Chapter 164. Systemic Necrotizing Arteritis

The term “vasculitis” can be defined broadly to mean inflammation of blood vessels. However, from the perspective of the practicing clinician, “vasculitis” is most commonly used to describe a group of diseases in which inflammation of the blood vessels is the major, but not only, pathologic process. The vasculitides are a wide-ranging set of diseases that are mostly idiopathic, rare, and multisystemic. These diseases involve such a variety of clinical presentations and pathologies that all clinicians in every medical and surgical specialty will encounter such patients.

Vasculitis of the skin is a frequent manifestation in many forms of vasculitis, especially small- and medium-vessel arteritis where skin lesions may be the presenting symptom of a systemic illness.

This chapter will focus on skin disease in the systemic vasculitides. Isolated forms of skin vasculitis and some of the systemic vasculitides are covered in Chapter 163. In addition to outlining the skin manifestations of vasculitis in general and for specific types of vasculitis, this chapter will provide an approach to patients with skin disease in which vasculitis is a diagnostic consideration.

With the probable exception of drug/toxin-induced vasculitis, all forms of idiopathic vasculitis are considered rare, “orphan” diseases in the United States (prevalences of less than 200,000 people); similar designations exist in Europe and elsewhere.

Vasculitis occurs in people of both sexes, all ages, and all major racial/ethnic groups. However, some forms are more common in certain groups. For example, Takayasu arteritis is substantially more common in women than men, Kawasaki disease is almost exclusively a disease of young children, and giant cell arteritis is limited to older adults. Granulomatosis with polyangilis (GPA) mostly occurs in Caucasians and Behçet disease is markedly more common in countries in the Eastern Mediterranean as well as Japan and Korea. The demographic differences among the vasculitides are of scientific interest as clues to etiology and can be helpful diagnostically.1 However, the epidemiologic tendencies are generally not so strong as to fully exclude the diagnosis of a specific form of vasculitis in any one person and exceptions to the typical epidemiology occur regularly.

Multiple systems for classifying vasculitis exist, a situation that reflects a lack of clear understanding of the underlying pathophysiology and the overlap of clinical features among many types of vasculitis.2–7 The most commonly accepted approach to classifying the vasculitides is to sort them by the size(s) of the predominant vessel involved (small, medium, or large) and then subdivide or group diseases, as appropriate (Fig. 164-1).

Classification criteria and definitions have been developed for many, but not all, specific types of vasculitis. These systems were designed for use in clinical research to create fairly homogenous study cohorts and were not meant to be used as “diagnostic” criteria.3 Nonetheless, clinicians will find these criteria helpful. The most widely used criteria for vasculitis are from the classification criteria of the American College of Rheumatology5–6 and the disease definitions of the Chapel Hill Consensus Conference.7 However, these systems do not contain several forms of vasculitis, including some with frequent skin manifestations, such as Behçet disease and cryoglobulinemia, nor any “secondary” vasculitides (associated with another underlying disease such as systemic lupus erythematosus or an infection). Furthermore, some classes are no longer advised for use (e.g., “hypersensitivity vasculitis” is a term that has lost specific meaning). It should be emphasized that the term “leukocytoclastic vasculitis” does not refer to a specific disease but is a pathological description that often, but not always, applies to vasculitis in the skin or other organs. Similarly, “cutaneous vasculitis” is a vague name that could apply to any of several skin lesions seen in vasculitis and is not a distinct entity. There are also some separate sets of criteria for pediatric patients.8

A new international initiative is underway to reconsider the classification of the vasculitides and take into consideration data regarding the clinical and pathophysiological aspects of vasculitis not available when the prior systems were created; such new elements include testing for antineutrophil cytoplasmic autoantibodies (ANCA) and greater availability of advanced imaging techniques for large arterial disease.3

When a patient presents with skin lesions that are concerning for possible vasculitis, answers to three questions should be sought quickly:

1. Is the lesion due to vasculitis?

2. Are other organ systems involved in the illness?

3. Are there additional findings on medical interview, physical examination, laboratory testing, or radiographic imaging that can help establish a specific diagnosis?

    If a diagnosis of vasculitis is obtained, then it is imperative to ask two more questions:

4. Is it possible to make a diagnosis of a specific type of vasculitis for the patient?

5. Does the patient need immediate treatment and/or hospitalization?

A suggested approach to patients with skin lesions suspected of being due to vasculitis is shown in Fig. 164-2. The answer to the first question is often obtained by a skin biopsy, which is indicated in many cases of palpable purpura or other lesions when a diagnosis of vasculitis is not otherwise easily established. The second question is addressed by a thorough review of systems and physical exam and routine laboratory testing that can usually be completed rapidly. The third question is addressed by more specialized laboratory tests for which results typically take several days to return. It is important to quickly identify organ system involvement and how “sick” the patient is (or might soon be), since some causes of cutaneous vasculitis require no treatment, but others require immediate hospitalization for initiation of immunosuppressive and supportive therapy.

Review of Systems

A full review of systems with assessment of the overall severity of illness is the single most important component of the early evaluation of a patient suspected of having vasculitis. Together, the diseases that cause cutaneous vasculitis can affect all organ systems and, in most cases, that involvement will cause symptoms—renal disease being a prominent exception. Although some symptoms are clearly more concerning than others (hemoptysis vs. dry cough, painful red eye vs. mild arthralgias), even relatively mild symptoms can be a clue that disease is not limited to the skin. A list of important signs and symptoms of vasculitis is shown in Table 164-1.

Past Medical History, Medication Use, and Exposures to Toxins or Infectious Diseases

It is critical to know the full medical history of any patient suspected of having vasculitis. Other diseases may either have vasculitis as a component of the illness (e.g., lupus) or may cause skin lesions that mimic vasculitis. Drug-induced vasculitis (DIV) is common and skin lesions, usually but not always purpura, are the most common manifestation of DIV.9 The list of drugs reported to cause vasculitis is enormous with almost every class of medication implicated in possible cases of DIV. It is useful to ask about prescription, nonprescription, and “alternative” or herbal mediation use in the prior 6–12 months since the effect of some medications may persist after usage ends. Patients should also be asked about use of illegal or recreational drugs since several such agents, including methamphetamines, cocaine, and others have been implicated in cases of vasculitis. Occupational or other exposure to nondrug toxins should be asked about.

The patient should be asked about not only usual signs and symptoms of infection, but also recent travel, contacts with sick individuals, and risks for sexually transmitted diseases.

Physical Examination

Beyond a careful and full assessment of the skin, a multisystem examination is useful to determine whether symptoms are associated with objective abnormalities, or whether there are findings that a patient has not noticed. Vital signs are essential, but a patient with normal blood pressure can still have severe glomerulonephritis. The eyes should be inspected for redness and proptosis. The anterior nasal cavity can be easily visualized with an otoscope. Evidence of lymphadenopathy should be sought. Cardiac, lung, and abdominal examinations can give clues to underlying disease, but normal examinations do not rule out pathology. Similarly, absent pulses, asymmetric blood pressure readings, and bruits are helpful but imperfect measures to screen for large-vessel vasculitis. A complete joint examination is important and any findings suggestive of synovitis (joint swelling, warmth, redness) must be further investigated; however, many patients with vasculitis will have arthralgias without joint effusions. A full neurological examination is one of the most valuable components of the evaluation and triage of a patient suspected of having vasculitis; subtle sensory and even motor abnormalities may be missed on initial evaluation.

The more detailed and expert examinations that can be performed by ophthalmologists and otolaryngologists are often extremely helpful in evaluating patients suspected of having vasculitis. Urgent referral is often indicated in patients with concerning symptoms such as new visual impairment, painful or red eyes, hoarseness or stridor, or hearing loss.

Diagnostic Testing for Suspected Vasculitis

Given the broad range of entities that fall under the category “vasculitis”, and the even larger number of diseases that are also reasonably considered when evaluating a patient suspected of having vasculitis, a vast number and range of diagnostic tests are often considered in such cases. However, obtaining a thorough medical history and conducting a detailed physical examination should enable the clinician to limit the types of vasculitis under consideration and prioritize the ordering of diagnostic tests. Not all tests need be ordered for all patients suspected of having vasculitis. This approach must of course be balanced by the possibility of atypical presentations of vasculitis as well as a range of infections, malignancies, and other diseases in the differential diagnosis of such patients. Evaluation for possible vasculitis usually occurs in parallel to evaluation for other processes.

Skin Biopsy

The method for diagnosing vasculitis depends on the type of vasculitis suspected, which is often based on the size of vessel involved. Vasculitides affecting the skin usually involve small- and medium-sized vessels and these vessels are amenable to biopsy (Fig. 164-3). Given the ease and low risk of skin biopsies, they play an important role in diagnosing vasculitis, and an equally important role in establishing a diagnosis other than vasculitis. A standard punch biopsy is sufficient to diagnose small-vessel vasculitis but a deeper and wider excision may be necessary to capture information on medium-sized vessels.10,11 Lesions that should be approached with a deeper biopsy include subcutaneous nodules, livedo reticularis, or deep ulcers (Fig. 164-4). Many types of small-vessel vasculitis may also involve medium-sized skin vessels. It is important to realize that the difference between “small” and “medium” vessels is somewhat subjective and skin pathologists make such distinctions more often than might other pathologists who see larger biopsy specimens.

Sometimes the presence of a typical clinical syndrome makes biopsy unnecessary. For example, Henoch–Schöenlein purpura in children is often diagnosed on clinical grounds alone and some cases of ANCA-associated or cryoglobulinemic vasculitis can be diagnosed confidently by combining clinical features with specific serologic tests. Behçet disease and Kawasaki disease are diagnosed based on the clinical syndromes; biopsy is usually not performed on the skin lesions that are common in these diseases, and such biopsies are often nondiagnostic.

It is generally recommended to biopsy a skin lesion that has been clinically apparent for less than 48 hours, if possible, to maximize the chance of finding the typical features of acute neutrophilic vasculitis, including fibrinoid necrosis, extravasation of erythrocytes, extravasation of neutrophils with release of nuclear debris (leukocytoclasia), and the presence of immune deposits.10,11 Processing of tissue is different for conventional histopathology or immunofluorescence testing; if immunofluorescence is desired, then either two specimens need to be obtained, or a single specimen needs to be divided before processing. The latter approach may however damage the tissue.10

As discussed throughout this chapter, the histologic finding of leukocytoclastic vasculitis is helpful in confirming the diagnosis of vasculitis but does nothing to establish an etiology from among the broad number of possibilities. Microscopy sometimes reveals features that are suggestive but not diagnostic of vasculitis, such as leukocytoclasia without fibrinoid necrosis. The finding of a perivascular infiltrate, particularly if it consists predominantly of mononuclear cells but even if it is neutrophilic, is also nonspecific. Certain features, when seen in addition to leukocytoclastic vasculitis, are strongly suggestive of particular diseases, such as extravascular granulomas with geographic necrosis (GPA), or eosinophil-rich extravascular granulomas (Churg–Strauss syndrome; CSS),12 but these features are seen in a minority of biopsies in these diseases.

A predominance of IgA over IgG/IgM by immunofluorescence is suggestive but not diagnostic of Henoch–Schönlein purpura. The presence of deposits of IgG, IgM, and/or complement is suggestive of one of several immune-complex-mediated etiologies, including drug hypersensitivity, postinfectious vasculitis, cryoglobulinemia, and vasculitis secondary to systemic lupus erythematosus, Sjögren syndrome, or rheumatoid arthritis.12

Other Biopsies

Vasculitis is often diagnosed by biopsy of other organs, such as kidney, lung, muscle, or peripheral nerve or even from surgical specimens (Fig. 164-5). Kidney or lung biopsies are more likely than skin biopsies to show pathology diagnostic of a particular disease. Nonetheless, a skin biopsy establishing the diagnosis of vasculitis may preclude the need for more invasive biopsies.

Laboratory Testing

Although individual laboratory tests on their own are almost never diagnostic for vasculitis, such tests are essential in the evaluation of a patient in whom cutaneous vasculitis is being considered. Laboratory testing may identify organ systems involved in the disease process, especially renal disease. Furthermore, in the proper setting, selected serologic tests may establish an etiology for vasculitis. However, serologic tests usually complement rather than substitute for biopsy, particularly in a patient with skin lesions that can be readily biopsied.

Tests of Renal Function

Tests for renal disease are the most important laboratory tests to order in evaluating a patient suspected of having vasculitis since renal disease is common in many vasculitides and is rarely accompanied by signs or symptoms until end-stage renal failure occurs. Urinalysis, including both dipstick and microscopic examinations, should be performed on all patients in whom vasculitis is suspected, and repeatedly in patients in whom vasculitis of small- or medium-sized vessels is established in another organ system. The presence of any blood on the routine dipstick tests needs to be followed by an examination for red blood cell casts by someone specifically trained to look for casts (many nephrologists, some rheumatologists, but few laboratory technicians in North America). Measurement of serum creatinine is critical to estimate the glomerular filtration rate (GFR). Small changes in creatinine, even within the normal range, may be early evidence of decline in GFR. Although small-vessel vasculitis affecting the glomeruli is expected to produce hematuria, usually accompanied by red blood cell casts and proteinuria, vasculitis affecting only medium-sized vessels (e.g., polyarteritis nodosa) typically produces either isolated hematuria or a normal urinalysis. Urinalysis and serum creatinine are equally important tests and are complementary; neither alone is sufficient to exclude renal disease in vasculitis.

Tests of Liver Function

Vasculitis, particularly polyarteritis nodosa, can involve the liver, but significant hepatic dysfunction is rare. Liver function tests are thus of limited value in diagnosing vasculitis, but they do provide a baseline against which future values can be compared if, as is often the case, potentially hepatotoxic drugs are to be used for treatment. Liver function tests can also provide an early hint at infection with hepatitis B or C viruses, both of which are associated with vasculitis, but do not substitute for serologic testing for these infections. Normal liver function tests do not rule out infectious hepatitis.

Complete Blood Count

A complete blood count should be ordered on all patients suspected of having vasculitis. Many patients with active vasculitis have anemia and/or thrombocytosis, but the same is true of a wide range of inflammatory diseases. Severe anemia can be a clue to serious gastrointestinal involvement from various forms of vasculitis. The white blood cell count and differential can also be clues to the presence of infection or hematologic malignancy. However, leucocytosis is usually nonspecific and is also commonly caused by use of glucocorticoids. An elevated absolute eosinophil count is found in most untreated patients with CSS and a count greater than 1,000 cells/μL helps differentiate this disease from asthma and atopy.

Acute Phase Reactants

The erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) are elevated in many patients with vasculitis, but the diagnostic sensitivity and specificity of these tests are not particularly high and thus these tests are not particularly helpful in either establishing or excluding a diagnosis of vasculitis. Furthermore, the levels of ESR and CRP do not correlate well with stage or severity of disease. ESR and CRP are often elevated in conditions that mimic vasculitis in the skin, as well as in many serious systemic diseases, including infections and malignancies. Patients with active vasculitis can have normal ESR and CRP values and patients may remain in clinical remission despite persistent elevation of these markers after treatment.

Autoimmune Serologies

Testing for autoantibodies is often a critical component of establishing the type of vasculitis present but it is important to recognize that serologic testing on its own is never diagnostic and should never substitute for clinical judgment.

Testing for ANCA and antiglomerular basement membrane (anti-GBM) antibodies, as well as antinuclear antibodies (ANA) to address the alternative possibility of systemic lupus erythematosus, is advised for any patient presenting with pulmonary hemorrhage and/or acute renal insufficiency with an active urinary sediment. ANCA-associated vasculitis and lupus can present with vasculitis of the skin, but anti-GBM disease does not, so the latter topic will not be discussed further.

Antineutrophil Cytoplasmic Antibodies

Approximately 90% of patients with microscopic polyangiitis, 75% of patients with GPA, and 40% of patients with CSS will test positive for ANCA.13–16 Modern ANCA testing includes both immunofluorescence staining of neutrophils for the cytoplasmic (c-ANCA) or perinuclear (p-ANCA) patterns and ELISAs for specific autoantigens [proteinase-3 (PR3) and myeloperoxidase (MPO)].16–18 Specificity of positive testing for anti-PR3 and anti-MPO antibodies for ANCA-associated vasculitis is quite high,17–19 but specificity of p-ANCA staining in the absence of anti-MPO antibodies is low. Thus, positive tests for ANCA by ELISA are essential to consider ANCA testing positive for purposes of diagnosing vasculitis.

The predictive value of positive ANCA testing depends on the setting. In cases of biopsy-proven vasculitis or clinical “surrogates” of a biopsy of vasculitis, such as diffuse alveolar hemorrhage or acute renal failure with an “active” urinary sediment, positive testing for anti-PR3/MPO ANCA is highly specific. In the setting of nonspecific constitutional and musculoskeletal symptoms, the positive predictive value of ANCA testing is lower.

Anti-Nuclear Antibodies

Testing for ANA and related autoantibodies is useful when there is suspicion of systemic lupus or Sjögren syndrome. ANA testing is extremely sensitive (>95%) but not specific for the diagnosis of lupus. With the exception of anti-Ro (SSA) antibodies, additional tests for specific nuclear antigens, including double-stranded DNA, Smith, RNP, and La (SSB), should only be ordered if the ANA is positive and lupus is still under consideration. Only 80% of patients with Sjögren syndrome test positive for rheumatoid factor (RF), anti-Ro (SSA), or anti-La (SSB) antibodies, so negative tests do not rule out this diagnosis.

Rheumatoid Factor

Testing for rheumatoid factor is rarely useful in establishing either the diagnosis or specific type of vasculitis. The sensitivity and specificity of rheumatoid factor for Sjögren syndrome or cryoglobulinemic vasculitis are low. While at least 70% of patients with rheumatoid arthritis test positive for rheumatoid factor, the test is positive in more than 95% of patients with rheumatoid vasculitis.20 However, since rheumatoid vasculitis typically occurs in patients with longstanding, severe rheumatoid arthritis, such testing has little additive value.

Paraproteins (Abnormal Immunoglobulins, Including Cryoglobulins)

Cryoglobulins are immune complexes (immunoglobulins and their target antigens) that precipitate in the cold and are associated with clinical syndromes in which vasculitis is a prominent component (see Chapter 169). Cryoglobulinemia most commonly results from chronic infection with hepatitis C virus, but rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and hematologic malignancies are also all associated with cryoglobulinemia. Testing for cryoglobulins requires careful attention to specimen handling and processing since incorrect practice at any one of several steps results in a high false-negative rate. Similarly, standard serum protein electrophoresis testing may not pick up some immunoglobulin clones, and immunofixation electrophoresis is a more comprehensive screen for clonal immunoglobulins.

Vasculitis has also been associated with monoclonal gammopathies (myeloma, plasmacytoma, or lymphoma) in the absence of cryoglobulinemia.21

Complement

Total hemolytic complement is measured using the CH50, but since this assay is cumbersome and suffers from variability between laboratories, measurement in serum of the complement proteins C3 and C4 is usually sufficient, and is useful for assessing patients with cutaneous vasculitis in several settings. In patients with cryoglobulinemic vasculitis C4 levels are usually severely depleted whereas C3 levels are less depleted or even normal.22,23 One or both of these components are low in 70% of patients with rheumatoid vasculitis,20 which is useful because rheumatoid arthritis is generally not associated with low circulating complement. In contrast, because systemic lupus erythematosus is commonly associated with low complement in a variety of settings, low complement helps raise the suspicion for lupus but is not specific for vasculitis in SLE. A subset of patients whose cutaneous vasculitis presents as urticaria (hence the term “urticarial vasculitis”), but who cannot be diagnosed with lupus or another underlying disease, have depletion of complement (see Chapter 163).

Selected Testing for Infectious Diseases

Many infections can cause skin lesions that either include vasculitis or mimic vasculitis. Chronic infection with hepatitis C virus is strongly associated with cryoglobulinemic vasculitis, and it can also be associated with polyarteritis nodosa in the absence of cryoglobulins.24 Chronic hepatitis B virus infection was the cause of many cases of polyarteritis nodosa prior to the widespread adoption of vaccination programs.25 Thus, patients with known or suspected vasculitis affecting small- or medium-sized arteries should be screened for hepatitis B and C infections.

Endocarditis can cause both true vasculitis, presumably through deposition of immune complexes, and lesions that mimic vasculitis, through septic emboli. Blood cultures are therefore appropriate to order for some patients suspected of small-vessel vasculitis.

Numerous and diverse infections have been implicated in causing secondary vasculitis, usually of small vessels and limited to the skin. Testing for specific organisms should therefore be based on a history of exposure or a suspicious clinical syndrome (e.g., sore throat or acute diarrhea).

Several uncommon infections directly infect and damage vascular endothelial cells and thus produce lesions that can either be regarded as vasculitis or as mimics of vasculitis; numerous organisms have been implicated, mostly in the form of case reports.

Screening for Drugs of Abuse

Toxicology screens for commonly used drugs of abuse may be appropriate for some clinical situations where vasculitis is suspected. In particular, both cocaine and methamphetamines have been associated with cutaneous vasculitis and/or arterial vasospasm, and nasal inhalation of cocaine can produce destructive nasal disease as severe as that seen in ANCA-associated vasculitis, although certain clinical features may help distinguish the two causes.26,27

Diagnostic Imaging Studies

Chest Imaging

A chest radiograph is an appropriate screening test for any patient suspected of having vasculitis. For a patient with pulmonary symptoms, computed tomography (CT) is usually indicated, since plain radiographs will frequently not detect small nodules or subtle but significant infiltrates. In patients diagnosed with GPA, microscopic polyangiitis, or CSS, a screening CT is indicated for staging purposes and to establish a baseline, even in asymptomatic patients.

If subglottic stenosis is suspected, CT of the neck/trachea can be a helpful adjunct to direct laryngoscopy.

Sinus Imaging

Sinus involvement is extremely common in GPA and CSS, and the ability to evaluate the sinuses on physical examination is limited even for an otolaryngologist. CT of the sinuses can help assess the possibility of GPA or CSS and is useful in staging and restaging disease once one of those diagnoses is made and treatment is initiated. However, the CT appearance of sinus inflammation in these diseases does not allow discrimination from other causes of sinusitis, and patients with prior damage from vasculitis often have persistent abnormalities. Nasal inflammation may be better assessed by physical exam than by CT.

Angiography

Angiography has a central role in the diagnosis and management of large- and medium-vessel vasculitis. Conventional catheter-based dye angiography has the highest resolution but is an invasive procedure and still does not allow visualization of most small vessels. Angiography based on CT and magnetic resonance (MR) is increasingly replacing the use of catheter-based angiography in large-vessel vasculitis (GCA and Takayasu's).28

The role of angiography in the diagnosis of vasculitis of the skin is limited to either establishing the underlying type of vasculitis (e.g., abdominal angiography demonstrating multiple aneurysms and stenoses in polyarteritis nodosa) or evaluating the arterial supply in patients with gangrene.

Other Diagnostic Studies

Nerve Conduction Studies and Electromyography

Nerve conduction studies should never replace a full neurologic examination and most patients with neurologic manifestations of vasculitis do not need such testing. Thus, nerve conduction testing is not recommended for screening asymptomatic patients, but can be useful for providing objective evidence of neuropathy and for distinguishing between compressive (i.e., mechanical) and noncompressive neuropathy, with the latter type including neuropathy due to vasculitis and many other medical causes. Electromyography (EMG) can establish the presence of myopathy, but usually not the cause. Nerve conduction studies are painful and require expertise not always readily available.

Audiology Testing

An audiogram is critical in diagnosing and distinguishing between conductive and/or sensorineural hearing loss. Hearing loss is a commonly missed manifestation of small-vessel vasculitis, including among elderly patients.29 Sensorineural hearing loss is a cranial neuropathy and may rapidly lead to irreversible hearing loss. Although an audiogram is not generally indicated for screening an asymptomatic patient, a baseline audiogram is advised for all patients with an established diagnosis of ANCA-associated vasculitis (GPA, microscopic polyangiitis, or CSS).

Microscopic Polyangiitis

Microscopic polyangiitis (MPA) is a multisystem vasculitis of small vessels and sometimes also of medium-sized vessels.30,31 Pauciimmune glomerulonephritis develops in the majority of patients, and pulmonary hemorrhage, peripheral and cranial neuropathy, musculoskeletal, and constitutional symptoms are also common; cardiac and gastrointestinal involvement are less common. Most patients with MPA are positive for ANCA, usually with specificity for antibodies to myeloperoxidase (MPO).32 Although rapidly progressive glomerulonephritis and/or diffuse alveolar hemorrhage commonly lead to diagnosis, MPA often features a prolonged prodrome limited to musculoskeletal and constitutional symptoms.33

The skin is frequently involved in MPA.15 The most common cutaneous lesion is palpable purpura and the pathology is indistinguishable from other types of leukocytoclastic vasculitis12,34 (Fig. 164-6). Vasculitis of medium-sized vessels, leading to digital ischemia, subcutaneous nodules, livedo reticularis, and deep ulcers, can rarely occur in MPA.

Granulomatosis with Polyangiitis (Wegener's)

GPA encompasses all the features of microscopic polyangiitis but also many additional manifestations caused by necrotizing granulomatous inflammation and the two syndromes are currently considered distinct entities. Chronic inflammation of the upper airway (nasal cavity, sinuses, auditory tube, and middle ear) is present in about 90% of patients, often but not always as the initial manifestation.13,35,36 Cavitary pulmonary nodules, orbital pseudotumor, and subglottic stenosis are also common and important features. Vasculitis of the eye (scleritis and episcleritis) is also much more common in GPA than in MPA.13,30,35–37 Most patients with GPA who have involvement of multiple organ systems will test positive for ANCA.37,38 The majority ANCA type in this disease is C-ANCA/antiproteinase-3 (PR3); however, P-ANCA/antimyeloperoxidase (MPO) is also not uncommon. Patients with disease seemingly restricted to the upper airway are only ANCA-positive in about 70% of cases, which can make diagnosis more challenging.16,37

In addition to palpable purpura and other presentations typical of small-vessel vasculitis, additional skin lesions occur in GPA and reflect a combination of vasculitis and necrotizing granulomatous disease, including neutrophilic and granulomatous dermatitis with papules (particularly on the extensor surfaces of the elbows), subcutaneous nodules, and ulcers12,39–42 (Figs. 164-7 and 164-8). Vasculitis and extravascular granulomatous disease are sometimes seen in the same biopsy, facilitating diagnosis. As with MPA, manifestations attributable to involvement of medium-sized vessels can also be seen (Fig. 164-9).

Churg–Strauss Syndrome

CSS is often included among the ANCA-associated vasculitides since approximately 40% of patients test positive for ANCA,43 and there is considerable overlap in features of CSS with both GPA and microscopic polyangiitis. However, CSS has unique features, the most prominent being a history of asthma (often severe or poorly controlled), and blood eosinophilia. Nasal polyps, constitutional symptoms, and rashes, all typical of atopy, are also common. The presence of pulmonary infiltrates on chest imaging (eosinophilic pneumonia) provides an important distinction from asthma. The most common presentation of severe vasculitis in CSS is acute peripheral neuropathy with involvement of the heart, gastrointestinal tract, brain, and eyes less common. Glomerulonephritis and pulmonary hemorrhage occur in about 10% and less than 5%, respectively, of patients with CSS.14,44,45

Cutaneous disease is more common in CSS than in GPA or microscopic polyangiitis.14,44,45 Palpable and nonpalpable purpura, reflecting vasculitis histologically, comprise about 50% of cutaneous lesions.12 Eosinophilic dermatitis and granulomatous dermatitis rich in both neutrophils and eosinophils are also common and produce erythematous macules, papules, and nodules. As with GPA, small-vessel vasculitis and extravascular eosinophilic and/or granulomatous disease are sometimes seen in the same biopsy. While the skin lesions of CSS often contain eosinophils, with or without vasculitis, eosinphil-rich skin biopsies are not unique to this disease and can be seen in other types of vasculitis.

Cryoglobulinemic Vasculitis

See Chapter 169.

Henoch–Schönlein Purpura

See Chapter 163.

Vasculitis Associated with Other Autoimmune Diseases

Vasculitis is seen relatively commonly in patients with systemic lupus (10%–36%)46,47 and Sjögren syndrome (10%),48 but is now extremely uncommon in rheumatoid arthritis.49,50 Vasculitis in these diseases affects mostly small vessels, with some medium-vessel disease. The vasculitis may cause peripheral neuropathy, gastrointestinal ischemia, and central nervous system disease with other visceral involvement rare. Inflammatory bowel disease and relapsing polychondritis51 have also been associated with vasculitis involving small, medium, or large vessels.

The cutaneous manifestations of systemic rheumatic diseases are covered in Chapters 155, 160, and 161. The cutaneous manifestations of small-vessel vasculitis (purpura, vesiculobullous lesions, shallow ulcers) and medium-vessel vasculitis (nodules, deep ulcers, digital gangrene) associated with connective-tissue diseases are generally similar to what is seen in other forms of cutaneous vasculitis (eFig. 164-9.1).

Malignancy-Associated Vasculitis

Vasculitis temporally associated with a solid malignancy has been reported in many case reports and in a few larger series.52 A diverse set of malignancies has been implicated. Small-vessel vasculitis of the skin appears to be most common manifestation, and reports of remission of vasculitis after surgical resection of the tumor (and no other therapy) are suggestive of a causal relationship. Hematologic malignancies with or without associated paraproteinemias can result in vasculitis.21 Furthermore, the often comprehensive medical testing and imaging associated with evaluating a patient with possible vasculitis can lead to discovery of a malignancy in a patient with vasculitis, and the two diagnoses may be unrelated.

Cutaneous Leukocytoclastic Angiitis

All of the diseases and syndromes described to this point are defined by a combination of clinical and laboratory parameters. Cutaneous leukocytoclastic angiitis, in contrast, is a histologic term defined by the absence of evidence of systemic disease and the term undoubtedly encompasses many etiologies, and appears in this list only to serve as a reminder that cutaneous vasculitis is not always a marker of systemic disease. If, and only if, a patient has biopsy-proven vasculitis, has no evidence of involvement of other organ systems by vasculitis, and has no clinical of laboratory evidence to support a specific form of vasculitis or a coexisting autoimmune inflammatory disease, should the diagnosis of cutaneous leukocytoclastic angiitis be tentatively made. This term appears in the nomenclature of the Chapel Hill Consensus Conference of 1994 to acknowledge that vasculitis limited to the skin is relatively common.7 It has been estimated that about 20% of such cases follow infections, and another 20% are associated with drug exposure.12 However, it is quite problematic to label skin-only vasculitis as a separate disease entity, and all such patients should be followed carefully for the possible evolution to a more systemic form of vasculitis.

Drug-Induced Vasculitis

Reactions to drugs have been implicated in about 20% of cases of cutaneous small-vessel vasculitis,10 but the exact frequency of drug-induced disease is hard to establish due to incomplete reporting of cases and difficulty in firmly establishing causality of any one agent. Most categories of drugs have been implicated as causing vasculitis, but the number of reports for a given drug may represent reporting bias rather than relative risk.9,53 Cutaneous small-vessel disease is the norm, but medium-vessel vasculitis and visceral involvement have been reported. The literature is undoubtedly biased toward severe cases, but there are numerous reports of serious or fatal internal organ involvement (particularly renal, pulmonary, and hepatic). There is also a now well-accepted subset of drug-induced ANCA-associated vasculitis (antibodies usually directed against myeloperoxidase), especially involving propylthiouracil and related agents, hydralazine, but also other drugs.54,55

The cutaneous presentation of DIV is indistinguishable from other causes of small-vessel vasculitis (i.e., usually purpura but sometimes other lesions) (Fig. 164-10).

It is essential that a comprehensive review of all prescription, over-the-counter, illegal, and “alternative” drugs and supplements be undertaken for all patients suspected of having vasculitis.

Establishing a diagnosis of DIV may lead to avoidance of treatment with glucocorticoids and immunosuppressive agents in favor of clinical follow-up after drug discontinuation. However, two important caveats must be kept in mind in such cases: (1) drug discontinuation alone may not resolve the disease and severe disease may be present necessitating treatment; (2) the diagnosis of DIV may be wrong and the patient really has another form of vasculitis; thus, careful and prolonged follow-up of all patients is required.

Behçet Disease

See Chapter 166.

Polyarteritis Nodosa

Idiopathic vasculitis of medium-sized vessels (i.e., small- or medium-sized muscular arteries) can present in one or multiple organ systems. “Classic” polyarteritis nodosa involves multiple organ systems and presents with some combination of skin disease, myalgia, hypertension (from renal artery involvement), abdominal pain, neuropathy, and/or testicular pain. However, many patients do not present with the full set of manifestations, and diseases limited to muscle and nerve, single internal organs, or to the skin are well-described variants. When the disease is limited to the skin, it is sometimes referred to as cutaneous poyarteritis nodosa; however, some of these patients will later manifest disease in other organs.

Interpreting the literature on poyarteritis nodosa is problematic since the term was formerly used to describe several forms of vasculitis now considered to be distinct diseases (particularly microscopic polyangiitis).56,57 Historically, many cases of poyarteritis nodosa were associated with chronic infection with hepatitis B, but that association has declined markedly in countries in which vaccination against hepatitis B has become routine.57 Whether the remaining, rare entity still known as poyarteritis nodosa represents one, a few, or many etiologies, or even whether there is a unified fundamental pathophysiology (e.g., immune complex disease), is unclear.

The most common cutaneous features of poyarteritis nodosa are livedo reticularis/racemosa (a lacy pattern of cutaneous blood vessels on the legs, and not always easy to distinguish from a benign consequence of vasoconstriction of more superficial vessels) (Fig. 164-11), painful cutaneous nodules or ulcers (Fig. 164-12), and digital ischemia.58,59 These manifestations reflect vasculitis of “medium-sized” arteries in the subcutis, which are frequently too deep to be sampled in a routine punch biopsy.10

Kawasaki Disease

See Chapter 167.

Primary Vasculitis of the Central Nervous System

This rare disease is limited to the central nervous system (hence, no cutaneous findings) and presents with symptoms of encephalopathy, multiple small strokes, and often headache.60,61

Giant Cell Arteritis

Giant cell arteritis (GCA; temporal arteritis) is currently considered strictly a disease of adults older than 50 years of age that is markedly more common with advancing age. It is mostly a disease of people of Northern European ancestry. Cranial arteritis is a common feature with this term indicating stenosis or occlusion of one or more branches of the carotid artery to produce headache (70%–80%), jaw claudication (50%), and monocular (and rarely binocular) blindness (15%). Polymyalgia rheumatica, which includes pain and stiffness of the shoulder and hip girdles, is seen in at least 30%–40% of patients and may occur without cranial disease. Constitutional symptoms are common, including fever, malaise, and weight loss. Involvement of the aorta and its major branches produces symptoms similar to Takayasu arteritis in 15%–20% of patients. Diagnosis of GCA is usually confirmed by temporal artery biopsy (Fig. 164-13).

Palpable nodularity of the temporal artery is present in 30%–40% of cases and is the only cutaneous manifestation of GCA apparent on examination. Scalp necrosis and digital ischemia are rare complications.62,63

Takayasu Arteritis

Takayasu's is a rare form of vasculitis (prevalence <1:100,000) involving the aorta and its major branches.64–69 Many patients are diagnosed as young adults, and 90% are female. The typical presentation of Takayasu's is limb claudication. Dizziness, constitutional symptoms, and severe hypertension (from renal artery stenosis) are also common. Cerebral infarction can occur. Coronary occlusions with angina or infarction and bowel ischemia are less common but life-threatening complication. Absent pulse(s), abnormal blood-pressure readings, and arterial bruits are common but not universal findings. Diagnosis is made by angiography.

Lesions resembling erythema nodosum or pyoderma gangrenosum70 have been described repeatedly in Takayasu's, with pathology of nodular lesions often, but not always, showing vasculitis and thereby differing from typical erythema nodosum.71,72 Although complete occlusion of subclavian arteries is common, digital ischemia is rare.

General Approach to Treatment of Systemic Vasculitis

When establishing a treatment regimen for a patient with vasculitis, consideration must be given to both the severity of the current presentation and the likelihood of disease progression and recurrence. For an increasing number of vasculitides, treatment is guided by results of relatively large, randomized, controlled trials. However, for many situations, clinicians still rely upon either extrapolation from trials in other diseases or empiric treatment based on small case series or personal experience.

For vasculitides expected to have extended courses and/or include severe manifestations, the general approach is to plan for two phases of treatment: remission induction and remission maintenance.73,74 Remission induction usually involves use of high-dose glucocorticoids with steady dose taper combined with a short course (3–6 months) of a fairly rapid-acting and potent immunosuppressive agent. For example, cyclophosphamide, rituximab, and methotrexate all have roles in remission induction for ANCA-associated vasculitis. Remission maintenance usually involves prolonged use of non-cyclophosphamide-based regimens to allow for glucocorticoids to be either fully discontinued or maintained at a low dose (e.g., ≤10-mg prednisone daily). However, while the preceding approach is usual for the ANCA-associated vasculitides, polyarteritis nodosa, and some other forms of severe systemic disease for which there are data from clinical trials to guide treatment, it is less commonly used for other vasculitides in which glucocorticoids alone may suffice as therapy.

Clinicians must always remain alert to the possibilities of (1) a different diagnosis (either a different form of vasculitis or an entirely different disease); (2) development of additional manifestations of vasculitis; (3) treatment-related side effects, some of which can mimic vasculitis (infections, skin reactions, etc.).

An important aspect of caring for patients with vasculitis is determining who and when not to treat. “Watchful waiting” may be a reasonable management approach when (1) a diagnosis is not clear and no major organ system appears threatened; (2) there is an obvious cause or etiology for the vasculitis that is either reversible (toxin/drug) or self-limited (some infections); (3) uncertainly exists as to whether the patient's symptoms are due to a flare of disease or the result of either chronic damage or another process.

A critical component to the care of patients with vasculitis is close, regular clinical follow-up. Vasculitis often progresses rapidly and most forms of vasculitis have high rates of relapse. Depending on the form of vasculitis, regular office visits should be accompanied by laboratory and radiographic monitoring. Close follow-up should occur not only at the start of the disease process, but also for years following diagnosis.

Treatments for Systemic Vasculitis

A comprehensive list of drugs used in the treatment of the various systemic vasculitides and details of treatment regimens is beyond the scope of this chapter (additional information about specific agents is available in Chapters 224, 227, 233, and 234.

Glucocorticoids

Glucocorticoids remain the mainstay of therapy for vasculitis given the rapidity of action, reliability of response, and physicians’ familiarity with dosing and side effects. Glucocorticoids are usually the initial drug used to treat vasculitis and may be the only agent used for some forms of the disease. However, additional agents are often prescribed because either the dose of glucocorticoids needed to maintain disease control is unacceptably high or disease control is not attained by glucocorticoids alone. The acute and chronic toxicities are often underappreciated and the potential cumulative damage from chronic or recurrent use of glucocorticoids may be substantial.

Other Immunosuppressive Agents

A wide variety of additional immunosuppressive agents are used for treatment of the vasculitides. The proven effectiveness of the alkylating agent cyclophosphamide for the ANCA-associated vasculitides and, to a lesser extent, other forms of vasculitis, have helped establish this drug as the standard of care for initial treatment of severe forms of vasculitis.35,75–77 Other alkylating agents are now rarely prescribed for vasculitis. Although effective in many, but certainly not all, cases, cyclophosphamide is also associated with serious toxicities, many of which are related to total cumulative dose (e.g., female and male infertility, bladder cancer). Therefore, the past three decades have seen the emergence of “cyclophosphamide-sparing” regimens78 that usually have patients transition from an initial course of treatment with cyclophosphamide to a more prolonged course of a less toxic immunosuppressive agent, especially either methotrexate79,80 or azathioprine76,81; mycophenolate, cyclosporine A, and other agents have also been used for maintenance therapy.

Biologic Agents

More recently, the so-called “biologic” agents, drugs created using recombinant DNA techniques to target specific components of the immune system, have been studied for use in treating vasculitis, often with a goal of being either cyclophosphamide sparing or glucocorticoid sparing. The recent demonstration that rituximab, a B cell-depleting therapy, is as effective as cyclophosphamide for induction of remission in AAV is considered a major advance for the field.82,83 However, studies examining the efficacy of anti-TNF agents for either GPA or giant cell arteritis have been highly disappointing.84,85 There are many new biologic agents under consideration for use in the treatment of vasculitis, and clinical trials are needed to properly evaluate these new treatments.

Other Treatments

Although a variety of other drug classes, including colchicine, antibiotics (dapsone and others), and “alternative” therapies have been promoted for treatment of various forms of vasculitis, good evidence is generally lacking for the efficacy of these agents.

The role of plasma exchange in the treatment of vasculitis remains controversial. There is some evidence for efficacy for plasma exchange for patients with AAV and severe renal disease86 and possibly forms of cryoglobulinemic vasculitis. A large, international, randomized trial of plasma exchange for AAV is under way.

Common Errors in the Diagnosis and Treatment of Systemic Vasculitis

Given the huge spectrum of disease manifestations in vasculitis, the potential toxicities of treatments for vasculitis, and the serious ramifications of missing alternative diagnoses, especially infections, diagnostic misclassification is a major concern. Establishing a firm diagnosis of vasculitis based on physical examination and laboratory findings alone is a common problem. This is especially true for skin disease since not all purpura is due to vasculitis and not all skin disease in vasculitis is purpuric. Clinicians are cautioned against making a diagnosis of vasculitis in the skin without a biopsy; the exception to this guideline is if the patient has a clearly established diagnosis of vasculitis based on other evidence but, even then, it may be necessary to know what is causing a skin lesion. Many types of skin lesions improve with treatment with glucocorticoids; so, response to empiric use of this treatment is not diagnostically useful.

Undertreatment or delayed initiation of immunosuppressive therapy is a common problem for patients with systemic vasculitis. Undertreatment may take the form of failure to recognize multiorgan system disease, delay or reluctance to initiate immunosuppressive medications other than glucocorticoids for those forms of vasculitis for which such therapy has been shown to be useful, or underdosing of immunosuppressive agents.

Another common mistake is extending the course of treatment with medium–high doses of glucocorticoids beyond what is necessary to control an acute flare of vasculitis or the more serious manifestations.

Medical Emergencies Related to the Primary Vasculitides

The systemic vasculitides vary greatly in their rate of progression and level of medical severity. However, it is imperative that all clinicians caring for patients with vasculitis understand that these diseases are often organ- and life-threatening and that progression to emergency situations may be rapid. Furthermore, vasculitis can accelerate rapidly even after a long period of slowly changing or even indolent disease. Table 164-2 outlines several of the most common situations in which patients require emergency care but this list is incomplete and clinicians must be vigilant about considering these and other potentially rapidly progressive problems.