Download Wegener Granulomatosis (Granulomatosis with Polyangiitis

Wegener Granulomatosis (Granulomatosis
with Polyangiitis): Evolving Concepts in
Treatment
Joseph P. Lynch, III, M.D.1 and Henry Tazelaar, M.D.2
Wegener granulomatosis (WG), the most common of the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract, lower respiratory tract
(bronchi and lung), and kidney, with varying degrees of disseminated vasculitis. The term
Granulomatosis with Polyangiitis (Wegener) was recently proposed to replace the older
term, WG. The term granulomatosis with polyangiitis can be abbreviated to GPA, with
the idea that the eponym Wegener would be omitted over time. Cardinal histologic
features include a necrotizing vasculitis involving small vessels, extensive ‘‘geographic’’
necrosis, and granulomatous inflammation. Clinical manifestations of WG are protean;
virtually any organ can be involved. The spectrum and severity of the disease are
heterogeneous, ranging from indolent disease involving only one site to fulminant,
multiorgan vasculitis. The pathogenesis of WG has not been elucidated, but both cellular
and humoral components are involved. Circulating antibodies against cytoplasmic components of neutrophils [anti-neutrophil cytoplasmic antibodies (c-ANCAs)] likely play a
role in the pathogenesis, and often correlate with activity of the disease. Treatment
strategies are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the
mainstay of therapy for generalized, multisystemic WG. Historically, the combination of
CYC plus CS was used for a minimum of 12 months, but concern about late toxicities
associated with CYC has led to novel treatment approaches. Currently, short-course (3 to
6 months) induction treatment with CYC plus CS, followed by maintenance therapy with
less toxic agents (eg, methotrexate, azathioprine) is recommended. Further, methotrexate
combined with CS may be adequate for limited, non-life-threatening WG. Recent studies
suggest that rituximab may be useful for induction therapy or CYC-refractory WG. The
role of other immunomodulatory agents (including trimethoprim-sulfamethoxazole) is also
explored.
KEYWORDS: Wegener granulomatosis, granulomatosis with polyangiitis,
granulomatous vasculitis, pulmonary vasculitis, capillaritis, anti-neutrophil cytoplasmic
antibodies, geographic necrosis
1
Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical
Immunology, Department of Medicine, The David Geffen School of
Medicine at UCLA, Los Angeles, California; 2Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona.
Address for correspondence and reprint requests: Joseph P. Lynch,
III, M.D., Division of Pulmonary, Critical Care Medicine, Allergy,
and Clinical Immunology, The David Geffen School of Medicine at
UCLA, 10833 Le Conte Ave., Rm. 37-131 CHS, Los Angeles, CA
274
90095-1690 (e-mail: [email protected]).
Lung Vasculitis and Alveolar Hemorrhage; Guest Editor, Loı̈c
Guillevin, M.D.
Semin Respir Crit Care Med 2011;32:274–297. Copyright # 2011
by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,
NY 10001, USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0031-1279825.
ISSN 1069-3424.
Downloaded by: World Health Organization ( WHO). Copyrighted material.
ABSTRACT
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
Epidemiology
The annual incidence of WG has been rising over the
decades from <1 per million in the 1970s to current
estimates of 4 to 12 cases per million.12,13 Published
annual incidence rates (per million) were 4.1 in Spain,14
8.4 to 10.3 in England,14,15 12 in Norway.13 Published
prevalence rates (per million) include 23.7 in Paris,16 30
in the United States,17 95.1 in Norway,13 112 in New
Zealand,18 160 in southern Sweden.19 WG affects predominantly Caucasians.12,13 The peak incidence is in the
fourth through sixth decades of life;2,3,5,17 children or
adolescents are rarely affected.1,20,21 There is no gender
predominance.4,15
Pediatric Age Group
WG in children is rare,1,20–22 but the incidence may be
increasing.23 An epidemiological study in Alberta, Can-
ada, from 1994 to 2008 cited an annual incidence of WG
in children of 0.93 cases/million from 1994 to 2003 that
increased to 6.39 during 2004 to 2008.23 Renal involvement is less common in childhood cases (53 to 79%)20–22
compared with adults (>80%).1–3 Subglottic stenosis
was noted in 48%22 and 41%21 of cases of WG in
children in two series.
Historical Aspects
In a previous publication in this journal, we discussed
historical aspects of WG in detail.1 Excellent reviews of
diagnostic criteria for WG and other vasculitides have
been published.24,25 Serum antibodies against cytoplasmic
components of neutrophils (c-ANCAs), initially described in the 1980s, are present in most patients with
WG and often correlate with active disease.1,26,27 However, c-ANCAs are not specific for WG,1 and treatment
strategies should not be based exclusively on c-ANCAs.1
Clinical Features
UPPER AIRWAY INVOLVEMENT
Upper respiratory tract symptoms occur in more than
90% of patients with WG.1–4,28 Chronic sinusitis, epistaxis, and otitis media are often the dominant clinical
features of WG.2,4,29 Sinus computed tomographic (CT)
scans are abnormal in over 85% of patients with WG.1,2
Characteristic features include thickening or clouding of
the sinuses (75%) and erosion or destruction of sinus
bones (25 to 50%).1,2 Magnetic resonance imaging
(MRI) scans of the sinuses are less sensitive than CT
in detecting bony destruction.1 Air–fluid levels suggest
secondary pyogenic infections.2,4
Otologic involvement occurs in 30 to 50% of
patients with WG.1,2,4 Otalgia, otitis media, chronic
mastoiditis, or hearing loss occurs in 15 to 25% of
patients.1–3 Hearing loss may reflect vasculitis of the
cochlear artery, chronic otitis media, perforation of the
tympanic membrane, or chronic mastoiditis.1,2 Adjunctive surgical procedures (eg, myringotomy tubes) may be
helpful in patients with chronic mastoiditis and otitis
media.30 Salivary1,31,32 and parotid1,33,34 glands are
rarely involved.
The nasopharynx is involved in 60 to 80% of
patients with WG.2,3,29,35 Clinical manifestations include epistaxis, nasal septal perforation, nasal congestion
or pain, nasal crusting, mucosal ulcers,2,4,30 and saddle
nose deformity.2,3,29
Sore throat or hoarseness may reflect ulcerations
or granulomatous involvement of the pharynx or vocal
cords.1,2 ‘‘Strawberry gingival hyperplasia’’ is a rare
manifestation of WG.30
A meticulous ears-nose-throat (ENT) exam by an
experienced otolaryngologist is warranted in any patient
Downloaded by: World Health Organization ( WHO). Copyrighted material.
WEGENER GRANULOMATOSIS
(GRANULOMATOSIS WITH POLYANGIITIS)
Wegener granulomatosis (WG), the most common of
the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract (e.g., sinuses, ears,
nasopharynx, oropharynx, trachea), lower respiratory
tract (bronchi and lung), and kidney, with varying
degrees of disseminated vasculitis.1–5 In November
2010, the boards of directors of the American College
of Rheumatology (ACR), American Society of Nephrology (ASN), and the European League Against
Rheumatism (EURL) recommended a gradual shift
from the term WG.6 The term granulomatosis with
polyangiitis (Wegener) was proposed to replace WG.6,7
This change was triggered by evidence that Dr.
Friedrich Wegener was a member of the Nazi party
before and after World War II.7,8 The term granulomatosis with polyangiitis can be abbreviated to GPA,
with the idea that the eponym Wegener would be
omitted over time.6
Major histological features of WG/GPA include a
necrotizing vasculitis involving small vessels (ie, arterioles, venules, and capillaries), extensive ‘‘geographic’’ necrosis, and granulomatous inflammation.2,9–11 Clinical
manifestations of WG are protean; virtually any organ
can be involved. The spectrum and severity of the disease
are heterogeneous, ranging from indolent disease involving only one site to fulminant, multiorgan vasculitis
leading to death. Many of the ‘‘classical’’ features of the
disease may be lacking early in the course, but may evolve
months or even years after initial presentation.1–4 Given
the rarity of WG, and nonspecificity of symptoms, the
diagnosis is often missed for several months after the
initial symptom(s).5 In a previous publication in this
journal, we discussed WG in depth.1 In this article, we
focus on advances in therapy since that publication.
275
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
with suspected WG; suspicious lesions should be biopsied.29,30 However, histological confirmation of WG
may be difficult. Biopsies of ENT lesions often demonstrate nonspecific findings of necrosis and chronic inflammation.11,36 The cardinal histological features of
vasculitis or granulomatous inflammation may be lacking.11 Biopsies of nasal septal perforations are rarely
diagnostic. Generous biopsies of involved sites are critical to substantiate the diagnosis. If upper respiratory
tract biopsies are nondiagnostic, biopsies of other sites
may be required.
WG involving the upper respiratory tract should
be treated with cytotoxic agents and corticosteroids
(CSs), consistent with WG at other sites. Adjunctive
therapy (eg, myringotomy tubes, sinus drainage procedures) may be necessary in some patients.2,29
OCULAR INVOLVEMENT
Ocular involvement occurs in 20 to 50% of patients with
WG.2,3,37–42 Clinical symptoms may result from primary
vasculitis of the retinal vessels or from extension of the
granulomatous process from the soft tissues or sinuses
into the orbit.43,44 Conjunctivitis, episcleritis, and scleritis occur in 15 to 20% of patients with WG.38,39
Necrotizing keratitis, corneoscleral perforation, posterior uveitis, and optic neuritis are rare but potentially
serious complications.38,45 Rarely, vasculitis of the posterior ciliary arteries supplying the optic nerves may lead
to visual loss.2,38,39 Conjunctivitis or episcleritis often
responds to topical corticosteroids; involvement of the
deeper ocular structures warrants systemic CS and cytotoxic therapy.38,39,46 Proptosis from a retro-orbital granulomatous inflammatory process develops in 10 to 22%
of patients during the course of the disease.2,29,38–40,47
Compression or primary involvement of the optic nerve
may lead to blindness in 2 to 9% of patients.2,37–40
Granulomatous involvement of the orbit may cause
pain, swelling, proptosis, oculomotor palsies, blurred
vision, diplopia, and reduction of eye motility.37–39,47
Sinusitis is present in >85% of patients with proptosis
due to WG.40 Nasolacrimal duct obstruction occurs in
25 to 52% of patients with orbital WG.40,48 Disease
localized to the orbit may be difficult to diagnose because
serum ANCAs are often negative.37,40 Orbital biopsies
in WG demonstrate the cardinal features of necrosis,
granulomatous inflammation, and vasculitis in a minority of patients.1,40 Adjunctive surgical techniques may be
required for mass lesions encroaching the orbit or optic
chiasm.29,49
INVOLVEMENT OF TRACHEA AND BRONCHI
Granulomatous involvement of the trachea or major
bronchi leads to stenosis in 10 to 30% of patients with
WG.1,2,50,51 Symptoms include dyspnea, wheezing,
stridor, and change in voice.50–52 Stenosis of large
airways may develop years after the initial diagnosis
2011
of WG and may develop in the absence of manifestations of WG at other sites.51,52 Concomitant involvement of the nasopharynx or sinuses is nearly invariably
present.1,50 In one series of 43 WG patients with
subglottic stenosis (SGS), saddle nose deformity was
present in 47%.50 Tracheal stenosis is usually circumferential and localized, extending 3 to 5 cm below the
glottis.50,51,53 However, more extensive involvement of
the distal trachea or mainstem bronchi may occur.51
Flow-volume loops may detect upper airway obstruction but are insensitive. With tracheal (subglottic)
stenosis, both inspiratory and expiratory limbs of the
flow-volume loop are truncated (flow-rate limitation)50,54 (Fig. 1). When stenosis is suspected, flexible
fiberoptic bronchoscopy (FFB) should be performed.
Circumferential narrowing of the trachea due to scarring is the most common finding; acute inflammation
is noted in one quarter of patients with SGS (26%).52
Histological confirmation of tracheal or endobronchial
WG is difficult; biopsies usually demonstrate nonspecific changes (e.g., necrosis or inflammation).50–52
Further, serum titers of c-ANCA do not correlate with
endobronchial inflammation.51 Thus, in the appropriate clinical context, the diagnosis of tracheal or endobronchial involvement in patients with known WG
must be presumed, even when histology is not definitive. Spiral (helical) CT scans using thin sections and
tracheobronchial reconstruction images are useful to
Figure 1 Wegener granulomatosis. Flow-volume loop demonstrating truncation of both inspiratory and expiratory
limbs due to a fixed, anatomical narrowing of the proximal
trachea (subglottic stenosis) in a 28-year-old male with WG.
Cyclophosphamide had been discontinued 4 months earlier
after he had been in continuous remission for nearly
18 months. Dyspnea, due to subglottic stenosis, was the
initial manifestation of recrudescent WG. Reproduced with
kind permission of Mosby, St. Louis. From Lynch and
Quint.54
Downloaded by: World Health Organization ( WHO). Copyrighted material.
276
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
demonstrate airflow obstruction, restriction, or mixed
patterns.1 Abnormalities on chest radiographs are noted
in more than 70% of patients during the course of the
disease.1–3,39,62 Single or multiple nodules or nodular
infiltrates are characteristic; cavitation occurs in 20 to
50% (Figs. 3, 4, 5 and 6).1,2,39,62 Fluffy alveolar or
consolidation may reflect granulomatous inflammation
(Figs. 7,8 and 9) or alveolar hemorrhage (Figs. 10 and
11).63–65 Enlarged intrathoracic lymph nodes are rare
( 2%) on conventional chest radiographs1 but are
detected by CT in 20% of patients with WG.66 Chest
CT scans typically reveal multiple pulmonary nodules
(with or without cavitation); other features of active WG
include focal infiltrates, consolidation, or ground-glass
opacities (GGOs).62,66 Additional manifestations of
Downloaded by: World Health Organization ( WHO). Copyrighted material.
assess the extent and severity of tracheobronchial involvement53,55 (Fig. 2). Importantly, progressive tracheal or bronchial stenosis can develop even when the
disease is quiescent at other sites.50–52
Severe stenosis of large airways requires urgent
and aggressive intervention.52,56 Life-threatening
upper airway obstruction can develop.50,51 Disease
localized to the airways may not respond to medical
treatment. In this context, treatment modalities include
CO2 or Nd:YAG laser, dilatation, intratracheal corticosteroid injections, placement of airway stents, laryngeal-tracheal reconstruction, partial tracheal
resection, and tracheostomy.2,50–52,56–58 Silastic stents
may provide sustained relief of symptoms in some
patients but are associated with numerous complications.51,59 Tracheal reconstruction may be required in
patients with severe tracheal stenosis refractory to
medical therapy.50,52
LUNG INVOLVEMENT
Pulmonary involvement is noted in 55 to 90% of patients
with WG.2,3,39,60,61 Pulmonary manifestations include
asymptomatic nodules or infiltrates on chest radiographs
or CT scans cough, dyspnea, impaired pulmonary function, bronchostenosis, and diffuse alveolar hemorrhage.2,3,39 Pulmonary function tests (PFTs) may
Figure 2 Wegener granulomatosis. Three-dimensional
shaded surface display created from helical computed
tomographic data shows severe stenosis of the left mainstem bronchus (arrow) in a patient with WG. Reproduced
with kind permission of Mosby, St. Louis. From Lynch and
Quint.54
277
Figure 3 (A) Wegener granulomatosis. Posteroanterior
chest radiograph demonstrates focal cavitary nodule in the
superior segment of the left lower lobe in a 15-year-old boy
with sinusitis, glomerulonephritis, and high-titer anti-neutrophil cytoplasmic antibody. The lesion resolved following
treatment with oral cyclophosphamide and prednisone.
(B) Wegener granulomatosis. Coronal view of the same
patient showing a left lower lobe cavitary lesion.
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
Figure 4 Wegener granulomatosis. Chest computed tomographic scan demonstrates multifocal nodules in a 40year-old man. Open-lung biopsy demonstrated a necrotizing
granulomatous vasculitis consistent with WG. Reproduced
with kind permission of Elsevier. From Orens et al.235
WG include mass lesions (Figs. 12A, B and C), pleural
effusions, stenosis of trachea or bronchi, atelectasis,
septal bands, parenchymal scarring, irregular pleural
thickening.63,66–68 With treatment, GGOs, cavitating
nodules, nodules >3 cm in diameter, or consolidation
typically resolves or regresses whereas linear lines persist,
reflecting fibrosis.63,67
Because of small sample size, the yield of endobronchial or transbronchial lung biopsies to diagnose
WG is low (3 to 18%).1,10,51 Cytologies of bronchoalveolar lavage (BAL) fluid in patients with WG may
demonstrate necrotic debris, acute inflammation, multinucleated giant cells, epithelioid cells, and hemosiderinladen macrophages.69 Transthoracic core needle biopsy
(guided by CT or fluoroscopy) may reveal inflammation
or vasculitis,70 but specificity is suboptimal. With
few exceptions, bronchoscopic or percutaneous needle
aspiration biopsies are inadequate to substantiate the
diagnosis.
Figure 5 Wegener granulomatosis. Chest computed tomographic scan shows a thick cavitary nodule in a 45-year-old
male with WG.
2011
Figure 6 Wegener granulomatosis. Chest computed tomographic scan demonstrates focal, thick-walled cavitary
lesions in a patient with WG.
Surgical lung biopsy (SLB) is optimal to establish
a firm diagnosis of pulmonary WG. When focal pulmonary infiltrates or nodules are present, vasculitis and
necrotizing granulomas are found on SLB in more
than 90% of patients.9,10 A review of 87 SLBs in
pulmonary WG cited the following features: vascular
Figure 7 Wegener granulomatosis. Posteroanterior chest
radiograph demonstrates dense focal infiltrates in an 18year-old female patient with sinusitis, cough, fever, and
cutaneous nodules. Serum circulating anti-neutrophil cytoplasmic antibody titer was 1:1200. Skin biopsy demonstrated a leukocytoclastic vasculitis. Sinus biopsies
revealed a granulomatous necrotizing vasculitis consistent
with WG. Chest radiographs normalized within 2 weeks of
initiation of cyclophosphamide and prednisone therapy.
Reproduced with kind permission of Wolters Kluwer.
From Lynch and Raghu.236
Downloaded by: World Health Organization ( WHO). Copyrighted material.
278
Figure 8 Wegener granulomatosis. Posteroanterior chest
radiographs from a 70-year-old woman demonstrate extensive airspace consolidation, particularly involving the right
lung. Sinus and lung biopsies demonstrated areas of necrosis
and granulomatous vasculitis. Although she initially improved
with medical therapy, she died 6 weeks later of opportunistic
infection.
inflammation (acute or chronic) in 94%, parenchymal
necrosis (84%), scattered giant cells (79%), areas of
geographic necrosis (69%), granulomatous microabscesses with giant cells (69%), neutrophilic microabscesses (65%), poorly formed granulomata (59%),
capillaritis (31%), and fibrinoid necrosis (11%).10 Bronchial or bronchiolar abnormalities included nonspecific
chronic inflammation (64%), acute inflammation (51%),
bronchiolitis obliterans (31%), and follicular bronchio-
Figure 9 Photomicrograph of open lung biopsy. Nearly
complete obliteration of a blood vessel with granulomatous
vasculitis consistent with Wegener granulomatosis. Note the
multinucleated giant cell within the vascular lumen.
Figure 10 Alveolar hemorrhage due to Wegener granulomatosis. Posteroanterior chest radiograph from a 13-year-old
girl demonstrates extensive, confluent, bilateral alveolar infiltrates. She presented with severe dyspnea, hemoptysis,
microscopic hematuria, and proteinuria. Open-lung biopsy
demonstrated massive pulmonary hemorrhage and capillaritis but no granulomas. Review of a prior sinus biopsy
demonstrated extensive necrosis and inflammatory exudate
with occasional multinucleated giant cells but no definite
vasculitis. Pulse methylprednisolone, followed by oral prednisone and cyclophosphamide was instituted. Her disease
remitted promptly. Reproduced with kind permission of
Wolters Kluwer. From Lynch and Raghu.236
litis (28%).10 Additional nonspecific features observed in
WG include cryptogenic organizing pneumonia
(COP),71,72 eosinophilic infiltration,72 chrondritis involving bronchial cartilage,73 and interstitial fibrosis.10
Figure 11 Alveolar hemorrhage due to Wegener granulomatosis. Posteroanterior chest radiograph from a 67-year-old
man demonstrates extensive, bilateral alveolar infiltrates.
Complete recovery was achieved with cyclophosphamide
and corticosteroid therapy.
279
Downloaded by: World Health Organization ( WHO). Copyrighted material.
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
2011
Figure 12 (A) Wegener granulomatosis. Posteroanterior (PA) chest radiograph demonstrating right upper lobe mass in a 36year-old woman with leukocytoclastic vasculitis, fever, sinusitis, and cough. Reproduced with kind permission of Wolters
Kluwer. From Lynch and Raghu.236 (B) Computed tomographic scan from the same patient reveals a mass lesion in the anterior
segment of the right upper lobe with areas of focal necrosis (see arrows). Transbronchial lung biopsies demonstrated
granulomatosis vasculitis with extensive necrosis and a polymorphous inflammatory cell infiltrate consistent with WG. (C)
PA chest radiograph from same patient 5 weeks after initiation of therapy with cyclophosphamide and prednisone showing near
complete resolution of right upper lobe mass.
ALVEOLAR HEMORRHAGE
Diffuse alveolar hemorrhage (DAH) due to capillaritis
of the pulmonary microvasculature is a rare but potentially fatal complication of WG.1,61,65 In this setting,
rapidly progressive glomerulonephritis (RPGN) is
present in >90% of patients.64,65 Chest radiographs
in DAH demonstrate bilateral alveolar infiltrates; the
classic nodular or cavitary lesions of WG are lacking64
(Figs. 10 and 11). SLB has no role to diagnose DAH.
Typically, SLB in DAH reveals nonspecific features of
alveolar hemorrhage and inflammation and necrosis of
the alveolar capillaries and walls (termed capillaritis)65
(Figs. 13A, B, C and D). Granulomatous vasculitis or
extensive parenchymal necrosis is usually not found.65
For severe DAH, the risk of SLB outweighs the
benefit. A presumptive diagnosis of DAH can often
be made on the basis of clinical and radiographic
features, circulating c-ANCAs, and bronchoscopy
with BAL. Bloody or serosanguinous BAL fluid, large
numbers of hemosiderin-laden macrophages, and absence of infectious etiologies support the diagnosis of
DAH (Fig. 14). Biopsy of extrapulmonary sites of
involvement may substantiate the diagnosis. If microscopic hematuria or renal failure is present, percutaneous renal biopsy may be warranted. Pauci-immune
RPGN is characteristic of WG in the context of
DAH.1 When severe DAH is suspected, we advise
prompt treatment with intravenous (IV) ‘‘pulse’’ methylprednisolone (1 g daily for 3 days).1,64 Cyclophosphamide (with or without plasmapheresis)1,74 is
appropriate once a firm diagnosis of WG has been
established.
Downloaded by: World Health Organization ( WHO). Copyrighted material.
280
281
Downloaded by: World Health Organization ( WHO). Copyrighted material.
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
Figure 13 Photomicrograph. Capillaritis and pulmonary hemorrhage in Wegener granulomatosis. (A) Numerous neutrophils
hug alveolar capillaries associated with recent alveolar hemorrhage. (B) Early fibrinoid necrosis of alveolar wall associated with
capillaritis. (C) Pulmonary hemorrhage with capillaritis. (D) Linear band of degenerating neutrophils from zone of necrotizing
capillaritis.
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
Figure 14 Photomicrograph. Hemosiderin-laden macrophages (siderophages) are prominent in the alveolar interstitium in a patient with recurrent alveolar hemorrhage
(hematoxylin and eosin). (Courtesy of Joseph Fantone, M.D.,
Department of Pathology, University of Michigan Medical
Center.) Reprinted from Lynch and Leatherman,64 with kind
permission of The McGraw-Hill Companies, Inc., New York.
RENAL INVOLVEMENT
Glomerulonephritis (GN) (pauci-immune) occurs in 70
to 85% of WG patients during the course of the disease,
but renal insufficiency (serum creatinine > 2.0 mg%)
occurs in only 11 to 17% of patients at presentation.1–4,39
Extrarenal manifestations usually precede the renal manifestations, often by several months. Microscopic hematuria, proteinuria, or red cell casts precede elevations in
serum creatinine.1,2,39 The characteristic renal lesion of
WG is a segmental focal GN.1,2 Immune complexes are
absent or infrequent, consistent with ‘‘pauci-immune
GN.’’1 With fulminant forms, crescentic RPGN is
observed1,75 (Fig. 15). Granulomatous vasculitis is observed in only 6 to 15% of renal biopsies from patients
with WG.1,2,39,75 The onset and course of renal involve-
2011
ment are variable. The course may be indolent (progressing over months to years)1,2,75 or fulminant,
progressing to end-stage renal failure (ESRF) within
days to weeks.1 Dialysis-dependent ESRF develops in 11
to 32% of patients with WG.1,2,75 Aggressive and
prompt institution of therapy with CS and cytotoxic
agents is mandatory to avert irreversible renal damage.
Even in oliguric renal failure, substantial recovery of renal
function can be achieved.75 However, chronic dialysisdependent renal failure is more common in patients with
severe loss of glomeruli on initial renal biopsy.75,76 In one
retrospective study of 23 patients with WG requiring
dialysis, only five (22%) had substantially improved renal
function at long-term follow-up.77 The role of plasma
exchange (PE) in WG is controversial. Among patients
with ANCA-associated vasculitis (AAV) and severe renal
failure (serum creatinine >500 mmol/L (5.7 mg/dL), PE
may be beneficial in improving early and late renal
function.78,79 The rationale for PE with less severe
degrees of renal failure has not been elucidated.74 Recently, Danish investigators randomized 32 patients with
WG to PE or no PE as part of initial induction therapy
(both groups received CYC þ CS for induction therapy).80 Multivariate analysis demonstrated that PE improved renal survival among patients with initial serum
creatinine > 250 mmol/L (2.85 mg/dL) (p < 0.01).
Mortality and morbidity did not differ between groups.
Renal transplantation may be considered for patients
with ESRF provided WG is quiescent.81 Recurrence of
WG has been rare following transplantation.
Rare urological complications of WG (principally
case reports) include1 necrotizing vasculitis involving the
ureters,82 ureteral stenosis,83 renal artery aneurysms,82,84
penile necrosis84 or ulcers,83 bladder pseudotumor,83
renal masses,85 urinary tract obstruction,86 and prostatic
involvement.1,2,83
CENTRAL OR PERIPHERAL NERVOUS SYSTEM
INVOLVEMENT
Figure 15 Photomicrograph. Percutaneous renal biopsy in
a 65-year-old man with Wegener granulomatosis presenting
with alveolar hemorrhage, rapidly progressive glomerulonephritis (RPGN), and serous otitis media. Note the typical
crescent formation indicative of RPGN. Reprinted from
Medical Rounds with kind permission of W.B. Saunders.
From Lynch et al.237
Central or peripheral nervous system involvement occurs
in fewer than 4% of WG patients at initial presentation
but develops in 10 to 54% during the course of the
disease.1,2,87–89 Patterns of central nervous system
(CNS) involvement include (1) primary CNS vasculitis,
(2) extension of granulomatous inflammation from contiguous structures (eg, nasopharynx, sinuses, orbit), and
(3) granulomatous lesions involving brain or meninges.1
Mononeuritis multiplex or polyneuritis is most common,
accounting for > 50% of neurological manifestations.1,2,87,88 Cerebral or meningeal involvement occurs
in 2 to 8% of patients with WG.1,2,87 Meningeal
thickening or enhancing lesions on CT are usually focal,
adjacent to nasal, orbital, or sinus disease.90 Clinical
CNS manifestations include cerebral infarction or hemorrhage, cranial nerve palsies,87 focal deficits or seizures,1,90 diabetes insipidus (secondary to granulomatous
Downloaded by: World Health Organization ( WHO). Copyrighted material.
282
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
involvement of the hypothalamus),1,91 pituitary insufficiency,92 altered mental status,93 cortical atrophy,94
chronic headaches,94 an visual loss.2,87,94 Two series
comprising 32487 and 85 patients39 cited cranial nerve
palsies in 6.5% and 9.4%, respectively. Mild cognitive
impairment has been noted in some patients with WG;
in this context, brain MRI scans reveal multiple periventricular or juxtacortical white matter lesions.93 Involvement of the spinal cord microvasculature may
cause quadriparesis or paraparesis.1,87,94,95 Vasculitis
of the CNS is rarely confirmed histologically because
of inaccessibility or risks associated with biopsies.1,94,95
The diagnosis is usually supported by histological
confirmation at extraneural sites or by noninvasive
studies [e.g., electromyogram (EMG), MRI or CT
scans of the brain or spinal cord].1,94 Findings on MRI
scans include diffuse or focal dural thickening and
enhancement, discrete lesions, infarcts, nonspecific
white matter areas of high signal intensity, enlarged
pituitary gland with infundibular thickening, and cerebral atrophy.1,94,95 In some patients, biopsy of the
sural nerve or other affected nerves may substantiate
the diagnosis.87
arrhythmias,100 cardiomyopathies,1,2 or coronary arterial
aneurysms.101 Necrotizing vasculitis affecting cardiac
valves has been described.1,98
SKIN INVOLVEMENT
OTHER ORGAN INVOLVEMENT
Cutaneous lesions are present in 14 to 50% of patients
during the course of the disease.1–3 Manifestations
include palpable purpura, subcutaneous nodules, papules, petechiae, ulcers, and nonspecific erythematous or
maculopapular rashes.1,2,96 Skin biopsies may demonstrate granulomatous vasculitis with necrosis; however,
leukocytoclastic vasculitis (LCV) is more common.1,2,97 In a series of 46 patients with WG and
dermatological manifestations, LCV and chronic inflammation were each noted in 31% of skin biopsies;
granulomatous vasculitis was never observed.97 Subcutaneous nodules reflect granulomatous inflammation, whereas petechiae and purpuric or hemorrhagic
lesions indicate vasculitis.1 Skin changes may parallel
the course of the systemic disease and have prognostic
significance.2,97 LCV often correlates with active, generalized disease, whereas granulomatous inflammation
can be found even when the systemic disease is quiescent.97 Cutaneous lesions in WG are associated with a
higher incidence of articular and renal involvement
compared with WG patients without cutaneous involvement.1
Constitutional symptoms (eg, malaise, fatigue, fever,
weight loss) occur in 30 to 80% of patients with WG
and may be the presenting features.1,2 Non-deforming
polyarthritis involving medium- and large-size joints
occurs in two thirds of patients and parallels activity of
the systemic disease.1,2
CARDIAC INVOLVEMENT
Cardiac involvement is rarely documented antemortem,
but prevalence rates of 8 to 15% have been estimated.1–3,98
Any portion of the heart may be involved, but coronary
arteritis and pericarditis are the most common clinical
features.1,98 Necrotizing vasculitis or granulomatous inflammation involving the myocardium or coronary arteries may give rise to conduction defects,99 fatal
283
INVOLVEMENT OF LARGE VESSELS
Involvement of large arteries is rare in WG, but anecdotal cases of WG involving the internal carotid artery,102 abdominal aorta (with dissection),103 or
mesenteric arteries104 have been published.
Gastrointestinal (GI) manifestations were cited in 4 to
10% of patients with WG.2,3,105–107 However, histological confirmation of WG involving the GI tract has
rarely been documented antemortem.105–108 A review of
59 necropsies in patients with WG cited GI tract
involvement in 23 (39%).109 Rarely, GI involvement
(eg, colitis, bleeding) may be the presenting feature of
WG.107 Rare cases of hepatic110,111 or splenic112,113
involvement have been cited. Splenic infarcts have
been documented at necropsies or on abdominal CT
(low attenuation lesions with peripheral enhancement).1,113
Histopathology
The cardinal histopathological features of WG include
a necrotizing vasculitis affecting arterioles, venules, and
capillaries; granulomatous inflammation; foci of parenchymal necrosis; microabscesses; fibrosis; and acute and
chronic inflammation.2,9 Irregularly shaped (geographic) necrosis surrounded by granulomatous inflammation is characteristic (Figs. 16A, B). Multinucleated
giant cells, epithelioid cells, and collections of histiocytes impart a granulomatous character to the inflammatory process, but well-formed sarcoid-like
granulomas are rare in WG2,9 (Fig. 9). Vascular walls
are infiltrated (and may be destroyed) by mononuclear
cells and neutrophils, with occasional multinucleated
giant cells and eosinophils (Figs. 17A, B). Fibrinoid
necrosis and thrombosis within vascular lumens are
early findings9 (Fig. 18). Later, fibrosis of vascular walls
may result in stenosis or obliteration of the lumens.9
Because granulomas and small vessel vasculitis may be
observed with infections (particularly due to mycobacteria or fungi), special stains should be performed in any
granulomatous or necrotic lesion to exclude infectious
causes.9
Downloaded by: World Health Organization ( WHO). Copyrighted material.
GASTROINTESTINAL INVOLVEMENT
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
2011
Figure 16 (A) Photomicrograph. Early Wegener lesion with features of a microabscess consisting of a collection of
neutrophils with giant cells in a fibrotic background. (B) Fully developed necrotizing granuloma with irregular (‘‘geographic’’)
borders surrounded by a background of fibrosis and chronic inflammation with giant cells.
Laboratory Features
Anemia, thrombocytosis, or leukocytosis occurs in 30
to 40% of patients with WG.1–4 Leukopenia or
thrombocytopenia is rare in untreated patients but
may develop as a consequence of cytotoxic therapy.2,39
Serum complement levels are normal or elevated.2,39
Striking increases in erythrocyte sedimentation rate
(ESR) and C-reactive protein (CRP) are characteristic
of active, generalized disease, and usually correlate
with disease activity.1,2 However, ESR or CRP can
be normal with active disease, particularly when only a
single site is involved.1,51 Serial determinations of the
ESR or CRP are useful to monitor the course of the
disease but are nonspecific.1 Autoantibodies directed
against cytoplasmic components of neutrophils
(c-ANCAs) are helpful in the initial diagnosis of
WG and to monitor response to therapy.1,4 Increases
in c-ANCA levels were noted in more than 90% of
patients with active generalized WG, and in 40 to
70% of patients with active regional disease.1,26,27,114
Among WG patients with c-ANCAs, >90% are
directed against proteinase 3 (PR3); <10% are directed against myeloperoxidase (MPO) or other antigenic epitopes.1,26,27 Changes in c-ANCAs usually
correlate with disease activity, and are unaffected by
intercurrent infections.1 However, c-ANCA titers
persist in 30 to 40% of patients even after complete
clinical remissions were achieved.1,4,114 Further, increases in c-ANCA titers do not necessarily predict
relapse.1,114 Serial c-ANCA assays provide useful
adjunctive information to clinical data, but treatment
Figure 17 (A) Photomicrograph. Segmental vasculitis in
Wegener granulomatosis with inflammation involving a portion of the arterial wall. (B) An elastic stain from a different
vessel shows that the inflammation involves not only a
thickened intima but is present in the media.
Figure 18 Photomicrograph. Transbronchial lung biopsy
from a patient with Wegener granulomatosis demonstrates
segmental vasculitis. The arrow highlights a zone of segmental inflammation, the asterisk is in a zone of fibrinoid
necrosis.
Downloaded by: World Health Organization ( WHO). Copyrighted material.
284
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
Pathogenesis of WG
The cause of WG is unknown. The presence of granulomas and vasculitis suggests an exaggerated cellular
immune or hypersensitivity response, but no identifiable etiologic agent has been identified.4,115 The preponderance of disease in the upper and lower
respiratory tract suggests that inhaled antigen(s) may
initiate the cellular immune response. T cells, monocytes, and neutrophils comprise key cellular elements,
suggesting that both cell-mediated and neutrophilmediated immune mechanisms are operative. Early
injury is likely mediated primarily by neutrophils,
whereas mononuclear phagocytes and lymphocytes are
involved in the late phases of the vasculitic process.1
Circulating PR3-ANCAs are present in 70 to 93% of
patients with untreated WG, suggesting a role for these
autoantibodies in the pathogenesis and evolution of
WG.1,4,26,27,115 The role of genes in influencing susceptibility to WG has not been elucidated,2 but major
histocompatibility complex (MHC) alleles or genetic
polymorphisms1,116–118 may play contributory roles.
The pathogenesis of ANCA-associated vasculitides is
reviewed extensively by Drs. Nachman and Henderson
in the first article in this issue.
Treatment
Prior to the introduction of effective therapy, mean
survival among patients with untreated active WG was
less than 6 months119; more than 80% of patients died
within 3 years of onset of symptoms, usually of progressive renal failure.120 Corticosteroids ameliorated
many of the inflammatory manifestations of WG but
were associated with only modest gains in survival (mean
survival of only 12.5 months).121 Seminal studies at the
National Institutes of Health (NIH) in the 1970s
employing oral cyclophosphamide (CYC) (1 to 2 mg/
kg/day) combined with CS (prednisone 1 mg/kg/day,
with taper) fundamentally improved the prognosis of
WG.39,120,122 Prednisone was gradually tapered and
discontinued by 6 to 9 months. Cyclophosphamide was
continued for a minimum of 1 year past remission and
was then tapered and discontinued. With this regimen,
favorable responses were noted in 70 to 95% of patients,
with 5-year mortality rates of <15%.1,39,122,123 Relapses
were noted in 30 to 70% of patients following cessation or
tapering of therapy, but reinstitution of therapy was
usually efficacious.1–3,124,125 However, sequelae of vasculitis (eg, cerebrovascular accidents, myocardial infarction,
renal failure, hypertension) or complications of CYC (eg,
opportunistic infections, neoplasms) contributed to late
mortality and morbidity.2,3,124,126–128 Recognition of
treatment-related toxicities and the chronically relapsing
nature of the disease led to a search for less toxic
therapeutic options. Recent regimens adopt an initial
‘‘induction phase’’ [to assure complete remission (CR)]
followed by less intense ‘‘maintenance’’ therapy (to minimize long-term toxicities).1,129–132
Staging of Disease
Treatment options for WG are stratified according to
acuity, extent, site(s), and severity of disease. Severe WG
is defined as disease that affects critical organs [eg,
kidneys, pulmonary hemorrhage, central nervous system
(CNS), etc.] or is life threatening.1,133 The current use of
the term limited WG implies that there is no immediate
threat to the patient’s life or irreversible damage to
affected organ(s).1,133 Objective criteria are critical to
assess disease activity and therapeutic responsiveness.
The Birmingham Vasculitis Activity Score (BVAS) is
a disease-specific activity index for WG.134 A modified
BVAS was shown to be a valid, disease-specific activity
index for WG, with good inter- and intraobserver
variability.135
Remission-Induction Therapy
We believe that CYC and CS are the preferred induction
therapy for severe, generalized WG.129 IV ‘‘pulse’’ CYC
achieves remission rates comparable to daily oral CYC,
but has been associated with higher relapse
rates.1,3,124,136 Recently, a multicenter European study
randomized 149 patients with newly diagnosed generalized AAV to IV pulse CYC (n ¼ 76) or daily oral CYC
(n ¼ 73) (both combined with CS).137 Time to remission
and percent of patients achieving CR were similar
between groups. Overall, CRs were achieved in 88.1%
receiving IV pulse CYC compared with 87.7% receiving
oral CYC. The cumulative dose of CYC was lower
among those receiving pulse versus oral therapy (8.2 g
vs 15.9 g, p < 0.001). A prospective study by French
investigators (WEGENT trial) treated 159 patients with
newly diagnosed AAV (WG, n ¼ 32 or MPA, n ¼ 8)
and 1 unfavorable prognostic factor with IV CYC plus
CS as initial induction therapy.138 Complete remissions
were achieved in 126 (79.2%); one stopped therapy
(allergy); 32 were refractory (WG, n ¼ 24; MPA,
n ¼ 8). Eleven patients died early (median 2.5 months),
either of uncontrolled disease, infections, or both.
Among patients failing induction therapy with IV
CYC, 20 were switched to oral CYC, with favorable
responses in 15 (75%) (combined with infliximab in one
patient). Hence oral CYC may be effective as rescue
therapy for patients failing IV pulse CYC, but additional
agents (particularly biologics) may be required. This
initial induction regimen (CYC and CS) is continued
for 3 to 6 months until complete remissions have been
Downloaded by: World Health Organization ( WHO). Copyrighted material.
decisions should not rely exclusively on c-ANCA
titers.1,4
285
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
achieved.129 At that point, less toxic agents [e.g., methotrexate (MTX), azathioprine (AZA), or mycophenolate mofetil (MMF)] can be substituted for CYC; this
maintenance regimen is continued for a total of 12 to
18 months.1,130,131,139 Further, for patients with mild or
limited WG and preserved renal function, MTX,140–142
MMF,143 or leflunamide (LEF)139 can be utilized in
place of CYC as induction therapy.1,133 If patients fail to
respond to these agents, CYC/CS should be substituted.
Alternatively, rituximab (discussed in detail later) can be
used in lieu of CYC for induction therapy or for treatment of CYC-refractory cases.144,145 Some granulomatous manifestations of WG (e.g., subglottic stenosis,
proptosis, sinus or orbital involvement) may require
adjunctive therapy via surgical or interventional techniques (e.g., laser).1,50 Trimethoprim-sulfamethoxazole
(T/S) may have an adjunctive role to reduce relapse rates
in WG (generalized or limited).1,146,147 Chronic persistent ‘‘grumbling’’ disease despite CYC/CS may require
additional treatment options such as rituximab or infliximab (discussed later).
Fulminant Generalized Disease
More aggressive therapeutic options may be required in
patients with fulminant disease (e.g., RPGN, DAH, or
CNS vasculitis). In this context, we employ pulse methylprednisolone (1000 mg daily IV) for 3 days (followed
by CS taper) and CYC (oral or IV pulse). PE may have
an adjunctive role for severe DAH and/or RPGN
complicating WG.1,74,148,149 In one retrospective study,
PE plus CYC/CS increased the rate of renal recovery in
patients with AAV and severe RPGN (serum creatinine
>5.7 mg%) compared with IV methylprednisolone plus
CYC/CS.78 However, given the lack of prospective data,
PE should be reserved for patients with severe RPGN or
life-threatening disease.
Maintenance Therapy
In this phase, less aggressive therapy is used to maintain
the remissions achieved with CYC/CS. MTX or AZA
(combined with low-dose CS) has been utilized most
often,129,131 but favorable responses have been noted
with other agents (e.g., MMF,143 LEF,139 cyclosporine80,150,151). The rationale for maintenance therapy
with agents other than CYC is the potential for serious
toxicities associated with long-term cumulative use of
CYC.2,126,128,150,152 In a recent open, randomized, multicenter European trial, 156 patients with AAV who
achieved CR with CYC/CS therapy were randomized to
maintenance therapy with AZA (2 mg/kg/day) or MMF
(1000 mg twice a day) and followed for a median of
39 months.132 Relapses were more common in the
MMF cohort (42/76, 55%) compared with 30/80
(37.5%) in the AZA cohort. Side effect profiles were
2011
similar. These data suggest that AZA is superior to
MMF for maintenance of remissions. Studies comparing
other maintenance regimens have not been done.
Specific Therapeutic Agents
CYCLOPHOSPHAMIDE
Cyclophosphamide, an alkylating agent with diverse
effects on cellular and humoral immunity,150,152 is the
initial treatment of choice for generalized WG.1,129,138
However, given its myriad toxicities152 (e.g., bone marrow suppression,153 heightened susceptibility to infections,152 bladder carcinoma,126,128 lymphoproliferative
disorders2,128 and other malignancies,128,154,155 and infertility150,152), less toxic agents are preferred for patients
with mild or localized disease.
Intermittent high-dose IV pulse CYC in WG
may reduce toxicities compared with daily oral CYC but
may be less effective.4,123,124,136,138,156,157 Several studies
reported similar remission rates with oral or IV pulse
CYC, but relapses were more common with pulse
CYC.123,124,136 It is possible that reducing the time
between cycles may improve prognosis, but this has
not been studied.
METHOTREXATE
Oral or IV MTX, administered once weekly, can be
used as (1) induction therapy for patients with mild to
moderate (non-life-threatening) WG,141,142,158 (2)
maintenance therapy for patients who have achieved
CRs after initial treatment with CYC,130,131,141,158–161
and (3) induction or salvage therapy for patients experiencing adverse effects from CYC.153,161 Acute renal
failure, DAH, serum creatinine > 2.0 mg%, and
chronic liver disease are contraindications to
MTX.141,161 The dose of MTX is 15 to 25 mg once
weekly (orally or parenterally); prednisone is administered concomitantly (initial dose 1 mg/kg/day, with
gradual taper).153,158,161,162 With this regimen, remissions were achieved in 59 to 88% of cases.3,141,160–163
Late relapses were noted in 36 to 66%, usually after
discontinuation of MTX.3,130,141,160–163 In this context, reintroduction of MTX plus CS usually induced
remissions.153,158 Five-year mortality rates with MTX
were low (3.7 to 14%).3,141,160–163 MTX has myriad
potential toxicities (heightened susceptibility to infections, stomatitis, GI and hepatitis toxicities), but lacks
bladder toxicity and is not oncogenic.150,152 Because the
kidneys are the major route of MTX elimination,
toxicity is increased in the presence of renal insufficiency.152 The concomitant use of MTX and T/S 160
mg/800 mg twice daily may cause severe pancytopenia.153 However, low-dose T/S (80/400) thrice weekly
is safe,1,153 and we use this as prophylaxis against
Pneumocystis jirovecii.
Downloaded by: World Health Organization ( WHO). Copyrighted material.
286
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
AZA, a purine analogue with protean immunosuppressive effects, is less effective than CYC and should
not be used as primary therapy for WG.1,39,120 However, AZA (1 to 3 mg/kg/day orally) has a role as
maintenance therapy in patients who remit with CYC
and CS.39,129,131 In a randomized trial by the European Vasculitis Study Group of AAV, AZA was as
effective as CYC for maintenance of remissions following induction of CR with CYC/CS.129 In that study,
155 patients with AAV were treated with daily oral
CYC/CS as induction therapy for 3 to 6 months.129
Ninety-five patients (61%) had WG; 60 (39%) had
MPA. Overall, 94% had renal involvement. With this
induction regimen, 144 patients (93%) achieved CRs
within 6 months. After CRs were achieved, patients
were randomly assigned to maintenance therapy with
either oral CYC (1.5 mg/kg/day) (n ¼ 73) or AZA
(2 mg/kg/day) (n ¼ 71) [both in addition to low-dose
prednisolone (10 mg/day)]. After 12 months of therapy, maintenance therapy was changed (in both
groups) to AZA (1.5 mg/kg/day) and prednisolone
(7.5 mg/day) for an additional 6 months. At 18 months,
relapse rates were similar between cohorts (15.5% with
AZA; 14% with CYC (p ¼ 0.65). Other outcome
measures (eg, Vasculitis Damage Index scores, quality
of life, CRP or ESR, rate of adverse effects) were
similar with AZA or CYC. Only two patients in each
group developed ESRF. Only eight patients died (5%
mortality); seven deaths occurred within the first
3 months, during the induction phase with CYC/CS.
A subsequent prospective, open-label multicenter trial
compared AZA and MTX as maintenance therapy for
AAV.131 In that study, 159 patients with WG or MPA
were initially treated with IV pulse CYC plus CS; 126
(79%) achieved CR. These 126 patients were randomized to maintenance therapy with either oral AZA
(2 mg/kg/day) (n ¼ 63) or oral MTX (0.3 mg/kg
once weekly, maximum dose 25 mg weekly) (n ¼ 63)
for 12 months.131 Outcomes (adverse effects, mortality, relapse rates) were similar with both agents. Relapse rates were similar [36% with AZA; 33% with
MTX (p ¼ 0.71)]. Twenty-four months after randomization, relapse-free survival rates were 71.8% in the
AZA group and 74.5% in the MTX group. A recent
randomized open trial of MMF or AZA as maintenance therapy for AAV cited a higher relapse rate with
MMF [(42/76) 55%] compared with AZA [(30/80)
37.5%].132 These studies129,131 support CYC/CS for
initial induction therapy in severe or generalized WG,
followed by early switch (within 3 to 6 months) to less
toxic agents once CRs have been achieved. AZA has
myriad potential toxicities (principally bone marrow
suppression, heightened susceptibility to infections,
and GI toxicities) but lacks bladder toxicity and has
low oncogenic potential.150,152 The decision about
whether to use MTX or AZA for remission maintenance must be made on an individual patient basis.
MYCOPHENOLATE MOFETIL
MMF, an inhibitor of purine synthesis, has been used
both to maintain or to induce remissions in WG.143,164–
166
In one study, nine patients with WG were treated
with MMF (2 g/day) following induction of remission
with CYC/CS.164 One patient relapsed during the
15-month study period. In a prospective study,
14 patients were treated with daily CYC plus CS to
induce CR, followed by MMF as maintenance therapy.143 Six patients relapsed (43%) at a median of
10 months after achieving CR.143 In another trial, 12
patients with AAV (seven had WG) were treated with
MMF; 10 had failed at least two courses of CYC and/or
AZA.166 All patients improved (by BVAS) at 24- and
52-week time points. MMF was discontinued in three
patients; one relapsed. Another patient relapsed while on
MMF.166 Although comparative data are limited, we
believe MMF is less effective than AZA132 or MTX to
maintain remissions in AAV.
LEFLUNOMIDE
LEF, an inhibitor of the enzyme dihydroorotate dehydrogenase, was used as maintenance therapy for 20
patients with generalized WG in a phase 2, open-label
study.167 All had remitted with CYC/CS. Overall,
disease activity was unchanged during a median follow-up of 1.75 years.167 A multicenter, prospective,
randomized trial compared LEF versus MTX to maintain remissions in WG patients following induction of
remissions with CYC.168 The study was terminated
because there were more relapses within 6 months in
the MTX group (13 of 28) compared with LEF (six of
26 relapsed). Adverse effects were more frequent in
LEF-treated patients. Henes et al treated five patients
with refractory WG with rituximab (4 weeks) and
maintenance therapy with LEF.169 CRs were achieved
in four patients at 6 months; three patients relapsed, but
all remitted with re-treatment with rituximab. In a
retrospective analysis, 51 WG patients with ‘‘minor
relapses’’ while on maintenance monotherapy with either
MTX (n ¼ 36) or LEF (n ¼ 16) were treated with
combination therapy with MTX plus LEF.170 Remissions
were achieved in 43 of 51 (84%) with combination
therapy, but only 14 achieved sustained remission. Further, MTX þ LEF treatment was discontinued in 18 of
51 (36%) patients because of adverse effects. Additional
studies are required to determine the role of LEF as
therapy for WG.139
CHLORAMBUCIL
Chlorambucil, an alkylating agent related to CYC,152
was used to treat WG in early studies, with anecdotal
successes,171,172 but is oncogenic and has myriad
Downloaded by: World Health Organization ( WHO). Copyrighted material.
AZATHIOPRINE
287
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
toxicities.152 Currently, chlorambucil has no role in the
treatment of WG.
TRIMETHOPRIM/SULFAMETHOXAZOLE
T/S may reduce relapse rates in patients with WG,146
but it is of doubtful value as primary therapy.1 Nonrandomized studies suggested that T/S may have a role
in patients with indolent but progressive WG173 or for
limited ‘‘initial phase’’ WG.147,174 However, T/S did not
induce remissions or reduce relapse rates in patients with
generalized WG.147,175 Nonetheless, a role for T/S in
ameliorating the course of the disease is plausible. In a
placebo-controlled, randomized trial, T/S (160/800 mg
twice daily) reduced relapse rates in patients with WG
who were in remission following treatment with CYC/
CS.146 These data are intriguing, but the impact of T/S
on WG remains controversial. The mechanism of action
of T/S is not known, but could reflect antimicrobial or
immunomodulatory effects.176 The most important role
of T/S in WG is to prevent pneumonia due to Pneumocystis jirovecii, a complication of immunosuppressive
therapy.2,124,177 Thrice weekly T/S (80 mg/400 mg) is
highly efficacious and cost-effective.
Treatment of Refractory Disease
Disease unresponsive to conventional therapy can be
treated with cytolytic agents, monoclonal antibodies, or
other immunosuppressive agents, but data are limited.
Anecdotal responses were cited with inhibitors of tumor
necrosis factor-a,178,179 rituximab (an anti-CD20 chimeric monoclonal antibody directed against B cells),180
high-dose IV immunoglobulin (IV IgG),46,181 alemtuzumab (CAMPATH-1H), (a monoclonal antibody directed against CD52),94,182,183 monoclonal antibodies
targeted against T cells,184,185 humanized anti-CD4
antibodies,186 anti-thymocyte globulin (ATG),187 15deoxyspergualin,188–190 etoposide,191,192 cyclosporin
A,193–195 rapamycin,196 and autologous hematopoietic
stem cell transplants,197 but data are limited to small
uncontrolled series and anecdotal cases.
TUMOR NECROSIS FACTOR-a INHIBITORS
Inhibitors of tumor necrosis factor-a (TNFa) have been
used to treat WG,178,179,192,198,199 but data are limited.
Etanercept, comprised of two p75 TNFa receptors
coupled to the Fc portion of a monoclonal human
IgG1, binds TNFa in a one-to-one fashion.179 In an
early pilot study, 20 WG patients were treated with
etanercept (in addition to standard therapy) for
6 months.192 Remissions were achieved in 16 (80%),
but major flares developed in three patients while on
etanercept. The Wegener Granulomatosis Etanercept
Trial (WGET) randomized 180 patients with WG to
either etanercept (25 mg subcutaneously twice weekly)
or placebo in addition to standard therapy with CYC or
2011
MTX.198 Patients were followed for a minimum of
12 months. The rate of sustained remissions, number
and severity of disease flares, and quality of life (QOL)
were similar between etanercept- and placebo-treated
groups. Solid organ cancers developed in six patients in
the etanercept group but in no control patient. Based on
this study, etanercept has no role as therapy for WG.
Conversely, infliximab, a chimeric mouse/human
monoclonal antibody that inhibits TNFa, may be effective as therapy for WG. Five clinical trials,199–203 and
anecdotal case reports204–206 suggest a possible role for
infliximab in refractory WG. Among patients with AAV
failing conventional therapy, IV infliximab was associated with favorable responses in 10 of 10,200 five of
six,203 and five of six201 patients, respectively. In one
open-label trial, 32 patients with AAV (19 with WG; 13
with MPA) received infliximab (5 mg/kg body weight)
plus conventional therapy as induction (n ¼ 16) or adjunctive therapy for patients with persistent disease
(n ¼ 16).202 For the first group, infliximab was administered on day 0, 2 weeks, 6 weeks, and 10 weeks and was
then stopped. For the group with persistent disease,
infliximab was continued every 6 weeks for a total of
12 months.202 Remissions were achieved in 14 patients
(87.5%) in each group. Others cited responses to infliximab in three of four WG patients with CNS involvement refractory to conventional therapy.204,205 Josselin
et al treated 15 patients with vasculitis (including 10
with WG) with infliximab for a median of 8 months. By
day 45, remissions were achieved in all 15 (CR in 11).199
Although immunosuppressive therapy was continued in
all but one patient, 10 patients relapsed, three while
receiving infliximab. These various studies suggest that
infliximab may have a role to treat selected WG patients
refractory to conventional therapy. However, dosages
and frequency of dosing were variable in these various
series, and the optimal regimen is not known. We are
unaware of data assessing adalimumab, another TNF-a
inhibitor, as therapy for AAV. TNF-a inhibitors have
potential serious toxicities including opportunistic infections, lymphoproliferative and solid malignancies,154,198 induction of autoimmune disorders,
vasculitis, or interstitial lung diseases.207 Placebo-controlled trials are necessary to ascertain the role of
infliximab or other TNFa inhibitors for WG or AAV.
RITUXIMAB
Rituximab, a chimeric monoclonal antibody that binds
CD20 on the surface of B cells and promotes B lymphocyte depletion,208 has been used to treat AAV, with
favorable responses.144,145,180,209–219 In early uncontrolled studies of AAV refractory to conventional therapy, favorable responses to rituximab were cited in 11 of
11211 and 10 of 10209 patients, respectively. Rituximab
(RITUX) may be less efficacious as therapy for granulomatous manifestations of WG. Aries et al treated
Downloaded by: World Health Organization ( WHO). Copyrighted material.
288
eight patients with active WG refractory to treatment
with CYC/CS plus TNF-a blockade.210 Rituximab was
administered every 4 weeks in combination with CYC
(n ¼ 5) or MTX (n ¼ 2). All manifested granulomatous
features [retroorbital granulomas (n ¼ 5), bronchostenosis (n ¼ 2), pulmonary nodules (n ¼ 1)]. Despite depletion of B lymphocytes, only three patients remitted (two
complete). Consistent with previous observations,
‘‘granulomatous’’ manifestations regressed more slowly
than constitutional or ‘‘vasculitic’’ symptoms.210 In another study of refractory/relapsing WG, RITUX combined with CS and immunosuppressants induced
remissions in six of eight patients; one relapsed 1 year
after stopping RITUX and responded to a second
cycle.215 In a retrospective study, 34 patients were
treated with RITUX for refractory WG affecting ears,
nose, throat, or eye.220 CRs were achieved in 21 (62%);
partial remissions (PRs) in nine (26%); no response in
four (12%). In a retrospective study, 10 patients with
ophthalmic WG refractory to conventional therapy were
treated with RITUX.221 All patients had failed at least
three different immunosuppressive agents; five had
failed anti-TNF therapy. All 10 improved with RITUX.
Rituximab was efficacious in a WG patient with necrotizing scleritis.222 Investigators in the United Kingdom
(UK) retrospectively assessed 65 patients with refractory
AAV treated with RITUX.218 Dosing regimens included four infusions of 375 mg/m2 body surface area
each week, or two infusions of 1 g each 2 weeks apart.
CRs were achieved in 49 (75%), PRs in 15 (23%).
Immunosuppressive medications were withdrawn in
62% of patients. Among 49 patients experiencing CR,
28 relapsed (57%). B cell return preceded relapse in 14 of
27 patients (52%). ANCA levels fell following RITUX,
but relapse was not associated with rise in ANCA levels.
Re-treatment of relapses was usually effective. A recent
open-label randomized trial by the European Vasculitis
Study Group (RITUXIVAS trial) compared RITUX
versus IV pulse CYC as induction therapy for AAV.144
Forty-four patients with newly diagnosed AAV and
renal involvement were randomized in a 3:1 ratio to
RITUX (n ¼ 33) or CYC (n ¼ 11). Rituximab was administered at a dose of 375 mg/m2 weekly for 4 weeks. In
the RITUX group, patients received CS and two pulses
of IV CYC. These patients did not receive AZA to
maintain remission. Patients in the control group received IV CYC for 3 to 6 months, followed by AZA.
Corticosteroid regimens and cumulative dosages did not
differ between the two groups. Remission rates were
similar. Sustained remissions were achieved in 25 of 33
(76%) patients in the RITUX group and nine of 11
(82%) controls (p ¼ 0.68). Median time to remission was
90 days in the RITUX group and 94 days in the control
group (p ¼ 0.87). Serious adverse effects occurred in 14
patients receiving RITUX group (42%) and four controls
(36%) (p ¼ 0.77). Six of 33 patients in the RITUX group
died (18%) as did two of 11 (18%) in the control group
(p ¼ 1.00). A multicenter, double-blind study (RAVE
trial) randomized 197 patients with AAV to either
RITUX (375 mg/m2 weekly for 4 weeks) (n ¼ 99) or
oral CYC (2 mg/kg/day) (n ¼ 98) for remission induction.145 The primary end point was remission of disease
without the use of prednisone at 6 months. In the
RITUX group, 63 of 99 (64%) met the primary end
point compared with 52 of 98 (53%) in the control group
(differences between groups were not significant). However, among AAV patients with relapsing disease,
RITUX was more effective than CYC; the primary end
point was achieved in 34 of 51 (67%) patients receiving
RITUX and in only 21 of 50 (42%) in the control group
(p ¼ 0.01). Among patients with WG, 46 of 73 (63%)
assigned to RITUX and 37 of 74 (50%) assigned to CYC
reached the primary end point (p ¼ 0.11). Among patients with microscopic polyangiitis, 16 of 24 (67%) in the
RITUX group and 15 of 24 (62%) in the control group
reached the primary end point (p ¼ 0.76). Among the
subset of patients with major renal disease or alveolar
hemorrhage, RITUX was as effective as CYC. These
various studies suggest an important role of RITUX as
therapy for WG and other AAVs. However, whether
RITUX should be used with CS alone or CS combined
with IV CYC has not been clarified.223 The role for longterm maintenance therapy has not been studied. Further,
the potential for serious complications with RITUX (eg,
progressive multifocal progressive encephalopathy,224 infections,225 malignancies145) is a concern. Additional
studies are required to assess indications for RITUX,
appropriate dosing and frequency of administration, role
for concomitant therapy, and long-term side effects.
Nonetheless, we believe RITUX has an important role
to treat relapsing WG or AAV, and may be considered as
first-line therapy for initial treatment of WG or AAV.
HIGH-DOSE INTRAVENOUS IMMUNOGLOBULIN
Intravenous immune globulin (IVIG) exhibits myriad
immunomodulatory effects, including regulating T cell
function, blockade of Fc receptors, preventing binding of
activated complement components C3b and C4b, modulating cytokine production, neutralizing autoantibodies
(including ANCA).226 High-dose IVIG (0.5 mg/kg/day
for 4 days) was shown to be efficacious in diverse autoimmune and inflammatory disorders226 and may have a
role to treat AAV refractory to or intolerant of conventional therapy. In several studies, favorable responses
were noted with IVIG (alone or combined with CS and/
or immunosuppressive agents) in 45 to 77% of patients
with AAV.1,181,227,228 In one placebo-controlled trial,
patients with relapsing AAV were treated with a single
course of IVIG.181 Favorable responses were noted in 14
of 17 (82%) receiving IVIG and six of 17 (35%) receiving
placebo. In another study, 22 patients with relapsing
AAV (19 had WG) were treated with IVIG monthly for
289
Downloaded by: World Health Organization ( WHO). Copyrighted material.
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
6 months.228 All received concomitant CS; immunosuppression was maintained at existing levels or reduced.
After 9 months, 17 patients (77%) had achieved CR.
Side effects of IVIG were mild and transient. These
studies suggest that IVIG may have a role in selected
patients with AAV refractory to conventional therapy,
but trials comparing IVIG with other salvage therapies
have not been done.
ANTITHYMOCYTE GLOBULIN
ATG has been used to treat WG refractory to other
agents. In one study, three of four patients with severe
orbital WG responded to rabbit ATG (two partial; one
complete).187 In an open-label study, 15 patients with
refractory WG were treated with ATG.229 Prior to
receipt of ATG, patients had received a mean of 5.2
different therapies without control of disease. Favorable
responses to ATG were cited in 13 (87%) (partial in
nine; complete in four); relapses occurred in 47%.229
DEOXYSPERGUALIN
Deoxyspergualin, a synthetic immunomodulatory agent
with effects on lymphocytes, macrophages, and neutrophils, has been associated with clinical responses in openlabel studies in patients with relapsing WG.188–190,230 In a
prospective, open-label, multicenter European trial,
44 patients with relapsing or refractory WG and previous
therapy with CYC or MTX were treated with subcutaneous (SC) deoxyspergualin.190 Deoxyspergualin
(0.5 mg/kg/day) was self-administered SC for up to
21 days each cycle, with a minimum drug-free period of
7 days between cycles for a total of 6 cycles. After
completion of 6 cycles, AZA (plus CS) was substituted
as maintenance therapy. Remissions were achieved in
42 of 44 patients (95%); 20 (45%) were CR. Relapses
occurred in 18 patients (43%). Two relapses occurred
during treatment with deoxyspergualin; the other relapses
occurred in the 6-month period when patients were
receiving maintenance therapy with AZA or MMF.
Two patients died. Adverse effects were noted in 53%.
Another open-label prospective study of deoxyspergualin
in 44 patients with crescentic GN (including AAV) cited
improvements in proteinuria and hematuria after
4 weeks.231 In a murine model of AAV, deoxyspergualin
was equivalent to CYC, and superior to MMF, in
attenuating nephritis.232 Additional randomized trials
are required to assess the role (if any) of deoxyspergualin
to treat WG.
WG IN THE ELDERLY
WG in the elderly (age 65 years) is associated with an
increased mortality rate156,233 and more frequent complications of therapy.233 Because of the heightened
susceptibility to opportunistic infections in elderly patients,233 less aggressive immunosuppressive therapy is
warranted in this age group.234 Further, initial induction
2011
therapy with agents less toxic than CYC (such as MTX)
can be considered in patients with localized or less severe
disease.1
REFERENCES
1. Lynch JP III, White E, Tazelaar H, Langford CA.
Wegener’s granulomatosis: evolving concepts in treatment.
Semin Respir Crit Care Med 2004;25(5):491–521
2. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener
granulomatosis: an analysis of 158 patients. Ann Intern
Med 1992;116(6):488–498
3. Reinhold-Keller E, Beuge N, Latza U, et al. An
interdisciplinary approach to the care of patients with
Wegener’s granulomatosis: long-term outcome in 155
patients. Arthritis Rheum 2000;43(5):1021–1032
4. Langford CA, Hoffman GS. Rare diseases.3: Wegener’s
granulomatosis. Thorax 1999;54(7):629–637
5. Abdou NI, Kullman GJ, Hoffman GS, et al. Wegener’s
granulomatosis: survey of 701 patients in North America:
changes in outcome in the 1990s. J Rheumatol 2002;29(2):
309–316
6. Falk RJ, Gross WL, Guillevin L, et al. Granulomatosis with
polyangiitis (Wegener’s): an alternative name for Wegener’s
granulomatosis. Ann Rheum Dis 2011;70(4):704
7. Falk RJ, Jennette JC. ANCA disease: where is this field
heading? J Am Soc Nephrol 2010;21(5):745–752
8. Woywodt A, Haubitz M, Haller H, Matteson EL. Wegener’s
granulomatosis. Lancet 2006;367(9519):1362–1366
9. Travis WD. Pathology of pulmonary vasculitis. Semin
Respir Crit Care Med 2004;25(5):475–482
10. Travis WD, Hoffman GS, Leavitt RY, Pass HI, Fauci AS.
Surgical pathology of the lung in Wegener’s granulomatosis.
Review of 87 open lung biopsies from 67 patients. Am J
Surg Pathol 1991;15(4):315–333
11. Devaney KO, Travis WD, Hoffman G, Leavitt R, Lebovics
R, Fauci AS. Interpretation of head and neck biopsies in
Wegener’s granulomatosis: a pathologic study of 126 biopsies
in 70 patients. Am J Surg Pathol 1990;14(6):555–564
12. Watts RA, Scott DG. Epidemiology of the vasculitides.
Semin Respir Crit Care Med 2004;25(5):455–464
13. Koldingsnes W, Nossent H. Epidemiology of Wegener’s
granulomatosis in northern Norway. Arthritis Rheum 2000;
43(11):2481–2487
14. Watts RA, Gonzales-Gay M, Garcia-Porrua C, Lane SE,
Bentham G, Scott DG. ANCA-associated vasculitis in two
European regions. Clin Exp Immunol 2000;120(suppl 1):60
15. Watts RA, Al-Taiar A, Scott DG, Macgregor AJ.
Prevalence and incidence of Wegener’s granulomatosis in
the UK general practice research database. Arthritis Rheum
2009;61(10):1412–1416
16. Mahr A, Guillevin L, Poissonnet M, Aymé S. Prevalences
of polyarteritis nodosa, microscopic polyangiitis, Wegener’s
granulomatosis, and Churg-Strauss syndrome in a French
urban multiethnic population in 2000: a capture-recapture
estimate. Arthritis Rheum 2004;51(1):92–99
17. Cotch MF, Hoffman GS, Yerg DE, Kaufman GI,
Targonski P, Kaslow RA. The epidemiology of Wegener’s
granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution
from population-based data sources. Arthritis Rheum 1996;
39(1):87–92
Downloaded by: World Health Organization ( WHO). Copyrighted material.
290
18. Gibson A, Stamp LK, Chapman PT, O’Donnell JL. The
epidemiology of Wegener’s granulomatosis and microscopic
polyangiitis in a Southern Hemisphere region. Rheumatology (Oxford) 2006;45(5):624–628
19. Mohammad AJ, Jacobsson LT, Mahr AD, Sturfelt G,
Segelmark M. Prevalence of Wegener’s granulomatosis,
microscopic polyangiitis, polyarteritis nodosa and ChurgStrauss syndrome within a defined population in
southern Sweden. Rheumatology (Oxford) 2007;46(8):
1329–1337
20. Stegmayr BG, Gothefors L, Malmer B, Müller Wiefel DE,
Nilsson K, Sundelin B. Wegener granulomatosis in children
and young adults: a case study of ten patients. Pediatr Nephrol
2000;14(3):208–213
21. Belostotsky VM, Shah V, Dillon MJ. Clinical features in 17
paediatric patients with Wegener granulomatosis. Pediatr
Nephrol 2002;17(9):754–761
22. Rottem M, Fauci AS, Hallahan CW, et al. Wegener
granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr 1993;122(1):26–31
23. Grisaru S, Yuen GW, Miettunen PM, Hamiwka LA.
Incidence of Wegener’s granulomatosis in children. J
Rheumatol 2010;37(2):440–442
24. Leavitt RY, Fauci AS, Bloch DA, et al. The American
College of Rheumatology 1990 criteria for the classification
of Wegener’s granulomatosis. Arthritis Rheum 1990;33(8):
1101–1107
25. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of
systemic vasculitides. Proposal of an international consensus
conference. Arthritis Rheum 1994;37(2):187–192
26. Kallenberg CG. Antineutrophil cytoplasmic autoantibodyassociated small-vessel vasculitis. Curr Opin Rheumatol
2007;19(1):17–24
27. Kallenberg CG. Pathogenesis of PR3-ANCA associated
vasculitis. J Autoimmun 2008;30(1-2):29–36
28. Gubbels SP, Barkhuizen A, Hwang PH. Head and neck
manifestations of Wegener’s granulomatosis. Otolaryngol
Clin North Am 2003;36(4):685–705
29. Cannady SB, Batra PS, Koening C, et al. Sinonasal
Wegener granulomatosis: a single-institution experience
with 120 cases. Laryngoscope 2009;119(4):757–761
30. Rasmussen N. Management of the ear, nose, and throat
manifestations of Wegener granulomatosis: an otorhinolaryngologist’s perspective. Curr Opin Rheumatol 2001;13(1):
3–11
31. Ah-See KW, McLaren K, Maran AG. Wegener’s granulomatosis presenting as major salivary gland enlargement.
J Laryngol Otol 1996;110(7):691–693
32. Gassling V, Wiltfang J, Hampe J, Bräsen JH, Both M,
Moosig F. Salivary gland swelling in Wegener’s granulomatosis: a rare cause of a frequent symptom. J Rheumatol
2010;37(12):2633–2635
33. Bucolo S, Torre V, Montemagno A, Beatrice F. Wegener’s
granulomatosis presenting with otologic and neurologic
symptoms: clinical and pathological correlations. J Oral
Pathol Med 2003;32(7):438–440
34. Liu SY, Vlantis AC, Lee WC. Bilateral parotid and
submandibular gland enlargement: rare features of Wegener’s granulomatosis. J Laryngol Otol 2003;117(2):
148–150
35. Lloyd G, Lund VJ, Beale T, Howard D. Rhinologic changes
in Wegener’s granulomatosis. J Laryngol Otol 2002;116(7):
565–569
36. Takwoingi YM, Dempster JH. Wegener’s granulomatosis:
an analysis of 33 patients seen over a 10-year period. Clin
Otolaryngol Allied Sci 2003;28(3):187–194
37. Newman NJ, Slamovits TL, Friedland S, Wilson WB.
Neuro-ophthalmic manifestations of meningocerebral
inflammation from the limited form of Wegener’s granulomatosis. Am J Ophthalmol 1995;120(5):613–621
38. Haynes BF, Fishman ML, Fauci AS, Wolff SM. The ocular
manifestations of Wegener’s granulomatosis: fifteen years
experience and review of the literature. Am J Med
1977;63(1):131–141
39. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s
granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med
1983;98(1):76–85
40. Woo TL, Francis IC, Wilcsek GA, Coroneo MT, McNab
AA, Sullivan TJ; Australasian Orbital and Adnexal Wagener’s
Study Group. Australasian orbital and adnexal Wegener’s
granulomatosis. Ophthalmology 2001;108(9):1535–1543
41. Harper SL, Letko E, Samson CM, et al. Wegener’s
granulomatosis: the relationship between ocular and systemic disease. J Rheumatol 2001;28(5):1025–1032
42. Tarabishy A, Schulte M, Papaliodis GN, Hoffman GS.
Wegener’s granulomatosis: clinical manifestations, differential diagnosis, and management of ocular and systemic
disease. Surv Ophthalmol 2010;55:193–214
43. Valmaggia C, Neuweiler J. Orbital involvement as the first
manifestation in classic Wegener’s granulomatosis. Orbit
2001;20(3):231–237
44. Lamprecht P, Reinhold-Keller E, Gross WL, Reuter M.
Clinical images: orbital granuloma and subglottic tracheal
stenosis in Wegener’s granulomatosis. Arthritis Rheum
2000;43(7):1654
45. Niskopoulou M, Du Toit N. Optic neuritis as a feature of
Wegener’s granulomatosis. Eye (Lond) 2002;16(3):320–
321
46. Blum M, Andrassy K, Adler D, Hartmann M, Völcker HE.
Early experience with intravenous immunoglobulin treatment in Wegener’s granulomatosis with ocular involvement.
Graefes Arch Clin Exp Ophthalmol 1997;235(9):599–602
47. Wardyn KA, Ycińska K, Matuszkiewicz-Rowińska J,
Chipczyńska M. Pseudotumour orbitae as the initial
manifestation in Wegener’s granulomatosis in a 7-year-old
girl. Clin Rheumatol 2003;22(6):472–474
48. Hardwig PW, Bartley GB, Garrity JA. Surgical management
of nasolacrimal duct obstruction in patients with Wegener’s
granulomatosis. Ophthalmology 1992;99(1):133–139
49. Pakrou N, Selva D, Leibovitch I. Wegener’s granulomatosis:
ophthalmic manifestations and management. Semin Arthritis Rheum 2006;35(5):284–292
50. Langford CA, Sneller MC, Hallahan CW, et al. Clinical
features and therapeutic management of subglottic stenosis
in patients with Wegener’s granulomatosis. Arthritis Rheum
1996;39(10):1754–1760
51. Daum TE, Specks U, Colby TV, et al. Tracheobronchial
involvement in Wegener’s granulomatosis. Am J Respir Crit
Care Med 1995;151(2 Pt 1):522–526
52. Gluth MB, Shinners PA, Kasperbauer JL. Subglottic
stenosis associated with Wegener’s granulomatosis. Laryngoscope 2003;113(8):1304–1307
53. Screaton NJ, Sivasothy P, Flower CD, Lockwood CM.
Tracheal involvement in Wegener’s granulomatosis: evaluation using spiral CT. Clin Radiol 1998;53(11):809–815
291
Downloaded by: World Health Organization ( WHO). Copyrighted material.
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
54. Lynch JP III, Quint LE. Tracheobronchial and esophageal
manifestations of systemic diseases. In: Cummings CE, ed.
Otolaryngology Head and Neck Surgery. 3rd ed. St. Louis:
Mosby-Year Book; 1998:2343–2367
55. Quint LE, Whyte RI, Kazerooni EA, et al. Stenosis of the
central airways: evaluation by using helical CT with
multiplanar reconstructions. Radiology 1995;194(3):871–
877
56. Nouraei SA, Obholzer R, Ind PW, et al. Results of
endoscopic surgery and intralesional steroid therapy for
airway compromise due to tracheobronchial Wegener’s
granulomatosis. Thorax 2008;63(1):49–52
57. Gotway MB, Golden JA, LaBerge JM, et al. Benign
tracheobronchial stenoses: changes in short-term and longterm pulmonary function testing after expandable metallic
stent placement. J Comput Assist Tomogr 2002;26(4):
564–572
58. Schokkenbroek AA, Franssen CF, Dikkers FG. Dilatation
tracheoscopy for laryngeal and tracheal stenosis in patients
with Wegener’s granulomatosis. Eur Arch Otorhinolaryngol
2008;265(5):549–555
59. Hoffman GS, Thomas-Golbanov CK, Chan J, Akst LM,
Eliachar I. Treatment of subglottic stenosis, due to
Wegener’s granulomatosis, with intralesional corticosteroids
and dilation. J Rheumatol 2003;30(5):1017–1021
60. Cordier JF, Valeyre D, Guillevin L, Loire R, Brechot JM.
Pulmonary Wegener’s granulomatosis: a clinical and imaging study of 77 cases. Chest 1990;97(4):906–912
61. Gómez-Puerta JA, Hernández-Rodrı́guez J, López-Soto A,
Bosch X. Antineutrophil cytoplasmic antibody-associated
vasculitides and respiratory disease. Chest 2009;136(4):1101–
1111
62. Shin MS, Young KR, Ho KJ. Wegener’s granulomatosis
upper respiratory tract and pulmonary radiographic manifestations in 30 cases with pathogenetic consideration. Clin
Imaging 1998;22(2):99–104
63. Komócsi A, Reuter M, Heller M, Muraközi H, Gross WL,
Schnabel A. Active disease and residual damage in treated
Wegener’s granulomatosis: an observational study using
pulmonary high-resolution computed tomography. Eur
Radiol 2003;13(1):36–42
64. Lynch JP III, Leatherman JW. Alveolar hemorrhage
syndromes. In: Fishman AE, ed. Pulmonary Diseases and
Disorders. 3rd ed. New York, NY: McGraw-Hill; 1997:
1193–1210
65. Travis WD, Colby TV, Lombard C, Carpenter HA. A
clinicopathologic study of 34 cases of diffuse pulmonary
hemorrhage with lung biopsy confirmation. Am J Surg
Pathol 1990;14(12):1112–1125
66. Lee KS, Kim TS, Fujimoto K, et al. Thoracic manifestation
of Wegener’s granulomatosis: CT findings in 30 patients.
Eur Radiol 2003;13(1):43–51
67. Reuter M, Schnabel A, Wesner F, et al. Pulmonary
Wegener’s granulomatosis: correlation between high-resolution CT findings and clinical scoring of disease activity.
Chest 1998;114(2):500–506
68. Sheehan RE, Flint JD, Müller NL. Computed tomography
features of the thoracic manifestations of Wegener granulomatosis. J Thorac Imaging 2003;18(1):34–41
69. Michael CW, Flint A. The cytologic features of Wegener’s
granulomatosis. Am J Clin Pathol 1998;110(1):10–15
70. Carruthers DM, Connor S, Howie AJ, et al. Percutaneous
image-guided biopsy of lung nodules in the assessment of
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
2011
disease activity in Wegener’s granulomatosis. Rheumatology
(Oxford) 2000;39(7):776–782
Uner AH, Rozum-Slota B, Katzenstein AL. Bronchiolitis
obliterans-organizing pneumonia (BOOP)-like variant of
Wegener’s granulomatosis: a clinicopathologic study of 16
cases. Am J Surg Pathol 1996;20(7):794–801
Katzenstein AL, Locke WK. Solitary lung lesions in
Wegener’s granulomatosis: pathologic findings and clinical
significance in 25 cases. Am J Surg Pathol 1995;19(5):
545–552
Yousem S. Bronchocentric injury in Wegener’s granulomatosis: a report of five cases. Hum Pathol 1991;22:534–540
Casian A, Jayne D. Plasma exchange in the treatment of
Wegener’s granulomatosis, microscopic polyangiitis, ChurgStrauss syndrome and renal limited vasculitis. Curr Opin
Rheumatol 2011;23(1):12–17
Aasarød K, Bostad L, Hammerstrøm J, Jørstad S, Iversen
BM. Renal histopathology and clinical course in 94 patients
with Wegener’s granulomatosis. Nephrol Dial Transplant
2001;16(5):953–960
Bajema IM, Hagen EC, Hermans J, et al. Kidney biopsy as
a predictor for renal outcome in ANCA-associated necrotizing glomerulonephritis. Kidney Int 1999;56(5):1751–
1758
Mekhail TM, Hoffman GS. Long-term outcome of
Wegener’s granulomatosis in patients with renal disease
requiring dialysis. J Rheumatol 2000;27(5):1237–1240
Jayne DR, Gaskin G, Rasmussen N, et al; European
Vasculitis Study Group. Randomized trial of plasma exchange
or high-dosage methylprednisolone as adjunctive therapy for
severe renal vasculitis. J Am Soc Nephrol 2007;18(7):2180–
2188
Lionaki S, Falk RJ. Removing antibody and preserving
glomeruli in ANCA small-vessel vasculitis. J Am Soc
Nephrol 2007;18(7):1987–1989
Szpirt WM, Heaf JG, Petersen J. Plasma exchange for
induction and cyclosporine A for maintenance of remission
in Wegener’s granulomatosis—a clinical randomized controlled trial. Nephrol Dial Transplant 2011;26:206–213
Aasarød K, Iversen BM, Hammerstrøm J, Bostad L, Vatten
L, Jørstad S. Wegener’s granulomatosis: clinical course in
108 patients with renal involvement. Nephrol Dial Transplant 2000;15(5):611–618
Hensle TW, Mitchell ME, Crooks KK, Robinson D.
Urologic manifestations of Wegener granulomatosis. Urology
1978;12(5):553–556
Huong DL, Papo T, Piette JC, et al. Urogenital
manifestations of Wegener’s granulomatosis. Medicine
(Baltimore) 1995;74(3):152–161
Baker SB, Robinson DR. Unusual renal manifestations of
Wegener’s granulomatosis: report of two cases. Am J Med
1978;64(5):883–889
Frigui M, Ben Hmida M, Kechaou M, Jlidi R, Bahloul Z.
Wegener’s granulomatosis presenting as multiple bilateral
renal masses: case report and literature review. Rheumatol
Int 2009;29(6):679–683
Gunnarsson R, Omdal R, Kjellevold KH, Ellingsen CL.
Wegener’s granulomatosis of the prostate gland. Rheumatol
Int 2004;24:120–122
Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi
JE. Neurological involvement in Wegener’s granulomatosis:
an analysis of 324 consecutive patients at the Mayo Clinic.
Ann Neurol 1993;33(1):4–9
Downloaded by: World Health Organization ( WHO). Copyrighted material.
292
88. de Groot K, Schmidt DK, Arlt AC, Gross WL, ReinholdKeller E. Standardized neurologic evaluations of 128
patients with Wegener granulomatosis. Arch Neurol
2001;58(8):1215–1221
89. Holle JU, Gross WL. Neurological involvement in Wegener’s
granulomatosis. Curr Opin Rheumatol 2011;23(1):7–11
90. Weinberger LM, Cohen ML, Remler BF, Naheedy MH,
Leigh RJ. Intracranial Wegener’s granulomatosis. Neurology 1993;43(9):1831–1834
91. Garovic VD, Clarke BL, Chilson TS, Specks U. Diabetes
insipidus and anterior pituitary insufficiency as presenting
features of Wegener’s granulomatosis. Am J Kidney Dis
2001;37(1):E5
92. Woywodt A, Knoblauch H, Kettritz R, Schneider W, Göbel
U. Sudden death and Wegener’s granulomatosis of the
pituitary. Scand J Rheumatol 2000;29(4):264–266
93. Mattioli F, Capra R, Rovaris M, et al. Frequency and patterns
of subclinical cognitive impairment in patients with ANCAassociated small vessel vasculitides. J Neurol Sci 2002;
195(2):161–166
94. Murphy JM, Gomez-Anson B, Gillard JH, et al. Wegener
granulomatosis: MR imaging findings in brain and
meninges. Radiology 1999;213(3):794–799
95. Mentzel HJ, Neumann T, Fitzek C, Sauner D, Reichenbach
JR, Kaiser WA. MR imaging in Wegener granulomatosis of
the spinal cord. AJNR Am J Neuroradiol 2003;24(1):18–21
96. Comfere NI, Macaron NC, Gibson LE. Cutaneous manifestations of Wegener’s granulomatosis: a clinicopathologic
study of 17 patients and correlation to antineutrophil
cytoplasmic antibody status. J Cutan Pathol 2007;34(10):
739–747
97. Barksdale SK, Hallahan CW, Kerr GS, Fauci AS, Stern JB,
Travis WD. Cutaneous pathology in Wegener’s granulomatosis: a clinicopathologic study of 75 biopsies in 46
patients. Am J Surg Pathol 1995;19(2):161–172
98. Morelli S, Gurgo Di Castelmenardo AM, Conti F, et al.
Cardiac involvement in patients with Wegener’s granulomatosis. Rheumatol Int 2000;19(6):209–212
99. Kouba DJ, Kirsch DG, Mimouni D, Nousari CH. Wegener’s
granulomatosis with cardiac involvement masquerading as
Lyme disease. Clin Exp Rheumatol 2003;21(5):647–649
100. Parry SD, Clark DM, Campbell J. Coronary arteritis in
Wegener’s granulomatosis causing fatal myocardial infarction. Hosp Med 2000;61(4):284–285
101. Musuruana JL, Cavallasca JA, Berduc J, Vicario J. Coronary
artery aneurysms in Wegener’s granulomatosis. Joint Bone
Spine 2010Dec 29. [Epub ahead of print]
102. Schmidt WA, Seipelt E, Molsen HP, Poehls C, Gromnicaihle EJ. Vasculitis of the internal carotid artery in Wegener’s
granulomatosis: comparison of ultrasonography, angiography, and MRI. Scand J Rheumatol 2001;30(1):48–50
103. Blockmans D, Baeyens H, Van Loon R, Lauwers G,
Bobbaers H. Periaortitis and aortic dissection due to
Wegener’s granulomatosis. Clin Rheumatol 2000;19(2):
161–164
104. Chang YJ, Kerr LD. Isolated abdominal vasculitis as an
atypical presentation of Wegener’s granulomatosis. Am J
Gastroenterol 2000;95(1):297–298
105. Haworth SJ, Pusey CD. Severe intestinal involvement in
Wegener’s granulomatosis. Gut 1984;25(11):1296–1300
106. Camilleri M, Pusey CD, Chadwick VS, Rees AJ. Gastrointestinal manifestations of systemic vasculitis. Q J Med
1983;52(206):141–149
107. Steele C, Bohra S, Broe P, Murray FE. Acute upper
gastrointestinal haemorrhage and colitis: an unusual presentation of Wegener’s granulomatosis. Eur J Gastroenterol
Hepatol 2001;13(8):993–995
108. Qian Q, Cornell L, Chandan V, Hartman R, Caples S.
Hemorrhagic colitis as a presenting feature of Wegener
granulomatosis. J Gastrointestin Liver Dis 2010;19(4):
445–447
109. Sokol RJ, Farrell MK, McAdams AJ. An unusual presentation of Wegener’s granulomatosis mimicking inflammatory
bowel disease. Gastroenterology 1984;87(2):426–432
110. Zen Y, Sunagozaka H, Tsuneyama K, et al. Incomplete
septal cirrhosis associated with Wegener’s granulomatosis.
Liver 2002;22(5):388–393
111. Holl-Ulrich K, Klass M. Wegener s granulomatosis with
granulomatous liver involvement. Clin Exp Rheumatol
2010;28(1, suppl 57):88–89
112. Rentsch J, McColl G. Splenic infarction in Wegener’s
granulomatosis. J Rheumatol 2000;27(6):1554–1555
113. Kalaitzoglou I, Drevelengas A, Palladas P, Asimaki A.
MRI appearance of pulmonary Wegener’s granulomatosis
with concomitant splenic infarction. Eur Radiol 1998;
8(3):367–370
114. Boomsma MM, Stegeman CA, van der Leij MJ, et al.
Prediction of relapses in Wegener’s granulomatosis by
measurement of antineutrophil cytoplasmic antibody
levels: a prospective study. Arthritis Rheum 2000;43(9):
2025–2033
115. Gómez-Puerta JA, Bosch X. Anti-neutrophil cytoplasmic
antibody pathogenesis in small-vessel vasculitis: an update.
Am J Pathol 2009;175(5):1790–1798
116. Dijstelbloem HM, Scheepers RH, Oost WW, et al.
Fcgamma receptor polymorphisms in Wegener’s granulomatosis: risk factors for disease relapse. Arthritis Rheum
1999;42(9):1823–1827
117. Savige JA, Chang L, Cook L, Burdon J, Daskalakis M,
Doery J. Alpha 1-antitrypsin deficiency and anti-proteinase
3 antibodies in anti-neutrophil cytoplasmic antibody
(ANCA)-associated systemic vasculitis. Clin Exp Immunol
1995;100(2):194–197
118. Borgmann S, Endisch G, Urban S, Sitter T, Fricke H. A
linkage disequilibrium between genes at the serine protease
inhibitor gene cluster on chromosome 14q32.1 is associated
with Wegener’s granulomatosis. Clin Immunol 2001;98(2):
244–248
119. Walton EW. Giant-cell granuloma of the respiratory tract
(Wegener’s granulomatosis). BMJ 1958;2(5091):265–270
120. Hoffman GS. ‘‘Wegener’s granulomatosis’’: the path traveled since 1931. Medicine (Baltimore) 1994;73(6):325–329
121. Hollander D, Manning RT. The use of alkylating agents in
the treatment of Wegener’s granulomatosis. Ann Intern
Med 1967;67(2):393–398
122. Fauci AS, Wolff SM. Wegener’s granulomatosis: studies in
eighteen patients and a review of the literature. Medicine
(Baltimore) 1973;52(6):535–561
123. Reinhold-Keller E, Kekow J, Schnabel A, et al. Influence of
disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide
therapy in patients with Wegener’s granulomatosis. Arthritis Rheum 1994;37(6):919–924
124. Guillevin L, Cordier JF, Lhote F, et al. A prospective,
multicenter, randomized trial comparing steroids and pulse
cyclophosphamide versus steroids and oral cyclophosphamide
293
Downloaded by: World Health Organization ( WHO). Copyrighted material.
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
in the treatment of generalized Wegener’s granulomatosis.
Arthritis Rheum 1997;40(12):2187–2198
Pagnoux C, Hogan SL, Chin H, et al. Predictors of treatment
resistance and relapse in antineutrophil cytoplasmic antibodyassociated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum 2008;58(9):2908–2918
Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients
with Wegener granulomatosis. Ann Intern Med 1996;124(5):
477–484
Charlier C, Henegar C, Launay O, et al. Risk factors for
major infections in Wegener granulomatosis: analysis of 113
patients. Ann Rheum Dis 2009;68(5):658–663
Faurschou M, Sorensen IJ, Mellemkjaer L, et al. Malignancies in Wegener’s granulomatosis: incidence and relation
to cyclophosphamide therapy in a cohort of 293 patients.
J Rheumatol 2008;35(1):100–105
Jayne D, Rasmussen N, Andrassy K, et al; European
Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;
349(1):36–44
Reinhold-Keller E, Fink CO, Herlyn K, Gross WL, De
Groot K. High rate of renal relapse in 71 patients with
Wegener’s granulomatosis under maintenance of remission
with low-dose methotrexate. Arthritis Rheum 2002;47(3):
326–332
Pagnoux C, Mahr A, Hamidou MA, et al; French Vasculitis
Study Group. Azathioprine or methotrexate maintenance
for ANCA-associated vasculitis. N Engl J Med 2008;
359(26):2790–2803
Hiemstra TF, Walsh M, Mahr A, et al; European Vasculitis
Study Group (EUVAS). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled
trial. JAMA 2010;304(21):2381–2388
Stone JH; Wegener’s Granulomatosis Etanercept Trial
Research Group. Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s
granulomatosis etanercept trial. Arthritis Rheum 2003;
48(8):2299–2309
Exley AR, Bacon PA, Luqmani RA, Kitas GD, Carruthers
DM, Moots R. Examination of disease severity in systemic
vasculitis from the novel perspective of damage using the
vasculitis damage index (VDI). Br J Rheumatol 1998;
37(1):57–63
Stone JH, Hoffman GS, Merkel PA, et al; International
Network for the Study of the Systemic Vasculitides
(INSSYS). A disease-specific activity index for Wegener’s
granulomatosis: modification of the Birmingham Vasculitis
Activity Score. Arthritis Rheum 2001;44(4):912–920
Hoffman GS, Leavitt RY, Fleisher TA, Minor JR, Fauci AS.
Treatment of Wegener’s granulomatosis with intermittent
high-dose intravenous cyclophosphamide. Am J Med 1990;
89(4):403–410
de Groot K, Harper L, Jayne DR, et al; EUVAS (European
Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil
cytoplasmic antibody-associated vasculitis: a randomized
trial. Ann Intern Med 2009;150(10):670–680
Seror R, Pagnoux C, Ruivard M, et al. Treatment strategies
and outcome of induction-refractory Wegener’s granulomatosis or microscopic polyangiitis: analysis of 32 patients with
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
2011
first-line induction-refractory disease in the WEGENT
trial. Ann Rheum Dis 2010;69:2125–2130
Jayne D. Leflunomide versus methotrexate in Wegener’s
granulomatosis. Rheumatology (Oxford) 2007;46(7):1047–
1048
Langford CA. Wegener’s granulomatosis: current and
upcoming therapies. Arthritis Res Ther 2003;5(4):180–191
Langford CA, Talar-Williams C, Sneller MC. Use of
methotrexate and glucocorticoids in the treatment of
Wegener’s granulomatosis. Long-term renal outcome in
patients with glomerulonephritis. Arthritis Rheum 2000;
43(8):1836–1840
De Groot K, Rasmussen N, Bacon PA, et al. Randomized
trial of cyclophosphamide versus methotrexate for induction
of remission in early systemic antineutrophil cytoplasmic
antibody-associated vasculitis. Arthritis Rheum 2005;
52(8):2461–2469
Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil for remission maintenance in the treatment of
Wegener’s granulomatosis. Arthritis Rheum 2004;51(2):
278–283
Jones RB, Tervaert JW, Hauser T, et al; European Vasculitis
Study Group. Rituximab versus cyclophosphamide in
ANCA-associated renal vasculitis. N Engl J Med 2010;
363(3):211–220
Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN
Research Group. Rituximab versus cyclophosphamide for
ANCA-associated vasculitis. N Engl J Med 2010;363(3):
221–232
Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG;
Dutch Co-Trimoxazole Wegener Study Group. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention
of relapses of Wegener’s granulomatosis. N Engl J Med
1996;335(1):16–20
Reinhold-Keller E, De Groot K, Rudert H, Nölle B, Heller
M, Gross WL. Response to trimethoprim/sulfamethoxazole
in Wegener’s granulomatosis depends on the phase of
disease. QJM 1996;89(1):15–23
Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL,
Henke DC, Falk RJ. Plasmapheresis therapy for diffuse
alveolar hemorrhage in patients with small-vessel vasculitis.
Am J Kidney Dis 2003;42(6):1149–1153
Wang CC, Shiang JC, Tsai MK, et al. Prompt plasmapheresis successfully rescue pulmonary-renal syndrome caused
by ANCA-negative microscopic polyangiitis. Clin Rheumatol 2009;28(12):1457–1460
Marder W, McCune WJ. Advances in immunosuppressive
therapy. Semin Respir Crit Care Med 2007;28(4):398–417
Haubitz M, Koch KM, Brunkhorst R. Cyclosporin for the
prevention of disease reactivation in relapsing ANCAassociated vasculitis. Nephrol Dial Transplant 1998;13(8):
2074–2076
Lynch JP III, McCune WJ. Immunosuppressive and
cytotoxic pharmacotherapy for pulmonary disorders. Am J
Respir Crit Care Med 1997;155(2):395–420
Langford CA, Talar-Williams C, Barron KS, Sneller MC.
A staged approach to the treatment of Wegener’s granulomatosis: induction of remission with glucocorticoids and
daily cyclophosphamide switching to methotrexate for
remission maintenance. Arthritis Rheum 1999;42(12):
2666–2673
Stone JH, Holbrook JT, Marriott MA, et al; Wegener’s
Granulomatosis Etanercept Trial Research Group. Solid
Downloaded by: World Health Organization ( WHO). Copyrighted material.
294
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
malignancies among patients in the Wegener’s Granulomatosis Etanercept Trial. Arthritis Rheum 2006;54(5):1608–
1618
Bernatsky S, Ramsey-Goldman R, Clarke AE. Malignancies
and cyclophosphamide exposure in Wegener’s granulomatosis. J Rheumatol 2008;35(1):11–13
Mahr A, Girard T, Agher R, Guillevin L. Analysis of
factors predictive of survival based on 49 patients with
systemic Wegener’s granulomatosis and prospective followup. Rheumatology (Oxford) 2001;40(5):492–498
de Groot K, Adu D, Savage CO; EUVAS (European
vasculitis study group). The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and
critical review. Nephrol Dial Transplant 2001;16(10):2018–
2027
Sneller MC, Hoffman GS, Talar-Williams C, Kerr GS,
Hallahan CW, Fauci AS. An analysis of forty-two Wegener’s
granulomatosis patients treated with methotrexate and
prednisone. Arthritis Rheum 1995;38(5):608–613
Langford CA, Sneller MC, Hoffman GS. Methotrexate use
in systemic vasculitis. Rheum Dis Clin North Am 1997;
23(4):841–853
de Groot K, Mühler M, Reinhold-Keller E, Paulsen J, Gross
WL. Induction of remission in Wegener’s granulomatosis
with low dose methotrexate. J Rheumatol 1998;25(3):
492–495
Villa-Forte A, Clark TM, Gomes M, et al. Substitution of
methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience. Medicine
(Baltimore) 2007;86(5):269–277
de Groot K, Reinhold-Keller E, Tatsis E, et al. Therapy for
the maintenance of remission in sixty-five patients with
generalized Wegener’s granulomatosis: methotrexate versus
trimethoprim/sulfamethoxazole. Arthritis Rheum 1996;
39(12):2052–2061
Stone JH, Tun W, Hellman DB. Treatment of non-life
threatening Wegener’s granulomatosis with methotrexate and
daily prednisone as the initial therapy of choice. J Rheumatol
1999;26(5):1134–1139
Nowack R, Göbel U, Klooker P, Hergesell O, Andrassy K,
van der Woude FJ. Mycophenolate mofetil for maintenance
therapy of Wegener’s granulomatosis and microscopic
polyangiitis: a pilot study in 11 patients with renal
involvement. J Am Soc Nephrol 1999;10(9):1965–1971
Iatrou C, Zerbala S, Revela I, et al. Mycophenolate mofetil
as maintenance therapy in patients with vasculitis and renal
involvement. Clin Nephrol 2009;72(1):31–37
Joy MS, Hogan SL, Jennette JC, Falk RJ, Nachman PH. A
pilot study using mycophenolate mofetil in relapsing or
resistant ANCA small vessel vasculitis. Nephrol Dial
Transplant 2005;20(12):2725–2732
Metzler C, Fink C, Lamprecht P, Gross WL, ReinholdKeller E. Maintenance of remission with leflunomide in
Wegener’s granulomatosis. Rheumatology (Oxford) 2004;
43(3):315–320
Metzler C, Miehle N, Manger K, et al; German Network of
Rheumatic Diseases. Elevated relapse rate under oral
methotrexate versus leflunomide for maintenance of remission in Wegener’s granulomatosis. Rheumatology (Oxford)
2007;46(7):1087–1091
Henes JC, Kanz L, Koetter I. Rituximab and leflunomide for
Wegener’s granulomatosis: a long-term follow-up. Rheumatol Int 2011;31:425–426
170. Bremer JP, Ullrich S, Laudien M, Gross WL, Lamprecht
P. Methotrexate plus leflunomide for the treatment of
relapsing Wegener’s granulomatosis: a retrospective uncontrolled study. Clin Exp Rheumatol 2010;28(1, suppl 57):
67–71
171. Israel HL, Patchefsky AS, Saldana MJ. Wegener’s granulomatosis, lymphomatoid granulomatosis, and benign
lymphocytic angiitis and granulomatosis of lung: recognition
and treatment. Ann Intern Med 1977;87(6):691–699
172. Weiner SR, Paulus HE. Treatment of Wegener’s granulomatosis. Semin Respir Med 1989;10:156–161
173. DeRemee RA. The treatment of Wegener’s granulomatosis
with trimethoprim/sulfamethoxazole: illusion or vision?
Arthritis Rheum 1988;31(8):1068–1074
174. Georgi J, Ulmer M, Gross WL. Cotrimoxazole in Wegener’s
granulomatosis—a prospective study [in German]. Immun
Infekt 1991;19(3):97–98
175. Hoffman GS. Immunosuppressive therapy is always required
for the treatment of limited Wegener’s granulomatosis.
Sarcoidosis Vasc Diffuse Lung Dis 1996;13(3):249–252
176. Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de
Jong PE, Kallenberg CG. Association of chronic nasal
carriage of Staphylococcus aureus and higher relapse rates in
Wegener granulomatosis. Ann Intern Med 1994;120(1):
12–17
177. Falagas ME, Manta KG, Betsi GI, Pappas G. Infectionrelated morbidity and mortality in patients with connective
tissue diseases: a systematic review. Clin Rheumatol 2007;
26(5):663–670
178. White ES, Lynch JP. Pharmacological therapy for Wegener’s granulomatosis. Drugs 2006;66(9):1209–1228
179. Mukhtyar C, Luqmani R. Current state of tumour necrosis
factor alpha blockade in Wegener’s granulomatosis. Ann
Rheum Dis 2005;64(suppl 4):iv31–iv36
180. Specks U, Fervenza FC, McDonald TJ, Hogan MC.
Response of Wegener’s granulomatosis to anti-CD20 chimeric monoclonal antibody therapy. Arthritis Rheum 2001;
44(12):2836–2840
181. Jayne DR, Chapel H, Adu D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with
persistent disease activity. QJM 2000;93(7):433–439
182. Dick AD, Meyer P, James T, et al. Campath-1H therapy in
refractory ocular inflammatory disease. Br J Ophthalmol
2000;84(1):107–109
183. Walsh M, Chaudhry A, Jayne D. Long-term follow-up of
relapsing/refractory anti-neutrophil cytoplasm antibody
associated vasculitis treated with the lymphocyte depleting
antibody alemtuzumab (CAMPATH-1H). Ann Rheum
Dis 2008;67(9):1322–1327
184. Lockwood CM. New treatment strategies for systemic
vasculitis: the role of intravenous immune globulin therapy.
Clin Exp Immunol 1996;104(suppl 1):77–82
185. Lockwood CM, Thiru S, Stewart S, et al. Treatment of
refractory Wegener’s granulomatosis with humanized
monoclonal antibodies. QJM 1996;89(12):903–912
186. Jayne DR, Rasmussen N. Treatment of antineutrophil
cytoplasm autoantibody-associated systemic vasculitis: initiatives of the European Community Systemic Vasculitis
Clinical Trials Study Group. Mayo Clin Proc 1997;72(8):
737–747
187. Kool J, de Keizer RJ, Siegert CE. Antithymocyte globulin
treatment of orbital Wegener granulomatosis: a follow-up
study. Am J Ophthalmol 1999;127(6):738–739
295
Downloaded by: World Health Organization ( WHO). Copyrighted material.
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 32, NUMBER 3
188. Schmitt WH, Birck R, Heinzel PA, et al. Prolonged
treatment of refractory Wegener’s granulomatosis with 15deoxyspergualin: an open study in seven patients. Nephrol
Dial Transplant 2005;20(6):1083–1092
189. Birck R, Warnatz K, Lorenz HM, et al. 15-Deoxyspergualin in patients with refractory ANCA-associated systemic
vasculitis: a six-month open-label trial to evaluate safety and
efficacy. J Am Soc Nephrol 2003;14(2):440–447
190. Flossmann O, Baslund B, Bruchfeld A, et al. Deoxyspergualin in relapsing and refractory Wegener’s granulomatosis.
Ann Rheum Dis 2009;68(7):1125–1130
191. Papo T, Le Thi Huong D, Wiederkehr JL, et al. Etoposide
in Wegener’s granulomatosis. Rheumatology (Oxford)
1999;38(5):473–475
192. Stone JH, Uhlfelder ML, Hellmann DB, Crook S, Bedocs
NM, Hoffman GS. Etanercept combined with conventional
treatment in Wegener’s granulomatosis: a six-month openlabel trial to evaluate safety. Arthritis Rheum 2001;44(5):
1149–1154
193. Clarke AE, Bitton A, Eappen R, Danoff DS, Esdaile JM.
Treatment of Wegener’s granulomatosis after renal transplantation: is cyclosporine the preferred treatment? Transplantation 1990;50(6):1047–1051
194. Allen NB, Caldwell DS, Rice JR, McCallum RM. Cyclosporin A therapy for Wegener’s granulomatosis. Adv Exp
Med Biol 1993;336:473–476
195. Ghez D, Westeel PF, Henry I, Pruna A, Fournier A,
Lassoued K. Control of a relapse and induction of long-term
remission of Wegener’s granulomatosis by cyclosporine. Am
J Kidney Dis 2002;40(2):E6
196. Koening CL, Hernández-Rodrı́guez J, Molloy ES, Clark
TM, Hoffman GS. Limited utility of rapamycin in severe,
refractory Wegener’s granulomatosis. J Rheumatol 2009;
36(1):116–119
197. Statkute L, Oyama Y, Barr WG, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation for
refractory systemic vasculitis. Ann Rheum Dis 2008;67:991–
997
198. Wegener’s Granulomatosis Etanercept Trial (WGET)
Research Group. Etanercept plus standard therapy for
Wegener’s granulomatosis. N Engl J Med 2005;352(4):
351–361
199. Josselin L, Mahr A, Cohen P, et al. Infliximab efficacy and
safety against refractory systemic necrotising vasculitides:
long-term follow-up of 15 patients. Ann Rheum Dis 2008;
67(9):1343–1346
200. Bartolucci P, Ramanoelina J, Cohen P, et al. Efficacy of the
anti-TNF-alpha antibody infliximab against refractory
systemic vasculitides: an open pilot study on 10 patients.
Rheumatology (Oxford) 2002;41(10):1126–1132
201. Booth AD, Jefferson HJ, Ayliffe W, Andrews PA, Jayne
DR. Safety and efficacy of TNFalpha blockade in relapsing
vasculitis. Ann Rheum Dis 2002;61(6):559
202. Booth A, Harper L, Hammad T, et al. Prospective study of
TNFalpha blockade with infliximab in anti-neutrophil
cytoplasmic antibody-associated systemic vasculitis. J Am
Soc Nephrol 2004;15(3):717–721
203. Lamprecht P, Voswinkel J, Lilienthal T, et al. Effectiveness of
TNF-alpha blockade with infliximab in refractory Wegener’s
granulomatosis. Rheumatology (Oxford) 2002;41(11):1303–
1307
204. Hermann J, Reittner P, Scarpatetti M, Graninger W.
Successful treatment of meningeal involvement in Wege-
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
2011
ner’s granulomatosis with infliximab. Ann Rheum Dis 2006;
65(5):691–692
Seror R, Mahr A, Ramanoelina J, Pagnoux C, Cohen P,
Guillevin L. Central nervous system involvement in Wegener
granulomatosis. Medicine (Baltimore) 2006;85(1):54–65
Cheung CM, Murray PI, Savage CO. Successful treatment of
Wegener’s granulomatosis associated scleritis with rituximab.
Br J Ophthalmol 2005;89(11):1542
Ramos-Casals M, Brito-Zerón P, Muñoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis
of 233 cases. Medicine (Baltimore) 2007;86(4):242–251
Hinze CH, Colbert RA. B-cell depletion in Wegener’s
granulomatosis. Clin Rev Allergy Immunol 2008;34:372–379
Stasi R, Stipa E, Del Poeta G, Amadori S, Newland AC,
Provan D. Long-term observation of patients with antineutrophil cytoplasmic antibody-associated vasculitis treated
with rituximab. Rheumatology (Oxford) 2006;45(11):1432–
1436
Aries PM, Hellmich B, Voswinkel J, et al. Lack of efficacy of
rituximab in Wegener’s granulomatosis with refractory
granulomatous manifestations. Ann Rheum Dis 2006;
65(7):853–858
Keogh KA, Wylam ME, Stone JH, Specks U. Induction of
remission by B lymphocyte depletion in eleven patients with
refractory antineutrophil cytoplasmic antibody-associated
vasculitis. Arthritis Rheum 2005;52(1):262–268
Memet B, Rudinskaya A, Krebs T, Oelberg D. Wegener
granulomatosis with massive intracerebral hemorrhage:
remission of disease in response to rituximab. J Clin
Rheumatol 2005;11(6):314–318
Tamura N, Matsudaira R, Hirashima M, et al. Two cases of
refractory Wegener’s granulomatosis successfully treated
with rituximab. Intern Med 2007;46(7):409–414
Omdal R, Wildhagen K, Hansen T, Gunnarsson R,
Kristoffersen G. Anti-CD20 therapy of treatment-resistant
Wegener’s granulomatosis: favourable but temporary
response. Scand J Rheumatol 2005;34(3):229–232
Brihaye B, Aouba A, Pagnoux C, Cohen P, Lacassin F,
Guillevin L. Adjunction of rituximab to steroids and
immunosuppressants for refractory/relapsing Wegener’s granulomatosis: a study on 8 patients. Clin Exp Rheumatol
2007;25(1, suppl 44):S23–S27
Hermle T, Goestemeyer AK, Sweny P, Burns A. Successful
therapeutic use of rituximab in refractory Wegener’s
granulomatosis after renal transplantation. Clin Nephrol
2007;68(5):322–326
Roccatello D, Baldovino S, Alpa M, et al. Effects of antiCD20 monoclonal antibody as a rescue treatment for
ANCA-associated idiopathic systemic vasculitis with or
without overt renal involvement. Clin Exp Rheumatol
2008;26(3, suppl 49):S67–S71
Jones RB, Ferraro AJ, Chaudhry AN, et al. A multicenter
survey of rituximab therapy for refractory antineutrophil
cytoplasmic antibody-associated vasculitis. Arthritis Rheum
2009;60(7):2156–2168
Sharma A, Kumar S, Wanchu A, et al. Successful treatment
of hypertrophic pachymeningitis in refractory Wegener’s
granulomatosis with rituximab. Clin Rheumatol 2010;29(1):
107–110
Martinez Del Pero M, Chaudhry A, Jones RB, Sivasothy P,
Jani P, Jayne D. B-cell depletion with rituximab for
refractory head and neck Wegener’s granulomatosis: a
cohort study. Clin Otolaryngol 2009;34(4):328–335
Downloaded by: World Health Organization ( WHO). Copyrighted material.
296
221. Taylor SR, Salama AD, Joshi L, Pusey CD, Lightman SL.
Rituximab is effective in the treatment of refractory
ophthalmic Wegener’s granulomatosis. Arthritis Rheum
2009;60(5):1540–1547
222. Onal S, Kazokoglu H, Koc A, Yavuz S. Rituximab for
remission induction in a patient with relapsing necrotizing
scleritis associated with limited Wegener’s granulomatosis.
Ocul Immunol Inflamm 2008;16(5):230–232
223. Falk RJ, Jennette JC. Rituximab in ANCA-associated
disease. N Engl J Med 2010;363(3):285–286
224. Major EO. Progressive multifocal leukoencephalopathy in
patients on immunomodulatory therapies. Annu Rev Med
2010;61:35–47
225. Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA.
Rituximab in systemic lupus erythematosus: a systematic
review of off-label use in 188 cases. Lupus 2009;18(9):767–
776
226. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous
immune globulin. N Engl J Med 2001;345(10):747–755
227. Ito-Ihara T, Ono T, Nogaki F, et al. Clinical efficacy of
intravenous immunoglobulin for patients with MPOANCA-associated rapidly progressive glomerulonephritis.
Nephron Clin Pract 2006;102(1):c35–c42
228. Martinez V, Cohen P, Pagnoux C, et al; French Vasculitis
Study Group. Intravenous immunoglobulins for relapses of
systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective,
open-label study of twenty-two patients. Arthritis Rheum
2008;58(1):308–317
229. Schmitt WH, Hagen EC, Neumann I, Nowack R, FloresSuárez LF, van der Woude FJ; European Vasculitis Study
230.
231.
232.
233.
234.
235.
236.
237.
Group. Treatment of refractory Wegener’s granulomatosis
with antithymocyte globulin (ATG): an open study in 15
patients. Kidney Int 2004;65(4):1440–1448
Flossmann O, Jayne DR. Long-term treatment of relapsing
Wegener’s granulomatosis with 15-deoxyspergualin. Rheumatology (Oxford) 2010;49(3):556–562
Imai H, Hotta O, Yoshimura M, et al. Deoxyspergualin, an
immunosuppressant, in patients suffering from nephropathies with crescent formation: an open-label trial to
evaluate safety and efficacy. Clin Exp Nephrol 2006;
10(1):40–54
Birck R, Newman M, Braun C, et al. 15-Deoxyspergualin
and cyclophosphamide, but not mycophenolate mofetil,
prolong survival and attenuate renal disease in a murine
model of ANCA-associated crescentic nephritis. Nephrol
Dial Transplant 2006;21(1):58–63
Krafcik SS, Covin RB, Lynch JP III, Sitrin RG. Wegener’s
granulomatosis in the elderly. Chest 1996;109(2):430–437
Koldingsnes W, Nossent JC. Baseline features and initial
treatment as predictors of remission and relapse in
Wegener’s granulomatosis. J Rheumatol 2003;30(1):
80–88
Orens JB, Sitrin RG, Lynch JP III. The approach to
nonresolving pneumonia. Med Clin North Am 1994;78(5):
1143–1172
Lynch JP III, Raghu G. Major disease syndromes of
unknown etiology. In: Baum G, Crapo J eds. Textbook of
Pulmonary Disease. 6th ed. Boston, MA: Little, Brown;
1998:431–476
Lynch JP III, Matteson E, McCune JW. Wegener’s granulomatosis: evolving concepts. Medical Rounds 1989;2:
67–80
297
Downloaded by: World Health Organization ( WHO). Copyrighted material.
WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)/LYNCH, TAZELAAR