Anti Neutrophil Cytoplasmic Antibody (ANCA) Associated

Vasculitis

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Nuvole sul mare, Laura Maddii Emmi (Private collection)
Renato Alberto Sinico • Loïc Guillevin
Editors

Anti-Neutrophil
Cytoplasmic Antibody
(ANCA) Associated
Vasculitis
Editors
Renato Alberto Sinico Loïc Guillevin
Department of Medicine and Surgery Department of Medicine
University of Milano-Bicocca Paris Descartes University Hospital Cochin
Monza Paris
Monza e Brianza France
Italy

ISSN 2282-6505     ISSN 2283-6403 (electronic)

Rare Diseases of the Immune System
ISBN 978-3-030-02238-9    ISBN 978-3-030-02239-6 (eBook)
https://doi.org/10.1007/978-3-030-02239-6

© Springer Nature Switzerland AG 2020

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Dedicated to my family.
Acknowledgements

We would like to thank all the prestigious colleagues and researches from around
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Without their help this book would not have been possible.

vii
Contents

Part I ANCA-Associated Vasculitis

1 Introduction: Nomenclature and Classification��������������������������������������   3
J. Charles Jennette and Ronald J. Falk
2 Genetics of ANCA-Associated Vasculitis�������������������������������������������������� 19
Federico Alberici, Paul Anthony Lyons, and Davide Martorana
3 Etiopathogenesis of ANCA-Associated Vasculitis ���������������������������������� 33
Delphine Sterlin, Alexis Mathian, and Makoto Miyara
4 ANCA: Methods and Clinical Significance �������������������������������������������� 47
Elena Csernok and Antonella Radice
5 Activity and Damage���������������������������������������������������������������������������������� 57
Raashid A. Luqmani
6 Eosinophilic Granulomatosis with Polyangiitis
(EGPA, Churg–Strauss)���������������������������������������������������������������������������� 77
Yann Nguyen and Loïc Guillevin
7 Granulomatosis with Polyangiitis������������������������������������������������������������ 97
Christian Pagnoux
8 Microscopic Polyangiitis���������������������������������������������������������������������������� 131
Renato Alberto Sinico, Filippo Maria Sala, Maria Rosa Pozzi,
Paolo Fabbrini, and Federico Pieruzzi

Part II Vasculitis/Organs Involvement

9 ANCA-Associated Vasculitis—ENT Involvement ���������������������������������� 147
Trimarchi Matteo, Galli Andrea, and Roberto Teggi
10 Lung Involvement in ANCA-Associated Vasculitis �������������������������������� 163
Marta Casal Moura and Ulrich Specks

ix
x Contents

11 Kidney Involvement ���������������������������������������������������������������������������������� 177

Renato Alberto Sinico, Fabio Pagni, Vincenzo L’Imperio,
Valentina Binda, Paolo Fabbrini, Federico Pieruzzi,
and Gabriella Moroni
12 Peripheral Nervous System Involvement ������������������������������������������������ 193
Michael P. Collins and P. James B. Dyck
13 Central Nervous System Involvement in ANCA-Associated
Vasculitis ���������������������������������������������������������������������������������������������������� 239
Hubert de Boysson
14 Skin Involvement���������������������������������������������������������������������������������������� 251
Angelo Valerio Marzano, Simona Tavecchio, and Emilio Berti
15 Miscellaneous Organ Involvement in ANCA-Associated Vasculitis������ 269
Giorgio Trivioli and Augusto Vaglio
16 Prognosis and Outcomes of ANCA-­Associated Vasculitis���������������������� 293
David Jayne
17 Treatment of ANCA-Associated Vasculitides������������������������������������������ 313
Loïc Guillevin, Loïc Raffray, Yann Nguyen, Benjamin Chaigne,
and Benjamin Terrier
Index�������������������������������������������������������������������������������������������������������������������� 329
 Part I
ANCA-Associated Vasculitis
Introduction: Nomenclature
and Classification 1
J. Charles Jennette and Ronald J. Falk

1.1 AAV Pathologic Features

Vasculitis is inflammation in blood vessel walls. Antineutrophil cytoplasmic anti-

body (ANCA)-associated vasculitis (AAV) is vasculitis accompanied by circulating
ANCAs, or phenotypically identical disease without detectable ANCA (ANCA-­
negative AAV). AAV is a necrotizing vasculitis with few or no immune deposits that
affects predominantly small vessels (i.e., capillaries, venules, arterioles, and small
arteries) (Table 1.1) [1–3].
An understanding of the pathologic features of AAV is required to understand the
historical and contemporary nomenclature and classification of AAV. Acute AAV
lesions in blood vessels are characterized by segmental neutrophil-rich inflamma-
tion and necrosis (Fig. 1.1). Vessel wall necrosis allows plasma constituents, includ-
ing coagulation factors, to spill from vessels into perivascular tissue or adjacent
spaces, for example, the urinary space adjacent to glomerular capillaries (Fig. 1.1a)
and the air space adjacent to alveolar capillaries (Fig. 1.2a). In perivascular tis-
sue, the coagulation factors contact thrombogenic substances (e.g., tissue factor)
and form fibrin. The accumulation of fibrin at sites of vascular necrosis is called
fibrinoid necrosis (Fig. 1.1a, b). The infiltrating neutrophils and other leukocytes
undergo nuclear fragmentation (leukocytoclasia) as a result of cell death produc-
ing a pattern of injury called leukocytoclastic vasculitis, which is seen most often

J. C. Jennette (*)
Department of Pathology and Laboratory Medicine, School of Medicine,
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
e-mail: [email protected]
R. J. Falk
Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 3

R. A. Sinico, L. Guillevin (eds.), Anti-Neutrophil Cytoplasmic Antibody (ANCA)
Associated Vasculitis, Rare Diseases of the Immune System,
https://doi.org/10.1007/978-3-030-02239-6_1
4 J. C. Jennette and R. J. Falk

Table 1.1 Vasculitis names Large-vessel vasculitis (LVV)

adopted by the 2012  Takayasu arteritis (TAK)
International Chapel Hill
 Giant cell arteritis (GCA)
Consensus Conference on the
Nomenclature of Vasculitides Medium-vessel vasculitis (MVV)
(2012 CHCC) [1]  Polyarteritis nodosa (PAN)
 Kawasaki disease (KD)
Small-vessel vasculitis (SVV)
 Antineutrophil cytoplasmic antibody (ANCA)–associated
vasculitis (AAV)
   Microscopic polyangiitis (MPA)
   Granulomatosis with polyangiitis (Wegener’s) (GPA)
  Eosinophilic granulomatosis with polyangiitis
(Churg-Strauss) (EGPA)
 Immune complex SVV
  Anti-glomerular basement membrane (anti-GBM)
disease
   Cryoglobulinemic vasculitis (CV)
   IgA vasculitis (Henoch-­Schönlein) (IgAV)
  Hypocomplementemic urticarial vasculitis (HUV)
(anti-C1q vasculitis)
Variable vessel vasculitis (VVV)
 Behcet’s disease (BD)
 Cogan’s syndrome (CS)
Single-organ vasculitis (SOV)
 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 vasculitis
 Others

in inflamed venules and arterioles (Fig. 1.1c). At a given site of inflammation, the
acute necrotizing lesions evolve within several days or weeks into chronic inflam-
matory lesions with a predominance of lymphocytes and monocytes, followed by
progressive scarring. In patients with active disease, there is ongoing onset of new
self-limited acute lesions concurrent with the evolution of chronic lesions. This is
1 Introduction: Nomenclature and Classification 5

a b c

Fig. 1.1 Necrotizing small-vessel vasculitis in patients with AAV. (a) Glomerulus with necrotiz-
ing and crescentic glomerulonephritis with segmental fibrinoid necrosis (long arrow) and cellular
crescent formation (short arrow) (Masson trichrome stain). (b) Necrotizing arteritis with circum-
ferential fibrinoid necrosis (arrow) and associated infiltration by leukocytes (Masson trichrome
stain). (c) Leukocytoclastic angiitis in the renal medulla with transmural accumulation of leuko-
cytes, including neutrophils, and multiple nuclear fragments (arrows) indicative of leukocytoclasia
(hematoxylin and eosin stain)

a b c

Fig. 1.2 Pulmonary inflammation in patients with AAV. (a) Hemorrhagic capillaritis with alveolar
air spaces filled with blood (hematoxylin and eosin stain). (b) Necrotizing granulomatous inflam-
mation in a GPA patient with infiltrating neutrophils, lymphocytes, monocytes, and macrophages,
including multinucleated giant cells (arrows) (hematoxylin and eosin stain). (c) Inflammatory infil-
trate in an EGPA patient showing conspicuous eosinophils (arrows) (hematoxylin and eosin stain)

observed in renal biopsy specimens that have different glomeruli with necrotizing,
mixed necrotizing and sclerotic, or purely sclerotic lesions.
Because AAV can affect vessels in every organ and tissue of the body, the clini-
cal manifestations of disease are extremely variable. These are classified into one
of several clinicopathologic categories, including microscopic polyangiitis (MPA),
granulomatosis with polyangiitis (GPA) (formerly Wegener’s granulomatosis),
eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss
syndrome), and organ limited AAV (e.g., renal limited vasculitis, RLV) [1].
MPA has AAV with no granulomatous inflammation, whereas GPA and EGPA
have necrotizing granulomatous inflammation, which is most frequent in the respi-
ratory tract (Table 1.1) [1]. Only EGPA is associated with asthma and blood eosino-
philia [1]. Pathologically indistinguishable vasculitis and glomerulonephritis occurs
in MPA, GPA, and EGPA (Fig. 1.1).
6 J. C. Jennette and R. J. Falk

a b c

Fig. 1.3 Patterns of glomerular staining for IgG indicative of immune complex glomerulonephri-
tis (a), anti-GBM glomerulonephritis (b), and pauci-immune ANCA glomerulonephritis (c) (FITC
anti-IgG stain)

Lung lesions exemplify the diversity of AAV inflammatory lesions. MPA, GPA,
and EGPA all can have hemorrhagic capillaritis (Fig. 1.2a), which evolves to inter-
stitial fibrosis. GPA and EGPA can have pulmonary granulomatous inflammation
(Fig. 1.2b) that begins as neutrophil-rich necrotizing lesions. These lesions have
progressive replacement of neutrophils by lymphocytes, monocytes, and macro-
phages (including multinucleated giant cells), often surrounding a central zone of
necrosis. These lesions may form cavities and may become fibrotic with minimal
or no residual inflammation. Vasculitis and granulomatosis in EGPA typically have
numerous eosinophils and neutrophils in active inflammatory lesions (Fig. 1.2c).
AAV is characterized immunopathologically by few or no immune deposits of
immunoglobulin and complement in vessel walls, which distinguishes AAV from
immune complex-mediated vasculitis and anti-glomerular basement membrane
antibody (anti-GBM)-mediated vasculitis (Fig. 1.3) [1].
AAV also can be classified based on ANCA antigen specificity, for example,
ANCA specific for proteinase 3 (PR3-ANCA AAV) or myeloperoxidase (MPO-­
ANCA AAV) or with negative serology for ANCA (ANCA-negative AAV) [1, 4,
5]. ANCA-negative AAV has clinical and pathologic features identical to those in
ANCA-positive AAV. The most informative classification and diagnosis of AAV
include both the clinicopathologic phenotype and the serotype [1]. The correla-
tion of ANCA serotypes with clinicopathologic variants and clinical outcomes is
reviewed later in this chapter.

1.2 Historical Background

The investigation of two different manifestations of vasculitis, which eventually

intersected, led to the discovery of AAV (Fig. 1.4). These two manifestations are
skin purpura caused by inflammation in small vessel in the dermis and segmental
inflammation of arteries (arteritis).
Purpura (purple spots on the skin) is caused by segmental inflammation of
small vessels in the skin resulting in localized hemorrhage. Robert Willian, a
1 Introduction: Nomenclature and Classification 7

Purpura (2012) Necrotizing arteritis

Clinical and pathologic

Schönlein (1837) Kussmaul and Maier

Henoch (1868) (1866)
Periarteritis nodosa
descriptions

Wohlwill
(1923)
Klinger
(1931)
Wegener
Osler (1914) Microscopic (1939)
periarteritis Churg and Strauss
(1951)
Henoch- Godman and Churg Churg- Kawasaki
(1954)
Schönlein Strauss (1967)
purpura Wegener’s syndrome Kawasaki Polyarteritis
granulomatosis
disease nodosa

Cryoglobulins
Biomarker
discovery

Meltzer ANCA
IgA ANCA
(1966) van der Wouda ANCA
Faille-Kuyper Falk and Jennette Unknown Unknown
et al. Tervaert et al.
et al. (1973) (1989)
(1985) (1990)
CHCC
(1994)

Henoch- Churg-
Cryoglobulinemic Microscopic Wegener’s Kawasaki Polyarteritis
Schönlein Strauss
vasculitis polyangiitis granulomatosis disease nodosa
purpura syndrome

Eosinophilic
Cryoglobulinemic Microscopic Granulomatosis Kawasaki Polyarteritis
IgA vasculitis granulomatosis
CHCC
(2012)

vasculitis polyangiitis with polyangiitis disease nodosa

with polyangiitis

Immune complex SVV ANCA associated SVV

Fig. 1.4 Historical sequence of advances in the recognition and classification of vasculitides that
cause purpura and/or necrotizing arteritis. These two pathways of discovery intersect and overlap
with AAV (shaded area) because AAV causes both purpura and necrotizing arteritis

dermatologist, reported in 1808 that purpura could be associated with systemic

manifestation, such as pain in the extremities and in the abdomen, suggesting that
the pathologic process causing purpura in the skin was also causing injury in other
organs [6]. The pediatricians, Johann Schönlein and Eduard Henoch, collectively
reported the association of purpura with arthralgias, abdominal pain and bleeding,
and nephritis [7–9]. The children seen by Schönlein and Henoch most likely had
IgA vasculitis (Henoch-Schönlein purpura) rather than AAV, because IgA vasculitis
occurs most often in children and AAV occurs most often in adults. On the other
hand, the internist William Osler described adults with purpura that was associ-
ated with arthritis, peripheral neuropathy, abdominal pain, pulmonary hemorrhage,
epistaxis, iritis, and nephritis [10, 11]. Many of his patients had nephritis and some
had rapid progression of uremia, and at autopsy had glomeruli “compressed” by
“crescentic” masses of cells in Bowman’s space [11]. Undoubtedly, some of Osler’s
patients had AAV.
In 1919, the pathologist Ernest Goodpasture reported the results of an autopsy on
a patient who died of pulmonary hemorrhage and rapidly progressive glomerulone-
phritis [11]. He observed vasculitis affecting small arteries in the spleen, arterioles
in the gut, and capillaries in the pulmonary alveoli and glomeruli. Because of this
8 J. C. Jennette and R. J. Falk

report, his name became associated with pulmonary–renal syndrome caused by anti-
GBM, although the presence of arteritis in his patient is not consistent with anti-
GBM disease and indicates that the patient probably had AAV, most likely MPA.
At the same time, Schönlein and Henoch were investigating purpura caused
by small-vessel vasculitis, Adolf Kussmaul (an internist) and Rudolf Maier (a
pathologist) published the first detailed report of a patient with systemic necrotiz-
ing arteritis [12]. They coined the name periarteritis nodosa because of the grossly
visible focal nodular lesions along medium-sized arteries caused by inflammation
extending through vessel walls and into the perivascular tissue [12]. The preferred
diagnostic term later became polyarteritis nodosa because the inflammation is trans-
mural rather than perivascular [13]. For over 50 years, virtually any patient who
was found to have arteritis was lumped under a diagnosis of periarteritis nodosa or
polyarteritis nodosa.
In 1923, Friedrich Wohlwill described two patients with a “microscopic form” of
periarteritis nodosa [14]. His observations were confirmed and extended by Davson
[15, 16]. This recognition that arteritis can occur along with small-vessel vasculitis
began to link studies of arteritis [14–19] with studies of small-vessel vasculitis with
purpura, glomerulonephritis, and pulmonary capillaritis [6–11] (Fig. 1.4).
From the 1920s to the 1960s, multiple variants of vasculitis were identified that
had arteritis resembling polyarteritis nodosa, but also had distinctive features that
warranted specific diagnoses, including microscopic polyarteritis [14], Wegener’s
granulomatosis [17, 18], Churg-Strauss syndrome [19], and Kawasaki disease [20,
21]. The recognition of specific variants of arteritis resembling polyarteritis nodosa
is ongoing (e.g., the discovery of adenosine deaminase-2 deficiency vasculitis) [22].
In 1954, Gabriel Godman and Jacob Churg published a breakthrough article that
astutely concluded that “microscopic periarteritis,” Wegener’s granulomatosis, and
Churg-Strauss syndrome were related and were distinct from polyarteritis nodosa
[23]. They also suggested that these three variants are probably related pathogeneti-
cally. This was a harbinger of the discovery of ANCA, which confirmed the relat-
edness of ANCA-positive MPA, GPA, and EGPA, and their distinctiveness from
ANCA-negative polyarteritis nodosa [24].
Multiple biomarkers related to specific pathogenic mechanisms that cause vas-
culitis facilitated the classification and diagnosis of vasculitis based on laboratory
results, such as vessel wall IgA-dominant immune deposits in Henoch-Schönlein
purpura (IgA vasculitis) [25], cryoglobulins in the circulation in cryoglobulinemic
vasculitis [26], and circulating ANCA in what is now called MPA, GPA, and EGPA
(Fig. 1.4) [27–29] (Fig. 1.4). This set the stage for establishing consensus names and
definitions for systemic vasculitides, including AAV [1, 30].

1.3 Vasculitis Nomenclature and Classification

Nomenclature, classification, and diagnosis of vasculitis is difficult because of

the broad spectrum of types and locations of vessels affected, multiple patterns of
injury, diverse known etiologies and pathogenic mechanisms, absence of known
1 Introduction: Nomenclature and Classification 9

etiologies and pathogenic mechanisms in some forms of vasculitis, and the myriad
overlapping and nonspecific signs and symptoms caused by vasculitides.
A nomenclature system provides names and definitions for diseases. A classifi-
cation system organizes patients into well-defined groups (classes). Classification
allows selection of standardized patient groups (classes) to study disease character-
istics or perform clinical trials. A diagnostic system uses validated criteria to make
a clinically actionable diagnosis in an individual patient. As stated by Hasan Yazici,
“diagnosis is nothing different than classification in the individual patient” [31].
Classification criteria are observations or data used to place groups of patients
into standardized classes. Diagnostic criteria are observations or data used to confi-
dently predict the presence of the defining features of a disease in a specific patient.
Diagnostic criteria allow diagnosing (classifying) a single patient in a specific class.
If useful, names and definitions can remain the same indefinitely. Classification
criteria and diagnostic criteria evolve more quickly, driven in part by advances in
diagnostic technologies and development of new clinical laboratory tests that were
not available when earlier criteria were established.
The goals of nomenclature, classification, and diagnostic systems are to enable
effective communication among biomedical investigators and healthcare providers,
guide clinical and basic research on well-defined cohorts (classes) of patients, and,
most importantly, facilitate diagnosis and effective treatment of individual patients.
Nomenclature, classification, and diagnostic systems should be under constant scru-
tiny and adjusted as new knowledge emerges. Homer Smith, a nephrologist, warns
us that “Though we name the things we know, we do not necessarily know them
because we name them” [32].
Two overarching etiologic categories of vasculitis are infectious vasculitis
caused by proliferation of microorganisms in vessel walls and noninfectious vas-
culitis not caused by proliferation of microorganisms in vessel walls. The latter
nevertheless may be caused indirectly by an infection that initiates a sequence of
event that results in vascular inflammation, for example, hepatitis C virus infection
secondarily causing cryoglobulinemic vasculitis.
A widely used approach to classifying vasculitis uses three categories based on
the types of vessel that are involved, that is, large-vessel vasculitis, medium-vessel
vasculitis, and small-vessel vasculitis. This approach was adopted in 1994 at an
international consensus conference on the nomenclature of systemic vasculitides
[30] and revised in 2012 by at a second consensus conference [1]. These Chapel
Hill Consensus Conferences (1994 CHCC and 2012 CHCC) provide standard-
ized names and definitions for different classes of vasculitis (Tables 1.1 and 1.2)
(Fig. 1.5), but do not provide validated criteria for classifying cohorts of patients
into these classes, or for diagnosing (classifying) individual patients.
According to 2012 CHCC, large-vessel vasculitis (LVV) is vasculitis affecting
large arteries more often than other vasculitides [1]. Large arteries are the aorta
and its major branches. Any size artery may be affected. Medium-vessel vascu-
litis (MVV) is vasculitis predominantly affecting medium arteries defined as the
main visceral arteries and their branches [1]. Any size artery may be affected.
Inflammatory aneurysms and stenoses are common. Small-vessel vasculitis (SVV)
10 J. C. Jennette and R. J. Falk

Table 1.2 AAV and AAV variant definitions from the 2012 International Chapel Hill Consensus
Conference on the Nomenclature of Vasculitides (2012 CHCC) [1]
2012 CHCC name 2012 CHCC definition
ANCA-associated Necrotizing vasculitis, with few or no immune deposits, predominantly
vasculitis (AAV) affecting small vessels (i.e., capillaries, venules, arterioles, and small
arteries), associated with myeloperoxidase (MPO) ANCA or proteinase 3
(PR3) ANCA. Not all patients have ANCA. Add a prefix indicating ANCA
reactivity, e.g., MPO-ANCA, PR3-ANCA, ANCA-negative
Microscopic Necrotizing vasculitis, with few or no immune deposits, predominantly
polyangiitis (MPA) 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 involving the upper and
polyangiitis (GPA) lower respiratory tract, 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 inflammation often
granulomatosis with involving the respiratory tract, and necrotizing vasculitis predominantly
polyangiitis (EGPA) affecting small to medium vessels, and associated with asthma and
eosinophilia. ANCA is more frequent when glomerulonephritis is present

Immune complex small vessel vasculitis

IgA vasculitis
Cryoglobulinemic vasculitis
Hypocomplementemic urticarial vasculitis

Medium vessel vasculitis

Anti-GBM disease
Polyarteritis nodosa
Kawasaki disease

Capillary
Arteriole Venule
Artery Vein

Aorta Artery

ANCA-associated small vessel vasculitis

Microscopic polyangiitis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
Large vessel vasculitis
Takayasu arteritis
Giant cell arteritis

Fig. 1.5 Diagram depicting the predominant vessel involvement by large-vessel vasculitis,
medium-vessel vasculitis, and small-vessel vasculitis. Note that AAV is a form of SVV that has a
greater diversity of vessel involvement than SVV caused by immune complex disease or anti-GBM
disease. Also note that arteritis caused by AAV overlaps with arteritis caused by medium-vessel
vasculitis. Reproduced with permission from [1]