Primer: ANCA-associated Vasculitis

PRIMER
ANCA-associated vasculitis
A. Richard Kitching1,2 ✉, Hans-Joachim Anders3, Neil Basu4, Elisabeth Brouwer5,
Jennifer Gordon6, David R. Jayne7, Joyce Kullman8, Paul A. Lyons7,9, Peter A. Merkel10,
Caroline O. S. Savage11, Ulrich Specks12 and Renate Kain13
Abstract | The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a
group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the
development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA)
or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with
polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according
to clinical features. However, genetic and other clinical findings suggest that these clinical
syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV
(MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA–, respectively).
Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys
are most commonly and severely affected. AAVs have a complex and unique pathogenesis,
with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated
neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy,
prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit
with considerable morbidity from glucocorticoids and other immunosuppressive medications.
Current challenges include improving the measures of disease activity and risk of relapse,
uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse
effects. Meeting these challenges requires a more detailed knowledge of the fundamental
biology of AAV as well as cooperative international research and clinical trials with meaningful
input from patients.
The anti-neutrophil cytoplasmic antibody (ANCA)- life-threatening disease, although less severe presenta-
associated vasculitides (AAVs) are diseases character- tions also occur. GPA is predominantly associated with
ized by inflammation of blood vessels, endothelial injury PR3-ANCA and its clinical features typically include
and tissue damage. The three types of small-vessel vas- sinonasal disease, lower respiratory tract involvement
culitis, namely granulomatosis with polyangiitis (GPA), with pulmonary haemorrhage and granulomatous
microscopic polyangiitis (MPA) and eosinophilic GPA inflammation, and glomerulonephritis. MPA is usu-
(EGPA; previously known as Churg–Strauss syndrome), ally associated with MPO-ANCA and clinical features
feature a loss of tolerance to neutrophil primary granule include more severe renal disease and some of the mani-
proteins, most often leukocyte proteinase 3 (PR3; also festations of GPA but without granulomatous inflamma-
known as myeloblastin) or myeloperoxidase (MPO) tion. EGPA is characterized by asthma, eosinophilia and,
(Table 1). The vessels involved in AAV are typically capil- in many (but not all) cases, vasculitis. EGPA is less com-
laries, arterioles and venules but small arteries and veins mon than GPA or MPA and, in some cases, is associated
may also be affected. Autoimmunity is documented clin- with ANCAs, mainly MPO-ANCA (Table 1). Although
ically by serum ANCAs to PR3 (PR3-ANCA) or MPO categorized as a form of AAV, EGPA has less overlap
(MPO-ANCA), which are generally associated with the with the other AAVs than that between GPA and MPA with
main syndromic AAV presentations (Box 1). AAVs col- regard to its genetic, pathogenetic, and clinical features
lectively represent one of several types of autoimmune and its management and is typically considered a separate
vasculitis (Fig. 1). entity.
✉e-mail: richard.kitching@ GPA and MPA can involve small blood vessels in any Improvements in treatment and prognosis for
monash.edu organ or tissue but commonly affect the upper and lower patients with AAV have resulted from the translation
https://doi.org/10.1038/ respiratory tract and the kidneys (Box 2). Patients with of both preclinical and clinical research findings. Here,
s41572-020-0204-y AAV typically present with severe organ-threatening or we provide an updated overview of the clinical and

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2020) 6:71 1
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Author addresses clinical immunologists and other physicians regularly

encounter patients with AAV. In fact, more recent studies
1
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash report prevalence rates of 300–421 per million persons2,3,
Medical Centre, Clayton, Victoria, Australia. an increase likely explained by improving survival and
2
Departments of Nephrology and Paediatric Nephrology, Monash Health, Clayton, better case definition.
Victoria, Australia.
The global effects of AAVs in terms of premature
3
Renal Division, Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians
University, Munich, Germany. mortality4, quality of life (QOL)5 and societal economic
4
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK. costs6 are considerable. Since the introduction of com-
5
Vasculitis Expertise Centre Groningen, Department of Rheumatology and Clinical mercially available ANCA assays in the mid-1990s and
Immunology, University of Groningen, University Medical Centre Groningen, Groningen, enhanced physician awareness, there has been a notice-
Netherlands. able apparent increase in AAV incidence. For example,
6
Department of Neuroscience and Center for Neurovirology, Temple University School of the incidence rate of GPA between 1975 and 2001 in
Medicine, Philadelphia, PA, USA. Sweden increased from 3.3 to 11.9 cases per million
7
Department of Medicine, University of Cambridge School of Clinical Medicine, persons per year7. The plateauing of incidence rates
University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. since then indicates that the true incidence has prob-
8
Vasculitis Foundation, Kansas City, MO, USA.
ably remained stable, although the lack of standardized
9
Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah
Biomedical Centre, University of Cambridge, Cambridge, UK. diagnostic criteria may affect case ascertainment.
10
Division of Rheumatology, Department of Medicine and Division of Clinical Wide geographical variation exists in AAV incidence
Epidemiology, Department of Biostatistics, Epidemiology, and Informatics, University of (Fig. 2), which is partly explained by methodological
Pennsylvania, Philadelphia, PA, USA. differences in study design, although specific patterns
11
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. can be observed. First, GPA (PR3-AAV) mainly affects
12
Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and countries/regions in which the population is predom-
Science, Rochester, MN, USA. inantly of European ancestry and is seldom observed
13
Department of Pathology, Medical University Vienna, Vienna, Austria. in East Asian countries/regions. By contrast, MPA
(MPO-AAV) predominates in Asian countries/regions,
molecular features of AAVs, present current patho- such as China and Japan8,9. Second, the incidence of
physiological concepts, discuss established and GPA is influenced by latitude, as the incidence is lower
upcoming therapeutic options, emphasize the value of towards the equator10,11. The disparity in incidence
patient-oriented outcomes, and provide a perspective on among ethnicities is further supported by studies exam-
future challenges in AAV research and treatment. ining multi-ethnic populations. Surveys in France and
the USA indicate at least twofold higher incidence
Epidemiology of GPA and MPA in white populations than in other
Incidence and prevalence ethnicities12,13. A more recent UK study identified a
Although fulfilling most definitions of a ‘rare disease’, similar signal but this was mostly explained by the
with a historical estimated prevalence of 48–184 cases older age of the white population14. EGPA is strongly
per million persons1, rheumatologists, nephrologists, linked to asthma and eosinophilia in terms of both its
Table 1 | Comparison of the three syndromic presentations of AAV

Feature GPA MPA Eosinophilic GPA
Incidence 0.4–11.9 cases per 1 million 0.5–24.0 cases per 1 million person-years 0.5–2.3 cases per 1 million person-years
person-years
Prevalence 2.3–146.0 cases per 1 million persons 9.0–94.0 cases per 1 million persons 2.0–22.3 cases per 1 million persons
Typical age of onset 45–65 55–75 38–54
(years)
Male: female ratio1:1 1:1 1:1
2012 revised CHCC Necrotizing granulomatous Necrotizing vasculitis, with few or no Eosinophil-rich and necrotizing
definition145 inflammation, usually involving the immune deposits, predominantly affecting granulomatous inflammation, often
upper and lower respiratory tract; small vessels (such as capillaries, venules or involving the respiratory tract;
necrotizing vasculitis affecting arterioles); necrotizing arteritis involving necrotizing vasculitis predominantly
predominantly small-to-medium small and medium arteries may be present; affecting small-to-medium vessels;
vessels (such as capillaries, venules, necrotizing glomerulonephritis is very associated with asthma and
arterioles, arteries and veins); common; pulmonary capillaritis often occurs; eosinophilia; ANCA+ is more frequent
necrotizing glomerulonephritis is granulomatous inflammation is absent when glomerulonephritis is present
common
Frequency of ANCA PR3-ANCA+: 65–75% PR3-ANCA+: 20–30% PR3-ANCA+: <5%
+ +
MPO-ANCA : 20–30% MPO-ANCA : 55–65% MPO-ANCA+: 30–40%
ANCA–: 5% ANCA–: 5–10% ANCA–: 55–65%
Key innate immune Neutrophil Neutrophil Eosinophil
cell
Relapse rate Higher than MPA (or MPO-AAV) Lower than GPA (or PR3-AAV) Relapse is frequent
AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; CHCC, Chapel Hill Consensus Conference; GPA, granulomatosis with polyangiitis;
MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, leukocyte proteinase 3.
2 | Article citation ID: (2020) 6:71 www.nature.com/nrdp
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Box 1 | Diagnostic testing methods in AAVs

key role in AAV aetiology. Some epidemiological studies
report a cyclical occurrence of GPA, which is consist-
Most cases of granulomatosis with polyangiitis and microscopic polyangiitis are ent with an infectious trigger. Although the majority of
characterized by anti-neutrophil cytoplasmic antibodies (ANCAs) directed to either studies describe an increase in the incidence of GPA in
leukocyte proteinase 3 (PR3) or myeloperoxidase (MPO). In clinical practice, these winter16–19, a higher summer incidence and no seasonal
antibodies are detected using indirect immunofluorescence (IIF) and various
change have also been reported20,21. Indeed, increased
antigen-specific immunoassays, most commonly enzyme-linked immunosorbent
assays (ELISAs) for either PR3-ANCA or MPO-ANCA. Improvements in antigen- rates of chronic Staphylococcus aureus nasal carriage
capture methods have resulted in better assay performance. In addition, several other observed among patients with GPA have been associated
types of solid-phase antigen-specific assay may be used to detect PR3-ANCA and with an increased relapse risk22,23.
MPO-ANCA162. More granular epidemiological inspections of puta-
IIF involves incubating diluted patient serum samples with ethanol-fixed, permeabilized tive environmental causes are limited to small explor-
neutrophils (sometimes pre-attached to glass slides) from healthy donors. Bound ANCAs atory studies. An association between silica exposure
are detected using a fluorescent secondary anti-human IgG antibody and the presence, and MPO-AAV has been consistently observed24,25. The
titre, and pattern of fluorescence are assessed by fluorescence microscopy. The two high prevalence of silica in the natural environment
patterns of fluorescence that are relevant to ANCA-associated vasculitis (AAV) diagnosis (for example, in cement) is one proposed explanation
are a cytoplasmic pattern of ANCA staining that is strongly associated with PR3-ANCA
for the apparent upsurge in AAV incidence follow-
and a perinuclear pattern (pANCA) that, in AAV, is strongly associated with MPO-
ANCA. The pANCA pattern is a consequence of ethanol fixation, as the highly cationic ing major earthquakes in 1995 and 2011 in Japan26,27.
MPO localizes around the negatively charged neutrophil nucleus after ethanol fixation. However, this correlation was not replicated in the
Approaches to ANCA testing when AAV is suspected are informed by consensus aftermath of the 2011 earthquake in Christchurch, New
statements, although substantial variation exists in practice267. With improved Zealand28, a discordance that highlights the potential
immunoassay performance, the approach recommended by an international consensus importance of AAV gene–environment interactions.
statement162 after a large multicentre study268 is to use antigen-specific assays for Anecdotally, clinicians commonly observe a disparity
PR3-ANCA and MPO-ANCA as the initial screening method when AAV is suspected, in prevalence between urban and rural areas, although
with IIF only performed if these assays are negative. Approaches based on guidelines the epidemiological data to support this disparity are
published in 1999 (ref.269), which are still used in some diagnostic laboratories, involve a mixed29. For example, in a rural region of the United
combination of IIF screening with specific PR3-ANCA and MPO-ANCA ELISAs for
Kingdom, farming has been identified as a risk factor
positive samples, or using both methods for each sample.
Although ANCAs are primarily associated with AAVs, a positive ANCA test by IIF for both GPA and MPA24, indirectly implicating pesti-
occurs in other diseases, including infections such as tuberculosis and Pseudomonas cide and fertilizer exposure as potential pathogenetic
aeruginosa infection in individuals with cystic fibrosis270,271. PR3-ANCA or MPO-ANCA factors. By contrast, pollution, specifically carbon mon-
can occur in infective endocarditis272–274, an important differential diagnosis as oxide levels, has been associated with increased AAV
unwarranted immunosuppression in infective endocarditis has life-threatening risk in population-dense regions of China30. Other pos-
consequences. An atypical ANCA pattern, resembling (but differing from) pANCA, can tulated risk factors include ultraviolet light31, smoking32,
occur in gastrointestinal tract diseases270, including ulcerative colitis, and some liver solvents24 and occupational solvent exposure24, but no
diseases. ANCAs can also occur in other autoimmune diseases, such as systemic lupus single environmental factor seems to confer a major
erythematosus and rheumatoid arthritis (notwithstanding the coexistence of AAV or population-attributable risk. Similarly, specific drugs are
AAV-like features in a minority of people with these diseases). Drug-associated AAV is
responsible for some cases of vasculitis with syndromes
associated not only with MPO-ANCA but also with anti-lactoferrin and anti-neutrophil
elastase antibodies. similar to AAV (Box 3).
Other proteins associated with a positive IIF ANCA test include azurocidin, bactericidal/ Ultimately, many epidemiological studies have
permeability-increasing protein and cathepsin G. Their clinical utility is unproven and treated AAV as a single disease construct and lack the
antigen-specific testing is not routinely performed in AAV. power to examine the possibility that distinct environ-
mental associations exist across the pathogenetically
distinct AAV subtypes.
clinical features and genetic make-up, although epide-
miological data for EGPA are limited, as are data from Mechanisms/pathophysiology
Africa and South Asia for all types of AAV. It is unclear AAVs are characterized by microvascular endothelial
whether a lack of access to ANCA testing in low-income inflammation leading to extravascular inflammation,
and middle-income countries/regions is resulting in progressive injury, tissue destruction, fibrosis and
a shortage of data as well as in under-diagnosis and loss of function. GPA and MPA develop by the loss of
under-treatment of AAV in these areas. immunological T cell and B cell tolerance to one of two
AAV in children is rare and less common than some neutrophil proteins, PR3 or MPO. Mechanisms of acute
other forms of vasculitis (including Kawasaki disease injury in GPA and MPA are unique to this group of dis-
and IgA vasculitis). GPA seems to be more common orders (see Fig. 3 for an overview). Specifically, loss of
than MPA or EGPA and, unlike in adults, AAV in tolerance leads to the development of ANCAs, auto
children is likely to be more common in females15. antibodies that activate neutrophils. ANCA-activated
neutrophils localize to vulnerable microvascular beds,
Risk factors and disease determinants where they induce injury and release the autoantigen
Compelling evidence exists to implicate genetic factors for presentation by antigen-presenting cells (such as
in the pathogenesis of AAV, although genetic predis- dendritic cells), allowing antigen recognition by effec-
position alone does not explain this complex disorder. tor T cells, which mediate further injury. The key ele-
As the age of onset typically ranges between middle to ments of loss of tolerance, the generation of effector
older age and there is an equal sex distribution in AAV responses and mechanisms of microvascular injury are
prevalence, it is likely that environmental factors have a summarized in Fig. 4 and Fig. 5.

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a b
Medium vessel vasculitis Immune complex small vessel vasculitis cANCA
• Polyarteritis nodosa • Cryoglobulinaemic vasculitis
• Kawasaki disease • IgA vasculitis (Henoch–Schönlein purpura)
• Hypocomplementemic urticarial
vasculitis (Anti-C1q vasculitis)
Anti-GBM disease
10 μm
pANCA
ANCA-associated small vessel vasculitis

Large vessel vasculitis • Microscopic polyangiitis
• Takayasu arteritis • Granulomatosis with polyangiitis
• Giant cell arteritis • Eosinophilic granulomatosis with polyangiitis 10 μm
Fig. 1 | Small vessel vasculitis. a | The updated 2012 Chapel Hill Consensus Conference classification of vasculitis145, which
is based on the size of the main vessels that are affected. The anti-neutrophil cytoplasmic antibody (ANCA)-associated
vasculitides, namely granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with
polyangiitis, are small vessel vasculitides. b | Patterns of ANCA staining by indirect immunofluorescence. A cytoplasmic
pattern of staining for ANCA (cANCA) is strongly associated with antibodies to leukocyte proteinase 3. A perinuclear pattern
of staining for ANCA (pANCA) is seen with antibodies to several different proteins but anti-myeloperoxidase antibodies are
most relevant for ANCA-associated vasculitides. GBM, glomerular basement membrane. Part a adapted with permission
from ref.145, Wiley.
The pathogenesis of AAVs has been explored in that the strongest associations were not with the clin-
in vitro assays and in vivo in animal models and human ical syndromes per se but with ANCA specificity. The
studies. In animal studies, MPO-AAV is characterized Vasculitis Clinical Research Consortium37,38 confirmed
by anti-MPO autoreactivity affecting the kidneys33. these associations and provided the first evidence for
Although glomerular and pulmonary vessels are par- genetic variants, for example, in PTPN22, which are
ticularly vulnerable, there is little evidence to indicate common to both PR3-AAV and MPO-AAV, suggesting
why some vascular beds are preferentially involved. that there is also a shared genetic component to these
Furthermore, the mechanisms underpinning the fre- diseases. How much of the clinical similarity between
quent occurrence of granulomatous inflammation in the two syndromes is driven by this shared genetic
PR3-AAV and its near absence in MPO-AAV are unde- architecture, rather than by antigenic similarity, awaits
fined. The response to injury, including the extent of the outcome of larger GWAS that are better powered
tissue destruction and/or fibrosis, is likely to be contin- to assess associations with PR3-AAV and MPO-AAV
gent on the characteristics of the affected tissue and the separately.
intensity and chronicity of local vasculitic inflammation. Although the causal variant or variants at each locus
remain unresolved, these genetic studies shed light on
Genetics the underlying disease pathogenesis. Some variants are
GPA and MPA. Evidence for a genetic contribution to the in genes (such as PTPN22) that are associated with other
aetiology of AAVs has come largely from registry studies, autoimmune diseases39 and larger studies are likely to
which revealed that the familial relative risk (RR 1.56) is identify further commonalities. Other variants are more
similar to that for rheumatoid arthritis (RR 1.5–5.0) but specific to AAV. Genetic variants in SERPINA1 (encod-
lower than that for other immune-mediated diseases34. ing α1-antitrypsin) or PRTN3 (encoding PR3) lead
Identifying robust genetic associations with AAV is to increased plasma levels of PR3, suggesting that the
challenging owing to its fairly low prevalence, although altered availability of circulating PR3 is a key driver in
candidate gene studies that utilized cohorts combining loss of tolerance to PR3 and the subsequent development
patients with GPA and those with MPA, and occasionally of PR3-AAV40. The association of HLA-DPB1*04:01 with
those with EGPA, found associations with the major his- PR3-AAV may simply reflect the role of HLA (MHC)
tocompatibility complex (MHC) genes, in particular the molecules in presenting PR3 peptides to the immune
HLA-DPB1*04:01 allele in PR3-AAV35. The European system. However, this HLA-DP molecule also binds
Vasculitis Genetics Consortium reported the first to the natural killer (NK) cell receptor NKp44 (also
genome-wide association study (GWAS) in AAV36, known as NCR2), leading to NK cell activation41, which
which identified both MHC and non-MHC associations might represent an alternative or additional mechanism
with disease and demonstrated that GPA and MPA are that underpins the relationship between HLA-DP and
genetically distinct. Furthermore, sub-analyses revealed PR3-AAV.
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Box 2 | Clinical features of the AAVs

sequence from some S. aureus strains by molecular
mimicry in MPO-AAV46.
Granulomatosis with polyangiitis (GPA)
Symptoms of systemic vasculitis, such as fever, weight loss, malaise and fatigue, are ANCA antigens
often present. Symptoms and signs of small vessel vasculitis are evident, often in the ear,
As autoreactivity to either MPO or PR3 is central to patho-
nose and throat (ENT) tract (nasal and oral ulcers and crusting, nose bleeds, nasal polyps,
genesis in most cases of AAV, the characteristics of the
paranasal sinusitis, cartilaginous destructions with granulomas on biopsy, hearing
impairment and otorrhea), the eyes (conjunctival injection, eye pain, diplopia, proptosis,key autoantigens are important. Most patients with AAV
uveitis and retroorbital mass), the airways and lungs (hoarseness, cough, dyspnoea, react to a single dominant autoantigen. PR3 and MPO
stridor, pleuritic pain, pulmonary nodules, infiltrates, cavities and haemorrhage with are found primarily in neutrophils and are also produced
granulomatous inflammation on biopsy), the kidneys (urinary abnormalities, elevated by monocytes and macrophages. Although PR3 and
serum creatinine with variable degrees of proteinuria and rapidly progressing pauci- MPO are mainly synthesized by immature neutrophils,
immune glomerulonephritis on biopsy), the peripheral nervous system (mononeuritis), altered DNA methylation and an increased expression of
and the skin (purpura, focal necrosis, ulcers and leukocytoclastic vasculitis on biopsy). PRTN3 and MPO in mature neutrophils are implicated
Microscopic polyangiitis (MPA) in disease pathogenesis47. PR3 and MPO are not only key
Symptoms of systemic vasculitis, such as fever, weight loss, malaise and fatigue, are AAV autoantigens but they also have damaging effects on
often present. Symptoms and signs of small vessel vasculitis are as for GPA but without the endothelium in microvascular inflammation; they are
granulomatous inflammation on biopsy. ENT tract manifestations are as in GPA but less released by multiple mechanisms, including by degran-
frequent. The kidneys (rapidly progressing necrotizing pauci-immune glomerulonephritis) ulation and microparticle release and as constituents
and the skin (necrotizing leukocytoclastic vasculitis) are commonly affected. of NETs48.
Eosinophilic GPA (EGPA) PR3 is a 29 kDa serine protease with a pro-form and
Many but not all individuals with EGPA have clear features of vasculitis. Symptoms of a mature form49, which are located within azurophilic
systemic vasculitis include fever, weight loss, malaise, fatigue and lymphadenopathy. granules. The variable expression of PR3 on the surface
Small vessel vasculitis of skin, peripheral nervous system, kidneys, heart and of neutrophils is in part dependent on its co-expression
gastrointestinal tract occurs. Cardiac involvement, including cardiomyopathy,
with CD177, which binds to and colocalizes with the β2
contributes considerably to mortality in EGPA. Asthma is a near universal feature of
EGPA and usually precedes vasculitis. Pulmonary infiltrates and >10% eosinophilia in integrin CD11b as part of the CD11b–CD18 complex50,51.
peripheral blood are common. ENT involvement is frequent, including serous otitis Cell surface PR3 expression is increased in apoptotic
media, allergic rhinitis, nasal obstruction, recurrent sinusitis and nasal polyposis. neutrophils, which limits their phagocytic clearance
by macrophages and promotes a pro-inflammatory
AAVs, anti-neutrophil cytoplasmic antibody-associated vasculitides.
microenvironment49. MPO is abundant in human neutro
phils as a major component of azurophilic granules.
EGPA. One GWAS examining EGPA identified 11 loci Mature MPO is a highly cationic homodimeric glyco
associated with EGPA42 and demonstrated that EGPA protein consisting of light and heavy chains, bound
comprises two genetically distinct subtypes, MPO- to a haem group. The heavy chain is extensively but
ANCA+ EGPA and ANCA– EGPA, which align with the variably glycosylated52,53. Pro-inflammatory stimuli
clinical differences between these patient subsets43,44. increase cell surface MPO levels and MPO is released
Some of the identified loci are associated with eosino- in inflammatory states, where it catalyses the formation
phil count in addition to EGPA and Mendelian random of reactive intermediates, including hypohalous acids.
ization revealed that an increased risk of eosinophilia Although the AAVs are typically considered systemic
underlies susceptibility to EGPA, with additional genetic autoimmune diseases, each with dominant autoreac-
or environmental factors required for the development tivity to only a single autoantigen, other autoantigens
of disease. have been associated with AAV. These autoantigens
include lysosome-a ssociated membrane protein 2
Environmental factors and infections (LAMP2)54, complementary PR3 (cPR3) peptides55,56,
The increasing incidence of AAV in the sixth and moesin57, plasminogen58,59, peroxidasin60 and pentraxin 3
later decades of life implies a role for ageing-related (ref.61). Infection has been implicated in loss of toler-
factors and various accumulating environmental fac- ance to some of these antigens. In rats, an epitope in
tors (discussed above), although these factors remain LAMP2, an endolysosomal protein found in myeloid
ill-defined. Whereas some observational studies impli- cells and endothelial cells, is identical to part of the bac-
cate infectious triggers in AAV pathogenesis, the precise terial adhesin FimH and induces AAV54. Reactivity to
infectious agents remain unclear. Mechanistic in vitro cPR3 peptides, which are derived from the non-coding
and in vivo animal model studies suggest several ways strand of PRTN3 cDNA and are potentially produced
in which infection might promote loss of tolerance or after infection55, may trigger anti-PR3 autoreactivity.
disease relapse in AAV, including autoantigen expo- Although several studies support a role for LAMP2
sure by the formation of neutrophil extracellular traps in MPA or GPA or for cPR3 in the pathogenesis of
(NETs) that may be resistant to degradation in AAV45, PR3-AAV, not all reports implicate these alternative
by molecular mimicry (that is, microbial antigens shar- antigens in disease62,63.
ing sequence similarity with a host protein) and by the
priming of neutrophils for ANCA-induced activation33 Loss of tolerance to ANCA antigens
(Fig. 4). Some attention has focused on S. aureus, with Central and peripheral mechanisms of tolerance.
reports of increased rates of nasal carriage in relapsing Central and peripheral mechanisms prevent damag-
patients with GPA22 and experimental data implicating ing autoreactivity and autoimmune diseases by main-
a plasmid-encoded 6-phosphogluconate dehydrogenase taining tolerance to self-antigens. In most autoimmune

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Norwich, 5.9 Lund,

11.3 10.1 9.8
UK Sweden
Schleswig-Holstein, 2.6
Germany 8.9
3.0 2.1 Vilnius, 1.1
Lithuania Edirne,
Saskatchewan, 7.1 4.6
Canada 3.3 Turkey
1.25
Western 2.1
Montana,
USA 9.1 Miyazaki
Prefecture,
18.2 Japan
Minnesota, 16.0 13.0

USA Australian
5.0 Capital Territory
8.4
0.5 and south-eastern
NSW, Australia
Lima, 2.3
Peru 4.0 Bethlehem,
West Bank
Lugo, 3.0
4.1
Spain 7.9
Incidence
(per million population) Crete,
GPA 10.2 6.6
Malaga, 2.1 Greece
MPA Spain 3.4
Fig. 2 | Global epidemiology of ANCA-associated vasculitides. The map depicts studies that have examined the
incidence of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) per 1 million individuals per year.
There is substantial variation in the relative incidences of GPA and MPA between Europe and Asia as well as an effect of
latitude. The regions studied include Australia254, Canada255, Germany256, Greece257, Japan258, Lithuania259, Turkey260, Peru261,
Spain (Lugo262 and Malaga263), Sweden264, the United Kingdom18, the USA (Minnesota2 and Western Montana265), and the
West Bank266. ANCA, anti-neutrophil cytoplasmic antibody; NSW, New South Wales.
diseases, loss of T cell tolerance allows the emergence These abnormal Treg cells have an effector IL-17-
of T helper (TH) cells that are crucial for autoantibody producing T helper (TH17)-like phenotype, and at least
production by cells of the B cell lineage and which also some are antigen specific68,71. To better understand loss
promote tissue injury themselves. Loss of B cell tolerance of tolerance and to move towards harnessing tolerogenic
allows the emergence of autoreactive B cells and plasma therapeutic platforms and developing more precise diag-
cells that produce damaging autoantibodies. Memory nostic tools and biomarkers, immunodominant T cell
T and B cells that develop over time are important in and B cell epitopes have been defined for MPO; however,
chronicity and relapse, as occurs in AAV (Fig. 4). Loss immunodominant epitopes have not yet been defined for
of tolerance to neutrophil proteins occurs before the PR3 (refs71–74). Conformational and linear B cell epitopes
onset of AAV symptoms64. Our understanding of this exist for both MPO-ANCA and PR3-ANCA75–77. An
process is imprecise; whereas dysregulated neutro MHC-promiscuous CD4+ T cell MPO epitope overlaps
phil apoptosis might predispose to loss of tolerance, with a linear B cell epitope and a CD8+ T cell epitope71–74
there is no clear evidence that this is essential. Defects in and is nephritogenic in mice. Knowledge of these
both central and peripheral tolerance are present in AAV. epitopes enables translational strategies to improve
Central tolerance to antigens in AAV is imperfect, as disease monitoring and re-establish tolerance.
autoantigen-specific T cells and ‘natural’ autoantibodies
are present in healthy individuals65. In the thymus, which Maintenance of autoreactive B cells. After the loss of
is crucial for T cell tolerance, MPO expression is under tolerance, the survival of autoreactive lymphocytes pro-
the control of the autoimmune regulator (AIRE) and motes ongoing and chronic disease (Fig. 4). In the case
Aire–/– mice exhibit increased autoimmunity to MPO66. of AAV, the B cell survival factor B cell-activating factor
However, AIRE-deficient individuals do not seem to (BAFF; also known as TNFSF13B or BLyS) is produced
develop AAV, consistent with the existence of multiple by ANCA-stimulated neutrophils and serum BAFF lev-
layers of tolerance to MPO. Animal studies support a els are elevated in patients with AAV78,79, suggesting that
role for regulatory T (Treg) cells in limiting autoimmune interactions between BAFF and its receptors on auto
disease66. Furthermore, patients with AAV have func- reactive B cells and plasmablasts promote autoimmunity.
tionally defective Treg cells and fewer regulatory B cells After therapeutic B cell depletion, BAFF may promote
than healthy individuals. Their Treg cells have a dimin- relapse by stimulating the recovery of autoreactive
ished capacity to suppress effector responses ex vivo67–70. B cells. B cells and B cell aggregates are present in more
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Box 3 | Drug-induced vasculitis

a neonate with pulmonary haemorrhage and micro-
scopic haematuria supports a role for ANCAs in AAV
Various drugs are associated with anti-neutrophil cytoplasmic antibody (ANCA)+ pathogenesis93. The in vivo pathogenicity of ANCA-
vasculitis, with at least some features of ANCA-associated vasculitis (AAV). activated neutrophils has been convincingly demon-
Propylthiouracil (PTU) and, to a lesser extent, some other antithyroid drugs are fairly strated in experimental MPO-AAV92,94 and evidence
commonly associated with myeloperoxidase (MPO)-ANCA, with some people
also exists for their pathogenetic role in PR3-AAV95,96.
developing a microscopic polyangiitis-like vasculitis275. Other drugs, including
hydralazine (an anti-hypertensive vasodilator), minocycline (a tetracycline antibiotic) ANCAs also activate monocytes ex vivo, as monocytes
and cocaine adulterated with the anti-helminthic agent levamisole, are associated with express PR3 and MPO, albeit at lower levels than neutro
ANCA+ vasculitis276. Leukotriene antagonists have been implicated in eosinophilic phils. Compared with studies in neutrophils, the patho-
granulomatosis with polyangiitis, although causality is unclear277. The therapeutic genetic implications of any direct effects of ANCAs on
agents associated with ANCA+ vasculitis have been listed in detail elsewhere275. monocytes is less certain97,98. Whether the 5–10% of
The epidemiology of drug-induced vasculitis largely reflects the patterns of use of patients with GPA or MPA who are ANCA– have a rele-
these drugs in different populations (for example, PTU is widely used in China, whereas vant autoantibody is unresolved. Patients may be MPO-
cocaine–levamisole is more common in the USA). ANCA+ but their ANCAs may bind to an epitope that
Clinically, a perinuclear-type ANCA pattern is most common, but concurrent is masked in conventional assays73 or to other antigens,
perinuclear-type ANCA and cytoplasmic-type ANCA positivity is common in cocaine–
including LAMP2 (ref.99) or pentraxin 3 (ref.61). Some
levamisole-induced vasculitis. Autoantibody specificities include MPO-ANCA and
other, non-classical ANCA antigens275,276 (Box 1). Patients are often younger. Clinical epitopes recognised by ANCAs are pathogenic and
manifestations can mimic AAV but are often less severe. Skin involvement may be more others are not, while other factors, including ANCA
prominent, variant in nature and severe, particularly with cocaine–levamisole, and sialylation and glycosylation, may contribute to the
neutropenia can be present in vasculitis secondary to PTU or cocaine–levamisole. inconsistent relationship between ANCA seropositivity
Anti-nuclear antibodies may be present, and hydralazine and minocycline are both and disease activity73,100,101.
associated with a lupus-like phenotype.
The mechanisms that underpin drug-induced vasculitis are unclear, although some Neutrophil priming and activation state. Although
clues exist. Levamisole and minocycline have immunomodulatory effects. PTU inhibits ANCAs may activate neutrophils without additional
thyroid peroxidase, which shares sequence homology with MPO, and alters the inflammatory signals, neutrophil priming by exogenous
structure and function of MPO in rats275,278. Furthermore, PTU induces abnormal
or endogenous pro-inflammatory signals promotes the
neutrophil extracellular trap formation in vitro and MPO-AAV in vivo in rats279.
These data, along with cocaine–levamisole’s effects on neutrophil extracellular trap damaging effects of these cells after ANCA-induced
formation280, support aberrant autoantigen exposure in the development of activation (Figs 3,4). In addition to the functional conse-
drug-induced AAV. quences of genetic variation in PRTN3 and its inhibitor
Recognition of drug-induced vasculitis using an appropriate index of clinical SERPINA1 (ref.40) and epigenetically mediated increases
suspicion, obtaining a medication history and enquiring as to illicit drug use, potentiallyin PR3 and MPO expression47,102, neutrophils from
with urinary screening, is central to the management of these conditions. Ceasing the patients with AAV, even from those in remission, produce
potential offending agent often results in improvement. However, immunosuppression more intracellular reactive oxygen species, display greater
may be required and severe, organ-threatening disease can occur. Re-challenge with NET release and have a greater capacity to active the
the suspected drug for diagnostic reasons is not recommended. alternative pathway of complement (see below)103,104.
The relative contribution of neutrophil intrinsic prop-
chronic lesions, implying additional roles for antigen- erties versus their response to priming events is unclear
specific B cells beyond antibody production, either as but both are likely to be relevant. Neutrophil prim-
pro-inflammatory cells or as antigen-presenting cells80,81. ing in AAV occurs by several mechanisms, of which
the most well defined are the complement system
The role of ANCA and neutrophils (see below), Toll-like receptor (TLR) signalling and
ANCAs activate neutrophils and monocytes. A critical cytokines (including tumour necrosis factor (TNF)
consequence of loss of T cell and B cell tolerance is the and IL-18)33. TLRs are expressed on several relevant cell
production of ANCAs that bind to and activate neutro- types, including neutrophils, monocytes and micro-
phils, so that they adhere onto vulnerable microvascular vascular endothelial cells. Engagement of TLRs by
beds and induce injury (Figs 3,5). ANCAs are usually of pathogen-associated molecular patterns or in sterile
the IgG isotype, but IgA and IgM isotypes have also been inflammation by damage-associated molecular patterns
reported82,83. ANCAs bind to their autoantigen, activate activates neutrophils and the endothelium105–108.
neutrophils and initiate injury84. In vitro studies support
a model whereby both ANCA F(ab')2 fragment–antigen Complement activation via the alternative pathway.
and Fc–FcγR interactions are required for neutrophil Complement, specifically the C5a receptor (C5aR), is a
activation by G protein-coupled pathways and SYK, validated therapeutic target in acute AAV109–111. Evidence
respectively85,86. The effects of ANCAs on neutrophils implicates neutrophil cell surface C5a–C5aR interactions
include changes in adhesion molecule expression87,88, in neutrophil priming and activation109,112–115. Although
alterations in cytoskeletal proteins (such as actin paracrine and autocrine sources of C5a are possible,
polymerization)89 and the generation of reactive oxy- circulating C5a may be more important116 and little evi-
gen species84,90. The release of inflammatory mediators dence exists for a role for the membrane attack complex
occurs by several mechanisms, including degranulation, (which comprises the complement subunits C5b, C6, C7,
NET formation and the release of microparticles90,91. C8 and C9)109 in neutrophil priming and activation. In
The release of cytokines, proteases and other molecules addition to activating neutrophils, C5a enhances neu-
induces necrotizing crescentic glomerulonephritis in trophil retention in the microvasculature and promotes
mice92. A report of placental MPO-ANCA transfer to antigen recognition by T cells by activating dendritic

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cells115. Three different pathways (classical, lectin and consistent with the aforementioned mechanisms elu-
alternative) can be responsible for C5 activation and, in cidated in vitro122,123. However, in the glomerulus, the
AAV, evidence points to the alternative pathway being mechanisms of ANCA-induced neutrophil adhesion
the key to pathological C5a–C5aR interactions. In mice, are dependent on the ANCA concentration, with adhe-
deficiency of complement factor B (which is impor- sion mediated by β2 integrin at low ANCA levels and by
tant for the alternative pathway) but not C4 (which is α4 integrin at high ANCA levels but without additional
important for the classical and lectin pathways) was stimuli (such as lipopolysaccharide) that would on their
protective in experimental anti-MPO antibody-induced own induce leukocyte recruitment to glomeruli88.
glomerulonephritis112, while complement factor Bb
immunostaining in glomeruli correlated with renal T cells and cellular immunity
injury117. Although not prominent, complement deposi- In addition to humoral immunity, cellular immunity
tion is present in the kidneys of some patients with AAV is important in AAV pathogenesis, as CD4+ T cells
and may also be relevant to tissue pathology118. Low promote ANCA production, and CD4+ T cells and
serum C3 levels in patients with AAV with renal involve- CD8+ T cells recognize ANCA antigens deposited in
ment are associated with unfavourable outcomes119,120. peripheral tissues by activated neutrophils (Figs 3,5).
Other potential roles for complement in AAV include The class-switched, high-affinity nature of IgG ANCA
tissue-damaging interactions with pattern recognition implies T cell help by T follicular helper cells124, the
receptors and with pro-coagulant molecules118. abundance of which is increased in patients with GPA125.
CD4+ effector memory T cell abundance is increased in
ANCA-induced neutrophil recruitment to the micro the blood and urine in patients with AAV126 and CD4+
vasculature. ANCA-activated neutrophils mediate T cells and CD8+ T cells are present in lesions127–129.
microvascular injury by adhering to microvascular Both TH1 and TH17 effector cytokine profiles have been
endothelial cells in vulnerable tissues, mediated by observed in patients with AAV130,131, including TH1 pro-
integrin–endothelial adhesion molecule and chemokine– files in granulomatous lesions132. CD4+CD28– cytotoxic
chemokine receptor interactions (Fig. 5). ANCAs enhance T cells found in the blood of patients with GPA are linked
contact between neutrophils and activated endothelial to cytomegalovirus (CMV) infection, which is itself
cells via β2 integrins and CXC-chemokine receptor 2 associated with poor AAV outcomes133. Furthermore,
(CXCR2) in flow chamber assays121. In vivo microscopy subclinical CMV infection and reactivation in immuno
studies using inflamed post-capillary venules showed suppressed patients with AAV may impair immune
incremental recruitment of ANCA-activated neutrophils, responses to infection, as the antiviral drug valacyclo-
vir improved vaccine responses in CMV-seropositive
Genetic and patients with AAV134.
environmental Analyses of CD8+ T cell transcriptomes of patients
factors, ageing with active AAV at diagnosis reveal that patients can be
stratified into two groups correlating with differences
Infection or Loss of tolerance in long-term outcomes135. CD8+ T cell and CD4+ T cell
Autoreactive T cells
inflammation to PR3 or MPO
transcriptome data show that reduced expression of
genes linked to T cell exhaustion correlates with relaps-
Neutrophil priming ing disease136. The correlation between exhaustion, with
progressive loss of effector T cell function, and favour-
Autoreactive
ANCA B cells able disease outcomes extends across a range of auto-
immune and autoinflammatory diseases136 and implies
that therapeutics targeting this process may improve the
Neutrophil activation Autoantigen Antigen recognition management of AAV.
by ANCA deposition by effector T cells Effector T cells participate in tissue injury in AAV.
When ANCA-activated neutrophils localize to inflamed
Endothelial and tissue injury tissues, they release their autoantigen48,129,137. The wide-
spread deposition of the autoantigens in inflamed tissues
Fig. 3 | Pathogenetic events in GPA and MPA. Simplified schematic showing events in AAV makes these antigens available for recognition
leading to acute tissue injury in two forms of anti-neutrophil cytoplasmic antibody by effector T cells. Experimental studies, mostly in a
(ANCA)-associated vasculitis (AAV), namely granulomatosis with polyangiitis (GPA) and mouse model of anti-MPO induced glomerulonephri-
microscopic polyangiitis (MPA). Risk factors for loss of tolerance and disease (green) tis, demonstrate a role for both MPO-specific TH17 cells
include genetic and environmental factors, age, and infection or inflammation. These (earlier in disease) and TH1 cells (later in disease)138,
AAVs involve autoreactive elements (blue), including effector cell responses to the while CD8+ T cells also cause experimental injury74.
neutrophil proteins leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO) by
autoreactive T cells and B cells, with the humoral response resulting in the production of Monocytes and macrophages
ANCAs. The key steps in the effector phase (yellow) are neutrophil priming and activation
Macrophages are prominent in AAV lesions as well as
by ANCA with subsequent neutrophil localization to the microvasculature and injury.
MPO and PR3 are deposited in and around the microvasculature of target tissues and the most abundant immune cell type in glomeruli128,129
effector T cells recognize these antigens, resulting in pro-inflammatory cytokine and are important in both acute and chronic injury
production and further recruitment of effector leukocytes. These responses lead to (Fig. 5). ANCAs bind to intermediate monocytes that
tissue injury and endothelial damage (orange). Less is known about the pathogenesis release pro-inflammatory cytokines and chemokines97,98
of the other form of AAV, namely eosinophilic GPA, than for GPA and MPA. while, in a mouse model of MPO-A NCA-i nduced
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Loss of tolerance and induction of autoimmunity Activated CD4+ Memory CD4+ Exhausted CD4+
and CD8+ T cell and CD8+ T cell and CD8+ T cell
HLA-II Naive lymphocytes
CD4+ T cell CD8+ T cell

IL-21 B cell Activated B cell Memory B cell
Thymus
BAFF
Secondary
Bone marrow lymphoid Neutrophil
organ TFH cell
Plasma cell
Treg cell B cell
Ineffective
IL-12 Treg cell PR3-ANCA or
Genetic factors Molecular IL-23 MPO-ANCA
• PTPN22 mimicry TH17 cell TH1
• PR3-AAV cell
- HLA, PR3 and Dendritic Dendritic IL-17A IFNγ Alternative
α1-antitrypsin cell priming cell complement
• MPO-AAV Ineffective Breg cell activation
- HLA
NET formation
C5 C3b C3
Ageing
Cytokines FcγR
Infection and Monocyte (e.g. TNF, IL-1β, Cell-surface
C5a
inflammation IL-6 and IL-17A) PR3 or MPO
PAMP–TLR or C5aR
Environmental DAMP–TLR Neutrophil
factors engagement
• Unknown factors
• Silica, medications, Cytokines
(e.g. TNF and IL-1β) Monocyte
cocaine and Neutrophil • ↑ PR3 or MPO expression activation
levamisole priming and • Epigenetic dysregulation Activated neutrophil
activation
Fig. 4 | Loss of tolerance and the generation of effector responses in GPA and MPA. Genetic risk factors in an ageing
host combine with known or unknown environmental factors (possibly including silica, certain medications or drugs) and,
potentially, infection to induce a loss of T and B cell tolerance to one of two clinically recognized neutrophil antigens,
leukocyte proteinase 3 (PR3) or myeloperoxidase (MPO). Autoantigen-specific T cells become activated and differentiate
into T helper (TH) cells, including T follicular helper (TFH) cells that provide help to B cells, type 1 T helper (TH1) cells and
IL-17A-producing T helper (TH17) cells; an exhausted phenotype is associated with a reduced risk of disease relapse. B cells
differentiate into plasma cells and memory cells. Plasma cells secrete autoantibodies to PR3 (PR3-ANCA) or MPO-ANCA.
Neutrophils are activated and primed by pro-inflammatory cytokines, pathogen-associated molecular pattern (PAMP)
and damage-associated molecular pattern (DAMP) engagement with Toll-like receptors (TLRs), and binding of C5a to
the C5a receptor on neutrophils. ANCAs bind to and activate neutrophils and monocytes in an antigen-specific and an
FcγR-dependent fashion. AAV, ANCA-associated vasculitis; BAFF, B cell-activating factor; Breg cells, regulatory B cells;
C5aR, C5a receptor; GPA, granulomatosis with polyangiitis; IFNγ, interferon-γ; MPA, microscopic polyangiitis;
NET, neutrophil extracellular trap; TNF, tumour necrosis factor; Treg cells, regulatory T cells.
glomerulonephritis, inflammatory monocytes partici- ANCA– patients with EGPA, the association with genes
pate in glomerular crescent formation139. Macrophages affecting barrier function (including GPA33) implies a
are activated by effector TH1 and TH17 cells at sites of role for mucosal dysfunction whereas, in MPO-ANCA+
injury, participate in granuloma formation, and form patients with EGPA, the HLA associations are consist-
macrophage extracellular traps in tissues129. Additionally, ent with MPO-ANCA+ EGPA being an eosinophilic
in chronic inflammation, profibrotic macrophages autoimmune disease.
contribute to disease progression and damage. In addition to genetic studies, observational studies
implicate eosinophil dysfunction in the pathogenesis of
The pathogenesis of EGPA EGPA. Eosinophil-m ediated injury by the release
The pathogenesis of EGPA is not well understood but is of granule proteins can induce tissue-resident cells to
likely to be substantially different to both GPA and MPA, release pro-inflammatory mediators. Some of these tis-
although the extent of the similarities and differences sue cell-derived molecules, such as IL-25, affect both
is unclear. Furthermore, the differing clinical presenta- adaptive immune cells (TH2 cells) and innate immune
tions, genetic associations and response to therapies of cells (group 2 innate lymphoid cells)140. Both TH2 cells
MPO-ANCA+ and ANCA– patients with EGPA imply and group 2 innate lymphoid cells produce IL-5 and
distinct elements to the pathogenesis of these forms of IL-13, which are key cytokines that promote eosino-
EGPA42–44. Genetic associations with genes that influ- phil proliferation and function141,142. The role of IL-5
ence eosinophil numbers and those that underlie asthma has been validated by trials of the anti-IL-5 monoclo-
are shared by both groups of patients. However, in nal antibody mepolizumab in patients with EGPA143.

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C5a FcγR
C5aR Cell-surface PR3 or MPO
Neutrophil PR3-ANCA or MPO-ANCA
CD4+ T cell (TH17 or TH1 cell)
Activated neutrophil
CD8+ T cell
TLRs Cytotoxic
Microparticles IL-17A IFNγ CD4+ T cell
β2 integrins CXCR2 MHC-II–Ag
NETosis
α4 integrins peptide
CXCL8
ROS Non-classical
TLR4 ICAM1 VCAM1 Proteases monocyte MHC-I–Ag NKG2D
ANCA Ag peptide MICA
Endothelial cell Granuloma

Basement membrane Tissue dendritic
cells present
Ag peptide antigen
• Antigen
TCR Fibroblast
presentation
• Cytokines MHC-II • Fibrosis
• In situ ANCA Tissue inflammatory • Tissue
macrophage destruction
production
B cell • Loss of
aggregates sCD163 function
Fig. 5 | Endothelial and tissue injury in GPA and MPA. Anti-neutrophil cytoplasmic antibody (ANCA)-activated,
primed neutrophils localize to endothelial cells in the microvasculature of the kidneys, respiratory tract and other tissues.
Recruitment is mediated by adhesion molecules and chemokines. Adherent neutrophils induce endothelial injury by
several mechanisms. They produce reactive oxygen species (ROS) and degranulate, releasing proteases and ANCA
antigens. They generate neutrophil extracellular traps (NETs) and undergo cell death by NETosis. ANCA antigens released
by neutrophils, and when in a complex with major histocompatibility complex class II (MHC-II) or MHC-I, can be recognized
as antigenic peptides by effector type 1 T helper (TH1) cells, IL-17-producing T helper (TH17) cells and CD8+ T cells, at least
in the case of myeloperoxidase (MPO). Antigen-presenting cells can include endothelial cells, intravascular monocytes
and dendritic cells. Cytotoxic CD4+ T cells expressing NKG2D recognize MHC-I-polypeptide-related sequence A (MICA),
which is upregulated on activated endothelial cells and in granulomas. Mechanisms of extravascular tissue injury include
the extravasation of inflammatory leukocytes and the formation of B cell aggregates that may present ANCA antigens
to T cells, produce pro-inflammatory cytokines and produce ANCA in situ. Tissue-resident and recruited dendritic cells
present antigen, whereas tissue-resident and recruited macrophages are pro-inflammatory and pro-fibrotic. These
macrophages shed soluble CD163 (sCD163), which is a potential biomarker of disease activity. Leukocytes within
granulomas contribute to inflammatory injury. Ag, antigen; C5aR, C5a receptor; CXCL8, CXC-chemokine ligand 8;
CXCR2, CXC-chemokine receptor 2; GPA, granulomatosis with polyangiitis; ICAM1, intercellular adhesion molecule 1;
IFNγ, interferon-γ; MPA, microscopic polyangiitis; PR3, leukocyte proteinase 3; TCR, T cell receptor; TLR, Toll-like receptor;
VCAM1, vascular cell adhesion protein 1.
TH2 cell-associated chemokines, such as CC-chemokine and determinants of T cell activity and exhaustion may
ligand 26 (CCL26; also known as eotaxin 3), enhance also be able to identify those at high risk of relapse22,135,144.
eosinophil recruitment 142. Other T cell-a ssociated
cytokines are also elevated in patients with EGPA but, Diagnosis, screening and prevention
to date, there is no clear evidence that a particular pat- Diagnostic and classification criteria
tern of cytokine or chemokine production characterizes Clear definitions of GPA, MPA, EGPA and other sys-
MPO-ANCA+ or ANCA– EGPA. A direct relationship temic vasculitides are provided by the updated 2012
between MPO-ANCA and eosinophils has not yet been Chapel Hill Consensus Conference145, which, as the name
demonstrated in MPO-ANCA+ patients with EGPA. implies, was consensus- rather than data-driven (Fig. 1;
Table 1). In 2006, an algorithm was developed for apply-
Chronicity and relapse in AAV ing the 1990 American College of Rheumatology clas-
The pathogenesis of AAV is characterized by complex sification, the 1993 Chapel Hill Consensus Conference
pathways to tissue injury and damage involving both definitions and ANCA specificity to streamline the
humoral and cellular effector systems. Much of the classification of patients with GPA, MPA and EGPA for
work on the pathogenesis of AAV has been in systems epidemiological studies and clinical trial purposes; how-
modelling acute injury. Although largely unexplored, ever, it cannot be regarded as providing diagnostic cri-
mechanisms operative in disease induction are also teria for clinical practice146. The current Diagnostic and
likely to be relevant to relapse. Some observational evi- Classification Criteria in Vasculitis Study (DCVAS)
dence points towards infection, in part related to chronic has further developed the classification and diagnostic
sinonasal mucosal damage, being important in relapse criteria in AAV147.
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Clinical presentation the systemic autoimmune pathophysiology (Box 2; Fig. 6).

The different types of AAV share non-specific clinical AAVs are frequently initially misdiagnosed as infections,
features of systemic inflammation, such as weight loss, malignancies, depression or osteoarthritis, especially in
malaise, fatigue, arthralgia and myalgia, which relate to older patients148. This is pertinent, as some conditions,
such as infective endocarditis, not only share clinical fea-
a tures with AAV but may also have a positive ANCA test by
Central nervous
Constitutional system indirect immunofluorescence (Box 1). Although asthma is
symptoms GPA = MPA = EGPA a typical early feature of EGPA, all forms of AAV can pres-
EGPA = GPA = MPA ent with manifestations relating to small vessel vasculitic
Nose and sinuses lesions and dysfunction of any organ149. Various organ
Eyes GPA > EGPA >> MPA
systems and tissues are affected in AAV, albeit at different
GPA >> MPA = EGPA
frequencies in GPA, MPA and EGPA (Fig. 6).
Upper airwaysa
GPA = EGPA > MPA
Necrotizing or granulomatous lesions can affect the
Ears and auditory
GPA > MPA = EGPA ear, nose and throat (ENT) tract and cause symptoms of
Lungsa chronic rhinitis, sinusitis or laryngitis. Similar processes
Heart EGPA > GPA > MPA in the respiratory tract, including pulmonary capillaritis,
EGPA > GPA = MPA present as shortness of breath, cough and haemoptysis
Gastrointestinal due to pulmonary haemorrhage (Fig. 6). Cavitating lung
Kidneys tract nodules can be present. Ophthalmological manifestations
MPA > GPA >> EGPA EGPA > GPA = MPA include granulomatous orbital or retroorbital masses,
anterior segment inflammation, retinal vasculitis or optic
Muscle Joints neuritis. A purpural or petechial rash is the most common
EGPA > MPA = GPA GPA > MPA = EGPA
dermal manifestation, with necrotizing dermal vasculi-
Skin Peripheral nerves
tis and other non-vasculitic skin rashes also occurring.
EGPA > GPA > MPA EGPA > MPA > GPA Kidney involvement usually presents as rapid-progressive
glomerulonephritis with haematuria, proteinuria and
hypertension. Interstitial nephritis without glomerular
b involvement occurs but is not common. The peripheral
nervous system is typically affected by mononeuritis
multiplex due to focal vasculitis of the vasa nervorum.
EGPA is characterized by the near-universal presence
of asthma, often for years before the onset of eosino-
philia and eosinophilic tissue inflammation, and dif-
ficult to control asthma not infrequently persists even
after treatment of EGPA. A subset of patients with EGPA
exhibit frank vasculitis. The tissues affected in EGPA are
similar to those affected in GPA and MPA, albeit at dif-
c ferent frequencies (Fig. 6). In particular, cardiomyopathy
due to eosinophilic myocarditis is not uncommon in
EGPA and can be life-threatening. Some of the differ-
ences in the manifestations of EGPA and MPA or GPA,
such as urticaria and eosinophilic pneumonia, align with
its characteristic eosinophil-dominated inflammation.
* Some patients with GPA or MPA present with vascu-
litis limited to a single organ, such as the kidneys, ENT
tract or lungs, which may represent the early stages of
AAV. However, in MPO-ANCA+ patients with MPA,
Fig. 6 | Clinical features of AAV. a | Schematic showing the organs, organ systems isolated renal disease or isolated pulmonary fibrosis is
and tissues that are affected in the anti-neutrophil cytoplasmic antibody-associated not infrequent. The recognition of pulmonary fibrosis
vasculitides (AAVs) granulomatosis with polyangiitis (GPA), microscopic polyangiitis as a feature of MPA in MPO-ANCA+ patients, often as
(MPA) and eosinophilic GPA (EGPA). The approximate relative frequency of involvement the sole manifestation of disease, has been of some
is also shown. b | Radiological features of sinonasal disease in AAV. Coronal CT images interest 150. This presentation may be more com-
(left) showing destruction of the nasal septum, inferior turbinates and right middle mon in Japan151,152, although it does occur in diverse
turbinate (white arrows) in a patient with newly diagnosed GPA. Chronic changes in geographical locations. MPO- A NCA- a ssociated
sinonasal GPA (right) showing simultaneous nasal septum destruction (white arrow) and pulmonary fibrosis may result from chronic low-
neo-osteogenesis (black arrow). c | Radiological features of pulmonary haemorrhage in grade pulmonary inflammation but this is not clear.
acute AAV. Chest X-ray (left) showing infiltrates and changes consistent with acute
A minority of MPO-ANCA+ patients with MPA also
pulmonary haemorrhage. Transverse CT image (right) showing acute pulmonary
haemorrhage and ‘ground-glass’ changes (*). =, rate of involvement approximately equal have anti-glomerular basement membrane antibod-
to; >, rate of involvement more frequent than; >>, rate of involvement substantially more ies and exhibit a hybrid disease phenotype153, whereas
frequent than. aFor EGPA, asthma and allergic manifestations are included in the frequency individuals with systemic lupus erythematosus or sys-
of involvement. Images in part b courtesy of J. Rimmer, Monash Health and Monash temic sclerosis can be MPO-ANCA+ and develop some
University. Images in part c courtesy of K. Lau, Monash Health and Monash University. features of AAV, especially the vasculitic pattern of

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glomerulonephritis154–156. As initial clinical presentations Biomarkers

are diverse and often non-specific, AAV is an infrequent ANCAs are unique markers that support the classifica-
but important differential diagnosis for many conditions tion and diagnosis of GPA, MPA and EGPA. The indirect
across many medical disciplines. AAV can remain undi- immunofluorescence test is commonly the initial screen-
agnosed for months or years until ANCA testing is per- ing test for ANCA but high-quality immunoassays are
formed. In view of the rarity of AAV and the existence preferred162 (Box 1). The ANCA test is useful in monitor-
of mimics of vasculitis, the diagnosis should be reviewed ing patients with persistently elevated ANCA, as those
periodically, particularly in cases of inadequate response with a reappearance of ANCA or an increase in ANCA
to treatment or if not all disease manifestations are levels have an increased likelihood of relapse, although
consistent with AAV. restarting or intensifying therapy based on ANCA
Children with AAV can develop a similar range of alone is not recommended. This aligns with an associ-
clinical features to adults. Constitutional, ENT, renal and ation between earlier relapse and a higher frequency of
pulmonary manifestations are most commonly found memory B cells163, while a higher plasmablast percent-
at presentation15. However, some features may be more age during remission is also predictive of relapse164. The
common in children. For example, a French Vasculitis acute-phase markers C-reactive protein and erythrocyte
Study Group Registry-based case–control study, with sedimentation rate are of limited use in evaluating dis-
most children having GPA, found that children were ease activity due to their lack of specificity. Other disease
more likely to have fever at onset than adults157. Rates of activity biomarkers, including urinary soluble CD163,
renal involvement were similar but myalgia and periph- are under evaluation for use in assessing disease activity
eral neuropathy were less common. Children were more but await validation for routine clinical use165–167.
likely to relapse than adults and more frequently accrued
damage, especially ENT damage, over time15,157. Assessing disease activity and damage
Patients with AAV should have access to medical special-
Clinical syndromes and antigenic specificity ists with expertise in the complex care of vasculitis, ideally
MPA and GPA are strongly associated with MPO-ANCA in a multidisciplinary context. Where needed, early refer-
and PR3-A NCA, respectively, whereas EGPA can ral to specialists experienced in assessing specific organ
be either ANCA+ (mostly MPO-ANCA) or ANCA– systems involved in AAV improves the quality of disease
(Table 1). Global variations in clinical manifestations assessment. Managing patients at, or in collaboration with,
reflect the relative rates of MPA (MPO-AAV) and GPA a dedicated vasculitis centre provides opportunities to
(PR3-AAV) discussed in Epidemiology (above) with, participate in clinical trials. Disease assessments in AAV
for example, clinical features associated with MPA should target activity, damage, prognosis and function or
being more common in East Asia. Given the presence QOL168. Validated tools to assess disease activity include
of overlapping signs and symptoms but also clear clinical the Birmingham Vasculitis Activity Score (BVAS) and the
differences (described in Table 1 and Box 2), another Five Factor Score (FFS). The BVAS comprises ten systems
approach to disease classification is by the autoantigen (one general, eight tissue-specific and one open) and is
involved (that is, PR3-AAV and MPO-AAV), although used in clinical research to assess disease activity, remis-
this approach also has limitations: ANCA can be neg- sion, response to therapy and flare169. Only items that are
ative, MPO-ANCA can be false positive in patients newly present or worsening over the preceding 4 weeks
without vasculitis158, assay standardization is lacking are recorded. Disease states of active disease, remission
and not all countries have ready access to high-quality and refractory disease are defined as follows: a BVAS
assays. Nonetheless, genetic and other studies demon- score of 0 represents remission, ≥1 represents active dis-
strate that the clinical differences between PR3-AAV and ease and refractory disease is active disease despite treat-
MPO-A AV are greater than those between GPA ment. Consensus definitions have been recommended
and MPA36,159, indicating that, from a pathogenetic per- by the European League Against Rheumatism (EULAR)
spective, antigen specificity is important. Furthermore, for disease activity states, including remission, response,
post hoc analyses of a large multicentre study suggest refractory disease and relapse, which can be useful for
that PR3-ANCA+ patients may respond better to the bio- clinical trials and studies170. The 1996 FFS is based on
logic agent rituximab than to the immunosuppressants serum creatinine, proteinuria, cardiomyopathy, gastro
cyclophosphamide and azathioprine, whereas these intestinal involvement and central nervous system
treatments seem to be equally effective in MPO-ANCA+ involvement and has been validated for MPA and EGPA
patients160. ANCA specificity also predicts differences in but not GPA. The revised 2009 FFS includes serum cre-
long-term prognosis: PR3-ANCA+ patients are at higher atinine, age (>65 years), cardiomyopathy, gastrointestinal
risk of relapse than MPO-ANCA+ patients161. In EGPA, involvement and absence of ENT manifestations (GPA
the presence or absence of ANCA in patients defines and EGPA only) but this version requires validation171.
its two subtypes. Most patients with EGPA are ANCA– To assess chronic damage, both from the disease itself and
but ~40% are (or have been) ANCA+. In these patients from treatments, such as glucocorticoids, the Vasculitis
with ANCA+ EGPA, ANCA is almost always specific Damage Index (VDI) predicts mortality risk and scores
for MPO. Clinically, renal involvement and periph- ten systems, namely musculoskeletal, skin and mucous
eral nerve involvement are more common in ANCA+ membranes, ocular, ENT, pulmonary, cardiovascular,
patients with EGPA, with cardiomyopathy and possibly the peripheral vasculature, gastrointestinal, renal, and
pulmonary infiltrates being more common in those who neuropsychiatric systems, with an eleventh category for
are ANCA– (refs43,44). other systems172.
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The BVAS and VDI are approved by the Outcomes Pathology

Measures in Rheumatology (OMERACT) group and Although sharing many features, the different forms
EULAR as key outcome measures to record disease activ- of AAV show histopathological differences (Fig. 7).
ity and damage, respectively, in clinical trials173. Measures Fibrinoid necrosis and inflammation of small vessels,
of QOL are important in the assessment of AAV. Generic sometimes accompanied by thrombosis, is the hallmark
tools have thus far been used but AAV-specific instruments of acute injury in all forms of AAV181. In MPA, these
have been developed (see QOL section, below). features are present without other defining features, such
as the granulomas in GPA or the prominent eosinophilic
Association with cardiovascular events infiltrates in EGPA. Chronic lesions are characterized by
An increased risk of cardiovascular events has been doc- transmural scarring with loss of the elastic internal lam-
umented in patients with AAV174. Indeed, during 5-years ina. Larger blood vessels can be affected, with leukocytic
of follow-up of four European Vasculitis Study Group infiltrates and fibrinoid necrosis, as seen in polyarteri-
trials of GPA and MPA, a cardiovascular event, defined tis nodosa. However, the involvement of larger vessels
as cardiovascular death, stroke, myocardial infarction, should not be interpreted as an ‘overlap’ with other forms
coronary artery bypass graft, or percutaneous coronary of vasculitis when small-vessel (capillary and arterioles)
intervention, occurred in 14% of patients. PR3-ANCA+ involvement is also present. Although the histopathol-
status was associated with a reduced cardiovascular risk ogy of EGPA features necrotizing small-vessel vasculitis
compared with MPO-ANCA+ or ANCA– status175. (as in GPA and MPA), an abundance of eosinophils is
Dysfunction of the immune and coagulation its defining feature. In the early stages of disease, eosin-
systems contributes to an increased risk of venous ophilic infiltrates (but no necrosis) are present in tissues
thromboembolism176, especially during active disease177. or in blood vessel walls whereas, in later stages of disease,
An increased incidence of venous thromboembolism, in eosinophils also surround the epithelioid cells within
both typical and atypical sites, and pulmonary embolism granulomas and necrosis is present.
has also been reported in GPA, MPA and EGPA178.
Renal involvement. In the kidneys, the characteris-
Role of imaging and biopsy tic lesion in AAV is segmental necrosis of glomerular
A chest X-ray helps dissect the underlying pathology capillary loops, with little or no deposition of immuno
in patients with pulmonary symptoms (Fig. 6), although globulin or complement, termed ‘pauci-immune’
CT has a higher sensitivity in detecting pulmonary nod- focal necrotizing (and crescentic) glomerulonephritis.
ules, cavities and alveolar opacities as well as masses Different lesions in different glomeruli within the same
in the retro-orbital space, paranasal sinuses and the biopsy specimen reveal the asynchronous nature of
mastoids179. Iodinated contrast agents are not required the vasculitic injury. Acute glomerular injury is char-
for these studies. High-resolution CT of the chest may acterized by segmental necrosis with extravasation of
be helpful for detecting interstitial pneumonia; a study of fibrin and erythrocytes into the urinary space, followed
high-resolution CT involving Japanese patients with MPA, by proliferation of parietal glomerular epithelial cells
all but three of whom were MPO-ANCA+, demonstrated forming a cellular crescent. Destruction of the Bowman
abnormalities in 93% of patients, with 51% having inter- capsule, the structure that encloses the glomerulus,
stitial pneumonia152. Although dynamic expiratory CT results from glomerular and periglomerular inflam-
and other modalities have been advocated as potentially mation. These inflammatory changes ultimately lead
useful in detecting subglottic stenosis or endobronchial to glomerulosclerosis that can be either segmental or
disease180, advanced imaging techniques may not be global and represent the evolution of injury over days
widely available or may only be available as research tools. to months.
The high diagnostic specificity for AAV of a positive Glomerular lesions are used to stage renal disease in
ELISA test for MPO-ANCA or PR3-ANCA may, in the AAV by a histopathological classification182, where the
appropriate clinical setting, preclude the need for biop- dominant lesion is linked to outcomes. There are four
sies. However, renal, lung, skin or other tissue biopsy is patterns of injury, namely sclerotic (≥50% globally scle-
often important in establishing the diagnosis and may, rosed glomeruli, worst outcome), focal (≥50% normal
especially in the case of nasal biopsy, provide the first glomeruli, best outcome), crescentic (≥50% cellular
evidence for AAV, particularly GPA. In the appropriate crescents, intermediate outcome) and mixed (no sin-
clinical context, granulomatous rhinitis or pneumonitis gle dominant type of lesion, outcome better than the
and ‘pauci-immune’ glomerulonephritis are more spe- sclerotic but worse than the crescentic class). In clinical
cific for AAV than dermal leukocytoclastic vasculitis. settings, this classification has been validated by some
Ultrasonography-guided percutaneous kidney biopsy, but not all studies, especially with regard to prognosis
although not mandatory, in the presence of haematuria in the crescentic and mixed classes183. The classification
and/or proteinuria can help make an initial diagnosis of does not currently include the extent of tubulointersti-
AAV. Kidney biopsy can also be used to diagnose relapse, tial lesions or renal function. A further classification
establish the degree of chronicity of nephritis and, in system has been proposed that includes these factors
chronic disease, may be useful in determining whether together with the proportion of normal glomeruli
impaired kidney function and proteinuria is related to at biopsy184.
active vasculitis or irreversible damage. Biopsy samples Glomerular injury is often accompanied by inflam-
from patients with suspected AAV should be assessed by mation of small arteries and a variable interstitial infil-
an experienced pathologist. trate around necrotic lesions, either glomeruli or blood

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a b c
N
*
N F
100 μm 200 μm 250 μm 500 μm
d e f
* *
C
*
100 μm 100 μm 100 μm
g h i
C
GC
G
100 μm 200 μm 50 μm
Fig. 7 | Histopathology of AAV. a | Fibrinoid vessel wall necrosis (N) is the surrounded by eosinophils. e | Early lesions in the lung in MPA often only
hallmark of anti-neutrophil cytoplasmic antibody-associated vasculitis show neutrophilic capillaritis (C) and fibrinous exudates (*). f | Giant cells
(AAV), accompanied by a ‘granuloma-like’ mixed inflammatory infiltrate with sometimes ‘smudged’ appearing nuclei (arrow), neutrophilic granulo-
(circled) composed of macrophages, lymphocytes, plasma cells and granu- cytes and nuclear debris (*) from neutrophils in epithelioid granulomas in the
locytes in microscopic polyangiitis (MPA). b | Resolution of inflammation lungs in GPA. g | Necrosis of glomerular capillaries (N) is seen adjacent to an
leads to transmural fibrous scars (F) (arrow) and substantial narrowing (*) or unaffected glomerulus (G) in MPA. h | Lesions of different age are seen with
even complete occlusion of the vessel lumen. c | ‘Geographic’ necrosis (N) of partial or circumferential crescents and variable destruction of the Bowman
confluent epithelioid granulomas in the lungs in granulomatosis with poly- capsule (arrows) in MPA. i | Neutrophilic capillaritis (C) and multinucleated
angiitis (GPA). Inset shows a subepithelial nasal granuloma in GPA, composed giant cells (GC) are characteristic features of GPA in the nasal mucosa.
of loose aggregates of epithelioid cells and giant cells. d | Epithelioid granu- Staining methods are haematoxylin and eosin (parts a–f), acid fuchsin
lomas (circled) in eosinophilic GPA in the nose are more compact and are orange G (part g), periodic acid–Schiff (part h) and Giemsa (part i).
vessels, in a granuloma-like pattern but multinucleated is surrounded by a palisade of epithelioid cells and, in
giant cells are rarely seen. The presence of sarcoid-type EGPA, by large numbers of eosinophils. Granulomatous
granulomas in renal biopsy specimens should lead to con- inflammation and areas of necrosis are often confluent,
sideration of other diagnoses, such as renal sarcoidosis with a ‘geographic’ appearance at low magnification.
or an allergic drug reaction. Multinucleated giant cells are almost invariably present
and are pathognomonic for GPA or EGPA when seen
Respiratory tract involvement. In GPA, upper and lower in isolation in lung or upper airway biopsy samples, in
respiratory tract injury classically involves granuloma- cytology specimens from bronchoalveolar lavage, or
tous inflammation. Small granulomas are composed in nasal swabs taken when clinical features suggestive of
of sometimes loose aggregates of epithelioid cells. The AAV are present.
granulomatous inflammation often shows central necro- In the lungs, neutrophilic capillaritis is common to
sis containing nuclear fragments of granulocytes and all forms of AAV. As vasculitic changes can be difficult
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to detect in small biopsy samples, samples should also point171. Ongoing factors influencing survival include
be stained with trichrome and Elastica van Gieson infectious burden, development of first relapse within
for optimal detection of any disruption to alveolar or 1 year and the amount of chronic damage measured by
vessel walls and of small areas of necrosis in arterioles the VDI175. As the VDI encompasses both disease and
and arteries, vascular inflammation, and characteris- treatment-related damage, the risks of immunosuppres-
tic scars affecting the full thickness of the vessel wall, sant drugs and glucocorticoids will also have an effect.
indicating past injury. Acute injury may consist of only Finally, other factors, including a diagnosis of GPA, the
non-specific inflammation or features resembling bron- presence of PR3-ANCA, and upper or lower respiratory
chiolitis obliterans and organizing pneumonia. However, involvement, seem to increase the likelihood of relapse,
signs of recurrent alveolar haemorrhage with extravasa- currently quoted as ~50% by 5 years after diagnosis190.
tion of erythrocytes, variable numbers of siderophages,
or small areas of fibrin, necrosis or micro-abscesses are Management
suggestive of AAV. In the nose, necrotizing granuloma- Following diagnosis, disease assessment in AAV should
tous inflammation in GPA can cause severe soft tissue consider activity and damage (the tools for assessing
destruction, including of the nasal cartilage. Large ulcers activity and damage are discussed above), prognosis (see
with denuded epithelium can be seen. Granulomatous above) and function or QOL (described below). Broadly
inflammation is also a feature of nasal involvement in speaking, therapy can be divided into a phase aiming to
EGPA, sometimes with eosinophilic necrosis but more induce remission with more intense therapy and a subse-
often containing epithelioid cell aggregates surrounded quent period in which the goal is to maintain remission
by a dense eosinophil infiltrate. (Fig. 8; clinical trials in GPA and MPA are summa-
rized in Tables 2,3). The goal of induction therapy is to
Other organ and tissue involvement. Similar vasculitic achieve remission by 3 months, which is then sustained.
changes are found in other tissues, such as the heart, Later remission, early relapse or refractory disease are
brain or gastrointestinal tract. In the gut, the finding of associated with worse outcomes191.
otherwise unexplained necrosis or haemorrhagic infarc- Treatment should be initiated as soon as a diagno-
tion should prompt extensive examination of mesenteric sis of AAV is at least probable and appropriate safety
vessels for vasculitis. Although most often seen in iso- investigations have been performed, as delays in diag-
lation, dermal leukocytoclastic vasculitis can represent nosis and treatment lead to worse outcomes. Initiation
systemic disease. Involvement of the peripheral nervous of treatment, especially in the setting of severe renal or
system as mononeuritis or mononeuritis multiplex is lung disease, should not be delayed by the need to obtain
due to ischaemia caused by vasculitic inflammation of a biopsy, as several days of treatment usually does not
the vasa nervorum185. markedly reduce the diagnostic yield of a biopsy.
Prognosis Remission induction

The 5-year survival for AAV has been steadily rising Before initiation of therapy, there should be an assess-
to around 70–80% over the past 40–50 years, follow- ment of any concurrent infection or risk of infection,
ing the introduction of immunosuppressant therapies, including chronic viral infections (which should be
increasing proficiency in their use and the introduction screened for) or immunodeficiency, and for con-
of ANCA testing, all of which promote earlier diagnosis ditions, such as diabetes mellitus, osteoporosis and
and improvements in supportive care186. Data also sug- psychiatric disorders, which increase the risk of
gest that there are ongoing improvements in mortality glucocorticoid-associated adverse events.
and end-stage kidney disease rates over the past decades
in the USA187,188. Globally, AAV mortality, based on the Glucocorticoids. Oral glucocorticoids (such as pred-
International Classification of Diseases 10th Revision nisone, prednisolone and others) are commenced when
(ICD-10) data, are falling189. These data, although imper- a diagnosis of AAV seems probable. These drugs exert a
fect, include mortality data from many countries and rapid effect. The initial dose for severe disease is 1 mg/kg
suggest, using 2014 data, similar age-standardized mor- daily of prednisone (or equivalent). The PEXIVAS
tality in North America and Europe, with lower mortal- trial demonstrated that a regimen that rapidly reduces
ity in Latin America and higher mortality in Oceania; the dose to 20 mg daily by 7 weeks and 5 mg daily by
data from Asia and Africa were limited. 19 weeks is as effective and safer than more traditional,
Initial clinical factors influencing outcomes include higher-dose regimens192. Glucocorticoids are the major
older age, severity of renal dysfunction, the presence modifiable cause of adverse events during the induction
of pulmonary haemorrhage (in some series) and dis- period and lower-dose regimens reduce the risk of severe
ease activity measured by BVAS186; the findings on infections. There is no consensus for glucocorticoid dos-
renal biopsy reflect the severity of renal dysfunction ing in non-severe disease and lower initial doses may be
and correlate with outcomes 182. The 2009 FFS can used. The RITAZAREM trial demonstrated that patients
also be applied to prognosis, as four factors are asso- with relapsing disease respond well to lower initial doses,
ciated with a poor prognosis (age, renal insufficiency, such as 0.5 mg/kg daily, whether or not they had severe
cardiac involvement and gastrointestinal manifesta- disease193. Intravenous pulse methylprednisolone (total
tions, where each is accorded +1 point); the fifth fac- dose 1–3 g) at the initiation of therapy for severe dis-
tor, ENT manifestations, is associated with a better ease is conventionally administered, but its benefits and
outcome and the absence of ENT symptoms scores 1 harms have not been adequately studied.

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a Treatment phase b Drug c Disease state

GCs CYC or RTX
IV
Induction Active disease
0 to (3–6) Oral Refractory

months disease
Maintenance RTX On-drug remission

AZA
(3–6) to MTX
(24–48) MMF
months Relapse
Long-term follow-up Off-drug remission
Indefinite Induction therapy

Maintenance therapy
Fig. 8 | Management of GPA and MPA cases that present with organ or life-threatening manifestations. a | Current
treatment approaches include an induction phase to induce remission, followed by a maintenance phase, then long-term
follow-up. b | Current induction treatment regimens for several diseases are centred on glucocorticoids (GCs), in
combination with either cyclophosphamide (CYC) or rituximab (RTX). Intravenous GCs are often administered after
treatment with high-dose oral prednisolone (or prednisone) at an initial dose of 50–75 mg. GC dose is tapered over several
months, with the standard of care being the quicker taper used in the PEXIVAS trial192. The optimal duration of GC therapy
in the maintenance phase of anti-neutrophil cytoplasmic antibody-associated vasculitis is unclear, but GCs are often
withdrawn over 4–36 months. CYC is recommended for induction, for between 3 and 6 months, and can be administered
by intravenous pulse or daily oral therapy, with a switch to maintenance therapy at remission (3–6 months). RTX can also be
given for induction therapy in 2–4 doses and is increasingly being used in preference to CYC. RTX is given for maintenance
therapy, after induction with RTX or CYC. Oral immunosuppressive agents, including azathioprine (AZA), methotrexate
(MTX) or mycophenolate mofetil (MMF), are alternatives for RTX for maintenance therapy. MTX or MMF are alternatives to
CYC or RTX for induction therapy in non-organ-threatening disease. c | Disease state corresponding with phase of therapy
in parts a and b. Some patients do not respond to one of the standard induction regimens and develop refractory disease,
whereas others relapse while on therapy or after maintenance therapy is halted and therefore require re-initiation of
induction therapy. GPA, granulomatosis withpolyangiitis; MPA, microscopic polyangiitis.
Other immunosuppressive or immunomodulating drugs. total of four doses, although two 1,000 mg doses (2-week
The combination of glucocorticoids with either cyclo- interval) are also widely used. There is a paucity of com-
phosphamide or rituximab is the current standard of parative data on the use of either cyclophosphamide or
care for remission induction in severe disease, although, rituximab in patients with low glomerular filtration rate
as further evidence supporting the efficacy of ritux- (for example, <20 ml/min/1.73 m2), with a lower dose of
imab emerges, it is becoming the preferred induction cyclophosphamide together with rituximab being used
agent for many patient subgroups, such as children and in the RITUXVAS trial198. The use of this combination
adults for whom the preservation of fertility is important, is controversial and may confer an additional risk of
PR3-ANCA+ patients and in relapsing disease. However, infection199.
rituximab is more expensive and is not as available glob- For non-severe disease, alternative immunosuppres-
ally as cyclophosphamide. Cyclophosphamide dosing is sive agents to cyclophosphamide, such as methotrexate
either by intermittent intravenous pulse treatments or and mycophenolate mofetil, are equivalent to cyclo-
by a daily oral dose. Doses are reduced for increasing phosphamide in terms of remission rates at 6 months
age and renal impairment; either regimen is usually but have higher subsequent rates of relapse and greater
discontinued after 3–6 months, with subsequent initi- accrual of damage, especially for PR3-ANCA+ disease.
ation of remission maintenance therapy. Close moni- Methotrexate has been recommended for patients
toring is essential to minimize the risk of myelotoxicity. with no threat of organ-damaging disease, although
Intravenous regimens deliver ~50% of the cumulative longer-term outcomes (such as relapse and damage
dose compared with daily oral dosing, with similar accrual) are worse than with cyclophosphamide200. Such
remission rates, but lower cyclophosphamide expo- patients are uncommon and often require later use of
sure is associated with a higher subsequent relapse cyclophosphamide or rituximab for control of more
risk194,195. severe or relapsing disease. The MYCYC trial found
In two randomized trials, rituximab was non-inferior similar responses with mycophenolate mofetil and
to cyclophosphamide for remission induction and, cyclophosphamide in MPO-ANCA+ patients, at both
in a post hoc analysis of the RAVE trial, it was supe- 6 and 18 months201, and two other small randomized
rior for PR3-ANCA+ patients or those with relapsing trials support a role for this agent as an alternative for
disease160,196,197. These trials used 375 mg/m2 weekly for a this subgroup.
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Adjunctive therapy. Although smaller studies demon- as chronic kidney disease. Many patients with AAV
strate that the use of plasma exchange is associated with a require prolonged low-dose glucocorticoids (pred-
reduced risk of end-stage kidney disease for patients with nisone ≤10 mg daily) to maintain remission, even if also
serum creatinine levels of >500 μmol/l at diagnosis202, the treated with rituximab or an oral immunosuppressive
results of the large PEXIVAS trial indicate that plasma drug.
exchange should not be routinely recommended for In the MAINRITSAN and RITAZAREM trials of
GPA or MPA with nephritis or lung haemorrhage192. interval treatment, rituximab was superior to azathio-
Whether specific patient subgroups, such as those that prine193,204. These findings are consistent with previous
are oliguric at presentation or with hypoxic respiratory observational data and are driving a revision of guide-
failure, benefit from plasma exchange requires further lines. Azathioprine, methotrexate or mycophenolate
study. In one study, high-dose intravenous immunoglob- mofetil, with or without oral glucocorticoids, can be
ulin (2 g/kg total dose) improved disease control of AAV used after cyclophosphamide to maintain remission in
that was refractory to usual therapy203 and can be consid- patients with AAV. The optimal duration for treatment
ered when conventional agents are contraindicated, such with these agents is uncertain, with the REMAIN trial
as in the setting of severe infection. supporting 3–4 years of treatment regardless of ANCA
subtype or positivity205. The MAINRITSAN trial results
Therapy to maintain remission indicate that, following the use of cyclophosphamide in
The goals of maintenance therapy are to prevent relapse, patients with new-onset disease, a reduction in relapse
minimize the risk of comorbidities and drug toxicity, rates occurs with the use of rituximab (500 mg every
and manage the consequences of organ damage, such 6 months over 2 years) compared with azathioprine.
Table 2 | Key clinical trials of induction therapies for GPA and/or MPA
Name Population Intervention Key result Other findings Refs
CYCLOPS Newly diagnosed GPA or MPA, IV versus oral CYC, plus GCs IV non-inferior to oral CYC Decreased relapse with oral 194,195
renal involvement, ANCA+a or in inducing remission; CYC (HR 0.50) at long-term

ANCA– if biopsy ~50% cumulative dose follow-up
with IV versus oral CYC
CORTAGE New diagnosis; age ≥65 yearsb IV-CYC (maximum 6 × 500 mg, Similar remission rates Fewer serious adverse 231
every 2–3 weeks) plus 9 events with lower dose CYC

months GCs versus IV-CYC and GCs
(~5.5 g) plus 26 months GCs
RAVE GPA or MPA newly diagnosed RTX versus oral CYC followed RTX non-inferior to CYC; Similar short-term adverse 196,197
or relapsing, ANCA+, SCr by AZA RTX may be better for effects, similar relapse rates
<353 μmol/l relapsing AAV with the single course of RTX
RITUVAS GPA or MPA newly diagnosed, 2 doses IV-CYC, then RTX Equivalent outcomes Similar relapse rates 198,232
renal involvement, ANCA+ versus IV-CYC

MEPEX GPA or MPA with biopsy-proven PLEX versus IV PLEX superior in rates of Long-term outcomes similar 202,233
glomerulonephritis, SCr methylprednisolone as add-on dialysis independence at

>500 μmol/l, ANCA+ or ANCA– to CYC and GCs 3 months and renal
survival at 12 months
PEXIVAS GPA or MPA newly diagnosed or 1) PLEX as add-on to CYC or 1) PLEX not superior Effects similar across 192
relapsing with renal involvement RTX and GCs 2) Low-dose GCs

subgroups
(eGFR <50 ml/min/1.73 m2) or 2) Low-dose GCs versus high- non-inferior, with fewer
pulmonary haemorrhage, ANCA+
dose GCs, plus RTX or CYC serious infections
CLEAR Phase II, newly diagnosed or Avacopan and reduced GCs or Avacopan not inferior Avacopan: faster reduction 110
relapsing GPA or MPA with renal no GCs, versus GCs in proteinuria, better quality
involvement, ANCA+ of life indices with no GCs
All groups received RTX or CYC
ADVOCATE Phase III, newly diagnosed or Avacopan versus GCs, plus Avacopan non-inferior to Less GC-related toxicity 111,234
relapsing GPA or MPA, ANCA+ RTX or CYC then AZA GCs, superior for sustained
remission at 1 year
IVIg Active GPA or MPA, >2 months CYC and GCs versus add-on Response: 14/17 IV-Ig, Effects did not extend 203
CYC and GCs, ANCA+ IV-Ig (single dose 2 g/kg) 6/17 placebo beyond 3 months
NORAM Newly diagnosed GPA or MPA, MTX (20–25 mg weekly) versus MTX non-inferior for MTX less effective for 200,235
less severe disease oral CYC remission induction extensive or pulmonary

disease; relapse more
frequent with MTX
MYCYC New diagnosis of GPA or MPA, IV-CYC versus MMF MMF non-inferior for Increased relapse with MMF, 201
eGFR >15 ml/min/1.73 m2 (2–3 g daily) remission induction especially PR3-AAV

AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; AZA, azathioprine; CYC, cyclophosphamide; eGFR, estimated glomerular
filtration rate; GCs, glucocorticoids; GPA, granulomatosis with polyangiitis; HR, hazard ratio; IV, intravenous; Ig, immunoglobulin; MMF, mycophenolate mofetil;
MPA, microscopic polyangiitis; MTX, methotrexate; PLEX, plasma exchange; PR3, leukocyte proteinase 3; RTX, rituximab; SCr, serum creatinine. aANCA+ refers to a
positive test at any time, not ANCA+ at the time of entry into study. bStudy also included polyarteritis nodosa (10 patients) and eosinophilic GPA (14 patients), out of
the 104 patients.

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Table 3 | Key clinical trials of maintenance therapies in GPA and/or MPA

Name Population Intervention Key result Other findings Refs
CYCAZAREM New diagnosis GPA or MPA, SCr Induction oral-CYC or GCs Similar relapse rates Relapse more common 236
<500 μmol/l, ANCA+a or ANCA– if 3–6 months (to remission), in GPA than MPA
biopsy then CYC 1.5 mg/kg daily
versus AZA to 12 months
WEGENT GPA or MPA in remission, initially AZA versus MTX Similar relapse rates and Long-term outcomes 237,238
treated with IV CYC and GCs, ANCA+ toxicity similar

or ANCA– if biopsy
IMPROVE GPA or MPA newly diagnosed, in MMF versus AZA Relapse more common Similar adverse event 239
remission, ANCA+ with MMF (HR 1.69) rates

REMAIN GPA or MPA in remission 18–24 months AZA or GCs for 48 months Relapse higher with More serious adverse 205
post diagnosis, ANCA+ or ANCA– with versus withdrawal by withdrawal (OR 5.96) events in continuation
biopsy 24 months group
MAINRITSAN GPA or MPA in remission after CYC RTX (500 mg, every Relapse higher with AZA at Similar rates of adverse 204,240
and GCs, ANCA+ 6 months) versus AZA 28 months (HR 6.61) events
Decreased relapse rate
at long-term follow-up
MAINRITSAN2 GPA or MPA, in remission, ANCA+ and Scheduled RTX versus RTX No difference in relapse Tailored RTX arm 209
ANCA– tailored to B cell return rates received fewer infusions

and/or ANCA
MAINRITSAN3 GPA or MPA, sustained remission, No additional treatment Relapse higher with No increase in adverse 206
2 years after RTX maintenance therapy (placebo) versus 2 further placebo: 26% versus 4% events with extended
years of RTX (HR 7.5) RTX
RITAZAREM Relapsed GPA or MPA re-induced with RTX (1 g every 4 months) RTX superior in preventing No increase in adverse 193,207
RTX and GCs, in remission, ANCA+ versus AZA relapse (HR 0.36) events with RTX
WGET GPA with active disease, ANCA+ or Standard therapyb No difference in relapse 6/89 etanercept-treated 241
ANCA– (pre-RTX era) versus add-on rates patients developed

etanercept (TNF inhibitor) solid organ tumours
Metzler et al. GPA, complete or partial remission LEF versus MTX Relapses: 13/28 patients LEF: 19% withdrawal 242
for MTX, 6/26 patients for with adverse effects at

LEF 30 mg dose
BREVAS GPA or MPA in remission 26 weeks AZA and low-dose GCs No improvement with Recruitment lower than 243
after induction, ANCA+ versus add-on belimumab belimumab, but low relapse planned due to change
rate in placebo group in clinical practice
Stegeman GPA in remission, ANCA+ or ANCA– Standard therapyb Fewer upper airways Fewer infections with 244
et al. (pre-RTX era) versus add-on relapses with co-trimoxazole

co-trimoxazole co-trimoxazole
ANCA, anti-neutrophil cytoplasmic antibody; AZA, azathioprine; CYC, cyclophosphamide; GCs, glucocorticoids; GPA, granulomatosis with polyangiitis; HR, hazard
ratio; IV, intravenous; LEF, leflunomide; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; MTX, methotrexate; OR, odds ratio; RTX, rituximab; SCr, serum
creatinine; TNF, tumour necrosis factor. aANCA+ refers to a positive test at any time, not ANCA+ at the time of entry into study. bSeveral treatment pathways were
available, depending on the severity and activity of disease and other factors, but usually involved either MTX plus GCs, then taper and try to cease GCs, or oral
CYC and GCs, then MTX or AZA taper, and try to cease GCs.
MAINRITSAN3 showed that following the initial regimens and a reduced frequency of redosing but more
2 years of treatment, a further 2 years of rituximab treat- relapse when based on biomarkers209.
ment also reduced relapse rates206. The RITAZAREM Several factors alter the risk of relapse in AAV, includ-
trial confirmed and extended these observations in a ing disease phenotype (GPA relapses more than MPA),
cohort of patients with relapsing disease in whom remis- ANCA subtype (PR3-ANCA+ patients relapse more than
sion was re-induced with rituximab and glucocorticoids, MPO-ANCA+ patients), a history of previous relapses,
with maintenance rituximab at 1,000 mg every 4 months the presence of ENT disease and the absence of severe
over 2 years193,207. Both the MAINRITSAN trial results renal disease208. Following induction therapy, persisting
and observational data point to an increase in relapse or the return of ANCA positivity, S. aureus infection,
risk after rituximab withdrawal, compared with contin- and lower cyclophosphamide exposure are linked to
uing treatment, with a mean time to flare of 2 years after increased risk of relapse, but confirmation of these
the last rituximab dose208. findings and testing in a clinical trial setting are needed
There remains widespread use of oral immuno before routine application to practice. As withdrawal of
suppressive drugs after induction of remission with therapy seems to increase the risk of relapse, patient-level
cyclophosphamide, at least until first relapse. The use factors to consider around drug withdrawal are the likely
of either CD19 counts or serum ANCA levels to guide consequences of relapse (for example, end-stage kidney
redosing of rituximab is controversial; a randomized trial disease in a patient with chronic kidney disease), adher-
comparing fixed-interval dosing to biomarker-based ence to monitoring, access to expert advice, and patients’
dosing showed a similar efficacy of these dosing views on the risks of relapse and ongoing drug exposure.
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Treatment of GPA and MPA relapses of substantial renal involvement (severe proteinuria or
Continued regular monitoring of patients with AAV impaired kidney function), cardiomyopathy, gastrointes-
after induction of remission enables the early detection tinal involvement or central nervous system involvement
of relapses with less advanced symptomatology than indicates a need for more intensive treatment, such as
at presentation and reduced delay. When a patient is a cyclophosphamide and glucocorticoid regimen anal-
considered to be having a relapse, a review of the pri- ogous to that used in GPA and MPA. Although one
mary diagnosis and vasculitis mimics, such as infection, trial failed to demonstrate a benefit of oral immuno
malignancy or recreational drug use, should be excluded. suppressive drugs in non-severe disease210, these agents
Non-adherence to prescribed medications is also often are widely used in an attempt to reduce the high glu-
a concern. One-third of relapses are severe, with conse- cocorticoid requirement typical for this disease. The
quences for renal and patient survival. The treatment of anti-IL-5 monoclonal antibody mepolizumab is a fur-
relapse follows the same principles as for initial therapy, ther therapeutic option that has demonstrated effects on
but rituximab is preferred in view of superior responses airways and allergic manifestations143. In a randomized
in the RAVE trial in relapsing patients and the beneficial clinical trial, mepolizumab was useful in most patients,
effects seen in the RITAZAREM trial193,196,197. especially for asthma and sinonasal disease, by main-
taining sustained remission, reducing relapse rates, or
Treatment of refractory disease substantially reducing the dosage or duration of gluco-
Refractory disease in AAV can be defined as a failure corticoid therapy211. Rituximab can also be used in EGPA
to achieve full control of the vasculitis-related disease but its efficacy is less well established than for GPA and
activity by 6 months, progressive disease within the first MPA, particularly for ANCA– patients with EGPA, who
3 months or relapse despite adequate ongoing therapy show frequent relapse of asthma and sinonasal disease
for maintenance of remission. It is important to differ- despite continued use of rituximab212.
entiate true ‘failure’ of a medication from non-adherence
or from symptoms caused by disease damage or mim- Monitoring disease activity
ics of vasculitis, which is most relevant in respiratory Clinical assessment and investigation follow the goals
tract disease, for which comprehensive assessment and of maintenance outlined above, namely early identifi-
treatment of any infection should accompany the eval- cation of return of disease activity, screening for drug
uation of the vasculitis. An increase in glucocorticoid toxicity, and management and recognition of comorbid-
dose, such as the use of intravenous methylprednisolone, ities. Serum creatinine measurement and urine analysis
is used in severe disease relapse but prolonged use of to detect haematuria and proteinuria should be under-
high-dose oral glucocorticoids should be avoided due taken regularly to assess disease activity and kidney
to the associated risks. Switching from cyclophospha- function. Additional elements include patient education
mide to rituximab can be considered. Adjunctive ther- and psychosocial support. Lower baseline IgG levels are
apies to consider are plasma exchange or intravenous associated with an increased risk of immunodeficiency
immunoglobin (discussed above). after rituximab treatment; IgG levels should be checked
periodically after treatment and falling levels should
Treatment of EGPA influence the decision on repeat dosing. Routine CD19
The approach to treat patients with EGPA with severe counts (a measure of B cell levels) are not required but
disease is similar to that in GPA and MPA (Table 4). may be informative in patients with incomplete response
Treatment strategies for EGPA vary according to disease to rituximab or early relapse. Microbiological assessment
manifestations and severity, and concomitant manifesta- of the nasopharynx and infection control with topical
tions of asthma should be managed assertively. The FFS antiseptic agents or antibiotics may improve sympto-
is used to stratify patients with EGPA and the presence matic management. More intensive monitoring may
Table 4 | Key clinical trials of therapies for EGPA

Trial Population Intervention (n) Key result Other findings Refs
Ribi et al. Treatment failure or relapse on GCs and IV-CYC (10) No significant differences in Most patients remained 245
GCs alone, limited disease, 1996 versus GCs and AZA (9) remission; CYC 5/10, AZA 7/9 on GCs
FFS = 0
Puéchal et al. New diagnosis, limited disease, GCs (25) versus add-on No effect on combined end No change in 210,246
1996 FFS = 0, included other AAV AZA (26) point of remission induction and exacerbations of asthma
relapse or rhinosinusitis; long-term
outcomes similar
MIRRA Relapsing or refractory EGPA, GCs (68) versus add-on Mepolizumab effective, mainly Post hoc analysis suggests 143,211
stable GC dose (7.5–50 mg) SC-mepolizumab every in allergy-related manifestations >75% of patients derived
4 weeks for 52 weeks (68) benefit
Guillevin et al. Non-severe EGPA (included PAN) GCs versus add-on PLEX No benefit, results grouped Reflects historical 247
(18 in total) together with patients with PAN grouping of disease

Guillevin et al. Severe EGPA (included PAN) IV-CYC and GCs (6) No benefit, results grouped Reflects historical 248
versus add-on PLEX (8) together with patients with PAN grouping of disease
AAV, anti-neutrophil cytoplasmic antibody-associated vasculitis; AZA, azathioprine; CYC, cyclophosphamide; EGPA, eosinophilic granulomatosis with polyangiitis;
FFS, Five Factor Score; GCs, glucocorticoids; IV, intravenous; PAN, polyarteritis nodosa; PLEX, plasma exchange; SC, subcutaneous.

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Box 4 | A patient’s experience of AAV

of malignancies, particularly non-melanoma skin can-
cer and urothelial malignancy216,217. The rates of these
Being diagnosed with a rare and potentially life-threatening disease is something that cancers are falling with reduced immunosuppressant
no one expects to happen to them. Many patients with anti-neutrophil cytoplasmic exposure, especially to cyclophosphamide, and with the
antibody-associated vasculitis (AAV) have substantial delays in time to diagnosis increased use of rituximab218. The relative risk of malig-
and may have had serious hospitalizations and organ damage by the time they are
nancy increases with therapy duration; therefore, screen-
diagnosed. However, once the initial crisis is over, the ongoing work to achieve and
maintain remission begins. It is important to note that AAV is typically a lifelong chronic ing for haematuria and skin malignancy in patients
condition that will require constant vigilance by patients and their doctors. Fortunately, exposed to cyclophosphamide should be lifelong.
there have been new treatment options for AAV in recent years, especially new biologic Prophylaxis against gastric toxicity is often prescribed
therapies. However, these medications have little or no impact on the fatigue and pain with high-dose glucocorticoids, which also increase the
caused by AAV. Thus, while patients may be ‘in remission’ with the help of ongoing risk of osteoporosis219.
immunosuppressive therapy, many of us still feel the relentless effects of this fatigue and The management of organ damage in patients with
pain daily. Patients also worry about the potential adverse effects from treatment AAV requires sub-specialist intervention by those
and about balancing treatment-induced toxicity against damage from the vasculitis with appropriate experience in coordination with the
itself. Better treatments for AAV are needed, especially less-toxic substitutes for primary physician overseeing the AAV treatment.
glucocorticoids. However, better ways to measure disease activity, such as biomarkers
Examples include surgical correction of lacrimal duct
that will distinguish our flares from symptoms caused by other factors, for example,
treatment toxicity or infections, are also needed. In addition, treatment options for obstruction, middle ear disease, nasal collapse, and
symptoms that have a major impact on our quality of life, such as fatigue and pain, and subglottic or endobronchial stenosis220. Renal trans-
which often remain unaddressed, are urgently needed. Greater patient input on setting plantation is generally successful in patients with AAV,
treatment priorities will help focus attention on our unmet quality of life needs. although opportunistic infections may be more common
Jennifer Gordon, PhD. Dr Gordon has eosinophilic granulomatosis with polyangiitis than in transplant recipients without AAV, reflecting the
and serves on the Vasculitis Foundation Vasculitis Patient-Powered Research Network. prior burden of immunosuppressive therapy for AAV.
Recurrence of vasculitis in the renal graft occurs in 2%
of transplant recipients with AAV and can lead to graft
be required for organ-specific issues, such as bronchos- failure. Long-term patient survival is similar to that of all
copy in tracheo-bronchial disease, repeat renal biopsy causes of end-stage renal disease221.
in advanced renal impairment with persisting urinary
abnormalities, and cardiac imaging (echocardiography Quality of life
and MRI) in cases of cardiac involvement. Patients are well aware of the challenges they face in
managing AAV and self-report substantial effects on
Comorbidities and treatment effects their QOL from AAV itself as well as from the burden
Infection is the most frequent serious problem in the of treatment and treatment-related toxicities (Box 4).
first year of AAV treatment. Routine prophylaxis The evolution in immunotherapeutics has transformed
against Pneumocystis jirovecii pneumonia with sulfa AAV into a chronic disease and, in consequence,
methoxazole–trimethoprim (or alternative agents) is patient priorities have realigned. Rather than focusing
recommended and may also reduce the frequency of on the spectre of major organ damage, patients rank
other bacterial infections. Independent of its value in QOL domains, such as fatigue and pain, as the greatest
Pneumocystis jirovecii prophylaxis, there is insufficient disease priorities222.
evidence to recommend the routine use of long-term sulfa There can be key differences between patient and
methoxazole–trimethoprim in PR3-ANCA+ patients clinician perceptions of these priorities. For example,
to prevent disease relapse. The avoidance of severe although patients and clinicians both rank weight gain as
drug-induced leukopenia is crucial. Rituximab-induced a major concern about glucocorticoid treatment, patients
immunodeficiency and any case of recurrent infection frequently cite ‘moon face’ and other effects on appear-
requires further immunological assessment. Cases of ance as highly concerning, whereas clinicians tend to
hypoimmunoglobulinaemia with frequent infections not consider these effects to be as important as the risk
may prompt the use of replacement immunoglobulin213. of infection. A closer assessment of patient-reported
Routine vaccination against influenza and pneumococ- QOL will provide an opportunity for better alignment
cal infection is recommended for all patients, although of patient and clinician priorities.
serological responses may be impaired, especially The characterization of a national cohort indicated
following rituximab treatment. that patients with AAV experienced substantially poorer
Venous thromboembolism should be treated with levels of physical and mental QOL than matched con-
anti-coagulation agents, although these can be problem- trols in the general population (physical QOL: OR 7.0,
atic in the setting of pulmonary haemorrhage214. The risk 95% CI 4.4–11.1; mental QOL: OR 2.5, 95% CI 1.7–3.6),
of cardiovascular events is markedly raised in patients even though the vast majority (80%) of patients had
with more extensive disease, those without PR3-ANCA achieved disease remission5.
and in the presence of renal impairment174,215. There is Modern induction agents certainly result in notice-
no current advice concerning the reduction of these able improvements in QOL but gains are modest and
risks that is specific to patients with AAV, although patient QOL rarely returns to normal levels196. Several
careful attention to the management of hypertension and factors may explain this situation. First, high-dose gluco-
hyperlipidaemia is recommended. corticoids remain integral to standard care but they have
Cyclophosphamide and other oral immuno multiple toxic effects, including on QOL domains such
suppressive drugs are associated with an increased risk as mental health223, which should be assessed using, for
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example, the Glucocorticoid Toxicity Index224. Second, with the development of effective biomarkers to better
almost all studies of QOL in patients with AAV have define disease activity and predict relapse. More precise,
used generic questionnaires, such as the 36-item Short effective and less toxic treatments require better knowl-
Form Health Survey (SF-36), the EuroQol-5 Dimension edge, a continued recognition of unmet clinical needs,
(EQ-5D) and the Health Assessment Questionnaire, and additional strategic, successful and well-designed
which may not capture AAV-specific issues. international collaborative clinical trials. These efforts
The OMERACT Vasculitis Working Group devel- must be combined with more explicit recognition of
oped a 29-item patient-reported outcome (PRO) tool, important patient-centred outcomes, both in trials and
the AAV-PRO questionnaire225,226, which covers six in clinical practice. EGPA, as an even less common form
domains (organ-specific symptoms, systemic symp- of AAV with different clinical features to GPA and MPA,
toms, treatment adverse effects, social and emotional poses great challenges. In EGPA, even more than in GPA
effects, concerns about the future, and physical func- and MPA, multidisciplinary and international collabo-
tion), following patient qualitative interviews to address rations are required to improve the QOL of people with
this unmet need. The AAV-PRO is being integrated into this disease. Table 5 summarizes some of the emerging
ongoing randomized controlled trials. Similarly, the therapies and biomarkers in AAV.
Patient-Reported Outcomes Measurement Information Better diagnostic and classification criteria of
System (PROMIS) covers fatigue, physical functioning AAV will assist in understanding the disease, in clin-
and pain interference. Both PRO systems assess func- ical studies and in improvements in patient care. The
tion and QOL, are complementary, and require further near-complete DCVAS has developed data-driven clas-
validation, but they offer options to ensure patients’ per- sification criteria for systemic vasculitides and should
spectives are considered when assessing disease activity provide improved standardized criteria. Furthermore,
in AAV225,226. whereas EGPA is clearly a distinct disease entity, for GPA
Impairments in QOL are the result of multiple fac- and MPA, the relationships and overlap between the syn-
tors, not only of active inflammatory disease but also dromic classifications (GPA and MPA) and the presence
of disease damage, although they seem to be primarily of autoreactivity to either PR3 or MPO (PR3-ANCA+ or
related to psychosocial factors, such as fatigue and dys- MPO-ANCA+) must be more clearly identified to aid
functional coping strategies5, and skeletal dysfunction. progress in understanding the disease, in clinical trial
Persistently high levels of fatigue that do not change after design and in management strategies. These efforts
treatment occurred in some patients in a SF-36 vitality are not only important for improved induction ther-
domain sub-analysis of the MYCYC and RITUXIVAS apies but also for defining treatment duration and the
studies227. Furthermore, there were marked disparities in management of relapse.
physical QOL, including reduced knee extension (76%), Epidemiologically, there is inadequate data pertain-
among patients with AAV compared with healthy con- ing to EGPA in general and a clear need to define the
trols. This reduced knee extension was associated with occurrence of all AAV types in Africa and South Asia. A
an impaired SF-36 physical component score, as were better definition of the nature and burden of the disease
metrics of pre-existing muscle strength228. is likely to improve clinical care and outcomes, while
As QOL differs for each patient, measuring QOL a more detailed understanding of the epidemiological
can also be helpful in developing more personalized associations will inform disease pathogenesis. The rec-
treatment approaches. Studies examining whether ognition that AAV is an autoimmune condition and the
physical activity improves fatigue in patients with AAV elucidation of the role of ANCAs in causing injury have
are underway229. As disease assessment in AAV should been major advances. Nonetheless, the complexity of
include function or QOL168, reliable PRO tools are cru- AAVs and the inadequacies of current therapies demand
cial not only for monitoring individual patients but also a more detailed understanding of pathogenesis. Many
for high-quality assessment of the effect of AAV and the questions remain. Can elucidating the genetic contribu-
success of its therapies. tions to AAV pathogenesis, including that of EGPA, lead
to pathway-directed therapies, either with new therapies
Outlook or by repurposing existing therapeutics? Why are only
Substantial progress has been made in understanding some ANCAs pathogenetic and, if we understand this,
and treating AAVs. GPA, MPA and EGPA have gone can we measure specific ANCA subtypes to develop more
from diseases with a high mortality within 1–2 years effective biomarkers? As there is substantial deposition
of the onset of symptoms to chronic conditions that of ANCA antigens in affected tissues, why is immuno-
require lifelong specialist management. However, major globulin deposition not more prominent? Why are some
challenges remain. AAVs are still responsible for sub- organs and tissues preferentially affected? Why do
stantial morbidity and mortality, both from the diseases some individuals lose tolerance to PR3 or MPO, whereas
themselves and from their treatments. Most treatments most do not, when these neutrophil proteins are fre-
are fairly non-specific and come with undesirable quently released in an immunologically ‘dangerous’ infec-
immune and metabolic adverse effects. Furthermore, tious and inflammatory context? Can immunological
the optimal duration of therapy is uncertain, in part tolerance be re-established by antigen-specific immuno
because of a lack of reliable predictors of relapse. More modulation? Although much is known about events in
effective management of AAV in the future will rely the acute effector phase of injury, key events in more
on a better understanding of the clinical aspects of chronic disease and the role of T cell and B cell memory
the disease and of disease-causing processes, together are unclear. A better understanding of these issues has the

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Table 5 | Selected potential new management strategies and biomarkers in AAVa

Treatment or biomarker Potential strategy Stage of development
Treatments
Complement inhibition Avacopan (small-molecule C5aR Phase III trial completed
antagonist)110 (NCT02994927)111
SYK inhibition Small-molecule inhibitors249 Preclinical model proof-of-concept
studies (MPO-AAV)
Eosinophils and TH2 cells Direct or indirect targeting of eosinophils Non-inferiority clinical trial comparing
in EGPA and TH2 cellsb, for example, anti-IL-5R mepolizumab with benralizumab
(benralizumab), TH2 cell and eosinophil (NCT04157348)
chemokines
BAFF inhibition Belimumab243 as add-on to rituximab Phase II trial in progress (NCT03967925)
Co-stimulatory signal Abatacept250 Phase II trial in progress (NCT02108860)
blockade
T cell or TH cell-defining Monoclonal antibodies, for example, Preclinical model proof-of-concept
cytokine inhibition ustekinumab (anti-IL-12p40)121,218 studies published (MPO-AAV)138,251
Tolerogenic therapies Peptide and antigen tolerogenic platforms Preclinical model proof-of-concept
studies published (MPO-AAV)252
Biomarkers
Renal activity or flare Urinary soluble CD163 with or without other Further clinical studies for biomarker
biomarkers, for example, soluble CD25 and utility
CCL2 (refs165,230)
Overall risk of flare Markers of T cell activity and exhaustion in Trials of 17-gene qPCR stratification for
AAV135,136 prognosis in other diseases144
Impending flare CD5+ B cells253 Clinical studies (NCT03906227)
AAV, anti-neutrophil cytoplasmic antibody-associated vasculitis; BAFF, B cell-activating factor; C5aR, C5a receptor; CCL2,
CC-chemokine ligand 2; EGPA, eosinophilic granulomatosis with polyangiitis; MPO, myeloperoxidase; qPCR, quantitative PCR;
SYK, spleen tyrosine kinase; TH cell, T helper cell. aOnly those for which a rationale has been established are included. bIn addition
to anti-IL-5 strategies already in clinical use.
potential to move the goalposts in developing treatments in inducing and maintaining remission. The goal in the
that induce long-lasting remission and tolerance. treatment of AAV is not only to supress disease but also
Key uncertainties in the care of patients with AAV to restore tolerance. Currently, there are no clear markers
include the optimal duration and intensity of mainte- of tolerance to reassure clinicians and patients when ceas-
nance therapy in an individual patient and the lack of ing immunosuppression and that can be used as surrogate
biomarkers that signal relapses. Better biomarkers, either markers in trials of new tolerogenic, curative therapies.
singly or in combination, to predict severity and relapse Whereas tolerogenic strategies that have been applied to
risk would lead to a more precise treatment approach. other diseases might be suitable for AAV, outcome measures
Emerging biomarkers include urinary sCD163, which in AAV are unclear although, at least in the case of MPO
could be useful in determining renal relapse with or as an autoantigen, progress has been made in defining
without other markers165,230. Following from observa- key epitopes.
tions that relapse risk in patients with AAV is associated A multidisciplinary approach and patient engage-
with an ‘active’ T cell signature (that is, reduced expres- ment would result in a more integrated treatment
sion of genes related to T cell exhaustion)136, prospec- strategy and improved outcomes in these complex multi
tive clinical trials are underway to determine whether system diseases. Clinicians and patients should work
markers of this signature can inform treatment inten- together in a clinical setting to increase the involvement
sity. Other potential biomarkers are emerging and are of patients in their own care and in treatment decisions.
undergoing further evaluation166. There are several dimensions to this issue. The educa-
The potential for complement inhibition (by targeting tional needs of patients newly diagnosed with AAV are
C5aR) is one of several therapeutic strategies aimed at limit- high and the rarity of the conditions makes meeting
ing neutrophil activation. Complement inhibition therapies these needs complicated. In the clinical trial environ-
could reduce or replace the current reliance on gluco- ment, the use of PRO measures, such as AAV-PRO,
corticoids in induction therapy regimens, as in phase II should be mandatory. Interventional trials that include
and III trials of C5aR inhibition110,111. Glucocorticoids are outcome measures that focus on improving physical and
a pillar of maintenance therapy for many patients and this mental QOL are just beginning229. AAVs are challeng-
reliance needs to be mitigated. In EGPA, further clinical ing and complex conditions but, with an integrated, col-
trials in IL-5–IL-5R blockade will hopefully improve the laborative approach that includes considerable patient
therapeutic options in this disease. Much attention has jus- involvement, great progress can be made in improving
tifiably been given to ANCA–neutrophil-mediated events the lives of people with these diseases.
in AAV but the more selective inhibition of the under-
pinning T cell and B cell autoimmunity also has potential Published online xx xx xxxx
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1. Watts, R. A. et al. Classification, epidemiology and 22. Stegeman, C. A. et al. Association of chronic nasal 44. Sinico, R. A. et al. Prevalence and clinical significance of
clinical subgrouping of antineutrophil cytoplasmic carriage of Staphylococcus aureus and higher relapse antineutrophil cytoplasmic antibodies in Churg-Strauss
antibody (ANCA)-associated vasculitis. Nephrol. Dial. rates in Wegener granulomatosis. Ann. Intern. Med. syndrome. Arthritis Rheumatol. 52, 2926–2935
Transplant. 30 (Suppl. 1), i14–i22 (2015). 120, 12–17 (1994). (2005).
A granular and comprehensive review of A study that provides evidence for a putative 45. Nakazawa, D. et al. Enhanced formation and disordered
contemporary AAV epidemiology. causal role for infection in the relapse of GPA. regulation of NETs in myeloperoxidase-ANCA-associated
2. Berti, A., Cornec, D., Crowson, C. S., Specks, U. & 23. Laudien, M. et al. Nasal carriage of Staphylococcus microscopic polyangiitis. J. Am. Soc. Nephrol. 25,
Matteson, E. L. The epidemiology of antineutrophil aureus and endonasal activity in Wegener’s 990–997 (2014).
cytoplasmic autoantibody-associated vasculitis in granulomatosis as compared to rheumatoid arthritis 46. Ooi, J. D. et al. A plasmid-encoded peptide from
Olmsted County, Minnesota: a twenty-year US and chronic rhinosinusitis with nasal polyps. Clin. Exp. Staphylococcus aureus induces anti-myeloperoxidase
population-based study. Arthritis Rheumatol. 69, Rheumatol. 28 (Suppl. 57), 51–55 (2010). nephritogenic autoimmunity. Nat. Comm. 10, 3392
2338–2350 (2017). 24. Lane, S. E., Watts, R. A., Bentham, G., Innes, N. J. & (2019).
3. Mohammad, A. J., Jacobsson, L. T., Mahr, A. D., Scott, D. G. Are environmental factors important in 47. Jones, B. E. et al. Gene-specific DNA methylation
Sturfelt, G. & Segelmark, M. Prevalence of Wegener’s primary systemic vasculitis? A case-control study. changes predict remission in patients with ANCA-
granulomatosis, microscopic polyangiitis, polyarteritis Arthritis Rheumatol. 48, 814–823 (2003). associated vasculitis. J. Am. Soc. Nephrol. 28,
nodosa and Churg-Strauss syndrome within a defined 25. Nuyts, G. D. et al. Wegener granulomatosis is 1175–1187 (2017).
population in southern Sweden. Rheumatology 46, associated to exposure to silicon-compounds-a case- 48. Kessenbrock, K. et al. Netting neutrophils in
1329–1337 (2007). control study. Nephrol. Dial. Transpl. 10, 1162–1165 autoimmune small-vessel vasculitis. Nat. Med. 15,
4. Tan, J. A. et al. Mortality in ANCA-associated (1995). 623–625 (2009).
vasculitis: a meta-analysis of observational studies. 26. Yashiro, M. et al. Significantly high regional morbidity 49. Martin, K. R. & Witko-Sarsat, V. Proteinase 3: the odd
Ann. Rheum. Dis. 76, 1566–1574 (2017). of MPO-ANCA-related angitis and/or nephritis with one out that became an autoantigen. J. Leuk. Biol.
5. Basu, N. et al. The characterisation and determinants respiratory tract involvement after the 1995 Great 102, 689–698 (2017).
of quality of life in ANCA associated vasculitis. Earthquake in Kobe (Japan). Am. J. Kidney Dis. 35, 50. Witko-Sarsat, V. et al. A large subset of neutrophils
Ann. Rheum. Dis. 73, 207–211 (2014). 889–895 (2000). expressing membrane proteinase 3 is a risk factor for
6. Raimundo, K., Farr, A. M., Kim, G. & Duna, G. Clinical 27. Takeuchi, Y. et al. The influence of the Great East vasculitis and rheumatoid arthritis. J. Am. Soc. Nephrol.
and economic burden of antineutrophil cytoplasmic Japan earthquake on microscopic polyangiitis: a 10, 1224–1233 (1999).
antibody-associated vasculitis in the United States. retrospective observational study. PLoS ONE 12, 51. Jerke, U. et al. Complement receptor Mac-1 is an
J. Rheumatol. 42, 2383–2391 (2015). e0177482 (2017). adaptor for NB1 (CD177)-mediated PR3-ANCA
7. Knight, A., Ekbom, A., Brandt, L. & Askling, J. 28. Farquhar, H. J. et al. Incidence of anti-neutrophil neutrophil activation. J. Biol. Chem. 286, 7070–7081
Increasing incidence of Wegener’s granulomatosis in cytoplasmic antibody-associated vasculitis before and (2011).
Sweden, 1975–2001. J. Rheumatol. 33, 2060–2063 after the February 2011 Christchurch Earthquake. 52. Odobasic, D., Kitching, A. R. & Holdsworth, S. R.
(2006). Intern. Med. J. 47, 57–61 (2017). Neutrophil-mediated regulation of innate and adaptive
8. Liu, L. J., Chen, M., Yu, F., Zhao, M. H. & Wang, H. Y. 29. Cotch, M. F. et al. The epidemiology of Wegener’s immunity: the role of myeloperoxidase. J. Immunol. Res.
Evaluation of a new algorithm in classification of granulomatosis. Estimates of the five-year period 2016, 2349817 (2016).
systemic vasculitis. Rheumatology 47, 708–712 prevalence, annual mortality, and geographic disease 53. Reiding, K. R. et al. Neutrophil myeloperoxidase
(2008). distribution from population-based data sources. harbors distinct site-specific peculiarities in its
9. Watts, R. A. et al. Renal vasculitis in Japan and the Arthritis Rheumatol. 39, 87–92 (1996). glycosylation. J. Biol. Chem. 294, 20233–20245
UK — are there differences in epidemiology and 30. Li, J. et al. The frequency of ANCA-associated (2019).
clinical phenotype? Nephrol. Dial. Transpl. 23, vasculitis in a national database of hospitalized 54. Kain, R. et al. Molecular mimicry in pauci-immune
3928–3931 (2008). patients in China. Arthritis Res. Ther. 20, 226 (2018). focal necrotizing glomerulonephritis. Nat. Med. 14,
10. Watts, R. A. et al. Geoepidemiology of systemic 31. Gatenby, P. A., Lucas, R. M., Engelsen, O., 1088–1096 (2008).
vasculitis: comparison of the incidence in two regions Ponsonby, A. L. & Clements, M. Antineutrophil 55. Pendergraft, W. F. et al. Autoimmunity is triggered by
of Europe. Ann. Rheum. Dis. 60, 170–172 (2001). cytoplasmic antibody-associated vasculitides: could cPR-3(105-201), a protein complementary to human
11. O’Donnell, J. L., Stevanovic, V. R., Frampton, C., geographic patterns be explained by ambient autoantigen proteinase-3. Nat. Med. 10, 72–79
Stamp, L. K. & Chapman, P. T. Wegener’s ultraviolet radiation? Arthritis Rheumatol. 61, (2004).
granulomatosis in New Zealand: evidence for a 1417–1424 (2009). 56. Yang, J. et al. ANCA patients have T cells responsive
latitude-dependent incidence gradient. Intern. Med. J. 32. McDermott, G. et al. Association of cigarette smoking to complementary PR-3 antigen. Kidney Int. 74,
37, 242–246 (2007). with antineutrophil cytoplasmic antibody-associated 1159–1169 (2008).
12. Cao, Y. et al. DRB1*15 allele is a risk factor for vasculitis. JAMA Intern. Med. 180, 1–7 (2020). 57. Suzuki, K. et al. A novel autoantibody against moesin
PR3-ANCA disease in African Americans. J. Am. Soc. 33. Hutton, H. L., Holdsworth, S. R. & Kitching, A. R. in the serum of patients with MPO-ANCA-associated
Nephrol. 22, 1161–1167 (2011). ANCA-associated vasculitis: pathogenesis, models, vasculitis. Nephrol. Dial. Transpl. 29, 1168–1177
13. Mahr, A., Guillevin, L., Poissonnet, M. & Ayme, S. and preclinical testing. Sem. Nephrol. 37, 418–435 (2014).
Prevalences of polyarteritis nodosa, microscopic (2017). 58. Bautz, D. J. et al. Antibodies with dual reactivity to
polyangiitis, Wegener’s granulomatosis, and Churg- 34. Knight, A., Sandin, S. & Askling, J. Risks and relative plasminogen and complementary PR3 in PR3-ANCA
Strauss syndrome in a French urban multiethnic risks of Wegener’s granulomatosis among close vasculitis. J. Am. Soc. Nephrol. 19, 2421–2429 (2008).
population in 2000: a capture-recapture estimate. relatives of patients with the disease. Arthritis 59. Berden, A. E. et al. Anti-plasminogen antibodies
Arthritis Rheumatol. 51, 92–99 (2004). Rheumatol. 58, 302–307 (2008). compromise fibrinolysis and associate with renal
14. Pearce, F. A. et al. Incidence of ANCA-associated 35. Jagiello, P. et al. New genomic region for Wegener’s histology in ANCA-associated vasculitis. J. Am. Soc.
vasculitis in a UK mixed ethnicity population. granulomatosis as revealed by an extended association Nephrol. 21, 2169–2179 (2010).
Rheumatology 55, 1656–1663 (2016). screen with 202 apoptosis-related genes. Hum. Genet. 60. McCall, A. S. et al. Inhibitory anti-peroxidasin
15. Iudici, M. et al. Childhood-onset granulomatosis with 114, 468–477 (2004). antibodies in pulmonary-renal syndromes. J. Am. Soc.
polyangiitis and microscopic polyangiitis: systematic 36. Lyons, P. A. et al. Genetically distinct subsets within Nephrol. 29, 2619–2625 (2018).
review and meta-analysis. Orphanet J. Rare Dis. 11, ANCA-associated vasculitis. N. Engl. J. Med. 367, 61. Simon, A. et al. Detection of anti-pentraxin-3
141 (2016). 214–223 (2012). autoantibodies in ANCA-associated vasculitis.
16. Falk, R. J., Hogan, S., Carey, T. S. & Jennette, J. C. 37. Xie, G. et al. Association of granulomatosis with PLoS ONE 11, e0147091 (2016).
Clinical course of anti-neutrophil cytoplasmic polyangiitis (Wegener’s) with HLA-DPB1*04 and 62. Roth, A. J. et al. Anti-LAMP-2 antibodies are not
autoantibody-associated glomerulonephritis SEMA6A gene variants: evidence from genome-wide prevalent in patients with antineutrophil cytoplasmic
and systemic vasculitis. The Glomerular Disease analysis. Arthritis Rheumatol. 65, 2457–2468 (2013). autoantibody glomerulonephritis. J. Am. Soc. Nephrol.
Collaborative Network. Ann. Intern. Med. 113, 38. Merkel, P. A. et al. Identification of functional and 23, 545–555 (2012).
656–663 (1990). expression polymorphisms associated with risk for 63. Tadema, H., Kallenberg, C. G., Stegeman, C. A.
17. Tidman, M., Olander, R., Svalander, C. & Danielsson, D. antineutrophil cytoplasmic autoantibody-associated & Heeringa, P. Reactivity against complementary
Patients hospitalized because of small vessel vasculitis. Arthritis Rheumatol. 69, 1054–1066 proteinase-3 is not increased in patients with
vasculitides with renal involvement in the period (2017). PR3-ANCA-associated vasculitis. PLoS ONE 6,
1975-95: organ involvement, anti-neutrophil Lyons et al. (2012), Xie et al. (2013) and Merkel e17972 (2011).
cytoplasmic antibodies patterns, seasonal attack rates et al. (2017) provide clear evidence for a genetic 64. Olson, S. W. et al. Asymptomatic autoantibodies
and fluctuation of annual frequencies. J. Intern. Med. contribution to differences between PR3-AAV and associate with future anti-glomerular basement
244, 133–141 (1998). MPO-AAV and link PR3-AAV to variation in the membrane disease. J. Am. Soc. Nephrol. 22,
18. Watts, R. A., Mooney, J., Skinner, J., Scott, D. G. & autoantigen itself. 1946–1952 (2011).
Macgregor, A. J. The contrasting epidemiology of 39. Siminovitch, K. A. PTPN22 and autoimmune disease. 65. Cui, Z., Zhao, M. H., Segelmark, M. & Hellmark, T.
granulomatosis with polyangiitis (Wegener’s) and Nat. Genet. 36, 1248–1249 (2004). Natural autoantibodies to myeloperoxidase,
microscopic polyangiitis. Rheumatology 51, 926–931 40. Sun, B. B. et al. Genomic atlas of the human plasma proteinase 3, and the glomerular basement
(2012). proteome. Nature 558, 73–79 (2018). membrane are present in normal individuals.
19. Draibe, J. et al. Seasonal variations in the onset of 41. Niehrs, A. et al. A subset of HLA-DP molecules serve Kidney Int. 78, 590–597 (2010).
positive and negative renal ANCA-associated vasculitis as ligands for the natural cytotoxicity receptor NKp44. 66. Tan, D. S. et al. Thymic deletion and regulatory T cells
in Spain. Clin. Kidney J. 11, 468–473 (2018). Nat. Immunol. 20, 1129–1137 (2019). prevent antimyeloperoxidase GN. J. Am. Soc. Nephrol.
20. Mahr, A. et al. Seasonal variations in onset of 42. Lyons, P. A. et al. Genome-wide association study of 24, 573–585 (2013).
Wegener’s granulomatosis: increased in summer? eosinophilic granulomatosis with polyangiitis reveals 67. Abdulahad, W. H. et al. Functional defect of circulating
J. Rheumatol. 33, 1615–1622 (2006). genomic loci stratified by ANCA status. Nat. Commun. regulatory CD4+ T cells in patients with Wegener’s
21. Aries, P. M., Herlyn, K., Reinhold-Keller, E. & Latza, U. 10, 5120 (2019). granulomatosis in remission. Arthritis Rheumatol. 56,
No seasonal variation in the onset of symptoms of 43. Sablé-Fourtassou, R. et al. Antineutrophil cytoplasmic 2080–2091 (2007).
445 patients with ‘Wegener’s granulomatosis. Arthritis antibodies and the Churg-Strauss syndrome. Ann. 68. Free, M. E. et al. Patients with antineutrophil
Rheumatol. 59, 904–904 (2008). Intern. Med. 143, 632–638 (2005). cytoplasmic antibody-associated vasculitis have

0123456789();
Primer
defective Treg cell function exacerbated by the 90. Jennette, J. C. & Nachman, P. H. ANCA pathogenesis of disease mediated by anti-neutrophil
presence of a suppression-resistant effector cell glomerulonephritis and vasculitis. Clin. J. Am. Soc. cytoplasmic autoantibodies. Am. J. Pathol. 170,
population. Arthritis Rheumatol. 65, 1922–1933 Nephrol. 12, 1680–1691 (2017). 52–64 (2007).
(2013). 91. Hong, Y. et al. Anti-neutrophil cytoplasmic antibodies 113. Huugen, D. et al. Inhibition of complement factor C5
69. Bunch, D. O. et al. Decreased CD5+ B cells in active stimulate release of neutrophil microparticles. protects against anti-myeloperoxidase antibody-
ANCA vasculitis and relapse after rituximab. Clin. J. J. Am. Soc. Nephrol. 23, 49–62 (2012). mediated glomerulonephritis in mice. Kidney Int. 71,
Am. Soc. Nephrol. 8, 382–391 (2013). 92. Xiao, H. et al. Antineutrophil cytoplasmic 646–654 (2007).
70. Wilde, B. et al. Regulatory B cells in ANCA-associated autoantibodies specific for myeloperoxidase cause 114. Hao, J., Meng, L. Q., Xu, P. C., Chen, M. & Zhao, M. H.
vasculitis. Ann. Rheum. Dis. 72, 1416–1419 (2013). glomerulonephritis and vasculitis in mice. J. Clin. p38MAPK, ERK and PI3K signaling pathways are
71. Free, M. E. et al. Restricted myeloperoxidase Invest. 110, 955–963 (2002). involved in C5a-primed neutrophils for ANCA-
epitopes drive the adaptive immune response in MPO- A key study that uses experimental models to mediated activation. PLoS ONE 7, e38317 (2012).
ANCA vasculitis. J. Autoimm. 106, 102306 (2020). demonstrate the pathogenicity of anti-MPO 115. Dick, J. et al. C5a receptor 1 promotes autoimmunity,
72. Ooi, J. D. et al. The immunodominant myeloperoxidase antibodies in vivo. neutrophil dysfunction and injury in experimental
T-cell epitope induces local cell-mediated injury in 93. Bansal, P. J. & Tobin, M. C. Neonatal microscopic anti-myeloperoxidase glomerulonephritis. Kidney Int.
antimyeloperoxidase glomerulonephritis. Proc. Natl polyangiitis secondary to transfer of maternal 93, 615–625 (2018).
Acad. Sci. USA 109, E2615–E2624 (2012). myeloperoxidase-antineutrophil cytoplasmic antibody 116. Freeley, S. J. et al. Experimentally-induced anti-
This study uses experimental models to demonstrate resulting in neonatal pulmonary hemorrhage and myeloperoxidase vasculitis does not require
the role of MPO-specific CD4+ T cells in effector renal involvement. Ann. Allergy Asthma Immunol. 93, properdin, MASP-2 or bone marrow-derived C5.
responses and defines a nephritogenic MPO T cell 398–401 (2004). J. Pathol. 240, 61–71 (2016).
epitope. 94. Xiao, H. et al. The role of neutrophils in the induction 117. Gou, S. J., Yuan, J., Wang, C., Zhao, M. H. & Chen, M.
73. Roth, A. J. et al. Epitope specificity determines of glomerulonephritis by anti-myeloperoxidase Alternative complement pathway activation products
pathogenicity and detectability in ANCA-associated antibodies. Am. J. Pathol. 167, 39–45 (2005). in urine and kidneys of patients with ANCA-associated
vasculitis. J. Clin. Invest. 123, 1773–1783 (2013). 95. Pfister, H. et al. Antineutrophil cytoplasmic GN. Clin. J. Am. Soc. Nephrol. 8, 1884–1891 (2013).
74. Chang, J. et al. CD8+ T cells effect glomerular injury in autoantibodies against the murine homolog 118. Chen, M., Jayne, D. R. W. & Zhao, M. H. Complement
experimental anti-myeloperoxidase GN. J. Am. Soc. of proteinase 3 (Wegener autoantigen) are in ANCA-associated vasculitis: mechanisms and
Nephrol. 28, 47–55 (2017). pathogenic in vivo. Blood 104, 1411–1418 implications for management. Nat. Rev. Nephrol. 13,
75. Falk, R. J., Becker, M., Terrell, R. & Jennette, J. C. (2004). 359–367 (2017).
Anti-myeloperoxidase autoantibodies react with native 96. Little, M. A. et al. Anti-proteinase 3 anti-neutrophil 119. Manenti, L. et al. Association of serum C3 concentration
but not denatured myeloperoxidase. Clin. Exp. Immunol. cytoplasm autoantibodies recapitulate systemic and histologic signs of thrombotic microangiopathy with
89, 274–278 (1992). vasculitis in mice with a humanized immune system. outcomes among patients with ANCA-associated renal
76. Bini, P. et al. Antineutrophil cytoplasmic autoantibodies PLoS ONE 7, e28626 (2012). vasculitis. Clin. J. Am. Soc. Nephrol. 10, 2143–2151
in Wegener’s granulomatosis recognize conformational 97. Charles, L. A., Falk, R. J. & Jennette, J. C. Reactivity (2015).
epitope(s) on proteinase 3. J. Immunol. 149, 1409–1415 of antineutrophil cytoplasmic autoantibodies with 120. Augusto, J. F. et al. Low serum complement C3 levels
(1992). mononuclear phagocytes. J. Leuk. Biol. 51, 65–68 at diagnosis of renal ANCA-associated vasculitis is
77. Audrain, M. A. et al. Anti-native and recombinant (1992). associated with poor prognosis. PLoS ONE 11,
myeloperoxidase monoclonals and human 98. O’Brien, E. C. et al. Intermediate monocytes in e0158871 (2016).
autoantibodies. Clin. Exp. Immunol. 107, 127–134 ANCA vasculitis: increased surface expression 121. Calderwood, J. W., Williams, J. M., Morgan, M. D.,
(1997). of ANCA autoantigens and IL-1β secretion in response Nash, G. B. & Savage, C. O. ANCA induces β2 integrin
78. Nagai, M. et al. Serum levels of BAFF and APRIL to anti-MPO antibodies. Sci. Rep. 5, 11888 (2015). and CXC chemokine-dependent neutrophil-endothelial
in myeloperoxidase anti-neutrophil cytoplasmic 99. Peschel, A. et al. Autoantibodies to hLAMP-2 in cell interactions that mimic those of highly cytokine-
autoantibody-associated renal vasculitis: association ANCA-negative pauci-immune focal necrotizing GN. activated endothelium. J. Leuk. Biol. 77, 33–43
with disease activity. Nephron Clin. Pract. 118, J. Am. Soc. Nephrol. 25, 455–463 (2014). (2005).
c339–c345 (2011). 100. Espy, C. et al. Sialylation levels of anti-proteinase 122. Little, M. A. et al. Antineutrophil cytoplasm antibodies
79. Holden, N. J. et al. ANCA-stimulated neutrophils 3 antibodies are associated with the activity of directed against myeloperoxidase augment leukocyte-
release BLyS and promote B cell survival: a clinically granulomatosis with polyangiitis (Wegener’s). Arthritis microvascular interactions in vivo. Blood 106,
relevant cellular process. Ann. Rheum. Dis. 70, Rheumatol. 63, 2105–2115 (2011). 2050–2058 (2005).
2229–2233 (2011). 101. Lardinois, O. M. et al. Immunoglobulins G from 123. Nolan, S. L. et al. Mechanisms of ANCA-mediated
80. Oleinika, K., Mauri, C. & Salama, A. D. Effector and patients with ANCA-associated vasculitis are atypically leukocyte-endothelial cell interactions in vivo.
regulatory B cells in immune-mediated kidney disease. glycosylated in both the Fc and Fab regions and the J. Am. Soc. Nephrol. 19, 973–984 (2008).
Nat. Rev. Nephrol. 15, 11–26 (2019). relation to disease activity. PLoS ONE 14, e0213215 124. Brouwer, E. et al. Predominance of IgG1 and IgG4
81. Steinmetz, O. M. et al. Analysis and classification (2019). subclasses of anti-neutrophil cytoplasmic
of B-cell infiltrates in lupus and ANCA-associated 102. Ciavatta, D. J. et al. Epigenetic basis for aberrant autoantibodies (ANCA) in patients with Wegener’s
nephritis. Kidney Int. 74, 448–457 (2008). upregulation of autoantigen genes in humans with granulomatosis and clinically related disorders.
82. Kelley, J. M. et al. IgA and IgG antineutrophil ANCA vasculitis. J. Clin. Invest. 120, 3209–3219 Clin. Exp. Immunol. 83, 379–386 (1991).
cytoplasmic antibody engagement of Fc receptor (2010). 125. Abdulahad, W. H. et al. Increased frequency of
genetic variants influences granulomatosis with 103. Ohlsson, S. M. et al. Neutrophils from vasculitis circulating IL-21 producing Th-cells in patients with
polyangiitis. Proc. Natl Acad. Sci. USA 108, patients exhibit an increased propensity for activation granulomatosis with polyangiitis (GPA). Arthritis Res.
20736–20741 (2011). by anti-neutrophil cytoplasmic antibodies. Clin. Exp. Ther. 15, R70 (2013).
83. Jayne, D. R. et al. Severe pulmonary hemorrhage Immunol. 176, 363–372 (2014). 126. Abdulahad, W. H., Kallenberg, C. G., Limburg, P. C. &
and systemic vasculitis in association with circulating 104. Ohlsson, S. et al. Neutrophils from ANCA-associated Stegeman, C. A. Urinary CD4+effector memory T cells
anti-neutrophil cytoplasm antibodies of IgM class only. vasculitis patients show an increased capacity to reflect renal disease activity in antineutrophil
Clin. Nephrol. 32, 101–106 (1989). activate the complement system via the alternative cytoplasmic antibody-associated vasculitis. Arthritis
84. Falk, R. J., Terrell, R. S., Charles, L. A. & Jennette, J. C. pathway after ANCA stimulation. PLoS ONE 14, Rheumatol. 60, 2830–2838 (2009).
Anti-neutrophil cytoplasmic autoantibodies induce e0218272 (2019). 127. Gephardt, G. N., Ahmad, M. & Tubbs, R. R.
neutrophils to degranulate and produce oxygen 105. Summers, S. A. et al. Intrinsic renal cell and leukocyte- Pulmonary vasculitis (Wegener’s granulomatosis).
radicals in vitro. Proc. Natl Acad. Sci. USA 87, derived TLR4 aggravate experimental anti-MPO Immunohistochemical study of T and B cell markers.
4115–4119 (1990). glomerulonephritis. Kidney Int. 78, 1263–1274 Am. J. Med. 74, 700–704 (1983).
This study links ANCAs to the pathogenesis of AAV (2010). 128. Weidner, S., Carl, M., Riess, R. & Rupprecht, H. D.
by demonstrating that ANCAs activate neutrophils 106. Tadema, H. et al. Bacterial DNA motifs trigger ANCA Histologic analysis of renal leukocyte infiltration in
in vitro. production in ANCA-associated vasculitis in remission. antineutrophil cytoplasmic antibody-associated
85. Williams, J. M. et al. Activation of the G(i) heterotrimeric Rheumatology 50, 689–696 (2011). vasculitis: importance of monocyte and neutrophil
G protein by ANCA IgG F(ab’)2 fragments is necessary 107. Holle, J. U. et al. Toll-like receptor TLR2 and TLR9 infiltration in tissue damage. Arthritis Rheumatol. 50,
but not sufficient to stimulate the recruitment of ligation triggers neutrophil activation in granulomatosis 3651–3657 (2004).
those downstream mediators used by intact ANCA with polyangiitis. Rheumatology 52, 1183–1189 129. O’Sullivan, K. M. et al. Renal participation of
IgG. J. Am. Soc. Nephrol. 14, 661–669 (2003). (2013). myeloperoxidase in antineutrophil cytoplasmic
86. Hewins, P., Williams, J. M., Wakelam, M. J. & 108. Wang, C. et al. High mobility group box 1 contributes antibody (ANCA)-associated glomerulonephritis.
Savage, C. O. Activation of Syk in neutrophils by to anti-neutrophil cytoplasmic antibody-induced Kidney Int. 88, 1030–1046 (2015).
antineutrophil cytoplasm antibodies occurs via Fcγ neutrophils activation through receptor for advanced 130. Ludviksson, B. R. et al. Active Wegener’s granulomatosis
receptors and CD18. J. Am. Soc. Nephrol. 15, glycation end products (RAGE) and Toll-like receptor 4. is associated with HLA-DR+CD4+ T cells exhibiting an
796–808 (2004). Arthritis Res. Ther. 17, 64 (2015). unbalanced Th1-type T cell cytokine pattern: reversal
87. Johnson, P. A., Alexander, H. D., McMillan, S. A. 109. Xiao, H. et al. C5a receptor (CD88) blockade protects with IL-10. J. Immunol. 160, 3602–3609 (1998).
& Maxwell, A. P. Up-regulation of the granulocyte against MPO-ANCA GN. J. Am. Soc. Nephrol. 25, 131. Nogueira, E. et al. Serum IL-17 and IL-23 levels and
adhesion molecule Mac-1 by autoantibodies in 225–231 (2014). autoantigen-specific Th17 cells are elevated in
autoimmune vasculitis. Clin. Exp. Immunol. 107, 110. Jayne, D. R. W. et al. Randomized trial of C5a receptor patients with ANCA-associated vasculitis. Nephrol.
513–519 (1997). inhibitor avacopan in ANCA-associated vasculitis. Dial. Transplant. 25, 2209–2217 (2010).
88. Kuligowski, M. P. et al. Antimyeloperoxidase antibodies J. Am. Soc. Nephrol. 28, 2756–2767 (2017). 132. Csernok, E. et al. Cytokine profiles in Wegener’s
rapidly induce alpha-4-integrin-dependent glomerular 111. Merkel, P. A. et al. A randomised, double-blind, granulomatosis: predominance of type 1 (Th1) in the
neutrophil adhesion. Blood 113, 6485–6494 (2009). active-controlled study of Avacopan in anti-neutrophil granulomatous inflammation. Arthritis Rheumatol. 42,
89. Tse, W. Y., Nash, G. B., Hewins, P., Savage, C. O. & cytoplasmic antibody (ANCA)-associated vasculitis. 742–750 (1999).
Adu, D. ANCA-induced neutrophil F-actin polymerization: Ann. Rheum. Dis. 79, 8 (2020). 133. Chanouzas, D. et al. The host cellular immune
implications for microvascular inflammation. Kidney Int. 112. Xiao, H., Schreiber, A., Heeringa, P., Falk, R. J. & response to cytomegalovirus targets the endothelium
67, 130–139 (2005). Jennette, J. C. Alternative complement pathway in the and is associated with increased arterial stiffness in
0123456789();
Primer
ANCA-associated vasculitis. Arthritis Res. Ther. 20, 155. Anders, H. J. et al. MPO-ANCA-positive crescentic 177. Merkel, P. A. et al. Brief communication: high incidence
194 (2018). glomerulonephritis: a distinct entity of scleroderma of venous thrombotic events among patients with
134. Chanouzas, D. et al. Subclinical reactivation of renal disease? Am. J. Kidney Dis. 33, e3 (1999). Wegener granulomatosis: the Wegener’s Clinical
cytomegalovirus drives CD4+CD28null T-cell expansion 156. Quéméneur, T. et al. Systemic vasculitis during Occurrence of Thrombosis (WeCLOT) study. Ann. Intern.
and impaired immune response to pneumococcal the course of systemic sclerosis: report of 12 cases Med. 142, 620–626 (2005).
vaccination in antineutrophil cytoplasmic antibody- and review of the literature. Medicine 92, 1–9 178. Whyte, A. F., Smith, W. B., Sinkar, S. N., Kette, F. E.
associated vasculitis. J. Infect. Dis. 219, 234–244 (2013). & Hissaria, P. Clinical and laboratory characteristics
(2019). 157. Iudici, M. et al. Childhood- versus adult-onset ANCA- of 19 patients with Churg-Strauss syndrome from a
135. McKinney, E. F. et al. A CD8+ T cell transcription associated vasculitides: a nested, matched case- single South Australian centre. Intern. Med. J. 43,
signature predicts prognosis in autoimmune disease. control study from the French Vasculitis Study Group 784–790 (2013).
Nat. Med. 16, 586–591 (2010). Registry. Autoimmun. Rev. 17, 108–114 (2018). 179. Mohammad, A. J. et al. Pulmonary involvement in
This study identifies CD8+ T cell transcription 158. Antonelou, M., Perea Ortega, L., Harvey, J. & antineutrophil cytoplasmic antibodies (ANCA)-
signatures that correlate with risk of remaining in Salama, A. D. Anti-myeloperoxidase antibody associated vasculitis: the influence of ANCA subtype.
remission or to flare in AAV, leading to prospective positivity in patients without primary systemic J. Rheumatol. 44, 1458–1467 (2017).
biomarker studies. vasculitis. Clin. Exp. Rheumatol. 37, 86–89 (2019). 180. Quinn, K. A. et al. Subglottic stenosis and
136. McKinney, E. F., Lee, J. C., Jayne, D. R., Lyons, P. A. 159. Berti, A. et al. Brief report: circulating cytokine endobronchial disease in granulomatosis with
& Smith, K. G. T-cell exhaustion, co-stimulation and profiles and antineutrophil cytoplasmic antibody polyangiitis. Rheumatology 58, 2203–2211 (2019).
clinical outcome in autoimmunity and infection. Nature specificity in patients with antineutrophil cytoplasmic 181. Churg, A. in Oxford Textbook of Vasculitis
523, 612–616 (2015). antibody-associated vasculitis. Arthritis Rheumatol. (eds Ball G. V., Fessler B. J., & Bridges S. L.) Ch. 9
137. Bajema, I. M., Hagen, E. C., de Heer, E., van der 70, 1114–1121 (2018). 101–108 (Oxford University Press, 2014).
Woude, F. J. & Bruijn, J. A. Colocalization of ANCA- 160. Unizony, S. et al. Clinical outcomes of treatment of anti- 182. Berden, A. E. et al. Histopathologic classification of
antigens and fibrinoid necrosis in ANCA-associated neutrophil cytoplasmic antibody (ANCA)-associated ANCA-associated glomerulonephritis. J. Am. Soc.
vasculitis. Kidney Int. 60, 2025–2030 (2001). vasculitis based on ANCA type. Ann. Rheum. Dis. 75, Nephrol. 21, 1628–1636 (2010).
138. Gan, P. Y. et al. Biologicals targeting T helper cell 1166–1169 (2016). A classification system based on glomerular
subset differentiating cytokines are effective in the 161. Cornec, D., Cornec-Le Gall, E., Fervenza, F. C. & histopathology, which is associated with the
treatment of murine anti-myeloperoxidase Specks, U. ANCA-associated vasculitis - clinical utility outcome of renal disease in AAV.
glomerulonephritis. Kidney Int. 96, 1121–1133 of using ANCA specificity to classify patients. Nat. Rev. 183. Rahmattulla, C., Bruijn, J. A. & Bajema, I. M.
(2019). Rheumatol. 12, 570–579 (2016). Histopathological classification of antineutrophil
139. Rousselle, A., Kettritz, R. & Schreiber, A. Monocytes 162. Bossuyt, X. et al. Position paper: Revised 2017 cytoplasmic antibody-associated glomerulonephritis:
promote crescent formation in anti-myeloperoxidase international consensus on testing of ANCAs in an update. Curr. Opin. Nephrol. Hyperten. 23, 224–231
antibody-induced glomerulonephritis. Am. J. Pathol. granulomatosis with polyangiitis and microscopic (2014).
187, 1908–1915 (2017). polyangiitis. Nat. Rev. Rheumatol. 13, 683–692 (2017). 184. Brix, S. R. et al. Development and validation of a renal
140. Terrier, B. et al. Interleukin-25: a cytokine linking Contemporary recommendations on ANCA testing risk score in ANCA-associated glomerulonephritis.
eosinophils and adaptive immunity in Churg-Strauss methods and procedures in suspected AAV. Kidney Int. 94, 1177–1188 (2018).
syndrome. Blood 116, 4523–4531 (2010). 163. Venhoff, N. et al. Reconstitution of the peripheral 185. Zhang, S., Yuan, D. & Tan, G. Neurological involvement
141. Kiene, M. et al. Elevated interleukin-4 and B lymphocyte compartment in patients with ANCA- in primary systemic vasculitis. Front. Neurol. 10, 430
interleukin-13 production by T cell lines from patients associated vasculitides treated with rituximab for (2019).
with Churg-Strauss syndrome. Arthritis Rheumatol. relapsing or refractory disease. Autoimmunity 47, 186. Flossmann, O. et al. Long-term patient survival in
44, 469–473 (2001). 401–408 (2014). ANCA-associated vasculitis. Ann. Rheum. Dis. 70,
142. Jakiela, B. et al. Increased production of IL-5 and 164. von Borstel, A. et al. CD27+CD38hi B cell frequency 488–494 (2011).
dominant Th2-type response in airways of Churg- during remission predicts relapsing disease in 187. Rhee, R. L. et al. Trends in long-term outcomes among
Strauss syndrome patients. Rheumatology 51, granulomatosis with polyangiitis patients. Front. patients with antineutrophil cytoplasmic antibody-
1887–1893 (2012). Immunol. 10, 2221 (2019). associated vasculitis with renal disease. Arthritis
143. Wechsler, M. E. et al. Mepolizumab or Placebo for 165. O’Reilly, V. P. et al. Urinary soluble CD163 in active Rheumatol. 68, 1711–1720 (2016).
Eosinophilic Granulomatosis with Polyangiitis. N. Engl. renal vasculitis. J. Am. Soc. Nephrol. 27, 2906–2916 188. Steinberg, A. W., Wechsler, M. E. &
J. Med. 376, 1921–1932 (2017). (2016). Fernandez Perez, E. R. Trends in antineutrophil
A clinical trial that demonstrates that the anti-IL-5 This study identifies soluble urinary CD163 as a cytoplasmic autoantibody-associated vasculitis-
therapy mepolizumab is an effective treatment for potential biomarker for renal flares of AAV. related mortality in the United States, 1999 to 2017.
EGPA. 166. Tedesco, M., Gallieni, M., Pellegata, F., Cozzolino, M. Ann. Intern. Med. 172, 160–163 (2020).
144. Biasci, D. et al. A blood-based prognostic biomarker & Alberici, F. Update on ANCA-associated vasculitis: 189. Scherlinger, M. et al. Worldwide trends in all-cause
in IBD. Gut 68, 1386–1395 (2019). from biomarkers to therapy. J. Nephrol. 32, 871–882 mortality of auto-immune systemic diseases between
145. Jennette, J. C. et al. 2012 Revised International (2019). 2001 and 2014. Autoimmun. Rev. 19, 102531 (2020).
Chapel Hill consensus Conference Nomenclature of 167. Dekkema, G. J. et al. Urinary and serum soluble CD25 190. Hogan, S. L. et al. Predictors of relapse and treatment
Vasculitides. Arthritis Rheumatol. 65, 1–11 (2013). complements urinary soluble CD163 to detect active resistance in antineutrophil cytoplasmic antibody-
A key classification paper that provides definitive renal anti-neutrophil cytoplasmic autoantibody- associated small-vessel vasculitis. Ann. Intern. Med.
definitions for each type of vasculitis. associated vasculitis: a cohort study. Nephrol. Dial. 143, 621–631 (2005).
146. Watts, R. A. & Robson, J. Introduction, epidemiology Transpl. 34, 234–242 (2019). 191. Gopaluni, S. et al. Effect of disease activity at three
and classification of vasculitis. Best Pract. Res. Clin. 168. Ponte, C., Agueda, A. F. & Luqmani, R. A. Clinical and six months after diagnosis on long-term outcomes
Rheumatol. 32, 3–20 (2018). features and structured clinical evaluation of vasculitis. in antineutrophil cytoplasmic antibody-associated
147. Luqmani, R. A., Suppiah, R., Grayson, P. C., Merkel, P. A. Best. Pract. Res. Clin. Rheumatol. 32, 31–51 (2018). vasculitis. Arthritis Rheumatol. 71, 784–791 (2019).
& Watts, R. Nomenclature and classification of 169. Mukhtyar, C. et al. Modification and validation of the 192. Walsh, M. et al. Plasma exchange and glucocorticoids
vasculitis - update on the ACR/EULAR Diagnosis and Birmingham Vasculitis Activity Score (version 3). in severe ANCA-associated vasculitis. N. Engl. J. Med.
Classification of Vasculitis Study (DCVAS). Clin. Exp. Ann. Rheum. Dis. 68, 1827–1832 (2009). 382, 622–631 (2020).
Immunol. 164, 11–13 (2011). An update of the BVAS, which is widely used in A clinical trial of induction therapies in severe AAV,
148. Kariv, R., Sidi, Y. & Gur, H. Systemic vasculitis clinical trials to assess disease activity. which demonstrates that lower-dose glucocorticoids
presenting as a tumorlike lesion. Four case reports 170. Hellmich, B. et al. EULAR recommendations for are non-inferior to standard doses and that routine
and an analysis of 79 reported cases. Medicine 79, conducting clinical studies and/or clinical trials in use of plasma exchange as adjuvant provides no
349–359 (2000). systemic vasculitis: focus on anti-neutrophil cytoplasm additional benefit.
149. Jennette, J. C. & Falk, R. J. Small-vessel vasculitis. antibody-associated vasculitis. Ann. Rheum. Dis. 66, 193. Smith, R., Jayne, D. & Merkel, P. A randomized,
N. Engl. J. Med. 337, 1512–1523 (1997). 605–617 (2007). controlled trial of rituximab versus azathioprine
This article reviews clinical and other aspects of 171. Guillevin, L. et al. The five-factor score revisited: after induction of remission with rituximab for
small-vessel vasculitides, including AAVs. assessment of prognoses of systemic necrotizing patients with ANCA-associated vasculitis and
150. Borie, R. & Crestani, B. Antineutrophil cytoplasmic vasculitides based on the French Vasculitis Study relapsing disease (abstract). Arthritis Rheumatol. 71
antibody-associated lung fibrosis. Semin. Respir. Crit. Group (FVSG) cohort. Medicine 90, 19–27 (2011). (Suppl. 10) (2019).
Care Med. 39, 465–470 (2018). 172. Exley, A. R. et al. Development and initial validation 194. de Groot, K. et al. Pulse versus daily oral
151. Furuta, S. et al. Comparison of phenotype and of the vasculitis damage index for the standardized cyclophosphamide for induction of remission in
outcome in microscopic polyangiitis between Europe clinical assessment of damage in the systemic antineutrophil cytoplasmic antibody-associated
and Japan. J. Rheumatol. 41, 325–333 (2014). vasculitides. Arthritis Rheumatol. 40, 371–380 (1997). vasculitis: a randomized trial. Ann. Intern. Med. 150,
152. Suzuki, A. et al. Chest high-resolution CT findings of 173. Merkel, P. A. et al. The OMERACT core set of outcome 670–680 (2009).
microscopic polyangiitis: a Japanese first nationwide measures for use in clinical trials of ANCA-associated 195. Harper, L. et al. Pulse versus daily oral cyclophosphamide
prospective cohort study. Am. J. Roentgenol. 23, vasculitis. J. Rheumatol. 38, 1480–1486 (2011). for induction of remission in ANCA-associated vasculitis:
1–11 (2019). 174. Morgan, M. D. et al. Increased incidence of long-term follow-up. Ann. Rheum. Dis. 71, 955–960
153. McAdoo, S. P. et al. Patients double-seropositive for cardiovascular events in patients with antineutrophil (2012).
ANCA and anti-GBM antibodies have varied renal cytoplasmic antibody-associated vasculitides: a 196. Stone, J. H. et al. Rituximab versus cyclophosphamide
survival, frequency of relapse, and outcomes matched-pair cohort study. Arthritis Rheumatol. 60, for ANCA-associated vasculitis. N. Engl. J. Med. 363,
compared to single-seropositive patients. Kidney Int. 3493–3500 (2009). 221–232 (2010).
92, 693–702 (2017). 175. Robson, J. et al. Damage in the ANCA-associated A clinical trial that demonstrates that rituximab is
154. Turner-Stokes, T. et al. Positive antineutrophil vasculitides: long-term data from the European at least equivalent to cyclophosphamide in the
cytoplasmic antibody serology in patients with lupus Vasculitis Study Group (EUVAS) therapeutic trials. induction of remission in AAV.
nephritis is associated with distinct histopathologic Ann. Rheum. Dis. 74, 177–184 (2015). 197. Specks, U. et al. Efficacy of remission-induction
features on renal biopsy. Kidney Int. 92, 1223–1231 176. Emmi, G. et al. Thrombosis in vasculitis: from regimens for ANCA-associated vasculitis. N. Engl.
(2017). pathogenesis to treatment. Thromb. J. 13, 15 (2015). J. Med. 369, 417–427 (2013).

0123456789();
Primer
198. Jones, R. B. et al. Rituximab versus cyclophosphamide vasculitis. Ann. Rheum. Dis. 76, 1064–1069 cytoplasmic autoantibodies. N. Engl. J. Med. 349,
in ANCA-associated renal vasculitis. N. Engl. J. Med. (2017). 36–44 (2003).
363, 211–220 (2010). 219. Buckley, L. & Humphrey, M. B. Glucocorticoid-induced 237. Pagnoux, C. et al. Azathioprine or methotrexate
199. Pepper, R. J. et al. A novel glucocorticoid-free osteoporosis. N. Engl. J. Med. 379, 2547–2556 maintenance for ANCA-associated vasculitis. N. Engl.
maintenance regimen for anti-neutrophil cytoplasm (2018). J. Med. 359, 2790–2803 (2008).
antibody-associated vasculitis. Rheumatology 58, 220. Martinez del Pero, M. et al. Long-term outcome of 238. Puéchal, X. et al. Long-term outcomes among
260–268 (2019). airway stenosis in granulomatosis with polyangiitis participants in the WEGENT trial of remission-
200. De Groot, K. et al. Randomized trial of (Wegener granulomatosis): an observational study. maintenance therapy for granulomatosis with
cyclophosphamide versus methotrexate for induction JAMA Otolaryngol. Head Neck Surg. 140, 1038–1044 polyangiitis (Wegener’s) or microscopic polyangiitis.
of remission in early systemic antineutrophil (2014). Arthritis Rheumatol. 68, 690–701 (2016).
cytoplasmic antibody-associated vasculitis. Arthritis 221. Hruskova, Z. et al. Characteristics and outcomes of 239. Hiemstra, T. F. et al. Mycophenolate mofetil vs
Rheumatol. 52, 2461–2469 (2005). granulomatosis with polyangiitis (Wegener) and azathioprine for remission maintenance in
201. Jones, R. B. et al. Mycophenolate mofetil versus microscopic polyangiitis requiring renal replacement antineutrophil cytoplasmic antibody-associated
cyclophosphamide for remission induction in ANCA- therapy: results from the European Renal Association- vasculitis: a randomized controlled trial. JAMA 304,
associated vasculitis: a randomised, non-inferiority European Dialysis and Transplant Association Registry. 2381–2388 (2010).
trial. Ann. Rheum. Dis. 78, 399–405 (2019). Am. J. Kidney Dis. 66, 613–620 (2015). 240. Terrier, B. et al. Long-term efficacy of remission-
202. Jayne, D. R. et al. Randomized trial of plasma 222. Herlyn, K., Hellmich, B., Seo, P., Merkel, P. A. & maintenance regimens for ANCA-associated
exchange or high-dosage methylprednisolone The Vasculitis Clinical Research Consortium. Patient- vasculitides. Ann. Rheum. Dis. 77, 1150–1156
as adjunctive therapy for severe renal vasculitis. reported outcome assessment in vasculitis may (2018).
J. Am. Soc. Nephrol. 18, 2180–2188 (2007). provide important data and a unique perspective. 241. Wegener’s Granulomatosis Etanercept Trial (WGET)
203. Jayne, D. R. et al. Intravenous immunoglobulin for Arthritis Care Res. 62, 1639–1645 (2010). Research Group. Etanercept plus standard therapy for
ANCA-associated systemic vasculitis with persistent 223. Robson, J. C. et al. Patient perceptions of Wegener’s granulomatosis. N. Engl. J. Med. 352,
disease activity. QJM 93, 433–439 (2000). glucocorticoids in anti-neutrophil cytoplasmic 351–361 (2005).
204. Guillevin, L. et al. Rituximab versus azathioprine for antibody-associated vasculitis. Rheumatol. Int. 38, 242. Metzler, C. et al. Elevated relapse rate under oral
maintenance in ANCA-associated vasculitis. N. Engl. 675–682 (2018). methotrexate versus leflunomide for maintenance of
J. Med. 371, 1771–1780 (2014). A study reporting the effects of glucocorticoids in remission in Wegener’s granulomatosis. Rheumatology
A clinical trial demonstrating that rituximab is a AAV, both positive and negative, from the patients’ 46, 1087–1091 (2007).
viable treatment and superior to azathioprine in perspective. 243. Jayne, D. et al. Efficacy and safety of belimumab and
the maintenance of remission in AAV. 224. Miloslavsky, E. M. et al. Development of a Glucocorticoid azathioprine for maintenance of remission in
205. Karras, A. et al. Randomised controlled trial of Toxicity Index (GTI) using multicriteria decision analysis. antineutrophil cytoplasmic antibody-associated
prolonged treatment in the remission phase Ann. Rheum. Dis. 76, 543–546 (2017). vasculitis: a randomized controlled study. Arthritis
of ANCA-associated vasculitis. Ann. Rheum. Dis. 76, 225. Robson, J. C. et al. Validation of the ANCA-associated Rheumatol. 71, 952–963 (2019).
1662–1668 (2017). vasculitis patient-reported outcomes (AAV-PRO) 244. Stegeman, C. A., Tervaert, J. W., de Jong, P. E.,
206. Charles, P. et al. Long-term rituximab use to maintain questionnaire. Ann. Rheum. Dis. 77, 1157–1164 Kallenberg, C. G. & Dutch Co-Trimoxazole Wegener
remission of antineutrophil cytoplasmic antibody- (2018). Study Group. Trimethoprim-sulfamethoxazole
associated vasculitis: a randomized trial. Ann. Intern. Validation study of an AAV-specific PRO measure. (co-trimoxazole) for the prevention of relapses of
Med. https://doi.org/10.7326/M19-3827 (2020). 226. Robson, J. C. et al. OMERACT endorsement of patient- Wegener’s granulomatosis. N. Engl. J. Med. 335,
207. Gopaluni, S. et al. Rituximab versus azathioprine reported outcome instruments in antineutrophil 16–20 (1996).
as therapy for maintenance of remission for anti- cytoplasmic antibody-associated vasculitis. J. Rheumatol. 245. Ribi, C. et al. Treatment of Churg-Strauss syndrome
neutrophil cytoplasm antibody-associated vasculitis 44, 1529–1535 (2017). without poor-prognosis factors: a multicenter,
(RITAZAREM): study protocol for a randomized 227. O’Malley, L. et al. The longitudinal course of fatigue prospective, randomized, open-label study of seventy-
controlled trial. Trials 18, 112 (2017). in antineutrophil cytoplasmic antibody-associated two patients. Arthritis Rheumatol. 58, 586–594
208. Tieu, J. et al. Rituximab for maintenance of remission vasculitis. J. Rheumatol. 47, 572–579 (2020). (2008).
in ANCA-associated vasculitis: expert consensus This study defines the incidence and time course 246. Puéchal, X. et al. Non-severe eosinophilic
guidelines. Rheumatology 59, e24–e32 (2020). of fatigue, an important symptom for patients granulomatosis with polyangiitis: long-term outcomes
209. Charles, P. et al. Comparison of individually tailored with AAV. after remission-induction trial. Rheumatology 58,
versus fixed-schedule rituximab regimen to maintain 228. Hessels, A. C. et al. Leg muscle strength is reduced 2107–2116 (2019).
ANCA-associated vasculitis remission: results of a and is associated with physical quality of life in 247. Guillevin, L. et al. Lack of superiority of steroids plus
multicentre, randomised controlled, phase III trial Antineutrophil cytoplasmic antibody-associated plasma exchange to steroids alone in the treatment
(MAINRITSAN2). Ann. Rheum. Dis. 77, 1143–1149 vasculitis. PLoS ONE 14, e0211895 (2019). of polyarteritis nodosa and Churg-Strauss syndrome.
(2018). 229. Harper, L. et al. Treatment of fatigue with physical A prospective, randomized trial in 78 patients.
210. Puéchal, X. et al. Adding azathioprine to remission- activity and behavioural change support in vasculitis: Arthritis Rheumatol. 35, 208–215 (1992).
induction glucocorticoids for eosinophilic study protocol for an open-label randomised 248. Guillevin, L. et al. Corticosteroids plus pulse
granulomatosis with polyangiitis (Churg-Strauss), controlled feasibility study. BMJ Open 8, e023769 cyclophosphamide and plasma exchanges versus
microscopic polyangiitis, or polyarteritis nodosa (2018). corticosteroids plus pulse cyclophosphamide alone in
without poor prognosis factors: a randomized, 230. Moran, S. M. et al. Urinary soluble CD163 and the treatment of polyarteritis nodosa and Churg-
controlled trial. Arthritis Rheumatol. 69, 2175–2186 monocyte chemoattractant protein-1 in the Strauss syndrome patients with factors predicting
(2017). identification of subtle renal flare in anti-neutrophil poor prognosis. A prospective, randomized trial
211. Steinfeld, J. et al. Evaluation of clinical benefit from cytoplasmic antibody-associated vasculitis. Nephrol. in sixty-two patients. Arthritis Rheumatol. 38,
treatment with mepolizumab for patients with Dial. Transplant. 35, 283–291 (2020). 1638–1645 (1995).
eosinophilic granulomatosis with polyangiitis. 231. Pagnoux, C. et al. Treatment of systemic necrotizing 249. Ma, T. K., McAdoo, S. P. & Tam, F. W. Targeting the
J. Allergy Clin. Immmunol. 143, 2170–2177 (2019). vasculitides in patients aged sixty-five years or older: tyrosine kinase signalling pathways for treatment
212. Teixeira, V., Mohammad, A. J., Jones, R. B., Smith, R. results of a multicenter, open-label, randomized of immune-mediated glomerulonephritis: from bench
& Jayne, D. Efficacy and safety of rituximab in the controlled trial of corticosteroid and cyclophosphamide- to bedside and beyond. Nephrol. Dial. Transpl. 32
treatment of eosinophilic granulomatosis with based induction therapy. Arthritis Rheumatol. 67, (Suppl. 1), i129–i138 (2017).
polyangiitis. RMD Open 5, e000905 (2019). 1117–1127 (2015). 250. Langford, C. A. et al. An open-label trial of abatacept
213. Roberts, D. M. et al. Immunoglobulin G replacement 232. Jones, R. B. et al. Rituximab versus cyclophosphamide (CTLA4-IG) in non-severe relapsing granulomatosis
for the treatment of infective complications of in ANCA-associated renal vasculitis: 2-year results of a with polyangiitis (Wegener’s). Ann. Rheum. Dis. 73,
rituximab-associated hypogammaglobulinemia in randomised trial. Ann. Rheum. Dis. 74, 1178–1182 1376–1379 (2014).
autoimmune disease: a case series. J. Autoimmun. 57, (2015). 251. Holdsworth, S. R., Gan, P. Y. & Kitching, A. R. Biologics
24–29 (2015). 233. Walsh, M. et al. Long-term follow-up of patients with for the treatment of autoimmune renal diseases.
214. De Sousa, E., Smith, R., Chaudhry, A., Willcocks, L. & severe ANCA-associated vasculitis comparing plasma Nat. Rev. Nephrol. 12, 217–231 (2016).
Jayne, D. Venous thromboembolism with concurrent exchange to intravenous methylprednisolone 252. Gan, P. Y. et al. Apoptotic cell-induced, antigen-
pulmonary haemorrhage in systemic vasculitis. treatment is unclear. Kidney Int. 84, 397–402 specific immunoregulation to treat experimental
Nephrol. Dial. Transplant. 27, 4357–4361 (2012). (2013). antimyeloperoxidase GN. J. Am. Soc. Nephrol. 30,
215. Suppiah, R. et al. A model to predict cardiovascular 234. Merkel, P. A., Jayne, D. R., Wang, C., Hillson, J. & 1365–1374 (2019).
events in patients with newly diagnosed Wegener’s Bekker, P. Evaluation of the safety and efficacy of 253. Bunch, D. O. et al. Gleaning relapse risk from B cell
granulomatosis and microscopic polyangiitis. Arthritis avacopan, a C5a receptor inhibitor, in patients with phenotype: decreased CD5+ B cells portend a shorter
Care Res. 63, 588–596 (2011). antineutrophil cytoplasmic antibody-associated time to relapse after B cell depletion in patients with
216. Westman, K. W., Bygren, P. G., Olsson, H., Ranstam, J. vasculitis treated concomitantly with rituximab or ANCA-associated vasculitis. Ann. Rheum. Dis. 74,
& Wieslander, J. Relapse rate, renal survival, and cyclophosphamide/azathioprine: protocol for a 1784–1786 (2015).
cancer morbidity in patients with Wegener’s randomized, double-blind, active-controlled, 254. Ormerod, A. S. & Cook, M. C. Epidemiology of
granulomatosis or microscopic polyangiitis with Phase 3 trial. JMIR Res. Protoc. 9, e16664 primary systemic vasculitis in the Australian Capital
renal involvement. J. Am. Soc. Nephrol. 9, 842–852 (2020). Territory and south-eastern New South Wales. Intern.
(1998). 235. Faurschou, M. et al. Brief report: long-term outcome Med. J. 38, 816–823 (2008).
217. Heijl, C. et al. Incidence of malignancy in patients of a randomized clinical trial comparing methotrexate 255. Anderson, K., Klassen, J., Stewart, S. A. &
treated for antineutrophil cytoplasm antibody- to cyclophosphamide for remission induction in early Taylor-Gjevre, R. M. Does geographic location affect
associated vasculitis: follow-up data from European systemic antineutrophil cytoplasmic antibody- incidence of ANCA-associated renal vasculitis in
Vasculitis Study Group clinical trials. Ann. Rheum. Dis. associated vasculitis. Arthritis Rheumatol. 64, northern Saskatchewan, Canada? Rheumatology 52,
70, 1415–1421 (2011). 3472–3477 (2012). 1840–1844 (2013).
218. van Daalen, E. E. et al. Effect of rituximab on 236. Jayne, D. et al. A randomized trial of maintenance 256. Reinhold-Keller, E., Herlyn, K., Wagner-Bastmeyer, R.
malignancy risk in patients with ANCA-associated therapy for vasculitis associated with antineutrophil & Gross, W. L. Stable incidence of primary systemic
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vasculitides over five years: results from the German of the value of indirect immunofluorescence (IIF) Acknowledgements
vasculitis register. Arthritis Rheumatol. 53, 93–99 versus antigen-specific immunoassays. Ann. Rheum. H-J.A., E.B., R.K., P.A.L. and A.R.K. are principle investigators,
(2005). Dis. 76, 647–653 (2017). and J.K and C.O.S.S. are scientific advisers of the European
257. Panagiotakis, S. H. et al. The epidemiology of primary 269. Savige, J. et al. International consensus statement on Union Horizon 20/20 RELENT (RELapses prevENTion in chronic
systemic vasculitides involving small vessels in Crete testing and reporting of antineutrophil cytoplasmic autoimmune disease) consortium that has received funding
(southern Greece): a comparison of older versus antibodies (ANCA). Am. J. Clin. Pathol. 111, 507–513 from the European Union Horizon 2020 research and innova-
younger adult patients. Clin. Exp. Rheumatol. 27, (1999). tion programme under grant agreement 668036. A.R.K.
409–415 (2009). 270. Weiner, M. & Segelmark, M. The clinical presentation acknowledges funding support from the Australian National
258. Fujimoto, S. et al. Comparison of the epidemiology and therapy of diseases related to anti-neutrophil Health and Medical Research Council of Australia (grant num-
of anti-neutrophil cytoplasmic antibody-associated cytoplasmic antibodies (ANCA). Autoimmun. Rev. 15, bers 1104422, 1084869 and 1115805). H-J.A. was sup-
vasculitis between Japan and the UK. Rheumatology 978–982 (2016). ported by the Deutsche Forschungsgemeinschaft (grant
50, 1916–1920 (2011). 271. Zhao, M. H. et al. Autoantibodies against bactericidal/ number AN372/24-1). P.A.L. acknowledges support from the
259. Dadoniene, J., Kirdaite, G., Mackiewicz, Z., permeability-increasing protein in patients with cystic Medical Research Council (grant number MR/L019027/1),
Rimkevicius, A. & Haugeberg, G. Incidence of fibrosis. QJM 89, 259–265 (1996). Versus Arthritis (grant number 20593) and the British Heart
primary systemic vasculitides in Vilnius: a university 272. Choi, H. K., Lamprecht, P., Niles, J. L., Gross, W. L. Foundation (grant number PG/13/64/30435).
hospital population based study. Ann. Rheum. Dis. & Merkel, P. A. Subacute bacterial endocarditis with
64, 335–336 (2005). positive cytoplasmic antineutrophil cytoplasmic Author contributions
260. Pamuk, O., Donmez, S. & Calayir, G. B. The incidences antibodies and anti-proteinase 3 antibodies. Arthritis All authors contributed to all sections of the Primer, with
of anti-neutrophil cytoplasmic antibody-associated Rheumatol. 43, 226–231 (2000). A.R.K. coordinating the project. The middle authors of the
vasculitis in northeastern part of Turkey. Ann. Rheum. 273. Mahr, A. et al. Brief report: prevalence of Primer are listed in alphabetical order.
Dis. 72, 638–638 (2013). antineutrophil cytoplasmic antibodies in infective
261. Sánchez Torres, A. et al. Epidemiology of primary endocarditis. Arthritis Rheumatol. 66, 1672–1677 Competing interests
systemic vasculitis in a Latin America population (2014). A.R.K. is Chair of the Board of the Australian and New
[Spanish]. Rev. Chil. Reumatol. 21, 145–150 (2005). 274. Ying, C. M., Yao, D. T., Ding, H. H. & Yang, C. D. Zealand Vasculitis Society and has been a consultant for CSL
262. Gonzalez-Gay, M. A., Garcia-Porrua, C., Guerrero, J., Infective endocarditis with antineutrophil cytoplasmic Limited and Visterra. N.B. has received research funding from
Rodriguez-Ledo, P. & Llorca, J. The epidemiology of antibody: report of 13 cases and literature review. Vifor and GSK and speaking fees from Roche and Vifor. E.B.
the primary systemic vasculitides in northwest Spain: PLoS ONE 9, e89777 (2014). received consultancy and speaker fees from Roche, which
implications of the Chapel Hill Consensus Conference 275. Chen, M., Gao, Y., Guo, X. H. & Zhao, M. H. were paid to her employer. D.R.J. has been a consultant for
definitions. Arthritis Rheumatol. 49, 388–393 (2003). Propylthiouracil-induced antineutrophil cytoplasmic ChemoCentryx, InflaRx and Insmed. P.A.L. holds founding
263. Romero-Gomez, C. et al. Epidemiological study of antibody-associated vasculitis. Nat. Rev. Nephrol. 8, equity in and receives consultation fees from PredictImmune
primary systemic vasculitides among adults in southern 476–483 (2012). Ltd. P.A.M. has been a consultant for AbbVie, Biogen, CSL
Spain and review of the main epidemiological studies. 276. Pendergraft, W. F. & Niles, J. L. Trojan horses: drug Behring, Genzyme, Insmed, Janssen, Kiniska and Sparrow,
Clin. Exp. Rheumatol. 33 (Suppl. 89), 11–18 (2015). culprits associated with antineutrophil cytoplasmic received research funding and consulting fees from
264. Mohammad, A. J., Jacobsson, L. T. H., Westman, K. W. A., autoantibody (ANCA) vasculitis. Curr. Opin. AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,
Sturfelt, G. & Segelmark, M. Incidence and survival Rheumatol. 26, 42–49 (2014). Celgene, ChemoCentryx, Genentech/Roche, GSK and InflaRx,
rates in Wegener’s granulomatosis, microscopic 277. Grau, R. G. Drug-induced vasculitis: new insights and and grant support from Kypha. U.S. has been a consultant for
polyangiitis, Churg-Strauss syndrome and polyarteritis a changing lineup of suspects. Curr. Rheumatol. Rep. AstraZeneca, Insmed, and ChemoCentryx and has received
nodosa. Rheumatology 48, 1560–1565 (2009). 17, 71 (2015). research funding from Genentech, Bristol-Myers Squibb,
265. Zeft, A. S. & Schlesinger, M. K. H. Wegener’s 278. Lee, E. et al. Inactivation of peroxidases of rat bone ChemoCentryx and GSK. The remaining authors declare no
granulomatosis and environmental factors in Western marrow by repeated administration of propylthiouracil competing interests.
Montana. Rheumatol. Rep. https://doi.org/10.4081/ is accompanied by a change in the heme structure.
rr.2010.e8 (2010). Biochem. Pharmacol. 37, 2151–2153 (1988).
Peer review information
266. Nesher, G., Ben-Chetrit, E., Mazal, B. & Breuer, G. S. 279. Nakazawa, D. et al. Abnormal conformation and
Nature Reviews Disease Primers thanks P. Van Paassen,
The incidence of primary systemic vasculitis in impaired degradation of propylthiouracil-induced
B. Hellmich, M.-H . Zhao, A. Vaglio, M. Segelmark and
Jerusalem: a 20-year hospital-based retrospective neutrophil extracellular traps: implications of
X. Puéchal for their contribution to the peer review of this
study. J. Rheumatol. 43, 1072–1077 (2016). disordered neutrophil extracellular traps in a rat
work.
267. Damoiseaux, J. et al. An international survey on model of myeloperoxidase antineutrophil cytoplasmic
anti-neutrophil cytoplasmic antibodies (ANCA) testing antibody-associated vasculitis. Arthritis Rheumatol.
in daily clinical practice. Clin. Chem. Lab. Med. 56, 64, 3779–3787 (2012). Publisher’s note
1759–1770 (2018). 280. Lood, C. & Hughes, G. C. Neutrophil extracellular Springer Nature remains neutral with regard to jurisdictional
268. Damoiseaux, J. et al. Detection of antineutrophil traps as a potential source of autoantigen in cocaine- claims in published maps and institutional affiliations.
cytoplasmic antibodies (ANCAs): a multicentre associated autoimmunity. Rheumatology 56, 638–643
European Vasculitis Study Group (EUVAS) evaluation (2017). © Springer Nature Limited 2020

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PRIMER

Author addresses clinical immunologists and other physicians regularly

Table 1 | Comparison of the three syndromic presentations of AAV

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Box 1 | Diagnostic testing methods in AAVs

ANCA-associated small vessel vasculitis

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Box 2 | Clinical features of the AAVs

Norwich, 5.9 Lund,

Minnesota, 16.0 13.0

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Box 3 | Drug-induced vasculitis

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HLA-II Naive lymphocytes

CD4+ T cell CD8+ T cell

Endothelial cell Granuloma

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Clinical presentation the systemic autoimmune pathophysiology (Box 2; Fig. 6).

glomerulonephritis154–156. As initial clinical presentations Biomarkers

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The BVAS and VDI are approved by the Outcomes Pathology

100 μm 200 μm 250 μm 500 μm

100 μm 100 μm 100 μm

14 | Article citation ID: (2020) 6:71 www.nature.com/nrdp

Prognosis Remission induction

a Treatment phase b Drug c Disease state

0 to (3–6) Oral Refractory

Maintenance RTX On-drug remission

Long-term follow-up Oﬀ-drug remission

Indeﬁnite Induction therapy

16 | Article citation ID: (2020) 6:71 www.nature.com/nrdp

renal involvement, ANCA+a or in inducing remission; CYC (HR 0.50) at long-​term

every 2–3 weeks) plus 9 events with lower dose CYC

renal involvement, ANCA+ versus IV-​CYC

glomerulonephritis, SCr methylprednisolone as add-​on dialysis independence at

relapsing with renal involvement RTX and GCs 2) Low-​dose GCs

less severe disease oral CYC remission induction extensive or pulmonary

eGFR >15 ml/min/1.73 m2 (2–3 g daily) remission induction especially PR3-​AAV

Table 3 | Key clinical trials of maintenance therapies in GPA and/or MPA

treated with IV CYC and GCs, ANCA+ toxicity similar

remission, ANCA+ with MMF (HR 1.69) rates

ANCA– tailored to B cell return rates received fewer infusions

ANCA– (pre-​RTX era) versus add-​on rates patients developed

for MTX, 6/26 patients for with adverse effects at

et al. (pre-​RTX era) versus add-​on relapses with co-​trimoxazole

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Table 4 | Key clinical trials of therapies for EGPA

(18 in total) together with patients with PAN grouping of disease

Box 4 | A patient’s experience of AAV

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Table 5 | Selected potential new management strategies and biomarkers in AAVa

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renal involvement, ANCA+a or in inducing remission; CYC (HR 0.50) at long-term

renal involvement, ANCA+ versus IV-CYC

glomerulonephritis, SCr methylprednisolone as add-on dialysis independence at

relapsing with renal involvement RTX and GCs 2) Low-dose GCs

eGFR >15 ml/min/1.73 m2 (2–3 g daily) remission induction especially PR3-AAV

ANCA– (pre-RTX era) versus add-on rates patients developed

et al. (pre-RTX era) versus add-on relapses with co-trimoxazole