Management of ANCA-associated vasculitis: Current trends and future prospects.

Abstract

The antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are a spectrum of heterogeneous autoimmune diseases characterized by necrotizing small vessel vasculitis and the presence of ANCA. These chronic multisystem disorders may be life-threatening if there is major organ involvement, such as acute renal failure or pulmonary hemorrhage, and require significant initial immunosuppression and long-term maintenance treatment. Long-established protocols using cyclophosphamide and prednisolone have resulted in dramatically improved outcomes for patients since the 1970s. Subsequently, international collaboration has contributed to a growing evidence base and consensus in the management of these rare disorders. Modifications to traditional treatment protocols by the use of azathioprine or methotrexate rather than cyclophosphamide, and the introduction of newer agents, such as rituximab, has maintained outcomes whilst decreasing toxicity. However, the treatment limitations of incomplete efficacy, infection, and cumulative toxicity persist. These issues have continued to drive the search for safer and more effective modulation of the immune system using targeted immunotherapy. This review will explore the current evidence base for management of ANCA-associated vasculitis and future treatment prospects.

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Management of ANCA-associated vasculitis:
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Sally Hamour
Alan D Salama
Charles D Pusey
Imperial College Kidney and Transplant
Institute, Imperial College,
London, UK
Correspondence: Charles Pusey
Imperial College Kidney and Transplant
Institute, Imperial College London,
Hammersmith Hospital Campus,
Du Cane Road, London W12 ONN, UK
Tel +44 20 8383 3152
Fax +44 20 8383 2062
Email c.pusey@imperial.ac.uk
Abstract: The antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are a
spectrum of heterogeneous autoimmune diseases characterized by necrotizing small ves-
sel vasculitis and the presence of ANCA. These chronic multisystem disorders may be
life-threatening if there is major organ involvement, such as acute renal failure or pulmonary
hemorrhage, and require significant initial immunosuppression and long-term maintenance
treatment. Long-established protocols using cyclophosphamide and prednisolone have
resulted in dramatically improved outcomes for patients since the 1970s. Subsequently,
international collaboration has contributed to a growing evidence base and consensus in
the management of these rare disorders. Modifications to traditional treatment protocols by
the use of azathioprine or methotrexate rather than cyclophosphamide, and the introduction
of newer agents, such as rituximab, has maintained outcomes whilst decreasing toxicity.
However, the treatment limitations of incomplete efficacy, infection, and cumulative toxicity
persist. These issues have continued to drive the search for safer and more effective modu-
lation of the immune system using targeted immunotherapy. This review will explore the
current evidence base for management of ANCA-associated vasculitis and future treatment
prospects.
Keywords: ANCA, vasculitis, treatment
Introduction
The antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are
characterized by the production of ANCA, reactive to either proteinase-3 (PR3-ANCA)
or myeloperoxidase (MPO-ANCA), which are constituents of neutrophil granules
and monocyte lysosomes. AAV are idiopathic multisystem vasculitides which cause
destructive inflammation of mainly small caliber arterial vessels and comprise several
clinically and pathologically defined disease entities: Wegener’s granulomatosis (WG),
microscopic polyangiitis (MPA), renal-limited vasculitis (RLV) and Churg–Strauss
syndrome (CSS).
AAV cause considerable morbidity and mortality, with end-stage renal failure
developing in over 20% of patients at five years.1 Prior to the introduction of steroids
and cyclophosphamide (CYP) in the early 1970s, survival was uniformly dismal, with
a median survival of five months for patients with generalized WG.2 In contrast, induc-
tion of remission is now achieved in over 90% patients by six months,3 and five-year
survival rates are around 75%.4 However, even with best available therapy, relapse
rates remain unacceptably high at up to 50% over five years,5 as does treatment-related
morbidity and mortality.
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Long-term management of these conditions therefore
requires balancing the burden of immunosuppression with
control of disease activity, and the impetus remains to refine
these protocols and to investigate newer agents that might
be equipotent but less toxic. A robust evidence base for
treatment regimens has historically been limited. However,
the European Vasculitis Study Group (EUVAS) has fostered
international collaboration and conducted prospective
studies addressing optimal therapy that have led to some
treatment consensus. Factors initiating disease and causing
relapse remain poorly defined and therefore it is imperative
to understand the pathogenesis of these conditions better,
so that more targeted and less toxic therapeutic protocols
can be devised.
Clinical features
AAV are characterized by a focal necrotizing vasculitis
affecting arterioles, capillaries, and venules which can
affect virtually any organ with varying degrees of severity.
Overall, the lungs (Figure 1) and kidneys (Figure 2) are the
most commonly involved organs, in around 70%–80% of
patients.6 There is heterogeneity between and within disease
entities in relation to extent and prognosis, and the Chapel
Hill Consensus Conference nomenclature7 is one of the
most widely used vasculitis classification systems. AAV
most commonly occur in the elderly and the incidence is
approximately 20 cases/million/year.8
WG is characterized by granulomatous inflammation of
the upper and lower respiratory tract and a high rate of relapse.
Granulomatous lung disease may be difficult to distinguish
from mycobacterial infection. Ear, nose and throat disease
in WG may be aggressive, with classical necrosis and col-
lapse of the nasal bridge, epistaxis, conductive deafness
due to Eustachian tube dysfunction, or subglottic stenosis.
Orbital disease in WG includes necrotizing scleritis and
primary orbital disease which may present with proptosis.
Both of these features and their attendant complications
may pose a severe risk to vision. WG is usually associated
with PR3-ANCA. In contrast, patients with MPA have small
vessel inflammation without granulomata, more often with
MPO-ANCA. CSS is characterized by late-onset asthma and
eosinophilia, sometimes with rhinitis or nasal polyps, and
ANCA more usually reactive to MPO. Renal-limited vasculi-
tis is an isolated pauci-immune crescentic glomerulonephritis
in which MPO- or PR3-ANCA may be found.
Patients with generalized disease may present with active
renal vasculitis or another immediate threat to life or organ
function. Without treatment, the most serious complications of
pulmonary hemorrhage and rapidly progressive glomerulone-
phritis may be rapidly fatal. Limited disease refers to patients
with AAV and one or more involved organ systems, but no
renal disease or immediately life-threatening complications
(Table 1).9 The intensity (and therefore tolerated potential
toxicity) of treatment depends on disease severity. Interest-
ingly, only about 60% of patients with limited disease will be
ANCA-positive and more than 10% of patients with pauci-
immune glomerulonephritis thought to be due to AAV will be
ANCA-negative.10 Overall, the accumulation of chronic tissue
damage with fibrosis and scarring contributes significantly to
morbidity. Patients are closely monitored by review of clinical
Figure 2 Renal biopsy from a patient with AAV and severe renal failure showing a
glomerulus containing an extensive cellular crescent with a break in the basement mem-
brane and surrounding fibrin deposition (arrowed) Methenamine silver stain, X400.
Abbreviation: AAV, ANCA-associated vasculititis.
Figure 1 Chest radiograph showing multiple cavitating lung lesions in a patient with
Wegener’s granulomatosis.

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symptoms and signs, urinalysis, and imaging and laboratory
blood tests, including autoantibody levels by indirect immu-
nofluorescence for ANCA or antigen-specific ELISA for anti-
PR3 or anti-MPO antibodies. Disease activity and severity
may be assessed using the well-characterized Birmingham
Vasculitis Activity Score,11 while disease-induced damage
is measured by the Vasculitis Damage Index.12 These scores
have been mostly used as research and clinical trial tools
enabling comparison of patients, but may be used to facilitate
patient management.
Pathogenesis
Both cellular and humoral arms of the immune system
are involved in the disease. The production of ANCA is a
hallmark of the small vessel vasculitides. However, T-cells,
macrophages, and other components of the immune system
have all been implicated in causation of disease. Better
understanding of pathogenesis is clearly required to develop
a treatment rationale for specific immunotherapies. However,
it is unclear to what extent these heterogeneous conditions
share similar pathologic mechanisms. ANCA are specific
for the serine protease PR3 or for MPO, both of which are
constituents of azurophilic neutrophil granules and monocyte
lysosomes. In vitro studies indicate that cytokine-primed
neutrophils and monocytes express PR3 and MPO on their
cell membranes. ANCA bind to the cell surface by both
Fc receptor engagement13 and (Fab’)2 binding,14 thereby
activating the cell. Neutrophils activated by ANCA release
oxygen radicals, lytic enzymes, and inflammatory cytokines,
such as IL-8.15,16 This in turn impedes neutrophil migration17
and results in excessive neutrophil accumulation within
the vasculature, allowing the released reactants to dam-
age the endothelium and cause vessel inflammation.18 The
normal process of noninflammatory clearance of apoptotic
neutrophils by professional phagocytes is disrupted by
ANCA15,19 and, as a result, neutrophils are likely to undergo
proinflammatory secondary necrosis. The presence of ANCA
has been shown to promote adhesion and transmigration
of primed neutrophils across tumor necrosis factor (TNF)-
stimulated endothelium.17
The most compelling in vivo evidence for the pathogenic-
ity of ANCA in humans comes from a single case report of
pulmonary hemorrhage and glomerulonephritis in a neonate
with transplacental transfer of ANCA IgG from a mother
with active MPO-ANCA vasculitis.20 Furthermore, recent
in vivo animal models of MPO-ANCA vasculitis suggest
that, at least in the rodent, MPO-ANCA are sufficient to
generate glomerulonephritis and renal vasculitis, in the
absence of antigen-specific T-cells.21 In addition, the renal
injury in this model is dependent on complement activation22
and on the presence of neutrophils.23 In rats injected with
MPO, MPO-ANCA are associated with focal necrotising
glomerulonephritis, enhance leucocyte-endothelial interac-
tions, and promote microvascular injury.24 In wild-type mice,
transfer of murine PR3-ANCA has been shown to amplify
local inflammation,25 although no convincing model of PR3-
ANCA vasculitis has been reported. In addition, no cases of
human disease transfer by PR3-ANCA have been reported.
What triggers the formation of ANCA is unknown, but
a role for septic episodes preceding episodes of AAV has
been suggested.26 This has received more attention recently
with a proposed model of molecular mimicry between ANCA
targets and bacterial fimbrial adhesion proteins.27 Patients
with focal necrotizing crescentic glomerulonephritis have
a high prevalence of circulating autoantibodies against
lysosomal-associated membrane protein-2 (LAMP-2), a
heavily glycosylated type 1 membrane protein involved in
cellular adhesion and homeostasis, and the majority of these
anti-LAMP-2-positive patients are also ANCA-positive.
Therefore, it is plausible that an early immune response to
pathogen-derived peptides which show significant homol-
ogy with peptide sequences in ANCA target antigens results
in immune cross-reactivity. A central role for infections
as triggers of disease has also been suggested following
the description of anticomplementary PR3 antibodies in a
proportion of patients with PR3-ANCA vasculitis.28 These
antibodies react to peptide sequences from the complemen-
tary PR3-sequence, which has significant homology with a
number of infectious pathogens, including Staphylococcus
aureus, previously implicated in disease relapse.29 It has
been proposed that antibodies induced by infection, which
are cross-reactive to the complementary PR3 peptide, can
Table 1 EUVAS disease categorization of ANCA-associated
vasculitis9
CategoryDefinition
LocalizedUpper and/or lower respiratory tract
disease without any other systemic
involvement or constitutional symptoms
Early systemic Any, without organ-threatening or life-
threatening disease
Generalized Renal or other organ threatening disease,
serum creatinine 500 µmol/L (5.6 mg/dL)
Renal or other vital organ failure, serum
creatinine 500 µmol/L (5.6 mg/dL)
Progressive disease unresponsive to
glucocorticoids and cyclophosphamide
Severe
Refractory

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then act as immunologic templates for anti-PR3 antibodies.
Regardless of the exact molecular mechanism operating,
infections appear to be a critical stimulus for inducing
immune responsiveness, and their prevention may promote
prolonged disease-free remissions.30
Paradoxically, in patients with AAV, the renal lesions are
pauci-immune, characterized by little or no immunoglobulin
deposition, but cellular infiltration with T-lymphocytes and
macrophages,31 and there is now significant evidence for
the role of cellular mediators, particularly T-cells, in AAV.
WG is characterized by granulomatous lesions, typical
of a delayed-type hypersensitivity reaction and reflecting
a cellular immune response.32 T-cells have been further
implicated in the process because patients’ lymphocytes
show in vitro reactivity to PR3 or MPO autoantigens,33 and
T-cell directed therapy can treat disease.34 Th17 cells are
implicated in autoimmunity and are likely to play a role in
the pathogenesis of AAV. Work in our laboratory has shown
that patients with AAV have elevated levels of IL-17 and
some patients have ANCA-specific memory Th17-cells.35
Monocyte activation has also been demonstrated in AAV,
with elevated levels of IL-6 and neopterin in acute disease
but not in convalescence.36
In terms of genetic risk determinants, patients with
WG have higher than expected carriage of the Z allele for
the protease inhibitor gene, which confers α1-antitrypsin
deficiency.37 Single nucleotide polymorphisms in the IL-2
receptor have been associated with systemic lupus ery-
thematosus (SLE) and also with AAV,38 and CTLA4 and
PTPN22 have been identified as susceptibility loci in AAV.39
Patients with AAV and PR3-ANCA have higher neutrophil
membrane expression of PR3 which is genetically deter-
mined and related to relapse.40 Finally, analysis of leucocyte
gene expression profiles in patients has demonstrated that
ANCA signature genes are expressed on neutrophils and
can be differentiated from healthy donors and patients with
SLE.41 However, no clear link with major histocompatibility
antigens has so far been demonstrated.
Current treatment
Treatment of AAV can be divided into two phases, ie, initial
immunosuppression for rapid and effective onset of remission
and subsequent maintenance therapy to prevent relapse. The
ideal regimen would minimize toxicity whilst maintaining
high levels of treatment success. The introduction of steroids
and CYP in the 1970s transformed outcomes for patients
with AAV, and subsequent multicenter randomized trials
have optimized their use. Consensus regarding indications for
plasma exchange (PE), the use of azathioprine (AZA) rather
than CYP in maintenance treatment, and the introduction
of methotrexate (MTX) for induction in less severe disease
has come about as a result of trials conducted by EUVAS.
However, despite significant evidence-based modification of
standard treatment protocols, 90% of patients will experience
drug-related toxicity, which is severe in 25%–50% of cases.42
Age and serum creatinine at diagnosis are the strongest pre-
dictors of both patient and renal survival, and elderly patients
have significantly higher early mortality.5
Induction therapy
Advanced renal failure at presentation correlates with an
increased risk of end-stage renal failure and death, and these
patients are treated aggressively with CYP and high-dose
intravenous (IV) steroids. However, this is associated with a
significant risk of treatment-related morbidity and mortality,
especially in older patients. Infectious adverse effects are the
most common cause of death or severe morbidity, and their
frequency is associated with increased age as well as steroid
dosage and leucopenia secondary to immunosuppressive
therapy. A diagnosis of WG, rather than MPA, and anti-PR3
rather than anti-MPO antibodies, are further markers of
a poor prognosis, with increased risk of disease relapse.5
Therefore, intensity of treatment during the induction phase
depends on both the extent and severity of disease, but almost
invariably consists of glucocorticoids with a second agent.
Serum creatinine, ANCA titer, and acute phase response all
usually improve with induction treatment (Figure 3). Current
EUVAS trials are attempting to define equipotent but less
toxic induction regimens, based on the use of agents such
500
400
300
200
100
0
400
SCreatinine
CRP
PR3-ANCA
300
200
100
0
0 255075
Time/days
Serum creatinine/mcmol/l
PR3-ANCA/IU/ml
CRP mg/dl
100125150
Figure 3 Biochemical changes over time in a patient with PR3-ANCA demonstrat-
ing rapid decrease in serum creatinine, ANCA titer and C-reactive protein following
initiation of immunosuppression.
Abbreviations: ANCA, antineutrophil cytoplasm antibody; PR3-ANCA, proteinase-3
antineutrophil cytoplasm antibody.

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as rituximab (RTX) and mycophenolate mofetil (MMF, see
www.vasculitis.org).
Cyclophosphamide and glucocorticoids
For many years, CYP has formed part of the usual high-dose
regimen for induction of remission in severe disease. CYP
is an alkylating agent which is an inactive cyclic phospha-
mide ester of mechlorethamine. It is transformed via hepatic
and intracellular enzymes to active alkylating metabolites,
ie, 4-hydroxycyclophophosphamide, aldophosphamide, acro-
lein, and phosphoramide mustard. The alkylated purine bases
result in the inhibition of DNA and RNA synthesis and func-
tion, and eventually promote cellular apoptosis. Side effects
of CYP are significant and cumulative, including short-term
risks of hemorrhagic cystitis, leucopenia, and sepsis, as well
as long-term risks of bladder cancer, lymphoproliferative
disease, myelodysplasia, and gonadotoxicity.
The initial regimen was developed at the National
Institutes of Health (NIH) and originally consisted of
CYP at 2 mg/kg/day and glucocorticoids at 1 mg/kg/day.43
CYP was continued for at least one year after remission
and steroids were tapered to an alternate day regimen, but
also continued for one year. This regimen reliably induces
remission in over 80% of patients, but causes significant
toxicity and morbidity,6 and relapses occur in up to 50%
of patients, despite continued immunosuppression.5,6,43
Numerous refinements of this approach have been tested in
clinical trials. A number of randomised studies including
the EUVAS CYCLOPS trial demonstrated that pulsed IV
CYP at a dose of between 7.5 and 15 mg/kg/pulse has the
benefit of a lower total cumulative dose but is as effective as
daily oral therapy in inducing remission.44 However, long-
term relapse rates are likely to be higher, although the risk
of leucopenia and sepsis is lower. The dose of CYP must
be adjusted for weight, age, and renal function (Table 2).44
Mesna (2-mercaptoethanesulfonate sodium), which binds
the toxic metabolite acrolein, and adequate prehydration,
particularly before IV therapy, help to reduce the risk of
bladder toxicity and hemorrhage.
Dosing of glucocorticoids has not so far been subjected to
randomized trials, and a starting induction dose of 1 mg/kg
is standard, with subsequent tapering to a maintenance dose
of ideally not more than 10–15 mg/day at three months or
when remission is achieved, whichever is later. For rapid
control of disease, pulsed IV methylprednisolone in doses
of 0.5–1.0 g daily for three days is often used, but without
supporting evidence. Side effects, including hypertension,
obesity, hyperglycemia, cataracts, and osteoporosis, should
not be underestimated and remain a considerable cause of
morbidity.
Prophylaxis against infection, peptic ulceration, and
bone resorption should be standard during induction therapy.
A combination of agents including Pneumocystis jiroveci
prophylaxis with trimethoprim-sulphamethoxazole, topical
oral antifungal treatment, a gastric protective agent, and
calcium-vitamin D supplementation is usually added to the
regimen. Biphosphonate therapy is contraindicated with more
severe degrees of renal impairment but should be used when
renal function permits.
Plasma exchange
PE is of additional benefit as induction therapy in severe
renal disease. The EUVAS MEPEX trial compared pulsed IV
methylprednisolone versus PE, in addition to standard treat-
ment with oral CYP and steroids, in 137 patients with serum
creatinine 500 µmol/L. It showed that PE decreased the
risk of progression to end-stage renal disease by 24% at
12 months.45 Although the mechanism of this is likely to
relate to rapid removal of ANCA, the depletion of circulating
cytokines, complement, and coagulation factors may also
be important. However, PE has not been shown to improve
overall survival and it is not known whether or not it benefits
patients with less severe disease. The proposed PEXIVAS
project aims to study the influence of PE and of a reduced
dose of steroids on mortality and ESRD in patients with less
advanced renal impairment (estimated glomerular filtration
rate of 50 mL/min).
Methotrexate
MTX is a folic acid analog that inactivates the enzyme dihy-
drofolate reductase and thus the production of thymidylate,
which is essential for DNA replication. MTX has similar
success rates to CYP in induction of remission in early
systemic vasculitis without significant renal disease. The
EUVAS NORAM trial demonstrated that MTX is a less toxic
alternative to CYP for patients with early systemic disease
Table 2 Dose modification of pulsed intravenous CYP as used in
the CYCLOPS trial44
Pulsed CYC dose reductions for renal function and age
Age (years)
Creatinine (µmol/L)

300
300–500
60
15 mg/kg/pulse12.5 mg/kg/pulse
60–7012.5 mg/kg/pulse10 mg/kg/pulse
70
10 mg/kg/pulse7.5 mg/kg/pulse
See www.vasculitis.org/protocols/CYCLOPS.pdf