Concise Clinical Review
The Pulmonary Vasculitides
Stephen K. Frankel1,2and Marvin I. Schwarz1
1Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Anschutz Medical Campus, University of Colorado, Aurora;
and2Division of Critical Care and Hospital Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
The pulmonary vasculitides are a rare group of heterogeneous
disorders unified by the histopathologic finding of inflammation
is exceptionally challenging, given their highly variable clinical
presentation, their relative rarity, and the overlap of the signs and
symptoms of vasculitis with much more common entities. However,
advances in the management of vasculitis allow for accurate diag-
nosis, risk stratification in the individual patient, and the implemen-
tation of evidence-based, effective pharmacologic therapies. This
concise clinical review addresses the diagnosis and management of
the patient with pulmonary vasculitis and provides an up-to-date
review of the state of the field.
Keywords: vasculitis; Churg-Strauss; granulomatosis with polyangiitis
(Wegener’s); alveolar hemorrhage
The vasculitides are a heterogeneous group of disorders unified
by the histopathologic finding of “vasculitis,” or inflammation
and necrosis of the blood vessel wall. Clinically, pulmonary
vasculitis may present in a variety of ways including alveolar
hemorrhage, pulmonary nodules, cavitating lesions, or airway
disease depending on both the specific underlying disorder and
the particular manifestations that develop in the individual
patient. The pulmonary vasculitides may be organized by the
size of vessel predominantly affected (e.g., small, medium, and
large vessel vasculitis) as well as by the pathophysiologic
mechanism of the disorder (e.g., pauci-immune or immune
complex–mediated disease). Ultimately, it is the small vessel
anti-neutrophil cytoplasmic antibody (ANCA)–associated vas-
culitides that most commonly affect the lung, and hence, it is
the ANCA-associated vasculitides (AAVs) of granulomatosis
with polyangiitis (GPA) (the entity formerly known as Wege-
ner’s granulomatosis), Churg-Strauss syndrome (CSS), micro-
scopic polyangiitis (MPA), and idiopathic pauci-immune
pulmonary capillaritis (IPIPC) that are the main focus of this
Pulmonary vasculitis is rare. The incidence of AAV is only 15–20
cases per million per year, which translates into a prevalence of
90–300 cases per million (1–4). GPA is more common than
either MPA or CSS in European and North American popula-
tions, with an incidence of 8–10 cases per million per year, but
data from Japan and China suggest a relatively higher rate of
MPA and lower rate of GPA in Asian populations (5–9). CSS is
even less frequent, with an incidence of 1–3 cases per million
per year and a prevalence of 10–15 cases per million (3, 7, 10,
11). The increased incidence of vasculitis among family mem-
bers of affected patients and its associations with HLA and
other immune response genes suggest a genetic component to
the disease (12). Long-term follow-up from patients enrolled in
European Vasculitis Study Group (EUVAS) clinical trials has
shown that the 1-, 2-, and 5-year survival rates of patients with
AAV are 88, 85, and 78%, respectively, which translates into
a mortality risk of 2.6 when compared with the general popula-
tion (13). Poor prognostic factors for long-term survival include
advanced age, higher degrees of disease activity, alveolar hem-
orrhage, cardiac involvement, and proteinase-3 positivity.
CLINICAL PRESENTATION AND DIAGNOSIS
The clinical presentation of the patient with vasculitis is highly
variable and the diagnosis of vasculitis is exceptionally challeng-
ing. Although the 1990 American College of Rheumatology and
1994 Chapel Hill Consensus Conference criteria for the classifi-
cation of the vasculitis have been validated and widely accepted,
they are not intended to be used as diagnostic criteria and per-
form poorly when used as such (14–17). The diagnosis of vas-
culitis is a clinical diagnosis that requires the clinician caring for
the patient to integrate clinical, laboratory, radiographic, and
histopathologic data and make a determination that the prepon-
derance of the data supports or does not support a diagnosis of
vasculitis. Hence, it is important that the clinician making this
determination be familiar with the common clinical features of
each of the pulmonary vasculitides as well as the competing
diagnostic considerations (Table 1).
sel vasculitis, especially GPA or MPA, include (1) alveolar
hemorrhage, (2) tracheal or subglottic stenosis, (3) pulmonary
nodules or cavities (especially once malignancy and infection
have been excluded), (4) glomerulonephritis, (5) destructive
or ulcerating upper airway disease, (6) mononeuritis multiplex,
(7) retro-orbital mass, and (8) palpable purpura (18, 19). Con-
sideration of CSS may also be prompted by the development of
severe or refractory maturity-onset asthma with or without pe-
ripheral eosinophilia or the identification of eosinophilic paren-
Granulomatosis with polyangiitis (the entity previously known
as Wegener’s granulomatosis) (20) commonly affects the upper
airways, tracheobronchial tree, and pulmonary parenchyma.
(Received in original form March 23, 2012; accepted in final form May 24, 2012)
Author Contributions: S.K.F.: literature review, synthesis and analysis of literature,
drafting of manuscript; M.I.S.: literature review, synthesis and analysis of litera-
ture, drafting of manuscript.
Correspondence and requests for reprints should be addressed to Stephen K.
Frankel, M.D., Division of Critical Care and Hospital Medicine, 1400 Jackson Street,
M-304, National Jewish Health, Denver, CO 80206. E-mail: firstname.lastname@example.org
CME will be available for this article at http://ajrccm.atsjournals.org or at http://
Am J Respir Crit Care Med
Copyright ª 2012 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201203-0539CI on June 7, 2012
Internet address: www.atsjournals.org
Vol 186, Iss. 3, pp 216–224, Aug 1, 2012
Upper respiratory tract involvement is quite common (.85%)
and presents as otitis, hearing loss, sinusitis, epistaxis, septal
perforation, mastoiditis, or the “classic” saddle nose defor-
mity. The lower respiratory tract is similarly involved in a ma-
jority of patients (.80%) and will frequently manifest with
cough, dyspnea, chest discomfort, hemoptysis, alveolar hem-
orrhage, pulmonary nodules, cavities, or infiltrates (Figure 1).
Tracheobronchial disease, although less common than paren-
chymal disease, still occurs in 50–60% of patients. Constitu-
tional symptoms frequently accompany or precede disease
onset. Common target organs outside the lung include the
kidney, skin, eyes, joints, muscles, nervous system, and heart
MPA is characterized by profound constitutional symptoms
and glomerulonephritis. Pulmonary involvement is less frequent
than in GPA and CSS; however, 10–30% of patients will develop
diffuse alveolar hemorrhage, and as such, will have life-
threatening pulmonary disease (Figure 2) (26, 27). Other pulmo-
nary complications of MPA may include radiographic infiltrates,
pulmonary artery aneurysms, fibrotic changes, and airway disease.
Churg-Strauss syndrome (CSS) is typically characterized by
the triad of asthma, eosinophilia, and vasculitis. Alternatively,
CSS is described as having three progressive phases, namely,
(1) a prodromal “allergic/atopic” phase of asthma and rhino-
sinusitis, (2) an eosinophilic phase in which eosinophil-rich
inflammatory tissue infiltrates develop, and (3) a vasculitic
phase that presents with manifestations common to AAV such
as palpable purpura or mononeuritis multiplex (28–33). Asthma in
CSS commonly precedes the onset of the vasculitis phase (7–8 yr
on average) and is often severe, frequently requiring oral cortico-
steroids. Upper airway involvement occurs in 70–90% of patients
and is generally characterized by chronic rhinosinusitis, with or
without nasal polyposis, often lacking the destructive features
found in patients with GPA. Chest imaging demonstrates ab-
normalities in 70–90% of patients with CSS, most commonly
patchy, bilateral, heterogeneous, migratory infiltrates combined
with features of airway disease (34). Extrapulmonary manifesta-
tions of CSS may include constitutional symptoms, mononeuritis
multiplex, cutaneous lesions, glomerulonephritis, and cardiac in-
volvement. The cardiac involvement is of particular importance
as roughly half of the attributable mortality in CSS is due to
cardiac complications that include cardiomyopathy, myocarditis,
coronary arteritis, conduction delays, and sudden death.
Idiopathic pauci-immune pulmonary capillaritis (IPIPC) is an
isolated small vessel vasculitis that by definition is isolated to the
lungs and, hence, presents with diffuse alveolar hemorrhage as
its primary clinical manifestation (35, 36). In a case series of
29 patients who presented with diffuse alveolar hemorrhage,
8 of these patients (28%) were found to have IPIPC (35). Clin-
ically, the entity appears to behave as a “lung-limited MPA,”
and as such, decisions regarding the management of IPIPC are
extrapolated from the AAV experience and data.
As with all complex diseases, the evaluation of the patient
with suspected vasculitis begins with a comprehensive history
and physical examination to identify all the potential signs
and symptoms that the patient may be experiencing and that
may contribute to the final diagnosis. Competing diagnostic con-
siderations often include complex systemic illnesses including
infections (or postinfection complications), malignancy, drug
reactions, and primary rheumatologic diseases. The review of
systems is exceptionally important, as patients will not necessarily
draw connections to seemingly unrelated problems. Labora-
tory testing generally includes a complete blood count, renal
function, liver function, urinalysis with sediment examination,
TABLE 1. CLINICAL MANIFESTATIONS OF PULMONARY VASCULITIS
>85%. May include epistaxis,
destructive and ulcerating lesions,
otitis, sinusitis, and mastoiditis
Approximately 60%. Manifestations
include subglottic or tracheal
stenosis, airway narrowing,
lesions, stenosis, or occlusion
.80% will have focal consolidation,
infiltrates, atelectasis, nodules,
cavities, or other abnormalities.
40–70% will have nodules
and/or cavities. Easily confused
with infection or malignancy
7 cases per 100 person-years.
Comparable to patients
with a known history of VTE
Common cause of morbidity
Pulmonary toxicity most commonly
with methotrexate but may
also be seen with other
Constitutional symptoms 50–90%
Cutaneous disease 45–60%
Musculoskeletal disease 30–70%
Ocular involvement 25–50%
Cardiac involvement 5–15%
<15%70–90%. Commonly manifests
as rhinitis and sinusitis
Asthma and airways
.95% present with asthma.
Variable severity, but
Up to 30% will have infiltrates,
often reflecting the presence
of alveolar hemorrhage
70% by plain film and up
to 90% by HRCT. Commonly
appears as patchy, bilateral,
heterogeneous disease with
areas of ground-glass
appearance and consolidation
Infiltrates seen in
Unknown incidenceUnknown incidence
InfectionSee GPASee GPA See GPA
See GPA See GPASee GPA
Constitutional symptoms . 90%
Musculoskeletal disease . 50%
Gl disease 35–45%
Cardiac involvement 10–20%
Constitutional symptoms 50–90%
Musculoskeletal disease . 50%
Cutaneous disease 40–70%
PNS . 50%
GI disease 30–50%
Cardiac involvement 30–50%
Generally considered a
symptoms and other
may be seen
Definition of abbreviations: CSS ¼ Churg-Strauss syndrome; GI ¼ gastrointestinal; GN ¼ glomerulonephritis; GPA ¼ granulomatosis with polyangiitis; IPIPC ¼
idiopathic pauci-immune pulmonary capillaritis; MPA ¼ microscopic polyangiitis; PNS ¼ peripheral nervous system; VTE ¼ venous thromboembolic disease.
Sources: References 22–25, 30, 31, 33, and 72–77.
Concise Clinical Review 217
electrocardiogram, connective tissue disease serologies, and
anti-neutrophil cytoplasmic antibody (ANCA) testing.
ANCAs are neutrophil-specific autoantibodies that play
a critical role in the pathogenesis of ANCA-associated vasculitis.
ANCAs promote neutrophil migration to and degranulation in
proteases, and other toxic metabolites (37–39). Animal models
have further demonstrated that these antibodies are capable of
producing disease characterized by glomerulonephritis and pul-
monary vasculitis (40, 41). Clinically, ANCA titers have been
shown to correlate with disease activity (although a rise in
ANCA titers alone is not sensitive or specific for predicting
impending relapse) (42). To date, three ANCA staining pat-
terns have been characterized on indirect immunofluorescence:
cytoplasmic, perinuclear, and atypical, designated as c-ANCA,
p-ANCA, and a-ANCA, respectively. c-ANCAs are associated
with specific autoantibodies directed against proteinase-3 (PR3),
and autoantibodies against proteinase-3 may be measured via
a separate ELISA. Both c-ANCA and PR-3 antibodies are
closely associated with GPA with 85–90% sensitivity and 95%
specificity for generalized active disease (43, 44). Patients with
limited disease or who are in disease remission may still be
ANCA positive, but at significantly lower rates (60 and 40%,
p-ANCAs are associated with MPA and CSS, but are less
specific than c-ANCA, and may be seen in a number of other
autoimmune diseases. Although p-ANCAs are commonly asso-
ciated with autoantibodies directed against myeloperoxidase,
which may also be measured directly via ELISA testing, they
have also been associated with autoantibodies against other anti-
gens. p-ANCA/myeloperoxidase positivity has a sensitivity of
50–75% for MPA and 35–50% for CSS (46, 47). Thus, a positive
test is helpful, but a negative test does not exclude the disease.
Indeed, ANCA-associated vasculitis need not be associated
with a positive ANCA in any individual patient.
Imaging studies are useful in both the diagnosis of vasculitis
and in fully characterizing disease manifestations in a given pa-
tient. Imaging studies are guided by the clinical manifestations
identified in an individual patient and by the established patterns
of target organ involvement specific to a given disease entity. As
such, high-resolution computed tomography (HRCT) of the
chest, CT of the sinuses, and echocardiography are central to
the evaluation of most patients with pulmonary vasculitis. Addi-
tional imaging studies are dictated by the clinical scenario.
The role of bronchoscopy in the evaluation in pulmonary
vasculitis is targeted to (1) the identification of diffuse alveolar
hemorrhage, (2) the diagnosis of lower respiratory tract infec-
tions, and (3) assessment of the large airways for complications
such as stenosis or endobronchial lesions. Transbronchial biop-
sies rarely provide a positive diagnosis of pulmonary vasculitis
as diagnostic tissue is seldom obtained (48).
Although the presence of a compelling clinical, radiologic,
and serologic profile may be sufficient to diagnosis vasculitis, his-
topathologic evidence of vasculitis is frequently required to con-
firm a suspected diagnosis. Biopsy of the skin or sinuses is
relatively safe and straightforward, but is less likely to yield a de-
finitive diagnosis than the more invasive renal biopsy or surgical
lung biopsy (49). Surgical lung biopsy (video assisted) is a high-
yield procedure that permits accurate diagnosis in the majority
of cases. Close coordination between providers is required to
ensure that the sample is processed to obtain as much informa-
tion as possible including frozen sections for immunofluores-
cence studies, samples in saline for microbiological culture,
and formalin-fixed tissue for histology.
The pharmacologic treatment of vasculitis necessitates the use of
cytotoxic medications and systemic corticosteroids. As such, the
pharmacologic therapies for vasculitis carry significant risk for
drug-associated adverse effects. Thus, the intensity of the immu-
nosuppressive regimen should be based on disease activity. To
Figure 1. (A) High-resolution computed tomography (HRCT) demon-
strating multiple pulmonary cavitary lesions in a patient with granulo-
matosis with polyangiitis (GPA). (B) HRCT demonstrating right lower
lobe consolidation, necrosis, and cavitation in a patient with GPA. Also
note the nodule in the left lower lobe with traction on the surrounding
Figure 2. High-resolution computed tomography demonstrating het-
erogeneous, bilateral, ground-glass infiltrates suggestive of diffuse al-
218 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 186 2012
this end, management is commonly divided into two phases: (1)
an induction of remission phase, in which more aggressive ther-
apies are used to induce remission of an active vasculitis, and (2)
a maintenance of remission phase in which therapy is deesca-
lated to reduce the potential for adverse side effects but is still
sufficient to keep the disease in remission. Induction therapies
are further tailored to disease severity with more aggressive
pharmacologic regimens for organ- and life-threatening disease
and less aggressive regimens for milder disease.
Grading Disease Severity
In order for the clinician to tailor pharmacologic therapy to dis-
ease activity, accurate and reproducible assessments of disease
activity are required to inform management decisions. The best
characterized system for risk stratification remains the EUVAS
classification, which groups patients into the following catego-
ries: (1) limited, (2) early, generalized, (3) generalized active,
(4) severe, (5) refractory, and (6) remission. Limited disease,
by definition, is non–organ-threatening, isolated disease of the
upper airway. Early generalized disease is characterized by con-
stitutional symptoms plus the presence of end-organ involve-
ment, but lacks a clear or immediate threat to organ function,
whereas generalized active disease is defined by the presence of
clearly impaired and threatened organ function. Severe disease
includes those manifestations that represent an immediate
threat of organ failure or death and include severe renal insuf-
ficiency (defined by a creatinine level . 5.7 mg/dl), alveolar
hemorrhage, central nervous system disease, cardiomyopathy,
and life-threatening gastrointestinal disease such as bowel ische-
mia or hemorrhage. Refractory disease is one that has failed to
respond to conventional therapy (Table 2).
An alternative approach to assessing disease severity/risk
stratification is the use of the Five Factor Score (FFS) developed
by the French Vasculitis Study Group, originally validated for
patients with MPA, polyarteritis nodosa, and CSS, but more re-
The calculation of the score attributes 11 point for the presence
of each of the following elements: (1) age 65 years or more, (2)
renal insufficiency, (3) cardiac involvement, (4) gastrointestinal
involvement, and (5) the absence of upper airway (i.e., ear,
nose, and sinus) involvement. A score of 2 or higher carries
a mortality of 40% and necessitates the use of more aggressive
therapies, whereas a score of 0 is associated with a mortality of
9%, arguing for less aggressive therapies.
The use of an inventory, specifically the Birmingham Vascu-
litis Activity Score (BVAS, version 3.0) permits objective, repro-
ducible, quantitative scoring of vasculitis disease activity (51).
Similarly, the Vasculitis Damage Index permits a similar quan-
titative scoring of vasculitic damage (52–54). These instruments
organize signs and symptoms commonly associated with vascu-
litis by organ system and offer the clinician or researcher a
systematic way to capture the detailed, multisystem clinical as-
sessment that is routinely performed by clinicians caring for these
patients. These instruments are well validated and are useful in
Induction of Remission
Limited disease. There are few data to inform management con-
cerning this subgroup of patients, but expert opinion suggests
that limited, localized disease may be managed with topical ther-
apies, oral corticosteroid monotherapy, and/or a single moderate
potency cytotoxic agent such as methotrexate, azathioprine, or
Early generalized disease. After the identificationof cyclophos-
phamide and corticosteroids as effective therapy for the induction
so treated (24). However, more recent studies suggest that
patients with milder disease may be candidates for treatment
with less potent agents. The Non-Renal Alternative with Meth-
otrexate Trial (NORAM) directly compared cyclophosphamide
with methotrexate for the induction of remission in this group of
patients and found that whereas the time to remission was lon-
ger in the patients in the methotrexate arm (5.2 vs. 3.2 mo), by
6 months the rate of remission was identical (84 vs. 83%) (55).
Moreover, methotrexate was better tolerated than cyclophos-
phamide and had a more favorable side effect profile. On the
other hand, relapse rates were significantly higher with metho-
trexate (42 vs. 74%). As such, both methotrexate and cyclo-
phosphamide may be considered as first-line therapy for the
induction of remission in patients with early, generalized dis-
ease and the choice of therapy should be individualized to each
In addition to methotrexate and cyclophosphamide, both
mycophenolate mofetil (MMF) and azathioprine have been
proposed as potential alternative, moderate-potency cytotoxic
agents that may be considered in this patient population. To this
end, Silva and colleagues evaluated MMF for patients with MPA
with mild–moderate renal involvement in a prospective, open-
label pilot study (56). In this small (17 patient) case series, 76%
of patients achieved disease remission with corticosteroids plus
MMF and 70% had sustained remission at 18 months. At present,
the EUVAS study group is conducting a larger, randomized,
controlled trial comparing MMF against cyclophosphamide
for the induction of remission in AAV, but results are not yet
Generalized active disease. In 1983, Fauci and colleagues pub-
lished their landmark study of 85 patients with GPA prospec-
tively studied at the National Institutes of Health (Bethesda,
MD) and definitely demonstrated that daily oral cyclophospha-
mide combined with oral corticosteroids was effective for the
treatment of GPA (24). Remission was achieved in 93% of
patients, and daily oral cyclophosphamide combined with oral
corticosteroids became the yardstick by which all other phar-
macologic regimens have been measured.
The Daily Oral versus Pulse Cyclophosphamide for Renal
Vasculitis (CYCLOPS) trial compared pulse intravenous cyclo-
phosphamide with daily oral cyclophosphamide and found that
there was no difference in the rate of or time to disease remission
between the groups (57). The pulsed intravenous cyclophospha-
mide group had a lower rate of leukopenia and received a lower
cumulative dose of cyclophosphamide compared with the oral
therapy group. However, retrospective data looking at long-
term outcomes found that the risk of relapse was significantly
lower in patients treated with daily oral therapy (20.8 vs. 39.5%)
(58). No significant differences were noted in survival, renal
function, or adverse events. Thus, arguments may be made sup-
porting either pulse intravenous or daily oral cyclophosphamide
and therapy should be tailored to individual circumstances. In-
terestingly, data from the Wegener’s Granulomatosis-Entretien
(WEGENT) trial suggest that patients who fail first-line induc-
tion with corticosteroids and intravenous cyclophosphamide
may respond to oral daily cyclophosphamide therapy (59).
On the basis of the role of ANCA and B lymphocytes in the
pathogenesis of AAV, a strong argument was made for the bi-
ological plausibility of rituximab, an anti-CD20 monoclonal an-
tibody, as a possible therapeutic agent for the treatment of
vasculitis. Indeed, a number of case series have been published
suggesting that rituximab may be efficacious for the treatment of
AAV. As such, two large, multicenter controlled trials evaluat-
ing the efficacy of rituximab for the treatment of generalized ac-
tive and severe disease were conducted.
Concise Clinical Review 219
The Rituximab versus Cyclophosphamide for ANCA-
Associated Vasculitis (RAVE) trial of 197 patients with either
GPA or MPA compared rituximab (375 mg/m2) given weekly
for 4 weeks with daily oral cyclophosphamide at 2 mg/kg/day
(adjusted for renal function) for induction of disease remission
(60). Both groups received a standardized corticosteroid taper.
The primary end point of the trial was a BVAS/WG of 0 and
successful completion of the prednisone taper at 6 months. The
rituximab arm reached the primary end point in 64% of subjects
as compared with 53% in the cyclophosphamide group, consis-
tent with noninferiority (P , 0.001) and, on the basis of these
findings, rituximab received a label indication for induction of
disease remission in AAV. No significant differences in total or
serious adverse events were noted between the treatment
groups. Subgroup analysis did suggest that rituximab may be
more effective than cyclophosphamide for relapsing disease
(67 vs. 42%; P ¼ 0.01) and was equally effective for the man-
agement of alveolar hemorrhage.
The Rituximab versus Cyclophosphamide in ANCA-
Associated Renal Vasculitis (RITUXVAS) trial similarly com-
pared rituximab with intravenous, pulsed cyclophosphamide as
induction therapy for the treatment of AAV in 44 patients with
generalized active or severe disease with renal involvement (61).
Of note, the rituximab group received concomitant pulsed cy-
clophosphamide with the first and third rituximab infusions, and
both groups received the same oral corticosteroid regimen.
Rates of sustained remission were similar (76 vs. 82%; P ¼
0.68), as were median time to remission (90 vs. 94 d; P ¼
0.87) and adverse event rates (P ¼ 0.77).
Although a number of investigators hypothesized that ritux-
imab would prove to have either a more favorable side effect
profile and/or greater efficacy than cyclophosphamide, this has
not been borne out. On the other hand, in both trials, rituximab
served as both the induction and maintenance agent, and no
maintenance cytotoxic agent was deployed in the rituximab
arm, whereas patients receiving cyclophosphamide required
on-going maintenance therapy with azathioprine. Furthermore,
the end points of the trials were at 6 and 12 months, respectively,
such that the longer term toxicities known to be associated with
cyclophosphamide use would not yet have been identified.
Hence, the ultimate role of rituximab in the management of
AAV remains to be fully elucidated, but clearly, the identifica-
tion of rituximab as an efficacious agent is a major advance.
Severe disease. On the basis of data from the Randomized
Trial of Plasma Exchange or High-Dosage Methylprednisolone
as Adjunctive Therapy for Severe Renal Vasculitis (MEPEX)
study, plasma exchange in addition to corticosteroids and cyto-
toxic therapy has been recommended for patients with severe dis-
ease (62). In MEPEX, patients with a new diagnosis of vasculitis
and severe renal impairment were treated with oral corticoste-
roids and oral cyclophosphamide and simultaneously randomized
to plasma exchange or high-dose intravenous methylpredniso-
lone. Dialysis-independent survival at 3 months was 69% among
the plasma exchange patients as opposed to 49% for the intra-
venous corticosteroid group. Furthermore, a 20-patient case
series supports this strategy in alveolar hemorrhage as well (63).
The RAVE and RITUXVAS trials suggest that rituximab may be
used as a potential alternative to cyclophosphamide in this patient
population. However, the optimal timing of cyclophosphamide
or rituximab administration in critically ill patients remains an
open question, as do the potential risks and benefits of intra-
venous versus oral cyclophosphamide, the optimal dose and
route of administration of corticosteroids, and whether or
not these principles of therapy apply equally to patients with
other life-threatening disease manifestations (i.e., CNS disease
or gastrointestinal disease.) Thus, referral of these patients to
a center of expertise should be strongly considered in this
Refractory disease. By definition, refractory disease is disease
that failed to respond to conventional therapy, and hence, inves-
tigational or compassionate use therapies are then considered.
Agents that have been considered for refractory disease include
anti-thymocyte globulin, intravenous immunoglobulin, inflixi-
mab, and deoxyspergualin. Ultimately, patients with refractory
TABLE 2. FIRST-LINE TREATMENT OPTIONS STRATIFIED BY DISEASE SEVERITY
EUVAS ClassificationClinical FeaturesFive Factor ScoreTreatment Options
Isolated upper airway disease
End-organ involvement that lacks a clear or
immediate threat to organ function. Examples
include glomerulonephritis with serum creatinine ,
1.4 mg/dl or the presence of minimally symptomatic
pulmonary nodules. Constitutional symptoms are
End-organ involvement with clinically significant
impairment of organ function. Examples include
glomerulonephritis with serum creatinine . 1.4 mg/dl
but , 5.7 mg/dl or pulmonary infiltrates with cough,
dyspnea, and impaired exercise tolerance
Immediate threat of organ failure or death. Examples
include severe renal disease with serum creatinine .
5.7 mg/dl, alveolar hemorrhage, and heart
Disease that has failed to respond to conventional therapy
0 Corticosteroids or methotrexate or azathioprine
Cyclophosphamide 1 corticosteroids or
methotrexate 1 corticosteroids (for MPA may
also consider mycophenolate 1 corticosteroids)
1–2 Rituximab 1 corticosteroids or
cyclophosphamide 1 corticosteroids
>2 Plasmapheresis 1 corticosteroids 1
cyclophosphamide (or rituximab)
RefractoryN/AReferral to a center of specialized expertise.
Consider investigational agents
If induced with cyclophosphamide then
azathioprine 6 low-dose oral corticosteroids or
methotrexate 6 low-dose oral corticosteroids
If induced with rituximab no additional maintenance
therapy may be required or may use low-dose oral
Remission (maintenance)No evidence of ongoing vasculitic activity (BVAS ¼ 0)N/A
Definition of abbreviations: BVAS ¼ Birmingham Vasculitis Activity Score; EUVAS ¼ European Vasculitis Study Group; MPA ¼ microscopic polyangiitis; N/A ¼ not
Sources: References 24, 55–57, 59, 60, 62–67, and 78–80.
220AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1862012
disease are best served by referral to a center with specialized
expertise in the management of vasculitis.
Maintenance of Remission
Throughout the 1980s and 1990s, patients would commonly
receive defined courses of oral cyclophosphamide therapy for
the management of active vasculitis as this represented the
only proven effective therapy, and conceptually, the idea of
“consolidating” disease remission appeared to be a conserva-
tive approach to management. However, in the landmark
CYCAZAREM study (Cyclophosphamide versus Azathioprine
for Remission in Generalized Vasculitis), transitioning patients
from cyclophosphamide to azathioprine as soon as clinical re-
mission was achieved did not increase the rate of disease relapse
and reduced total cyclophosphamide exposure (64). In this trial,
patients with a new diagnosis of generalized active vasculitis
received oral cyclophosphamide plus a corticosteroid taper for
the induction of disease remission. Patients who achieved dis-
ease remission within 3 to 6 months were then randomized to
either azathioprine or cyclophosphamide therapy. At 12 months,
all patients were transitioned to azathioprine. Analysis at 18
months demonstrated that the rate of relapse was similar in
both groups (15.5% in the azathioprine group and 13.7% in
the cyclophosphamide group; P ¼ 0.65), as were the rates of
serious adverse events (11 vs. 10%; P ¼ 0.94).
Methotrexate has similarly been proposed as a safer alterna-
tive to cyclophosphamide for the maintenance of disease remis-
sion in AAV. The WEGENT trial compared the safety and
of disease remission (65). One hundred and eighty patients were
randomized to daily oral azathioprine (2 mg/kg/d) or weekly
methotrexate (progressively dose escalated to a goal dose of
25 mg/wk) after the induction of disease remission. Relapse-
free survival rates were 71.8% in the azathioprine group and
74.5% in the methotrexate group, suggesting equivalent efficacy
(relative risk of 0.92; P ¼ 0.78), although 11% of the azathio-
prine group and 19% of the methotrexate group suffered an
adverse event leading to death or study drug discontinuation
for a hazard ratio of 1.65 (P ¼ 0.29).
Mycophenolate mofetil has also been suggested as a potential
alternative to azathioprine for the maintenance of disease remis-
sion. Although smaller studies suggested potential benefit to this
strategy, the International Mycophenolate Mofetil Protocol to
Reduce Outbreaks of Vasculitides (IMPROVE) trial compared
mycophenolate mofetil head-to-head against azathioprine for
maintenance of remission (66). Relapses were found to be more
common in the MMF group compared with azathioprine (P ¼
0.03). Adverse event rates were similar between groups. As
such, azathioprine must be considered the superior agent and
mycophenolate should be reserved for patients who cannot tol-
erate azathioprine or methotrexate.
Although almost all of the major randomized, controlled tri-
als use a corticosteroid regimen during both the induction and
maintenance of remission phases of management, the specific
regimens used vary from study to study. In general terms,
high-dose steroids are used during the induction of remission
(e.g., an initial dose of oral prednisone or equivalent of 1 mg/kg/d)
and slowly tapered toward a “low” maintenance dose (e.g., oral
prednisone at 5–10 mg/d) until the steroids are ultimately ta-
pered to off as long as disease remission is maintained. How-
ever, there is no widely accepted, well-validated corticosteroid
protocol. A meta-analysis published by Walsh and colleagues
analyzed 13 studies to determine whether low-dose glucocorti-
coids (GCs) contributed to the maintenance of disease remission.
The authors found a lower disease relapse rate in patients
receiving a low dose of GCs (67). Only 14% of patients on
GCs suffered a relapse compared with 43% not receiving GCs.
However, given the difference between GC regimens, main-
tenance therapies, and other confounders, it is difficult to ex-
trapolate further from this analysis. Nevertheless, it would
appear that GC dosage and duration itself are deserving of
Another open question in the management of AAV is the du-
ration of maintenance therapy. Although one may extrapolate
from clinical trials that 18 months represents the lower end of
an acceptable duration of therapy, the true optimal duration
of therapy remains unknown. The Randomized Trial of Pro-
longed Remission-Maintenance Therapy in Systemic Vasculitis
(REMAIN) study should further inform this question, directly
comparing 24 months of maintenance therapy with 48 months
of therapy. This trial completed recruitment in 2010, and results
should become available in 2014–2015.
Another point of debate is the optimal management of
patients after rituximab induction. Although the RAVE and
therapies beyond low-dose corticosteroids, whether this repre-
sents optimal management is unknown. In published cases, dis-
ease relapse after rituximab is often managed with repeated
uximab in conjunction with other disease-modifying therapies
such that the long-term management of patients with AAV trea-
ted with rituximab is also deserving of further study.
One cannot overemphasize the role of a comprehensive ap-
proach to the care of the patient with vasculitis, ideally by a mul-
tidisciplinary team of health care professionals experienced in its
management. Drug-specific monitoring of cytotoxic therapies is
the American College of Chest Physicians guidelines on the
monitoring of immunosuppressive agents, expected to be pub-
lished soon, for further information on the specifics of monitor-
ing each of these individual agents.
Disease-specific monitoring with regular assessments to look
for early evidence of disease activity, infections, and complica-
tions of therapy should be incorporated into the plan of care. In-
deed, these frequent clinical evaluations will more clearly
establish the patient’s baseline function and identify vasculitic
“damage” that is not amenable to escalation of immunosuppres-
sive therapy. Patients should receive vaccinations for influenza
and pneumococcus. A regular exercise regimen to optimize
musculoskeletal conditioning is recommended, and when ap-
propriate, formal physical therapy, occupational therapy, and
rehabilitation consultation. Bone health should be assessed by
periodic bone densitometry as well as prophylaxis with calcium,
vitamin D, and when indicated, other bone mineral–preserving
therapies. Proper nutrition and sleep hygiene should be addressed.
Trimethoprim–sulfamethoxazole (T/S) therapy should be
deployed for Pneumocystis jirovecii prophylaxis. Additional
benefit might also accrue to patients receiving T/S therapy by
the suppression of Staphylococcus aureus nasal carriage, which
in turn is associated with a higher risk of disease relapse in GPA
(68). At least one randomized trial has demonstrated reduced
relapse rates in patients with GPA maintained on T/S as ad-
junctive therapy after the induction of remission with cyclo-
phosphamide and corticosteroids (69).
DISEASE RELAPSE AND COMPLICATIONS
Vasculitis is a chronic, systemic disease characterized by periods
of waxing and waning disease activity and many patients will
Concise Clinical Review 221
suffer one or more disease relapses. In any patient with vasculitis
with new signs or symptoms the differential diagnosis must al-
ways consider (1) vasculitis flare/disease activity, (2) infection,
(3) thromboembolic disease, (4) drug toxicity, as well as (5)
disease states unrelated to the vasculitis or its therapy. Indeed,
the leading causes of death in patients with vasculitis are in-
fection, pneumonia, and sepsis in particular, active vasculitis,
cardiovascular disease (myocardial infarction, cerebrovascular
accident, pulmonary embolus), and malignancy (13).
Infection represents a major cause of both morbidity and
mortality in patients with vasculitis and the importance of iden-
tifying infection in these patients cannot be overemphasized.
Infections account for 13–48% of deaths among patients with
vasculitis (13, 29, 70). Patients may present with atypical clinical
presentations and/or atypical infectious organisms. Infection
represents not only a complication of vasculitis and the immu-
nosuppressive therapies required for its treatment, but also
serve as a triggering factor for disease flares, setting up a vicious
negative reinforcing cycle of disease activity, immune dysfunc-
tion, and infection.
Similarly, venous thromboembolic disease (VTED) repre-
sents another underrecognized complication of vasculitis. The
incidence of VTED in patients with GPA is 7.0 per 100 person-
years, the same rate as for patients with a known prior history
of VTED (71). As such, VTED should be considered in the dif-
ferential diagnosis of any patient with vasculitis who presents with
new chest or lower extremity symptoms.
Although the diagnosis of pulmonary vasculitis remains chal-
lenging, the identification and diagnosis of pulmonary vasculitis
are critical to the care of these patients. Even though the vascu-
litides are both rare and heterogeneous, clinical investigators
have been able to perform numerous well-designed controlled
trials that have clearly advanced the field. Appropriate risk
stratification and implementation of evidence-based, effective
pharmacologic therapies combined with a comprehensive, mul-
tidisciplinary approach to care allows the clinicians who care for
these patients to truly optimize individual outcomes.
Author disclosures are available with the text of this article at www.atsjournals.org.
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