CHAPTER
53  VASCULITIS
J. Charles Jennette, Eric T. Weimer, Jason Kidd
INTRODUCTION, 1016
DIAGNOSTIC CLASSIFICATION
OF VASCULITIS, 1016
LARGE VESSEL   VASCULITIS, 1022
VASCULITIS, 1017
Takayasu Arteritis, 1018
Giant Cell Arteritis, 1019
MEDIUM VESSEL   Cryoglobulinemic Vasculitis, 1027
VASCULITIS, 1020
KEY POINTS
• Vasculitis affects blood vessels of any type in any organ or tissue and
thus causes extremely diverse signs and symptoms of disease that
overlap with many other diseases.
• Even if it is not the final diagnosis, vasculitis often is in the differential
diagnosis in a patient with evidence for single organ or systemic
inflammatory disease.
• Laboratory tests for vasculitis identify a specific etiologic factor or
measure perturbations in physiological molecular and cellular events
that result from specific pathogenic events.
• Clinical laboratory tests for the diagnosis of vasculitis include tests
that document active inflammation (e.g., C reactive protein assay),
demonstrate injury to a specific organ (e.g., urinalysis), or implicate a
specific category of vasculitis (e.g., cryoglobulin assay).
• Vasculitis is categorized into infectious vasculitis that is caused by
vessel wall invasion by pathogens and noninfectious vasculitis that is
not known to be caused by infection in vessel walls.
• Noninfectious vasculitis is categorized as immune complex–mediated,
antineutrophil cytoplasmic autoantibody (ANCA)–mediated, or
cell-mediated immune vasculitis.
• Clinical diagnosis of vasculitis is based on both the presence and
absence of multiple clinical, pathologic, and laboratory features.
• Accurate and precise diagnosis of a specific category of vasculitis is
essential for optimum patient outcome.
INTRODUCTION
Vasculitis is inflammation of blood vessel walls. Blood vessels of any type
in any organ or tissue may be affected. Thus the signs and symptoms of
disease are extremely diverse and overlap with many other diseases. As a
consequence, vasculitis often is in the differential diagnosis for both single
organ and systemic disease, especially in a patient with evidence for an
inflammatory condition. Clinical laboratory tests (i.e., tests for biomarkers)
that are used for the diagnosis of vasculitis fall into three categories: those
that document the presence of an inflammatory process (e.g., C reactive
protein assay), those that demonstrate injury to a specific organ (urinalysis),
and those that are indicative of a specific category of vasculitis (e.g., cryo-
globulin assay). This chapter reviews the clinical and pathologic features
of the major categories of vasculitis and discusses the role of laboratory
testing in the diagnosis and management of these diseases.
DIAGNOSTIC CLASSIFICATION
OF VASCULITIS
Laboratory tests for a disease often are based on identification of a specific
etiologic factor or measurement of perturbations in physiological molecu-
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Polyarteritis Nodosa, 1020 IgA Vasculitis (Henoch-Schönlein
Kawasaki Disease, 1021 Purpura), 1028
Hypocomplementemic Urticarial
SMALL VESSEL  
Vasculitis, 1029
Rheumatoid Vasculitis, 1030
ANCA-Associated Small Vessel
Vasculitis, 1022 SUMMARY, 1031
Anti-Glomerular Basement SELECTED REFERENCES, 1031
Membrane Disease, 1026
lar and cellular events that are caused by specific pathogenic events. This
approach is difficult to apply to all forms of vasculitis because the etiology
and pathogenesis of some forms are unknown. Vasculitis can be catego-
rized into infectious vasculitis that is known to be caused by vessel wall
invasion by pathogens that incite the inflammation (Pagnoux et al, 2006),
and noninfectious vasculitis that is not known to be caused by infection
in vessel walls (Jennette et al, 2013) (Box 53-1). For example, the infec-
tious vasculitis of Rocky Mountain spotted fever (RMSF) is caused by
proliferation of Rickettsia rickettsii in endothelial cells and smooth muscle
cells in small vessels in many tissues (Silverman & Bond, 1984). The
immune response to vessel wall rickettsiae causes vascular inflammation
that results in hemorrhage that produces the skin spots that are typical
for RMSF. Bacterial sepsis can cause small vessel vasculitis that can mimic
noninfectious immune-mediated vasculitis ( Jain et al, 2007) and clearly
must be diagnosed correctly and treated with antimicrobial drugs and not
immunosuppression.
Noninfectious vasculitis is caused by inflammation that is not known
to be caused by pathogens in vessel walls. However, it is important to
realize that the etiology and pathogenesis of some forms of vasculitides are
currently not known, so an infectious etiology cannot be completely ruled
out. For example, although the etiology is not known for Kawasaki disease,
giant cell arteritis, and Takayasu arteritis, some theories propose that an
unidentified pathogen may be the cause. For example, Mycobacterium
tuberculosis has been incriminated but not proven to be involved in the
pathogenesis of Takayasu arteritis and a Burkholderia bacterium in the
pathogenesis of giant cell arteritis (van Timmeren et al, 2014).
Noninfectious vasculitis can be caused indirectly by an infection that
initiates a sequence of pathogenic events that causes vasculitis. For example,
cryoglobulinemic vasculitis can be caused by hepatitis C virus infection in
the liver, which induces polyclonal, oligoclonal, and monoclonal B cell
proliferations that produce rheumatoid factors (antiantibodies) that bind
to other immunoglobulins to form pathogenic immune complexes (Tede-
schi et al, 2007). Laboratory tests for cryoglobulinemic vasculitis comprise
identification of the infectious agent (hepatitis C virus serology) that initi-
ated the autoimmune response, the autoantibodies (rheumatoid factor
assay), the pathogenic immune complexes (cryoglobulin assay), secondary
disturbances in inflammatory mediators (e.g., hypocomplementemia), and
the evidence for end organ damage (hematuria and proteinuria).
Laboratory testing for RMSF provides a good example of testing strate-
gies for infectious vasculitis. The most direct laboratory test for RMSF is
immunohistologic visualization of R. rickettsii in vessel walls in a skin
biopsy specimen. This test has excellent specificity and 70% sensitivity
during the acute phase before antibiotic treatment is started. Serologic
testing for antibodies to R. rickettsii has poor sensitivity during the first 10
to 12 days but increases to more than 90% after 2 weeks (Nathavitharana
& Mitty, 2015). The most definitive serologic finding for RMSF is a rise
in titer over several weeks. Analogous testing is applicable to other infec-
tious vasculitis—that is, testing to identify the etiologic infection and
testing to demonstrate a specific immune response to the pathogen.
Based on known or putative pathogenic mechanisms, noninfectious
vasculitis can be categorized as immune complex–mediated, antineutrophil
BOX 53-1  BOX 53-2 
Putative Pathogenic Mechanisms for Vasculitis Names for Vasculitides Adopted by the 2012 International
Chapel Hill Consensus Conference on the Nomenclature
Vasculitis Caused by Vessel Wall Infection
of Vasculitides
Bacterial (e.g., neisserial vasculitis, syphilitic aortitis)
Rickettsial (e.g., Rocky Mountain spotted fever) Large Vessel Vasculitis (LVV)
Fungal (e.g., cryptococcal vasculitis) Takayasu arteritis (TAK)
Viral (e.g., cytomegalovirus vasculitis) Giant cell arteritis (GCA)
Parasitic (e.g., toxoplasmosis vasculitis
Medium Vessel Vasculitis (MVV)
Immune Complex–Mediated Vasculitis
Polyarteritis nodosa (PAN)
Cryoglobulinemic vasculitis Kawasaki disease (KD)
Polyarteritis nodosa
Small Vessel Vasculitis (SVV)
IgA vasculitis (Henoch-Schönlein)
Hypocomplementemic urticarial vasculitis Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV)
Lupus vasculitis Microscopic polyangiitis (MPA)
Rheumatoid vasculitis Granulomatosis with polyangiitis (Wegener’s) (GPA)
Drug-induced immune complex vasculitis Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)
Cancer-induced (paraneoplastic) immune complex vasculitis Immune complex SVV
Anti-glomerular basement membrane disease Anti-glomerular basement membrane (anti-GBM) disease
Cryoglobulinemic vasculitis (CV)
Antineutrophil Cytoplasmic Antibody (ANCA)–Mediated Vasculitis
IgA vasculitis (Henoch-Schönlein) (IgAV)
Microscopic polyangiitis Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis)
Granulomatosis with polyangiitis (Wegener’s)
Variable Vessel Vasculitis (VVV)
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Drug-induced ANCA vasculitis Behçet’s disease (BD)
Cogan’s syndrome (CS)
Cell-Mediated Immune Vasculitis
Single-Organ Vasculitis (SOV)
Takayasu arteritis

Giant cell arteritis
Sarcoid vasculitis
cytoplasmic autoantibody (ANCA)–mediated, or cell-mediated immune
vasculitis (see Box 53-1). Immune complex vasculitis can be caused by
antibodies directed against a non–self-antigen (e.g., hepatitis B immune
complex vasculitis caused by antibodies to viral antigens) or autoantibodies
directed against an autoantigen (e.g., lupus vasculitis caused by autoanti-
bodies against nuclear antigens). Cell-mediated immunity also can cause
vascular inflammation. The pattern of inflammatory injury in giant
cell arteritis and in Takayasu arteritis suggests possible cell-mediated
immune injury; however, definitive self or non-self targets have not been
conclusively identified. In idiopathic vasculitides, another possibility is an
autoinflammatory process that is mediated by a disturbance in the regula-
tion of the innate immune response in the absence of a specific antigen
target.
The absence of identifiable etiologies or distinctive pathogenic mecha-
nisms in many forms of vasculitis does not allow diagnosis or classification
of vasculitides based only on these characteristics. Alternatively, classifica-
tion and diagnosis is most often based on the presence and absence of
multiple clinical, pathologic, and laboratory features. The most widely
used approach to categorizing vasculitis is based on the nomenclature of
vasculitis proposed by the Chapel Hill Consensus Conferences (CHCC)
held in 1994 ( Jennette et al, 1994) and modified in 2012 ( Jennette et al,
2013). The CHCC nomenclature provides consensus names (Box 53-2;
Fig. 53-1) and definitions for many, but not all, forms of systemic and
single organ vasculitis. Three major categories are large vessel vasculitis
(LVV), medium vessel vasculitis (MVV), and small vessel vasculitis (SVV).
This terminology can be misleading if it is taken too literally. In general,
LVV more often affects the aorta and its major branches than any other
form of vasculitis, MVV is confined to arteries, with a preference for major
visceral arteries, and SVV involves not only arteries but also vessels smaller
than arteries. Especially with respect to arterial involvement, there is
substantial overlap among the categories. For example, although large
vessel involvement is the most specific finding, giant cell arteritis can affect
any size artery from the aorta to the smallest arterial vessels, such as those
in the uveal tract of the eye (Waldman et al, 2013).
In addition to SVV, MVV, and LVV, the 2012 CHCC also recognized
variable vessel vasculitis (VVV), single organ vasculitis (SOV), vasculitis
associated with systemic disease, and vasculitis associated with probable
etiology ( Jennette et al, 2013). VV is vasculitis with no predominant type
of vessel involved that can affect vessels of any size (small, medium, and
large) and type (arteries, veins, and capillaries), such as Behçet’s disease and
Cogan’s syndrome. SOV is vasculitis in arteries or veins of any size in a
single organ that has no features that indicate that it is a limited expression
of a systemic vasculitis. Some patients originally diagnosed with SOV will
develop additional disease manifestations that warrant redefining the case
PART 6
Cutaneous leukocytoclastic angiitis
Cutaneous arteritis
Primary central nervous system vasculitis
Isolated aortitis
Others
Vasculitis Associated with Systemic Disease
Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Others
Vasculitis Associated with Probable Etiology
Hepatitis C virus–associated cryoglobulinemic vasculitis
Hepatitis B virus–associated vasculitis
Syphilis-associated aortitis
Drug-associated immune complex vasculitis
Drug-associated ANCA-associated vasculitis
Cancer-associated (paraneoplastic) vasculitis
Others
From Jennette JC, Falk RJ, Bacon PA, et al: 2012 Revised International Chapel Hill
Consensus Conference Nomenclature of Vasculitides, Arthritis Rheum 65:1–11,
2013.
as one of the systemic vasculitides (e.g., cutaneous arteritis later becoming
systemic polyarteritis nodosa). Vasculitis associated with systemic disease
should have a prefix term specifying the systemic disease (e.g., rheumatoid
vasculitis, lupus vasculitis, etc.). Likewise, vasculitis associated with prob-
able etiology should have a prefix term specifying the association (e.g.,
hydralazine-associated microscopic polyangiitis, hepatitis B virus–
associated vasculitis, hepatitis C virus–associated cryoglobulinemic vascu-
litis, etc.).
LARGE VESSEL VASCULITIS
CHCC 2012 defines LVV as vasculitis affecting the aorta and its major
branches more often than other vasculitides, although any size artery may
be affected ( Jennette et  al, 2013). In fact, in some patients the number
of medium and small arteries affected is greater than the number of large
arteries affected. For example, in giant cell arteritis, very few branches of
the carotid arteries may be affected, although there is involvement of
numerous small arteries extending into the head and neck (Waldman
et  al, 2013).
The two major variants of LVV are Takayasu arteritis (TA) and giant
cell arteritis (GCA) (Table 53-1). Both have similar pathologic features,
so they cannot be distinguished based on pathologic features alone
( Jennette et al, 2013). Demographic and clinical features are required to
make the distinction, especially age. The differential diagnosis for LVV
includes syphilitic aortitis, which is an infectious vasculitis caused by
tertiary syphilis, and very rarely by secondary syphilis (Dietrich et al,

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 Immune complex small vessel vasculitis
53  Vasculitis
IgA vasculitis
Cryoglobulinemic vasculitis
Hypocomplementemic urticarial vasculitis

Medium vessel vasculitis Anti-GBM disease

Polyarteritis nodosa
Kawasaki disease

Capillary
Venule
Arteriole
Vein
Artery

Artery
Aorta

ANCA-associated small vessel vasculitis

Microscopic polyangiitis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis

Large vessel vasculitis

Takayasu arteritis
Giant cell arteritis
Figure 53-1  The predominant distribution of vessel involvement by large vessel vasculitis, medium vessel vasculitis,
and small vessel vasculitis. Note that all categories of vasculitis can affect all types of arteries. The aorta and the largest
arteries are most often affected by large vessel vasculitis. Medium vessel vasculitis most often affects medium arteries,
although large and small arteries may be affected. Small vessel vasculitis preferentially affects venules and capillaries, although
arteries and veins may be affected. ANCA (antineutrophil cytoplasmic antibody)–associated vasculitis affects the broadest
spectrum of vessels, whereas immune complex vasculitis usually is restricted to capillaries or venules or both. (Modified from
Jennette JC, Falk RJ, Bacon PA, et al: 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vascu-
litides, Arthritis Rheum 65:1–11, 2013, with permission.)

TABLE 53-1  40 years of age. TAK occurs worldwide with an estimated incidence of 1.2
Names and Definitions for Large Vessel Vasculitis Adopted by to 2.6/million per year in the Western countries. TAK occurs in all races,
the 2011-2012 International Chapel Hill Consensus but the incidence is higher in Southeast Asia, Central and South America,
and Africa (Vaideeswar & Deshpande, 2013).
Conference Nomenclature of the Vasculitides
Large vessel vasculitis Vasculitis affecting large arteries more often
Pathology
(LVV) than other vasculitides. Large arteries are the The pathology of TAK in the acute active phase is characterized by inflam-
aorta and its major branches. Any size artery mation of the aorta or larger arteries with a predominance of mononuclear
may be affected. leukocytes, often, but not always, accompanied by multinucleated giant
Takayasu arteritis Arteritis, often granulomatous, predominantly cells ( Jennette, 2015; Vaideeswar & Deshpande, 2013). Even if disease
affecting the aorta and/or its major branches. appears more localized clinically, postmortem pathologic examination
Onset usually in patients younger than 50. usually shows more extensive involvement. Involved vessels may have well-
Giant cell arteritis Arteritis, often granulomatous, usually affecting demarcated skip areas resulting in localized narrowing or dilation of
the aorta and/or its major branches, with a lumens. This inflammation causes arterial stenosis, thrombosis, and aneu-
predilection for the branches of the carotid rysms. There are at least two classification systems based on distribution
and vertebral arteries. Often involves the of vessel involvement (Vaideeswar & Deshpande, 2013). One classifies
temporal artery. Onset usually in patients TAK into five types: type I, aortic arch and its branches; type II, descending
older than 50 and often associated with thoracic and abdominal aorta; type III, aortic arch and thoraco-abdominal
polymyalgia rheumatica. aorta; type IV, pulmonary artery in addition to the aforementioned types;
and type V, coronary artery in addition to the other types (Gulati & Bagga,
From Jennette JC, Falk RJ, Bacon PA, et al: 2012 Revised International Chapel Hill
2010). Another classifies TAK into six types: type I, aortic arch and its
Consensus Conference Nomenclature of Vasculitides, Arthritis Rheum 65:1–11,
2013. branches; type IIa, ascending aorta, arch, and its branches; type IIb,
ascending aorta, arch, and its branches, and descending thoracic aorta;
type III, thoracic aorta and abdominal aorta; type IV, abdominal aorta; and
2014). The resulting aortic inflammation may lead to aneurysms of the type V, combination of type IIb and type IV (Hata et al, 1996).
aorta that can be life-threatening or fatal if not treated appropriately with The pathologic differential diagnosis includes syphilitic aortitis that
antibiotics. also has inflammatory infiltrates with predominantly mononuclear leuko-
cytes, including plasma cells. The only diagnostic pathologic finding that
TAKAYASU ARTERITIS can identify syphilitic aortitis is immunohistochemical identification of
Treponema pallidum.
Definition and Epidemiology
Takayasu arteritis (TAK), is often granulomatous, with a predilection for Etiology and Pathogenesis
the aorta and its major branches ( Jennette et al, 2013). Onset is usually in An autoimmune or infectious etiology that is influenced by genetic and
patients younger than 50. TAK most often affects women between 10 and environmental factors and results in cell-mediated immune injury to

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vessels is incriminated in the pathogenesis of TAK; however, specific etio-
logic factors have not been identified (Vaideeswar & Deshpande, 2013).
Clinical Laboratory Testing
In part because the specific etiology and unique pathogenic mechanisms
are not known for TAK, no laboratory tests have been identified that are
specific for this disease. Erythrocyte sedimentation rate (ESR) and
C-reactive protein (CRP) are the laboratory tests that are used most often
to support a diagnosis of TAK and to follow disease activity and response
to therapy. The ESR is elevated in 75% to 100% of patients with active
disease and tends to return to normal over time. ESR is thought to be a
reliable index of inflammatory activity and has been used as a tool to
monitor the effectiveness of therapy. Resolution of the disease, both
symptomatically and angiographically, has been found to correlate with
decline of the ESR, although one surgical series observed that 44% of
patients thought to be quiet clinically were not upon arterial biopsy
(Langford, 2003).
In a study of TAK treatment response, ESR decreased from 55.5 +/−
14.7 mm/h to 21.9 +/− 9.5 mm/h within 3 months (p < 0.001) and further
to 20.8 +/− 15.2 at 1 year (p = NS). CRP concentrations fell from 4.8
+/− 5.2 mg/dL to 0.5 +/− 0.2 mg/dL at 3 months (p = 0.004) and remained
at 0.5 +/− 0.3 mg/dL at 1 year (p = NS) (Valsakumar et al, 2003).
In addition to ESR and CRP, multiple biomarkers have been evaluated
as diagnostic and prognostic tests in TAK: interleukin (IL)-6, serum
amyloid A, fibrinogen, complement split fragments, B cell activating
factor (BAFF), interleukin (IL)-12, matrix metalloproteinase 9 (MMP-9),
and pentraxin 3 (PTX3) (Chatterjee et al, 2014). To date, none of these
have been adopted for widespread use.
Laboratory testing to rule out syphilitic aortitis includes the VDRL
(Venereal Disease Research Laboratory) test, TPPA (Treponema pallidum
particle agglutination assay), and IgG and IgM FTA-Abs (fluorescent
treponemal antibody-absorption) (Dietrich et al, 2014). A definitive test is
positive immunohistochemical staining for Treponema pallidum organisms
in tissue specimens (e.g., a resected aneurysm). A negative test is not as
predictive.
Diagnosis, Treatment, and Prognosis
The diagnosis of TAK is based primarily on clinical signs and symptoms
and on imaging studies to document involved vessels. Unlike in GCA,
pathologic examination of biopsies or resected vessels is not a routine
component of a diagnostic workup for TAK. TAK has three phases of
progression (Vaideeswar & Deshpande, 2013). The first is characterized
by low-grade fever, malaise, night sweats, arthralgia, anorexia, and weight
loss, with no clinical evidence for large vessel narrowing. The second phase
is the vasculitic stage in which the first-phase constitutional symptoms are
accompanied by evidence for large vessel inflammation, such as tenderness
or pain over vessels (angiodynia). These first two phases may last for
several months before signs of more chronic injury appear. The final phase,
which may evolve over months or years, has various manifestations of
chronic sclerosing vasculopathy affecting the aorta and its major branches,
including pulseless disease, related to arterial stenosis or occlusion.
In patients with active disease, corticosteroid therapy is the initial treat-
ment of choice. If active disease persists despite corticosteroids, cyclophos-
phamide or methotrexate may be administered. Vasodilators, anticoagulants,
and nonsteroidal anti-inflammatory agents are used for symptomatic relief.
Surgical intervention may be necessary for symptomatic vascular stenosis
or occlusion (Hoffman, 2003).
GIANT CELL ARTERITIS
Definition and Epidemiology
Giant cell arteritis (GCA) is arteritis, often granulomatous, with a predilec-
tion for the aorta and its major branches ( Jennette et al, 2013). In contrast
to TAK, GCA occurs in patients more than 50 years old. GCA is more
common in Western countries with the highest incidence and prevalence
in Caucasians of Scandinavian descent (González-Gay & Pina, 2015).
There is a north-south gradient in the incidence of GCA in Europe, with
high rates in Sweden and Norway, which has an incidence of over 20 new
cases per 100,000 individuals aged 50 and older per year, and a lower
incidence in southern Europe, which has an annual incidence of 10 cases
per 100,000 people aged 50 years and older in northwestern Spain
(González-Gay & Pina, 2015).
Pathology
The pathology of GCA in the acute active phase is characterized by inflam-
mation of the aorta or larger arteries, with a predominance of mononuclear
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Figure 53-2  Histopathologic features in the media of the aorta of a patient
with giant cell aortitis. Note that the elastic fibers are spread apart by numerous
infiltrating mononuclear leukocytes with admixed multinucleated giant cells (H&E
stain, ×500).
PART 6
leukocytes often accompanied by multinucleated giant cells ( Jennette,
2015) (Fig. 53-2). The chronic inactive phase has nonspecific chronic
inflammation and scarring. Although minor focal necrosis may occur,
extensive fibrinoid necrosis, especially in arteries, should raise the possibil-
ity of another variant of arteritis. The concurrence of another pathologic
process that causes chronic inflammation and scarring (e.g., atherosclero-
sis) complicates the pathologic diagnosis of chronic LVV.
The most common pathologic pattern in active GCA is transmural
inflammation, which is identified in more than 75% of patients, although
a minority of specimens will have inflammation confined to the adventi-
tial tissues, including the vasa vasorum (Cavazza et al, 2014). In a study
of 274 temporal artery biopsies that had transmural inflammation, most
as a result of GCA, 100% had inflammation with predominantly mono-
nuclear leukocytes (lymphocytes, monocytes macrophages, and plasma
cells), 75% giant cells, 8% admixed eosinophils, and 2% admixed neutro-
phils (Cavazza et al, 2014). Although small zones of laminar degeneration
(necrosis) may occur in areas of medial inflammation, overt fibrinoid
necrosis, especially if accompanied by neutrophils and/or neutrophils
with leukocytoclasia, should raise the possibility of a vasculitis other than
GCA, such as polyarteritis nodosa or ANCA vasculitis (Hamidou et al,
2003; Cavazza et al, 2014).
Etiology and Pathogenesis
Cell-mediated immune mechanisms are incriminated in the pathogenesis
of GCA, although the initiating etiologic factors are not known. For
example, in GCA, investigations have demonstrated that dendritic cells in
vessel walls initiate the recruitment of T cells and macrophages that are
the basis for the granulomatous inflammation (Weyand & Goronzy, 2014).
Two major immune-response networks have been identified in inflamed
arteries: the interleukin-12, type 1 helper T cell (Th1), and interferon-γ
axis; and the interleukin-6, type 17 helper T cell (Th17), and interleukin-17
or interleukin-21 axis. Cytokines released by these inflammatory pathways
activate leukocytes as well as endothelial cells, vascular smooth muscle
cells, and fibroblasts, leading to intimal and medial hyperplasia and fibrosis.
Elastolytic and proteolytic enzymes (e.g., matrix metalloproteinases) and
growth factors (e.g., vascular endothelial growth factor and platelet derived
growth factor) promote both degenerative and proliferative and sclerosing
changes that cause pathologic damage in vessel walls (Weyand & Goronzy,
2014). A large-scale genetic analysis comprising 1651 patients with GCA
and 15,306 unrelated control subjects from six different European coun-
tries of European ancestry identified multiple HLA loci, PTPN22, and
other loci that influence Th1, Th17, and Treg cell function as risk factors
for GCA (Carmona et al, 2015). The involvement of these genes supports
a role for a pathogenic autoimmune response in the pathogenesis of GCA.
Clinical Laboratory Testing
Temporal artery biopsy is the current gold standard for diagnosis of GCA;
however, a biopsy that is not considered diagnostic does not exclude GCA.
False-negative results are estimated to occur in up to 15% of patients and
1019
 are influenced by the length of the biopsy specimen and the duration of TABLE 53-2
53  Vasculitis
corticosteroid treatment prior to biopsy (Achkar et al, 1994; Poller et al, Names and Definitions for Medium Vessel Vasculitis Adopted
2000; Kermani et al, 2013). by the 2011-2012 International Chapel Hill Consensus
Especially in the absence of a tissue diagnosis, laboratory data are very Conference Nomenclature of the Vasculitides
important in reaching an actionable diagnosis of GCA. Laboratory find-
ings that support a diagnosis of GCA are increased erythrocyte sedimenta- Medium vessel Vasculitis predominantly affecting medium arteries
tion rate (ESR) and C-reactive protein (CRP), and thrombocytosis vasculitis (MVV) defined as the main visceral arteries and their
(Kermani et al, 2012; Waldman et al, 2013). An elevated platelet count is branches. Any size artery may be affected.
an early laboratory marker that can be detected a year before GCA is Inflammatory aneurysms and stenoses are
diagnosed (Lincoff et al, 2000). In a study of patients with GCA confirmed common.
by temporal artery biopsy, elevated CRP and elevated ESR had a sensitivity Polyarteritis nodosa Necrotizing arteritis of medium or small arteries
of 87% and 84%, respectively, and 4% had a normal ESR and CRP without glomerulonephritis or vasculitis in
(Kermani et al, 2012). ACR-EULAR Classification Criteria for GCA arterioles, capillaries, or venules, and not
(Dasgupta et al, 2012) require, in part, abnormal elevations in CRP, ESR, associated with ANCA.
or both. An additional laboratory criterion is absence of rheumatoid factor Kawasaki disease Arteritis associated with the mucocutaneous lymph
or antibodies to cyclic citrullinated peptides. node syndrome and predominantly affecting
medium and small arteries. Coronary arteries are
Diagnosis, Treatment, and Prognosis often involved. Aorta and large arteries may be
The diagnosis of GCA is most accurate when it is to be based on clinical involved. Usually occurs in infants and young
manifestations, laboratory tests, and confirmation by biopsy of the tempo- children.
ral artery or other affected artery (Waldman et al, 2013; Weyand &
From Jennette JC, Falk RJ, Bacon PA, et al: 2012 Revised International Chapel Hill
Goronzy, 2014). Bilateral temporal artery biopsies increase diagnostic sen- Consensus Conference Nomenclature of Vasculitides, Arthritis Rheum 65:1–11,
sitivity (Durling et al, 2014). Corticosteroid therapy should not be discon- 2013.
tinued after a negative biopsy result if there is enough evidence to make
the diagnosis. GCA with normal ESR and/or normal CRP levels is rare
but does occur; thus laboratory testing cannot completely rule out GCA
(Kermani et al, 2012).
Imaging studies of large arteries and the aorta—for example, with
positron emission tomography (PET)—are a helpful adjunct to pathology
and laboratory testing for making a diagnosis and assessing the status of
patients with GCA (Prieto-Gonzalez et al, 2014). One-quarter of patients
with GCA have involvement of the aorta and its major branches that can
be detected with imaging studies (Weyand & Goronzy, 2014). PET also
is useful in the early diagnosis of syphilitic aortitis (Treglia et al, 2013).
Most cases of GCA are effectively managed with glucocorticoid mono-
therapy (Weyand & Goronzy, 2014). Disease flares are common when the
glucocorticoids are tapered and often require a short-term increase to
induce and maintain remission. Patients with visual impairment or evidence
of unstable blood supply to the eyes benefit from high doses of intravenous
glucocorticoids. If disease flares, patients may need to be treated with
glucocorticoid-sparing agents, including methotrexate or infliximab.
Corticosteroids are the treatment of choice for TAK but may not be
sufficiently effective 50% of the time. An immunosuppressive regimen of
azathioprine and prednisolone is safe, well tolerated, and effective in ame-
liorating systemic symptoms and laboratory abnormalities in TA, and it
halts the progression in lesions based on angiographic studies, although it
does not seem to lead to complete resolution of arterial lesions (Valsaku-
mar et al, 2003). Other agents may be considered, including cyclophos-
phamide and methotrexate.
The differential diagnosis for LVV also includes variable vessel vascu- Figure 53-3  Necrotizing arteritis caused by polyarteritis nodosa. Note the
litis (VVV), including Behçet’s disease and Cogan’s syndrome, and by replacement of most of the media by deeply acidophilic fibrinoid necrosis and the
infectious vasculitis (e.g., aortitis caused by tertiary syphilis) and lympho- perivascular inflammation with a mixture of polymorphonuclear leukocytes and
mononuclear leukocytes (H&E stain, ×300).
plasmocytic disease (e.g., aortitis as a component of IgG4-related disease)
(Miller & Maleszewski, 2011). There is controversy about whether isolated
aortitis or isolated giant cell arteritis of a visceral artery is a limited expres-
sion of Takayasu arteritis or GCA or a distinct form of single organ vas- associated with ANCA ( Jennette et al, 2013). PAN is a diagnosis of exclu-
culitis. When single organ LVV is detected, follow-up should include sion that is made after omitting many other categories of large, medium,
vigilance for additional organ involvement. and small vessel vasculitis that can affect medium arteries ( Jennette & Falk,
2007). PAN affects patients of all ages, genders, and racial backgrounds,
although it is more common in older adults. The annual incidence ranges
MEDIUM VESSEL VASCULITIS from 0 to 1.6 cases/million in European countries, and its prevalence is
MVV is vasculitis that predominantly affects medium arteries defined as about 31 cases/million (Hernández-Rodríguez et al, 2014). Before vaccina-
the main visceral arteries and their branches; however, any size artery may tion against HBV was available, more than one-third of adults with PAN
be affected ( Jennette et al, 2013). The two major categories are polyar- were infected by HBV; however, currently, less than 5% of patients with
teritis nodosa (PAN) and Kawasaki disease (KD) (Table 53-2). Inflamma- PAN are infected with HBV in developed countries (Mahr et al, 2004).
tory aneurysms and stenoses are common. It is important to note that
medium arteries also can be affected by large vessel vasculitis and small Pathology
vessel vasculitis. Thus multiple clinical, laboratory, and pathologic findings Any type of artery in any organ can be affected; however, main visceral
must be taken into consideration to make an accurate diagnosis of the arteries and their initial branches in the parenchyma are the most frequent
disease that is causing arteritis. targets, such as the major mesenteric arteries, renal arteries, hepatic arter-
ies, and coronary arteries. Epineural arteries of peripheral nerves and
POLYARTERITIS NODOSA subcutaneous arteries of the skin also are common targets. When main
arteries are involved, nodular inflammatory lesions and pseudoaneurysms
Definition and Epidemiology can be observed grossly or with imaging studies (or palpated in the skin).
PAN is necrotizing arteritis of medium or small arteries without glomeru- The inflammation has a predilection for arterial branch points. The his-
lonephritis or vasculitis in arterioles, capillaries, or venules, and it is not topathologic features of PAN (Fig. 53-3) begin as fibrinoid necrosis with

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Figure 53-4  Cross section of a kidney from a patient with polyarteritis nodosa
showing multiple pseudoaneurysms (black arrow) and infarcts (white arrow).
intense acute neutrophil-rich inflammation, evolve through chronic
inflammation and fibroplasia, and eventually result in fibrosis that may
completely or partially impede blood flow ( Jennette & Falk, 2007; Jen-
nette, 2015). Acute occlusion causing infarction may result from throm-
bosis of arteries at sites of segmental acute inflammation, necrosis, and
pseudoaneurysm formation (Fig. 53-4).
Etiology and Pathogenesis
The etiology and pathogenesis of PAN are unknown. A role for infections
has been incriminated. During the 1970s, about half of the patients with
PAN were infected with HBV, and HBe antigen to anti-HBe antibody
seroconversion usually paralleled recovery (Pagnoux et al, 2006). This
suggested that PAN was caused by hepatitis B virus infection. However,
the frequency of HBV-associated PAN has declined from 35% in the 1980s
to less than 5% in the early 2000s (Mahr et al, 2004). Additional infections
that have been incriminated as but not proven to be etiologies for PAN
include hepatitis C virus (HCV), human immunodeficiency virus (HIV),
cytomegalovirus, and parvovirus B19 (Hernández-Rodríguez et al, 2014).
Most cases are idiopathic.
Clinical Laboratory Testing
Laboratory testing in patients with PAN often demonstrates thrombocy-
tosis, low serum albumin, and ESR and CRP. Liver enzymes may be
abnormal in patients who have viral hepatitis. Testing for HBV, HCV, and
HIV in patients with necrotizing arteritis is important because antiviral
treatment must be added to immunosuppressive treatment for optimum
outcome (Guillevin, 2013). ANCA testing is important to rule out ANCA
vasculitis with a component of necrotizing arteritis that is mimicking PAN.
Other laboratory abnormalities are dictated by the organ systems that are
involved, such as kidneys, pancreas, skeletal muscle, heart, gastrointestinal
tract, and so on.
Diagnosis, Treatment, and Prognosis
Clinical manifestations of PAN are protean and depend on the organs that
are affected (Hernández-Rodríguez et al, 2014). Most patients have non-
specific constitutional symptoms, such as fever, malaise, arthralgias, myal-
gias, and weight loss. Peripheral neuropathy occurs in approximately 75%
of patients, and gastrointestinal involvement in approximately half. The
major cutaneous manifestations are inflammatory nodules, infarction, and
livido reticularis. Renal involvement manifests as flank pain and hematuria
and, rarely, as retroperitoneal hemorrhage from rupture of an aneurysm.
Greater than 2 g/day proteinuria and hematuria with red blood cell casts
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are not features of PAN and raise the possibility of a small vessel vasculitis
such as microscopic polyangiitis. Involvement of the gastrointestinal tract,
kidneys, heart, and central nervous system is associated with higher mortal-
ity. Laboratory abnormalities reveal a prominent acute phase response but
are nonspecific. Histologic confirmation of vasculitis in medium-sized
arteries is valuable for diagnosis. Positive pathologic finds are more likely
if biopsies are obtained from symptomatic organs if feasible. Skin or
muscle and nerve are preferred because of higher diagnostic yield and
safety. If biopsies are negative or cannot be obtained, visceral angiography
may reveal multiple micro-aneurysms, supporting the diagnosis of PAN.
Current treatment includes high-dose corticosteroids, which are com-
bined with immunosuppressive agents when critical organ involvement or
life-threatening complications occur. IV pulse cyclophosphamide in the
remission induction phase, later switched to a safer immunosuppressant
for remission maintenance, is a frequently used therapeutic approach
(Hernández-Rodríguez et al, 2014).
KAWASAKI DISEASE
Definition and Epidemiology
Kawasaki disease (KD) is arteritis associated with the mucocutaneous
lymph node syndrome and predominantly affecting medium and small
arteries ( Jennette et al, 2013). Coronary arteries are often involved. Aorta
and large arteries may be involved. KD usually occurs in infants and young
children. Clinical manifestations include persistent fever for a week or
more, erythematous rash, conjunctivitis, oropharyngeal erythema, and
lymphadenopathy. Over 80% of KD cases occur between the ages of 6
PART 6
months and 4 years. The annual incidence varies from approximately 3 per
100,000 children under 5 years of age in South America to 4 in Australia,
8 in the United Kingdom, 4 to 15 in the United States, 20 to 30 in China,
50 in Taiwan, 90 in Korea, and more than 130 in Japan (Burgner &
Harnden, 2005). Kawasaki disease is more common in boys, with a
male : female ratio of 1.6 : 1.
A number of epidemiological observations suggest but do not prove an
infectious etiology for KD (Burgner & Harnden, 2005). Geographical
clustering of KD cases and epidemics has been reported. The onset of KD
has seasonal variations, but the predominant season varies in different
countries. In the United Kingdom, Australia, and the United States, KD
is most common in the winter and spring; in China, in the spring and
summer; and in Korea, during the summer months.
Pathology
Active KD arteritis is characterized by segmental necrotizing arteritis (Fig.
53-5). In the acute phase, in general, KD has more infiltration by mono-
cytes, whereas PAN has more infiltration by neutrophils ( Jennette & Falk,
2007). Fibrinoid necrosis occurs with both PAN and KD, but it is less
conspicuous in KD. The chronic sclerotic phase is characterized by seg-
mental transmural chronic inflammation and scarring. Special stains for
elastica demonstrate focal disruption of the internal elastica.
The acute lesion of KD is characterized by transmural necrotizing
inflammation that is rich in neutrophils and monocytes (Orenstein et al,
2012; Jennette, 2015). Degeneration of artery walls results in aneurysm
and pseudoaneurysm formation, with the latter having complete erosion
of the necrotizing process into the perivascular tissues. Thrombosis may
occur at sites of arteritis, especially sites of aneurysm/pseudoaneurysm
formation. Acute arteritis wanes by 2 weeks after fever onset, and it is
replaced by varying degrees of subacute and chronic inflammation, includ-
ing intimal myofibroblast proliferation (Orenstein et al, 2012; Reindel
et al, 2014).
Etiology and Pathogenesis
Infection also has been suspected as a cause of KD because concurrent
infection with pathogens has been detected by culture, molecular methods,
or serological testing in patients with KD; however, although more than
20 different pathogens have been incriminated, none have been proven to
be a direct cause of KD, and many are infectious diseases that are common
in young children (Burgner & Harnden, 2005; Principi et al, 2013). Medi-
ation by an immune response to a superantigen (possibly of microbial
origin) has been studied extensively. KD shares many clinical features
with superantigen-mediated diseases—for example, rash, conjunctivitis,
and skin sloughing—and KD has been reported in children with toxic
shock syndrome, which can be caused by superantigens (Burgner &
Harnden, 2005). However, there is no proof that superantigens are
involved in the pathogenesis of KD. Multiple inflammatory pathways are
upregulated in the inflamed arteries of KD, including a pathway that
involves the lymphocyte activation molecule CD84 (Reindel et al, 2014).
1021

53  Vasculitis
Figure 53-5  Kawasaki disease arteritis showing segmental transmural necro-
tizing inflammation with residual areas of intact muscularis adjacent to intense
medial inflammation that is continuous with intimal inflammation and adven-
titial inflammation (H&E stain, ×400).
CD84 was upregulated 16-fold in acute coronary arteritis caused by KD
and 32-fold in chronic coronary arteritis caused by KD (5 months to years
after onset). CD84 was detected in leukocytes in KD tissues.
Clinical Laboratory Testing
Diagnosis of KD is based primarily on clinical signs and symptoms. Non-
specific laboratory indicators of acute inflammation (i.e., acute phase reac-
tants, including CRP and ESR) are consistently elevated in the acute phase
of KD. One study suggests that elevated serum levels of the cardiac natri-
uretic peptide called N-terminal of the prohormone brain natriuretic
peptide (NT-pro-BNP) might be a useful diagnostic tool for KD, espe-
cially in patients with cardiac injury and atypical clinical presentations
(Cho et al, 2011). The cutoff level of NT-pro-BNP that best distinguished
KD from other childhood febrile illnesses was 235.2 pg/mL. The same
study concluded that serum levels of high-sensitivity CRP are not useful
in distinguishing KD from other childhood febrile illnesses.
Diagnosis, Treatment, and Prognosis
Features of the mucocutaneous lymph node syndrome, especially in a child
5 years of age or younger, are important for diagnosis of KD, but some
patients present with other KD manifestations before full-blown mucocu-
taneous lymph node syndrome, including signs and symptoms of myocar-
dial ischemia caused by coronary arteritis. Although timely treatment with
intravenous gamma globulin (IVIG) plus aspirin has profoundly reduced
the frequency and severity of coronary arteritis in KD, approximately 10%
to 20% of patients develop clinically significant sequelae of coronary arte-
ritis (Orenstein et al, 2012). Myocardial infarction occurs in approximately
2% of KD patients with coronary arteritis (Burgner & Harnden, 2005).
SMALL VESSEL VASCULITIS
Small vessel vasculitis (SVV) is vasculitis predominantly affecting small
vessels, defined as small intraparenchymal arteries, arterioles, capillaries,
and venules ( Jennette et al, 2013). Medium arteries and veins may be
affected.
As with other vasculitides, an important diagnostic dichotomy is
between infectious SVV and immune-mediated SVV. Viral infection and
bacterial infection can mimic immune-mediated SVV, and the diagnostic
distinction between these forms of vasculitis is critically important for
appropriate treatment with antimicrobial therapy versus immunosuppres-
sive therapy. Detection of the pathogen by culture or by genomic or
proteomic assays or serologic detection of an immune response to the
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TABLE 53-3
Names and Definitions for ANCA-Associated Small Vessel
Vasculitis Adopted by the 2011-2012 International Chapel Hill
Consensus Conference Nomenclature of the Vasculitides
ANCA-associated Necrotizing vasculitis, with few or no immune
vasculitis (AAV) deposits, predominantly affecting small vessels
(i.e., capillaries, venules, arterioles, and small
arteries), associated with MPO-ANCA or
PR3-ANCA. Not all patients have ANCA. Add a
prefix indicating ANCA reactivity—for example,
PR3-ANCA, MPO-ANCA, ANCA-negative.
Microscopic Necrotizing vasculitis, with few or no immune
polyangiitis (MPA) deposits, predominantly affecting small vessels
(i.e., capillaries, venules, or arterioles). Necrotizing
arteritis involving small and medium arteries may
be present. Necrotizing glomerulonephritis is very
common. Pulmonary capillaritis often occurs.
Granulomatous inflammation is absent.
Granulomatosis with Necrotizing granulomatous inflammation usually
polyangiitis involving the upper and lower respiratory tract,
(Wegener’s) (GPA) and necrotizing vasculitis affecting predominantly
small to medium vessels (e.g., capillaries, venules,
arterioles, arteries, and veins). Necrotizing
glomerulonephritis is common.
Eosinophilic Eosinophil-rich and necrotizing granulomatous
granulomatosis inflammation often involving the respiratory tract,
with polyangiitis and necrotizing vasculitis predominantly affecting
(Churg Strauss) small to medium vessels, and associated with
(EGPA) asthma and eosinophilia. ANCA is more frequent
when glomerulonephritis is present.
From Jennette JC, Falk RJ, Bacon PA, et al: 2012 Revised International Chapel Hill
Consensus Conference Nomenclature of Vasculitides, Arthritis Rheum 65:1–11,
2013.
pathogen reveals the etiologic infection ( Jain et al, 2007; D’Alessandro
et al, 2014).
Based on immunopathologic features, noninfectious SVV is divided
into ANCA-associated vasculitis with few or no vessel-immune deposits,
and immune complex SVV with moderate to marked vessel wall deposits
of immunoglobulin and/or complement components.
ANCA-ASSOCIATED SMALL VESSEL VASCULITIS
Definition and Epidemiology
ANCA-associated vasculitis is necrotizing vasculitis, with few or no
immune deposits, that predominantly affects small vessels (i.e., capillaries,
venules, arterioles, and small arteries) and is associated with myeloper-
oxidase (MPO)–ANCA, or proteinase 3 (PR3)–ANCA ( Jennette et  al,
2013) (Table 53-3). However, not all patients have MPO-ANCA or PR3-
ANCA, at least using current analytic methods. The few or no immune
deposits distinguishes ANCA vasculitis from immune complex vasculitis
that has moderate to marked vessel wall deposits of immunoglobulin
and/or complement components ( Jennette et  al, 2013). Because of this
paucity of immune deposits, ANCA vasculitis is also called pauci-immune
vasculitis.
ANCA SVV is classified based on clinicopathologic phenotypes and by
the antigen-specificity of ANCA. The clinicopathologic variants are
microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA)
(formerly called Wegener’s granulomatosis), eosinophilic granulomatosis
with polyangiitis (EGPA) (formerly called Churg-Strauss syndrome), and
renal limited vasculitis (RLV) ( Jennette et al, 2013). An additional variant
is drug-induced ANCA vasculitis, which may manifest as MPA, GPA, or
RLV (Pendergraft & Niles, 2014). An optimum diagnosis should include
both the ANCA serology status and the clinicopathologic phenotype—for
example, MPO-ANCA MPA, PR3-ANCA GPA, ANCA-negative EGPA,
and so on ( Jennette et al, 2013).
MPA is multiorgan pauci-immune small vessel vasculitis with no
granulomatous inflammation or asthma. MPA often has necrotizing glo-
merulonephritis and pulmonary capillaritis. GPA has necrotizing granu-
lomatous inflammation usually involving the upper and lower respiratory
tract, as well as vasculitic lesions indistinguishable from those of MPA.
EGPA has eosinophil-rich and necrotizing granulomatous inflammation
often involving the respiratory tract, as well as asthma and blood
 A B

PART 6
C D
Figure 53-6  ANCA disease can cause many forms of vascular injury. These include: A, dermal leukocytoclastic angiitis
with intense neutrophil-rich infiltrates centered in small dermal vessels (H&E stain, ×400); B, hemorrhagic pulmonary alveolar
capillaritis with destruction of alveolar walls by neutrophil-rich inflammation (H&E stain, ×500); C, glomerulonephritis with
fibrinoid necrosis of glomerular capillaries (white arrow) and adjacent cellular crescent formation (black arrow) (Masson tri-
chrome stain, ×500); and D, arteritis with extensive irregular fibrinoid necrosis (Masson trichrome stain, ×400).

eosinophilia. Although there appears to be a prevasculitic phase that is
ANCA-negative, ANCA-positive EGPA patients typically have pauci-
immune small vessel vasculitis and pauci-immune necrotizing and cres-
centic glomerulonephritis that is indistinguishable from MPA and GPA.
ANCA vasculitis confined to a single organ may occur. One example is
ANCA renal-limited vasculitis (RLV) causing pauci-immune necrotizing
and crescentic glomerulonephritis.
The incidence of ANCA vasculitis increases with age, with a peak
around 60 years old, although children can develop ANCA vasculitis.
Gender distribution is about equal, with a possible slight male predomi-
nance. The incidence and prevalence of ANCA vasculitis varies among the
different clinicopathologic phenotypes and among different geographic
locations (Watts et al, 2015). Roughly, the incidence of all forms of ANCA
vasculitis is 15 to 20/million, and the prevalence is roughly 50 to 150/
million. There is a higher ratio of GPA : MPA in northern Europe (e.g.,
Germany and Scandinavia) and northern U.S. states (e.g., Montana and
Minnesota), and a lower ratio of GPA : MPA in southern Europe (e.g.,
Greece and Spain) and southern U.S. states (e.g., North Carolina). This
is accompanied by the expected differences in ratio of PR3:MPO ANCA
specificity in accord with more frequent PR3-ANCA with GPA and more
frequent MPO-ANCA with MPA. The precise ratios are not known, but
in general there is a reversal of preponderance of MPO-ANCA MPA
versus PR3-ANCA GPA from north to south in both Europe and North
America. There is a striking preponderance of MPO-ANCA and of MPA
in Asia. For example, in one study of ANCA-associated vasculitis in Japan,
the estimated annual incidence was 15 per million adults (over age 15) and
45 per million older adults (over age 65). Ninety-one percent of the
patients were MPO-ANCA positive, but none were PR3-ANCA positive,
and none had GPA or EGPA (Fujimoto et al, 2006).
Pathology
ANCA vasculitis can affect arteries (usually small arteries), arterioles, capil-
laries, venules, and veins (usually small veins). In all organs and in all
clinicopathologic variants (e.g., MPA, GPA, EGPA), acute ANCA arteritis
is characterized by segmental fibrinoid necrosis (Fig. 53-6), and mural
and perivascular neutrophil-rich infiltration ( Jennette & Falk, 2007;
Jennette, 2015). Eosinophils may be numerous, especially in EGPA.
Within several days, the neutrophil-rich inflammation is replaced by pre-
dominantly mononuclear leukocytes, with numerous monocytes and mac-
rophages and fewer lymphocytes. Within a week, the active inflammatory
process wanes and vasculitic lesions develop progressive sclerosis/fibrosis.
In a given tissue, such as skin, gut, or kidney, vasculitic lesions of different
ages often are observed because persistently active ANCA vasculitis has
multiple acute vasculitic lesions developing while prior active lesions are
undergoing scarring. Patients in complete remission should have only
chronic quiescent lesions. ANCA arteritis is histopathologically indistin-
guishable from other forms of necrotizing arteritis (e.g., PAN).
When ANCA vasculitis affects venules—for example, in the dermis—
acute lesions have less conspicuous fibrinoid necrosis and more prominent
leukocytoclasia (Fig. 53-6, A). This pattern of injury may be called leuko-
cytoclastic angiitis, and it can also be caused by other forms of SVV,
especially immune complex SVV.

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53  Vasculitis

A B
Figure 53-7  Pulmonary lesions in GPA and EGPA include necrotizing granulomatous inflammation and vasculitis.
A, Necrotizing granulomatous inflammation in a GPA patient showing neutrophil-rich necrotic debris in the upper left with
a marginal zone of macrophages, including a giant cell in the lower right (H&E stain, ×500). B, Necrotizing arteritis in the
lung of a patient with EGPA showing intense eosinophil-rich inflammation (H&E stain, ×400).

Acute pulmonary alveolar capillaritis is characterized by accumulation
of neutrophils in alveolar capillary lumens, destruction of capillary base-
ment membranes (seen with silver stains), and hemorrhage into alveolar
air spaces (Fig. 53-6, B).
The necrotizing glomerulonephritis that often is a component of
ANCA vasculitis and that may occur as renal limited vasculitis is character-
ized by segmental fibrinoid necrosis with adjacent cellular crescent forma-
tion in the acute phase (Fig. 53-6, C) and segmental sclerosis with adjacent
fibrous crescents in the chronic phase. The pathology of ANCA glomeru-
lonephritis is the same in MPA, GPA, EGPA, and renal limited disease. In
addition to necrotizing and crescentic glomerulonephritis, kidney lesions
in ANCA disease also include necrotizing arteritis (most often affecting
interlobular and arcuate arteries) (Fig. 53-6, D) and leukocytoclastic med-
ullary angiitis affecting the vasa rectae.
Immunohistology demonstrates an absence or paucity of immuno-
globulin deposition, which distinguishes ANCA vasculitis from immune
complex vasculitis. However, most specimens, including glomeruli affected
by ANCA disease, have at least a small amount of immune complex–type
staining for immunoglobulins and complement, and a small amount of
immune complex–type electron-dense deposits by electron microscopy.
ANCA disease also can occur concurrently with anti-GBM disease or
immune complex disease, and in this context, there is substantial immu-
nostaining for immunoglobulins and complement.
The necrotizing granulomatous inflammation of GPA and EGPA
begins as a focus of neutrophil-rich inflammation that may resemble a
microabscess. EGPA lesions also contain numerous eosinophils ( Jennette,
2011). These lesions may be small and spherical, or they may be large
and irregular, creating so-called geographic necrosis. Within days, the
focus of acute inflammation is surrounded by a rim of monocytes
and macrophages, including multinucleated giant cells (Fig. 53-7, A). The
central zone of inflammation becomes completely necrotic and evolves
from basophilic or eosinophilic cellular fragments (derived primarily from
degenerated neutrophils and eosinophils) to amorphous necrotic debris.
The adjacent granulomatous inflammation becomes more organized with
palisades of elongated macrophages adjacent to the necrosis. Eventually,
the central zone forms a cavity or becomes fibrotic. Necrotizing granulo-
matous inflammation occurs most often in the upper and lower respira-
tory tract, but occasionally in other tissues, such as the nasal tissues, orbit,
skin, and kidneys. The differential diagnosis for pulmonary granuloma-
tous inflammation includes mycobacterial and fungal infectious disease.
The presence of pulmonary vasculitis along with the granulomatous
inflammation is more specific evidence for GPA or EPGA. Numerous
eosinophils in the granulomatous inflammation and the vasculitis favor
EGPA (Fig. 53-7, B).
Etiology and Pathogenesis
Clinical and experimental observations support a direct role of ANCA in
the pathogenesis of vasculitis ( Jennette & Falk, 2014; Kallenberg, 2014).
Clinical observations that support a pathogenic role include the high
frequency of ANCA in the blood, the general correlation of ANCA titers
with disease activity (especially if capture assays are used), increased risk
for disease when there are higher levels of ANCA antigens on the surface
of circulating neutrophils, induction of ANCA as well as vasculitis by
certain drugs (e.g., hydralazine, propylthiouracil, penicillamine, minocy-
cline), and the therapeutic efficacy of apheresis and targeted B cell
therapy (e.g., rituximab).
The best experimental evidence is induction of ANCA-mediated pauci-
immune crescentic glomerulonephritis and small-vessel vasculitis in exper-
imental animals. The first animal model that was described used intravenous
injection of mouse anti-MPO IgG (derived from immunizing MPO
knockout mice with purified mouse MPO) into wild-type mice, resulting
in the induction of a pauci-immune glomerulonephritis with segmental
fibrinoid necrosis and crescent formation that closely resembled human
ANCA glomerulonephritis (Xiao et al, 2002). Some of the mice that
received anti-MPO IgG also developed systemic small-vessel vasculitis,
including alveolar capillaritis and necrotizing arteritis that was histologi-
cally indistinguishable from human ANCA disease.
Numerous in vitro and in vivo experiments support the hypothesis that
ANCA in the circulation can interact with ANCA antigens (MPO, PR3)
on the surface of neutrophils that have been primed by cytokines or
complement fragments (e.g., C5a) (Jennette & Falk, 2014). ANCA-
activated neutrophils release factors that activate the alternative comple-
ment pathway, which in turn recruits more neutrophils and primes and
activates neutrophils by engaging the C5a receptors (Xiao et al, 2014).
Neutrophils that are activated in the circulation adhere to and penetrate
vessel walls and release destructive enzymes and oxygen radicals that cause
vascular injury. Hypothetically, primed neutrophils in the extravascular
tissues that are activated by ANCA are the cause for the granulomatous
inflammation of GPA and EGPA ( Jennette & Falk, 2014).
Drugs can induce the development of ANCA, especially MPO-ANCA
(Pendergraft & Niles, 2014). Hydralazine, minocycline, propylthiouracil,
and levamisole-adulterated cocaine are major causes. A hypothesis has
been proposed to explain the induction of ANCA by hydralazine. Patients
with ANCA vasculitis have circulating neutrophils that aberrantly tran-
scribe and express neutrophil granule proteins, including the MPO and
PR3, because of altered epigenetic regulation of gene expression (McInnis
et al, 2015). Hydralazine can function as a nonnucleoside DNA methyla-
tion inhibitor, so it can reverse epigenetic silencing of PR3 and MPO,
which could result in increased expression of both autoantigens and loss
of tolerance (Pendergraft & Niles, 2014).
Except for the small minority of cases caused by drugs, the etiology of
ANCA disease is not known. Various theories postulate the result of infec-
tions (e.g., Staphylococcus aureus), environmental exposures (e.g., silica), or
dysregulated gene expression (e.g., of PR3 antisense peptides) ( Jennette &
Falk, 2014; Kallenberg, 2014). One novel theory posits that a protein that
is complementary to the autoantigen PR3 triggers the PR3-ANCA

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 A B
Figure 53-8  IIF assay using ethanol-fixed, normal human neutrophils as substrate showing: A, C-ANCA cytoplasmic stain-
ing; B, P-ANCA perinuclear staining; and C, atypical-ANCA showing heaped-up, very perinuclear staining (×1000).
autoimmune response through an anti-idiotypic network (Pendergraft
et al, 2004). This complementary protein could be an endogenous protein
resulting from age-related dysregulation of antisense gene expression or
an exogenous protein derived from a pathogen that makes an antisense
peptide mimic that is an inhibitor of the antimicrobial function of comple-
mentary PR3.
Clinical Laboratory Testing
In 1999, an International Consensus Statement on Testing and Reporting
of Antineutrophil Cytoplasmic Antibodies recommended that testing in
new patients should be by indirect immunofluorescence (IIF) assay and
that samples that are positive by IIF should be tested by ELISAs for PR3-
ANCA and MPO-ANCA (Savige et al, 1999). The recommendation for
optimum testing of patients suspected of having ANCA disease was to test
by ELISA for PR3-ANCA and MPO-ANCA on all serum samples irre-
spective of IIF results. Although immunoassays have become more effec-
tive since this recommendation was made, most laboratories continue to
employ both IIF and antigen-specific immunoassays for MPO and PR3
for ANCA testing. An automated ANCA-pattern recognition system
(Damoiseaux et al, 2012) and a digital indirect immunofluorescence assay
(Sowa et al, 2014) have been evaluated as alternatives to IIF, but they are
unlikely to replace conventional IIF microscopy assays anytime soon.
IIF assay using ethanol-fixed, normal human neutrophils as substrate
produces two different staining patterns: cytoplasmic (C-ANCA) (Fig.
53-8, A) and perinuclear (P-ANCA) (Fig. 53-8, B) (Savige et al, 2000). The
perinuclear staining is an artifact of substrate preparation that results from
diffusion of the cationic MPO antigen from the cytoplasm to the nucleus
during substrate preparation. This perinuclear relocation does not occur
when formalin is used to fix plasma protein in place before preparing
neutrophils for IIF. Thus a true P-ANCA will produce cytoplasmic stain-
ing on formalin-fixed neutrophils, whereas an antinuclear antibody will
stain the nucleus in both ethanol- and formalin-fixed preparations (Falk &
Jennette, 1988).
When the antigen specificity is determined by immunoassays, PR3-
ANCA typically produces the C-ANCA staining pattern by IIF, and MPO-
ANCA typically produces a P-ANCA staining pattern. ANCAs that cause
a P-ANCA pattern in IIF assays are not restricted to MPO and include a
variety of autoantibodies that occur in inflammatory diseases, including
ulcerative colitis, sclerosing cholangitis, autoimmune hepatitis, rheuma-
toid arthritis, and Felty’s syndrome (Savige et al, 2000). Positive ANCA
IIF results in serum from patients with inflammatory bowel disease and
other nonvasculitic inflammatory diseases may have an atypical pattern
that shows more intense and heaped-up perinuclear staining (very peri-
nuclear staining) (Fig. 53-8, C). Antibodies that produce an atypical ANCA
IIF pattern usually are not specific for MPO or PR3 (Savige et al, 2000).
Antigen-specific, quantitative immunoassays are the standard of care
for diagnosis and some management decisions in patients with ANCA
disease. ANCA serotype may be more important than clinicopathologic
classification for predicting outcome, including the likelihood of recur-
rence after induction of remission (Kallenberg, 2014). Detection of
ANCA to monitor disease activity and adjust treatment remains contro-
versial; however, epitope-specific assays that can distinguish between
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C
pathogenic and nonpathogenic ANCA may change this in the future
(Roth et  al, 2013).
First-generation ANCA assays were direct noncompetitive enzyme-
PART 6
linked immunosorbent assay (ELISA). The second-generation tests
(capture ELISA) or third-generation tests (anchor ELISA) are more sensi-
tive and specific for ANCA testing (Cohen Tervaert & Damoiseaux, 2012).
Fourth-generation assays may be epitope specific and more effective in
guiding therapy (Roth et al, 2013).
Chemiluminescence assays (CIAs) have been used to detect PR3-
ANCA and MPO-ANCA with comparable results to ELISAs (Mahler
et al, 2012). A combination of cell- and microbead-based digital indirect
immunofluorescence analysis of ANCA in one reaction environment by
the novel multiplexing bead technology for simultaneous screening and
confirmatory ANCA testing has been developed (Sowa et al, 2014). ANCA
results by classical testing (IIF and ELISA) compared with multiplex bead
analysis were very good (κ = 0.831) with no significant difference (p =
0.735). Automated ANCA titer detection in one dilution demonstrated
very good agreement with classical analysis requiring dilution of samples
(κ = 0.985).
Even using current ANCA testing capabilities, patients with clinical
features and pathologic findings consistent with ANCA vasculitis can test
negative for ANCA. In a study of 539 patients with a clinical diagnosis of
ANCA vasculitis, positive ANCA serology was demonstrated in 98% of
MPA patients, 96% of GPA patients, 94% of renal-limited pauci-immune
crescentic glomerulonephritis patients, and 64% of EGPA patients (Kal-
lenberg, 2014). Of the 364 patients with GPA in this analysis, 12 tested
negative for ANCA, but 10 had GPA limited to the ear, nose, and throat.
EGPA patients usually have P-ANCA with MPO-ANCA specificity
(Sinico et al, 2005). EGPA patients with a positive ANCA have more
glomerulonephritis, pulmonary capillaritis, peripheral neuropathy, and
biopsy-proven vasculitis, whereas patients with a negative ANCA have
more myocarditis (Sablé-Fourtassou et al, 2005; Sinico et al, 2005). All
EGPA patients who have biopsy-proven pauci-immune necrotizing and
crescentic glomerulonephritis are ANCA positive (Sinico et al, 2006). It
appears that EGPA may have two serologically defined phenotypes:
ANCA-positive EGPA with vasculitis and ANCA-negative EGPA without
vasculitis.
ANCA specificity correlates with clinical symptoms. Ninety percent of
patients with ANCA who have destructive upper respiratory tract disease
(e.g., saddle-nose deformity) have PR3-ANCA, whereas most patients with
exclusively or predominantly renal involvement have MPO-ANCA
(Lionaki et al, 2012). Dual positivity for both MPO-ANCA and PR3-
ANCA is rare except in the setting of drug-induced ANCA (Pendergraft
& Niles, 2014).
ANCAs are in approximately one third of patients with anti-GBM
disease ( Jennette, 2003; Rutgers et al, 2005). The dual anti-GBM and
ANCA specificity is the result of two different antibody populations rather
than one cross-reacting population (Rutgers et al, 2005), and the antigen
specificities of anti-GBM antibodies are the same in patients with anti-
GBM antibodies only or combined ANCA and anti-GBM antibodies
(Hellmark et al, 1997). Compared with patients with anti-GBM alone,
patients with both autoantibodies are older, often have features of systemic
1025
 small-vessel vasculitis, and have a better prognosis for renal survival with TABLE 53-4
53  Vasculitis
treatment. Names and Definitions for Immune Complex Small Vessel
The possibility of drug-induced disease should be considered in Vasculitis Adopted by the 2011-2012 International Chapel Hill
patients with ANCA vasculitis. The most common are hydralazine, mino- Consensus Conference Nomenclature of the Vasculitides
cycline, propylthiouracil, and levamisole-adulterated cocaine. If cocaine
abuse is a possibility, the urine should be tested for cocaine, and if positive, Immune complex Vasculitis with moderate to marked vessel wall
should be tested for levamisole (Pendergraft & Niles, 2014). Most drug- vasculitis deposits of immunoglobulin and/or
induced vasculitis is not caused by ANCA. A recent study of 239 patients complement components predominantly
with all forms of drug-associated cutaneous vasculitis demonstrated that affecting small vessels (i.e., capillaries, venules,
the most common laboratory abnormalities were increased ESR (40%) and arterioles, and small arteries).
cryoglobulins (26%), while leukocytosis and positive ANA were found in Glomerulonephritis is frequent.
less than 25% (Ortiz-Sanjuán et al, 2014). Only rare examples of drug- Anti-GBM disease Vasculitis affecting glomerular capillaries,
induced immune complex vasculitis have been described, and most of these pulmonary capillaries, or both, with basement
have been caused by therapeutic agents that are proteins, such as mono- membrane deposition of antibasement
clonal antibodies (Baldo, 2013). membrane autoantibodies. Lung involvement
The diagnostic value in patients with vasculitis of ANCA with other causes pulmonary hemorrhage, and renal
specificities has been investigated; however, to date, the only routine involvement causes glomerulonephritis with
testing that has been adopted is for MPO-ANCA and PR3-ANCA. ANCA necrosis and crescents.
with specificity for lysosomal membrane protein 2 (LAMP2) has been Cryoglobulinemic Vasculitis with cryoglobulin immune deposits
reported to have high sensitivity and specificity for pauci-immune SVV vasculitis affecting small vessels (predominantly
(Kain et al, 2008); however, not all investigators have confirmed this capillaries, venules, or arterioles) and associated
finding (Roth et al, 2012). with cryoglobulins in serum. Skin, glomeruli,
and peripheral nerves are often involved.
Diagnosis, Treatment, and Prognosis IgA vasculitis (Henoch- Vasculitis, with IgA1-dominant immune deposits
The diagnosis of ANCA-associated vasculitides as MPA, GPA, or EGPA Schönlein) affecting small vessels (predominantly
is based on algorithms that have been derived from the Chapel Hill Con- capillaries, venules, or arterioles). Often
sensus Conference definitions (Watts et al, 2007; Abdulkader et al, 2013). involves skin and gut, and frequently causes
The diagnostic evaluation of patients with ANCA disease should include arthritis. Glomerulonephritis indistinguishable
from IgA nephropathy may occur.
both testing for ANCA specificity—that is, for proteinase 3 (PR3-ANCA)
or myeloperoxidase (MPO-ANCA)—as well as classification as MPA, Hypocomplementemic Vasculitis accompanied by urticaria and
GPA, EGPA, or renal-limited vasculitis (RLV). Assessment of the disease urticarial vasculitis hypocomplementemia affecting small vessels
stage and severity also is important for tailoring treatment. (anti-C1q vasculitis) (i.e., capillaries, venules, or arterioles), and
associated with anti-C1q antibodies.
Treatment of ANCA disease begins with induction of remission, fol-
Glomerulonephritis, arthritis, obstructive
lowed by maintenance of remission (Kallenberg, 2014). In patients with
pulmonary disease, and ocular inflammation
active generalized disease, remission is most often induced with an immu-
are common.
nosuppressive agent (e.g., cyclophosphamide or rituximabrituximab) and
high-dose glucocorticoids. Rituximab has been shown to be noninferior to From Jennette JC, Falk RJ, Bacon PA, et al: 2012 Revised International Chapel Hill
cyclophosphamide for induction of remission. Patients presenting with Consensus Conference Nomenclature of Vasculitides, Arthritis Rheum 65:1–11,
severe kidney failure (i.e., requiring dialysis or an estimated GFR less than 2013.
15) or diffuse alveolar hemorrhage should receive plasma exchange as well
as the usual induction therapy. Mild localized disease, especially with no
renal or pulmonary disease, may be controlled with methotrexate and
glucocorticoids. When disease is in remission, patients should be transi- Pathology
tioned to oral azathioprine, although the use of rituximab as remission The light microscopic features of anti-GBM glomerulonephritis (GN) are
maintenance therapy is increasing (Kallenberg, 2014). Once a patient is in indistinguishable from ANCA glomerulonephritis, although on average
remission, glucocorticoids should be tapered within 6 months to reduce the extent of injury is more severe in anti-GBM GN compared to ANCA
the likelihood of infectious complications (McGregor et al, 2012). Other GN. For example, at the time of biopsy, anti-GBM GN has an average of
treatment options for refractory disease are IVIg, infliximab, alemtu- 77% crescents compared to 49% for ANCA GN ( Jennette, 2003). Con-
zumab, and deoxyspergualin (Kallenberg, 2014). current anti-GBM plus ANCA GN has an average of 62% crescents. The
Drug-induced ANCA vasculitis may require not only cessation of the activity and chronicity of anti-GBM GN lesions tend to be more synchro-
drug and supportive care but also immunosuppression, plasma exchange nous than the lesions of ANCA GN. That is, anti-GBM lesions are either
in severe cases, and dialysis as needed (Pendergraft & Niles, 2014). mostly acute or mostly chronic, whereas ANCA GN lesions more often
have a mixture of acute and chronic lesions. This is in accord with the
ANTI-GLOMERULAR BASEMENT   clinical and serologic observations that anti-GBM disease and anti-GBM
MEMBRANE DISEASE seropositivity typically occur as one episode with uncommon relapses,
whereas ANCA disease and ANCA seropositivity often are persistent with
Definition and Epidemiology multiple recurrences even after initial induction of remission.
Anti-glomerular basement membrane (anti-GBM) disease is an autoim- Anti-GBM pulmonary disease is characterized by extensive hemor-
mune disease caused by autoantibodies that target the noncollagen domain rhage into the alveolar air spaces but with less overt influx of neutrophils
of the α3 chain of type IV collagen (Cui & Zhao, 2011; Greco et al, 2015). into alveolar capillaries than is observed with ANCA pulmonary capil-
This form of vasculitis can be grouped with immune complex vasculitis laritis. Identification of arteritis in the kidney or lung of a patient with
because it results from immune complexes forming in situ along capillary anti-GBM disease is strong evidence for concurrent anti-GBM plus ANCA
basement membranes (Table 53-4). The glomerular capillaries of the disease.
kidneys and alveolar capillaries of the lungs contain this autoantigen, and The most definitive pathology finding is demonstration by direct
either or both can be injured in anti-GBM disease. When both are immunofluorescence microscopy of linear staining for IgG along glomeru-
involved, the resultant pulmonary-renal syndrome is called Goodpasture lar capillary basement membranes or pulmonary alveolar capillary base-
syndrome. Most patients with anti-GBM disease have rapidly progressive ment membranes (Fig. 53-9). This usually is accompanied by staining for
glomerulonephritis, approximately half have pulmonary disease, and only C3 and other complement components and variable staining for IgM and
a few have lung disease. IgA. This is distinct from the granular staining for immunoglobulin in
The incidence of anti-GBM disease is estimated to be 1 per million vessel walls with immune complex vasculitis or the paucity of immuno-
per year (Cui & Zhao, 2011; Greco et al, 2015). It occurs more commonly globulin staining in vessel walls in ANCA vasculitis ( Jennette et al, 2013).
in Caucasians than African Americans. Age distribution is bimodal, with
the most common ages being between 20 and 30 and between 60 and 70. Etiology and Pathogenesis
The younger patients are predominantly men, and there is a higher fre- Both humoral and cellular autoimmune responses have been incriminated
quency of pulmonary disease. The older patients are predominantly in the pathogenesis of anti-GBM disease (Pusey, 2003; Cui & Zhao, 2011).
women, and there is a lower frequency of pulmonary disease. There is compelling evidence that anti-GBM antibodies are pathogenic,

1026
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 A B
Figure 53-9  Linear immunofluorescence staining for IgG along glomerular basement membranes (A) and pulmonary
alveolar capillary basement membranes (B); demonstration by direct immunofluorescence microscopy (FITC rabbit antihu-
man IgG, ×400).
which includes (1) the close association of circulating and basement
membrane–bound anti-GBM antibodies with disease; (2) relatively good
correlation of autoantibody levels with activity of disease; (3) clinical
response to therapy that reduces circulating anti-GBM levels, such as
apheresis and immunosuppressive therapy; (4) recurrence of disease in
kidney transplants in the presence of residual circulating anti-GBM anti-
bodies in the recipient; (5) development of anti-GBM glomerulonephritis
in patients with hereditary type IV collagen abnormalities who make neph-
ritogenic autoantibodies directed against donor GBM; and (6) experimen-
tal animal studies, including direct transfer of glomerulonephritis to
primates by intravenous injection of human anti-GBM antibodies.
Although anti-GBM antibodies appear to be major pathogenic factors,
T cells also play an important role. T cell help is required for class-
switching to produce high-affinity IgG antibodies, and T cell involvement
is indicated by MHC associations.
The etiology of anti-GBM disease is not known. One hypothesis pro-
poses that anti-GBM disease is an autoimmune “conformeropathy” that
involves pathogenic conformational changes in the alpha 3 and alpha 5
noncollagen domains of type IV collagen, revealing cryptic epitopes that
in turn elicit an autoimmune response (Pedchenko et al, 2010).
Another hypothesis is that autoimmunity to the alpha 3 chain of type
IV collagen is triggered by “autoantigen complementarity” that begins
with an immune response against a peptide that is antisense or comple-
mentary to the autoantigen (Reynolds et al, 2015). Autoantigen comple-
mentarity also is incriminated as a cause for ANCA disease (Pendergraft
et al, 2004).
Clinical Laboratory Testing
Anti-GBM assays using ELISAs, chemiluminescence assays, dot blots, and
Western blots are highly specific (>90%) and sensitive (>95%) for anti-
GBM disease (Pusey, 2003). Most commercial assays use bovine or sheep
GBM enriched for the noncollagen domain of the α3 chain of type IV
collagen (Pusey, 2003). Positive results can be confirmed by Western blot-
ting using collagenase-solubilized human GBM. Indirect immunofluores-
cence microscopy assays using normal human or primate kidney as
substrate were used historically, but they are not sensitive enough for
current clinical use.
Rapid screening assays are available for concurrently detecting PR3-
ANCA, MPO-ANCA, and anti-GBM antibodies in the same assay for
rapid diagnosis of patients with clinical evidence for rapidly progressive
glomerulonephritis, hemorrhagic pulmonary capillaritis, or both, using
either ELISA (Westman et al, 1997) or dot-blot technology (Rutgers et al,
2005). A rapid, random access chemiluminescence assay (CIA) also has
been developed to detect anti-GBM antibodies with 95.6% sensitivity and
99.6% specificity (Mahler et al, 2012).
All patients with anti-GBM disease should be tested for ANCA to rule
out concurrent anti-GBM plus ANCA disease, which occurs in approxi-
mately one third of patients with anti-GBM disease ( Jennette, 2003;
Rutgers et al, 2005). The double anti-GBM and ANCA reactivity in assays
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PART 6
is the result of two different antibody populations rather than one cross-
reacting population (Rutgers et al, 2005).
Diagnosis, Treatment, and Prognosis
Standard treatment is a combined therapy of plasmapheresis, predniso-
lone, and cyclophosphamide (Pusey, 2003; Cui & Zhao, 2011). Anecdotal
reports of success with anti-CD20 targeted B cell therapy have emerged
but are not conclusive. The important determinant for the response to
therapy and long-term prognosis for anti-GBM disease is early diagnosis
to prevent end-stage kidney disease and life-threatening pulmonary hem-
orrhage. If treatment is started before the serum creatinine is above 5 mg/
dL, there is a good chance of renal survival. Even in patients with advanced
renal disease, treatment may result in improvement and may also be ben-
eficial in preventing or ameliorating concurrent pulmonary disease.
Patients should not be transplanted until circulating anti-GBM autoanti-
bodies can no longer be detected by standard assays.
CRYOGLOBULINEMIC VASCULITIS
Definition and Epidemiology
Cryoglobulinemic vasculitis (CV) is vasculitis with cryoglobulin-immune
deposits affecting small vessels (predominantly capillaries, venules, or arte-
rioles) and is associated with serum cryoglobulins (Tedeschi et al, 2007;
Jennette et al, 2013). Skin, glomeruli, and peripheral nerves are often
involved.
Cryoglobulins are immunoglobulins that reversibly precipitate in the
cold (Damoiseaux, 2014). Type I cryoglobulins consist of a monoclonal
immunoglobulin, generally either IgM or IgG. Type II cryoglobulins
contain a monoclonal immunoglobulin with rheumatoid factor (RF) activ-
ity and polyclonal immunoglobulins. Most often this is a combination of
a monoclonal IgM with polyclonal IgG. Type III cryoglobulins contain
polyclonal immunoglobulins, typically IgM and IgG, with RF activity in
the IgM fraction. Types II and III are called mixed cryoglobulins.
Type I cryoglobulins often are associated with B cell lymphoprolifera-
tive diseases, such as Waldenström’s macroglobulinemia or multiple
myeloma. Type II cryoglobulins are often associated with HCV infection,
as well as other chronic viral infections and systemic autoimmune diseases.
Type III cryoglobulins often are associated with chronic viral infections
and systemic autoimmune diseases and may be a transient state between
polyclonal hypergammaglobulinemia and type II cryoglobulinemia
(Damoiseaux, 2014).
Pathology
CV usually is confined to capillaries (e.g., glomerular capillaries), venules
(e.g., dermal venules), and arterioles or very small arteries (e.g., epineural
arteries in peripheral nerves). Involvement of medium arteries is extremely
rare. The acute inflammation is neutrophil-rich with leukocytoclasia. The
inflammation may be accompanied by luminal or vessel wall deposits
of PAS-positive hyaline material that is a coagulum of cryoglobulins.
1027
53  Vasculitis
A B
Figure 53-10  Cryoglobulinemic glomerulonephritis with “hyaline thrombi” seen by light microscopy (A, Masson tri-
chrome stain, ×500) and by direct immunofluorescence microscopy using FITC-labeled rabbit antihuman C3 (B, ×500).
Cryoglobulinemic glomerulonephritis occurs as a renal-limited process or
as a component of systemic CV. Cryoglobulinemic glomerulonephritis
usually has a membranoproliferative pattern but may have other patterns
of proliferative glomerulonephritis. A useful diagnostic finding is hyaline
material in glomerular capillary lumens (“hyaline thrombi”) that are com-
posed of cryoglobulins (Fig. 53-10). By immunofluorescence microscopy,
these deposits contain the immunoglobulins of the cryoglobulins as well
as complement components that have been activated by the cryoglobulin
immune complexes (see Fig. 53-10).
Etiology and Pathogenesis
Hepatitis C virus (HCV) is the main etiologic agent of mixed cryoglobu-
linemic vasculitis (Cacoub et al, 2014). In some European settings, mixed
cryoglobulinemia has been associated with HCV infection in more than
80% of the patients, although only a minority develop signs and symptoms
of vasculitis (Pagnoux et al, 2006). Although the association of CV with
HCV is approximately 85% in the Mediterranean region, it varies from
30% to 100% in other geographic locations (Damoiseaux, 2014).
Deposition of cryoglobulins in vessel walls incites vasculitis by comple-
ment activation. Monoclonal cryoglobulins (type I) are not as effective at
activating inflammatory mediator systems as are mixed cryoglobulins
(types II and III), which are immune complexes composed of antiantibod-
ies (rheumatoid factors) bound to target antibodies. An important cause
for cryoglobulinemia is hepatitis C infection. In HCV-CV, immune
complex deposits contain viral proteins (Damoiseaux, 2014).
Clinical Laboratory Testing
Clinical laboratory testing for cryoglobulins is divided into three phases:
the preanalytic phase, the analytic phase, and the typing phase (Damoi-
seaux, 2014). The preanalytic phase entails collecting the sample in pre-
warmed (37° C) tubes, transporting at 37° C, allowing coagulation of the
blood sample at 37° C for at least 1 hour, and centrifugation at 37° C to
separate the serum. The analytic phase entails incubating two fractions of
the sample at 4° C for 3 to 7 days, visual assessment of precipitation, incu-
bating one fraction at 37° C to assess resolution, and isolating the cryo-
globulin from the other fraction for typing. The typing phase includes
determining the immunoglobulin composition (e.g., by immunofixation or
immunoelectrophoresis) and quantifying the cryoglobulin by assessing
cryocrit, total protein content, and/or content of immunoglobulin isotypes
(Damoiseaux, 2014).
In addition to a positive cryoglobulin assay, in a patient with clinical
evidence for SVV, laboratory detection of low C4, rheumatoid factor,
and evidence for HCV infection add additional support for a diagnosis of
CV (Lamprecht et al, 2001).
Diagnosis, Treatment, and Prognosis
Detection of mixed cryoglobulins, especially accompanied by low C4,
along with purpura, peripheral neuropathy, and/or glomerulonephritis, is
strong evidence for CV.
One set of classification criteria for CV requires the detection of cryo-
globulins in at least two determinations more than 12 weeks apart (DeVita
1028
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et al, 2011). In addition to the detection of cryoglobulins, at least two
additional patient-reported symptoms, clinical observations, or laboratory
findings must be documented to make a diagnosis of CV.
Antiviral therapy with pegylated interferon-α and ribavirin is recom-
mended for induction therapy for HCV-CV with mild to moderate disease
severity and activity (Cacoub et al, 2014). In patients with more severe
disease, an immunosuppressive treatment regimen is required for the
induction phase while awaiting the response to antiviral treatments—for
example, pegylated interferon-α and ribavirin plus steroids and cyclophos-
phamide or rituximab. If there is life-threatening disease or rapidly pro-
gressive glomerulonephritis, apheresis may be beneficial.
The 1-year, 3-year, 5-year, and 10-year survival rates for HCV-CV are
95%, 85%, 75%, and 65%, respectively. Mortality is mainly related to
infections and end-stage liver disease. Factors associated with a poor prog-
nosis are severe liver fibrosis (HR 5.31), central nervous system involve-
ment (HR 2.74), kidney involvement (HR 1.91), and heart involvement
(HR 4.2) (Terrier et al, 2011).
IgA VASCULITIS (HENOCH-SCHÖNLEIN
PURPURA)
Definition and Epidemiology
IgA vasculitis (IgAV) (formerly called Henoch-Schönlein purpura) is vas-
culitis with IgA1-dominant immune deposits affecting small vessels (pre-
dominantly capillaries, venules, or arterioles) ( Jennette et al, 2013). IgAV
often involves the skin and gastrointestinal tract, and it frequently causes
arthritis. Glomerulonephritis indistinguishable from IgA nephropathy may
occur.
IgA vasculitis is most common in children, especially children under
10 years old, which differs from ANCA vasculitis and CV, which are more
common in older patients. In fact, IgAV is the most common systemic
small-vessel vasculitis in children (Chen & Mao, 2015). Depending on
ethnic background, 6 to 24 per 100,000 children younger than 17 years of
age will develop IgAV. In Asia, the incidence is as high as approximately
70 cases per 100,000 children every year. IgAV is rare in adults, with an
annual incidence of 0.1 to 1.8 per 100,000 individuals (Audemard-Verger
et al, 2015). Disease is more frequent in males (male : female ratio of 5 : 1).
Pathology
The histopathologic features of inflammation in venules, arterioles, and
small arteries, caused by IgAV, are indistinguishable from other forms of
SVV. In the dermis, this takes the form of a leukocytoclastic angiitis affect-
ing predominantly venules and arterioles. The presence of hyaline aggre-
gates in areas of inflammation or the lumen increases the likelihood of CV.
Arteritis affecting arteries in the deep dermis, and especially arteries in
the subcutaneous tissue, increases the likelihood of ANCA vasculitis.
Numerous eosinophils increase the likelihood of hypersensitivity drug-
induced vasculitis or EGPA. However, it is best to correlate the histopa-
thology with immunostaining for IgA, IgG, IgM, C3, and C1q, and with
serologic testing for ANCA, cryoglobulins, HCV antigen and antibody,

Figure 53-11  Direct immunofluorescence microscopy of small vessels in the
upper dermis of a patient with IgA vasculitis demonstrating coarsely granular
deposits of IgA in vessel walls (FITC-labeled rabbit antihuman C3, ×600).
anti-C1q, ANA, C3, and C4 before reaching a diagnosis. Patients with
IgAV have immune complex deposits in small dermal vessels that stain
brightly by direct immunofluorescence microscopy using antibodies spe-
cific for IgA (Fig. 53-11).
The glomerulonephritis of IgAV is indistinguishable from IgA
nephropathy (IgAN), although glomerular necrosis and crescents are
somewhat more frequent in IgA vasculitis. Because glomerulonephritis is
a frequent component of many forms of immune complex SVV, immuno-
pathologic features are very helpful in distinguishing among different
forms of SVV—for example, IgAV with IgA1-dominant glomerular depos-
its, CV with membranoproliferative lesions and IgG/IgM deposits, anti-
GBM disease with necrosis and linear IgG, and ANCA vasculitis with
necrosis and a paucity of immunoglobulin deposits in glomeruli.
Etiology and Pathogenesis
Patients with IgAV and IgAN have increased serum levels of IgA1 with
abnormal glycosylation of the hinge region (Suzuki et al, 2009, 2011;
Mestecky et al, 2013). This abnormality is caused by combined genetic and
environmental/infectious influences. There is strong evidence that IgAV
and IgAN are caused by vessel wall deposition of aggregates of abnormally
glycosylated IgA1 molecules or by deposition of immune complexes com-
posed of IgA1 complexed to anti-IgA1 IgG that recognizes the abnormal
hinge region glycosylation (Suzuki et al, 2009, 2011; Mestecky et al, 2013).
Abnormally glycosylated IgA1 molecules also could induce disease
through a variety of other mechanisms, such as reduced clearance from
the circulation because of lack of Fc receptor engagement by the abnormal
IgA, increased self-aggregation of IgA1 in the circulation resulting in
deposition in vessel lumens and vessel walls, and increased affinity of the
abnormal IgA1 for perivascular and glomerular mesangial matrix.
Vascular deposits containing IgA1 appear to mediate inflammation by
activating complement via the lectin pathway and the alternative pathway.
Clinical Laboratory Testing
Abnormally glycosylated IgA1 has been detected in serum using lectin-
binding assays and proteomic mass spectroscopy analysis. For example, a
lectin that recognizes N-acetylgalactosamine was used in an ELISA to
measure serum galactose-deficient IgA1 (Moldoveanu et al, 2007). This
study concluded that the assay for abnormal IgA1 had diagnostic sensitivity
of 76.5%, specificity of 94%, positive predictive value of 88.6%, and nega-
tive predictive value of 78.9% for IgAN.
Anti-IgA antibodies with specificity for the IgA1 hinge region have
been detected in serum using monoclonal human IgA1 as substrate and by
identifying IgA1 in circulating immune complexes. One study concluded
that IgA1 glycan-specific IgG antibodies have 88% specificity and 95%
sensitivity for IgA nephropathy (Suzuki, 2009). In addition to diagnosis,
serologic tests for abnormally glycosylated IgA1 and IgA1 immune
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complexes may be of value in monitoring disease activity. Serum levels of
galactose-deficient IgA1 and IgA1-IgG immune complexes are associated
with disease activity of IgA nephropathy (Suzuki et al, 2014).
To date, these research observations on abnormal IgA1 glycosylation
and anti-IgA1 antibodies in IgAV and IgAN have not been translated into
analytically and clinically validated diagnostic tests, although multiple
research laboratories are working on this.
Diagnosis, Treatment, and Prognosis
Until alternative clinical tests are validated, pathologic identification of
IgA-dominant immune deposits in vessel walls or glomeruli by direct
immunofluorescence microscopy is the gold standard method for confirm-
ing a diagnosis of IgAV or IgAN. Immunostaining is required in biopsy
specimens because the light microscopic patterns of injury are not as
conclusive for distinguishing among the many forms of SVV. For example,
a skin biopsy that has leukocytoclastic angiitis by light microscopy could
be found by immunofluorescence microscopy to be IgAV with IgA-
dominant deposits, CV with IgM and C3 deposits, or ANCA vasculitis
with a paucity of immunoglobulin and complement deposits.
The classic triad of symptoms and signs for IgAV are purpura, arthral-
gia, and abdominal pain. The frequency of renal disease varies from 45%
to 85% in different cohorts (Audemard-Verger et al, 2015). The European
League Against Rheumatism (EULAR), the Paediatric Rheumatology
International Trials Organization, and the Paediatric Rheumatology Euro-
pean Society have proposed classification criteria for pediatric patients
(Audemard-Verger et al, 2015). Based on these criteria, a patient is classi-
fied as IgAV if there are purpura with lower-extremity predominance plus
PART 6
one of the following four criteria: abdominal pain, histopathology demon-
strating IgA-dominant deposits in vessels or glomeruli, arthritis or arthral-
gia, or renal involvement. These criteria have not been adopted for adults
and would be problematic in adults because the prevalence of IgAV is much
lower than the prevalence of other forms of SVV that cause similar signs
and symptoms, especially ANCA disease. For example, a patient who has
purpura, arthralgias, and nephritis fulfills the EULAR criteria for IgAV.
Such a patient could also have ANCA vasculitis, cryoglobulinemic vascu-
litis, or other forms of SVV. Especially if applied to adults, the pediatric
EULAR criteria should be combined with testing for ANCA, cryoglobu-
lins, HCV infection, and hypocomplementemia.
Because the clinical course of IgAV is relatively benign in most patients,
treatment is usually conservative and directed at symptom relief. Patients
who develop severe gastrointestinal complications may require steroids or/
and immunosuppressive drugs. When kidney disease develops with IgAV,
the following Kidney Disease Improving Global Outcome (KDIGO)
guidelines can be used (Chen & Mao, 2015). Persistent proteinuria should
be treated with angiotensin-converting enzyme inhibitors or angiotensin
receptor blockers. If the proteinuria persists and the glomerular filtration
rate is greater than 50 mL/min per 1.73 m2, a 6-month course of cortico-
steroid therapy should be given. If severe renal failure and crescentic
glomerulonephritis are documented, immunosuppressive therapy similar
to that used for other forms of crescentic glomerulonephritis should be
provided.
HYPOCOMPLEMENTEMIC  
URTICARIAL VASCULITIS
Definition and Epidemiology
Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis) is
vasculitis accompanied by urticaria and hypocomplementemia affecting
small vessels (i.e., capillaries, venules, or arterioles), and it is often associ-
ated with anti-C1q antibodies ( Jennette et al, 2013). Glomerulonephritis,
arthritis, obstructive pulmonary disease, and ocular inflammation are com-
monly present in HUV, and HUV has overlapping clinical and laboratory
features with SLE, though it also occurs independently of SLE (Venzor
et al, 2002; Kallenberg, 2008; Grotz et al, 2009).
HUV is a rare disease. The incidence of all forms of leukocytoclastic
vasculitis affecting the skin in a population-based study in Minnesota from
1996 to 2010 identified an incidence rate of 4.5 per 100,000 person-years
(Arora et al, 2014). The cohort included 38 patients with leukocytoclastic
vasculitis not otherwise specified (45%), 25 with IgA vasculitis (30%), 10
with urticarial vasculitis (12%), 8 with ANCA vasculitis (10%), and 3 with
cryoglobulinemic vasculitis (4%) (Arora et al, 2014). Thus HUV has an
incidence of less than 0.5 per 100,000 person-years in this population.
HUV affects women more frequently than men (ratio 2 : 1) and has a
peak incidence in the fifth decade of life, although HUV has been observed
in children (Grotz et al, 2009).
1029

53  Vasculitis
Pathology
The dermal vasculitis in HUV is a leukocytoclastic angiitis that cannot be
readily distinguished from other forms of SVV by histology alone. Direct
immunofluorescence microscopy demonstrates complement-rich immune
complex deposits with prominent C1q in dermal vessels and along the
dermal-epidermal junction.
By immunofluorescence microscopy, glomerulonephritis in HUV has
extensive capillary wall and mesangial immune complex deposits contain-
ing immunoglobulin and complement, including prominent C1q. The
most frequent histologic pattern is membranoproliferative glomerulone-
phritis with thickened capillary walls and endocapillary hypercellularity,
although focal or diffuse proliferative glomerulonephritis may also occur.
In this respect, HUV glomerulonephritis resembles lupus nephritis, and
patients with HUV who also meet clinical criteria for SLE should be
considered to have lupus nephritis.
Etiology and Pathogenesis
Experimental studies strongly support a pathogenic role for anti-C1q anti-
bodies in forming pathogenic immune complexes in SLE and HUV, and
anti-C1q antibodies may interfere with the clearance of apoptotic cells and
enhance induction of autoimmunity (Kallenberg, 2008). The hypocomple-
mentemia appears to be secondary to classical complement pathway activa-
tion with reduced C1, C2, C4, and C3 (Kallenberg, 2008). The extensive
deposition of immune complexes in the walls of inflamed vessels—for
example, dermal venules and glomerular capillaries—supports an immune
complex pathogenesis for the inflammation.
Clinical Laboratory Testing
The typical laboratory test profile is elevated anti-C1q antibodies (essen-
tially 100% sensitive) and hypocomplementemia with low C1q, C3, and
C4. In patients who have HUV without overt SLE, ANA often is present
without anti–double-stranded DNA. Positive testing for cryoglobulins
supports a diagnosis of CV rather than HUV.
C1q has a collagen-like portion attached to globular heads, resembling
a bouquet of tulips (Venzor et al, 2002; Kallenberg, 2008). Immune
complex Fc regions bind to these globular portions, whereas anti-C1q
autoantibodies instead bind to the collagen-like portion. Anti-C1q usually
is detected by ELISA using human C1q as the substrate. High ionic
strength conditions (0.5 to 1.0 M NaCl) are used to inhibit binding of
immune complexes (Kohro-Kawata et al, 2002). Anti-C1q is detected in a
variety of inflammatory diseases, including HUV (100%), rheumatoid
vasculitis (77%), Felty syndrome (76%), lupus nephritis (63%), membra-
noproliferative glomerulonephritis (54%), and SLE without nephritis
(33%) (Seelen et al, 2003; Kallenberg, 2008). HUV patients who do not
have overt SLE may have low-titer antinuclear antibodies, rheumatoid
factor, lupus anticoagulant, and cryoglobulins.
While the presence of anti-C1q antibodies is highly sensitive for HUV
(found in 100% of patients), they are neither sensitive nor specific for SLE.
Anti-C1q antibodies are more prevalent in SLE patients with lupus nephri-
tis than in patients without nephritis. In a study of 43 patients with SLE,
anti-C1q antibodies were identified in 82% of patients with nephritis,
compared to only 38% of patients who did not have nephritis (Coremans
et al, 1995). In a study of 228 patients with lupus nephritis, the evaluation
of anti-C1q, C3, and C4 provided the best prediction of renal flares (Sinico
et al, 2009). However, some SLE patients with high titers of anti-C1q
antibodies do not develop nephritis.
Diagnosis, Treatment, and Prognosis
HUV is characterized by recurrent episodes of urticaria with underlying
leukocytoclastic vasculitis. Skin manifestations include painful, tender,
burning, or pruritic urticarial skin lesions that persist for greater than
24 hours, often with central areas of hemorrhage. Once the urticaria
resolves, there may be residual purpura. Additional manifestations
include angioedema, laryngeal edema, pulmonary involvement, arthritis,
arthralgia, glomerulonephritis, and uveitis. Compared to patients with
urticaria and vasculitis who do not have hypocomplementemia, HUV
patients are more likely to have abdominal pain and chronic obstructive
pulmonary disease (Mehregan et  al, 1992). Chronic obstructive pulmo-
nary disease and acute laryngeal edema are important causes for morbid-
ity and mortality. Around 30% of HUV patients suffer gastrointestinal
symptoms: pain, nausea, vomiting, diarrhea, and sometimes ascites in
connection with serositis, hepatomegaly, and splenomegaly (Grotz et  al,
2009).
The two major diagnostic criteria are chronic urticaria and hypo-
complementemia. Minor criteria include anti-C1q antibodies, leuko­
1030
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cytoclastic vasculitis, arthralgia and arthritis, uveitis or episcleritis,
glomerulonephritis, and abdominal pain (Grotz et al, 2009).
Glucocorticoids are standard therapy for HUV. Depending on clinical
severity, additional immunosuppressive agents such as methotrexate, aza-
thioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil
may be added. Apheresis is reserved for very aggressive disease (Grotz et al,
2009).
RHEUMATOID VASCULITIS
Definition and Epidemiology
Rheumatoid vasculitis is an uncommon extra-articular complication of
rheumatoid arthritis (RA) and primarily affects small to medium vessels
(Ntatsaki et al, 2014; Makol et al, 2015). There has been a decrease in the
incidence of rheumatoid vasculitis in the last decade in both Europe and
the United States (Ntatsaki et al, 2014). The average annual incidence of
rheumatoid vasculitis in the United Kingdom declined from 9.1 per
million between 1988 and 2002 to 3.9 per million between 2001 and 2010
(Ntatsaki et al, 2014). This reduction may be the result of the use of
current disease-modifying antirheumatic drugs (DMARDs), including
methotrexate.
Pathology
Rheumatoid vasculitis involves small and medium vessels, including
medium and small arteries and venules. It is a necrotizing arteritis that is
histologically indistinguishable from other forms of necrotizing arteritis,
such as PAN and MPA. Its venulitis, especially in the dermis, is histologi-
cally indistinguishable from the leukocytoclastic angiitis of ANCA or
immune complex disease. In patients with rheumatoid vasculitis, dermal
necrotizing venulitis has been identified as the cause of palpable purpura,
maculopapular erythema, erythema elevatum diutinum, and hemorrhagic
blisters; arteritis has been identified as the cause of subcutaneous nodules,
livedo reticularis, and deep ulcers (Chen et al, 2002). Some patients have
both patterns of vasculitis.
Etiology and Pathogenesis
There is a strong association between rheumatoid vasculitis and particular
HLA genotypes that suggests a role for immune recognition of antigens
in its pathogenesis. A role for immune complexes containing autoantibod-
ies has been proposed based on the observed high prevalence and high
titer of rheumatoid factor (RF), anticitrullinated peptide antibodies
(ACPA), antinuclear antibodies, and circulating or tissue-deposited
immune complexes in patients with rheumatoid vasculitis (Makol et al,
2015). However, many RA patients with high titers of RF and ACPA do
not develop rheumatoid vasculitis. Immunoglobulin and complement have
been detected by immunofluorescence in dermal vessels of patients with
dermal rheumatoid vasculitis (Chen et al, 2002).
Clinical Laboratory Testing
Rheumatoid vasculitis should be suspected in a patient with clinical or
pathologic evidence for vasculitis who has rheumatoid factor (RF), anti­
citrullinated peptide antibodies (ACPA), antinuclear antibodies, and circu-
lating or tissue-deposited immune complexes (Makol et al, 2015). Less
specific features that are often observed include anemia, leukocytosis,
thrombocytosis, elevated erythrocyte sedimentation rate, increased
C-reactive protein, and polyclonal hypergammaglobulinemia. The absence
of RF and ACPA has a high negative predictive value for rheumatoid
vasculitis (Makol et al, 2015).
In a study of 19 patients with rheumatoid vasculitis, all of the patients
were seropositive for RF, no patients were C-ANCA positive, 5 patients
were P-ANCA positive by IIF but had negative ELISA for MPO-ANCA,
1 patient with P-ANCA was positive for PR3-ANCA by ELISA, all of the
patients were negative for ANA, and 1 patient was positive for antimito-
chondrial antibodies (Ntatsaki et al, 2014). Anti-C1q antibody testing is
positive in approximately 75% of patients with rheumatoid vasculitis
(Seelen et al, 2003; Kallenberg, 2008). This raises the possibility of a
relationship with HUV, but anti-C1q positive patients with rheumatoid
vasculitis typically do not have other features of HUV, including no hypo-
complementemia, or urticarial or immune complex glomerulonephritis.
Diagnosis, Treatment, and Prognosis
The Scott and Bacon diagnostic criteria for rheumatoid vasculitis require
the presence of one or more of the following in a patient with RA: mono-
neuritis multiplex or peripheral neuropathy, peripheral gangrene, biopsy
evidence of acute necrotizing arteritis plus systemic illness (e.g., fever and
weight loss), deep cutaneous ulcers or extra-articular disease (e.g., pleurisy,
pericarditis, scleritis) if associated with typical digital infarcts, or biopsy
evidence of vasculitis (Scott & Bacon, 1984).
Hydroxychloroquine and low-dose aspirin are associated with lower
odds of developing rheumatoid vasculitis among RA patients, suggesting
a possible protective effect (Makol et al, 2015). Among 86 patients treated
for rheumatoid vasculitis at Mayo Clinic between 2000 and 2010, 99%
received glucocorticoids, 29% received cyclophosphamide, 55% received
another disease-modifying antirheumatic drug (methotrexate, azathio-
prine, mycophenolate mofetil, hydroxychloroquine, minocycline), and
28% received a biologic agent (anti-TNF, rituximab, abatacept, anakinra)
(Makol et al, 2014). However, despite aggressive use of cyclophosphamide
and biologics, rheumatoid vasculitis remained difficult to treat, with high
relapse rates and mortality rates of 12% at 1 year and 60% at 5 years.
patient demographics, clinical signs and symptoms, laboratory tests, and
pathologic findings. Positive as well as negative laboratory test results are
critically important in the diagnostic evaluation of patients with suspected
vasculitis, and they are useful for prognostication, predicting and monitor-
ing response to therapy, and predicting or detecting relapse. Over the past
20 years, there has been a valuable increase in the menu of laboratory tests
that facilitate the care of patients with vasculitis (e.g., ANCA). More are
currently on the verge of entering clinical practice (e.g., IgA1 glycosylation
and anti-IgA1 antibody assays), and undoubtedly more will be discovered
before the next edition of this text is published.
REFERENCES
Access the complete reference list online at ExpertConsult.com.

SUMMARY
The diagnosis of vasculitis is difficult. Accurate and precise diagnosis
requires knowledgeable integration of evidence from the medical history,

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