Tre a t m e n t G u i d e l i n e s i n

Vas c u l i t i s
Tanaz A. Kermani, MD, MSa, Kenneth J. Warrington, MDb, Anisha B. Dua, MD, MPHc,*

KEYWORDS
 Vasculitis  Giant cell arteritis  Takayasu arteritis  Polyarteritis nodosa
 Granulomatosis with polyangiitis  Microscopic polyangiitis
 Eosinophilic granulomatosis with polyangiitis  Treatment Guidelines

KEY POINTS
 The American College of Rheumatology/Vasculitis Foundation guidelines aim to provide
advice on diagnostic/evaluation strategies, therapeutic options, and long-term manage-
ment of these complex diseases based on the best available evidence to date.
 The diagnosis of vasculitis often requires a combination of clinical, serologic, radio-
graphic, and pathologic evaluation.
 There are differences in recommendations across rheumatologic societies due to vari-
ability in available diagnostic modalities and access to and cost of therapeutics.
 Specific biomarkers for the diagnosis and monitoring of vasculitis and availability of safe,
targeted therapeutics are needed and ongoing areas of active research in vasculitis.

GIANT CELL ARTERITIS

Introduction
Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that involves the
cranial arteries, the aorta and its proximal branches.1 It clinically affects the elderly
population with ischemic complications including vision loss, stroke, and limb claudi-
cation. The treatment of GCA has historically relied heavily on long-term glucocorti-
coids (GC), with resultant adverse effects, toxicities, as well as frequent relapses. A
better understanding of the pathophysiology of GCA has led to the development of
GC-sparing therapies, whereas advances in imaging have allowed insight into the
prevalence and implications of extracranial large-vessel involvement.

a
University of California Los Angeles, 2020 Santa Monica Boulevard, Suite 540, Santa Monica,
CA 90404, USA; b Mayo Clinic, 200 First Street Northwest, Rochester, MN 55905, USA;
c
Northwestern University Feinberg School of Medicine, 675 North St. Clair Street, Suite 14-100,
Chicago, IL 60611, USA
* Corresponding author.
E-mail address: [email protected]

Rheum Dis Clin N Am - (2022) -–-

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2 Kermani et al

Discussion
Overview
The American College of Rheumatology/Vasculitis Foundation (ACR/VF) Guideline
included 7 recommendations on diagnostic testing and 15 on medical management,
surgical intervention, and disease monitoring2,3 (Table 1). Ungraded position state-
ments were made by the voting panel when there was not enough evidence to support
a graded recommendation but the question addressed a commonly encountered clin-
ical question, thus guidance was provided based on general views of the voting panel.
There were 2 ungraded position statements, and all recommendations were condi-
tional except 1 strong recommendation to clinically monitor patients long-term who
are in clinical remission. The European Alliance of Associations of Rheumatology
(EULAR) has also published recommendations on the diagnosis and management
of GCA4 (Table 2).

Diagnostic evaluation
Early diagnosis and initiation of treatment in GCA is critical to improve outcomes. The
ACR/VF guideline recommends obtaining a temporal artery biopsy over a temporal ar-
tery ultrasound in patients suspected of having GCA.2,3 Further recommendations
include obtaining a unilateral biopsy of at least 1 cm within 2 weeks of initiating GC
therapy. However, EULAR recommends an early imaging test with ultrasound of the
temporal  axillary arteries as the first imaging modality in patients with suspected
predominantly cranial GCA.5 Much of this discrepancy centers on expertise in ultra-
sound for diagnosing GCA. Ultrasound is a noninvasive, inexpensive, and accessible
test that can be used to assess various arteries affected by GCA. However, ultrasound
is highly user-dependent, and features, such as the halo sign, tend to resolve soon af-
ter GC exposure. In one study, the sensitivity of ultrasound decreased following the
use of GC, from 92% after 0 to 1 days, to 80% after 2 to 4 days, to 50% after more
than 4 days of GC6. There has been interest and research in incorporating ultrasound
into fast-track clinics to develop and validate algorithmic approaches that might help
risk stratify patients and allow for low-probability patients to avoid undergoing further
testing and unnecessary medications.7–9 Although ultrasound demonstrates utility in
the diagnostic algorithm including the ability to assess some extracranial vessels,
pathologic diagnosis may have utility in prognostication, and histologic features
remain positive for a longer period of time in patients exposed to GC. In one study,
repeat temporal artery biopsy remained positive in 70% of patients at 3 months after
GC exposure and in 44% of patients at 12 months.10 To date, an ideal radiographic,
serologic, or pathologic biomarker that can consistently and accurately diagnose,
detect relapses, and risk-stratify patients in need of specific types of immunomodulat-
ing therapy in GCA has remained elusive.
The ACR/VF guideline recommends large-vessel imaging in all suspected and
confirmed cases of GCA, whereas EULAR recommendations note that noninvasive
imaging may be helpful to support the diagnosis of large-vessel involvement in GCA
but do not specifically recommend it in all suspected cases.2,3,5 The optimal modality
and frequency of noninvasive imaging for monitoring patients with GCA has not been
established and likely should reflect baseline large-vessel involvement along with their
clinical course.

Glucocorticoids
One of the most feared complications of GCA is vision loss and early initiation of GC
once diagnosis is suspected is important in the prevention of vision loss.11,12 In pa-
tients with threatened vision loss, the ACR/VF guideline recommends intravenous

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 Table 1
Summary of recommendations from the American College of Rheumatology/Vasculitis foundation guideline
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GCA TAK PAN GPA/MPA EGPA

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Diagnosis Temporal artery biopsy, No specific Deep-skin biopsy, nerve No specific No specific
noninvasive large- recommendations and muscle biopsy, recommendations recommendations
vessel imaging abdominal vascular but echocardiogram
imaging in all patients at
diagnosis
Glucocorticoid (GC) use High dose oral GC, IV GC High-dose oral GC, IV High-dose oral GC, IV IV GC or high-dose oral IV GC or high-dose oral
for cranial ischemia GC for severe disease, GC for life- GC GC
Duration guided by organ-threatening threatening or organ- Reduced-dose GC Duration guided by
patient’s condition, ischemia and if threatening disease regimen for taper patient’s condition,
values, and needed for pediatric Duration guided by values, and
preferences patients patient’s condition, preferences
Taper to 0 mg after 6– values, and
12 mo preferences
Remission induction High-dose GC and High-dose GC and AZA High-dose GCA and High-dose GC and RTX High-dose GC and RTX
(severe disease) tocilizumab or MTX or TNFi cyclophosphamide No plasma exchange or cyclophosphamide
Remission maintenance Tocilizumab AZA or MTX or TNFi Immunosuppressive Fixed-dose RTX AZA or MTX or MMF
agent (other than

Treatment Guidelines in Vasculitis

CYC)
Monitoring Clinical evaluation, Clinical evaluation, Abdominal vascular No specific No specific
acute phase reactants acute phase imaging recommendations recommendations
Long-term clinical reactants, large-vessel
monitoring imaging
Long-term clinical
monitoring
Management of specific Not applicable Not applicable TNFi for patients with MTX for induction in Mepolizumab for
disease phenotype/ DADA2 nonsevere GPA/MPA patients with
subset nonsevere disease

Abbreviations: DADA2, Deficiency of adenosine deaminase 2; EGPA, eosinophilic granulomatosis with polyangiitis; GC, glucocorticoids; GCA, giant cell arteritis;
GPA, granulomatosis with polyangiitis; IV, intravenous; MPA, microscopic polyangiitis; MTX, methotrexate; PAN, polyarteritis nodosa; RTX, rituximab; TAK, Ta-
kayasu arteritis; TNFi, tumor necrosis factor inhibitor.

3
 4
Kermani et al
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Table 2
Comparison of American college of rheumatology/vasculitis foundation guideline and European alliance of associations of rheumatology recommendations
for the management of large-vessel vasculitis2–4

GCA TAK
ACR/VF EULAR ACR/VF EULAR
Diagnosis Temporal artery biopsy Temporal artery No recommendations Referral to a tertiary care
Noninvasive large-vessel ultrasound  axillary arteries center if possible for
imaging in ALL suspected Noninvasive large-vessel diagnosis and confirmation
and newly diagnosed GCA imaging to support a with large-vessel imaging
diagnosis of large-vessel GCA
GC use IV pulse GCs in cranial ischemia Same High-dose GC, IV pulse in High-dose GC, no comment
High-dose oral GC in GCA Same severe disease about IV use
without cranial ischemia
Adjunctive therapy In newly diagnosed GCA, use Use adjunctive TCZ or MTX MTX, AZA or TNFi in all Adjunctive
oral GC 1 TCZ only in select patients patients with active disease immunosuppression with
(relapsing, refractory, high MTX, AZA, leflunomide or
risk of GC side effects) MMF in all patients with
active disease
Biologic therapy TNFi favored over tocilizumab. If fail immunosuppressive
TNFi can be used as first line therapy with DMARD, either
adjunctive therapy TNFi or tocilizumab may be
used

Abbreviations: ACR/VF, American College of Rheumatology/Vasculitis Foundation; DMARD, disease modifying antirheumatic drug; EULAR, European alliance of
associations of rheumatology; GC, glucocorticoids; GCA, giant cell arteritis; IV, intravenous; MMF, mycophenolate mofetil; MTX, methotrexate; TAK, takayasu
arteritis; TNFi, tumor necrosis factor inhibitor.
 Treatment Guidelines in Vasculitis 5

(IV) pulse GC,2,3 although this is based on very-low level evidence from conflicting
retrospective studies.2,3 Given the concern for progressive vision loss in this at-risk
population, IV GC are used in clinical practice for patients who present with signs of
cranial ischemia. In line with this ACR/VF guideline, EULAR also recommends using
0.25 to 1g IV methylprednisolone daily for up to 3 days in GCA patients with acute vi-
sual loss or amaurosis fugax.4
In patients with newly diagnosed GCA without cranial ischemic symptoms, recom-
mendations are to initiate high-dose GC (over moderate or pulse dose GC).2,3 This is in
keeping with EULAR recommendations to use 40 to 60 mg/d of GC for the induction of
remission.4 The trial of tocilizumab (TCZ) in GCA (GiACTA) demonstrated that we have
historically been using more GCs than necessary.13 Although GCs are still central in
our management of GCA, strategies to limit their use while still optimizing the health
of our GCA patients have been discovered.

Controversies: the role of tocilizumab

Because of the significant toxicities associated with high-dose, long-term GC expo-
sure, multiple other therapeutics have been evaluated for their GC-sparing effect.
The ACR/VF guideline recommends the use of oral GC with TCZ over oral GC alone
for patients with newly diagnosed GCA.2,3
Although the efficacy of TCZ has clearly been demonstrated in GCA, the questions
of cost, allocation, and whether there is a subset of patients that would benefit most
from this initial treatment remains controversial. Between 30% and 60% of patients
do not relapse on GC monotherapy and are able to taper to less than 5 mg/d at
1 year.14–17 EULAR recommends the treatment with GC monotherapy with adjunc-
tive therapy such as TCZ reserved for select patients who have refractory or relaps-
ing disease, or for those at increased risk of GC-related adverse effects or
complications.4,18
EULAR recommendations also include methotrexate (MTX) as an alternative and
less costly, GC-sparing agent. Data around the efficacy of MTX in patients with
GCA has been debated with clinical trials providing conflicting results.19–21 The
METOGiA trial (NTC03892785) will compare weekly TCZ to 0.3 mg/kg/wk of MTX
over 1 year to evaluate the efficacy and cost-effectiveness of these 2 agents in
GCA.
Questions remain regarding the optimal length of TCZ treatment. Long-term data
show that less than 50% of patients with GCA who discontinued TCZ after 1 year
had sustained remission during the next 2 years, with most patients suffering from
relapse.22 Furthermore, there were no clear clinical, biomarker, or imaging features
that reliably predicted GCA patients at higher risk of relapse.

Summary
The ACR/VF guideline supports the use of temporal artery biopsy for the initial diag-
nosis of GCA, which is in contrast to EULAR recommendations to use temporal ar-
tery ultrasound. Although both societies endorse large-vessel imaging, the
indications for and frequency of imaging remains unclear. TCZ has been demon-
strated to allow for GC reduction and is recommended by the ACR/VF along with
GC at diagnosis for patients with GCA, whereas EULAR recommends TCZ or MTX
in relapsing and resistant cases. This discordance likely reflects the limited availabil-
ity and high cost of TCZ. Fortunately, multiple other medications/biologics are being
tested in phase 2 and 3 clinical trials in GCA, so the landscape will continue to
change.

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6 Kermani et al

TAKAYASU ARTERITIS
Introduction
Takayasu arteritis (TAK) is a granulomatous large-vessel vasculitis predominantly
affecting the aorta and/or its major branches.1 The revised International Chapel Hill
Consensus Conference suggests using age of less than 50 years to distinguish TAK
from GCA.1 The estimated incidence is 1.11 per million person years with an estimated
prevalence ranging from 8.4 per million in the United States to 40 per million in
Japan.23 Vascular inflammation in TAK leads to vascular damage with arterial steno-
sis, occlusion, or dilatation.24

Discussion
Overview
The ACR/VF guideline for TAK included 20 recommendations (19 conditional, 1 strong)
and 1 ungraded position statement.2,3 For all of the recommendations, the level of ev-
idence available was rated as low or very low. The only strong recommendation was to
monitor patients over time. EULAR has also published recommendations on the man-
agement of large-vessel vasculitis.4,5
Diagnostic evaluation
The ACR/VF guideline includes no statements about diagnostic modalities for TAK.2,3
EULAR recommends confirmation of large-vessel vasculitis with imaging modalities
and referral to a center with expertise for diagnosis of TAK.4 Computed tomography
(CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) su-
persede conventional angiography given their ability to assess the vessel wall for signs
of inflammation, and, the lumen.25 EULAR recommends MRI as the modality of choice
to diagnose TAK, with PET, CT, or ultrasound as alternatives, with the caveat that ul-
trasound cannot assess the thoracic aorta.5
Glucocorticoids
The ACR/VF guideline recommends the treatment with high-dose GC over IV GC for
both newly diagnosed and relapsing active, severe disease.2,3 They recommend
consideration of IV GC for those with the most severe disease, recognizing that there
is no evidence supporting use of IV GC over oral GC.2,3 Despite the absence of well-
designed clinical trials, pulse steroids are often used to treat severe manifestations in
rheumatic diseases given anti-inflammatory effects on a wide range of immune cells
via genomic mechanisms.26 IV steroids were also considered for children if needed
for compliance or to reduce adverse effects on growth.2,3 EULAR also recommends
initiation of high-dose GC for the induction of remission in TAK without any statement
about pulse steroids.4 As opposed to EULAR recommendations to taper GC to a
target dose of 10 mg or less after 1 year, the ACR/VF recommends tapering off GC
for patients in remission after 6 to 12 months of therapy.2,3
Controversies: adjunctive therapy and the role of biologics
It is increasingly recognized that most patients with TAK have relapsing disease.24
Both EULAR and the ACR/VF recommend initiation of additional immunosuppressive
therapy at diagnosis over treatment with GC alone.2–4 The data for GC-sparing med-
ications in TAK is based on retrospective and open label studies, and therefore, the
choice is based on patient-specific factors including plans for childbearing, comorbid-
ities, and adverse effect profile. As opposed to EULAR recommendations to start with
conventional immunosuppressive therapy and add biologic therapy in cases of refrac-
tory disease, the ACR/VF guideline considers tumor necrosis factor inhibitors (TNFi) as
first line along with conventional immunosuppressive therapy.2–4 This difference may

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 Treatment Guidelines in Vasculitis 7

reflect other factors including cost and access to biologic therapies. The recommen-
dations on choice of biologic therapy also differ. EULAR recommends TNFi or TCZ for
refractory disease, whereas based on currently available data, ACR/VF favors TNFi
over TCZ in TAK.2–4 Although TCZ was studied in a randomized phase III clinical trial,
the study only included 36 patients and the primary endpoint of time to first relapse
was no different between those treated with TCZ or placebo, although there was
some steroid-sparing effect of TCZ.27

Surgical management
ACR/VF guideline recommends medical management over surgical intervention in
nearly all cases including worsening ischemia (except coronary involvement or
impending/progressive tissue or organ infarction), persistent limb claudication,
renovascular hypertension, cranial/cervical disease (without symptoms or multi-
vessel involvement).2,3 Both EULAR recommendations and the ACR/VF guideline
recommend deferring intervention in patients with active disease when possible
with ACR/VF also including a statement recommending the use of high-dose
GC in those with active disease perioperatively.2–4 Neither provides any guidance
on preference of surgical treatment versus noninvasive vascular interventions
in patients with TAK, and EULAR recommends a multidisciplinary team
approach.2–4

Controversies: the role of imaging in disease activity assessment

Despite their limitations, the use of acute phase reactants is recommended along with
clinical assessment to evaluate disease activity in the EULAR recommendations and
the ACR/VF guideline.2–4 In patients who are in clinical remission but with elevated
markers of inflammation, ACR/VF recommends observation.2,3
Most experts agree imaging is an important in the care of patients with TAK.28 ACR/
VF guideline recommends routine noninvasive imaging in TAK.2,3 In contrast, EULAR
does not recommend routine imaging for disease activity assessment in patients in
clinical and biochemical remission but in cases of suspected relapse, or, to monitor
structural damage.2–5
The significance of imaging findings such as vessel wall edema and enhancement
remain unclear and debated.29–31 A controversial recommendation of the ACR/VF
guideline is the escalation of therapy in cases of clinical remission with signs of
inflammation on imaging including edema or enhancement in a new vascular terri-
tory.2,3 Although experts would agree a new area of stenosis warrants escalation
of therapy, there is no clear evidence that vessel wall edema or enhancement,
even in a new area, represents active inflammation or risk for progression/develop-
ment of new vascular damage.2,3 The guideline acknowledges this uncertainty and
recommends the imaging findings be reviewed with a radiologist before making
any treatment decisions.24

Summary
The ACR/VF guideline provides helpful recommendations for the medical and surgical
management of TAK. Areas of uncertainty include the best imaging modalities for
diagnosis and monitoring. Furthermore, the significance of findings such as vessel
wall edema or enhancement and whether they represent disease activity or vessel
remodeling are unknown. The role of TCZ for the treatment of TAK needs to be further
investigated. There remains a need for therapeutics that better control the inflamma-
tion and reduce risk of relapses and damage over time.

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8 Kermani et al

POLYARTERITIS NODOSA
Introduction
Polyarteritis nodosa (PAN) is a rare, systemic necrotizing vasculitis that predominantly
involves medium-sized and small arteries without involvement of arterioles, venules, or
capillaries.1 Generally, antineutrophil cytoplasmic antibodies (ANCA) are absent. The
incidence of PAN is about 1 to 8 per million population, and the estimated prevalence
is 31 per million; this form of vasculitis occurs mainly between the age of 40 and
60 years and is more common in men.23 PAN can be broadly divided into primary (idio-
pathic) and secondary (related to Hepatitis B virus [HBV] infection) forms. Deficiency of
adenosine deaminase 2 (DADA2) has overlapping clinical features with PAN; this
monogenic form of vasculitis which is caused by mutations in the ADA2 gene generally
presents in childhood but may also manifest in young adults.32

Discussion
Overview
The 2021 ACR/VF guideline included 16 recommendations and 1 ungraded position
statement for the evaluation and treatment of patients with the systemic, idiopathic
form of PAN33,34 (Table 3). The guideline addresses neither the management of pa-
tients with cutaneous PAN nor the management of patients with HBV-related
PAN.33,34 In contrast, the older EULAR recommendations review treatment of both
idiopathic PAN as well as HBV-related PAN, noting that antiviral therapy is an essential
component of the treatment strategy for the latter condition.35 It should be empha-
sized that most of the ACR/VF recommendations for PAN are conditional due to the
lack of consistent high-quality evidence in this field.

Diagnostic evaluation
PAN should be included in the differential diagnosis of patients with a systemic, in-
flammatory multisystem illness and progressive end organ dysfunction. The diagnosis
of PAN may be delayed due to the rare nature of disease, the often nonspecific initial
patient symptoms, and the necessity to exclude vasculitis mimics particularly infec-
tion. Unfortunately, specific diagnostic biomarkers are not available for PAN, although
the presence of elevated inflammatory markers may be a useful clue to the diagnosis.
Therefore, imaging studies and tissue biopsy constitute essential components of the
diagnostic evaluation.33,34 The ACR/VF guideline emphasizes the use of abdominal
vascular imaging for the diagnosis of PAN, recognizing that CT angiography, magnetic
resonance angiography, and catheter-direct angiography are all reasonable diag-
nostic modalities, with the latter providing greatest resolution and sensitivity.33,34
Characteristic findings on conventional angiography such as multiple microaneurysms
of the hepatic, mesenteric, and renal artery branches are often diagnostic of PAN.
Depending on the pattern of clinical involvement, muscle, nerve, or deep-skin biopsies
for histopathologic confirmation of medium vessel vasculitis may be required. The
characteristic histologic findings may be missed in a superficial “punch” skin biopsy;
therefore, ACR/VF guidelines specify that a deep biopsy (“double” punch or exci-
sional) is preferable based on expert opinion.33,34 Although not specifically addressed
in the ACR/VF recommendations, it is generally advisable that patients with suspected
PAN should be evaluated and subsequently managed at (or in close collaboration
with) centers that have expertise in vasculitis, as noted in the EULAR guidelines.35

Treatment recommendations
Once a diagnosis of PAN is established, and mimics have been reasonably excluded,
the clinician should assess the degree of disease severity to tailor treatment

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 Treatment Guidelines in Vasculitis 9

Table 3
Comparison of American College of Rheumatology/Vasculitis Foundation Guideline and
European Alliance of Associations of Rheumatology Recommendations for Management of
Polyarteritis nodosa33–35

ACR/VF EULAR
Diagnosis Abdominal vascular imaging Biopsy confirmation of
Deep-skin biopsy vasculitis is recommended;
Nerve and muscle biopsy site not specified in
guideline
GC use IV GC initially High-dose GC
Remission induction CYC and high-dose GC Same
Plasmapheresis Not recommended Recommended for patients
with HBV-related PAN
Remission maintenance Immunosuppressive agent Same
(other than CYC)

Abbreviations: ACR/VF, American College of Rheumatology/Vasculitis Foundation; CYC, cyclophos-

phamide; EULAR, European alliance of associations of rheumatology; GC, glucocorticoids; HBV,
hepatitis B virus; IV, intravenous; PAN, polyarteritis nodosa.

accordingly. Severe disease with life-threatening or organ-threatening manifestations

(eg, renal disease, mononeuritis multiplex, mesenteric ischemia, coronary involve-
ment, limb/digit ischemia) should be treated with GC combined with cyclophospha-
mide (CYC) to induce disease remission.36 The use of initial IV GC can be
considered for patients with urgent need to limit end organ damage, although this is
based on very-low level of evidence and most patients can be treated with high-
dose oral GC.33,34,36 This treatment strategy outlined in the ACR/VF guidelines is
consistent with the EULAR recommendations for the management of medium vessel
vasculitis.33–35
Treatment with CYC is typically continued for 3 to 6 months (adjusted for renal and
hematologic parameters), after which it is replaced with a remission maintenance
agent such as MTX or azathioprine (AZA), for total treatment duration of about
18 months—a strategy that is based on expert opinion and extrapolation of data
from clinical trials of other forms of vasculitis. The ACR/VF guidelines discourage
the use of rituximab (RTX) over CYC and recommend against the use of plasma ex-
change for the treatment of PAN due to the lack of evidence supporting these treat-
ment modalities.33,34 Patients with intolerance to CYC and those with nonsevere
disease manifestations should be treated with immunosuppressive agents such as
MTX or AZA (in combination with GC).33,34 It is worth noting that the ACR/VF guideline
does not support treating patients with PAN with GC monotherapy due to risk of
toxicity, although there is some evidence to support this strategy for patients with
limited disease. Given the lack of clinical trial data evaluating the optimal duration of
GC treatment in PAN, the ACR/VF guideline committee did not provide specific rec-
ommendations on when to discontinue GC; they suggested individualized therapy
and shared decision-making incorporating patient preferences.33,34 The treatment
of refractory vasculitis is particularly challenging, and the ACR/VF guideline addresses
this by recommending that if a patient is on immunosuppressive therapy with MTX or
AZA and has ongoing active disease, then treatment should be escalated to use of
CYC.33,34 Although this is entirely appropriate, clinicians should also remain vigilant
for other conditions for example, infection that can mimic “refractory vasculitis” and
may need an entirely different approach to management.33–35

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10 Kermani et al

The only strong recommendation in the ACR/VF guideline pertains to the manage-
ment of patients with DADA2. Based on clinical experience, patients with DADA2
seem to respond remarkably well to the treatment with TNFi resulting in reduction in
the risk of stroke.37 Given the apparent difference in treatment response between idio-
pathic PAN and DADA2, clinicians should consider testing for DADA2 when younger
patients with medium vessel vasculitis have atypical PAN manifestations such as
stroke.

Summary
The recent ACR/VF guideline provides clinicians with a framework for the evaluation
and treatment of patients with systemic idiopathic PAN. The diagnostic evaluation
for PAN hinges on vascular imaging and tissue biopsy as specific biomarkers are lack-
ing. Treatment is directed at abrogating the systemic inflammatory process to limit
end organ damage; GC and CYC are the mainstay of therapy for remission induction
in severe disease. Maintenance of remission is generally achieved with a conventional
immunosuppressive agent, and optimal duration of treatment remains unclear.
Several unmet needs remain in the management of PAN, including the availability of
targeted and safer therapeutic agents.

GRANULOMATOSIS WITH POLYANGIITIS AND MICROSCOPIC POLYANGIITIS

Introduction
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are ANCA-
associated vasculitides (AAV) that cause necrotizing inflammation of the small-sized
and medium-sized blood vessels. These two disease entities have many overlapping
clinical manifestations and management considerations; thus, they have been studied
together in randomized clinical trials and were addressed simultaneously in the ACR/
VF guideline.38,39

Discussion
Overview
Twenty-six conditional recommendations and 5 ungraded position statements were
developed to guide the management of MPA/GPA.38,39 All of them had very low to
moderate levels of supporting evidence. Most recommendations address remission
induction and remission maintenance in severe and nonsevere disease. EULAR/the
European Renal Association-European Dialysis and Transplant Association (ERA-
EDTA) have also developed guidelines for the management of AAV40 (Table 4).

Glucocorticoids
A major advancement in the management of AAV has been seen with our ability to use
less GCs than ever before. Recent trials have demonstrated that we can use signifi-
cantly less GCs without compromising clinical efficacy and with improvements in qual-
ity of life measures. A large randomized trial in patients with severe MPA and GPA
showed that a reduced dose GC arm was as effective as the standard GC arm in
regards to end-stage renal disease or death, with fewer serious infections, and
more than 50% less GC exposure at 3 months.41 The ACR/VF recommends a
reduced-dose GC regimen over a standard regimen for remission induction in severe
disease.38,39 Since the literature review for the guidelines, 2 other important trials have
evaluated the role of lower dose GCs in AAV. These trials reinforced the importance of
and the noninferiority of a lower dose GC regimen as well as the ability of avacopan, an
oral C5a inhibitor, to reduce GC burden in severe MPA/GPA.42,43

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 Treatment Guidelines in Vasculitis 11

Controversies: rituximab or cyclophosphamide for remission induction in severe

disease
In severe, active GPA/MPA, the ACR/VF guidelines recommend induction of remission
using RTX over CYC in addition to high-dose GCs.38,39 In contrast, EULAR/ERA-EDTA
recommends either CYC or RTX for the induction of remission.40,44 RTX was shown to
be noninferior to CYC in a pivotal clinical trial but this trial excluded patients on me-
chanical ventilation or with a creatinine level of more than 4 mg/dL.45 The clinical trial
that evaluated RTX in newly diagnosed AAV with severe renal manifestations was
confounded by additional use of IV CYC as part of the induction regimen.46 Various
factors can influence the choice of induction therapy including patient comorbidities,
childbearing plans, infectious risks, MPO or PR3 positivity, new or relapsing disease,
as well as cost and availability. Access to RTX in the United States, comparable effi-
cacy, and favorable side effect profile, led to the ACR/VF recommendation of RTX over
CYC for induction in severe disease.38,39
Importantly, in refractory disease, both ACR/VF guideline and EULAR/ERA-EDTA
recommend switching to the alternative agent (RTX/CYC or CYC/RTX).38–40 The
ACR/VF also recommends that severe relapses in patients not on RTX for mainte-
nance therapy should be reinduced with RTX but those who are on RTX for mainte-
nance therapy should be induced with CYC.38,39 The timing of the relapse in
relation to RTX, the maintenance regimen being used, patient comorbidities, and clin-
ical history should all be incorporated into the decision-making process in individual
cases.38,39

Clinical controversies: the role of plasmapheresis

Another area of controversy in the induction of remission is the role of plasmapheresis
in those with severe renal involvement and/or alveolar hemorrhage. The ACR/VF
guideline recommends against adding plasmapheresis for the induction of remission
in active glomerulonephritis or diffuse alveolar hemorrhage.38,39 The MEPEX trial
required a serum creatinine level of greater than 5.8 mg/dl for entry and showed
that plasmapheresis decreased the risk of end-stage renal disease but did not
decrease mortality.47 The more recent PEXIVAS trial demonstrated that there was
no benefit to adding plasmapheresis to standard induction therapy (with CYC/RTX
and GCs) in terms of progression to end-stage renal disease or mortality (28% plas-
mapheresis vs 31% no plasmapheresis, P 5 .27).41 These results informed the
ACR/VF recommendation against plasmapheresis in severe GPA and MPA.38,39 Inter-
estingly, a meta-analysis including both of these trials showed a decreased risk of
end-stage renal disease with plasmapheresis (HR 0.27; 95% CI 0.53–0.98).48
EULAR/ERA-EDTA recommendations, published before the PEXIVAS trial, recom-
mend plasmapheresis for AAV patients with severe renal failure
(creatinine >500 mmol/L, 5.7 mg/dL) and state that it be should be considered in those
with other life-threatening manifestations of disease, such as diffuse alveolar hemor-
rhage.40 Although the ACR/VF guideline recommends using RTX for induction and no
plasmapheresis in cases of severe renal and/or pulmonary involvement, a patient’s
specific clinical scenario will undoubtedly inform therapeutic decision-making.38,39

Treatment of nonorgan or life-threatening disease

In nonsevere GPA/MPA, the ACR/VF recommends induction with a combination of
GCs and MTX over using RTX, CYC, AZA, mycophenolate mofetil (MMF), trimetho-
prim/sulfamethoxazole, or GCs alone.38,39 EULAR/ERA-EDTA recommends induction
with a combination of GCs with either MTX or MMF for induction in nonorgan threat-
ening disease.40

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 12
Kermani et al
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Table 4
Comparison of American College of Rheumatology/Vasculitis Foundation Guideline and European Alliance of Associations of Rheumatology/European Renal
Association- European Dialysis and Transplant Association Recommendations for Management of Anti-neutrophil cytoplasmic antibody-associated
vasculitis38–40

GPA/MPA EGPA
ACR/VF EULAR/ERA-EDTA ACR/VF EULAR/ERA-EDTA
Diagnosis No specific recommendations Biopsy to establish diagnosis No specific recommendations Biopsy to establish diagnosis
apart from echocardiogram
in all patients
GC use Reduced-dose GC regimen Target prednisone dose High-dose GC, duration guided High dose GC, goal 7.5–10 mg
between 7.5 and 10 mg daily by patient’s condition, by month 3, continuation of
after 3 mo of treatment values, and preferences low-dose GC for remission
maintenance
Remission induction High-dose or pulse GC 1 RTX in GC 1 RTX or CYC in severe High-dose GC and RTX or CYC Same
severe disease disease
Plasmapheresis Do not use Consider in glomerulonephritis No specific comment for EGPA Same
and severe diffuse alveolar (guidelines as for GPA/MPA)
hemorrhage
Remission maintenance RTX Low-dose GC 1 AZA, RTX, AZA or MTX or MMF Same
Duration of GC and non-GC MTX, or MMF Duration of GC use guided by Low-dose GC continued
therapy guided by patients’ Continue for 24 mo following patient’s condition, values, Duration therapy 24 mo
clinical condition, induction of sustained and preferences
preferences, and values remission No comment about duration of
therapy

Abbreviations: ACR/VF, American College of Rheumatology/Vasculitis; AZA, azathioprine; CYC, cyclophosphamide; EGPA, eosinophilic granulomatosis with poly-
angiitis; EULAR/ERA-EDTA, European Alliance of Associations of Rheumatology/European Renal Association- European Dialysis and Transplant Association; GC,
glucocorticoids; GPA, granulomatosis with polyangiitis; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; MTX, methotrexate; RTX, rituximab.
 Treatment Guidelines in Vasculitis 13

Remission maintenance
Once remission is induced with either CYC or RTX, the ACR/VF recommends the use
of RTX for maintenance therapy.38,39 Second-line options for maintenance therapy are
AZA or MTX, with third-line options including MMF or leflunomide. A trial using RTX
500 mg IV on day 0, 14, then q 6 months compared with AZA, after induction with
IV CYC, showed superiority of RTX with fewer major relapses and improved quality
of life measures.49 When AZA was compared with MTX after CYC induction, there
was no significant difference in relapse rates or serious adverse events.50 We do
not have comparative trials for specific dosing and timing of RTX for maintenance
but based on available data, the dose ranges between 500 and 1000 mg of IV RTX
every 4 to 6 months.51,52 The ACR/VF recommendations are to use scheduled or fixed
dosing RTX rather than dosing based on CD19 B cell count or ANCA titers.38,39
EULAR/ERA-EDTA recommendations for remission maintenance support using a
combination of low-dose GCs and either AZA, RTX, MTX, or MMF and continuing ther-
apy for at least 24 months following induction of sustained remission.40 The length of
maintenance therapy is not specifically detailed in the ACR/VF guideline and providers
should consider patient factors such as infections, medication tolerance, disease
phenotype, history of relapses, and risk for further relapses.

Summary
The ACR/VF guidelines recommend RTX over CYC for the induction of remission in se-
vere MPA/GPA and recommend against plasmapheresis. This is in contrast to EULAR/
ERA-EDTA recommendations that support the use of either CYC or RTX for the induc-
tion of remission as well as plasmapheresis in cases of glomerulonephritis or diffuse
alveolar hemorrhage. Trials have increasingly demonstrated that we are able to effec-
tively induce remission with less GC exposure in our patients with MPA/GPA. Mainte-
nance therapy with fixed-dose RTX should be used, although the length of optimal
treatment is unclear. In nonsevere disease, the ACR recommends treatment with
MTX for remission induction.

EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS

Introduction
Eosinophilic granulomatosis with polyangiitis (EGPA, previously Churg-Strauss) is a
small-vessel vasculitis characterized by eosinophil-rich and necrotizing granuloma-
tous inflammation often involving the respiratory tract with features including asthma
and peripheral eosinophilia along with vasculitic manifestations.1,53 It is the rarest of
the 3 forms of AAV with an estimated incidence of 0.14 to 4.0 per million and estimated
prevalence up to 32.9 per million.23 As opposed to GPA and MPA, ANCA is frequently
absent (55%–65% negative).53

Discussion
Overview
The ACR/VF guideline for EGPA included 15 conditional recommendations and 5 un-
graded position statements.38,39 For all of the recommendations, the level of evidence
available was rated as low or very low. The guideline also addressed the use of immu-
nosuppression to treat vasculitic manifestations of EGPA but did not specifically
address asthmatic and allergic manifestations of EGPA. EULAR/ERA-EDTA recom-
mendations for treatment of AAV do not separate management of EGPA from GPA/
MPA.40

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14 Kermani et al

Glucocorticoids
Both statements relating to GC use in the ACR/VF guideline for EGPA were ungraded
position statements. The first recommendation is for IV pulse GC or high-dose oral GC
for active severe diseases.38,39 The only other statement related to GC use is that the
duration of therapy be guided by the patient’s clinical condition, values, and prefer-
ences. EULAR/ERA-EDTA recommendations for the management of AAV include
high-dose GC (1 mg/kg/d) for the induction of remission in EGPA with taper to 7.5
to 10 mg/d by month 3.40 They recommend continuation of low-dose GC for remis-
sion-maintenance.40

Controversies: rituximab, cyclophosphamide, or mepolizumab for remission induction

Clinical trials in EGPA are scarce with the treatment based on data from other forms of
AAV. For remission induction, the ACR/VF guideline also appropriately considers the
severity of disease manifestations.
Despite long-standing experience with CYC and limited data for RTX, ACR/VF
guideline includes an ungraded position statement recommending CYC or RTX for
remission induction in patients with active, severe EGPA.38,39 They cite the absence
of comparative effectiveness of CYC and RTX as the basis for this recommendation.
They did provide scenarios where one drug might be preferred over another including
CYC in patients with active cardiac involvement, whereas RTX may be favored in pa-
tients with positive ANCA, glomerulonephritis, prior CYC use, or those at risk for
gonadal toxicity from CYC.38,39 A recent systematic review of currently available
observational studies for RTX in EGPA found that 80% of patients treated with RTX
achieved complete or partial remission with higher response in the p-ANCA-positive
subgroup but the high degree of heterogeneity limited applicability to clinical prac-
tice.54 The Rituximab in Eosinophilic Granulomatosis with Polyangiitis (REOVAS) trial
(NTC02807103) is a phase III randomized controlled trial comparing CYC versus RTX
in EGPA and should provide much needed data on this important question. EULAR/
ERA-EDTA recommendations also include CYC or RTX for remission induction for
EGPA but although 88% of the panel agreed with use of CYC, only 59% agreed
with use of RTX.40
The ACR/VF guideline also conditionally recommends CYC or RTX over mepolizu-
mab in patients with active, severe EPGA.38,39 This is appropriate because patients
with active, severe disease were excluded from the clinical trial evaluating mepolizu-
mab in EGPA.55
In patients with active but nonsevere disease, the ACR/VF guideline has several
conditional recommendations.38,39 Overall, treatment with mepolizumab and GC
was generally favored for this patient population.38,39 However, GC along with adjunc-
tive immunosuppressive therapy such as AZA, MTX, or MMF was preferred to GC
monotherapy, whereas the use of CYC or RTX was discouraged.38,39 For nonorgan
threatening disease, EULAR/ERA-EDTA recommends treatment with GC and MTX
or MMF.40 There are no statements regarding the use of mepolizumab in the
EULAR/ERA-EDTA recommendations because the recommendations were published
before the results of the trial were available.40,55

Remission maintenance
The ACR/VF guideline conditionally recommends treatment with MTX, AZA, or MMF
for remission maintenance in patients who received induction therapy with CYC,
extrapolating from studies in other forms of AAV.38,39 These therapies were favored
over mepolizumab given paucity of data for mepolizumab in this subset of patients.
RTX was not recommended for remission maintenance given lack of data but was

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 Treatment Guidelines in Vasculitis 15

suggested if it was used as induction therapy or in cases where there were contrain-
dications to the other options.38,39 No recommendations are made about duration of
therapy.38,39 EULAR/ERA-EDTA recommendations include AZA, MTX, MMF, or RTX
for remission maintenance (only data for AZA available for EGPA) with continuation
of therapy for 2 years.40
Treatment of relapses
The ACR/VF guideline includes 5 conditional recommendations on the treatment of re-
lapses.38,39 In patients who relapse with severe manifestations after an initial response
to the treatment with CYC, they recommend switching to RTX over retreating with
CYC based on data from an observational study of RTX in relapsing/refractory
EGPA.38,39 Cardiac involvement is listed as an exception again where retreatment
with CYC may be considered. In patients with initial response to RTX who relapse
with severe manifestations, retreatment with RTX is suggested over switching to
CYC.38,39 They recommend using mepolizumab to treat a nonsevere relapse occur-
ring in patients on immunosuppressive therapy, as supported by the clinical trial of
mepolizumab in EGPA.38,39,55 Mepolizumab is also favored over adjunctive immuno-
suppressive therapy in patients on GC monotherapy who have a relapse, and, over
omalizumab including in patients with elevated IgE.38,39 For relapsing disease,
EULAR/ERA-EDTA recommend using the same algorithm as new disease with GC
and retreatment with CYC or RTX to induce remission.40
Summary
It is clear that EGPA is different from the other forms of AAV. Whether there are subsets
within EGPA with the ANCA-positive subtype more closely resembling MPA/GPA re-
mains unclear. As opposed to GPA/MPA, the role of CYC or RTX for remission induc-
tion needs to be elucidated. The role of mepolizumab as adjunctive therapy in patients
with severe manifestations also needs further study.
Clinics Care Points
 Temporal artery biopsy of at least 1 cm on the affected side is the preferred
method for confirming a diagnosis of giant cell arteritis (GCA).
 Large-vessel involvement is underrecognized and screening with noninvasive
imaging should be pursued in patients with suspected/newly diagnosed GCA.
 In newly diagnosed GCA with threatened vision loss, pulse IV glucocorticoids
(GC) should be used.
 Newly diagnosed GCA patients should be induced with glucocorticoids plus to-
cilizumab (TCZ), though the optimal length of TCZ treatment has not been
defined.
Clinics Care Points
 The diagnosis of Takayasu arteritis (TAK) should be confirmed by large-vessel
imaging.
 Patients with active TAK should be treated with high-dose GC and started on
adjunctive immunosuppressive therapy.
 TNFi is currently preferred over the use of TCZ.
 Longitudinal follow-up should include clinical assessment, measurement of
acute phase reactants and large-vessel imaging.
Clinics Care Points
 Patients with suspected polyarteritis nodosa (PAN) should be evaluated with
abdominal vascular imaging.

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16 Kermani et al

 Patients with suspected PAN may require tissue biopsy for confirmation of the
diagnosis; the optimal site for biopsy depends on specific vasculitic
manifestations.
 Severe, idiopathic PAN should be treated with GC and cyclophosphamide (CYC)
for 3 to 6 months before transitioning to less intense immunosuppressive
therapy.

Clinics Care Points

 Patients with new onset severe granulomatosis with polyangiitis (GPA)/micro-
scopic polyangiitis (MPA) should be induced with rituximab (RTX) over CYC along
with a rapid GC taper.
 Once remission is achieved, scheduled RTX dosing should be used for mainte-
nance, although the length of treatment is unclear.
 In refractory disease, RTX should be switched to CYC or vice-versa.
 In severe relapsing disease, RTX should be used for induction unless the patient
is on RTX maintenance therapy, in which case, CYC should be used.
 In nonsevere GPA/MPA, methotrexate (MTX) along with GCs should be used for
the induction of remission.

Clinics Care Points

 The treatment of eosinophilic granulomatosis with polyangiitis (EGPA) is based
on the severity of the disease and organs affected.
 The decision regarding CYC or RTX for remission induction should be made
considering several factors including organs affected, ANCA positivity, patient
preferences (eg, desire to preserve fertility), and currently available data.
 Adjunctive immunosuppressive therapy in addition to GC is recommended in
most cases.
 Mepolizumab plays a role in the management of nonsevere manifestations and
relapsing disease but further studies are needed regarding its utility in patients
with severe disease.

SUMMARY

The recent ACR/VF guideline provides a useful framework for the evaluation and treat-
ment of patients with systemic vasculitis. Most of the recommendations were condi-
tional given absence of strong data for many important clinical questions. Diagnostic
modalities such as imaging studies are important for large-vessel vasculitis and PAN,
whereas tissue biopsy for diagnosis is important for GCA, PAN, and AAV. Common
themes include the use of GC with adjunctive therapy for remission induction. With
more effective GC-sparing therapies, strategies evaluating shorter GC exposure to
minimize adverse effects are becoming increasingly important. Duration of therapy re-
mains unclear for many of these conditions, and the decision is often individualized
based on the severity of disease and damage, clinical course including relapses,
and patient preferences. All patients with vasculitis warrant long-term follow-up to
evaluate for relapses but also complications of the disease and its treatment.

DISCLOSURE

Dr T.A. Kermani has nothing to disclose. Dr K.J. Warrington has received clinical trial
support from Kiniksa and Eli Lilly & Co; honoraria from Chemocentryx. Dr A.B. Dua has
received honoraria from Chemocentryx, Novartis, and Abbvie.

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 Treatment Guidelines in Vasculitis 17

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