The Vasculitis Syndromes

2803CHAPTER 363

which damage the vessel wall. As the process becomes subacute or

chronic, mononuclear cells infiltrate the vessel wall. The common

denominator of the resulting syndrome is compromise of the vessel

lumen with ischemic changes in the tissues supplied by the involved

vessel. Several variables may explain why only certain types of immune

complexes cause vasculitis and why only certain vessels are affected

in individual patients. These include the ability of the reticuloendothelial system to clear circulating complexes from the blood, the size

and physicochemical properties of immune complexes, the relative

degree of turbulence of blood flow, the intravascular hydrostatic

pressure in different vessels, and the preexisting integrity of the vessel

endothelium.

■ ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES

ANCA are antibodies directed against certain proteins in the cytoplasmic granules of neutrophils and monocytes. These autoantibodies are

present in a high percentage of patients with active granulomatosis

with polyangiitis and microscopic polyangiitis and in a lower percentage of patients with eosinophilic granulomatosis with polyangiitis

(Churg-Strauss). Because these diseases share the presence of ANCA

and small-vessel vasculitis, they have been grouped collectively as

“ANCA-associated vasculitis.” However, these diseases possess unique

clinical phenotypes, such that they should continue to be viewed as

separate entities.

There are two major categories of ANCA based on different targets

for the antibodies. The terminology of cytoplasmic ANCA (cANCA)

refers to the diffuse, granular cytoplasmic staining pattern observed

by immunofluorescence microscopy when serum antibodies bind to

indicator neutrophils. Proteinase-3, a 29-kDa neutral serine proteinase

present in neutrophil azurophilic granules, isthe major cANCA antigen.

More than 90% of patients with active granulomatosis with polyangiitis

have detectable antibodies to proteinase-3 (see below). The terminology

of perinuclear ANCA (pANCA) refers to the more localized perinuclear

or nuclear staining pattern of the indicator neutrophils. The major

target for pANCA is the enzyme myeloperoxidase; other targets that

can produce a pANCA pattern of staining include elastase, cathepsin G,

lactoferrin, lysozyme, and bactericidal/permeability-increasing protein.

However, only antibodies to myeloperoxidase have been convincingly

associated with vasculitis. Antimyeloperoxidase antibodies have been

reported to occur in variable percentages of patients with microscopic

polyangiitis, eosinophilic granulomatosis with polyangiitis (ChurgStrauss), isolated necrotizing crescentic glomerulonephritis, and granulomatosis with polyangiitis (see below). A pANCA pattern of staining

that is not due to antimyeloperoxidase antibodies has been associated

with nonvasculitic entities such as rheumatic and nonrheumatic

autoimmune diseases, inflammatory bowel disease, certain drugs,

and infections such as endocarditis and bacterial airway infections in

patients with cystic fibrosis.

It is unclear why patients with these vasculitis syndromes develop

antibodies to myeloperoxidase or proteinase-3 or what role these

antibodies play in disease pathogenesis. There are a number of in vitro

observations that suggest possible mechanisms whereby these antibodies can contribute to the pathogenesis of the vasculitis syndromes.

Proteinase-3 and myeloperoxidase reside in the azurophilic granules

and lysosomes of resting neutrophils and monocytes, where they are

apparently inaccessible to serum antibodies. However, when neutrophils or monocytes are primed by tumor necrosis factor α (TNF-α)

or interleukin 1 (IL-1), proteinase-3 and myeloperoxidase translocate

to the cell membrane, where they can interact with extracellular

ANCA. The neutrophils then degranulate and produce reactive oxygen

species that can cause tissue damage. Furthermore, ANCA-activated

neutrophils can adhere to and kill endothelial cells in vitro. Activation

of neutrophils and monocytes by ANCA also induces the release of

proinflammatory cytokines such as IL-1 and IL-8. Adoptive transfer

experiments in genetically engineered mice provide further evidence

for a direct pathogenic role of ANCA in vivo. In contradiction, however, a number of clinical and laboratory observations argue against a

primary pathogenic role for ANCA. Patients may have active granulomatosis with polyangiitis in the absence of ANCA; the absolute height

TABLE 363-2 Potential Mechanisms of Vessel Damage in

Vasculitis Syndromes

Pathogenic immune-complex formation and/or deposition

IgA vasculitis (Henoch-Schönlein)

Lupus vasculitis

Serum sickness and cutaneous vasculitis syndromes

Hepatitis C virus–associated cryoglobulinemic vasculitis

Hepatitis B virus–associated vasculitis

Production of antineutrophilic cytoplasmic antibodies

Granulomatosis with polyangiitis

Microscopic polyangiitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Pathogenic T lymphocyte responses and granuloma formation

Giant cell arteritis

Takayasu arteritis

Granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Source: Reproduced with permission from MC Sneller, AS Fauci: Pathogenesis of

vasculitis syndromes. Med Clin North Am 81:221, 1997.

syndromes. The distinguishing and overlapping features of these syndromes are discussed below.

PATHOPHYSIOLOGY AND PATHOGENESIS

Generally, most of the vasculitic syndromes are assumed to be mediated at least in part by immunopathogenic mechanisms that occur in

response to certain antigenic stimuli. However, evidence supporting

this hypothesis is for the most part indirect and may reflect epiphenomena as opposed to true causality. Furthermore, it is unknown why

some individuals might develop vasculitis in response to certain antigenic stimuli, whereas others do not. It is likely that a number of factors

are involved in the ultimate expression of a vasculitic syndrome. These

include the genetic predisposition, environmental exposures, and the

regulatory mechanisms associated with immune response to certain

antigens. Although immune complex formation, antineutrophil cytoplasmic antibodies (ANCA), and pathogenic T lymphocyte responses

(Table 363-2) have been among the prominent hypothesized mechanisms, it is likely that the pathogenesis of individual forms of vasculitis

is complex and varied.

■ PATHOGENIC IMMUNE-COMPLEX FORMATION

Deposition of immune complexes was the first and most widely

accepted pathogenic mechanism of vasculitis. However, the causal role

of immune complexes has not been clearly established in most of the

vasculitic syndromes. Circulating immune complexes need not result

in deposition of the complexes in blood vessels with ensuing vasculitis,

and many patients with active vasculitis do not have demonstrable

circulating or deposited immune complexes. The actual antigen contained in the immune complex has only rarely been identified in vasculitic syndromes. In this regard, hepatitis B antigen has been identified

in both the circulating and deposited immune complexes in a subset

of patients who have features of a systemic vasculitis clinically similar

to polyarteritis nodosa (see “Polyarteritis Nodosa”). Cryoglobulinemic

vasculitis is strongly associated with hepatitis C virus infection;

hepatitis C virions and hepatitis C virus antigen-antibody complexes

have been identified in the cryoprecipitates of these patients (see

“Cryoglobulinemic Vasculitis”).

The mechanisms of tissue damage in immune complex–mediated

vasculitis resemble those described for serum sickness. In this model,

antigen-antibody complexes are formed in antigen excess and are

deposited in vessel walls whose permeability has been increased by

vasoactive amines such as histamine, bradykinin, and leukotrienes

released from platelets or from mast cells as a result of IgE-triggered

mechanisms. The deposition of complexes results in activation of complement components, particularly C5a, which is strongly chemotactic

for neutrophils. These cells then infiltrate the vessel wall, phagocytose

the immune complexes, and release their intracytoplasmic enzymes,

2804 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

of the antibody titers does not correlate well with disease activity; and

patients with granulomatosis with polyangiitis in remission may continue to have high ANCA levels for years (see below).

■ PATHOGENIC T LYMPHOCYTE RESPONSES AND

GRANULOMA FORMATION

The histopathologic feature of granulomatous vasculitis has provided

evidence to support a role of pathogenic T lymphocyte responses and

cell-mediated immune injury. Vascular endothelial cells can express

human leukocyte antigen (HLA) class II molecules following activation by cytokines such as interferon (IFN) γ. This allows these cells to

participate in immunologic reactions such as interaction with CD4+

T lymphocytes in a mannersimilarto antigen-presenting macrophages.

Endothelial cells can secrete IL-1, which may activate T lymphocytes

and initiate or propagate in situ immunologic processes within the

blood vessel. In addition, IL-1 and TNF-α are potent inducers of

endothelial-leukocyte adhesion molecule 1 (ELAM-1) and vascular cell

adhesion molecule 1 (VCAM-1), which may enhance the adhesion of

leukocytes to endothelial cells in the blood vessel wall.

APPROACH TO THE PATIENT

General Principles of Diagnosis

The diagnosis of vasculitis should be considered in any patient

with an unexplained systemic illness. However, there are certain

clinical abnormalities that when present alone or in combination

should suggest a diagnosis of vasculitis. These include palpable purpura, pulmonary infiltrates and microscopic hematuria,

chronic inflammatory sinusitis, mononeuritis multiplex, unexplained ischemic events, and glomerulonephritis with evidence of

multisystem disease. A number of nonvasculitic diseases may also

produce some or all of these abnormalities. Thus, the first step in

the workup of a patient with suspected vasculitis is to exclude other

diseases that produce clinical manifestations that can mimic vasculitis (Table 363-3). It is particularly important to exclude infectious

diseases with features that overlap those of vasculitis, especially if

the patient’s clinical condition is deteriorating rapidly and empirical immunosuppressive treatment is being contemplated.

Once diseases that mimic vasculitis have been excluded, the

workup should follow a series of progressive steps that establish the

diagnosis of vasculitis and determine, where possible, the category

of the vasculitis syndrome (Fig. 363-1). This approach is of considerable importance since several of the vasculitis syndromes require

aggressive therapy with glucocorticoids and other immunosuppressive agents, whereas other syndromes usually resolve spontaneously

and require symptomatic treatment only. The definitive diagnosis

of vasculitis is usually made based on biopsy of involved tissue.

The yield of “blind” biopsies of organs with no subjective or objective evidence of involvement is very low and should be avoided.

When syndromes such as polyarteritis nodosa, Takayasu arteritis, or primary central nervous system (CNS) vasculitis are suspected, arteriogram of organs with suspected involvement should

be performed.

GENERAL PRINCIPLES OF TREATMENT

Once a diagnosis of vasculitis has been established, a decision

regarding therapeutic strategy must be made (Fig. 363-1). If an

offending antigen that precipitates the vasculitis is recognized, the

antigen should be removed where possible. If the vasculitis is associated with an underlying disease such as an infection, neoplasm, or

connective tissue disease, the underlying disease should be treated.

If the syndrome represents a primary vasculitic disease, treatment

should be initiated according to the category of the vasculitis syndrome. Specific therapeutic regimens are discussed below for the

individual vasculitis syndromes; however, certain general principles regarding therapy should be considered. Decisions regarding

treatment should be based on the use of regimens for which there

TABLE 363-3 Conditions That Can Mimic Vasculitis

Infectious Diseases

Bacterial endocarditis

Disseminated gonococcal infection

Pulmonary histoplasmosis

Coccidioidomycosis

Syphilis

Lyme disease

Rocky Mountain spotted fever

Whipple’s disease

Coagulopathies/Thrombotic Microangiopathies

Antiphospholipid syndrome

Thrombotic thrombocytopenic purpura

Neoplasms

Atrial myxoma

Lymphoma

Carcinomatosis

Drug Toxicity

Cocaine

Levamisole

Amphetamines

Ergot alkaloids

Methysergide

Arsenic

Other

Sarcoidosis

Atheroembolic disease

Antiglomerular basement membrane disease (Goodpasture’s syndrome)

Amyloidosis

Migraine

Fibromuscular dysplasia

Heritable disorders of connective tissue

Segmental arterial mediolysis (SAM)

Reversible cerebral vasoconstrictive syndrome

has been published literature supporting efficacy for that particular vasculitic disease. Since the potential toxic side effects of

certain therapeutic regimens may be substantial, the risk-versusbenefit ratio of any therapeutic approach should be weighed carefully. Glucocorticoids and/or other immunosuppressive agents

should be instituted immediately in diseases where irreversible

organ system dysfunction and high morbidity and mortality rates

have been clearly established. Granulomatosis with polyangiitis

is the prototype of a severe systemic vasculitis requiring such a

therapeutic approach (see below). Conversely, aggressive therapy

should be avoided for vasculitic manifestations that rarely result in

irreversible organ system dysfunction such as isolated idiopathic

cutaneous vasculitis. Glucocorticoids should be initiated in those

systemic vasculitides that cannot be specifically categorized or for

which there is no established standard therapy, with other immunosuppressive agents being added if an adequate response does not

result or if remission can only be achieved and maintained with an

unacceptably toxic regimen of glucocorticoids. When remission is

achieved, one should continually attempt to taper glucocorticoids

and discontinue when possible. When using other immunosuppressive regimens, one should base the choice of agent upon the available therapeutic data supporting efficacy in that disease, the site and

severity of organ involvement, and the toxicity profile of the drug.

Physicians should be thoroughly aware of the acute and longterm side effects associated with the agents that are commonly used

to treat different forms of vasculitis (Table 363-4).

The Vasculitis Syndromes

2805CHAPTER 363

Morbidity and mortality can occur as a result of treatment, and

strategies to monitor for and prevent toxicity represent an essential

part of patient care.

Addressing the risk of bone loss is important in all patients

receiving glucocorticoids. Daily cyclophosphamide should be taken

all at once in the morning with a large amount of fluid throughout

the day to reduce the risk of bladder injury, and monitoring for

bladder cancer should continue indefinitely.

Maintaining the white blood cell (WBC) count at >3000/μL and

the neutrophil count at >1500/μL is essential to reduce the risk

of life-threatening infections. Monitoring of the complete blood

count every 1–2 weeks for as long as the patient receives cyclophosphamide can effectively prevent cytopenias. Methotrexate, azathioprine, and mycophenolate mofetil are also associated with bone

marrow suppression, and complete blood countsshould be obtained

every 1–2 weeks for the first 1–2 months after their initiation and

once a month thereafter. To lessen toxicity, methotrexate is often

given together with folic acid, 1 mg daily, or folinic acid, 5–10 mg

once a week 24 h following methotrexate. Methotrexate is eliminated by the kidney and contraindicated in renal insufficiency as

this increases the risk for toxicity. Prior to initiation of azathioprine,

thiopurine methyltransferase (TPMT), an enzyme involved in the

metabolism of azathioprine, should be assayed because inadequate

levels may result in severe cytopenia.

Rituximab can be associated with infusion reactions. In addition

to administering this within a skilled infusion center, these reactions can be lessened by the use of premedications. There is a risk of

hepatitis B reactivation with rituximab such that all patients should

be screened for this infection prior to its use.

Tocilizumab is associated with cytopenias, hepatotoxicity, and

hyperlipidemia. Laboratory monitoring for drug toxicity should

be performed 4–8 weeks after start of therapy and every 3 months

thereafter.

Properly categorize to a

specific vasculitis syndrome

Determine pattern and

extent of disease

Presentation of patient

with suspected vasculitis

Clinical findings

Laboratory workup

Establish diagnosis

Biopsy

Angiogram where

appropriate

Look for

offending antigen

Look for

underlying disease Characteristic

syndrome (i.e.,

granulomatosis

with polyangiitis

PAN, Takayasu

arteritis)

Treat vasculitis

Remove antigen

Syndrome

resolves

Treat underlying

disease

No further action Treat vasculitis

Yes No Yes No

Yes No

FIGURE 363-1 Algorithm for the approach to a patient with suspected diagnosis of

vasculitis. PAN, polyarteritis nodosa.

Infection represents a significant toxicity for all vasculitis patients

treatedwith immunosuppressive therapy.Infectionswith Pneumocystis

jirovecii and certain fungi can be seen even in the face of WBCs

that are within normal limits, particularly in patients receiving

glucocorticoids. All vasculitis patients who are receiving daily

glucocorticoids in combination with another immunosuppressive

TABLE 363-4 Major Toxic Side Effects of Drugs Used in the

Treatment of Vasculitisa

CONVENTIONAL IMMUNOSUPPRESSIVE AGENTS

Glucocorticoids

Osteoporosis

Cataracts

Glaucoma

Diabetes mellitus

Electrolyte abnormalities

Metabolic abnormalities

Severe and opportunistic infections

Cushingoid features

Growth suppression in children

Hypertension

Avascular necrosis of bone

Myopathy

Alterations in mood

Psychosis

Pseudotumor cerebri

Peptic ulcer diathesis

Pancreatitis

Cyclophosphamide

Bone marrow suppression

Cystitis

Bladder carcinoma

Gonadal suppression

Gastrointestinal intolerance

Hypogammaglobulinemia

Pulmonary fibrosis

Myelodysplasia

Oncogenesis

Teratogenicity

Severe and opportunistic infections

Methotrexate

Gastrointestinal intolerance

Stomatitis

Bone marrow suppression

Hepatotoxicity (may lead to fibrosis or

cirrhosis)

Pneumonitis

Teratogenicity

Severe and opportunistic infections

Azathioprine

Gastrointestinal intolerance

Bone marrow suppression

Hepatotoxicity

Severe and opportunistic infections

Hypersensitivity

Mycophenolate mofetil

Bone marrow suppression

Gastrointestinal intolerance

Severe and opportunistic infections

Teratogenicity

BIOLOGIC AGENTS

Rituximab (granulomatosis with polyangiitis and microscopic

polyangiitis)

Infusion reactions

Progressive multifocal

leuko-encephalopathy

Mucocutaneous reactions

Hypogammaglobulinemia

Severe and opportunistic infections

Hepatitis B reactivation

Tumor lysis syndrome

Late-onset neutropenia

Tocilizumab (giant cell arteritis)

Bone marrow suppression

Hepatotoxicity

Hyperlipidemia

Severe and opportunistic infections

Gastrointestinal perforation

Hypersensitivity reactions

Mepolizumab (eosinophilic granulomatosis with polyangiitis

[Churg-Strauss])

Hypersensitivity reactions Opportunistic infections: herpes zoster

Apremilast (Behçet’s disease; see Chap. 364)

Diarrhea, nausea, and vomiting

Depression

Weight decrease

a

Consult the drug package insert for a full listing of side effects.

2806 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

agent should receive trimethoprim-sulfamethoxazole (TMP-SMX)

or another prophylactic therapy to prevent P. jirovecii infection.

In recent years, national and regional organizations have published treatment guidelines that can provide additional direction

to clinicians. It should be emphasized that each patient is unique

and requires individual decision-making. Information provided

through guideline documents as well as this chapter should serve

as a framework for the application of evidence-based approaches;

however, flexibility should be practiced to provide maximal therapeutic efficacy with minimal toxic side effects in each patient.

GRANULOMATOSIS WITH POLYANGIITIS

■ DEFINITION

Granulomatosis with polyangiitis is a distinct clinicopathologic entity

characterized by granulomatous vasculitis of the upper and lower

respiratory tracts together with glomerulonephritis. In addition, variable degrees of disseminated vasculitis involving both small arteries

and veins may occur.

■ INCIDENCE AND PREVALENCE

Granulomatosis with polyangiitis is an uncommon disease with an

estimated prevalence of 3 per 100,000. It is extremely rare in blacks compared with whites; the male-to-female ratio is 1:1. The disease can be

seen at any age; ~15% of patients are <19 years of age, but only rarely does

the disease occur before adolescence; the mean age of onset is ~40 years.

■ PATHOLOGY AND PATHOGENESIS

The histopathologic hallmarks of granulomatosis with polyangiitis are

necrotizing vasculitis of small arteries and veins together with granuloma formation, which may be either intravascular or extravascular

(Fig. 363-2). Lung involvement typically appears as multiple, bilateral,

nodular cavitary infiltrates (Fig. 363-3), which on biopsy can reveal

necrotizing granulomatous vasculitis. Upper airway lesions, particularly those in the sinuses and nasopharynx, typically reveal inflammation, necrosis, and granuloma formation, with or without vasculitis.

In its earliest form, renal involvement is characterized by a focal and

segmental glomerulitis that may evolve into a rapidly progressive crescentic glomerulonephritis. Granuloma formation is only rarely seen

on renal biopsy. In contrast to other forms of glomerulonephritis, evidence of immune complex deposition is not found in the renal lesion

of granulomatosis with polyangiitis. In addition to the classic triad of

FIGURE 363-2 Lung histology in granulomatosis with polyangiitis. This area

of geographic necrosis has a serpiginous border of histiocytes and giant cells

surrounding a central necrotic zone. Vasculitis is also present with neutrophils

and lymphocytes infiltrating the wall of a small arteriole (upper right). (Courtesy of

William D. Travis, MD; with permission.)

FIGURE 363-3 Computed tomography scan of a patient with granulomatosis with

polyangiitis. The patient developed multiple, bilateral, and cavitary infiltrates.

disease of the upper and lower respiratory tracts and kidney, virtually

any organ can be involved with vasculitis, granuloma, or both.

The immunopathogenesis of this disease is unclear, although the

involvement of upper airways and lungs with granulomatous vasculitis

suggests an aberrant cell-mediated immune response to an exogenous

or even endogenous antigen that enters through or resides in the

upper airway. Chronic nasal carriage of Staphylococcus aureus has been

reported to be associated with a higher relapse rate of granulomatosis

with polyangiitis; however, there is no evidence for a role of this organism in the pathogenesis of the disease.

Peripheral blood mononuclear cells obtained from patients with

granulomatosis with polyangiitis manifest increased secretion of

IFN-γ but not of IL-4, IL-5, or IL-10 compared to normal controls. In

addition, TNF-α production from peripheral blood mononuclear cells

and CD4+ T cells is elevated. Furthermore, monocytes from patients

with granulomatosis with polyangiitis produce increased amounts of

IL-12. These findings indicate an unbalanced TH1-type T-cell cytokine

pattern in this disease that may have pathogenic and perhaps ultimately

therapeutic implications.

A high percentage of patients with granulomatosis with polyangiitis

develop ANCA, and these autoantibodies may play a role in the pathogenesis of this disease (see above).

■ CLINICAL AND LABORATORY MANIFESTATIONS

Involvement of the upper airways occurs in 95% of patients with granulomatosis with polyangiitis. Patients often present with severe upper

respiratory tract findings such as paranasal sinus pain and drainage

and purulent or bloody nasal discharge, with or without nasal mucosal

ulceration (Table 363-5). Nasal septal perforation may follow, leading

to saddle nose deformity. Serous otitis media may occur as a result

of eustachian tube blockage. Subglottic stenosis resulting from active

disease or scarring occurs in ~16% of patients and may result in severe

airway obstruction.

Pulmonary involvement (85–90% of patients) may be clinically

expressed as cough, hemoptysis, dyspnea, and chest discomfort, or

active disease may be asymptomatic in up to 30% of cases. Endobronchial disease, either in its active form or as a result of fibrous scarring,

may lead to obstruction with atelectasis.

Eye involvement(52% of patients) may range from a mild conjunctivitis

to dacryocystitis, episcleritis, scleritis, granulomatous sclerouveitis, ciliary

vessel vasculitis, and retroorbital mass lesions leading to proptosis.

Skin lesions (46% of patients) appear as papules, vesicles, palpable

purpura, ulcers, orsubcutaneous nodules; biopsy reveals vasculitis, granuloma, or both. Cardiac involvement (8% of patients) manifests as pericarditis, coronary vasculitis, or, rarely, cardiomyopathy. Nervous system

manifestations (23% of patients) include cranial neuritis, mononeuritis

multiplex, or, rarely, cerebral vasculitis and/or granuloma.

Renal disease (77% of patients) generally dominates the clinical

picture and, if left untreated, accounts directly or indirectly for most

of the mortality rate in this disease. Although it may smolder in some

cases as a mild glomerulitis with proteinuria, hematuria, and red blood

cell casts, it is clear that once clinically detectable renal functional

The Vasculitis Syndromes

2807CHAPTER 363

impairment occurs, rapidly progressive renal failure usually ensues

unless appropriate treatment is instituted.

While the disease is active, most patients have nonspecific symptoms and signs such as malaise, weakness, arthralgias, anorexia, and

weight loss. Fever may indicate activity of the underlying disease but

more often reflects secondary infection, usually of the upper airway.

Characteristic laboratory findings include an elevated erythrocyte

sedimentation rate (ESR) and/or C-reactive protein (CRP), mild anemia and leukocytosis, mild hypergammaglobulinemia (particularly of

the IgA class), and mildly elevated rheumatoid factor. Thrombocytosis may be seen as an acute-phase reactant. Approximately 90% of

patients with active granulomatosis with polyangiitis have a positive

antiproteinase-3 ANCA. However, in the absence of active disease,

the sensitivity drops to ~60–70%. A small percentage of patients with

granulomatosis with polyangiitis may have antimyeloperoxidase rather

than antiproteinase-3 antibodies, and up to 20% may lack ANCA.

Patients with granulomatosis with polyangiitis have been found to

have an increased incidence of venous thrombotic events. Although

routine anticoagulation for all patients is not recommended, a

TABLE 363-5 Granulomatosis with Polyangiitis: Frequency of

Clinical Manifestations in 158 Patients Studied at the

National Institutes of Health

MANIFESTATION

PERCENTAGE AT

DISEASE ONSET

PERCENTAGE

THROUGHOUT COURSE

OF DISEASE

Kidney

Glomerulonephritis 18 77

Ear/Nose/Throat 73 92

Sinusitis

Nasal disease

Otitis media

Hearing loss

Subglottic stenosis

Ear pain

Oral lesions

51

36

25

14

1

9

3

85

68

44

42

16

14

10

Lung 45 85

Pulmonary infiltrates

Pulmonary nodules

Hemoptysis

Pleuritis

25

24

12

10

66

58

30

28

Eyes

Conjunctivitis

Dacryocystitis

Scleritis

Proptosis

Eye pain

Visual loss

Retinal lesions

Corneal lesions

Iritis

5

1

6

2

3

0

0

0

0

18

18

16

15

11

8

4

1

2

Othera

Arthralgias/arthritis

Fever

Cough

Skin abnormalities

Weight loss (>10% body weight)

Peripheral neuropathy

Central nervous system disease

Pericarditis

Hyperthyroidism

32

23

19

13

15

1

1

2

1

67

50

46

46

35

15

8

6

3

a

Fewer than 1% had parotid, pulmonary artery, breast, or lower genitourinary

(urethra, cervix, vagina, testicular) involvement.

Source: GS Hoffman et al: Ann Intern Med 116:488, 1992.

heightened awareness for any clinical features suggestive of deep-vein

thrombosis or pulmonary emboli is warranted.

■ DIAGNOSIS

The diagnosis of granulomatosis with polyangiitis can be established

by the demonstration of necrotizing granulomatous vasculitis on tissue

biopsy in a patient with compatible clinical features. Pulmonary tissue

offers the highest diagnostic yield, almost invariably revealing granulomatous vasculitis. Biopsy of upper airway tissue usually reveals granulomatous inflammation with necrosis but may not show vasculitis. Renal

biopsy can confirm the presence of pauci-immune glomerulonephritis.

The specificity of a positive antiproteinase-3 ANCA for granulomatosis with polyangiitis is very high, especially if active glomerulonephritis is present. However, the presence of ANCA should be viewed as

adjunctive with tissue diagnosis being pursued when clinically inconsistent features are present or when ANCA is absent. False-positive

ANCA has been reported in certain infectious and neoplastic diseases.

In its typical presentation, the clinicopathologic complex of granulomatosis with polyangiitis usually provides ready differentiation from

other disorders. However, if all the typical features are not present at

once, it needs to be differentiated from the other vasculitides, antiglomerular basement membrane disease (Goodpasture’s syndrome)

(Chap. 314), relapsing polychondritis (Chap. 366), tumors of the

upper airway or lung, and infectious diseases such as histoplasmosis

(Chap. 212), endocarditis (Chap. 128), mucocutaneous leishmaniasis

(Chap. 226), and rhinoscleroma (Chap. 218) as well as noninfectious

granulomatous diseases.

Of particular note isthe differentiation from othermidline destructive diseases. These diseases lead to extreme tissue destruction and mutilation

localized to the midline upper airway structures including the sinuses;

erosion through the skin of the face commonly occurs, a feature that

is extremely rare in granulomatosis with polyangiitis. Although blood

vessels may be involved in the intense inflammatory reaction and

necrosis, primary vasculitis is not seen. Upper airway neoplasms and

specifically extranodal natural killer (NK)/T-cell lymphoma (nasal type)

are important causes of midline destructive disease. These lesions are

diagnosed based on histology, which reveals polymorphous atypical

lymphoid cells with an NK cell immunophenotype, typically EpsteinBarr virus (Chap. 194). Such cases are treated based on their degree

of dissemination, and localized lesions have responded to irradiation.

Upper airway lesions should never be irradiated in granulomatosis with

polyangiitis. Cocaine-induced tissue injury can be another important

mimic of granulomatosis with polyangiitis in patients who present with

isolated midline destructive disease. ANCA that target human neutrophil elastase can be found in patients with cocaine-induced midline

destructive lesions and can complicate the differentiation from granulomatosis with polyangiitis. This has been further confounded by the high

frequency of levamisole adulteration of cocaine, which can result in

cutaneous infarction and serologic changes that may mimic vasculitis.

Granulocytopenia is a common finding in levamisole-induced disease

that would not be associated with granulomatosis with polyangiitis.

Granulomatosis with polyangiitis must also be differentiated from

lymphomatoid granulomatosis, which is an Epstein-Barr virus–positive

B-cell proliferation that is associated with an exuberant T-cell reaction.

Lymphomatoid granulomatosis is characterized by lung, skin, CNS,

and kidney involvement in which atypical lymphocytoid and plasmacytoid cells infiltrate nonlymphoid tissue in an angioinvasive manner.

In this regard, it clearly differs from granulomatosis with polyangiitis

in that it is not an inflammatory vasculitis in the classic sense but an

angiocentric perivascular infiltration of atypical mononuclear cells. Up

to 50% of patients may develop a true malignant lymphoma.

TREATMENT

Granulomatosis with Polyangiitis

Prior to the introduction of effective therapy, granulomatosis with

polyangiitis was universally fatal within a few months of diagnosis.

Glucocorticoids alone led to some symptomatic improvement, with

little effect on the ultimate course of the disease. The development

2808 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

of treatment with cyclophosphamide dramatically changed patient

outcome such that marked improvement was seen in >90% of

patients, complete remission in 75% of patients, and 5-year patient

survival was seen in >80%.

Despite the ability to successfully induce remission, 50–70%

of remissions are later associated with one or more relapses. The

determination of relapse should be based on objective evidence of

disease activity, taking care to rule out other features that may have a

similar appearance such as infection, medication toxicity, or chronic

disease sequelae. Many patients who achieve remission continue to

have a positive ANCA for years, and changes in ANCA should not

be used as a measure of disease activity. Results from a large prospective study found that increases in ANCA were not associated

with relapse and that only 43% of patients relapsed within 1 year of

an increase in ANCA levels. Thus, a rise in ANCA by itself is not a

harbinger of immediate disease relapse and should not lead to reinstitution or increase in immunosuppressive therapy. Reinduction of

remission after relapse is almost always achieved; however, a high

percentage of patients ultimately have some degree of damage from

irreversible features of their disease, such as varying degrees of renal

insufficiency, neurologic impairment, hearing loss, subglottic stenosis, saddle nose deformity, and chronic sinus dysfunction. Patients

who developed irreversible renal failure but who achieved subsequent remission have undergone successful renal transplantation.

Treatment of granulomatosis with polyangiitis is currently

viewed as having two phases: induction, where active disease is put

into remission, followed by maintenance. The decision regarding

which agents to use for induction and maintenance is guided by

experience from published data, determination of disease severity, and individual patient factors that include contraindications,

relapse history, and comorbidities.

Current induction regimens consist of glucocorticoids plus

another immunosuppressive agent. For severe disease, glucocorticoids have historically been given as prednisone 1 mg/kg per day for

the first month, followed by gradual tapering on an alternate-day

or daily schedule. Recently, use of a reduced-dose glucocorticoid

regimen was found to be noninferior to a standard-dose regimen in

a randomized trial and was associated with a lower rate of serious

infection. For patients with nonsevere disease, use of lower initial

glucocorticoid doses can be considered.

In patients presenting with disease that is life-threatening, methylprednisolone 1000 mg daily for 3 days has been used. Adjunctive

plasmapheresis was recently found to provide no added benefit

in reducing the composite outcome of end-stage renal disease or

death. Whether it may still play a role in selected patients with the

most fulminant disease remains uncertain.

CYCLOPHOSPHAMIDE INDUCTION FOR SEVERE DISEASE

Daily cyclophosphamide combined with glucocorticoids was the

first regimen proven to effectively induce remission and prolong

survival. Cyclophosphamide is given in doses of 2 mg/kg per day

orally, but because it is renally eliminated, dosage reduction should

be considered in patients with renal insufficiency. Although we

continue to favor the use of daily cyclophosphamide, some reports

have indicated therapeutic success using IV cyclophosphamide. In

a randomized trial, IV cyclophosphamide 15 mg/kg, three infusions

given every 2 weeks, then every 3 weeks thereafter, was compared

to cyclophosphamide 2 mg/kg daily given for 3 months followed by

1.5 mg/kg daily. Although IV cyclophosphamide was found to have

a comparable rate of remission with a lower cumulative cyclophosphamide dose and occurrence of leukopenia, the use of a consolidation phase and an insufficient frequency of blood count monitoring

may have negatively influenced the results in those who received

daily cyclophosphamide. Of note in this study was that relapse

occurred in 19% of those who received IV cyclophosphamide as

compared to 9% who received daily oral administration.

RITUXIMAB INDUCTION FOR SEVERE DISEASE

Rituximab is a chimeric monoclonal antibody directed against

CD20 present on normal and malignant B lymphocytes that is U.S.

Food and Drug Administration (FDA) approved for the treatment

of granulomatosis with polyangiitis and microscopic polyangiitis.

In two randomized trials that enrolled ANCA-positive patients

with severe active granulomatosis with polyangiitis or microscopic

polyangiitis, rituximab 375 mg/m2 once a week for 4 weeks in

combination with glucocorticoids was found to be as effective

as cyclophosphamide with glucocorticoids for inducing disease

remission. In the trial that also enrolled patients with relapsing disease, rituximab was found to be statistically superior to cyclophosphamide. Although rituximab does not have the bladder toxicity or

infertility concerns, as can occur with cyclophosphamide, in both of

the randomized trials, the rate of adverse events was similar in the

rituximab and cyclophosphamide arms.

The decision about whether to utilize cyclophosphamide or rituximab for remission induction must be individually based. Factors to

consider include the severity of the disease, whether the patient has

newly diagnosed or relapsing disease, medication contraindications,

and individual patient factors particularly including fertility concerns.

In patients with rapidly progressive glomerulonephritis with a creatinine >4.0 mg/dL or pulmonary hemorrhage requiring mechanical

ventilation, daily cyclophosphamide and glucocorticoids are favored.

REMISSION MAINTENANCE

When cyclophosphamide is given for induction, it should be stopped

after 3–6 months and switched to another agent for remission

maintenance. Medications used in this setting with which there has

been published experience from randomized trials are rituximab,

azathioprine, methotrexate, and mycophenolate mofetil. A lower rate

of relapse was seen with rituximab given at 500 mg for two doses

followed by 500 mg every 6 months when compared to azathioprine

2 mg/kg per day. In a randomized trial comparing methotrexate to

azathioprine for remission maintenance, similar rates of toxicity and

relapse were seen. Methotrexate is administered orally or subcutaneously at a starting not to exceed 15 mg/week, which is increased by

2.5 mg every 2 weeks up to a dosage of 20–25 mg/week. In patients

who are unable to receive methotrexate or azathioprine or who have

experienced relapse on such treatment, mycophenolate mofetil

1000 mg twice a day may also sustain remission, but it is associated

with a higher rate of relapse compared to azathioprine.

For patients who receive rituximab for remission induction, a

recent randomized trial found that rituximab 1000 mg given every

4 months had a lower rate of relapse compared to azathioprine.

The optimal duration of maintenance therapy is uncertain. With

regard to glucocorticoids, it has been unclear whether maintaining

patients on prednisone 5 mg/d has greater risks or benefits compared

to discontinuation after 6–9 months. Maintenance therapy with azathioprine, methotrexate, or mycophenolate mofetil is usually given

for a minimum of 2 years. Because there is evidence that the risk of

relapse is higher once maintenance medication has been stopped, the

decision is individualized regarding whether to continue treatment

or taper these agents over a 6- to 12-month period until discontinuation. Patients with significant organ damage or a history of relapse

may benefit from longer-term maintenance therapy. Although rituximab has been found to have a lower relapse rate, its long-term safety

remains uncertain such that the decision for how long to continue

this agent beyond 2 years must be weighed in each patient.

REMISSION INDUCTION OF NONSEVERE DISEASE

For patients whose disease is not immediately organ- or lifethreatening, methotrexate or mycophenolate mofetil together with

glucocorticoids may be given to induce and then maintain remission. Treatment with cyclophosphamide is rarely if ever justified for

the treatment of nonsevere granulomatosis with polyangiitis.

OTHER BIOLOGIC AGENTS AND SMALL MOLECULE

INHIBITORS

Abatacept (CTLA4-Ig) was examined in an open-label pilot study

of nonsevere relapsing disease with favorable results, but further investigation is needed before application to clinical practice.

Etanercept, a dimeric fusion protein containing the 75-kDa TNF

The Vasculitis Syndromes

2809CHAPTER 363

receptor bound to human IgG1, was not found to sustain remission

when used adjunctively to standard therapy and should not be used

in the treatment of granulomatosis with polyangiitis. Belimumab

(anti-B lymphocyte stimulator) was examined as an adjunctive

therapy to azathioprine for remission maintenance but showed no

added benefit in reducing the risk of relapse.

Avacopan (a C5a receptor inhibitor) was recently investigated in

a randomized trial as an alternative to glucocorticoids in patients

receiving induction with either cyclophosphamide or rituximab.

At 52 weeks, sustained remission was higher in those who received

avacopan as compared to prednisone with a similar rate of serious

adverse events. Although glucocorticoids were given within the

first few weeks to some patients receiving avacopan, glucocorticoid

exposure remained markedly less than those randomized to the

prednisone treatment arm. Based on these findings, avacopan holds

promise in being able to reduce the need for glucocorticoids in the

treatment of ANCA-associated vasculitis.

TRIMETHOPRIM-SULFAMETHOXAZOLE

Although certain reports have indicated that TMP-SMX may be of

benefit in the treatment of granulomatosis with polyangiitis isolated

to the sinonasal tissues, it should never be used alone to treat active

granulomatosis with polyangiitis involving other organs. In a study

examining the effect of TMP-SMX on relapse, decreased relapses

were shown only with regard to upper airway disease, and no differences in major organ relapses were observed.

ORGAN-SPECIFIC TREATMENT

Not all manifestations of granulomatosis with polyangiitis require

or respond to immunosuppressive therapy, and differentiation of

active disease from damage is necessary. As sinus disease can disrupt the mucociliary barrier, patients should be instructed on the

use of local care with moisturization and humidification. Subglottic

stenosis can often scar and responds optimally to nonmedical intervention with dilation and glucocorticoid injection.

MICROSCOPIC POLYANGIITIS

■ DEFINITION

The term microscopic polyarteritis was introduced into the literature by

Davson in 1948 in recognition of the presence of glomerulonephritis in

patients with polyarteritis nodosa. In 1992, the Chapel Hill Consensus

Conference on the Nomenclature of Systemic Vasculitis adopted the

term microscopic polyangiitis to connote a necrotizing vasculitis with

few or no immune complexes affecting small vessels (capillaries, venules, or arterioles). Glomerulonephritis is very common in microscopic

polyangiitis, and pulmonary capillaritis often occurs. The absence of

granulomatous inflammation in microscopic polyangiitis is said to

differentiate it from granulomatosis with polyangiitis.

■ INCIDENCE AND PREVALENCE

The incidence of microscopic polyangiitis is estimated to be

3–5/100,000. The mean age of onset is ~57 years, and males are slightly

more frequently affected than females.

■ PATHOLOGY AND PATHOGENESIS

Microscopic polyangiitis has a predilection to involve capillaries and

venules in addition to small- and medium-sized arteries. Immunohistochemical staining reveals a paucity of immunoglobulin deposition

in the vascular lesion of microscopic polyangiitis, suggesting that

immune-complex formation does not play a role in the pathogenesis of

this syndrome. The renal lesion seen in microscopic polyangiitis is identical to that of granulomatosis with polyangiitis. Like granulomatosis with

polyangiitis, microscopic polyangiitis is highly associated with ANCA,

which may play a role in pathogenesis of this syndrome (see above).

■ CLINICAL AND LABORATORY MANIFESTATIONS

Because of its predilection to involve the small vessels, microscopic

polyangiitis and granulomatosis with polyangiitis share similar clinical

features. Disease onset may be gradual, with initial symptoms of fever,

weight loss, and musculoskeletal pain; however, it is often acute. Glomerulonephritis occurs in at least 79% of patients and can be rapidly

progressive, leading to renal failure. Hemoptysis may be the first symptom of alveolar hemorrhage, which occurs in 12% of patients. Other

manifestations include mononeuritis multiplex and gastrointestinal

tract and cutaneous vasculitis. Upper airway disease and pulmonary

nodules are not typically found in microscopic polyangiitis and, if

present, suggest granulomatosis with polyangiitis.

Features of inflammation may be seen, including an elevated ESR

and/or CRP, anemia, leukocytosis, and thrombocytosis. ANCA are

present in 75% of patients with microscopic polyangiitis, with antimyeloperoxidase antibodies being the predominant antigen association.

■ DIAGNOSIS

The diagnosis is based on histologic evidence of vasculitis or pauciimmune glomerulonephritis in a patient with compatible clinical

features of multisystem disease. Although microscopic polyangiitis is

strongly ANCA-associated, tissue biopsy should continue to be pursued in patients who do not have a clinically compatible picture.

TREATMENT

Microscopic Polyangiitis

The 5-year survival rate for patients with treated microscopic

polyangiitis is 74%, with disease-related mortality occurring from

alveolar hemorrhage or gastrointestinal, cardiac, or renal disease.

Studies on treatment have come from trials that have included

patients with granulomatosis with polyangiitis or microscopic

polyangiitis. Currently, the treatment approach for microscopic

polyangiitis is the same as is used for granulomatosis with polyangiitis (see “Granulomatosis with Polyangiitis” for a detailed description of this therapeutic regimen). Disease relapse has been observed

in at least 34% of patients. Treatment for such relapses would be

based on site and severity of disease.

EOSINOPHILIC GRANULOMATOSIS WITH

POLYANGIITIS (CHURG-STRAUSS)

■ DEFINITION

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) was

described in 1951 by Churg and Strauss and is characterized by asthma,

peripheral and tissue eosinophilia, extravascular granuloma formation,

and vasculitis of multiple organ systems.

■ INCIDENCE AND PREVALENCE

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is an

uncommon disease with an estimated annual incidence of 1–3 per

million. The disease can occur at any age with the possible exception

of infants. The mean age of onset is 48 years, with a female-to-male

ratio of 1.2:1.

■ PATHOLOGY AND PATHOGENESIS

The necrotizing vasculitis of eosinophilic granulomatosis with

polyangiitis (Churg-Strauss) involves small- and medium-sized muscular arteries, capillaries, veins, and venules. A characteristic histopathologic feature of eosinophilic granulomatosis with polyangiitis

(Churg-Strauss) is granuloma that may be present in the tissues or even

within the walls of the vessels themselves. These are usually associated

with infiltration of the tissues with eosinophils. This process can occur

in any organ in the body; lung involvement is predominant, with skin,

cardiovascular system, kidney, peripheral nervous system, and gastrointestinal tract also commonly involved. Although the precise pathogenesis of this disease is uncertain, its strong association with asthma

and its clinicopathologic manifestations, including eosinophilia, granuloma, and vasculitis, point to aberrant immunologic phenomena.

■ CLINICAL AND LABORATORY MANIFESTATIONS

Patients with eosinophilic granulomatosis with polyangiitis (ChurgStrauss) often exhibit nonspecific manifestations such as fever, malaise,

2810 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

anorexia, and weight loss, which are characteristic of a multisystem

disease. The pulmonary findings in eosinophilic granulomatosis with

polyangiitis (Churg-Strauss) dominate the clinical picture with severe

asthmatic attacks and the presence of pulmonary infiltrates. Mononeuritis multiplex is the second most common manifestation and occurs

in up to 72% of patients. Allergic rhinitis and sinusitis develop in up to

61% of patients and are often observed early in the course of disease.

Clinically recognizable heart disease with myocarditis, pericarditis,

endocarditis, or coronary vasculitis occurs in ~14% of patients and is

an important cause of mortality. Skin lesions occur in ~51% of patients

and include purpura in addition to cutaneous and subcutaneous nodules. The renal disease in eosinophilic granulomatosis with polyangiitis

(Churg-Strauss) is less common and generally less severe than that of

granulomatosis with polyangiitis and microscopic polyangiitis.

The characteristic laboratory finding in virtually all patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is a striking

eosinophilia, which reaches levels >1000 cells/μL in >80% of patients.

Evidence of inflammation as evidenced by elevated ESR and/or CRP,

fibrinogen, or α2

-globulins can be found in 81% of patients. The otherlaboratory findings reflect the organ systems involved. Approximately 48%

of patients with eosinophilic granulomatosis with polyangiitis (ChurgStrauss) have circulating ANCA that is usually antimyeloperoxidase.

■ DIAGNOSIS

Although the diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is optimally made by biopsy in a patient with the

characteristic clinical manifestations (see above), histologic confirmation can be challenging because the pathognomonic features often do

not occur simultaneously. In order to be diagnosed with eosinophilic

granulomatosis with polyangiitis (Churg-Strauss), a patient should

have evidence of asthma, peripheral blood eosinophilia, and clinical

features consistent with vasculitis.

TREATMENT

Eosinophilic Granulomatosis with Polyangiitis

(Churg-Strauss)

The prognosis of untreated eosinophilic granulomatosis with

polyangiitis (Churg-Strauss) is poor, with a reported 5-year survival

of 25%. With treatment, prognosis is favorable, with one study finding a 78-month actuarial survival rate of 72%. Myocardial involvement is the most frequent cause of death and is responsible for 39%

of patient mortality. Echocardiography should be performed in all

newly diagnosed patients because this may influence therapeutic

decisions.

Glucocorticoids alone appear to be effective in many patients.

Dosage tapering is often limited by asthma, and many patients

require low-dose prednisone for persistent asthma many years

after clinical recovery from vasculitis. In patients who present with

fulminant multisystem disease, particularly cardiac involvement,

the treatment of choice is a combined regimen of daily cyclophosphamide and prednisone followed by azathioprine or methotrexate

(see “Granulomatosis with Polyangiitis” for a detailed description of

this therapeutic regimen).

Mepolizumab (anti-IL-5 antibody) 300 mg given subcutaneously once a month was studied in a randomized trial and found

to be more effective than placebo. Patients with life-threatening

eosinophilic granulomatosis with polyangiitis (Churg-Strauss) were

excluded from the mepolizumab trial and should continue to be

treated with cyclophosphamide and glucocorticoids. As mepolizumab is FDA approved for both eosinophilic granulomatosis with

polyangiitis (Churg-Straus) and severe eosinophilic asthma, it may

have a particularly beneficial role in the setting of relapsing or resistant asthma requiring glucocorticoids.

Rituximab has been examined in retrospective series and may

have a role in patients with active or relapsing vasculitis despite

conventional agents or intolerance of these medications.

POLYARTERITIS NODOSA

■ DEFINITION

Polyarteritis nodosa was described in 1866 by Kussmaul and Maier.

It is a multisystem, necrotizing vasculitis of small- and medium-sized

muscular arteries in which involvement of the renal and visceral arteries is characteristic. Polyarteritis nodosa does not involve pulmonary

arteries, although bronchial vessels may be involved; granulomas, significant eosinophilia, and an allergic diathesis are not observed.

■ INCIDENCE AND PREVALENCE

It is difficult to establish an accurate incidence of polyarteritis nodosa

because previous reports have included polyarteritis nodosa and

microscopic polyangiitis as well as other related vasculitides. Polyarteritis nodosa, as currently defined, is felt to be a very uncommon

disease.

■ PATHOLOGY AND PATHOGENESIS

The vascular lesion in polyarteritis nodosa is a necrotizing inflammation of small- and medium-sized muscular arteries. The lesions are

segmental and tend to involve bifurcations and branchings of arteries.

They may spread circumferentially to involve adjacent veins. However,

involvement of venules is not seen in polyarteritis nodosa and, if present, suggests microscopic polyangiitis (see below). In the acute stages

of disease, polymorphonuclear neutrophils infiltrate all layers of the

vessel wall and perivascular areas, which results in intimal proliferation and degeneration of the vessel wall. Mononuclear cells infiltrate

the area as the lesions progress to the subacute and chronic stages.

Fibrinoid necrosis of the vessels ensues with compromise of the lumen,

thrombosis, infarction of the tissues supplied by the involved vessel,

and, in some cases, hemorrhage. As the lesions heal, there is collagen

deposition, which may lead to further occlusion of the vessel lumen.

Aneurysmal dilations up to 1 cm in size along the involved arteries are

characteristic of polyarteritis nodosa.

Multiple organ systems are involved, and the clinicopathologic

findings reflect the degree and location of vessel involvement and the

resulting ischemic changes. As mentioned above, pulmonary arteries

are not involved in polyarteritis nodosa, and bronchial artery involvement is uncommon. The pathology in the kidney in polyarteritis

nodosa is that of arteritis without glomerulonephritis. In patients with

significant hypertension, typical pathologic features of glomerulosclerosis may be seen. In addition, pathologic sequelae of hypertension

may be found elsewhere in the body.

The presence of a polyarteritis nodosa–like vasculitis in patients

with hepatitis B together with the isolation of circulating immune

complexes composed of hepatitis B antigen and immunoglobulin and

the demonstration by immunofluorescence of hepatitis B antigen, IgM,

and complement in the blood vessel walls strongly suggest the role of

immunologic phenomena in the pathogenesis of this disease. A polyarteritis nodosa–like vasculitis has also been reported in patients with

hepatitis C. Hairy cell leukemia can be associated with polyarteritis

nodosa; the pathogenic mechanisms of this association are unclear.

A polyarteritis nodosa–like vasculitis has being described in conjunction with deficiency of adenosine deaminase type 2 (DADA2).

Patients with DADA2 usually present in childhood with a variable

pattern of clinical features and vascular pathology that is responsive to

TNF inhibitors. As this differs from the usual treatment for polyarteritis nodosa, DADA2 should be considered in patients with suggestive

clinical features, particularly those with early-onset disease.

■ CLINICAL AND LABORATORY MANIFESTATIONS

Nonspecific signs and symptoms are the hallmarks of polyarteritis

nodosa. Fever, weight loss, and malaise are present in over one-half of

cases. Patients usually present with vague symptoms such as weakness,

malaise, headache, abdominal pain, and myalgias that can rapidly

progress to a fulminant illness. Specific complaints related to the vascular involvement within a particular organ system may also dominate

the presenting clinical picture as well as the entire course of the illness

The Vasculitis Syndromes

2811CHAPTER 363

(Table 363-6). In polyarteritis nodosa, renal involvement most commonly manifests as hypertension, renal insufficiency, or hemorrhage

due to microaneurysms.

There are no diagnostic serologic tests for polyarteritis nodosa. In

>75% of patients, the leukocyte count is elevated with a predominance

of neutrophils. Eosinophilia is seen only rarely and, when present at

high levels, suggests the diagnosis of eosinophilic granulomatosis with

polyangiitis (Churg-Strauss). The anemia of chronic disease may be

seen, and an elevated ESR and/or CRP is almost always present. Other

common laboratory findings reflect the particular organ involved.

Hypergammaglobulinemia may be present, and all patients should be

screened for hepatitis B and C. ANCA are rarely found in patients with

polyarteritis nodosa.

■ DIAGNOSIS

The diagnosis of polyarteritis nodosa is based on the demonstration

of characteristic findings of vasculitis on biopsy material of involved

organs. Biopsy of symptomatic organs such as nodular skin lesions,

painful testes, and nerve/muscle provides the highest diagnostic yields.

In the absence of easily accessible tissue for biopsy, the arteriographic

demonstration of involved vessels, particularly in the form of aneurysms of small- and medium-sized arteries in the renal, hepatic, and

visceral vasculature, is sufficient to make the diagnosis. This should

consist of a catheter-directed dye arteriogram because magnetic resonance and computed tomography arteriograms do not have sufficient

resolution at the current time to visualize the vessels affected in polyarteritis nodosa. Aneurysms of vessels are not pathognomonic of polyarteritis nodosa; furthermore, aneurysms need not always be present,

and arteriographic findings may be limited to stenotic segments and

obliteration of vessels.

TREATMENT

Polyarteritis Nodosa

The prognosis of untreated polyarteritis nodosa is extremely poor,

with a reported 5-year survival rate between 10 and 20%. Death

usually results from gastrointestinal complications, particularly

bowel infarcts and perforation, and cardiovascular causes. Intractable hypertension often compounds dysfunction in other organ

systems, such as the kidneys, heart, and CNS, leading to additional

late morbidity and mortality in polyarteritis nodosa. The combination of prednisone and cyclophosphamide has been found to

significantly improve the survival rate (see “Granulomatosis with

Polyangiitis” for a detailed description of this therapeutic regimen).

In less severe cases of polyarteritis nodosa, glucocorticoids alone

TABLE 363-6 Clinical Manifestations Related to Organ System

Involvement in Polyarteritis Nodosa

ORGAN SYSTEM

PERCENT

INCIDENCE CLINICAL MANIFESTATIONS

Renal 60 Renal failure, hypertension

Musculoskeletal 64 Arthritis, arthralgia, myalgia

Peripheral

nervous system

51 Peripheral neuropathy, mononeuritis multiplex

Gastrointestinal

tract

44 Abdominal pain, nausea and vomiting,

bleeding, bowel infarction and perforation,

cholecystitis, hepatic infarction, pancreatic

infarction

Skin 43 Rash, purpura, nodules, cutaneous infarcts,

livedo reticularis, Raynaud’s phenomenon

Cardiac 36 Congestive heart failure, myocardial

infarction, pericarditis

Genitourinary 25 Testicular, ovarian, or epididymal pain

Central nervous

system

23 Cerebral vascular accident, altered mental

status, seizure

Source: Reproduced with permission from TR Cupps, AS Fauci: The vasculitides.

Major Probl Intern Med 21:1, 1981.

have resulted in disease remission. In patients with hepatitis B or

C who have a polyarteritis nodosa–like vasculitis, antiviral therapy

represents an important part of management and has been used in

combination with glucocorticoids and plasma exchange in some

series. Careful attention to the treatment of hypertension can lessen

the vascular complications of polyarteritis nodosa. Following successful treatment, relapse of polyarteritis nodosa has been estimated

to occur in 10–20% of patients.

GIANT CELL ARTERITIS AND

POLYMYALGIA RHEUMATICA

■ DEFINITION

Giant cell arteritis, historically referred to as temporal arteritis, is an

inflammation of medium- and large-sized arteries. It characteristically

involves one or more branches of the carotid artery, particularly the

temporal artery. However, it is a systemic disease that can involve

arteries in multiple locations, particularly the aorta and its main

branches.

Giant cell arteritis is closely associated with polymyalgia rheumatica,

which is characterized by stiffness, aching, and pain in the muscles

of the neck, shoulders, lower back, hips, and thighs. Most commonly,

polymyalgia rheumatica occurs in isolation, but it may be seen in

40–50% of patients with giant cell arteritis. In addition, ~10–20% of

patients who initially present with features of isolated polymyalgia

rheumatica later go on to develop giant cell arteritis. This strong

clinical association together with data from pathophysiologic studies

has increasingly supported that giant cell arteritis and polymyalgia

rheumatica represent differing clinical spectrums of a single disease

process.

■ INCIDENCE AND PREVALENCE

Giant cell arteritis occurs almost exclusively in individuals aged

>50 years. It is more common in women than in men and is rare in

blacks. The incidence of giant cell arteritis varies widely in different

studies and in different geographic regions. A high incidence has been

found in Scandinavia and in regions of the United States with large

Scandinavian populations, compared to a lower incidence in southern

Europe. The annual incidence rates in individuals aged ≥50 years range

from 6.9 to 32.8 per 100,000 population. Familial aggregation has been

reported, as has an association with HLA-DR4. In addition, genetic

linkage studies have demonstrated an association of giant cell arteritis

with alleles at the HLA-DRB1 locus, particularly HLA-DRB1*

04 variants. In Olmsted County, Minnesota, the annual incidence of polymyalgia rheumatica in individuals aged ≥50 years is 58.7 per 100,000

population.

■ PATHOLOGY AND PATHOGENESIS

Although the temporal artery is most frequently involved in giant cell

arteritis, patients often have a systemic vasculitis of multiple mediumand large-sized arteries, which may go undetected. Histopathologically,

the disease is a panarteritis with inflammatory mononuclear cell infiltrates within the vessel wall with frequent giant cell formation. There

is proliferation of the intima and fragmentation of the internal elastic

lamina. Pathophysiologic findings in organs result from the ischemia

related to the involved vessels.

Experimental data support that giant cell arteritis is an antigendriven disease in which activated T lymphocytes, macrophages, and

dendritic cells play a critical role in pathogenesis. Sequence analysis of

the T-cell receptor of tissue-infiltrating T cells in lesions of giant cell

arteritis indicates restricted clonal expansion, suggesting the presence

of an antigen residing in the arterial wall. Giant cell arteritis is believed

to be initiated in the adventitia where CD4+ T cells enter through the

vasa vasorum, become activated, and orchestrate macrophage differentiation. T cells recruited to vasculitic lesions in patients with giant

cell arteritis produce predominantly IL-2 and IFN-γ, and the latter has

been suggested to be involved in the progression to arteritis. Laboratory-based data demonstrate that at least two separate lineages of CD4

2812 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

T cells—IFN-γ-producing TH1 cells and IL-17-producing TH17 cells—

participate in vascular inflammation and may have differing levels of

responsiveness to glucocorticoids.

■ CLINICAL AND LABORATORY MANIFESTATIONS

Giant cell arteritis is most commonly characterized clinically by the

complex of fever, anemia, high ESR and/or CRP, and headaches in a

patient aged >50 years. Other phenotypic manifestations include features of systemic inflammation, including malaise, fatigue, anorexia,

weight loss, sweats, arthralgias, polymyalgia rheumatica, or large-vessel

disease.

In patients with involvement of the cranial arteries, headache is the

predominant symptom and may be associated with a tender, thickened, or nodular artery, which may pulsate early in the disease but

may become occluded later. Scalp pain and claudication of the jaw and

tongue may occur. A well-recognized and dreaded complication of

giant cell arteritis, particularly in untreated patients, is ischemic optic

neuropathy, which may lead to serious visual symptoms, including

sudden blindness in some patients. However, most patients have complaints relating to the head or eyes before visual loss. Attention to such

symptoms with institution of appropriate therapy (see below) lessens

the risk of this complication. Other cranial ischemic complications

include strokes and scalp or tongue infarction.

Up to one-third of patients can have large-vessel disease that can

be the primary presentation of giant cell arteritis or can emerge at a

later point in patients who have had previous cranial arteritis features

or polymyalgia rheumatica. Manifestations of large-vessel disease can

include subclavian artery stenosis that can present as arm claudication

or aortic aneurysms involving the thoracic and to a lesser degree the

abdominal aorta, which carry risks of rupture or dissection.

Characteristic laboratory findings in addition to the elevated ESR

and/or CRP include a normochromic or slightly hypochromic anemia.

Liver function abnormalities are common, particularly increased alkaline phosphatase levels. Increased levels of IgG and complement have

been reported.

■ DIAGNOSIS

The diagnosis of giant cell arteritis can often be suggested clinically

by the demonstration of the complex of fever, anemia, and high ESR

and/or CRP with or without symptoms of polymyalgia rheumatica in a

patient >50 years old. The diagnosis can be confirmed by biopsy of the

temporal artery but may not be positive in all patients due to patchy

histologic findings. Since involvement of the vessel may be segmental,

positive yield is increased by obtaining a biopsy segment of 3–5 cm

together with serial sectioning of biopsy specimens. Ultrasonography

of the temporal artery has been reported to be helpful in diagnosis and

has been increasingly used by some physicians. Therapy should not be

delayed pending the performance of diagnostic studies. In this regard,

it has been reported that temporal artery biopsies may show vasculitis

even after ~14 days of glucocorticoid therapy. A dramatic clinical

response to a trial of glucocorticoid therapy can further support the

diagnosis.

Large-vessel disease may be suggested by symptoms and findings

on physical examination such as diminished pulses or bruits. It is

confirmed by vascular imaging, most commonly through magnetic

resonance or computed tomography. Positron emission tomography

has become increasingly investigated, although its role in diagnosis and

monitoring remains unclear.

Isolated polymyalgia rheumatica is a clinical diagnosis made by

the presence of typical symptoms of stiffness, aching, and pain in the

muscles of the hip and shoulder girdle, an increased ESR and/or CRP,

the absence of clinical features suggestive of giant cell arteritis, and

a prompt therapeutic response to low-dose prednisone. Polymyalgia

rheumatica can be associated with a peripheral arthritis that can mimic

rheumatoid arthritis (Chap. 358). Rheumatoid factor and anti-cyclic

citrullinated peptide (CCP) shoulder be negative. In patients who

develop a worsening pattern of peripheral arthritis, the potential for a

seronegative rheumatoid arthritis or other inflammatory arthropathy

should be considered. Levels of enzymes indicative of muscle damage

such as serum creatine kinase are not elevated.

TREATMENT

Giant Cell Arteritis and Polymyalgia Rheumatica

Acute disease–related mortality directly from giant cell arteritis is

uncommon, with fatalities occurring from cerebrovascular events

or myocardial infarction. However, patients are at risk of late mortality from aortic aneurysm rupture or dissection as patients with

giant cell arteritis are 18 times more likely to develop thoracic aortic

aneurysms than the general population.

The goals of treatment in giant cell arteritis are to reduce symptoms and, most importantly, to prevent visual loss. The treatment

approach for cranial and large-vessel disease in giant cell arteritis is

currently the same. Giant cell arteritis and its associated symptoms

are responsive to glucocorticoid therapy. Treatment should begin

with prednisone 40–60 mg/d for ~1 month, followed by a gradual

tapering. When ocular signs and symptoms occur, consideration

should be given for the use of methylprednisolone 1000 mg daily for

3 days to protect remaining vision. Although the optimal duration

of glucocorticoid therapy has not been established, most series have

found that patients require treatment for ≥2 years. Symptom recurrence during prednisone tapering develops in 60–85% of patients

with giant cell arteritis, requiring a dosage increase. The ESR and/or

CRP can serve as a useful indicator of inflammatory disease activity

in monitoring and tapering therapy and can be used to judge the

pace of the tapering schedule. However, minor increases in the ESR

and/or CRP can occur as glucocorticoids are being tapered and

do not necessarily reflect an exacerbation of arteritis, particularly

if the patient remains symptom-free. Under these circumstances,

the tapering should continue with caution. Glucocorticoid toxicity

occurs in 35–65% of patients and represents an important cause of

patient morbidity.

Tocilizumab (anti-IL-6 receptor) was found to be effective in

giant cell arteritis in a randomized trial and is FDA approved for

this indication. The recommended dose of tocilizumab is 162 mg

given subcutaneously once every week or once every other week

in combination with a tapering course of glucocorticoids. The

decision about when to use tocilizumab in giant cell arteritis is individually based, taking into account patient comorbidities, potential

for glucocorticoid toxicity, and the side effects of tocilizumab. By

nature of its mechanism of action, tocilizumab impacts laboratory

parameters of ESR and CRP, which will eliminate the ability to utilize these in disease activity assessment.

The use of methotrexate as a glucocorticoid-sparing agent has

been examined in two randomized placebo-controlled trials that

reached conflicting conclusions. It may be considered in select

patients with glucocorticoid toxicity who are unable to take or

intolerant of tocilizumab.

Abatacept (CTLA4-Ig) was examined in a small randomized trial

in giant cell arteritis and demonstrated greater efficacy than glucocorticoids alone. Infliximab, a monoclonal antibody to TNF, was

studied in a randomized trial and was not found to provide benefit.

Aspirin 81 mg daily has been found to reduce the occurrence of

cranial ischemic complications in giant cell arteritis and should be

given in addition to glucocorticoids in patients who do not have

contraindications.

Patients with isolated polymyalgia rheumatica respond promptly

to prednisone, which can be started at a lower dose of 10–20 mg/d.

Similar to giant cell arteritis, the ESR and/or CRP can serve as a useful indicator in monitoring and prednisone reduction. Recurrent

polymyalgia symptoms develop in the majority of patients during

prednisone tapering. One study of methotrexate found that the use

of this drug reduced the prednisone dose on average by only 1 mg

and did not decrease prednisone-related side effects. A randomized

trial in polymyalgia rheumatica did not find infliximab to lessen

relapse or glucocorticoid requirements.