is associated with either hepatitis B or hepatitis C infections.^13,14 Importantly, there is a difference between hepatitis C–associated PAN and hepatitis C–associated cryoglobulinemic vasculitis (CV, see later section). Cardiac manifestations of PAN are due to coronary arteritis or malignant hypertension (secondary to renal artery disease) and include myocardial ischemia, heart failure, and arrhythmias.

Figure 41-2 Polyarteritis nodosa (PAN) with stenotic lesions (A) and wall thickening and enhancement (B) of celiac and superior mesenteric arteries imaged using three-dimensional (3D) dynamic gadolinium-enhanced magnetic resonance angiography (MRA).

Treatment of PAN almost always involves high-dose glucocorticoids followed by a slow tapering of the dose. In more severe cases, an immunosuppressive agent is added. Hepatitis-associated PAN is now often treated with short courses of glucocorticoids and prolonged courses of antiviral agents. The rate of disease relapse in PAN is lower than that for many other types of vasculitis, and this relatively good prognosis is another important factor to take into consideration when deciding on a therapeutic regimen. Due to the rarity of the disease, controlled clinical trials for PAN are unlikely to occur; treatment is based on case series and expert opinion.

Granulomatosis with Polyangiitis (Wegener’s)

Granulomatosis with polyangiitis is characterized by the triad of inflammation and destruction of tissue in the upper airway and sinuses (Fig. 41-3), lower airway (Fig. 41-4), and kidneys (Fig. 41-5), as well as the development of ANCAs.^15,16 Approximately 70% of patients with GPA are positive for ANCA at diagnosis, although some will develop the antibodies later in the course of their illness. Among patients with GPA and glomerulonephritis, more than 90% are positive for ANCA. Although the combination of these features is common in GPA, many patients present with only a subset of these findings. Granulomatosis with polyangiitis also frequently involves many other organ systems. The upper airway lesions include destructive rhinitis, often leading to nasal bridge collapse and the “saddle nose” deformity, sinusitis, and subglottic inflammation that can lead to life-threatening tracheal stenosis. The most severe form of pulmonary disease in GPA is alveolar hemorrhage, and this is a common cause of early death. Other common pulmonary lesions include nodules, with or without cavitation, and tracheobronchitis. Other common features of GPA are retroorbital pseudotumor with resulting proptosis, conductive and sensorineural hearing loss, mononeuritis multiplex, arthritis, and purpura. Peripheral vascular involvement with gangrene is seen in GPA and may be the presenting feature (Fig. 41-6).

Figure 41-3 (See also Color Plate 41-3.) Severe sinusitis in a patient with granulomatosis with polyangiitis (GPA; Wegener’s).

A, Computed tomography (CT) scan during an acute flare of disease. B, H&E stain of a sinus biopsy from this patient demonstrates characteristic inflammation, including a giant cell.

Figure 41-4 Pulmonary hemorrhage in a patient with granulomatosis with polyangiitis (GPA; Wegener’s) as seen on chest computed tomography (CT) scans.

A,During acute flare of disease. B, Same patient after treatment with glucocorticoids and cyclophosphamide. Patient’s dyspnea and plain radiographic changes mostly resolved within 2 weeks of starting glucocorticoids.

Figure 41-5 (See also Color Plate 41-5.) Renal biopsy in a patient with granulomatosis with polyangiitis (GPA; Wegener’s same patient as in Fig. 41-4) with rapidly progressive glomerulonephritis.

A, H&E stain demonstrates marked glomerular destruction as well as a multinucleated giant cell (upper left). B, Characteristic “pauci-immune” immunofluorescent staining seen in GPA and microscopic polyangiitis (MPA).

Figure 41-6 (See also Color Plate 41-6.) Gangrenous toe in a patient with granulomatosis with polyangiitis (GPA; Wegener’s).

A,Gangrenous left second toe pretreatment. B, Conventional angiogram of left foot at time of gangrene seen in A, demonstrating marked stenosis/occlusion of dorsal pedal artery and runoff. C, Same toe months after initiation of glucocorticoids and cyclophosphamide. Only minimal tissue loss resulted, and toe is now well perfused.

Inflammatory cardiac disease is rare in GPA but can include myocarditis and pericarditis. Aortic or large-vessel involvement in GPA is extremely uncommon.

Venous thromboses, including both deep vein thromboses (DVTs) and pulmonary emboli (PEs), occur frequently in GPA and may be associated with active disease.^17,18 Although some of the pathology in GPA is indeed granulomatous with histiocytes, piecemeal necrosis, and occasional giant cells and eosinophils, other manifestations of inflammation are also seen in the disease. True vasculitis occurs and includes capillaritis. The renal disease of GPA is identical to other ANCA-positive diseases, and the pathology is that of rapidly progressive glomerulonephritis.

Untreated, GPA most often leads to death or serious damage.¹⁹ Glucocorticoids are always used for treatment, but the prognosis of GPA changed considerably when a protocol using cyclophosphamide was introduced in the 1970s at the National Institutes of Health (NIH). The morbidity and mortality of GPA was markedly improved by cytotoxic therapy: 1-year mortality changed from more than 80% to less than 20%.^16,19,20 However, serious side effects are common with the use of cyclophosphamide, and the rate of recurrent disease in GPA after therapy is above 50%. In recent years, new treatment protocols have been tested in open and controlled trials that incorporate less toxic immunosuppressive drugs, including methotrexate and azathioprine.^21–23 Two multicentered randomized controlled trials (RCTs) have demonstrated that treatment with rituximab, a monoclonal antibody directed against the CD20 receptor on B cells, was equivalent to cyclophosphamide for induction of remission in ANCA-associated vasculitis (GPA and MPA).^24,25 In 2011, the U.S. Food and Drug Administration (FDA) approved rituximab for the treatment of GPA and MPA, and it has quickly become an established alternative to cyclophosphamide.

Microscopic Polyangiitis

With the publication of the Chapel Hill Consensus Conference classification system, recognition of MPA as a separate entity gained acceptance.^2,13 Microscopic polyangiitis is a mostly small- to medium-vessel ANCA-associated vasculitis with manifestations that strongly overlap with GPA. Its key features include glomerulonephritis, alveolar hemorrhage, skin lesions, and mononeuritis multiplex, but many other organ systems may be involved as well. Unlike GPA, the pathology of MPA is nongranulomatous and does not involve the type of nonvascular disease seen in GPA or CSS. The glomerulonephritis of MPA is identical to that seen in GPA. Most patients with MPA are positive for ANCA, and the predominant ANCA antigen specificity is myeloperoxidase. Cardiac manifestations of MPA are uncommon, but peripheral artery disease (PAD) and gangrene are seen and may be confused with noninflammatory vascular disease. Microscopic polyangiitis should be differentiated from classic PAN. Polyarteritis nodosa is more of a medium-vessel disease and does not include glomerulonephritis or pulmonary capillaritis. Microscopic polyangiitis does not produce the microaneurysms seen in PAN. Treatment of MPA is essentially identical to that for GPA.

Churg-Strauss’ Syndrome

Churg-Strauss’ syndrome, also known as allergic granulomatous angiitis, is a rare disease characterized by the triad of asthma, pulmonary infiltrates, and hypereosinophilia.^26,27 Churg-Strauss’ syndrome can, however, involve almost all the clinical features seen in GPA, including the presence of ANCA in some cases (30%-40%). As with GPA, much of the pathology seen in CSS is due to inflammation that is not “vasculitis” per se but is every bit as damaging as vascular inflammation. Tissue eosinophilia, although seen in other types of vasculitis, is particularly common in CSS and often striking. More than 90% of patients have asthma, often severe; the hypereosinophilia may be a marker of disease activity for some patients but is not always present. Pulmonary manifestations include dense infiltrates that rapidly clear with glucocorticoid therapy. Additionally, neuropathies—especially mononeuritis multiplex and gastrointestinal ischemia—are common features and quite damaging. Diagnosis is based on the combination of clinical findings, hypereosinophilia, and pathology specimens that often show granulomatous and eosinophilic inflammation.

Cardiovascular manifestations of CSS are fairly common and include myocarditis with resultant congestive heart failure (CHF) and pericarditis. Angina is rare in CSS. Cardiac involvement in CSS may be rapid in onset and fatal.

Glucocorticoids are the mainstay of treatment for CSS, but immunosuppressive agents are increasingly being used for more severe cases and to help wean patients from glucocorticoids. It is important to avoid overtreating the asthma component of the syndrome; asthma is not in itself a reason to start cytotoxic medications.

Kawasaki Disease

Kawasaki disease, a vasculitis of young children involving medium and small arteries, is a leading cause of acquired CAD in children.²⁸ The disease manifests as a systemic illness with high fevers, conjunctival injection, erythematous oropharyngeal lesions, erythematous rashes and skin desquamation, lymphadenopathy, and other signs and symptoms. Cardiac involvement is frequent in Kawasaki disease and can result in long-term morbidity. Myocarditis and pericarditis are common and can be serious, but coronary artery aneurysms are the most feared aspect of the disease. Both panarteritis and granulomas can be seen in the vessels, with subsequent scarring and aneurysm formation. Treatment includes aspirin and intravenous immunoglobulin (IVIG); such regimens have been shown to markedly reduce the incidence of coronary complications. Kawasaki disease is described in detail in Chapter 45.

Henoch-Schönlein Purpura

Henoch-Schönlein purpura is a small-vessel vasculitis that classically involves the clinical triad of inflammatory arthritis, ischemic abdominal pain, and purpura, although not all cases exhibit all three manifestations.²⁹ The most feared manifestation of HSP is glomerulonephritis, which can lead to renal failure. Cardiac disease is not a feature of HSP, but hypertension from renal insufficiency can be severe. The lesions in HSP often involve leukocytoclasia and immunoglobulin (Ig)A deposition. An elevated serum IgA level is commonly seen in patients with HSP.

Henoch-Schönlein purpura is much more common among young children and is probably the most common type of vasculitis in this age group. Nevertheless, HSP is also seen in adults. The disease is more often self-limited among children and more likely to lead to chronic renal insufficiency in adults. Relapse is common in all age groups. Treatment of HSP varies from watchful waiting in some cases of pediatric HSP, to high-dose glucocorticoids, to the addition of immunosuppressive agents. However, it is not clear whether immunosuppressive therapy substantially alters long-term outcomes for HSP.

Cryoglobulinemic Vasculitis

Cryoglobulinemic vasculitis occurs when cryoglobulins, any of various types of Igs that precipitate from serum at temperatures below body temperature, induce an immune complex–mediated inflammatory process in any organ.³⁰ Several types of cryoglobulins can occur, and cryoglobulinemia is subclassified based on the mix of IgG and IgM antibodies that make up the cryoglobulin portion of serum (the “cryocrit”), and whether the excess cryoproteins are polyclonal or monoclonal.

Cryoglobulinemic vasculitis was previously considered to be a quite rare phenomenon sometimes seen in chronic inflammatory diseases such as lupus or rheumatoid arthritis or associated with lymphoproliferative disorders. Once the association between hepatitis C infection and type 2 mixed CV was established, however, it became apparent that coincident with the worldwide rise in hepatitis C infection, CV has been increasingly identified as a cause of vasculitis. The vast majority of cases of CV now seen are associated with hepatitis C infection.

Major clinical manifestations of CV include cutaneous vasculitis (purpura), arthralgias, peripheral neuropathy, and nephropathy with associated renal insufficiency or nephrotic syndrome (or both). Cardiovascular manifestations of CV include Raynaud’s phenomenon, hypertension, and congestive heart failure. The hypertension in CV, which is often associated with renal disease, can be severe and lead to cardiac failure.

The histopathology of CV includes necrotizing vasculitis but may also involve Ig and complement deposition detected by immunofluorescence staining.

Treatment of CV is somewhat controversial. However, there is consensus that for patients with CV who are infected with hepatitis C virus, treatment with antiviral agents, even in the absence of significant liver disease, is important. For acute disease exacerbations or when antiviral therapy is not efficacious or possible, treatment may include glucocorticoids, cytotoxic agents, and plasmapheresis. There is increasing evidence that rituximab (ant-CD20 B cell depleting agent) is effective in treating CV.

Primary Angiitis of the Central Nervous System

Primary angiitis of the central nervous system (PACNS) is a quite rare necrotizing angiitis limited to the central nervous system (CNS).^31,32 PACNS is frequently associated with subacute nonfocal neurological deficits and chronic meningitis, although strokes and hemorrhage can also be seen.

Diagnosis of PACNS necessitates first suspecting this rare disease. Conventional angiography may be helpful in identifying other entities, such as aneurysms and emboli, but is often not diagnostic for vasculitis for several reasons (Fig. 41-7). First, in older patients the endothelial changes of atherosclerosis may mimic those of vasculitis. Second, vasospasm can be confused with stenosis from either atherosclerosis or inflammation. Finally, the resolution of conventional angiography is such that small arteries are not well visualized, and thus many cases of vasculitis may be missed by this technique. Leptomeningeal biopsies or larger tissue samples from affected brain areas are often necessary to demonstrate PACNS and provide the level of evidence required to institute therapy. The histopathology is that of vasculitis, but granulomas and giant cells are not always seen; there may be no inflammation in the vasospastic variant. Tests of cerebrospinal fluid are often normal in patients with PACNS, but are important in evaluating patients for other conditions, especially infection or malignancy.

Figure 41-7 Multiple areas of brain infarction secondary to primary angiitis of the central nervous system (PACNS) as seen on gadolinium-enhanced magnetic resonance angiography (MRA).

The cerebral angiogram on this patient was unremarkable, but brain biopsy demonstrated small-vessel vasculitis.

Experts in vascular medicine need to be aware of PACNS because it can easily be mistaken for atherosclerotic disease with multiple infarcts. PACNS is extremely rare, but the approach to treatment is quite different from atherosclerotic disease.

Treatment recommendations are based solely on case series and an incomplete understanding of the pathophysiology. PACNS is treated with glucocorticoids, with immunosuppressive agents often added.

It is imperative to differentiate PACNS from the increasingly recognized set of reversible cerebral vasoconstrictive syndromes (RCVS) previously referred to as benign PACNS³³; RCVS is not a vasculitis. It is characterized by acute onset of severe headache (“thunderclap headaches”) and a focal neurological event. RCVS is treated with aggressive vasodilators, including calcium channel blockers, and strict avoidance of smoking and vasoconstricting drugs and substances, such as caffeine, cocaine, sympathomimetics, and serotonin receptor agonists (e.g., sumatriptan).

Vasculitis Secondary to Autoimmune/Connective Tissue Diseases

Vasculitis, especially of small arteries, can be seen in various systemic autoimmune diseases, including SLE, rheumatoid arthritis, Sjögren’s syndrome, and systemic sclerosis (scleroderma). In these diseases, vasculitis usually accompanies evidence of severe disease in other organs or long-standing disease (e.g., rheumatoid arthritis). Skin vasculitis is common, but mesenteric and CNS vasculitis are the most feared and dangerous vascular manifestations seen in these diseases.

Although coronary arteritis is rarely seen in these systemic autoimmune disorders, there is an increased recognition of early accelerated atherosclerotic CAD among patients with SLE, rheumatoid arthritis, and other chronic inflammatory diseases. The pathophysiology of this problem is under active investigation and parallels the increased attention vascular biologists are paying to the contribution of inflammation to atherosclerosis. When vasculitis occurs in SLE or rheumatoid arthritis, it is frequently severe and often necessitates treatment with high-dose glucocorticoids and cyclophosphamide.

Drug-Induced Vasculitis

Many drugs or other toxins have been implicated as causing inflammatory vasculitis involving vessels of all sizes, especially small arteries. A full list of drugs considered to be causative for vasculitis and details regarding the clinical syndromes of drug-induced vasculitis are available in recent reviews.^34,35 There is an interesting subset of patients with ANCA-associated vasculitis whose disease is caused by exposure to certain medications.³⁶

The clinical manifestations of drug-induced vasculitis range from skin-only disease to widespread life-threatening multisystemic disease. No clinical, laboratory, or pathological findings differentiate drug-induced from other types of vasculitis. Given that agents from most classes of drugs have been implicated in vasculitis, it is important that clinicians consider the possible contribution of not only every medication the patient was taking at the time of clinical presentation but also medications, supplements, and illegal drugs used in the previous year. The temporal association between drug exposure and disease, combined with the pattern of illness and evidence for or against a different vasculitic process, are helpful in establishing a diagnosis of drug-induced vasculitis.

Management of drug-induced vasculitis always includes discontinuation of the putative causative agent when possible, but may also involve treatment with clinical observation alone, glucocorticoids, or immunosuppressive agents. Patients should be followed for an extended period, even after apparent disease resolution, to ensure the diagnosis of drug-induced vasculitis rather than waxing and waning idiopathic vasculitis.

Medical History

Medical history and physical examination remain key elements of evaluation for vasculitis. A comprehensive review of systems is essential, and the potential queries related to vasculitis are numerous. Examples of symptoms to inquire about include any visual changes or eye symptoms, changes in hearing, nasal discharge or epistaxis, sinusitis, headaches, any mental status change, any neurological symptom, stridor, wheezing, cough, hemoptysis, pleuritic chest pain, jaw or limb claudication, abdominal pain, any skin lesion, arthralgias, arthritis, myalgias, weakness, fevers, weight loss, and many other symptoms.

A full and accurate medication and drug use history is mandatory and should include any prescription drugs, over-the-counter products, illegal drugs, and alternative/herbal products taken within the prior 6 to 12 months, as well as accurate stop and start dates. If patients have been prescribed medications to address specific symptoms that may be vasculitic, documenting the response to these treatments may be important.

Physical Examination

A full physical examination is required whenever a patient is evaluated for potential vasculitis, and several examination findings should always prompt consideration of vasculitis in any patient. Blood pressure should be measured in both arms for discrepancies. Obtaining pressures in the legs may be appropriate if lower-extremity stenoses are suspected. Hypertension may result from renal artery stenoses (RAS) from vasculitis, and similar physiology occurs with some tight suprarenal aortic stenoses. A full examination of bilateral pulses should include radial, ulnar, brachial, carotid, femoral, popliteal, posterior tibial, and dorsalis pedis pulses. Bruits should be listened for over the aorta and the carotid, femoral, axillary, subclavian, and renal arteries. Presence of blood pressure discrepancies, absent pulses, or arterial bruits are each highly specific for major arterial disease but are not highly sensitive for major arterial lesions in large-vessel vasculitis.³⁷

Careful examination of skin and mucosal surfaces can reveal many clues to vasculitis. Although palpable purpura is the classic vasculitis skin lesion, not all purpura is vasculitis, and not all skin vasculitis manifests as purpura. Macular lesions, both flat and raised, as well as bullae and nonerythematous lesions, can all occur in vasculitis. Livedo reticularis may be a clue to vasculitis or vasospasm. One should examine the patient for oral or genital aphthous ulcers. Extremity cyanosis and pallor may be seen and may be variable depending on the ambient temperature and limb positioning. Ulcerations and crusting should be sought in the nasopharynx. Nailfold capillary changes can be seen on bedside microscopic examination with an ophthalmoscope. Signs of capillary fragility, especially over sites of blood pressure cuff or tourniquet application, may be seen.

The rest of a full physical examination is also essential in evaluating for vasculitis. Lung examination may reveal any of the many abnormalities commonly seen in vasculitis, including rhonchi, pleural rubs, dullness due to effusions, and wheezing. Careful cardiac auscultation might reveal evidence of aortic regurgitation, as seen in aortitis or pericardial rubs. Gross inspection of the eyes may reveal signs of inflammation, and funduscopic examinations may show retinal pallor or other signs of ischemia. A full ophthalmological examination including slit lamp is necessary for any patient suspected of vasculitis with eye symptoms. A full joint examination may reveal even asymptomatic effusions. Detailed neurological examination is essential; subtle cranial and peripheral neuropathies often go unnoticed by both patients and physicians, but are clues to severe disease.

Laboratory Studies

Diagnostic Vascular Imaging

Radiographic assessment of vascular structures has long been an important tool for diagnosing patients with vasculitis. This is especially true when medium and large vessels are involved because they are much more likely to be visualized by the techniques available.⁴⁰ Although small- and even medium-sized arteries can often be seen on diagnostic biopsies or surgical specimens, large vessels are not usually amenable to tissue biopsy. Thus diagnostic imaging is crucial to assessment and management of patients with large-vessel vasculitis. The two great challenges inherent in interpretation of imaging of large vessels are (1) differentiating inflammatory disease from atherosclerotic disease and (2) trying to determine whether vascular lesions represent “active” disease. In recent years, interest in large-vessel vascular imaging has greatly increased as investigators and clinicians working in vasculitis strive to properly incorporate advances in various radiological modalities into practice. Imaging of organs and tissues other than arteries themselves is of obvious benefit for specific syndromes to help understand the extent of disease, facilitate choice of tissue biopsy, and rule out other pathology.

Specialists in vascular medicine need to be aware of the capabilities and limitations of various modalities for imaging the vascular system and differentiating atherosclerotic from inflammatory disease. Vascular imaging is much more commonly obtained to evaluate suspected atherosclerotic or structural disease, and thus it is vital that inflammatory disease is recognized, even when it is not expected. The increased recognition that atherosclerosis may have an inflammatory component and that vasculitis can result in some changes seen in atherosclerosis makes this differentiation even more challenging. Marked differences in treatment and prognosis for these different disorders make continued cooperative work by experts in cardiology, rheumatology, radiology, vascular surgery, and other specialties essential in evaluating patients and interpreting imaging data. The following sections summarize the progress to date in using various imaging modalities for evaluating vascular disease in the inflammatory vasculitides.

Tissue Biopsy

Given the need to often exclude infection, malignancy, or other processes, as well as the need for immunosuppressive medications for vasculitis, biopsy evidence is often crucial, and empirical therapy is strongly discouraged. With the exception of some cases of large-vessel vasculitis and some situations in patients with ANCA-positive disease, tissue biopsy is usually necessary to establish a firm diagnosis of vasculitis.

A temporal artery biopsy is almost always appropriate when GCA is a consideration, even if there are no cranial symptoms. A positive biopsy is such strong evidence for GCA that although a negative temporal artery biopsy does not exclude the diagnosis, a second contralateral biopsy is sometimes advised if the initial specimen is nondiagnostic.

For large-vessel diseases other than GCA, a vessel biopsy is almost never obtained because a medium- to full-thickness biopsy of the aorta or its main branches has obvious morbidity. Obtaining surgical specimens during bypass procedures or biopsies under highly controlled situations such as during aortic valve or graft surgery should, however, be considered when a diagnosis of large-vessel disease has not yet been established or when disease activity status is unclear.

For the other vasculitides, it is usually preferred to obtain a biopsy from the most accessible tissue. Skin biopsies are simple, have low risk of morbidity, and can be instrumental in diagnosis. Too often, purpuric lesions are assumed to be vasculitis, and biopsies not performed. Additionally, skin biopsies can be examined for evidence of embolic, thrombotic, or infectious diseases.

In the proper setting, biopsies of kidneys or lungs involve moderate risks but can be of high yield, whereas biopsies of other tissues (e.g., sinus mucosa, nerve, myocardium) are lower risk but also have lower diagnostic yields. Biopsies of other organs, such as intestine and liver, offer low yields and higher risks but may be appropriate, especially during a surgical procedure, in certain circumstances.

Medical Therapies for Vasculitis

Medical management of patients with vasculitis should only be directed by physicians familiar with both the use of chronic immunosuppressive agents and the clinical presentation and management of vasculitis. The acute and chronic toxicities of these drugs should not be underestimated and can result in significant morbidity. Treatment protocols are beyond the scope of this chapter, but the most commonly used medications for vasculitis are briefly outlined. Many different agents have been used for vasculitis (see Box 41-2).

Glucocorticoids are used for almost all patients with almost all types of vasculitis during the acute presentation or during flares. They have a rapid onset of action, and high doses often stabilize patients even with severe manifestations such as alveolar hemorrhage or glomerulonephritis. The toxicities of glucocorticoids, especially with prolonged use, are serious and common and include weight gain, osteoporosis, osteonecrosis, glucose intolerance, Cushingoid habitus, adrenal suppression, hypertension, mood disturbances, frank psychosis, cataracts, glaucoma, and many others (IV).

Immunosuppressive drugs are often used in conjunction with glucocorticoids, either to provide more effective therapy and induce a remission or to act as “steroid-sparing” drugs, allowing for safe tapering of the glucocorticoids.

Cyclophosphamide is widely considered the most effective agent for inducing and maintaining remission in various types of vasculitis.¹⁶ The introduction of cyclophosphamide-based therapy changed the prognosis of many of these diseases. Although cyclophosphamide is extremely effective, its multiple toxicities are severe and include cytopenias, especially neutropenia with associated infections, gonadal failure, teratogenicity, hemorrhagic cystitis, transitional cell carcinoma of the bladder, myelodysplasia, mucositis, hair loss, and others. Controversy exists about the best route of administration for cyclophosphamide, orally or intravenously (IV).

Multiple alternative agents have been tested and proposed to limit use of cyclophosphamide. Methotrexate, taken orally or intramuscularly (IM) weekly, has demonstrated efficacy as both a remission-induction agent and remission-maintenance agent for GPA and is used for both purposes for multiple vasculitides.⁴¹ The toxicities of methotrexate include cytopenias, gastrointestinal upset, oral ulcers, teratogenicity, and hepatic disease. Azathioprine is another commonly used agent for remission maintenance in vasculitis.²¹ Azathioprine can cause cytopenias, infections, nausea, mucositis, hair loss, pancreatitis, and other problems, but like methotrexate, is usually well tolerated even for extended periods. Mycophenolate mofetil is also used for vasculitis. Cyclosporine has long been used in Behçet’s disease and occasionally in other vasculitides.

Rituximab has been demonstrated in two RCTs to have similar efficacy to cyclophosphamide for induction of remission in ANCA-associated vasculitis (GPA and MPA). The risks of rituximab include allergic reactions and potential for infections.

Plasmapheresis (plasma exchange) has a central role in treating anti–glomerular basement membrane antibody-associated disease (Goodpasture’s syndrome) and is used at some centers to treat both alveolar hemorrhage and severe glomerulonephritis in ANCA-associated vasculitis. The role of plasmapheresis in GPA and MPA is the focus of a currently enrolling international clinical trial. Pheresis is frequently used to treat acute manifestations of CV and occasionally other vasculitides. Intravenous IG is a mainstay of therapy for Kawasaki disease and has been advocated for several other types of vasculitis, often as a second- or third-line regimen, and based mostly on small case series.

Many biological agents (“biologics”) have been and continue to be studied as treatment for vasculitides²³ (see Box 41-2). This rapidly expanding group of agents that inhibit specific targets within the immune system are having a remarkable impact on the care of patients with a wide variety of autoimmune and systemic inflammatory diseases. The studies of rituximab for GPA and MPA demonstrated efficacy of the new agent.^24,25 However, despite initial enthusiasm from open-label studies, randomized trials studying the use of inhibitors of TNF-α did not demonstrate efficacy of this class of drug for treatment of either GPA⁴² or GCA.⁴³ This experience highlights the need for properly conducted randomized clinical trials in vasculitis. Studies testing the efficacy of several other biologics for various forms of vasculitis are either currently in process or in the planning stages.

Surgical or Procedural Interventions for Vasculitis

In addition to medical therapies, interventional and surgical treatments for vasculitis remain options for certain types of problems, especially in larger vessels after damage has become permanent. Angioplasty and stent placement have been performed for patients with TA and other diseases when severe arterial stenoses occur in large vessels. Results of these interventions are mixed, with restenosis a commonly reported problem. Whether or not drug-eluting stents (DESs) will offer advantages for the vasculitides remains to be demonstrated.

Surgical bypass or grafts of stenotic vessels, including the aorta and coronary, subclavian, carotid, and renal arteries, are an option for patients with large-vessel vasculitides. Several questions are unanswered regarding the proper timing of such surgery in the presence of “active” disease or when patients are on chronic glucocorticoids. Reconstructive surgery also plays a role in the care of patients with vasculitis, especially in patients with GPA who suffer deforming damage from nasal collapse or other upper airway and retroorbital disease.

Miscellaneous Issues in the Treatment of Vasculitis