Joint Bone Spine 74 (2007) 427e435

http://france.elsevier.com/direct/BONSOI/

Review

Antineutrophil cytoplasmic antibody-associated vasculitides

Xavier Puéchal*
Rheumatology Department, Centre Hospitalier Le Mans, 194, avenue Rubillard, 72037 Le Mans Cedex 9, France
Received 7 October 2006; accepted 15 February 2007
Available online 14 May 2007

Abstract

The identification of antineutrophil cytoplasmic antibodies (ANCA) proved a major breakthrough in the classification, diagnosis, monitoring,
and understanding of vasculitides. Vasculitides associated with ANCA selectively affect the small vessels; they include Wegener granulomatosis,
microscopic polyangiitis, and ChurgeStrauss syndrome. Evidence supporting a direct pathogenic role for ANCA has accumulated over the
years. The clinical, laboratory, and histological findings vary across diseases; they are discussed here based on a review of published data
from over 1600 patients. The course and prognosis also vary according to the disease. New treatment strategies tailored to the type and extent
of the vascular disease have improved survival and treatment safety. Induction therapy, which should be given on an emergency basis in a spe-
cialized unit, consists of glucocorticoid therapy and cyclophosphamide in Wegener granulomatosis; microscopic polyangiitis and ChurgeStrauss
syndrome, without poor prognostic factors, can be managed with glucocorticoid therapy alone as the first-line treatment. A full recovery or com-
plete remission is now achieved in over 80% of patients. Maintenance therapy is mandatory to reduce the relapse rate, which varies across dis-
eases. Among patients with Wegener granulomatosis, up to 50% relapse within the first 5 years. Azathioprine is the main maintenance drug,
although methotrexate, mycophenolate mofetil, or leflunomide may be used as second-line drugs. Biotherapies such as rituximab and TNFa
antagonists are currently under evaluation as promising rescue agents for patients with refractory disease.
Ó 2007 Elsevier Masson SAS. All rights reserved.

Keywords: Vasculitis; Antineutrophil cytoplasmic antibody; Wegener granulomatosis; Microscopic polyangiitis; ChurgeStrauss syndrome

Small-vessel vasculitides are defined as selective inflamma-
tion of the arterioles, venules, and capillaries (Fig. 1) [1]. The
identification of antineutrophil cytoplasmic antibodies
(ANCA) about two decades ago in patients with pauci-
immune small-vessel vasculitis proved a breakthrough in the
classification, diagnosis, monitoring, and understanding of
the vasculitides. ANCA were found to be associated with
four vasculitides: microscopic polyangiitis, Wegener granulo-
matosis, ChurgeStrauss syndrome, and necrotizing crescentic
glomerulonephritis. The incidence of ANCA-associated vas-
culitides is rising; it has been estimated at more than 20/106
population, with a peak between 65 and 75 years of age [2].
Advances in the characterization of individual vasculitides
have highlighted the existence of major differences in
* Tel.: þ33 2 43 43 26 56; fax: þ33 2 43 43 28 10.
E-mail address: xpuechal@ch-lemans.fr
outcomes, leading to the development of new treatment strat-
egies tailored to each type of vasculitis. These strategies are
associated with better survival and improved treatment safety.
This review of ANCA-associated vasculitides places spe-
cial emphasis on the relevance of positive ANCA tests to the
diagnosis and follow-up of patients with vasculitides, on clin-
ical manifestations, and on treatment strategies, which have
benefited recently from the introduction of biotherapies.
1. Antineutrophil cytoplasmic antibodies
1.1. Targets
Converging lines of evidence indicate a role for ANCA in
the pathogenesis of ANCA-associated vasculitides and in the
development of tissue lesions [3,4]. ANCA are autoantibodies
to components of azurophilic granules in neutrophils and lyso-
somes in monocytes. The only clinically relevant ANCA are

1297-319X/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2007.02.001
428 X. Puéchal / Joint Bone Spine 74 (2007) 427e435

Capillary
Arteriole Venule
Small artery Vein
Large and medium-
sized arteries

Aorta
Cutaneous leukocytoclastic angiitis

Henoch-Schönlein purpura and cryoglobulinemia

Microscopic polyangiitis

Wegener granulomatosis and Churg-Strauss syndrome

Polyarteritis nodosa and Kawasaki

Giant cell arteritis and Takayasu arteritis

Fig. 1. Size of the vessels involved, as defined at the Chapel Hill consensus conference [1]. Small vessels comprise venules, capillaries, arterioles, and small ar-
teries. Small arteries are distal intraparenchymatous arteries that connect to arterioles. Medium-sized vessels are vessels that supply and drain the main organs.
Small-vessel vasculitis may involve medium-sized arteries, whereas vasculitis of medium-sized vessels does not involve smaller vessels. Therefore, the main dis-
tinction between vasculitides of small vessels and medium-sized vessels is that only the former involve small vessels.

those directed to proteinase 3 (PR3) or myeloperoxidase
(MPO). ANCA to lactoferrin, cathepsin G, elastase, bacteri-
cidal permeability increasing (BPI) protein, lysozyme, or other
antigens are devoid of clinical significance.
1.2. Assays
Both indirect immunofluorescence (IIF) on smears of etha-
nol-fixed normal human neutrophils and ELISA are used in ev-
eryday clinical practice [5,6]. IIF serves to detect ANCA. When
the test is positive, the fluorescence may be cytoplasmic (C-
ANCA), perinuclear (P-ANCA), or atypical. Specific ELISAs
identify the specific antigen targeted by the ANCA. C-ANCA
detected by IIF are nearly always directed against PR3, whereas
P-ANCA are directed against MPO in 90% of cases. Occasion-
ally, P-ANCA may target other antigens, in which case their
significance is unclear. Atypical fluorescence may be seen in
a broad range of conditions including inflammatory bowel
disease, autoimmune diseases, and a number of infections
(including tuberculosis). The target is usually lactoferrin, elas-
tase, or BPI protein. The P-ANCA pattern of fluorescence may
be difficult to distinguish from atypical fluorescence.
Patients with positive IIF tests must be investigated using
ELISAs for anti-PR3 and anti-MPO antibodies. Furthermore,
ELISAs are mandatory when vasculitis is present, as they are
positive in about 5% of patients with negative IIF findings [5].
the presence of ANCA lends valuable assistance to the dia-
gnosis. In patients who have suggestive clinical manifesta-
tions, positive tests for ANCA strongly support a diagnosis
of small-vessel vasculitis, and identification of the antigen tar-
get by ELISA may point to a specific disease [4]. However,
ANCA assays may be negative in ANCA-associated vasculit-
ides. A positive IIF test for ANCA with negative results from
anti-PR3 and anti-MPO assays is of limited value.
1.4. Relevance of ANCA during follow-up
International recommendations mandate ANCA titer deter-
mination at regular intervals during follow-up, although inter-
pretation of the results is not standardized [5,6]. A review of
15 studies showed that no relapses occurred after 155 (42%)
of 365 ANCA increases by IIF and 75 (25%) of 295 increases
by ELISA [7]. Thus, approximatively one third of patients
would receive unnecessary treatment if ANCA testing was
used alone to diagnose relapses [3]. ANCA titers correlate
poorly with disease activity, and titer increases do not reliably
predict relapses. Only low-level evidence is available to support
treatment intensification in patients with isolated ANCA-titer
increases [8]. There is widespread agreement that an isolated
ANCA-titer increase should be viewed as indicating a risk of
relapse and, therefore, a need for close monitoring rather than
treatment intensification, in the absence of other signs [3,5].

1.3. Diagnostic relevance of ANCA 2. Clinical manifestations

Although the identification of ANCA has improved the
classification of vasculitides, the diagnosis of ANCA-associ-
ated vasculitis usually relies on a careful interpretation of
histological findings in the light of the clinical presentation.
Nevertheless, when the histological studies are inconclusive,
2.1. Manifestations shared by all ANCA-associated
vasculitides
Shared manifestations stem chiefly from vessel inflammation
within organs. Their frequencies vary from one disease to the
 X. Puéchal / Joint Bone Spine 74 (2007) 427e435 429

next. Table 1 lists the main clinical, laboratory, and histological
manifestations in each of the ANCA-associated vasculitides.
The frequencies shown in the table are based on over 1600 pa-
tients, including more than 700 with Wegener granulomatosis
[9e13], more than 200 with microscopic polyangiitis [14e
18], and more than 700 with ChurgeStrauss syndrome [19e31].
Fever and weight loss are common and may be inaugural.
Migratory arthralgia or arthritis is often the first manifestation,
however. Both the large and the small joints may be affected,
and synovitis develops in 10e20% of patients. Arthritis that an-
tedates the systemic manifestations of Wegener granulomatosis
or microscopic polyangiitis may lead to a mistaken diagnosis of
nondestructive rheumatoid arthritis, particularly as tests for
rheumatoid factor may be positive. Therefore, a search for the
cardinal signs of ANCA-associated vasculitis (Tables 1 and 2)
should be incorporated into the evaluation of unexplained
oligoarthritis or polyarthritis.
The skin lesions are directly related to the vascular inflam-
mation and vary with the size of the vessels involved. Purpura
predominating on the lower limbs or urticarial lesions indicate
leukocytoclastic vasculitis involving the capillaries and ve-
nules (Fig. 2). A less common pattern is necrotizing vasculitis

Table 1
Clinical, laboratory, and histological manifestations of ANCA-associated vasculitides, based on over 1600 reported cases [9e31]
Wegener granulomatosis Microscopic polyangiitis ChurgeStrauss syndrome
ANCA ANCA in 80%e90% of cases ANCA in 50%e70% of cases ANCA in 35%e45% of cases
90% C-ANCA anti-PR3 10% C-ANCA anti-PR3 10% C-ANCA anti-PR3
10% P-ANCA anti-MPO 80% P-ANCA anti-MPO 75% P-ANCA anti-MPO
Histology Small-vessel necrotizing vasculitis Small-vessel necrotizing vasculitis Small-vessel necrotizing vasculitis
Middle-sized arteries may be involved Middle-sized arteries may be involved Eosinophilic infiltrate in vessels and tissues
Granulomatous inflammation No granulomas Extravascular granulomas
Otolaryngological 80%e90% 20%e30% 50%e80%
involvement
Chronic bloody nasal discharge with Oral ulcers, epistaxis, sinusitis Allergic rhinitis, nasal polyposis,
crusting, sinusitis, nasal or oral ulcers, sinusitis hearing loss
nasal septum perforation, saddle-nose
deformity, serous otitis media, hearing
loss, subglottic stenosis
Pulmonary 50%e80% 20%e60% 96%e100%
involvement
Pulmonary infiltrates, nodules (often Pulmonary infiltrates, Asthma
cavitated), alveolar hemorrhage alveolar hemorrhage, pleural effusion 40%e70%
Transient pulmonary infiltrate, pleuritis,
alveolar hemorrhage
Kidney involvement 50%e80% 90%e100% 15%e40%
Extracapillary glomerulonephritis, Extracapillary glomerulonephritis Extracapillary glomerulonephritis
few granulomas
Cardiac involvement 10%e20% 10%e20% 20%e45%
Pericarditis, valvulopathy, infarction Pericarditis Specific cardiomyopathy, pericarditis
APNa involvement 10%e50% 15%e60% 70%
Mononeuropathy multiplex, Mononeuropathy multiplex, Mononeuropathy multiplex,
sensory-motor polyneuropathy sensory-motor polyneuropathy sensory-motor polyneuropathy
CNSb involvement 10% 10% 15%
Cranial nerve involvement, space- Cerebral ischemia Central nervous system involvement
occupying lesion, pachymeningitis
Articular involvement 50%e80% 30%e70% 25%e60%
Arthralgia, arthritis Arthralgia, arthritis Arthralgia, arthritis
Skin involvement 30%e60% 40%e70% 50%e80%
Purpura, ulcers, granulomatous Purpura, papules, ulcers Purpura, papules, ulcers
subcutaneous nodules
Eye involvement 30%e60% 20%e30% 10%
Scleritis, episcleritis, uveitis granulomatous Scleritis, episcleritis, uveitis Scleritis, episcleritis, uveitis
retro-orbital pseudo-tumor
Average age 47 years 49 years 47 years
Sex 54% male 59% male 51% male
Eosinophilia Rare Absent 90%e100%
The percentages were computed from the main reported series, which included 705 patients with Wegener granulomatosis [9e13], 235 with microscopic poly-
angiitis [14e18], and 703 with ChurgeStrauss syndrome [19e31].
a
APN: Axonal peripheral neuropathy.
b
CNS: Central nervous system.
430 X. Puéchal / Joint Bone Spine 74 (2007) 427e435
Table 2
Manifestations that should prompt a search for ANCA-associated vasculitis
A Unexplained inflammatory arthralgia
A Unexplained decline in general health
A Vascular purpura (infiltrated lesions)
Skin necrosis
A
A Digital gangrene or ulcer
A Myalgia
A Axonal mononeuropathy or polyneuropathy
A Pneumorenal syndrome
A Hematuria or proteinuria
Positive tests for ANCA
A
A Unexplained elevated acute phase reactants
ANCA-associated vasculitis should be considered in patients with any of the
manifestations listed below. Presence of more than one manifestation is partic-
ularly suggestive.
of the dermal arterioles and arteries, which manifests as nod-
ules, necrotic lesions, ulcers, or livedo reticularis.
Axonal peripheral neuropathy is common. Although mono-
neuropathy multiplex is suggestive, sensory-motor or sensory
polyneuropathy is not rare. Recovery may require more than
a year, as with all axonal neuropathies. Permanent incapacitat-
ing motor or sensory loss may develop. A considerably less
common manifestation is central nervous system involvement
due to involvement of meningeal vessels or, exceptionally,
cerebral vessels.
The muscles constitute a frequent target of ANCA-associ-
ated vasculitides. Myalgia, weakness, and muscle enzyme
elevation may be seen. Biopsies may show an interstitial infil-
trate of mononuclear cells that extend far beyond the vessels,
denoting concomitant moderate myositis.
Gastrointestinal involvement is a potential source of life-
threatening complications. Vasculitis of the mesenteric vessels
may manifest as abdominal pain, bleeding, or intestinal perfo-
ration. Pancreatitis develops in some patients.
Respiratory tract manifestations develop in many patients,
with the upper airways being oftenly affected. The clinical
Fig. 2. Purpura of the lower limbs during the fourth relapse of microscopic pol-
yangiitis of 7 years’ duration (from the collection of Dr Puéchal).
manifestations vary according to the underlying vasculitis.
Signs of pulmonary involvement range from focal infiltrates
to alveolar hemorrhage due to vasculitis of the alveolar capil-
laries, which can cause life-threatening hemoptysis (Fig. 3).
Extracapillary glomerulonephritis indicates involvement of
the glomerular capillaries and interlobular arterioles smaller
than 70 mm in diameter. Rapidly progressive renal failure is
a common outcome that may require dialysis in the short
term. Extracapillary glomerulonephritis requires emergency
treatment, as the prognosis correlates closely with the time
to treatment initiation.
Less often, small vessels in other organs are involved.
2.2. Specific features of Wegener granulomatosis
The upper and lower respiratory tract and the kidneys are
the main targets of Wegener granulomatosis (Table 1) [9e
13]. About 90% of patients experience otolaryngological in-
volvement that may manifest as episodes of rhinitis, sinusitis,
epistaxis, or nasal crusting. Nasal inflammation may cause
septal erosions or perforations and saddle-nose deformity.
Conductive or sensorineural hearing loss may occur concom-
itantly with vestibular involvement. Pulmonary vasculitis man-
ifests as nodules, infiltrates, or alveolar hemorrhage. The
nodules are usually multiple and bilateral; cavitation may
occur. Granulomas occasionally lead to cutaneous nodules,
most notably about the olecranon. Ocular pseudo-tumor, scler-
itis, or peripheral ulcerative keratitis constitute the main ocular
manifestations. Subglottic or bronchial stenosis is a potentially
life-threatening complication. Extracapillary glomerulone-
phritis develops in over 50% of patients with Wegener
granulomatosis.
The pathology of Wegener granulomatosis combines vascu-
litis of the small vessels or, less often, the medium-sized ves-
sels; irregularly contoured foci of ischemic necrosis with the
development of sterile abscesses; and formation of granulomas
Fig. 3. Bilateral alveolar hemorrhage in a patient with Wegener granulomatosis
that manifested during the first 3 years as flares of polyarthritis responsive to
low-dose glucocorticoid therapy, without systemic symptoms (from the collec-
tion of Dr Puéchal).
 X. Puéchal / Joint Bone Spine 74 (2007) 427e435
composed of neutrophils, lymphocytes, and giant multinuclear
cells. ANCA against PR3 are found in 80e90% of patients
with systemic Wegener granulomatosis, of whom only 10%
have anti-MPO ANCA. Focal Wegener granulomatosis
involves the eyes, ears, nose, and lungs. Histology may
show granulomatous airway inflammation in addition to small-
vessel vasculitis. Only 60% of these patients have detectable
titers of ANCA.
2.3. Specific features of microscopic polyangiitis
Otolaryngological and pulmonary involvement is far less
common in microscopic polyangiitis than in Wegener granulo-
matosis and ChurgeStrauss syndrome (Table 2) [14e18]. Ex-
tracapillary glomerulonephritis is a feature in 90% of cases.
Over one-third of the patients experience pulmonary
involvement, whose most dreaded manifestation is alveolar
hemorrhage (Fig. 3). Microscopic polyangiitis is the leading
cause of pneumorenal syndrome. Histology shows pauci-
immune necrotizing vasculitis of the small vessels, without
granulomas. The medium-sized vessels may be involved.
About 50e70% of patients have ANCA, which are usually
directed to MPO.
2.4. Specific features of ChurgeStrauss syndrome
Three phases can usually be distinguished in the course of
ChurgeStrauss syndrome. Asthma and various allergic mani-
festations such as allergic rhinitis occur initially. Eosinophilia
and pulmonary infiltrates characterize the second phase.
Finally, systemic manifestations usually develop several years
after the onset of asthma. Asthma and eosinophilia are virtu-
ally always present. The pulmonary infiltrates are typically
transient. Rapidly progressive glomerulonephritis and alveolar
hemorrhage are less common in ChurgeStrauss syndrome
than in Wegener granulomatosis or microscopic polyangiitis.
Specific cardiac involvement is the leading cause of death.
Necrotizing vasculitis, eosinophilic infiltrates within tis-
sues, and granulomas are the three main histological abnor-
malities. They are rarely present in combination. The
vasculitis involves the small arteries and veins, which contain
eosinophil-rich infiltrates. The granulomas develop outside the
vessels; they have a central area of necrosis that is surrounded
by epithelioid cells.
ANCA are detected in 35% of patients by ELISA and 45%
by IIF with a perinuclear fluorescence and anti-MPO specific-
ity for three-fourths of ANCA-positive tests, according to data
from 327 and 128 patients with ChurgeStrauss syndrome
[23e26,28e31] (Table 1). Negative tests for ANCA are asso-
ciated with manifestations related to eosinophilic infiltrates
(such as myocarditis or pericarditis) or nonhemorrhagic
pulmonary involvement (e.g., infiltrates and eosinophilic
pleuritis) [30,31]. Presence of ANCA, in contrast, is associated
with direct signs of vascular involvement, including glomeru-
lonephritis, alveolar hemorrhage, and purpura.
431
2.5. Necrotizing crescentic glomerulonephritis
Necrotizing crescentic glomerulonephritis is an ANCA-
associated vasculitis that is confined to the kidneys. Immuno-
globulin deposits are not a feature. ANCA are found in 90% of
cases and are usually directed to MPO.
2.6. Diagnosis
The first step is to consider vasculitis in patients with one or
more suggestive symptoms (Table 2). Confirmation of the di-
agnosis is usually obtained from a biopsy of an involved organ
(skin, muscle, kidney, nasal mucosa and, less often, lung) and
tests for ANCA. Then, the type of vasculitis must be deter-
mined, as well as its extent and prognosis, which dictate treat-
ment decisions. No validated diagnostic criteria are available.
The 1990 American College of Rheumatology (ACR) criteria
are intended for classification purposes; they do not constitute
a diagnostic tool [32,33]. In addition, they are ill-suited to
small-vessel vasculitides, as they fail to individualize micro-
scopic polyangiitis. Table 3 lists ACR classification criteria
for Wegener granulomatosis and ChurgeStrauss syndrome.
The definitions adopted by the 1994 Chapel Hill consensus
conference individualize small-artery vasculitides, including
microscopic polyangiitis, although they do not suggest diag-
nostic criteria (Fig. 1) [1].
2.7. Course and sequelae
Disease activity should be evaluated at diagnosis and at
regular intervals during follow-up. The Birmingham Vascu-
litis Activity Score (BVAS) is a validated instrument used
in clinical trials and everyday practice [34]. Signs of disease
activity must be differentiated from sequelae related to the
disease (e.g., renal or neurological impairment) or treatment
(e.g., vertebral fractures). The Vasculitis Damage Index
Table 3
Classification criteria for Wegener granulomatosis and ChurgeStrauss
syndrome developed by the American College of Rheumatology [32,33]
Wegener granulomatosis ChurgeStrauss syndrome
A Painful or painless A Asthma
oral ulcers; or purulent A Eosinophilia greater
or bloody nasal discharge than 10% in peripheral blood
A Chest radiograph A Mono- or polyneuropathy
showing nodules, fixed A Migratory or transitory
infiltrates, or cavities pulmonary infiltrates
A Microhematuria or red cell A Tenderness, pain,
casts in urine sediment or radiographic opacification
A Granuloma within of the paranasal sinuses
the wall of an artery A Artery, arteriole,
or arteriole or in the perivascular or venule showing
or extravascular area accumulations of eosinophils
in extravascular areas
In a patient with vasculitis, presence of two or more of these four criteria is
88.2% sensitive and 92% specific for Wegener granulomatosis.
In a patient with vasculitis, presence of four or more of these six criteria is
85% sensitive and 99.7% specific for ChurgeStrauss syndrome.
432 X. Puéchal / Joint Bone Spine 74 (2007) 427e435
(VDI) is useful for quantifying the impact of sequelae [35].
Quality of life can be assessed using the 36-item Short
Form survey.
2.8. Outcomes
Since the introduction of glucocorticoids and immunosup-
pressants to treat ANCA-associated vasculitides, 5-year
survival has exceeded 80%. However, early mortality due
to alveolar hemorrhage or severe renal failure remains com-
mon, most notably in older patients. Infection is also a major
cause of early death. The Groupe Français d’Etude des
Vascularites (GFEV, French Study Group on Vasculitides)
is investigating a less aggressive treatment regimen for older
patients. Despite the improved survival, some patients fail to
achieve long-term remissions. About 50% of patients experi-
ence one or more relapses within the first 4e5 years. Persis-
tently positive tests for ANCA are associated with an
increased risk of relapse.
Relapses are more common in Wegener granulomatosis
than in the other ANCA-associated vasculitides [36,37].
They may be related to the presence of granulomas and to
colonization of the airways by pathogens such as Staphylo-
coccus aureus [38]. As relapses occur in more than 50% of
patients with Wegener granulomatosis, prolonged immuno-
suppressant therapy is often required, at the cost of frequent
and severe adverse events. With regimens involving long-
term oral cyclophosphamide therapy, a risk increase of
33-fold occurred for urinary bladder carcinoma, 11-fold for
lymphoma, and 2.4-fold for solid tumors [9]. Although
relapses are often less severe than the initial presentation,
they may add to the burden of sequelae, thereby worsening
the functional impairment.
In patients with ChurgeStrauss syndrome, relapses are
common but often mild and adequately controlled by a tran-
sient increase in the glucocorticoid dosage. Residual asthma
may require long-term systemic glucocorticoid therapy.
In patients with microscopic polyangiitis or ChurgeStrauss
syndrome, the Five Factor Score (FFS) is a validated instru-
ment that is convenient for evaluating the severity of the initial
vasculitis (Table 4) [39,40]. FFS results help to tailor the treat-
ment to the clinical presentation.
Table 4
Factors of adverse prognostic significance in microscopic polyangiitis and
ChurgeStrauss syndrome [39,40]
A Proteinuria greater than 1 g/24 h
A Serum creatinine greater than 140 mmol/L (15.8 mg/L)
A Specific cardiomyopathy
A Specific digestive system involvement: bleeding, perforation, closely
spaced episodes of abdominal pain, and pancreatitis
A Specific central nervous system involvement
The Five Factor Score (FFS) equals 0 when none of these criteria is present.
Each criterion contributes 1 point to the total score. Thus, the FFS can range
from 0 to 5.
Five-year mortality rate is: 12% when the FFS ¼ 0, 25% when the FFS ¼ 1,
50% when the FFS  2.
The FFS has not been validated in Wegener granulomatosis.
3. Treatment
3.1. Treatments used in all ANCA-associated vasculitides
3.1.1. General principles
The treatment should be started on an emergency basis in
a specialized department. Induction treatment seeks to obtain
a remission, after which maintenance treatment is given to
lower the relapse risk. The treatment should be tailored to
the individual patient based on the type of vasculitis, its sever-
ity, whether the patient is experiencing the first episode or a
relapse, whether a remission has been achieved, age, renal
function, and potential adverse effects of each drug.
3.1.2. Induction treatment
Induction treatment achieves a remission in over 80% of pa-
tients with ANCA-associated vasculitides [12,18,25,36,37,41].
In severe microscopic polyangiitis and ChurgeStrauss
syndrome (FFS  1), induction treatment is the same as in
Wegener granulomatosis. In milder cases of microscopic poly-
angiitis and ChurgeStrauss syndrome (FFS ¼ 0), a remission
can usually be achieved with glucocorticoid therapy alone,
so that the patient is not exposed to the adverse effects of con-
comitant immunosuppressant therapy [42,43]. Should first-line
glucocorticoid therapy fail, add-on immunosuppressant ther-
apy is effective in the overwhelming majority of cases.
3.1.2.1. Glucocorticoid therapy. The starting dosage is 1
mg/kg/day. Patients with severe disease are first given three
methylprednisolone boluses of 15 mg/kg each. After 3e4 weeks
of full-dose treatment, the dosage should be tapered more rapidly
than previously recommended in most French units [12], to
about 10e30 mg/day over a 3-month period [9,13]. This faster
tapering strategy minimizes adverse treatment effects. Never-
theless, measures to counterbalance adverse effects remain
crucial; they should include treatment to preserve bone mass.
3.1.2.2. Cyclophosphamide. Cyclophosphamide boluses are
given at 2-week intervals for 1 month then at 3-week intervals
in Wegener granulomatosis and 4-week intervals in micro-
scopic polyangiitis and ChurgeStrauss syndrome. The dosage
is usually 0.6 g/m2; however, a lower dosage of 0.5 g/m2 is
appropriate in elderly individuals and in patients with renal
dysfunction. Prevention of hemorrhagic cystitis and cancer
of the urinary bladder rests on a high fluid intake, in combina-
tion with uromitexan. Prophylactic therapy of Pneumocystis
jiroveci infection usually relies on trimethoprim-sulfamethox-
azole. Cyclophosphamide can also be given orally in dosages
2e3 times higher than those used for bolus therapy. However,
continuous oral administration is associated with high rates of
potentially severe adverse events [12,17,44]. According to
a metaanalysis, intravenous bolus therapy is less toxic than
oral administration while being similarly effective in inducing
remissions, although the relapse rate may be higher [45]. Sim-
ilar results were obtained in a study by the GFEV [12] and in
the randomized controlled European trial CYCLOPS, which is
in press [46]. After exclusion of patients with the most severe
 X. Puéchal / Joint Bone Spine 74 (2007) 427e435
forms, remission rates are 77% after 3 months and 93% after 6
months of cyclophosphamide therapy [36]. Oral administra-
tion produces a remission in most patients who fail bolus cy-
clophosphamide therapy.
3.1.2.3. Plasma exchange. Plasma exchange is reserved for
severe forms of ANCA-associated vasculitis with advanced re-
nal failure. In a randomized controlled trial, plasma exchange
was significantly more effective than methylprednisolone
bolus therapy in reducing 3- and 12-month dialysis rates in
patients whose creatinine levels were greater than 500 mmol/L
at baseline [47]. Nevertheless, survival was not improved, and
no information was obtained about the maintenance of renal
benefits over time. Plasma exchange has been advocated for
patients with alveolar hemorrhage, although there is only
week evidence to support this approach.
3.1.2.4. Immunoglobulin therapy. Immunoglobulins as adju-
vant therapy were investigated in a few open-label studies
and one placebo-controlled study [48]. Benefits were modest
and short-lived. Nevertheless, immunoglobulin therapy may
help to tide the patient over a difficult period until concomitant
immunosuppressant therapy takes effect.
3.1.3. Maintenance treatment
Azathioprine is widely used as maintenance treatment. The
18-month relapse rate was not higher with azathioprine main-
tenance therapy than with continued cyclophosphamide ther-
apy after successful remission induction with
cyclophosphamide and glucocorticoid therapy [36]. The
long-term safety profile is better with azathioprine than with
cyclophosphamide. A European study is under way to deter-
mine the optimal duration of azathioprine maintenance
therapy.
In patients with Wegener granulomatosis, other immuno-
suppressants are occasionally used, either as maintenance ther-
apy or to treat relapses. Methotrexate in a dosage of 0.3 mg/kg/
week may be given. Methotrexate is less effective than cyclo-
phosphamide for induction therapy [41] but maintains previ-
ously induced remissions in over 80% of cases [49]. The
relapse rate after methotrexate discontinuation is greater than
50%, however [50]. In a study by the GFEV comparing meth-
otrexate to azathioprine for 1 year after remission induction,
methotrexate was comparable to azathioprine in preventing
relapses, which nevertheless occurred in over 40% of patients
over a 4-year period in both groups [37]. Mycophenolate mo-
fetil, leflunomide, or deoxyspergualin have been advocated
for maintenance treatment. The limited experience acquired
with these drugs suggests usefulness for maintenance therapy
in patients who cannot tolerate azathioprine and in those with
relapses that fail to respond to conventional therapy.
3.1.4. Rescue therapy
Rituximab (humanized anti-CD20 monoclonal antibody)
holds promise for the treatment of refractory ANCA-associ-
ated vasculitides. Several international controlled trials are
currently evaluating rituximab for induction or maintenance
433
therapy. In preliminary open-label studies, three-fourths of pa-
tients had Wegener granulomatosis [51e57]. Of seven studies,
all but one [57] found evidence of efficacy. A complete remis-
sion was achieved in 44 (83%) of 53 patients in all. The time
to maximum effect was up to 3 months. Patients with retro-
orbital granulomas usually failed to respond.
Infliximab used without concomitant immunosuppressants
may have a role for short-term induction treatment of Wegener
granulomatosis refractory to conventional medications. Open-
label studies in a total of 35 patients with refractory Wegener
granulomatosis showed a greater than 80% remission rate
[58e61]. An ongoing therapeutic trial conducted by the
GFEV is designed to compare rituximab to infliximab in
patients having failed several lines of immunosuppressant
therapy. The only controlled study available to date compared
add-on etanercept to a placebo in patients with Wegener gran-
ulomatosis who were receiving conventional treatment [62].
Etanercept was not better than the placebo when used as main-
tenance therapy, and neither were there any convincing
benefits for induction. Solid malignancies developed more
often in the etanercept group than in the placebo group.
3.1.5. Adjuvant treatments for Wegener granulomatosis
Trimethoprim-sulfamethoxazole is used to treat focal
Wegener granulomatosis and to prevent P. jiroveci pneumonia.
In addition, this combination significantly reduced the relapse
rate compared to a placebo in patients who were in complete
remission [63].
3.2. Future prospects
ANCA-associated vasculitides are challenging to diagnose
and to treat. Several of their characteristics mandate manage-
ment in specialized units: these diseases are both rare and
protean, and therefore difficult to recognize; refractory forms
are difficult to treat; and the high relapse rate leads to the
administration of large cumulative dosages of immunosup-
pressants, which generate numerous adverse effects. In France,
a national reference center for necrotizing vasculitides was
created to optimize patient management at centers located
near their place of residence. The GFEV website supplies
up-to-date information on diagnostic criteria, follow-up inves-
tigations, therapeutic recommendations, and ongoing studies
(www.vascularite.com). The many multicenter and multidisci-
plinary studies conducted by the GFEV, European Vasculitis
Study Group (EUVAS), and North-American groups have
provided major advances in the understanding of pathogenic
mechanisms, optimization of treatment strategies, and evalua-
tions of new medications. The result is a better diagnostic and
therapeutic approach to these fascinating diseases about which
much remains to be discovered.
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